Salivary Gland Diseases

9
Salivary Gland Diseases

Leah M. Bowers, DMD

Arjan Vissink, DDS, MD, PhD

Michael T. Brennan, DDS, MHS, FDS, RCSEd

INTRODUCTION

The most common presenting complaints of a patient with salivary gland disease are oral dryness (xerostomia) or a glandular swelling or mass. This chapter discusses how to evaluate a patient with these and other signs and symptoms suggestive of salivary gland disease, including clinical examination techniques and imaging. Diseases, disorders, and some neoplasms affecting the salivary glands are introduced as well as management of xerostomia, hyposalivation, and sialorrhea.

Optimal function of the salivary glands results in the production of adequate amounts of saliva: a complex and unique biologic fluid with myriad functions. The importance of saliva in maintaining oral, dental, and general health cannot be understated. It provides lubrication to the oral and oropharyngeal mucosae, protects dental and mucosal surfaces, facilitates speech, mastication, and swallowing, and is involved in taste and digestion, among other functions. Hyposalivation, or even the perception of a lack of saliva, can have a significant impact on quality of life. Quantified salivary hypofunction or a significant change in the composition of saliva can increase the risk of oral diseases such as dental caries, dental erosion, and fungal infections.

SALIVARY GLAND ANATOMY AND PHYSIOLOGY

Saliva is produced by three paired major salivary glands (the parotid, submandibular, and sublingual glands), and numerous minor salivary glands (Figure 9‐1). The parotid glands, the largest of the major salivary glands, are located on the lateral aspects of the face overlying the posterior surface of the mandible, anteroinferiorly to the auricle. The parotid gland is often described as being divided into superficial and deep lobes by the intraparotid facial nerve and its branches. Encapsulation of lymphoid tissue during embryogenesis results in the presence of intraglandular lymphoid tissue; a feature not seen in the other major salivary glands and one that results in a predilection for development of parotid gland lymphomas, most notably in patients with Sjögren’s syndrome.

Schematic illustration of the major salivary glands and associated ducts.

Figure 9‐1 Diagrammatic representation of the major salivary glands and associated ducts.

The submandibular glands are a pair of organs shaped like flattened hooks that reside in the submandibular triangle. Although they are often described as being a pair of glands, the two parts are contiguous forming a “U” shape enveloping the posterior border of the mylohyoid muscle.

Each of the paired sublingual glands is composed of a major sublingual gland and approximately 8 to 30 minor sublingual glands. The glands lie on opposite sides of the lingual frenulum, superior to the mylohyoid muscle. Bimanual palpation, using one hand intraorally on the floor of the mouth and the other hand extraorally below the mandible, is necessary to evaluate these glands adequately.

There are an estimated 450 to 1000 minor salivary glands distributed primarily in the oral cavity and oropharynx, but they may be found anywhere along the aerodigestive tract as well as in the sinonasal cavity and middle ear. The minor salivary glands are named for the sites they occupy (e.g., labial, buccal, lingual, palatal, retromolar) and contribute approximately 8% to 10% of the total volume of saliva.1

There are also three sets of minor salivary glands of the oral tongue: the glands of Weber, found along the lateral borders of the tongue; the glands of von Ebner, surrounding the circumvallate papillae; and the glands of Blandin and Nuhn (also known as the anterior lingual glands), found in the musculature of the anterior ventral tongue. Distinctive mucoceles may arise in the glands of Blandin and Nuhn, highlighting their unique anatomic location.

Salivary glands can be classified based on the dominant saliva‐producing acinar cell type: serous, mucous, or a mix of serous and mucous cells. Serous cells produce a watery, enzyme‐rich saliva, while mucous cells secrete a more viscous fluid with plentiful salivary glycoproteins known as mucins. Salivary mucins expressed from the submandibular and minor salivary glands act as lubricants and help to form a selectively permeable barrier of mucosal membranes. Their presence helps maintain tissue hydration and an overall sense of comfort.

The parotid gland is composed primarily of serous cells; the submandibular gland is a mix of mucous and serous types, and the sublingual and minor salivary glands are of the mucous type. The glands of Weber are mucus‐secreting, the glands of von Ebner are purely serous, and the glands of Blandin and Nuhn are of mixed type.

Parotid gland saliva is secreted through Stensen’s ducts which emerge from the glands, traverse the buccal fat pad superficial to the masseter muscles, and pierce the buccinator muscles to open at papillae in the vicinity of the maxillary first or second molars (Figure 9‐2). Stensen’s duct is, on average, between 4 and 6 cm in length and has a diameter between 2.0 and 2.5 mm with the narrowest portions typically appearing at the papilla and where it pierces the buccinator.2 The masseteric bend, where the duct curves around the anterior border of the masseter, may present a navigational challenge; for example, during an endoscopic procedure.

Saliva from each submandibular gland is secreted through a submandibular (Wharton’s) duct. Each Wharton’s duct is approximately 5 cm in length and between 1 and 3 mm in diameter. Along its course, two bends are encountered; a typically obtuse angle is formed as the duct curves around the mylohyoid muscle, resulting in a propensity for stone formation and obstructive kinks.3 A second bend occurs adjacent to the duct punctum just before the duct opens into the oral cavity at the sublingual caruncles on either side of the lingual frenulum (Figure 9‐3). As Wharton’s duct traverses the glandular parenchyma, it demonstrates an abrupt transition in diameter, in contrast to that of the parotid gland which shows a more gradual decrease.

Photo depicts arrow indicating opening of Stensen’s duct on the left buccal mucosa.

Figure 9‐2 Arrow indicating opening of Stensen’s duct on the left buccal mucosa.

Photo depicts arrows indicating openings of Wharton’s ducts on the floor of mouth.

Figure 9‐3 Arrows indicating openings of Wharton’s ducts on the floor of mouth.

Saliva from the anterior, major portion of each sublingual gland drains through the sublingual (Bartholin’s) duct into the submandibular (Wharton’s) duct, while saliva from the smaller, posterior portion of the sublingual glands drains directly onto the floor of the mouth via multiple smaller ducts of Rivinus. The minor salivary glands secrete their mucinous product onto the mucosa through short ducts. A minor salivary gland may share an excretory duct with an adjacent minor salivary gland or may have a duct of its own.

Histologically, the major salivary glands are composed of acinar (secretory cells) and ductal cells arranged like a cluster of grapes on a stem. The clustered acinar cells (the “grapes”) make up the secretory end pieces, while the ductal cells (the “stems”) form an extensively branching system that modifies and transports the saliva from the acini into the oral cavity. There are three types of ductal cells: intercalated, striated, and interlobular (Figure 9‐4).

Production of saliva involves water transport from the serum into the terminal portion of the acinar cell followed by selective reabsorption of sodium and chloride and the secretion of potassium and bicarbonate to produce a hypotonic solution. Upon stimulation of salivary flow, sodium, chloride, and bicarbonate concentrations increase while potassium decreases via ion exchange in the ductal system. Salivary proteins are contributed mostly from the acinar cells.4

Whole saliva (WS; the mixed fluid contents of the oral cavity) is composed of more than 99% water and less than 1% proteins and salts. It is hypotonic relative to blood plasma and contains secretions from the major and minor salivary glands along with variable amounts of gingival crevicular fluid, microorganisms, food debris, exfoliated mucosal cells, and mucous. Salivary proteins are numerous and serve a variety of functions including digestion (e.g., α‐amylase, lipase, proteinases, DNase and RNase), and protection (e.g., immunoglobulins, lysozyme, lactoferrin, lactoperoxidase, and mucins).

Schematic illustration of salivary gland acini and ducts.

Figure 9‐4 Diagrammatic representation of salivary gland acini and ducts.

Normal daily production of WS ranges from 0.5 to 1.5 L. The composition of WS follows a circadian rhythm: at night and in the resting state, the submandibular and sublingual glands are the main contributors with some saliva being produced by the minor salivary glands.5 At stimulation, the parotid and submandibular glands are responsible for the majority of saliva production with minor gland secretions accounting for less than 10% of the volume. Stimulation of salivation typically occurs between 10% and 20% of the day, influenced by olfactory, gustatory, and mechanical stimuli.

The secretion of salivary fluid and salivary proteins is controlled by both the sympathetic and parasympathetic subsystems of the autonomic nervous system. Stimulus for fluid secretion is transmitted via muscarinic‐cholinergic receptors, which release acetylcholine, inducing the secretion of saliva by acinar cells. The stimulus for salivary protein secretion is transmitted via sympathetic β‐adrenergic receptors that release noradrenaline.6

Electrolyte concentrations and volume of saliva may be influenced by a number of factors including circadian rhythm, various stimuli, and number of functional secretory units. Factors that may increase salivary flow include taste and olfactory stimuli, mechanical stimulation (chewing), pain, hormonal changes, aggression, and sympathomimetic and parasympathomimetic drugs. Menopause‐related hormonal changes, stress, antiadrenergic and anticholinergic drugs will decrease salivary flow rate.7 A loss of acini, seen in a number of clinical conditions, particularly in Sjögren’s syndrome, also results in decreased saliva production.

Whether salivary flow diminishes with normal aging has been the subject of much debate. Many studies suggest age‐related changes in either volume or salivary constituents, while others have found no related changes. Postmortem histologic studies show that with aging, parenchymal tissue of the salivary glands undergo replacement with fat, connective tissue, and oncocytes. Acinar atrophy, ductal dilatation, and inflammatory infiltration have also been observed with aging in normal subjects.8

In reports that assert that in healthy, unmedicated adults, salivary production remains stable with age despite the loss of acinar cells, it is hypothesized that a secretory reserve capacity exists and that disease, surgery, radiotherapy, and chemotherapy, for example, tax this reserve resulting in compromised function.9,10 A gradual, age‐related loss of this reserve capacity may explain the greater magnitude of effect from conditions adversely affecting saliva production in older individuals compared to their younger counterparts.

DIAGNOSIS OF THE PATIENT WITH SALIVARY GLAND DISEASE

The most common complaint associated with salivary gland disease is xerostomia, denoting subjective mouth dryness. Hyposalivation refers to a quantified reduction in salivary flow rate which may or may not be accompanied by xerostomia. Similarly, xerostomia may or may not be associated with hyposalivation and can be the result of a change in salivary composition. The term “salivary gland dysfunction” is commonly used to indicate decreased salivary flow (hyposalivation) or other quantifiable alteration in salivary performance. Hypersalivation (sialorrhea or ptyalism) refers to an increase in production of saliva and/or a decrease in oral clearance of saliva.

Since the causes of xerostomia and salivary gland dysfunction are numerous, a systematic approach to establish a diagnosis is necessary. Salivary gland dysfunction may be the result of a systemic disorder and therefore early recognition and accurate diagnosis may be of great benefit to an individual’s general health and well‐being.

Where salivary gland dysfunction is suspected, a thorough examination to identify the cause of the condition is warranted. Patients should be queried regarding the severity and duration of their complaint, inciting events, whether the condition is progressive or intermittent, known relieving and exacerbating factors, possible circadian associations, and effect on quality of life. Patients should also be asked about dryness affecting other areas, especially the eyes, nose, and other mucosal surfaces.

An initial evaluation should also include a detailed inquiry into associated symptoms, medical and dental history, medications, and dietary habits. A head/neck/oral examination and an assessment of salivary function involving quantification of unstimulated and stimulated salivary flow should be performed (see section: Sialometry). Additional techniques that may be indicated are analysis of salivary constituents, imaging, biopsy, and clinical laboratory assessment, some of which are described below in greater detail.

Some causes of salivary gland hypofunction include xerogenic medications (including many antidepressants, anticholinergics, antispasmodics, antihistamines, antihypertensives, sedatives, diuretics, and bronchodilators) and other xerogenic agents (e.g., caffeine, alcohol, cigarette smoking), head and neck radiation (i.e., external and internal beam radiation therapy), systemic disease (e.g., diabetes mellitus), salivary gland masses, psychological conditions (e.g., depression, anxiety), malnutrition (e.g., bulimia, dehydration), and autoimmune disease (e.g., Sjögren’s syndrome).11 A list of some differential diagnoses for salivary gland dysfunction is outlined in Table 9‐1.

Table 9‐1 Partial list of differential diagnoses for salivary gland dysfunction.

Abbreviations: MRSA, methicillin‐resistant Staphylococcus aureus; CMV, cytomegalovirus; HIV, human immunodeficiency virus

Autoimmune
Chronic graft‐versus‐host disease
Sjögren’s syndrome
Developmental
Salivary gland aplasia and hypoplasia
Iatrogenic
Botulinum toxin injection
External beam radiation
Internal radiation (e.g., Radioactive iodine [131I])
Postsurgical (e.g., adenectomy, ductal ligation)
IgG4‐related disease (i.e., Küttner tumor; Mikulicz’s disease)
Infectious
Bacterial: Staphylococcus aureus, MRSA, Haemophilus influenzae
Viral: CMV, HIV, hepatitis C, paramyxovirus
Inflammatory
Granulomatous: Tuberculosis, sarcoidosis
Medication‐associated
Neoplastic
Benign and malignant salivary gland tumors
Non‐neoplastic
Sialolithiasis
Systemic
Anorexia nervosa, chronic alcoholism, diabetes mellitus,

Symptoms of Salivary Gland Dysfunction

Symptoms of salivary gland hypofunction are related to decreased fluid in the oral cavity affecting mucosal hydration and oral functions. Patients may complain of dryness of all the oral mucosal surfaces, including the lips and throat, and difficulty chewing, swallowing, and speaking due to dryness. Other associated complaints may include oral pain, an oral burning sensation, chronic sore throat, and pain on swallowing (odynophagia). The mucosa may be sensitive to spicy or coarse foods limiting the patient’s enjoyment of meals, which may compromise nutrition.12

Patients experiencing chronic salivary gland dysfunction may carry water with them at all times and drink frequently in an attempt to relieve oral dryness. However, as wettability of the oral mucosa and enamel by water is poor, relief of xerostomia is usually very temporary.13 Patients may describe drinking copious amounts of water throughout the day which may effectively wash away saliva as well as disrupt sleep due to nocturia.

A complaint of oral dryness (xerostomia) does not always correlate with a quantified decrease in salivary function, although related specific symptoms may.14 For example, complaints of oral dryness while eating, the need to sip liquids in order to swallow food, or difficulties in swallowing dry foods (i.e., activities that rely on stimulated salivary function), have all been highly correlated with measurable decreases in secretory capacity. In contrast, complaints of oral dryness at night or upon awakening have not been consistently found to be associated with reduced salivary function. Furthermore, xerostomia, particularly in the elderly, may be due to an impaired or altered perception of oral moisture or change in the composition of saliva rather than due to true hyposalivation.

Medical History

A thorough review of the patient’s medical history may reveal medical conditions, both past and present, medications, or procedures associated with salivary gland dysfunction leading to a direct diagnosis (e.g., a patient who received radiotherapy for a head and neck malignancy or an individual taking a tricyclic antidepressant). Medications can have a number of adverse effects on salivary gland function (see section: Medication‐Induced Salivary Dysfunction). The most well‐known of these are hyposalivation and xerostomia but medications may also produce objective or subjective sialorrhea. More than 400 drugs with xerogenic potential have been identified including antidepressants, anticholinergics, antispasmodics, antihistamines, antihypertensives, sedatives, and bronchodilators, and attempts have been made to compile a comprehensive list of medications with documented effects on salivary gland function.15

A thorough review of all the patient’s medications (including over‐the‐counter medications, supplements, and herbal preparations) must be performed. Often, upon further inquiry, a temporal association of symptom onset with a culpable agent may be made. Some side effects, however, including xerostomia and hyposalivation, may not appear until years after initiation of treatment, upon increase in dose, or other change in medication regimen. Furthermore, it is possible that certain drugs taken individually do not exert a xerogenic effect, but xerostomia arises as a result of a drug–drug interaction.16 When history alone does not offer an obvious diagnosis, further exploration of the symptomatic complaint should be undertaken. For example, a report of eye, throat, nasal, skin, or vaginal dryness, in addition to xerostomia and fatigue, may be an indication of the presence of a systemic condition, such as Sjögren’s syndrome.

Clinical Examination

Signs of salivary gland hypofunction may affect several areas of the oral cavity and mouth. The lips are often dry with cracking, peeling, and atrophy; the buccal mucosa may be pale and corrugated; and the dorsal tongue may appear smooth, erythematous, and depapillated, or fissured.

In the absence of the buffering capacity usually afforded by saliva, there is often an increase in dental caries and erosive lesions. These lesions often affect root surfaces and cusp tips of teeth: areas usually resistant to decay. The decay may be progressive, even where good oral hygiene is maintained, and recurrent decay is common. An increased accumulation of food debris and plaque may occur in interproximal areas due to a lack of cleansing salivary flow. Patients with hyposalivation, therefore, may have increased plaque indices and bleeding on probing scores.17

Two additional indicators of oral dryness are the “lipstick” and “tongue blade” signs. The former denotes the presence of lipstick or shed epithelial cells on the labial surfaces of the anterior maxillary teeth. A positive “tongue blade” sign results when a tongue blade, pressed gently and then lifted away from the buccal mucosa, adheres to the tissue. Both signs suggest that the mucosa is not sufficiently moisturized by saliva.

Oral candidiasis is often associated with salivary gland hypofunction and may be due to the effect of hyposalivation on the oral microbiome. The erythematous form of candidiasis (red patches of mucosa) is more prevalent in the presence of hyposalivation than the more familiar white, curd‐like pseudomembranous (thrush) form (Figure 9‐5). Angular cheilitis (persistent cracking or fissuring of the oral commissures) may also be present. Clinical examination should include noting the presence of the stigmata of an oral colonization and may include taking a smear or buccal swab for diagnosis.

Photo depicts erythematous candidiasis of the hard palate in a patient with salivary gland hypofunction.

Figure 9‐5 Erythematous candidiasis of the hard palate in a patient with salivary gland hypofunction.

Salivary gland dysfunction can present as enlargement of the salivary glands due to inflammatory, infectious, neoplastic, or other conditions. Inspection and palpation of the normal salivary gland should be painless and without detection of masses. The consistency of the glands should be slightly rubbery but not hard. Enlarged glands that are painful on palpation are indicative of infection, acute inflammation, or tumor. Neoplasms of the salivary glands, either benign or malignant, usually present as painless masses but may present with dull pain suggestive of an inflammatory‐based process.

The major salivary glands should also be massaged to express saliva from the main excretory ducts. Normally, saliva can be easily expressed from each major gland orifice by gently compressing the glands and drawing pressure toward the orifice. The expressed saliva should be colorless, transparent, and of sufficient volume. In health, saliva should be seen to pool on the floor of the mouth during examination. Viscous or scant secretions suggest chronically reduced function. Saliva that appears frothy, ropy, or stringy also indicates hyposalivation. A cloudy exudate may be a sign of infection, although some patients with very low salivary function will have hazy, flocculated secretions that are sterile. In these cases, mucoid accretions and clumped epithelial cells result in a cloudy appearance. The exudate should be cultured if it does not appear clinically normal, particularly in the case of an enlarged gland.

Sialometry

Sialometry refers to the measurement of salivary flow. Sialometric techniques and specialized devices can be used to ascertain the production rate of whole saliva, saliva from individual major salivary glands, and in the stimulated and unstimulated state. Although no single sialometric technique is perfect, these methods allow for objective assessment of salivary flow where salivary gland dysfunction is suspected.

Since the resting, unstimulated state of the salivary glands is predominant, it has a greater influence on perceived oral comfort and health of the tissues. Normal subjects typically report mouth dryness when unstimulated whole salivary flow is reduced by approximately 50% or more.18 Examination of stimulated salivary flow allows for assessment of the relative functional capacity of the salivary glands and can determine whether sialogogues are likely to be of benefit. It is therefore important to assess both unstimulated and stimulated salivary flow when investigating a complaint of xerostomia.

To prepare for sialometry, the patient is instructed to refrain from eating, drinking, smoking, chewing gum, and oral hygiene practices or any other oral stimulation for at least 90 minutes prior to the assay. Excessive movement and talking is discouraged during the testing period. At least 10 minutes before the test begins, the patient should rinse the mouth gently with water to remove debris.

The main methods of whole saliva collection are the passive and active drainage methods, suction, and absorption methods. In the passive drainage method, saliva is allowed to passively flow from the oral cavity into a pre‐weighed graduated container (Figure 9‐6). This method is reproducible and reliable, but is vulnerable to inaccuracy if there is significant evaporation of saliva. The active drainage method requires the patient to allow saliva to accumulate in the mouth and expectorate into a pre‐weighed tube, usually every 60 seconds for 5–15 minutes. This method is also reproducible and reliable but is susceptible to inaccuracy due to saliva evaporation and stimulation of salivary flow by the act of spitting.

In sialometric methods employing suction, saliva pooling at the floor of the mouth is suctioned into a pre‐weighed graduated container. The advantage of this technique is that it does not rely on patient collaboration. The vacuuming of saliva during the assay, however, may act as a stimulus for salivary flow.

Absorption sialometric methods involve placing a pre‐weighed absorbent swab or roll into the patient’s mouth for a set period of time after which it is re‐weighed. This technique is potentially portable to outpatient clinics and does not require specialized equipment. It is not considered as reliable as the aforementioned methods, however. The absorbent material may act as a stimulus for salivary flow and this method cannot be used to determine the constituents of saliva as the concentration of some salivary components may be altered due to the interaction of saliva with the absorbent material.19

Photo depicts patient demonstrating the active drainage method of whole saliva collection by spitting into a pre-weighed graduated container.

Figure 9‐6 Patient demonstrating the active drainage method of whole saliva collection by spitting into a pre‐weighed graduated container.

With respect to assessing stimulated salivary flow, the type of stimulus will influence how the glands are affected. Mechanical stimulation (chewing) results in a marked response of the parotid glands while a gustatory stimulus activates all three pairs of major salivary glands.19 Mechanical stimulation may be elicited by instructing the patient to chew a piece of paraffin wax, silicone, or unflavored gum base at a controlled rate (usually 60 times per minute, paced using a metronome). Gustatory stimulation may be provoked by application of a 2% citric acid solution to the lateral borders of the tongue at timed intervals. This stimulation technique, often used in a research setting, should not be used where analysis of whole saliva is required but can be used when assessing parotid gland saliva via the use of Lashley cups, for example (see below).

Using specific apparatuses, it is possible to collect saliva from the right or left parotid or submandibular/sublingual glands. Isolation of saliva from either the submandibular or sublingual glands is not possible as they share a common duct. Quantitative and qualitative analyses may reveal changes such as selective hyposecretion or changes in electrolyte and protein (enzyme) levels, such as observed in Sjögren’s syndrome. Collection of saliva from the parotid glands can be achieved using Carlson–Crittenden collectors or Lashley cups placed over Stensen’s duct orifices and held in place with gentle suction (Figure 9‐7). Collection of saliva from the submandibular/sublingual glands may be accomplished using a Wolff collector or Schneyer apparatus placed over the opening of Wharton’s duct or by using an alginate‐held collector called a segregator.20

Photo depicts patient with Carlson–Crittenden collectors in place undergoing collection of parotid gland saliva.

Figure 9‐7 Patient with Carlson–Crittenden collectors in place undergoing collection of parotid gland saliva.

Flow rates are determined gravimetrically in milliliters per minute, assuming that the specific gravity of saliva is 1 (i.e., 1 mL of saliva is equivalent to 1 g). Samples to be retained for compositional analysis should be collected on ice and frozen until tested. Flow rates may be affected by many factors such as patient position, hormonal status, hydration status, diurnal and seasonal variation, and time since stimulation. Regardless of the technique chosen, it is important to use a well‐defined, standardized, and clearly documented procedure which allows for meaningful comparisons between individuals and for repeat measurement in an individual over time.

It is difficult to define absolute “normal” values for salivary output due to great interindividual variability and, consequently, a large range of normal values exists. About 0.3–0.4 mL/min for unstimulated flow and 1.5–2.0 mL/min for stimulated flow are considered normal. Unstimulated whole saliva flow rates of < 0.1 mL/min and stimulated whole saliva flow rates of < 0.7 mL/min are abnormally low and indicative of marked salivary gland hypofunction.21 Higher levels of output do not guarantee that function is normal, however, as they may represent marked hypofunction for some individuals. Therefore, these stated values represent a lower limit of normal and should serve only as a guide for the clinician.

Sialochemistry

Normal saliva is a colorless, transparent fluid with a pH between 6 and 7. It is composed of approximately 99% water with inorganic ions of, amongst others, sodium, chloride, calcium, potassium, bicarbonate (HCO3), phosphate (i.e., dihydrogen phosphate, H2PO4), fluorine (i.e., fluoride, F), iodine (i.e., iodide, I), magnesium, and thiocyanate (SCN). Bicarbonate ions buffer saliva, while calcium and phosphate ions neutralize acids detrimental to tooth structure and contribute to remineralization of the tooth surface.

The organic components of saliva include urea, ammonia, uric acid, glucose, cholesterol, fatty acids, lipids, amino acids, steroid hormones, and proteins. Many of the constituent proteins such as mucins, amylases, agglutinins, lactoferrin, and secretory IgA play a role in protection of the oral tissues.22 The proline‐rich proteins (PRPs), another group of protective proteins, are amongst the most prevalent group of proteins in saliva accounting for 70% of all salivary proteins in humans.23 PRPs are antimicrobial and contribute to lubrication of oral surfaces, formation of the salivary pellicle, and tooth mineralization.24

When investigating a complaint of xerostomia, it is important to recognize that changes in salivary composition may be as important as a reduction in salivary output. That is, demonstration of apparently adequate salivary flow alone is not a guarantee of normal salivary gland function. While changes in saliva chemistries have been associated with a variety of salivary gland disorders as well as the sequela of radiation therapy, most alterations are changes in electrolytes related to reduced gland function as a result of damaged parenchyma, reduced salivary secretion, or a combination of both, rather than a specific disorder. Therefore, most salivary constituent changes are nonspecific diagnostically and have minimal utility in determining the cause of the salivary gland dysfunction.

An example of how systemic disease may affect sialochemistry is in patients with renal failure. These patients often develop high levels of salivary urea because of reduced renal clearance. Salivary urea is converted into ammonia and CO2 by plaque bacteria resulting in an increase in plaque pH which can cause supersaturation and precipitation of the calcium phosphate species hydroxyapatite, dicalcium phosphate dihydrate (brushite), β‐tricalcium phosphate (whitlockite), and octacalcium phosphate. Consequently, these patients have a tendency to develop greater amounts of calculus. Similarly, in patients who are exclusively tube fed, with no oral consumption of fermentable carbohydrates, plaque pH tends to remain high, favoring supersaturation of the aforementioned calcium phosphates leading to a greater propensity for calculus formation.25

Salivary Diagnostics

Saliva is an important medium in disease detection and can provide information about both local and systemic health. The use of saliva in diagnostics has many advantages over blood, for example, including relative ease of collection with no requirements for special equipment or training, non‐invasiveness, and cost‐effectiveness for screening large populations.22

Salivary diagnostics can allow for monitoring of hormone levels and other endocrine functions through the use of dynamics tests (e.g., dexamethasone suppression tests), determining the concentration and metabolism of hormones used as drugs (e.g., hormone replacement therapy), and in determining the free fraction of many hormones. Saliva can be used to help in diagnosis and monitoring of a number of systemic conditions, including Sjögren’s syndrome, for screening for drugs of abuse such as alcohol, cocaine, and MDMA (3,4‐methylenedioxy‐methamphetamine), and for the presence of viral infection (e.g., HIV, hepatitis C, and human papilloma virus).

Established tests for the detection of antibodies to HIV‐1 and HIV‐2 in saliva, such as the Food and Drug Administration [FDA]‐approved OraQuick ADVANCE Rapid HIV‐1/2 Antibody Test (OraSure Technologies, Bethlehem, PA), provide for rapid, convenient, and relatively inexpensive screening. Other saliva‐based assays can detect and quantify specific periodontal pathogens and high‐risk human papilloma viruses (e.g., MyPerioPath® and OraRisk HPV®, OralDNA Labs, Eden Prairie, MN).

Saliva can serve as a source of biomaterial for DNA extraction and screening for the presence of biomarkers (objectively measurable markers indicating presence of a disease, condition, or susceptibility) which may be used in diagnosis, staging, prognosis, and to indicate response to treatment. Using saliva for detection of disease biomarkers presents many advantages. Apart from being readily available and easy to collect, some disease‐discriminating biomarkers are present only in saliva or are found at a greater concentration in saliva compared to other biofluids.26

At present, various salivary biomarkers have been proposed and few have shown promise. MMP‐8 (matrix metalloproteinase‐8), for example, has been proposed as a salivary biomarker for diagnosis and prediction for progression of periodontal disease. Given the complex nature of disease, however, it is unlikely that any single biomarker will be both sufficiently sensitive and specific. In future, biomarkers will likely be used in combination with other data as in the “precision medicine” model where genetic, genomic, environmental, and clinical information is used to identify the most effective patient care. Prior to this, however, large‐scale multicenter research is needed to establish normative biomarker values.

Saliva‐based assays for early detection and diagnosis of cancer and Sjögren’s syndrome are in development. Research into the presence of tumor markers in saliva for oral cancers and precancers and variation in the salivary microbiome associated with other cancers shows promise.27 A “liquid biopsy” refers to the use of a biofluid (such as saliva, serum, or urine) to detect circulating tumor cells and fragments of tumor DNA shed from tumor cells into the circulatory system. Circulating tumor DNA (ctDNA) can be distinguished from normal cell‐free DNA by the presence of mutations, thereby potentially allowing for early, noninvasive detection. Since the mutations and amplifications caused by ctDNA are closely related to the occurrence and development of tumors, it is hoped that they may also be used to monitor therapeutic effect.28

Salivaomics

Salivaomics refers to the study of diagnostic components such as the salivary genome, proteome, transcriptome, metabolome, and microbiome. The salivary genome, composed of approximately 70% host and 30% oral microbiota DNA, allows access to the host genome via saliva collection.29 This feature has been exploited by companies (e.g., 23andMe®, AncestryDNA®) who provide direct‐to‐consumer genetic testing kits that can determine the presence of genomic variants (e.g., single nucleotide polymorphisms), gene mutations (e.g., in BRCA1 and BRCA2), and provide information regarding ancestry.26

The salivary proteome, composed of the entire set of proteins produced or modified by an organism, allows comparison of proteins produced in health versus disease. The human salivary proteome has been characterized for several diseases including oral squamous cell carcinoma, chronic graft‐versus‐host disease, and Sjögren’s syndrome.30

The salivary microbiome refers to the nonpathogenic, commensal bacteria present in healthy salivary glands as distinct from the oral microbiome of the oral cavity. The Salivaomics Knowledge Base (SKB) is a data repository management system and web resource dedicated to salivaomic studies.31 It is likely that information gleaned from the SKB will be used to develop saliva‐based diagnostic point‐of‐care technologies for the detection of salivary biomarkers for human diseases.

Salivary Gland Imaging

Imaging in patients with suspected salivary gland disease can help confirm the salivary gland(s) as the origin of pathosis and can distinguish inflammatory from neoplastic processes. Some imaging modalities may also provide information on gland function, anatomic alterations, and space‐occupying lesions. The following describes the application of plain film radiography, ultrasonography (US), computed tomography (CT), including cone beam computed tomography (CBCT), magnetic resonance imaging (MRI), positron emission tomography (PET) fused with CT or MRI (i.e., PET/CT, PET/MRI), sialography, salivary gland scintigraphy, and sialendoscopy as they relate to the diagnosis of salivary gland disorders. A summary of indications, advantages and disadvantages of each modality is presented in Table 9‐2.

Advances in imaging have resulted in a shift from reliance on plain films and sialograms to nearly sole use of US, CT, MRI, and sialendoscopy. When selecting the best imaging modality or modalities, consideration should be made for relative accuracy, reliability, cost, radiation exposure, and patient desires, among other factors.

Plain Film Radiography

Plain film radiography may be the initial imaging modality employed in investigating a chief complaint involving the major salivary glands due to its availability; however, its clinical value may be limited. Use of conventional radiography has diminished with time in favor of cross‐sectional imaging.

Signs and symptoms suggestive of salivary gland obstruction (e.g., painful, acute swelling of a gland, clinical detection of a sialolith) (Figure 9‐8) warrant plain film radiography to help confirm or refute the presence of calcified blockages. Plain film may also depict bony destruction associated with malignant neoplasms and can provide a background for interpretation of a sialogram.

While plain film radiography is particularly useful for visualization of radiopaque sialoliths, phleboliths, hemangiomas with calcifications, and calcified lymph nodes may mimic sialoliths while smaller or poorly calcified sialoliths may not be visible.32 If a stone is not evident on plain film but clinical evaluation and history are suggestive of salivary gland obstruction, additional imaging, such as CBCT, may be necessary.

Since the salivary glands are located relatively superficially, radiographic images may be obtained using standard dental radiographic techniques. Panoramic or lateral oblique projections can be used to image the parotid glands; however, overlap of anatomic structures, particularly in panoramic views, may obscure the appearance of a stone. A standard occlusal film placed intraorally adjacent to the parotid duct can help visualize a stone close to the gland orifice but may not capture the entire gland. The submandibular gland can be imaged in anterior posterior (AP) and ipsilateral oblique projections with the chin extended, mouth open, and the tongue pressed down to the floor of the mouth.32 Sialoliths obstructing the submandibular gland may also be visualized in panoramic, occlusal, or lateral oblique views.

Table 9‐2 Salivary gland imaging modalities: indications, advantages, and disadvantages.

Imaging Modality Indications Advantages Disadvantages
Plain film Sialolithiasis Readily available; Inexpensive Prone to anatomic overlap;
Radiolucent sialoliths not visualized
Ultrasonography Mass detection; Biopsy guidance;
Helpful in assessment of Sjögren’s syndrome
Noninvasive;
Cost‐effective
No visualization of deep parotid; No quantification of
function; Observer variability
Computed Tomography Inflammatory conditions;
Calcified structures;
Bony erosion
Differentiates osseous structures from soft tissue No quantification; Requires contrast injection;
Radiation exposure
Cone Beam Computed Tomography Sialolithiasis Can be combined with sialography; Reduced image degradation from metallic artefacts Some radiation exposure
Magnetic Resonance Imaging Neoplastic processes Superior soft tissue resolution;
No radiation exposure
Contraindicated with ferromagnetic materials and some pacemakers;
High cost
Positron Emission Tomography fused with CT
(PET/CT)
Staging and re‐staging of malignant salivary gland tumors Combines functional data with anatomic imaging Radiation exposure; Cannot reliably distinguish malignant from benign tumors
Positron Emission Tomography fused with MRI
(PET/MRI)
Salivary gland tumors High sensitivity for detecting perineural spread;
Reduced radiation exposure compared to PET/CT
Not widely available
Sialography Sialolithiasis; Abnormalities of ductal system Visualizes ductal anatomy/blockages;
Superior spatial resolution
Invasive;
No quantification; Contraindicated in active infection
Salivary Gland Scintigraphy Assessment of salivary gland function after surgery, radiation therapy and in Sjögren’s syndrome Relatively easy to perform Lengthy procedure; High cost; Radiation exposure; No morphologic data; Invasive
Sialendoscopy Sialolithiasis;
Ductal strictures and stenosis;
Treatment of mucus plugs in Sjögren’s syndrome
May allow for simultaneous visualization and treatment Invasive;
Cannot be used in acute sialadenitis

Photos depict left: Sialolith within the left submandibular gland duct. Right: Surgical exploration of a sialolith within the left submandibular duct.

Figure 9‐8 Left: Sialolith within the left submandibular gland duct. Right: Surgical exploration of a sialolith within the left submandibular duct.

Source: Courtesy of Dr. Michael D. Turner, New York University.

Ultrasonography

Using sound waves, ultrasound (US) generates a two‐dimensional picture based upon the relative echogenicity of tissue; that is, the tissue’s capacity to reflect or transmit ultrasound waves. US is often used during an initial evaluation, particularly where there is suspicion of sialolithiasis, acute sialadenitis or parotitis, and salivary gland abscesses. It is relatively inexpensive, widely available, safe and patient‐friendly, even for children and pregnant women, and can delineate superficial salivary gland lesions as precisely as CT and MRI. High‐frequency US also provides excellent resolution and characterization of tissue without exposure to radiation.33

US can also help distinguish focal from diffuse disease, assess adjacent vascular structures, distinguish solid from cystic lesions, guide fine‐needle aspiration biopsy (FNAB), and evaluate lymph nodes for nodal staging.34 It can also correctly differentiate malignant from benign lesions in 90% of cases and distinguish glandular from extraglandular masses with an accuracy of 98%.35 Initial use of US, therefore, may guide the clinician in determining whether further imaging is required.

Due to their peripheral locations, the superficial portion of the parotid gland and the submandibular glands are easily visualized by US (Figure 9‐9); the overlying mandibular ramus impedes evaluation of the deep portion of the parotid. Although US cannot directly visualize the facial nerve, it can suggest its position by accurate identification of intraglandular vessels within the parotid. Superficial lesions of the parotid and the submandibular glands may be amenable to core biopsy or fine‐needle aspiration cytology (FNAC) under US guidance. US can also be used to guide procedures such as ductal stricture dilation and injection of botulinum toxin into a salivary gland as treatment for sialorrhea.

Photo depicts ultrasound image with arrows indicating a sialolith within the left submandibular gland.

Figure 9‐9 Ultrasound image with arrows indicating a sialolith within the left submandibular gland.

Salivary gland US can be a very helpful adjunct in the diagnosis and monitoring of Sjögren’s syndrome. When compared to other diagnostic modalities, including scintigraphy, sialography, and salivary gland biopsy, salivary gland US consistently demonstrates high specificity and diagnostic accuracy. It provides a means to evaluate all the major salivary glands in one procedure, can highlight intraglandular calcifications and abnormal lymph nodes, and has been shown to be effective in identifying changes indicative of lymphoma development.36 Further clinical testing, however, is needed with large cohorts to determine its overall diagnostic value in Sjögren’s syndrome.

In order to be visible during US, the salivary ductal system must be filled. Filling may have occurred secondary to an obstructive pathology, or may be induced by oral administration of ascorbic acid. Retrograde administration of a contrast agent, similar to the procedure described for sialography (see below), can further aid in the visualization of the ductal system.

Sialoliths of less than 2 mm or those that are semicalcified may not be detected by US. Since it lacks the sensitivity required to fully visualize the internal ductal architecture, mucus plugs will also not be detected. In addition, US may not always allow for discrimination of phleboliths, arterial calcifications, and calcified lymph nodes from salivary gland calculi.

Ultrasound elastography, an imaging technique which evaluates the relative elasticity or stiffness of tissues, has been proposed to help differentiate between benign and malignant salivary gland tumors since malignant tumors are usually harder than benign ones. Current research suggests that real‐time elastography could be used as an adjunct to conventional US for evaluation of salivary gland masses. Ultrasound elastography has already proven to be able to distinguish salivary glands affected by Sjögren’s syndrome from normal glands.37

Conventional Computed Tomography

Conventional computed tomography (CT) is often the preferred initial imaging modality for evaluation of suspected calcifications and inflammatory conditions of the salivary glands owing to its high sensitivity and spatial resolution.38 It is especially useful in the evaluation of malignant processes since it is able to depict mandibular cortical bone erosion and destruction, and cutaneous changes. Since CT can help define cystic walls and highlight the characteristic enhancing wall seen in abscesses, it is possible to distinguish fluid‐filled masses (i.e., cysts) from abscesses. Landmark structures such as the retromandibular vein, carotid artery, and deep lymph nodes can also be identified on CT.

Imaging the major salivary glands can be optimally achieved using a standard neck CT protocol, which includes the skull base, nasopharynx, and oral cavity extending to include potentially enlarged lymph nodes in the neck, using continuous fine cuts through the gland(s) of interest. Both pre‐ and postcontrast studies must be performed in order to detect calcifications (precontrast) and enhancement patterns (postcontrast), and to allow distinction from normal anatomy. The initial precontrast scans are also reviewed for the presence of sialoliths (Figure 9‐10), masses, glandular enlargement or asymmetry, nodal involvement, and loss of tissue planes.

Since glandular damage from chronic disease often alters the density of the salivary glands making identification of masses more difficult, contrast‐enhanced images are often indicated as they will accentuate pathology. With contrast, tumors, abscesses, and inflamed lymph nodes may show abnormal enhancement when compared to normal structures. Enhanced CT can therefore help in staging malignant disease of the salivary glands by assessing lymphadenopathy of the pharynx and neck. Coronal and sagittal reconstructions are particularly useful in the evaluation of perineural spread, which, when present, implies a poor prognosis.39

CT maintains several advantages over MRI: it is less costly, more readily available, and it can be used in patients for whom MRI is contraindicated (e.g., individuals with certain implanted medical devices). CT may also be an alternative for patients who are unable to lie still long enough for an MRI (e.g., pediatric or geriatric patients or patients with mental or physical disabilities), and for whom MRI is otherwise contraindicated.

Photo depicts axial CT image showing a sialolith of the left submandibular duct.

Figure 9‐10 Axial CT image showing a sialolith of the left submandibular duct.

Source: Courtesy of Dr. Michael D. Turner, New York University.

Dental restorations, maxillofacial fixation hardware, or other metallic hardware residing in the area imaged may produce streak artifact which may necessitate additional CT scans acquired with a different head position or gantry tilt angle and application of metal artifact reduction techniques. Additional disadvantages of CT include radiation exposure and the administration of iodine‐containing contrast media for enhancement. Significantly impaired renal function and prior allergic reaction to a contrast agent may be contraindications for contrast‐enhanced CT.

Cone Beam CT (CBCT)

Using a cone‐shaped x‐ray beam and two‐dimensional detectors, a CBCT scanner collects volume data by means of a single rotation around the patient taking 9–40 seconds. It provides reduced superimposition and distortion of anatomic structures and higher sensitivity over two‐dimensional radiography.

When compared with conventional CT, CBCT provides higher spatial resolution of osseous structures at a lower radiation dose, requires a shorter scan time, demonstrates reduced image degradation from metallic artifacts, and is less costly and more likely to be available in outpatient clinics and dental offices.33,40 After plain film radiography, CBCT may be employed in patients with signs and symptoms consistent with sialolithiasis (see section: Sialolithiasis).41

Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) employs strong, dynamic magnetic fields and radio waves to produce diagnostic images. It has proven value in assessment of major salivary gland diseases, especially neoplastic processes (Figure 9‐11). It is the imaging modality of choice for preoperative evaluation of salivary gland tumors, especially where there is a strong suspicion for malignancy, because of its ability to differentiate soft tissues and availability of multiplanar imaging.42 When comparing US, CT, MRI, PET/CT, and real‐time elastography, MRI has demonstrated the greatest potential to discriminate malignant from benign neoplasms (see section: Imaging in the differentiation of benign and malignant salivary gland tumors).

MRI provides a higher degree of accuracy in assessing malignant perineural invasion, intracranial spread, deep tissue extension, and marrow infiltration/edema over CT.34,43 It is also optimal for detection of extracapsular spread in regional lymph nodes.44 For these reasons, MRI is indicated to assess complete tumor extent, local invasion, and perineural spread in deep tissues for staging and treatment planning purposes. MRI can also highlight postoperative recurrences.34

Photo depicts axial MRI demonstrating a pleomorphic adenoma of the right parotid gland.

Figure 9‐11 Axial MRI demonstrating a pleomorphic adenoma of the right parotid gland.

MRI may also be useful in the discrimination of disorders that mimic parotid gland swelling such as hypertrophy of the muscles of mastication and for detection of parotid gland changes associated with undiagnosed Sjögren’s syndrome.33,45 Such changes on MRI that can be associated with Sjögren’s syndrome are an inhomogeneous internal pattern in both T1‐ and T2‐weighted images giving a “salt‐and‐pepper” or “honeycomb‐like” appearance.46 A head and neck MRI can also help detect central nervous system and cranial nerve involvement in Sjögren’s syndrome and can highlight changes associated with the development of malignant B‐cell lymphomas, in particular mucosa associated lymphoid tissue (MALT) lymphomas; a true advantage as lymphomas arise in approximately 5–10% of Sjögren’s syndrome patients.

The superior soft tissue contrast that MRI affords allows excellent discrimination of the salivary gland parenchyma and ductal structures. The utility of MRI is further enhanced by combining it with sialography allowing for a much finer evaluation of ductal alterations and filling defects (see section: MR Sialography). With respect to causes of ductal obstruction, however, MRI does not allow for differentiation between calcified sialoliths, fibrin, and mucus plugs and it may overestimate the size of calcified sialoliths from 10% to 30%.47

Additional advantages of MRI are that it does not expose patients to radiation, intravenous contrast media is not routinely required, and it is less susceptible to artifact from dental restorations than CT. MRI is contraindicated in patients with some cardiac pacemakers, automatic cardioverter defibrillators, or ferromagnetic metallic implants. Patients who cannot maintain a still position for the required scan time or those with claustrophobia may have difficulty tolerating the MRI procedure. Open bore or wide bore scanners are becoming more available to address these issues; however, the image quality is inferior to that of closed bore scanners.

PET/CT and PET/MRI

PET/CT is a whole‐body imaging technique which combines the functional imaging provided by positron emission tomography (PET) with anatomic data from the CT scan. PET typically employs the radioactive tracer 2‐deoxy‐2‐(18F) fluoro‐D‐glucose (FDG); a glucose analogue taken up by cells with high glucose demand such as in the brain and kidneys, and cancer cells. A low level of physiologic uptake also occurs in normal tissues such as in the parotid and submandibular glands and tonsils. Uptake is increased at sites of active inflammation and infection and in benign, non‐neoplastic processes, such as sarcoidosis and radiation‐induced sialadenitis.38

PET/CT has an established role in staging head and neck cancer, searching for an unknown primary, assessing response to treatment, and differentiating relapse or recurrence from treatment effects.48 It is considered a useful complementary technique to conventional imaging for staging malignant salivary gland tumors and for follow‐up and restaging of treated tumors. In discriminating benign from malignant salivary gland processes, however, the PET/CT suffers from unacceptably high rates of false‐positive and false‐negative results.38

PET/CT has also demonstrated utility in assessing patients with primary Sjögren’s syndrome. It can depict systemic manifestations such as lymphadenopathy and pulmonary and salivary gland involvement in these patients. In the parotid glands, a maximum standardized uptake value (SUVmax), a measure of FDG uptake, of ≥4.7 and/or the presence of focal lung lesions has been associated with the diagnosis of lymphoma in primary Sjögren’s syndrome patients.49

The use of fused PET/MRI has recently been explored. Studies using retrospective fusion of MRI and PET datasets demonstrated that the fused PET/MRI images offered higher sensitivity and specificity with respect to the presence of head and neck malignancy than with the unfused MRI and PET images. When compared with PET/CT, PET/MRI offers two additional advantages: the relative high sensitivity of MRI for detecting perineural spread, a route of metastasis favored by many salivary gland tumors, and reduced radiation dose.50

Sialography

Sialography achieves radiographic visualization of parotid and submandibular gland ducts, ductules, and parenchyma following retrograde instillation of soluble contrast material into Stensen’s or Wharton’s ducts, respectively. Since cannulation of multiple smaller ducts can be technically challenging, it is not typically used to image the sublingual glands. The most common sialographic findings include calcified sialoliths, noncalcified obstructive lesions (e.g., fibrin or mucus plugs), granulomatous collections on ductal walls, stenoses, strictures, and ductal kinks.

Because of its superior spatial resolution over CT, MRI, and scintigraphy, sialography allows for examination of the microanatomy of salivary duct systems.51 It is used for evaluating intrinsic and acquired abnormalities (e.g., ductal stricture, obstruction, dilatation, and ruptures), and for identifying and localizing sialoliths, because it provides the clearest images of branching ducts and acinar end pieces.

In a patient who presents with a history of rapid‐onset, painful swelling of a single gland (typically brought on by eating), sialography may be of value to detect the presence of calculi, ductal stricture, or obstruction due to mucus plugging. Sialoliths usually appear as voids (Figure 9‐12) while focal collections of contrast medium within the gland usually indicate sialectasis (abnormal salivary ductal dilation) such as seen in sialadenitis and Sjögren’s syndrome.

Photo depicts sialogram showing an uncalcified sialolith in Wharton’s duct visualized where the submandibular duct overlies the inferior alveolar canal.

Figure 9‐12 Sialogram showing an uncalcified sialolith in Wharton’s duct visualized where the submandibular duct overlies the inferior alveolar canal.

Source: Courtesy of Dr. Elisa Mozaffari, University of Pennsylvania.

Sialography may also be a valuable tool in presurgical planning for removal of salivary gland masses or to estimate ductal diameter prior to sialendoscopy. One of the chief advantages of sialography is that salivary stones can be localized to the salivary gland duct or gland parenchyma, which may influence the choice of treatment.52 The ability to manipulate patient head position during examination may also provide enhanced visualization.

There are three main types of sialography: conventional sialography (with or without digital subtraction), CT sialography (including CBCT sialography), and MR sialography. In conventional sialography, the papilla of Stensen’s or Wharton’s duct is identified and, if required to facilitate access, the ductal orifice is dilated using incremental sizes of lacrimal probes. Once maximum ductal dilation is achieved, a sialographic catheter is introduced. Prior to infusion of a water‐ or fat‐soluble sialographic contrast agent, an image is obtained to aid in distinguishing structures enhanced by the contrast agent or as a precontrast image for digital subtraction sialography (see below). Ductal filling is achieved by application of gentle, constant pressure on the syringe plunger until complete opacification of the ductal system is observed.

During sialography of a normal salivary gland, contrast medium will be seen initially in the peripheral portions of the duct extending towards the gland, filling and infiltrating into the intraglandular ductal branches (ductal phase). The image will resemble tree branches, initially leafless, gradually bursting into bloom, which represents introduction of the contrast material into the salivary gland parenchyma (parenchymal phase).52 Radiographic views employed in conventional sialography include panoramic, lateral oblique, AP, and “puffed‐cheek” AP views.

Following the sialographic procedure, the patient is instructed to massage the gland and/or to suck on lemon drops to promote the flow of saliva and contrast material out of the gland. Postprocedure imaging is performed to ensure that all contrast material elutes or is fully resorbed. Incomplete clearing can be due to obstruction of salivary outflow, extraductal or extravasated contrast medium, collection of contrast material in abscess cavities, or impaired secretory function.

Digital subtraction radiography refers to an image analysis technique which allows for detection of small radiographic changes between successive radiographs by “subtracting” distracting static anatomic structures. In digital subtraction sialography (DSS), precontrast images are subtracted from postcontrast images to provide high‐resolution imaging of the extraglandular and intraglandular salivary ductal system, permitting detection of even small sialoliths.53 A distinct advantage DSS has over conventional sialography is that the former allows images to be captured during the initial filling of the main duct thereby preventing obscuration of mucus plugs by contrast medium.54 Functional information can also be obtained after sialogogue administration.

Clinical indications for DSS are an acute swelling or palpable mass in the submandibular or parotid regions or gradual or chronic enlargement of a salivary gland where sialolithiasis or sialadenitis is suspected.55 The principle weaknesses of DSS are that it is invasive (since it requires ductal cannulation), it requires the use of contrast and ionizing radiation, and that it has a high incidence of technical failure.33

Potential complications of sialography include ductal rupture, activation of clinically dormant infection, and adverse reaction to contrast agents.32 Sialography is contraindicated in the presence of active infection (acute sialadenitis) and in a patient with a history of allergy to contrast agents. Performing sialography during an active infection may cause further glandular irritation and potential ductal rupture. Injection of contrast material may also force bacteria throughout the ductal structures, thereby spreading infection.

CT Sialography

CT sialography employs sialographic contrast to delineate the salivary ducts and enable the evaluation of the salivary gland parenchyma in fine detail. It is performed in the same manner as conventional sialography except that the patient is positioned in a CT scanner in a neutral supine position. Although CT sialography has a number of potential advantages over conventional sialography, it is not routinely performed for the following reasons: conventional CT without sialography typically provides adequate visualization of the main duct while the inability to dynamically visualize filling of the ducts in real time may lead to overfilling and subsequent rupture.

CBCT Sialography

Combining CBCT with sialography represents a relatively new approach that is showing promise as a supplementary noninvasive diagnostic method for visualizing the intraglandular ductal system. Using 3D and multiplanar reconstruction (i.e., converting data acquired in a one plane into another plane or planes), accurate mapping of salivary ducts can be achieved.56

CBCT sialography may be especially useful where US or sialendoscopy have failed to demonstrate pathology in patients with suspected salivary gland disease. It may serve as an advanced imaging modality since, following injection of contrast agent, visualization up to the sixth division of the ductal system is possible. While CBCT sialography is not a substitute for sialendoscopy (see section: Sialendoscopy), its selective use may eliminate the need for sialendoscopy if the causative pathology is identified in the intraglandular duct system or in the area around the hilum as these areas are not accessible to sialendoscopy.57

CBCT sialography provides several advantages over conventional sialography with respect to imaging the intraglandular ductal system including three‐dimensional reconstruction, greater image manipulation, and generation of various cross‐sectional slices. These advantages are particularly valuable in cases of complex anatomy.39 By selecting appropriate parameters, the effective radiation dose from CBCT sialography can be equivalent to that of conventional sialography and it is less costly and more widely available than CT or MRI.

MR Sialography

Magnetic resonance sialography represents a fairly sensitive and reliable method for evaluating the salivary glands and may be used as the diagnostic method of choice in patients with suspected sialolithiasis where unenhanced CT has failed to demonstrate pathology. It provides several advantages over other imaging modalities: it can be employed in the diagnosis of parenchymal and ductal lesions with simultaneous visualization of all major salivary glands, it does not employ radiation, and, since it does not always require ductal cannulation and injection of contrast medium, it can be noninvasive and used in cases of acute sialadenitis.58

MR sialography is considered as accurate as conventional sialography in detecting obstructions, stenosis, and strictures of the main salivary gland ducts.51 Advances in 3‐D volumetric techniques and the ability to reformat images allow for the generation of virtual endoscopic views.59 Disadvantages of MR sialography include a more limited availability and higher cost. It is also considered to have a lower sensitivity with respect to ductal pathologies, since its resolution does not extend beyond secondary divisions.51

Salivary Gland Scintigraphy

Scintigraphy using technetium (Tc) 99m pertechnetate is a dynamic and minimally invasive diagnostic assay employed to assess salivary gland function.60 Technetium 99m pertechnetate is a pure gamma ray‐emitting radiopharmaceutical, which, following intravenous injection, is taken up and transported by the salivary glands and secreted into the oral cavity generating quantitative information on the glands’ function (Figure 9‐13).61 Salivary gland scintigraphy (SGS) can provide information on both the parenchyma and function of the parotid and submandibular glands after a single intravenous injection: a clear advantage over other imaging techniques.62 Both uptake, which indicates the presence of functional epithelial tissue, and secretory phases can be recognized. SGS is indicated for the evaluation of patients when sialography is contraindicated or cannot be performed (i.e., in cases of acute sialadenitis or iodine allergy), or when the major duct cannot be cannulated successfully.

Photo depicts (A, left) Technetium 99m pertechnetate radionuclide image (scintigram) of the parotid and submandibular glands. This sequential salivary scintigram is an anterior Water’s projection of an individual with normal salivary gland function. The four glands are outlined in frame 1 as regions of interest for further analyses. In frame 7, the dark arrow denotes Stensen’s duct and the white arrow indicates Wharton’s duct.

Figure 9‐13 (A, left) Technetium 99m pertechnetate radionuclide image (scintigram) of the parotid and submandibular glands. This sequential salivary scintigram is an anterior Water’s projection of an individual with normal salivary gland function. The four glands are outlined in frame 1 as regions of interest for further analyses. In frame 7, the dark arrow denotes Stensen’s duct and the white arrow indicates Wharton’s duct. A secretagogue, usually citric acid, is placed in the oral cavity between frames 9 and 10, inducing a rapid emptying of the glands. In frame 12, 10 minutes following the secretagogue, tracer is absent in the salivary glands and concentrated in the outlined oral cavity.

(Courtesy of Dr. Frederick Vivino, University of Pennsylvania.)

(B, right) A single frame of a salivary scintigram demonstrating significant uptake in both parotid and submandibular glands (four lower windows) with excretion into the oral cavity. The two upper windows represent background activity from blood flow, which is subtracted from the four regions of interest to determine specific salivary activity.

Source: Courtesy of Dr. Frederick Vivino, University of Pennsylvania.

SGS can also estimate the severity of salivary gland involvement and functional change—even that which is not accurately reflected by morphologic damage.63 As such, it has been used to assess salivary gland function following surgery, radiation, and radioiodine therapy. It has also been used to aid in the diagnosis of ductal obstruction, sialolithiasis, gland aplasia, and Sjögren’s syndrome.32 SGS has been proposed as a valid alternative to other forms of functional evaluation of the salivary glands in patients with Sjögren’s syndrome. An abnormal SGS result is accepted as part of the 2002 American–European consensus group classification criteria for Sjögren’s syndrome, but is not included in the 2012 ACR or 2016 ACR/EULAR criteria.6466

A normal scintigraphic time–activity curve may be separated into three phases: flow, concentration, and washout. The flow phase is about 15–20 seconds and represents the time immediately following radionuclide injection when the isotope is equilibrating in the blood and accumulating in the salivary gland at a submaximal rate. The concentration (uptake) phase represents the accumulation of Tc 99m pertechnetate in the gland via active transport. With normal salivary gland function, the radionuclide will be secreted and tracer activity should be apparent in the oral cavity after 10–15 minutes. Approximately 15 minutes after administration, tracer concentration begins to increase in the oral cavity and decrease in the salivary glands. A normal image will demonstrate symmetric uptake of Tc 99m by both the parotid and submandibular glands.

In the excretory or washout phase, the patient is given a lemon drop, or citric acid is applied to the tongue, to stimulate secretion. Normal clearing of Tc 99m should be prompt, uniform, and symmetric. Activity remaining in the salivary glands after stimulation is suggestive of obstruction, certain tumors, or inflammation. With some exceptions, neoplasms arising within the salivary glands do not concentrate Tc 99m and will appear as voids or areas of decreased activity on the scintigram. The notable exceptions are Warthin’s tumor and oncocytomas which will retain Tc 99m because they do not communicate with the ductal system and hence will appear as areas of increased activity on static images.67

Several rating scales have been used for the evaluation of salivary scintigrams; however, no standard method exists. Current approaches to functional assessment include visual interpretation, time–activity curve analysis, and numeric indices. Semiquantitative methods are also used in which Tc 99m uptake and secretion are calculated by computer analysis of user‐defined regions of interest.

Although salivary gland scintigraphy is considered the gold standard for assessing salivary function and it is relatively easy to perform and reproducible, its use has fallen out of favor to noninvasive methods that do not subject the patient to radiation, such as US and MR imaging, including MR sialography.68

Sialendoscopy

Sialendoscopy has emerged as a valuable diagnostic and therapeutic technique for many salivary gland disorders affecting the submandibular and parotid glands. Using a small camera, it allows visualization of intraductal anatomy and strictures or other pathoses within the ducts. Insertion of surgical instruments or lasers through the endoscope may permit simultaneous fragmentation and removal of calcified material, biopsy, or stricture dilation. Typically, US, conventional sialography, contrast‐enhanced CT, or MR sialography is employed prior to the sialendoscopic procedure to assess the ductal system. In many cases, the use of sialendoscopy may obviate the need for additional procedures or adenectomy.47

Sialendoscopy has also been used to flush out mucus plugs and irrigate the ductal system with saline or corticosteroids to enhance salivary flow and diminish xerostomia in patients with Sjögren’s syndrome.69 Following the sialendoscopic procedure, a stent may be placed to allow for healing of the duct and maintenance of salivary flow.

One limitation of sialendoscopy is that it can only be used for extraglandular duct pathologies or those close to the hilum.57 The deepest portions of the gland (i.e., the proximal ductules) may not always be accessible, especially where stenosis is present. Very small stones, the presence of multiple smaller stones within different ductal branches, very large (> 9 mm) or immobile stones may also present a challenge.41 Sialendoscopy is contraindicated in the presence of acute sialadenitis due to the increased risk of duct perforation.70

Imaging in the Differentiation of Benign and Malignant Salivary Gland Tumors

The ideal imaging modality would allow definitive discrimination between benign and malignant salivary gland tumors. In comparing US, CT, MRI, PET/CT, and real‐time elastography (RTE), there is no statistically significant difference and no consensus on the use of one single modality or combination of modalities for this task. Of these, however, MRI shows the greatest potential.43

Histopathologic analysis remains the gold standard in evaluating the malignant potential of a neoplasm and imaging characteristics alone may never allow for definitive distinction between benign and malignant processes. One reason for this is because on imaging, lesions can demonstrate overlapping features; for example, a low‐grade malignancy may appear well‐defined with smooth borders.

Salivary Gland Biopsy

Definitive diagnosis of salivary gland pathology often requires histologic examination. The labial minor salivary glands are the most commonly biopsied, especially where Sjögren’s syndrome is suspected, since they are the most accessible. Biopsy of the minor glands can also be used to diagnose amyloidosis, sarcoidosis, and chronic graft‐versus‐host disease (cGVHD), among other pathoses.

Minor Salivary Gland Biopsy

The minor salivary gland biopsy (MSGB) is a minimally invasive procedure that can be performed with limited morbidity using appropriate techniques.71 An incision is made on the inner aspect of the lower lip, to one side of the midline, through normal‐appearing mucosa, avoiding areas of trauma or inflammation that could influence the appearance of the underlying tissue. Six to ten minor gland lobules from just below the mucosal surface are removed and submitted for histopathologic examination. Clinicians should ensure an adequate specimen is obtained when Sjögren’s syndrome is suspected, as generation of a focus score (see below) requires at least 8 mm2 of evaluable salivary gland tissue.

The MSGB performed as part of a work‐up for Sjögren’s syndrome is considered the most accurate sole criterion for diagnosis of the salivary component of this disorder.72 Histologically, the presence of focal lymphocytic sialadenitis is supportive of the diagnosis. The pathologic grading system results in a Focus Score (FS) which relates to the number of aggregates of ≥ 50 lymphocytes per 4 mm2 of salivary gland tissue. A FS ≥ 1 is considered positive for Sjögren’s syndrome.

Recent use of corticosteroids, smoking, and radiation exposure to the area of biopsy may adversely affect results. Complications associated with MSGB include long‐term lower lip numbness (reported at 0–10%) and mucocele formation.71

Major Salivary Gland Biopsy

The parotid gland biopsy has been shown to be superior to the MSGB with respect to diagnosis of several conditions including sarcoidosis and lymphomas.73 Where salivary gland lymphoma is suspected, histopathologic analysis is often combined with techniques such as flow cytometry, and fluorescence in situ hybridization for definitive diagnosis and characterization. Here, the parotid gland as a biopsy site offers important advantages over the MSGB. The larger gland size offers multiple sites and opportunities for sampling and, since mucosa‐associated lymphoid tissue (MALT) and non‐Hodgkin lymphomas (NHL) are rarely observed in labial salivary glands, there is the opportunity to make a diagnosis even prior to clinical manifestation.74 In addition, histopathologic results from the parotid gland can be directly compared with imaging or assays involving the same gland (e.g., scintigraphy, US, sialometry).71

With respect to Sjögren’s syndrome, while the sensitivity and specificity of the parotid and minor salivary gland biopsies are comparable, the former may offer unique value in assessing disease activity, progression, and response to treatment. Risks that have been associated with biopsy of the parotid gland include sialocele and salivary fistula formation, injury to the facial nerve, and visible external incision, but these have not occurred where an appropriate technique has been applied. There are no reports of permanent morbidity associated with the parotid gland biopsy in contrast to the relatively higher hazard of permanent damage to the sensory nerves of the lower lip with the MSGB.71

Fine‐Needle Aspiration Biopsy

Fine‐needle aspiration biopsy (FNAB) is a simple technique that aids in the diagnosis of lesions using a fine‐gauge needle to obtain a biopsy specimen for histopathologic analysis. Its use may prevent a significant number of patients from undergoing an open surgical procedure. The diagnostic sensitivity and specificity of FNAB for salivary gland lesions has been reported as above 80% and 95%, respectively. Limitations include difficulty in obtaining an adequate specimen, inability to determine tumor grade (i.e., discerning between high and low grade), reduced accuracy for non‐neoplastic processes, and lack of information with respect to tissue architecture, capsular invasion, and lymphovascular involvement.75

Core Needle Biopsy

A core needle biopsy (CNB), in which a large bore needle is used to remove cylinders of tissue, may be used in the preoperative evaluation of salivary gland lesions. CNB has the advantages of having a lower rate of complications (bruising being the most commonly reported problem), and reduced risk of tumor seeding over FNAB.75 CNB also provides increased material over the FNAB, allows preservation of histologic architecture, and can allow for assessment of extracapsular tumor invasion. Immunohistochemical stains are also more likely to be reliable with core biopsy specimens. Disadvantages of CNB include the requirement for local anesthesia and possibly increased pain and morbidity.

Ultrasound‐Guided Core Needle Aspiration

US‐guided core needle aspiration is indicated for distinct salivary gland masses of the major salivary glands and can also be used to investigate cervical lymphadenopathy.76 Employing US significantly improves the safety, accuracy, and diagnostic rate over non‐US guided biopsies.77 A cytopathologist familiar with salivary gland cytology should inspect the aspirated specimen and offer a diagnosis or differential diagnoses based upon the cellular characteristics observed. Even if a definitive diagnosis is not rendered, it may be possible to determine whether a lesion is benign or malignant, which is helpful as awareness of the biologic aggressiveness of the tumor prior to definitive surgery aids in treatment planning.

Frozen Section Analysis

Frozen section analysis is a procedure in which specimens are rapidly processed and analyzed during a surgical procedure. It can help confirm or refine a presurgical diagnosis, including establishing whether a neoplasm is benign or malignant, and is used to evaluate margins for tumor involvement, and determine if there is neural or lymph node involvement. Frozen section analysis in parotid gland surgery has important implications. For example, discovery of involvement of the facial nerve by a malignancy will require sacrifice of one or more of its branches; lymph node involvement may necessitate neck dissection or radiation therapy. Frozen section analysis is estimated to have a 90% sensitivity and 99% specificity for salivary gland lesions.78

Serologic Evaluation

In addition to a review of medical history and clinical examination, serologic analyses can be helpful in the evaluation of a patient with dry mouth especially where an autoimmune process such as Sjögren’s syndrome is suspected. Indeed, detection of serum autoantibodies has a central role in the diagnosis and classification of Sjögren’s syndrome. The most extensively studied of these autoantibodies are the antinuclear antibodies (namely subtypes anti‐SSA/Ro and anti‐SSB/La), and rheumatoid factor (RF): 59–85% of patients with primary Sjögren’s syndrome will display antinuclear antibodies and, of these, 50–70% will show anti‐Ro/SSA and anti‐La/SSB antibodies.79 Although the anti‐SSA/Ro autoantibody is considered the most specific marker for Sjögren’s syndrome, it may be found in a small percentage of patients with systemic lupus erythematous or other autoimmune connective tissue disorders and even in some normal individuals.

Serologic evaluation can also help to distinguish between Sjögren’s syndrome and IgG4‐related disease (IgG4‐RD) since they may present similarly (i.e., salivary gland enlargement, sicca symptoms, arthralgias). In both, patients may have circulating antinuclear antibodies; however, anti‐SSA/Ro and anti‐SSB/La reactivity is not frequently found in patients with IgG4‐RD. Similarly, in suspected cases of Sjögren’s syndrome/sicca syndrome triggered by the cancer immunotherapy drugs known as immune checkpoint inhibitors, the serologic profile can be helpful as anti‐SSA/Ro and anti‐SSB/La antibody screening is usually, but not always, negative. However, as this phenomenon has a distinct phenotype with respect to histopathology and other features, additional assays including a minor salivary gland biopsy may be required to distinguish it from idiopathic Sjögren’s syndrome (see section: Sjögren’s Syndrome/Sicca Syndrome Triggered by Cancer Immunotherapies).80

SPECIFIC DISEASES AND DISORDERS OF THE SALIVARY GLANDS

Developmental Abnormalities

Salivary Gland Aplasia and Hypoplasia

Patients with salivary gland aplasia (incomplete development or absence) experience hyposalivation, xerostomia, and increased dental caries; in fact, rampant dental caries in children without other significant risk factors has led to the diagnosis of congenitally missing salivary glands. Although rare, salivary gland aplasia may occur with other developmental defects, especially malformations of the first and second branchial arches seen as various craniofacial anomalies. Enamel hypoplasia, congenital absence of teeth, and extensive occlusal wear are other oral manifestations associated with salivary gland aplasia.81 There is often a hereditary pattern but some patients have no relevant familial history.

Parotid gland aplasia has been reported alone and in conjunction with congenital conditions, including hemifacial microsomia, mandibulofacial dysostosis (Treacher Collins syndrome), cleft palate, lacrimo‐auriculodento‐digital syndrome, and anophthalmia.82 It has also been observed in patients with ectodermal dysplasia. Hypoplasia of the parotid gland has been associated with Melkersson–Rosenthal syndrome.

The Stafne Bone Defect

The Stafne bone defect (SBD; also known as the Stafne bone cyst) is an asymptomatic depression of the lingual surface of the mandible often associated with ectopic salivary gland tissue. It is, however, not a true cyst as there is no epithelial lining. The most common location of the SBD is inferior to the mandibular canal between the angle of the mandible and the mandibular first molar. There is also an anterior variant of the SBD occurring in the premolar, canine, or incisor regions of the mandible.83

SBDs are often diagnosed on plain film where they typically appear as a round, unilocular, well‐circumscribed radiolucency. The characteristic location and radiographic appearance make the SBD easily recognizable. They can appear radiographically akin to a residual cyst and therefore may require further investigation including advanced imaging. Surgical intervention is reserved for atypical situations in which the diagnosis is unclear or a neoplasm or other pathology is suspected. Where indicated, fine‐needle aspiration biopsy can be an accurate, cost‐effective diagnostic tool for these lesions.84

The definitive etiology of the SBD has not been established. One theory suggests they result from pressure exerted by adjacent glandular tissue. The finding of salivary gland tissue upon surgical exploration of these defects is evidence to support this theory; however, other case reports have described finding muscle, lymphatic, or vascular tissues within the cavity.83

Ectopic Salivary Gland Tissue

Ectopic salivary gland tissue may occur as accessory tissue, associated with branchial cleft anomalies, or as heterotopic tissue (described below). Ectopic salivary glands have been reported in a variety of locations, including the middle and external ear, neck, mandible, pituitary gland, thyroglossal duct, thyroid and parathyroid gland capsules, lymph nodes, and cerebellopontine angle.85

The parotid gland is the most common major salivary gland associated with accessory tissue.86 An accessory parotid gland is present in about 21% of the population and is considered a normal anatomic variant.85 The most frequent location of the accessory gland is superior and anterior to the normal location of Stensen’s duct. Ectopic salivary gland tissue associated with branchial cleft anomalies, such as the rare Huschke foramen (also known as foramen tympanicum), have been reported as presenting with fistula formation between the parotid gland and the external auditory meatus.87 True heterotopic salivary gland tissue consists of mature salivary gland tissue found in a nonphysiological site usually in coexistence with original tissue in its usual anatomical location. The tissue has an independent ductal system and will clinically present as a saliva‐draining skin fistula or an asymptomatic nodule.88

The histological features of the ectopic tissue are usually identical to those of the original major gland, but the ectopic tissue is more susceptible to neoplasms. Heterotopic salivary gland tissue is typically treated with excision for definitive diagnosis and serves to prevent neoplastic transformation.89

Diverticula

A diverticulum is a pouch or sac protruding from the wall of a duct. Diverticula in the ducts of the major salivary glands can be visualized by sialography. They often lead to local pooling of saliva and recurrent sialadenitis. Patients with diverticula are encouraged to regularly milk the involved salivary gland to promote salivary flow through the duct.90

Sialolithiasis (Salivary Stones)

Etiology and Pathogenesis

Sialoliths (salivary calculi or salivary stones) are calcified organic masses that form within the secretory system of the salivary glands. Although the exact mechanism of sialolith formation has not been established, it has been proposed that microcalculi are frequently formed in salivary ducts during periods of secretory inactivity. Migration of food debris and bacteria from the oral cavity into the main ducts and along into the smaller intraglandular ducts at the site of the impacted microcalculi eventually result in a focal obstructive atrophy. Since the nidus is protected from flushing, the antimicrobial effects of saliva, and the systemic immunity, bacteria may proliferate resulting in local inflammation and further atrophy. The inflammatory process may then spread to involve adjacent lobules resulting in swelling and fibrosis of the large intraglandular ducts. The resulting partial obstruction leads to ductal dilatation and stagnation of calcium‐rich secretory material resulting in further lamellar calcification.91

The etiologic factors favoring sialolith formation may be classified into two groups: factors favoring decreased saliva production or stasis (i.e., dehydration, use of anticholinergics or diuretics, irregularities in the duct system, local inflammation), and changes in saliva composition (i.e., calcium saturation, deficit of crystallization inhibitors such as phytate). Bacterial infection also promotes sialolith formation due to an associated increase in salivary pH favoring calcium phosphate supersaturation.92

Sialoliths may be composed of a variety of organic and inorganic substances including calcium carbonates and phosphates, cellular debris, glycoproteins, and mucopolysaccharides.93 They contain cores that vary from purely organic to heavily calcified material, surrounded by less‐calcified or purely organic lamellae.91 Hydroxyapatite is the most common mineral found in sialoliths, but other minerals such as β‐tricalcium phosphate (whitlockite), dicalcium phosphate dihydrate (brushite), and octacalcium phosphate, are variably present depending on the mineral microenvironment.94 Trace amounts of magnesium, potassium chloride, and ammonium salts are often also present.

Epidemiology

The true prevalence of sialolithiasis is difficult to definitively establish since many cases are asymptomatic or involve sialomicroliths which can only be detected microscopically. Sialolithiasis is more common in males and can occur in a wide age range of patients including children. The average age of patients with sialolithiasis in the submandibular gland is 40.5 years, it is 47.8 years for the parotid gland, and 50 years for the minor salivary glands. Since the underlying cause is frequently unidentified and uncorrected, the recurrence rate is estimated at around 20%.95

Sialoliths occur most commonly in the submandibular glands (80–90%), followed by the parotid (5–15%) and sublingual (2–5%) glands, and only very rarely occur in the minor salivary glands. Spontaneous secretion in the minor and sublingual salivary glands may provide continuous salivary flow, thereby preventing stasis.90

The higher rate of sialolith formation in the submandibular glands is due to: (1) the torturous course of Wharton’s duct; (2) the higher calcium and phosphate levels of the secretions contained within; (3) the dependent position of the submandibular glands which leaves them prone to stasis; and (4) the increased mucoid nature of the secretion. In addition, since the submandibular and parotid glands’ secretion is dependent on nervous stimulation, in its absence, secretory inactivity increases the risk of stone development.

When sialoliths form within the submandibular glands, they usually occur within the ductal system, predominantly in the proximal section of Wharton’s duct or hilar area. These stones are more likely to produce symptoms indicative of inflammation, such as pain, than when stones form in the glandular parenchyma.52 Sialoliths within the duct are also more likely to be calcified due to the increased alkalinity of submandibular saliva, increased calcium and phosphate concentrations, and increased mucin content.47 Calcified sialoliths especially are most commonly found at the mylohyoid turn of the duct, due to the relative stasis at this approximately 90‐degree turn, and at the orifice to Wharton’s duct.

Up to 80% of parotid gland sialoliths and 20% of submandibular gland sialoliths are poorly calcified, and as such, may not be detected on plain film. Noncalcified obstructions may be due to fibrin or mucus plugs, especially in Stensen’s duct and the secondary ducts of the parotid.47

Risk factors for sialolithiasis include hypovolemia, infection, inflammation, diabetes mellitus, Sjögren’s syndrome, the use of diuretics and anticholinergic medications, trauma, gout, smoking, and a history of nephrolithiasis. There are also reported associations between sialolith formation and chronic periodontal disease and between sialolith formation and higher salivary concentrations of calcium, magnesium, and phosphorus.94,96 Some studies indicate that the saliva of patients with calcified sialoliths contains more calcium and less phytate (a potent inhibitor of hydroxyapatite crystallization found in wheat bran and seeds), than in that of a healthy group and in patients with purely organic sialoliths.92

With the exception of gout, in which the associated calculi consist mainly of uric acid, there is no proven link between sialolithiasis and development of stones in other areas of the body. There are, however, shared risk factors between sialolithiasis and urolithiasis (stones of the kidney, ureter, and urinary bladder), namely hypovolemia and diabetes mellitus, and there may be a familial predisposition.97 Patients with hyperparathyroidism demonstrate an increased incidence of sialolithiasis and those with hyperparathyroidism and sialolithiasis show a greater incidence of nephrolithiasis than those without sialolithiasis, indicating that hypercalcemia may be a common contributing factor.91

Clinical Manifestations

Patients with sialoliths most commonly present with a history of acute, colicky, periprandial pain and intermittent swelling of the affected gland(s). The severity of symptoms is dependent on the extent of duct obstruction and whether secondary infection is present. Since the submandibular and parotid glands are encapsulated with limited space for expansion, their enlargement will likely result in pain. Typically, salivary gland swelling will be evident upon eating since the stone completely or partially blocks the flow of saliva resulting in salivary pooling within the ductal system. Where there is partial obstruction, swelling will subside when salivary stimulation ceases and output decreases.98

Sialolithiasis without infectious sialadenitis is predominately unilateral without drainage or overlying erythema, and presents without systemic manifestations such as fever. Often, there is a history of sudden onset swelling and pain. The involved gland is often enlarged and tender to palpation, and the soft tissue adjacent to the duct may be edematous and inflamed. Using bimanual palpation along the course of the involved duct directed from the affected gland towards its orifice, it may be possible to palpate or even express a stone.99

Chronic salivary stasis may lead to infection, fibrosis, and gland atrophy. If there is concurrent infection, there may be expressible suppurative or nonsuppurative drainage, and erythema or warmth of the overlying dermis. Fistulae, a sinus tract, or ulceration may also develop in the tissue overlying the stone. Other complications from sialoliths include acute sialadenitis, ductal stricture, and ductal dilatation.100

Imaging

Imaging modalities which can help visualize sialoliths include plain film radiography, ultrasonography, computed tomography including cone beam computed tomography, sialography, and sialendoscopy.

Plain Film

Plain film radiography can be a helpful initial imaging modality to visualize sialoliths. It is inexpensive, readily available, and has minimal radiation exposure; however, small and poorly calcified stones may not be readily visualized. Plain film is most useful in cases of suspected submandibular sialolithiasis using an occlusal film positioned 90 degrees from the floor of the mouth, or using panoramic film. Other calcified entities, some of which have a similar appearance to sialoliths, such as phleboliths (stones that lie within blood vessels), tonsoliths, calcified cervical lymphadenopathy, and arterial atherosclerosis of the lingual artery, can also appear on these films.99

Stones in the parotid gland can be difficult to visualize on plain film due to superimposition of anatomic structures and their tendency to be poorly calcified. The choice of radiographic views is important to minimize overlap: an AP view of the face, an occlusal film placed intraorally adjacent to Stensen’s duct, or a panoramic film may be useful in these cases.

Computed Tomography (CT)

Of all the available imaging modalities, conventional CT demonstrates the highest accuracy in detection of salivary stones and is often the method of choice where it is readily available. It is capable of detecting very small and semicalcified calculi, but is associated with a high radiation exposure. In cases of suspected sialolithiasis, noncontrast imaging with a slice thickness of 0.2–0.5 mm is used since this can help distinguish sialoliths from similarly‐appearing, small opacified blood vessels.41 Studies have indicated, however, that the majority of calcifications detected on CT scans of the salivary glands represent incidentally‐discovered parotid parenchymal calcifications not associated with sialadenitis, but rather due to etiologies such as alcoholism, chronic kidney disease, HIV infection, and autoimmune disease, among others.101

Cone Beam Computed Tomography (CBCT)

CBCT can be of great diagnostic value in the initial imaging of patients with suspected sialolithiasis as it is helpful not only in detection of sialoliths, but it can also provide accurate information on stone size and position. As it is relatively inexpensive, is increasing in availability, and has limited radiation exposure, it is often used as first‐line imaging (or second‐line after plain film) for patients with signs and symptoms consistent with sialolithiasis.41

The use of CBCT for the detection of sialoliths is associated with high specificity, sensitivity, positive and negative predictive values.41 CBCT also has reduced superimposition and distortion of anatomic structures and higher sensitivity over two‐dimensional radiography, and reduced radiation exposure, cost, and greater availability in offices and clinics over conventional CT.102 The sensitivity and specificity of CBCT for this indication is also considered comparable or superior to conventional CT.40

Ultrasonography

Ultrasonography (US), typically transoral sonography using an intraoral transducer, is widely used as first‐line imaging in cases of suspected sialolithiasis, especially in emergency and urgent care settings, since it allows rapid visualization of the course of the main ducts and body of the major salivary glands. Sialoliths characteristically produce hyperechoic areas with distal signal loss (posterior acoustic shadowing) and there may be accompanying dilatation or inflammation of the ductal system and enlargement of the involved gland.103

While noninvasive and less costly than other imaging, US may not always allow for accurate determination of the number of calculi where there are multiple stones. Stones that are semi‐calcified and calculi less than 2 mm in diameter also may not be accurately depicted as they may not produce an acoustic shadow. Scarring or calcifications in the duct or adjacent blood vessels, adjacent normal anatomic structures, and even air bubbles within saliva, may erroneously be interpreted as sialoliths.

The reported sensitivity (77–94%) and specificity (80–100%) of US in identification of sialoliths varies widely among studies, and therefore the use of US alone may not be sufficient for definitive diagnosis.104,105 Sensitivity may be enhanced with sonopalpation (digital palpation of the floor of mouth with simultaneous placement of the ultrasound probe extraorally), and concurrent administration of a sialogogue such as ascorbic acid, which promotes filling of the ducts with salivary secretions.106

Sialography

Conventional sialography, using panoramic, occlusal, and periapical radiographs, can be an appropriate first‐line imaging approach where there is strong clinical suspicion of sialolithiasis.39 It can help distinguish between mucus plugs, salivary stones, and ductal strictures, which are the most common findings in patients with obstructive salivary signs and symptoms. Contrast sialography, using an iodinated contrast media, can help visualize the parotid and submandibular glands’ ductal systems and aid in differentiating calcified phleboliths from sialoliths since the former lie within a blood vessel while the latter occur within the duct or gland.

CBCT sialography is another supplementary noninvasive diagnostic technique which may be superior to conventional sialography with respect to imaging salivary gland parenchyma and sialoliths.107 It may be especially useful where plain film sialography has been inadequate, such as in more complex cases of salivary duct obstruction.108 Similar to CT or CBCT, CBCT sialography can determine the number and location of salivary stones, including those smaller than 2 mm in diameter.56

MR sialography provides high sensitivity, specificity, and positive and negative predictive values with respect to the detection of salivary gland stones.109 It does not require ductal cannulation and does not employ a contrast medium, and can therefore be used in patients with iodine or contrast media allergies. It also does not employ ionizing radiation and can be used in patients with acute sialadenitis.

Sialendoscopy

Sialendoscopy can be employed for direct visualization and, often, simultaneous treatment of sialoliths of the parotid and submandibular glands. Mobile and smaller stones may be relatively easily removed, whereas larger stones may require prior fragmentation (see below).110

Management

During the acute phase of sialolithiasis, initial therapy is primarily supportive. Standard treatment often involves the use of analgesics, hydration, antibiotics, and antipyretics, as indicated. Sialogogues, massage, and heat applied to the affected area may also be beneficial. Smaller stones at or near the duct orifice can often be removed transorally by milking the gland, but deeper and larger stones may require sialendoscopy or surgical intervention.

The mainstay of treatment has shifted away from open surgical procedures such as gland resection to endoscopic‐based, gland preservation methods such as interventional sialendoscopy. Preservation of glandular structure maintains normal facial fullness and contour and diminishes the risk of injury to adjacent nerves. This approach is also supported by several studies that have shown that glandular function is regained after stone removal, with few cases of recurrent sialolithiasis or complications.111

A series of CBCT scans may be performed on the day of surgery. A preoperative CBCT provides superior intraoperative orientation by allowing for determination of spatial topography, size, number, and location of calculus relative to the surrounding anatomic structures, and it minimizes the risk of calculus migration between CBCT evaluation and the beginning of surgery. A postoperative CBCT provides a means of confirming removal of all sialoliths.112

Interventional sialendoscopy is employed for removal of stones up to 4–5 mm in diameter and cases involving multiple smaller stones, especially those that lie freely in the duct lumen. Larger stones may require fragmentation with shock wave impulses via intracorporeal lithotripsy (i.e., laser or pneumatic lithotripsy), or extracorporeal shock wave lithotripsy (ESWL), which facilitate retrieval or may permit passage of the fragments with physiologic salivary flow.113,114 Treatment of sialoliths by ESWL may require multiple treatments and is contraindicated where there is complete distal duct stenosis, acute sialadenitis, or other acute inflammatory processes of the head and neck, in pregnancy, and in patients with cardiac pacemakers.115

To prepare for interventional sialendoscopy, dilation of the ductal opening or papillotomy is performed to allow introduction of surgical instruments such as the Dormia basket, graspers, or lasers. Saline or steroid instillation is performed to flush out debris and treat ductal inflammation.116 Following removal of the stone, the endoscope is used to explore the duct and ensure all calculi have been removed. A stent may be placed to maintain ductal patency.117

Failing gland‐sparing techniques and where there are fixed intraparenchymal stones, sialoadenectomy, such as superficial parotidectomy or transcervical submandibulectomy, may be required.118 Very large stones and a longstanding history of recurrent sialadenitis may also be an indication for gland removal.

Some postoperative complications associated with parotidectomy include transient (2–76%) or permanent (1–3%) facial nerve injury, sensory loss of the greater auricular nerve (2–100%), and Frey’s syndrome (8–33%). Risks associated with submandibular gland removal include temporary (1–2%) or permanent (1–8%) injury to the marginal mandibular nerve, temporary (1–2%) or permanent (3%) hypoglossal nerve palsy, or temporary (2–6%) or permanent (2%) lingual nerve damage. Other complications include hematomas, salivary fistulas, sialoceles, wound infection, hypertrophic scars, and inflammation caused by residual stones.115

Mucoceles and Ranulas

Mucoceles

Etiology and Pathogenesis

Mucocele is a clinical term that describes a swelling caused by the accumulation of saliva at the site of a traumatized or obstructed minor salivary gland duct. Although often called a “mucous retention cyst”, this is a misnomer as the mucocele does not have an epithelial lining. Mucoceles can be classified histologically as extravasation types or retention types. Extravasation mucoceles develop secondary to trauma to a minor salivary gland excretory duct resulting in pooling of saliva in the adjacent submucosal tissue, whereas retention mucoceles are caused by obstruction of a duct, often by a sialolith, periductal scaring, or tumor, resulting in the accumulation of saliva and ductal dilation.119

Superficial mucoceles are a rare variant of mucocele that are typically smaller and more often appear as multiples. Development of superficial mucoceles has been attributed to the accumulation of sialomucins at the epithelial–connective tissue interface occurring idiopathically or secondary to trauma.120 They have also been reported associated with oral lichen planus and lichenoid reactions, chronic graft‐versus‐host disease (cGVHD) following allogeneic bone marrow transplant, chronic minor oral trauma (e.g., use of an orthodontic splint), use of tartar‐control toothpastes and alcohol‐containing mouth rinses, smoking, taking alginate impressions, and in patients with oral cancer following chemoradiation therapy.121,122 Superficial mucoceles have also been reported at the margins of excised oral cancer specimens.123

Epidemiology

The true incidence of mucoceles is difficult to definitively state since the term “mucocele” has been used to refer to both the extravasation and retention types and often it is unclear whether epidemiologic data has been reported for each type separately or in aggregate.124 Mucoceles in general occur most commonly in patients aged 10 to 29 years which may reflect a higher prevalence of exposure to trauma or presence of parafunctional oral habits in this age group.125 There is no significant gender predilection for the extravasation and retention type mucoceles. The extravasation type of mucocele is the more common histological subtype and it mainly affects the lower lip. The floor of mouth, ventral tongue, and buccal mucosa are other common sites of mucoceles, with the palate and retromolar area representing less frequent sites of involvement.124

Determination of the true incidence of superficial mucoceles is also challenging as these lesions are uncommon, and, because of their transient nature, they are often not biopsied or reported. They most commonly arise in women 30 years of age or older. The most commonly involved sites include the soft palate, retromolar pad, and buccal mucosa.124

Clinical Manifestations

Mucoceles present as discrete, smooth surfaced swellings that may or may not be painful. They range in size from a few millimeters to a few centimeters in diameter. Mucoceles occurring closer to the mucosal surface often have a characteristic blue hue, whereas deeper lesions are more diffuse and are usually covered by normal‐appearing mucosa. The lesions may vary in size over time; superficial mucoceles in particular are frequently traumatized, causing them to drain and deflate. Mucoceles that continue to be traumatized are most likely to recur and may develop surface ulceration (Figure 9‐14).

Photo depicts mucocele of the lower right labial mucosa with surface ulceration.

Figure 9‐14 Mucocele of the lower right labial mucosa with surface ulceration.

Extravasation mucoceles appear most frequently in areas where trauma occurs: the lower lip, buccal mucosa, tongue, floor of the mouth, and retromolar region. These types of mucoceles are most common in children and teenagers. Retention mucoceles are more commonly found on the upper lip, palate, buccal mucosa, floor of the mouth, and rarely the lower lip, and usually afflict an older patient population. Distinctive‐appearing mucoceles can also arise in the glands of Blandin and Nuhn on the ventral surface of the tongue. These have a characteristic appearance of a soft, fluctuant polypoid mass.126 Superficial mucoceles typically appear as multiple, smaller (usually < 3mm) lesions of the soft palate and buccal mucosa. They are short‐lived, burst easily, leaving an ulcerated surface, and have a tendency to recur. Diagnosis can often be made clinically.

Differential Diagnosis

Although the development of a bluish lesion after trauma is highly suggestive of a mucocele, other lesions (including salivary gland neoplasms, soft tissue neoplasms, and vascular malformations) should be considered in the differential diagnosis. Differential diagnoses to consider for superficial mucoceles include vesiculobullous diseases, including mucous membrane pemphigoid and bullous lichen planus. Biopsy for definitive diagnosis may be warranted.

Management

Small or superficially located mucoceles may spontaneously resolve whereas persistent lesions may require treatment. Conventional definitive surgical treatment of mucoceles involves removal of the entire lesion along with the feeder salivary glands and duct. Incomplete removal of the mucocele may result in recurrence. Surgical management can be challenging since it can cause trauma to adjacent minor salivary glands (leading to the development of a new mucocele), or to adjacent nerves, such as the branches of the mental nerve. Alternative treatments that have been used with varying degrees of success include electrosurgery, cryosurgery using liquid nitrogen, laser therapy and micromarsupialization, intralesional injections of corticosteroids, and sclerotherapy with pingyangmycin.127129

Since the natural course of superficial mucoceles is typically self‐limited, no treatment is usually necessary. Identification of a source of trauma or inciting agent and its elimination may prevent recurrence. Additional treatments that have been used include topical corticosteroids and laser therapy.130 Persistence of the lesions or atypical appearance may prompt biopsy.121

Ranulas

Etiology and Pathogenesis

A form of mucocele located in the floor of the mouth is known as a ranula (Figure 9‐15), named due to its resemblance to the underbelly of a frog (Latin rāna [“frog”]). Ranulas are believed to arise from the sublingual gland usually following mechanical trauma to its ducts of Rivinus, resulting in extravasation of saliva. Other proposed causes include an obstructed salivary gland duct (e.g., due to sialolith) or ductal aneurysm. The tendency of ranulas to develop in the sublingual gland is thought to be due to the gland’s continuous salivary secretion which precludes effective sealing of mucous extravasation via fibrosis.

Ranulas are categorized anatomically as being oral (“simple,” “superficial,” “nonplunging”), plunging (“cervical,” “diving”), or mixed, having both oral and plunging components.131 The oral ranula remains confined to the sublingual space, while in the plunging ranula, extravasated mucus from ruptured sublingual gland acini passes around the posterior border of the mylohyoid muscle or through a hiatus in the muscle, and dissects along facial planes beyond the sublingual space.132 There is also the rare congenital ranula, which may be detected in utero, which is speculated to develop due to narrowing and obstruction of the main sublingual duct or acini causing extravasation of mucous into the surrounding tissues.133

Photo depicts ranula of the right floor of mouth.

Figure 9‐15 Ranula of the right floor of mouth.

Source: Courtesy of Dr. Michael D. Turner, New York University.

Epidemiology

Ranulas appear most commonly in the second and third decades of life but have been reported in a wide age range of patients including infants and the elderly. The incidence of ranulas appears to vary between populations. Studies indicate that those of Maori and Pacific Island Polynesian descent are 10 times more likely to develop plunging ranulas than Europeans. There is also a significantly greater incidence of plunging ranula in those of Asian descent, especially those with familial origins in China.131

While the oral ranula is more common in females, the plunging ranula has a distinct male predilection.131 This too, however, appears to vary between populations. Studies from Asia and Finland indicate a male predominance, whereas in New Zealand, there appears to be an equal gender distribution.134 Interestingly, oral ranulas tend to form on the left side, whereas plunging and mixed ranulas occur more often on the right side.131 The reason for these patterns is unclear.

Trauma, surgery, or other manipulation of the floor of the mouth are risk factors for the development of ranulas. A congenital predisposition toward ranulas has been suggested associated with anatomic variation in the sublingual gland ductal system, dehiscence of the mylohyoid muscle, and presence of ectopic sublingual gland tissue.135,136

Clinical Manifestations

An oral ranula typically appears as a painless, slow‐growing, fluctuant, movable mass in the floor of the mouth. Ranulas in the area of the sublingual caruncle may obstruct Wharton’s duct causing a temporary swelling in the submandibular region upon gustatory stimulus. Usually, oral ranulas form to one side of the lingual frenulum, but if the ranula extends deeper into the soft tissue, it can cross the midline. As with mucoceles, oral ranulas located more superficially can have a bluish hue. Oral ranulas vary in size; most are less than 1 cm in diameter but they may reach up to and beyond 5 cm with larger lesions causing elevation or deviation of the tongue.

The plunging component of a ranula will present as a soft, fixed swelling of the neck often involving the submandibular space or deeper cervical fascial spaces. While most are painless, some patients experience pain. The lesions may undergo intermittent spontaneous drainage but never fully resolve. In a patient with an early mixed ranula, the intraoral swelling may present prior to the cervical swelling becoming clinically evident.131 Congenital ranulas in a newborn present clinically in a similar manner to other ranulas. Additional signs in an infant may include feeding difficulties, airway compromise, failure to thrive, dysphagia, snoring, and obstructive sleep apnea.137

Differential Diagnosis

The diagnosis of a ranula is based on clinical examination, imaging, and, ultimately, excisional biopsy. The characteristic clinical appearance of the oral ranula makes its identification easy, but imaging is indicated to determine the extent of the lesion, for surgical planning purposes, and to help rule out other similarly appearing lesions such as a hemangioma, lymphangioma, dermoid cyst, or benign or malignant salivary gland neoplasm. Where there is a cervical swelling consistent with a plunging ranula, the differential diagnosis includes other causes of neck swelling such as a thyroglossal duct cyst, epidermoid cyst, and cystic hygroma, for example. Presence of both an oral and cervical swelling is highly suggestive of a mixed ranula.

Fine‐needle aspiration biopsy, ultrasound, CT with contrast, and MRI have been used to characterize ranulas. Fine‐needle aspiration biopsy will demonstrate inflammatory cells and mucus while biochemical analysis of aspirated fluid will show a high protein content and amylase. Ultrasound is often used for oral ranulas and to diagnose congenital ranulas in utero, while CT with contrast and MRI are suggested modalities for evaluation of suspected plunging ranulas.138 MRI, in particular, allows for superior localization of the lesion and allows for evaluation of the associated ductal anatomy. Ultimately, definitive diagnosis requires excisional biopsy.

Management

While no standard treatment for ranulas has been established, for both oral and plunging ranulas, transoral resection of the sublingual gland is associated with the highest cure rate overall and is most likely to prevent recurrences.119,139 While a transoral resection is the preferred approach for the isolated oral ranula, in the mixed ranula, a combined transcervical and transoral approach is often used to access the lesion below the mylohyoid muscle as this can be difficult using a transoral approach alone.140

Since resection of the sublingual gland is an invasive procedure requiring general anesthesia and is associated with complications such as nerve injury, damage to Wharton’s duct, or bleeding, other treatments have been investigated. These include micromarsupialization or marsupialization to form a drainage tract, injection of a sclerosing agent (e.g., OK‐432) to induce fibrosis, aspiration only, and laser excision or cryosurgery, all of which are associated with varying degrees of success, recurrence, and complications. Reports of spontaneous regression of ranulas also exist and, therefore, some would advocate an initial period of surveillance.137

Congenital ranulas may be discovered on routine obstetric ultrasound allowing for optimal treatment planning. Management of the congenital ranula may involve the ex utero

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Nov 28, 2021 | Posted by in General Dentistry | Comments Off on Salivary Gland Diseases
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