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Salivary glands and saliva play a critical role in mainte-nance of oral and systemic health. Salivary glands are fre-quently involved in a wide array of conditions which result in glandular dysfunction. These may be subdivided into five categories which include:

1. Developmental disturbances2. Saliva and salivary flow alterations3. Inflammatory conditions

4. Non-inflammatory conditions5. Tumors.

Many of these conditions result in salivary gland hypo-function, enlargement, pain and facial nerve paresthesia that will prompt the patient to seek evaluation and treat-ment from the dentist. This chapter will address each of these five subgroups focusing on the etiology, clinical fea-tures, diagnosis and treatment of these conditions.

➧ Developmental DisturbancesAplasia/Agenesis and Related Aberrancy of

Salivary GlandsHyperplasia of Minor Salivary Glands

➧ Saliva, Xerostomia, Hyposalivation, and SialorrheaSalivaHypofunction and XerostomiaXerostomia and Salivary Gland Hypofunction

due to MedicationsXerostomia and Salivary Gland Hypofunction

due to Radiation TherapySjögren’s SyndromeBenign Lymphoepithelial Lesion (Mikulicz’s Disease)Sialorrhea

➧ Inflammatory Conditions of Salivary GlandsMucoceleRanulaSialolithiasis, Salivary Duct Stone, Salivary CalculiSialadenitisNon-specific SialadenitisBacterial SialadenitisSubacute Necrotizing SialadenitisCheilitis GlandularisNecrotizing SialometaplasiaChronic Sclerosing Sialadenitis (Kuttner Tumor)

➧ Viral-induced Salivary Gland PathologyMumpsHuman Immunodeficiency Virus (HIV)

➧ Non-inflammatory Conditions of Salivary GlandsSialadenosisAnorexia/Bulimia-related SialadenosisSialadenosis Associated with Alcoholic CirrhosisDiabetes MellitusMedication-induced SialadenosisOrofacial GranulomatosisSarcoidosis

➧ Salivary Gland Tumors

➧ Benign TumorsPleomorphic Adenoma (Benign Mixed Tumor)Canalicular AdenomaBasal Cell AdenomaPapillary Cystadenoma Lymphomatosum

(Warthin’s Tumor)Oncocytoma (Oxyphilic Adenoma)

➧ Malignant TumorsMucoepidermoid CarcinomaIntraosseous Mucoepidermoid CarcinomaAcinic Cell AdenocarcinomaMalignant Mixed Tumor (Carcinoma Ex Pleomorphic

Adenoma)Metastasizing Mixed TumorAdenoid Cystic CarcinomaPolymorphous Low-Grade Adenocarcinoma

C H A P T E R

11Diseases of Salivary GlandsCarol M Stewart, Indraneel Bhattacharyya, Madhu K Nair, James C Pettigrew, Seunghee Cha, Joseph Katz

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Section IV – Diseases of Specific Structures

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DEVELOPMENTAL DISTURBANCES

Aplasia/Agenesis and Related Aberrancy of Salivary Glands

Congenital aplasia or agenesis of the major salivary glands is an uncommon finding, characterized by partial or total lack of development of the gland. Agenesis may involve one gland, pairs, or multiple glands, and be unilateral or bilateral. It may be a single independent finding or be associated with other developmental anomalies.

Congenital agenesis of major salivary glands was fi rst reported by Gruber in 1985. A recent search of the world literature reported 30 documented cases. Three cases of unilateral aplasia of the parotid have been reported. As it may be asymptomatic and go unnoticed, the true incidence is unknown. Bilateral agenesis is more common, with 10 cases reported in the English literature. Sometimes con-genital absence of one parotid or submandibular gland is associated with hypertrophy of the contralateral gland.

Aplasia may occur as a single event or with autosomal dominant inherited developmental conditions such as fi rst branchial arch anomalies, hemifacial microsomia and man-dibulofacial dysostosis. Parotid gland aplasia may be asso-ciated with malformations of the lacrimal apparatus as well. A combination of multiple developmental anomalies is found in the lacrimo-auriculo-dento-digital (LADD) syndrome (Levy–Hollister syndrome). This is an autosomal-dominant multiple congenital anomaly disorder character-ized by hypoplasia, aplasia or atresia of the lacrimal and salivary systems, ear anomalies, hearing loss, digital mal-formations and dental alterations. As the parotid gland develops during the 4th week of uterine life, and the sub-mandibular and sublingual, and minor glands develop between 6th and 12th weeks, association of salivary gland aplasia with other congenital abnormalities is easily understood. Bilateral aplasia of the parotid gland has also been reported in a patient with Down’s syndrome. In ecto-dermal dysplasia, aplasia of the submandibular glands and alterations in salivary gland function have been reported as well.

Clinical features and diagnosis

Salivary gland agenesis may be asymptomatic if only par-tial agenesis occurs or if the condition is isolated to one gland. If more extensive involvement occurs, agenesis can produce profound hyposalivation in children resulting in advanced dental caries, candidiasis, ascending sialadeni-tis, and even laryngitis and pharyngitis. A child with sub-jective xerostomia and functional hyposalivation should be carefully examined for salivary gland dysfunction to include partial or complete salivary gland agenesis. Famil-ial parotid gland aplasia has been reported, hence exami-nation of the siblings of a child with agenesis, might be

prudent. Sometimes, congenital absence of salivary glands is not noticed until adulthood resulting in unfortunate sequelae. However, clinical suspicion of salivary gland agenesis should be heightened in the setting of the ‘non-drooling baby’. Lack of complete development of the sub-mandibular gland duct has been reported in two infants which presented as unilateral cystic swellings in the floor of the mouth. Both cases responded to simple incision and decompression of the fluid-filled ducts. Early treatment is important to avoid feeding difficulties and possible later complications such as ranula or sialadenitis.

Diagnostic imaging

When a unilateral glandular anomaly is observed clini-cally, bilateral imaging should be considered to examine for possible lesions on the contralateral side. Computed tomography (CT) can be used to demonstrate congenital total or partial absence of salivary glands.

Management

Salivary gland aplasia has been associated with rampant dental decay in children. Treatment for potential hypo-salivation resulting from salivary gland agenesis would include frequent dental examinations, salivary stimulants for glands that might remain, meticulous home care and a customized fluoride program.

Hyperplasia of Minor Salivary Glands

Clinical features

Adenomatoid hyperplasia of the minor salivary glands is a rare lesion characterized by localized swelling that clini-cally mimics a neoplasm. The lesion most often develops on the hard or soft palate, although it has been reported in other oral minor salivary gland sites. The most common presentation is during the 4th to 6th decades of life. The typical presentation is a painless, indolent palatal swelling which may be soft or firm to palpation. The overlying mucosa is usually normal in color, although some lesions are red or bluish in color. The etiology is uncertain. In one report, the occurrence of adenomatoid hyperplasia on the palate occurred in patients who were tobacco smokers or denture wearers or both. The authors, Barrett and Speight suggested that chronic, local trauma could be a factor in the development of the condition.

Histopathology

Histopathologic examination demonstrates lobular aggre-gates of normal appearing mucous acini that are greater in number (hyperplasia) than normally would be found in the area. These glands may appear to be increased in size (hypertrophy). Chronic inflammation, if present, is usually mild and localized. Shimoyama et al reported that Ki-67


Chapter 11 – Diseases of Salivary Glands

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staining for cell proliferative activity demonstrated no sta-tistically significant differences among adenomatoid hyper-plasia and a matched group of normal palatal salivary glands. The conclusion was that adenomatoid hyperplasia had limited growth potential.

Treatment

To determine the true nature of a clinical enlargement, a biopsy is necessary. After the diagnosis of adenomatoid hyperplasia has been established via histopathologic exam-ination, no further treatment is indicated.

SALIVA, XEROSTOMIA, HYPOSALIVATION AND SIALORRHEA

Saliva

Saliva is an essential fluid for maintaining oral and sys-temic health and a satisfactory quality of life. While saliva is sometimes considered bothersome during restorative procedures, the alteration in quality and/or quantity of saliva has serious sequelae for the patient. Saliva is the product of three paired major salivary glands (the parotid, submandibular, and sublingual), and minor glands found in the hard and soft palate, lips, tongue, and buccal mucosa (Figure 1). Major salivary glands are composed of ductal and acinar structures. The acinar cells are the secretory components and ductal cells are the branching network that transports saliva into the oral cavity. The acinar cells of the parotid gland are purely serous elements and upon

stimulation, parotid secretions account for at least half of the volume of whole saliva. Serous secretions are ‘watery’ and contain digestive enzymes, water, salts, and ions. They aid in mastication, clearing agents from the oral cavity, and facilitate swallowing and speech. Fluid from the parotid gland enters the oral cavity through the main excretory duct, Stensen’s duct, located in the buccal mucosa next to the maxillary second molars. In the submandibular gland, the acinar components are mixed mucous–serous, but predominantly serous. At rest, the submandibular gland secretions account for approximately two-thirds of the unstimulated saliva production. Wharton’s duct is the main duct of the submandibular gland and enters the floor of the mouth on either side of the lingual frenum. The sublingual gland, the smallest of the three major glands, is located above the mylohyoid muscle. Acinar elements are mixed, but predominantly mucous. The mucin produced facilitates lubrication and swallowing. The main excretory duct of the sublingual gland, Bartholin’s duct, may join Wharton’s duct resulting in a blending of secretions, or open into the oral cavity with a separate sublingual papilla. Numerous sublingual ducts may join the submandibular gland duct or open separately into the floor of the mouth. Minor salivary glands are named according to their location—lingual (anterior and posterior), labial, buccal, palatine and glossopalatine. Table 1 summarizes the nomen-clature for the major and minor salivary glands and their acinar components.

In health, approximately 750 ml of saliva is produced in a day. The principal control of salivary secretion is medi-ated by sympathetic and parasympathetic innervation. The adrenergic (� and �) receptors are regulated by the sym-pathetic nervous system and the muscarinic receptors by the parasympathetic nervous system. At least fi ve musca-rinic-cholinergic receptor subtypes exist and it has been determined that the muscarinic receptor that medicates secretion of saliva is the M3 subtype. The parasympathetic

Figure 1

Parotidgland

Submandibulargland

Sublingualgland

Major salivary glands. Courtesy: Roger Hoover

Table 1 Major and minor salivary glands and secretion

Glands Type of secretion

Parotid Purely serous

Submandibular Mixed, however predominantly serous

Sublingual Mixed, however predominantly mucous

Lingual minor salivary glands Anterior lingual (glands of Blandin and

Nuhn) Posterior lingual (glands of von Ebner)

Primarily mucous

Purely serous

Labial and buccal minor salivary glands Mixed

Glossopalatine and palatine minor salivary glands (Weber’s glands)

Purely mucous



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nerve stimulation leads to an increased volume of saliva, whereas the sympathetic stimulation has an effect on pro-tein content and salivary composition.

Saliva plays a major role in the local and systemic pro-tection of the oral cavity, oropharyngeal region, and the upper gastrointestinal tract. Normal quantity and protein composition is essential for buffering the acidity of the oral cavity, lubrication of tissues, maintaining the integ-rity of the oral tissues, providing antimicrobial proteins and digestive enzymes, and remineralization of the teeth. Lack of saliva, hyposalivation, may increase a patient’s sus-ceptibility to dental decay, oral ulcers, fungal infections, and dysphagia or diffi culty in swallowing.

Saliva contains many antimicrobial proteins that help maintain a normal oral fl ora. The histatins provide anti-fungal properties, and proline-rich proteins help reduce bacterial colonization by modifying the ability of organ-isms to attach to tissues. Mucins are salivary glycoproteins that play a role in mucosal lubrication and assist in aggre-gation of oral microorganisms. Statherin and proline-rich proteins have calcium-binding properties to assist reminer-alization. These proteins combined with the cleansing and fl ushing ability of saliva constitute signifi cant protective mechanisms for the oral cavity and upper gastrointestinal system. Of special importance to the dentition is the presence of buffers to help maintain a neutral pH and the remineral-izing capacity. The pH range of saliva will vary from 6.7 to 7.4 in health. Of concern is pH below 5.5, which will pro-mote enamel dissolution and increase caries susceptibility.

Hypofunction and Xerostomia

Altered saliva production, both qualitatively and quanti-tatively, creates significant oral health concerns for the patient and challenges the dentist to provide appropriate patient education and treatment. Patients frequently pres-ent with the complaint of a ‘dry mouth’. Xerostomia is the subjective sensation of dry mouth and may be determined by questioning individuals about their perceptions of oral dryness. The need to sip water while eating dry foods, dif-ficulty in swallowing food without liquids, and a feeling of ‘too little’ saliva in the mouth have been correlated with salivary gland hypofunction. Hyposalivation is the produc-tion of inadequate or less than normal amount of saliva, usually from gland hypofunction. A few simple chairside assessments could be performed to quickly assess oral dry-ness. The lack of salivary pooling in the floor of the mouth is a basic clinical indicator of hyposalivation. Another indicator is the ‘cracker sign’. If a patient states that they cannot eat a cracker without drinking fluids, xerostomia and hyposalivation should be suspected. Another indicator is the ‘lipstick sign’. Patients with hyposalivation may have lipstick adhere to the incisal edges of the anterior teeth because they lack saliva that would normally pre-vent adherence. Another clinical clue to hypofunction is

the ‘mouth mirror test’. The clinician places the mirrored surface of the mouth mirror over the buccal mucosa and attempts to move it. If the mirror glides effortlessly over the tissue, one can deduce that salivation is adequate.

The prevalence of xerostomia in the population varies widely due to the lack of a clear defi nition for xerostomia. Some clinicians use the terms ‘xerostomia’ and ‘hyposali-vation’ interchangeably. Hyposalivation or salivary gland hypofunction results when the salivary gland fl ow rate is lower than normal. Defi ning ‘normal’ is problematic due to variations in the literature on collection methods, time of day collections were performed, and the inability to control for medications. Unstimulated whole salivary fl ow rates of less than 0.15 ml/min might provide a good reference for hyposalivation. The determination of hypo-salivation and xerostomia do not consistently correlate as one might expect. Patients with salivary gland hypofunc-tion are sometimes without complaints of oral dryness, or xerostomia. Conversely, patients with complaints of ‘dry mouth’ may not have reduced salivary fl ow rates. Xerosto-mia and salivary hypofunction affect the oral health-related quality of life. Reported reasons include the negative impact of oral dryness on speaking, eating, and wearing dental prostheses. Both xerostomia and salivary gland hypofunc-tion require a careful systematic evaluation to determine causative factors.

Dry mouth has a variety of causes as indicated in Box 1. Common causes of salivary gland dysfunction leading to hyposalivation include medications, irradiation to the head and neck, and autoimmune diseases such as systemic lupus erythematosus (SLE) and Sjögren’s syndrome (SS). Other systemic conditions affecting salivary glands include sar-coidosis, sialadenosis, and viral infections such as HIV and hepatitis C.

Mouth-breathing, tobacco smoking, alcohol use, and con-sumption of beverages containing caffeine can contribute to oral dryness as well. Age-related hyposalivation has been reported due to structural changes in salivary glands with increasing age. Other studies have reported no age-dependent decrease in saliva fl ow rate in healthy elderly populations. The incidence of xerostomia will increase and

Box 1 Possible causes of salivary gland hypofunction

Medications

Radiation to head and neck

Systemic diseases Sjögren’s syndrome Sarcoidosis Systemic lupus erythematosus Primary biliary cirrhosis

Viral infections HIV Hepatitis C



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the oral manifestations will continue to be a challenge for the clinician.

Treatment of xerostomia is symptomatic and support-ive, but should be aggressively proactive in prevention of dental decay associated with salivary hypofunction. Patient education and patient empowerment so they become par-ticipants in their oral healthcare are key to successful outcomes. Hydration, dietary modifi cations and meticulous oral hygiene are especially helpful. Symptomatic treat-ment is aimed at minimizing the subjective complaints, and includes drinking water or fi nely crushed ice chips and sugar-free fl uids. Patients should be advised that caffeine can contribute to the feeling of oral dryness and conse-quently, caffeine-free and sugar-free drinks should be strongly encouraged. Avoiding alcohol, including alcohol-based mouthrinses, spicy foods, and strong fl avorings, such as cinnamon and mint, should also minimize oral dis-comfort. Artifi cial saliva is helpful for many patients due to the coating action, but does not provide long-lasting relief. Some patients fi nd relief by chewing sugar-free gum or sucking on sugar-free candies. Lip balms and moistur-izers may be helpful as well.

Because patients with hyposalivation are at increased risk for dental decay, oral applications of topical fl uorides should be initiated. The fl uoride is incorporated into the enamel of the teeth to increase resistance to demineraliza-tion and decay. Fluoride products are available over-the-counter as rinses and as more highly concentrated brush-on gels (0.4% stannous fl uoride gel). Prescription products are available which provide 1.1% neutral sodium fl uoride treatment in convenient brush-on gels or rinses. These should be used after regular toothbrushing in the evening just before retiring. Patients should be reminded to avoid rinsing, eating or drinking for 30 minutes following the fl uoride application. Stannous fl uoride or neutral sodium fl uoride treatments can be provided using fl uoride carri-ers, or custom trays fabricated from a cast of the patient’s mouth. The carriers are particularly helpful in treating severe hyposalivation resulting from head and neck radia-tion therapy. Preventive fl uoride programs should be cus-tomized by the dentist to meet the specifi c needs and conditions of the patient.

Xerostomia and Salivary Gland Hypofunction due to Medications

Jacobsen and Chavez in their article describe that indi-vidual above 65 years of age comprise 13% of the popula-tion, but consume approximately one-third of all drugs prescribed. Loesche et al and Foc have reported many studies that have demonstrated a link between dry mouth in the elderly and polypharmacy. Shinkai et al reported that in a group of 1,163 adults (age range 32–81 years), 57% reported dry mouth to be the most frequent side effect of their medications. Hundreds of medications can

cause subjective complaints of dry mouth and many induce hyposalivation. The drugs most frequently impli-cated in dry mouth include the tricyclic antidepressants, antipsychotics, atropinics, beta blockers and antihistamines. In another study as reported by Thomson, the unstimu-lated (resting) salivary flow rate was reduced among indi-viduals who were older, female, or taking antidepressants, and higher among smokers or people who were taking hypolipidemic drugs. Other studies have correlated dry mouth with the number of medications taken, rather than specific types of medications. Field et al have demon-strated that medication is a better predictor of risk status for dry mouth than either age or gender. Medications that induce salivary hypofunction are a concern among the elderly, but xerostomia can also be a concern for young adults. Thomson et al in his study involving a large cohort of 32-year-old subjects, reported that the prevalence of xerostomia was found to be 10%, with no apparent gender difference. There was a strong association between xero-stomia and diminished oral health-related quality of life. Xerostomia was significantly higher among those taking antidepressants, iron supplements, or narcotic analgesics, and those subjects taking antidepressants at both 26 and 32 years of age demonstrated 22 times the odds of reporting xerostomia.

A study of medications and caries among older indi-viduals by Thomson et al revealed that an adjusted coro-nal caries increment (AdjCI) was higher among males and those taking a beta blocker or an anti-asthma drug for the previous 5 years. Several classes of drugs have been asso-ciated with dry mouth (Box 2). The most common groups include those with: (i) anticholinergic effects such as tricy-clic antidepressants, drugs for urinary retention and over-active bladder, antipsychotics, diuretics, and antihistamines; (ii) sympathomimetic drugs such as antihypertensives, anti-depressants, decongestants, and bronchodilators; (iii) skel-etal muscle relaxants; (iv) benzodiazepines; (v) proton pump inhibitors; and (vi) anti-migraine agents. Dry mouth has

Box 2 Drugs associated with xerostomia and hyposalivation

Tricyclic antidepressants

Antipsychotic medications such as phenothiazines

Diuretics

Antihistamines

Anti-migraine agents

Proton pump inhibitors and H2 antagonists

Anti-HIV drugs such as dideoxyinosine and protease inhibitors

Opioids

Benzodiazepines

Decongestants

Selective serotonin reuptake inhibitors (SSRIs)



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been reported to be a consequence of cytotoxic drugs such as 5-fl uorouracil. Medications used for treatment of HIV have also been associated with dry mouth. These include didanosine and protease inhibitors.

It is important for the dentist to inquire about all medi-cations, both prescription and over-the-counter agents, during the health history review. Sometimes the dentist can provide assistance by sharing concerns of medication-induced hyposalivation with the primary care physician. In some situations, the dentist might suggest medications such as pilocarpine or cevimeline to promote salivation. These medications will be discussed in the section on Sjögren’s syndrome.

Xerostomia and Salivary Gland Hypofunction due to Radiation Therapy

The role of saliva in oral health and function relates both to its fluid characteristics and to its specific components. The water (fluid) phase accounts for 99% of the volume and the remainder is salts and proteins. Essential functions of these components include flushing, buffering the acidity, and mucosal coating to maintain tissue integrity. Mucosal coating and tissue lubrication are essential for speech, taste perception, mastication, and swallowing. Cancer patients undergoing treatment for head and neck disease often experience severe difficulties maintaining such functions. Salivary function can also be diminished by radioiodine therapy for thyroid carcinoma, especially if multiple doses are administered. Deterioration of oral health and radiation-induced oral dryness has a significant influence on patients’ overall quality of life during and after treatment.

Together with surgery, radiation therapy is the main treatment for head and neck tumors. All or part of the major and minor salivary glands may be included within the radiation fi eld due to the site and extension of the tumor and the lymphatic spread. Exposing the glands to radiation often results in severe salivary gland hypofunction and changes in saliva composition. A profound decrease in salivary fl ow occurs during the 1st week of radiation therapy and continues throughout the course of therapy. In general, fully irradiated parotid glands exposed to doses exceeding 60 Gy sustain permanent damage resulting in severe hypofunction, and there is no recovery of gland function over time. Partial salivary fl ow recovery may occur at lower doses.

Radiation mucositis may begin during the 2nd week of therapy. Primary sites are intraoral mucosal surfaces within the direct portals of radiation. A whitish discoloration will appear from keratin accumulation, which is followed by sloughing, revealing atrophic erythematous, and friable mucosa. Ulceration then develops producing burning and pain which is exacerbated by eating and oral hygiene. Symptomatic support for radiation mucositis is important to assist the patient in maintaining adequate nutrition.

The mucositis will slowly resolve 2–3 weeks after ces-sation of the treatment. A loss of taste has been reported which generally is recovered after 6 months.

Minimizing the probability of osteoradionecrosis (ORN) includes a dental examination at least 2 weeks prior to the initiation of radiation therapy to address or remove teeth that have a hopeless long-term prognosis. Daily fl uoride treatments in custom carriers and close follow-up aid in reducing the incidence of xerostomia-induced dental caries. Due in part to more effi cient radiation techniques, the inci-dence of ORN has been declining in radiation patients over the last two decades. Advances in radiation techniques, including the use of fractionated radiation doses, have minimized the incidental damage to adjacent tissues. Fur-thermore, use of three-dimensional dosimetric intensity-modulated radiation therapy (IMRT) has been shown to reduce late salivary toxicity, since the portion of tissue exposed to low radiation doses has a potential for repair. Based on recent publications, the prevention of ORN remains controversial. A recent report compiled by Chang et al after reviewing a large series of ORN studies stated that extrac-tion of teeth with poor prognosis before radiation therapy did not appear to reduce the risk of ORN. The investigation of IMRT by Wu et al to achieve sparing of the parotids and yet achieve higher tumor control appears to show promise. Until additional evidence is available to defi ne guidelines, a pre-radiation referral for a dental evaluation is necessary. To facilitate prevention of ORN, irradiated dental patients should maintain a high level of oral health. Pre- and post-therapy close collaboration by a multidisciplinary team can be invaluable for patients receiving head and neck radiation therapy.

Sjögren’s Syndrome

Sjögren’s syndrome (SS) is a chronic autoimmune disease affecting the exocrine glands, primarily the salivary and lacrimal glands. Patients most commonly complain of a subjective persistent feeling of dry mouth (xerostomia) and of dry eyes (keratoconjunctivitis sicca). This is due to lymphocytic infiltrates and destruction of salivary and lacrimal glands and systemic production of autoantibod-ies. In 1933, Henrik Sjögren, a Swedish ophthalmologist, presented his doctoral thesis entitled ‘Zur Kenntnis der Keratoconjunctivitis Sicca’, and described the clinical and histopathological aspects of the disease.

Sjögren’s syndrome occurs worldwide and while it may occur at any age, the peak incidence is between 40 and 50 years. Sjögren’s syndrome has one of the highest female-to-male ratio (9:1) of any autoimmune rheumatic disease. In addition to ocular and oral dryness, a wide spectrum of extraglandular manifestations may occur as well. The musculoskeletal, hematological, vascular, pulmo-nary, gastrointestinal, dermatological, renal and nervous systems may be involved. Patients with SS have an increased



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risk of developing lymphoma. Early reports estimated that patients with SS had up to 44 times increased risk of developing lymphoma compared with the general popula-tion. Chronic fatigue, depression, and a diminished quality of life are also common components of SS.

Classification

Two forms of the disease are recognized. Primary SS is the presence of sicca syndrome, xerostomia, or ‘dry mouth’, and xerophthalmia, or ‘dry eyes’ together, with no other autoimmune disease. Secondary SS is sicca syndrome plus another associated autoimmune disease such as rheumatoid arthritis (RA), SLE, or scleroderma. Based upon the classi-fication criteria applied, the prevalence of SS may range from 0.5 to 3.0% of the population. All classification sys-tems use a combination of both subjective and objective findings in the diagnostic process. The most recent 2002 criteria include subjective symptoms of dry mouth and dry eyes, and the following objective tests: ocular signs by Schirmer’s test and/or Rose Bengal score; focal sialadenitis by histopathology; salivary gland involvement by either salivary scintigraphy, parotid sialography or unstimulated salivary flow rate; and autoantibodies of SS-A/Ro and/or SS-B/La specificity. Box 3 presents the 2002 American-European Consensus Group Criteria for SS.

Etiopathogenesis

Currently, the etiology of SS is not clearly understood, but appears to be multifactorial. It has been suggested that environmental agents may trigger SS in genetically pre-disposed individuals. Experimental and clinical evidence suggest that immune reactivity is modulated by gender. Immune reactivity is higher in females than males, and lymphocytes and monocytes from female subjects show higher antigen presenting activity and mitogenic responses. Taiym et al have found higher prolactin levels in SS patients than controls. Estrogens might be pro- or anti-inflammatory, based on dose-related metabolite conver-sions. The role of sex hormones in rheumatic autoimmune diseases has yet to be clarified. Potential mechanisms underlying SS include disturbances in apoptosis, circulat-ing autoantibodies against the ribonucleoproteins Ro and La or cholinergic muscarinic receptors in salivary and lac-rimal glands or cytokines. These processes interfere with normal glandular function; and as the mucosal surfaces become sites of chronic inflammation, the disease appears to enter a self-perpetuating inflammatory cycle.

While a genetic predisposition to SS appears to exist, no simple Mendelian inheritance pattern has been demon-strated. Cases of two or more individuals with SS per fam-ily and SS in twins have been described. However, the level of genetic contribution is not known. Because large twin studies in SS are lacking, the twin concordance rate cannot be estimated. Familial clustering of different autoimmune

diseases and co-association of multiple autoimmune dis-eases has been reported by Becker et al. Reports have also indicated that a SS proband may have relatives with other autoimmune diseases in approximately 30–35% of the cases. Assessing human leukocyte antigen (HLA)-DR and HLA-DQ gene segments in patients with SS reveals an increased use of haplotypes B, Drw52 and DR3. Correlations

Box 3 European American Consensus Group criteria for Sjögren’s syndrome

Ocular symptoms (must have 1 of 3) 1. Daily dry eyes � 3 months 2. Recurrent sand or gravel sensation in the eyes 3. Use of tear substitutes more than 3 times per day

Oral symptoms (must have 1 of 3) 1. Feeling of dry mouth for more than 3 months 2. Recurrent or persistently swollen salivary glands as an adult 3. Need frequent liquids to aid in swallowing dry food

Ocular signs (1 of 2) 1. Schirmer’s test, performed without anesthesia (� 5 mm in

5 minutes) 2. Rose Bengal score or other ocular dye score (� 4 according to

van Blijsterveld’s scoring system)

Histopathology in minor salivary gland biopsy Focal lymphocytic sialoadenitis, with focus score � 1 (focus is

� 50 lymphocytes per 4 mm2 tissue adjacent to normal appearing mucous acini)

Salivary gland involvement (1 of 3) 1. Unstimulated whole salivary flow (� 1.5 ml/15 minutes) 2. Parotid sialography showing the presence of diffuse sialectasis

(punctuate, cavitary of destructive pattern) without evidence of obstruction in the major ducts

3. Salivary scintigraphy, showing delayed uptake, reduced concentration and/or delayed excretion of tracer

Autoantibodies Antibodies to SS-A/Ro or SS-B/La or both

For primary SS a. Any 4 of the 6, as long as either item 4 (histopathology) or

item 6 (serology) is positive b. Presence of any 3 of the 4 objective criteria items

(items 3, 4, 5, 6)

For secondary SS In the presence of another connective tissue disease, the presence

of item 1 or 2 plus any 2 from 3, 4, and 5

Exclusion criteria Past head and neck radiation Hepatitis C infection Acquired immunodeficiency syndrome (AIDS) Pre-existing lymphoma Sarcoidosis Graft-vs-host disease Use of anticholinergic drugs (since a time shorter than four-fold

half-life of the drug)

Source: Vitali et al. Annals of Rheumatic Diseases 2002;61:554–58.



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have been found between presence of HLA-DR haplotype and the presence of Ro/LA in SS. Gene polymorphisms have been analyzed, but no clear-cut relationship between these and primary SS have been identifi ed. Clustering of non-major histocompatibility complex (MHC) susceptibil-ity candidate loci in human autoimmune diseases supports a hypothesis that, in some cases, clinically distinct auto-immune diseases may be controlled by a common set of susceptibility genes.

Clinical features and diagnosis

Dry mouth and dry eyes are the most common complaints of patients with SS. Patients’ ocular concerns may include a history of dry eyes, a sensation of sand or gravel in the eyes, and/or frequent (� 3 times per day) use of tear sub-stitutes. Objective ocular tests for dry eyes include a Schirmer’s test for tear production. Using sterile strips of filter paper placed just inside the lower lid, tear production can be assessed by measuring the length of wetness on the filter paper. Less than 5 mm of wetness in 5 minutes, with-out local anesthesia is considered a positive test, meeting the 2002 Sjögren’s consensus criteria. A second ocular test utilizes Rose Bengal staining of the cornea, and measures areas of increased dye intensity. With the use of a slit-lamp, the stain will detect devitalized tissue. The ocular dryness is sufficient to produce disruption in the integrity of corneal and conjunctival epithelium and dye will accu-mulate in these areas. The total areas identified are used to determine the extent of ocular damage. Patients with com-plaints of ocular dryness, especially if combined with other symptoms of SS, should be referred to the ophthalmologist for evaluation. Untreated keratoconjunctivitis sicca can progress to corneal ulcerations and even blindness.

The most frequent oral signs and symptoms a dentist will encounter are xerostomia, a subjective sensation of oral dryness, and hyposalivation, or a diminished salivary fl ow rate. These will vary between patients, and the sub-jective dryness may not directly correlate with objective measures of hyposalivation. Initial indications of a dimin-ished salivary output would be a lack of pooling in the fl oor of the mouth, thick or frothy saliva, and observing exam-ination gloves sticking to the tongue or buccal mucosa. Patients may complain of diffi culty chewing and swallow-ing, diffi culty wearing their dentures, and altered taste. They will relate the necessity for drinking liquids to aid in swallowing food or to enhance their ability to speak. They may admit to keeping water by their bedside at night or frequently waking with a dry mouth. Patients with SS fre-quently carry water with them and often need to sip every 10–15 minutes during a consultation appointment. Upon intraoral examination, the tongue may appear fi ssured, slightly erythematous, and sometimes depapillated. If the patient complains of a ‘burning tongue’ and dysgeusia, oral candidiasis should be suspected (Figure 2). Salivary

fl ow rate is diminished in primary SS patients compared with controls. In addition to quantitative changes, the pro-tein content of the saliva is altered as well. Proteins neces-sary for buffering the oral acidity, countering fungal and microbial organisms may be altered. The lack of adequate salivary fl ow and qualitative changes in protein content may predispose the patient to dental decay, particularly in the cervical area, tooth loss, candidiasis and oral ulcer-ations (Figure 3). The change in saliva is linked to the lymphocytic infi ltrate in the glands and subsequent dam-age to the functional units.

From one-fourth to two-thirds of patients with pri-mary SS will have a diffuse enlargement of the major sali-vary glands during the course of their disease (Figure 4).

Figure 3

Oral cavity of Sjögren’s syndrome patient showing dental caries and fissured tongue. Courtesy: Dr Carol Stewart

Figure 2

Xerostomia and fissured tongue. Courtesy: Dr Carol Stewart



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Figure 4

Sjögren’s syndrome patient with enlarged parotid gland. Courtesy: Dr Carol Stewart

Figure 5

Sialograph of Sjögren’s syndrome. Courtesy: Dr James Pettigrew

Figure 6

Sialograph of Sjögren’s syndrome of the submandibular salivary gland. Courtesy: Dr Ajit Auluck and

Dr Chandrakant Shetty

This swelling may be unilateral or bilateral, intermittent or constant in nature. If the parotid swelling initially is uni-lateral, it often becomes bilateral with time. It commonly produces mild to no discomfort. However, diminished fl ow will enhance a patient’s susceptibility to bacterial infection in the glands and recurrent sialadenitis, which will produce pain. Although SS is considered primarily a disease of middle-aged females, it has also been reported in children and adolescents. Recur rent bilateral parotitis in children and adolescents should include the possibility of SS in the differential diagnosis.

Conventional sialography renders useful information about the gland architecture and changes within it. Water-based radiopaque dye is injected into the major gland ducts followed by conventional imaging. Peripheral ducts within the glands are usually affected fi rst with the inner ductal structure relatively well preserved. However, punc-tuate collections of the contrast material may be visible in the early stages of the disease followed by globular or larger collections as the condition progresses as shown in Figures 5–7. Once extensive intraglandular destruction has taken place and infection has become established, dilata-tion of central ducts is noted. Abscesses within the gland may be noted with a uniform distribution, unlike focal abscesses caused by other types of infections. However, sialography is an invasive procedure and other imaging modalities may be considered.

Imaging with CT and MRI is common. The glands enlarge with time, assuming a denser appearance on CT. A honeycomb appearance is not infrequent but this is also seen with granulomatous conditions. Bilateral enlarge-ment with cystic and solid lesions is noted (Figure 8A, B). In the early stage, the parotids appear normal. Multiple cysts appear during the intermediate stage. These eventu-ally grow with time. If the mass assumes an invasive

appearance, malignant transformation may be suspected. Foci of calcifi cation within the glands are not uncommon. Heterogeneous enhancement may therefore be expected (Figure 9A, B). The glands could eventually appear smaller in size. In MRI, numerous punctuate areas appear within the glands with low signal intensity on T1 and T2 weighted images as the disease progresses. This is considered diag-nostic of the condition. But, a lymphoma arising in a benign lymphoepithelial lesion (BLEL) does not have char-acteristic features that would help differentiate it from other tumors. However, it may be considered in patients who present with a parotid mass. Function of the glands is



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directly correlated with the amount of fat deposition, thereby indicating that a monitoring of this feature may be useful in diagnosing the condition. Another imaging technique that is useful is magnetic resonance sialography. It has been shown to be highly accurate with excellent sensitivity and specifi city. Globular, punctuate or a lytic appearance is typical of the condition. If cysts develop within BLEL, these are detected using CT or MR. The absence

of lymphadenopathy helps exclude HIV-related lympho-epithelial cyst formation.

Another test to confi rm altered salivary gland function is whole unstimulated sialometry. Sialometry is the mea-surement of salivary fl ow rate. It is instrumental in reach-ing a diagnosis of hyposalivation (below normal salivary fl ow rate), a common fi nding in patients with SS. In an ideal situation, patients should not eat, drink, smoke, or brush their teeth for 90 minutes before the sialometric assess-ment. The patient is asked to expectorate into a preweighed container, while sitting upright for 15 minutes. After re-weighing the tube post-collection, dividing by 15 and apply-ing the conversion factor (1 g � 1 ml), a fl ow rate can be determined. Unstimulated salivary fl ow � 1.5 ml/15 min or � 0.1 ml/min is considered consistent with Sjögren’s diag-nosis. After an SS diagnosis has been established, periodic fl ow rates (every 3–6 months) may provide meaningful information to assess disease progression. Sub sequent sal-ivary assessments should be collected at the same time each sampling, preferably either 9:00 AM–noon or 1:00 PM–3:00 PM, to avoid fl uctuations due to circadian rhythm of salivary secretion and composition. Often, an SS patient will be prescribed a sialogogue to enhance salivary fl ow. Periodic fl ow rates are helpful to track medication effi cacy as well.

Lymphocytic infi ltration in the lacrimal and salivary glands is a major feature of SS. One of the criteria for clas-sifi cation of SS includes the biopsy of the labial salivary glands. A 1.5-cm incision is made on normal appearing mucosa of the lower lip lateral to the midline (Figure 10).

Figure 7

Sialograph of Sjögren’s syndrome showing atelectasia. Courtesy: Dr James Pettigrew

Figure 8

BA

Sjögren’s syndrome. CT images showing diffuse sialadenitis affecting the submandibular and parotid glands bilaterally. Courtesy: Dr Madhu Nair



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Five or more accessory salivary gland lobules are examined histopathologically for the presence of focal chronic infl ammatory aggregates. A focus is 50 or more lympho-cytes and some plasma cells within a 4 mm2 fi eld in the salivary gland biopsy specimen. As noted in Figure 11A, B, these aggregates are adjacent to normal-appearing acini

and are found throughout the glands. A fi nding of more than one focus within a 4 mm2 area of glandular tissue is supportive of a SS diagnosis. Manthorpe et al have reported an interesting fact that the focus scores are lower in SS patients who are cigarette smokers.

While the labial salivary gland biopsy is widely consid-ered one of the best diagnostic tools for SS, it is not 100% reliable. Personal experience has shown that minor sali-vary gland histopathology may not present the classic pic-ture, yet be supportive of an SS diagnosis. Some SS patients may show areas of classic patchy lymphocytic foci with other areas more consistent with chronic sclerosing sialad-enitis in confi rmed primary SS patients. In addition, sali-vary gland biopsies of patients with long-standing SS demonstrate areas of fi brosis more prominently than the classic criteria allow. In more chronic cases, repeated biopsy attempts reveal only fi brosis and no viable labial salivary gland lobules. Sampling and timing of the biopsy may be more critical than previously considered.

Laboratory diagnosis values

Patients presenting with signs and symptoms of SS should have an appropriate laboratory assessment. Common find-ings include a positive rheumatoid factor (RF). RFs are autoantibodies against antigenic determinants that are present on the Fc portion of human IgG, and are found in sera and saliva of 60–80% of patients with primary SS. A positive RF does not confirm that the patient has rheu-matoid arthritis. Positive antinuclear antibodies (ANA) are

Figure 10

Sjögren’s labial salivary gland biopsy procedure. Courtesy: Dr Carol Stewart

Figure 9

A B

Chronic Sjögren’s syndrome. Contrast CT demonstrating a granular appearance of parotid glands that have been reduced in size. Courtesy: Dr Madhu Nair



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found in most patients, particularly anti-SS-A/anti-Ro and anti-SS-B/anti-La. Reports have demonstrated that precipi-tating autoantibodies to Ro and La occur in patients with SLE, but are more prevalent in primary SS, occurring in 60–80% (anti-Ro) and 40–60% (anti-La) of SS patients.

Management

The patient with SS must be treated by a multi-specialty team for an optimal outcome. The rheumatologist will monitor the inflammatory components related to core dis-ease and any extraglandular manifestations. The ophthal-mologist will manage the ocular health of the patient on a routine basis. A variety of treatment modalities might be appropriate to help maintain ocular secretions, such as lachymal duct plugs and laser occlusion. Prescription eye drops containing 0.05% cyclosporine emulsion may help some patients with ocular moisture. Many patients use over-the-counter artificial tears as well. As many SS patients seem to be sensitive to agents in cosmetics and preserva-tives in over-the-counter products, hypoallergenic products may be preferred.

The dental management for patients with SS is critical to their long-term oral health. Patients demonstrating hypo salivation may also demonstrate increased suscepti-bility to dental decay. Follow-up visits every 4 months may assist in monitoring and treating active dental caries. Patients should be educated and empowered to assist in the management of their own oral health. Artifi cial saliva substitutes and oral hygiene products that contain lacto-peroxidase and lysozyme (e.g. Biotene® toothpaste and mouthrinse) may be helpful. Meticulous home care with a home fl uoride program customized for the patient is essential. Nutritional counseling might be helpful, which

includes minimizing carbonated drinks and avoiding snack-ing on sticky sugary processed foods. Salivary stimulants such as sugar-free gums and lozenges will assist in enhanc-ing the salivary fl ow. If available, xylitol sweetened gums and lozenges are benefi cial due to their reported anticario-genic effects. Prescription sialogogues, such as pilocarpine and cevimeline can be very helpful as long as functional salivary gland tissue remains. However, prescription sialo-gogues are not recommended for all SS patients. These should not be used in patients with uncontrolled asthma or narrow-angle glaucoma, and should be used with cau-tion with certain types of cardiovascular disease, eye, lung, and liver conditions. Consultation with the patient’s rheu-matologist before prescribing these medications is prudent to confi rm the lack of contraindications. Not only are SS patients more susceptible to dental decay and candida, their periodontal status should be monitored as well. While some reports indicate no signifi cant difference between the periodontal status of SS patients and controls, others report more severe peri odontitis in SS patients. Patients should be given all assistance possible to maintain their dentition in the optimal condition. As many of these patients are taking bisphosphonates for osteoporosis, the option of implant replacements for lost teeth, or implant supported dentures is one that should be approached with utmost care and patient’s informed consent. The potential of bisphosphonate-associated osteo necrosis should be reviewed with the patient prior to extractions, implants, or any oral surgical procedures.

While SS often follows an indolent course, of critical importance is the concern for development of lymphoma. Kassan et al reported that SS patients have 40 times higher risk of development of lymphoma than the normal popu-lation. Lymphoma has been reported by Voulgarelis et al

Figure 11

BA

Sjögren’s labial salivary gland histopathology (5 and 40). Courtesy: Dr Carol Stewart. (A) Magnification 5; (B) magnification 40



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in 4.3% of patients with SS. These tumors may arise in the salivary gland or within lymph nodes. What was consid-ered a BLEL in the past might currently be diagnosed as a low-grade non-Hodgkin’s B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT) lymphoma. Figure 12 demonstrates a patient with SS demonstrating a bluish area in the hard palate, which was diagnosed as BLEL. In addition, SS patients may develop caries that involve root surfaces. MALT is normally found in Peyer’s patches in the ileum of the lower gastrointestinal tract, where it plays a role in normal humoral immune response. Mononuclear cell lymphocytic infi ltrates in the exocrine glands can develop into marginal zone B cell lesions or acquired MALT. A recent enlargement or persistent parotid enlarge-ment could be a lymphoma. MALT lymphomas have even been discovered though SS labial salivary gland biopsies. Patients with SS have an increased risk of developing monoclonal B-cell MALT lymphoma due to perhaps pro-longed autoimmune infl ammation or persistent antigenic stimulation to virus or bacteria. Occasionally, high-grade lymphomas develop which can demonstrate aggressive behavior. A patient demonstrating a persistent swelling of the major salivary glands or lymph nodes, or sudden parotid gland enlargement or pain should be evaluated to rule out possible lymphoma.

Currently, SS patients suffer from diminution in quality of life resulting from the sicca complex, extraglandular manifestations, and the depression from disease chronicity and anxiety associated with development of lymphomas. Educating patients and helping them to understand their disease and empowering them with knowledge is an impor-tant management strategy. The prognosis for SS patients may improve as greater understanding of the pathogenesis is achieved through continued research. Currently, systemic

immunosuppressives are reserved for treatment of severe extraglandular manifestations of SS. Anti-B-cell therapy is a new potential therapy for the glandular and extra-glandular manifestations in addition to the management of lymphoma associated with SS. Gene-transfer modalities used in animal models continue to show future promise. The dentist should be an integral part of the medical man-agement team, along with the rheumatologist and oph-thalmologist, for optimal patient care.

Benign Lymphoepithelial Lesion (Mikulicz’s Disease)

In the late 1800s, Johann von Mikulicz-Radecki described a patient with an unusual bilateral painless swelling of the lacrimal glands and all the major and minor salivary glands. Histopathologic examination showed an intense lymphocytic infiltrate, with features that were recognized as the BLEL. The clinical presentation became known as Mikulicz’s disease and the term was used to describe cases of bilateral parotid and lacrimal enlargement. With time, the histopathological diagnosis of these cases proved to be inconsistent with Mikulicz’s disease. The clinical pic-ture of symmetrical lacrimal and salivary gland enlarge-ment was attributed to other diseases such as tuberculosis, sarcoidosis and lymphoma. Consequently, these cases were later described as Mikulicz’s syndrome, restricting the term Mikulicz’s disease for use with a histopathologic diagnosis of BLELs. Over the years, the use of these terms became interchanged and confusing, so their use has been discouraged.

Clinical features

Mikulicz’s disease is reportedly characterized by symmetric and persistent swelling of the lacrimal glands and either or both of the major salivary glands (parotid and subman-dibular) and the exclusion of other diseases that may mimic this presentation, such as sarcoidosis, viral infection or lymphoproliferative disorders. Many cases of BLELs were a component of SS. The lymphoepithelial lesion was com-monly found in adults, primarily women, and usually in the parotid gland. The affected gland was diffusely enlarged, asymptomatic or mildly painful.

Diagnosis

Microscopic examination demonstrates a heavy lympho-cytic infiltrate associated with the destruction of the sali-vary acini. The ductal epithelial cells and surrounding myoepithelial cells become hyperplastic, and form groups of cells known as ‘epimyoepithelial islands’. These islands, once considered benign, are currently recognized to be indicative of low-grade salivary lymphoma of the MALT. A review of Mikulicz’s initial case report concluded that

Figure 12

Palatal MALT lymphoma and carious roots in Sjögren’s syndrome patient. Courtesy: Dr Carol Stewart



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Mikulicz actually reported the first case of MALT lym-phoma, based on the published histopathology. The authors, Ihrler and Harrison further urged that the terms Mikulicz’s disease and Mikulicz’s syndrome should no longer be used. Conversely, a recent report by Yamamoto et al concluded that Mikulicz’s disease is a distinct entity and different from SS both clinically and histopathologically. Addition-ally, the authors reported that Mikulicz’s disease was an IgG4-related systemic disease.

Treatment

The affected gland must be surgically removed. Fortunately, most MALT lymphomas are low-grade tumors that tend to remain localized with good survival rates. Occasionally, tumors transform to high-grade lymphomas with aggressive behavior.

Sialorrhea

Clinical features

Sialorrhea or ptyalism is a condition characterized by increased salivary flow. Sialorrhea can occur with various neurologic disorders, infections, the secretory phase of the menstrual cycle, heavy metal poisoning, Wilson dis-ease, paroxysmal sialorrhea, and rabies. Older aged indi-viduals in chronic care facilities and chronically debilitated with cerebrovascular accident may demonstrate chronic drooling.

Parkinson’s disease (PD), amyotrophic lateral sclerosis (ALS), and cerebral palsy are neurodegenerative diseases associated with sialorrhea. The appearance of excess saliva in neuropathologic conditions may be due to excessive saliva, but is usually related to impaired cerebral control of orofacial function. Weakness of the facial and perioral muscle tone inhibits the normal retention, movement, and/or swallowing of saliva. Excessive salivation has been reported in familial dysautonomia (FD) due to subman-dibular and sublingual salivary gland hyperactivity. These changes may be the result of ongoing parasympathetic denervation characteristic in FD. The consequences of ‘drooling’ are not restricted to medical issues, but can cause major social handicaps. Severe psychosocial conse-quences and social stigmatization may be emotionally devastating for patients and families. Drug-induced sialor-rhea has been reported as well. Major medication groups associated with drooling are anti-psychotics, particularly clozapine, and direct and indirect cholinergic agonists that are used to treat dementia of the Alzheimer’s type and myasthenia gravis. Other drugs cited include risperidone, lithium and digoxin. Heavy metal toxins, such as mercury and thallium produce sialorrhea as does exposure to irre-versible acetylcholinesterase inhibitors such as insecticides and nerve agents.

Patients reporting to the dental offi ce will present due to concern about the unknown condition which carries signifi cant social stigmas. The patient may bring their ‘spit cup’ with them and describe their saliva as ‘foamy’. Several conditions should be considered.

Minor sialorrhea may be associated with minor oral irritations and ill-fi tting or new dentures. Episodic sialor-rhea may be a subtle manifestation of gastroesophageal refl ex disease (GERD). Excessive saliva is produced as a protective buffering mechanism in patients with GERD. This is called ‘water brash’. A similar condition of sialor-rhea with unknown etiology termed ‘idiopathic paroxys-mal sialorrhea’ is reported to consist of episodes of increased salivary fl ow occurring 1 or 2 times per week at 2–5 minutes in duration. The episodes are preceded by a prodrome consisting of nausea or epigastric pain, but without progression to vomiting. These may be variants of the same condition. Sialorrhea may be associated with esophageal obstruction (foreign body, cancer, or stricture formation), infection, and nasogastric intubation with symptomatic sequelae of sialorrhea.

Treatment

Treatment of sialorrhea depends on its etiology. Some causes of mild or transitory sialorrhea may need no treat-ment. If the salivation is believed to be due to GERD, referral to their physician for evaluation and treatment would be appropriate. If the condition is due to inadequate motor control, speech therapy might improve the situa-tion, if the patient is able to cooperate. Botulism toxin injected into the parotid gland has been reported to have efficacy for ALS and PD as reported by Lagalla et al and Contarino et al. Surgical techniques might be needed to modify the salivary glands or ductal structures. A recent report by McAloney et al showed efficacy and safety from bilateral submandibular duct relocation and bilateral sub-lingual gland excision. The prognosis of sialorrhea will vary with the degree to which the causal factors can be managed.

INFLAMMATORY CONDITIONS OF SALIVARY GLANDS

Inflammatory conditions are the most common pathol-ogy affecting the salivary glands. Dentists should be famil-iar with their clinical manifestations and recommended treatment.

Mucocele

The mucocele is a common lesion that results from rupture of a salivary gland duct and spillage of mucin into the



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surrounding tissues. For that reason, the term ‘mucus extra-vacation’ phenomenon is used to describe this lesion. The rupture of the gland or duct may be due to local trauma, but many cases develop without a history of trauma. These will be found most frequently in the lower lip.

Clinical features

Mucoceles typically present as fluctuant, non-ulcerated dome-shaped mucosal swellings that range from 2 mm to several centimeters in size. Mucoceles have been reported in patients of all ages. The lesions typically have a bluish translucent hue due to the spilled mucin under the tissue surface (Figure 13). Deep mucoceles may appear normal in color, and may feel firmer to palpation than superficial ones. Duration may be days to years. Patients will often report that the lesion intermittently gets larger, and then shrinks. This history is consistent with the nature of the lesion which will enlarge, sometimes during eating, and then spill contents into the surrounding tissue, and even-tually shrink in size. The most common location is the lower lip, but mucoceles may also be found in the buccal mucosa, anterior ventral tongue and floor of the mouth (ranula).

Histopathology

They consist of a circumscribed cavity in the connective tissue, producing an elevation of the mucosa with thinning of the epithelium. The cavity wall is made up of a lining of compressed fibrous connective tissue and fibroblasts. The connective tissue wall may demonstrate granulation tissue infiltrated by polymorphonuclear leukocytes, lymphocytes

and plasma cells. The lumen is filled with an eosinophilic coagulum containing inflammatory cells.

Treatment

Treatment of the mucous retention phenomenon is exci-sion. If only incised, the contents will be released, but the lesion may recur when the area has healed.

Ranula

Clinical features

‘Ranula’ is the term used for mucoceles that occur in the floor of the mouth in association with ducts from the sub-mandibular or the sublingual gland. Generally these are larger than mucoceles occurring in other locations and can elevate the tongue. The ranula is usually located lateral to the midline and appears as a dome-shaped fluctuant swelling in the floor of the mouth as seen in Figure 14. The color may be translucent blue or normal in color if deep seated. A rare plunging type that has herniated through the mylohyoid muscle has been described by Davison et al.

Histopathology

The histopathology of a mucocele and ranula are similar, however, the ranula may be a true cyst with an epithelial lining. Spilled mucin may elicit a granulation tissue response that contains foamy histiocytes.

Treatment

Treatment of a ranula includes unroofing the lesion, exci-sion of the lesion, or removal of the sublingual gland.

Figure 13

Mucocele of the lower lip. Bluish dome-shaped lesion of short duration on the mucosal aspect of lower lip.

Courtesy: Dr Indraneel Bhattacharyya

Figure 14

Ranula. Courtesy: Dr Praveen, Department of Oral Medicine, KLE Institute of Dental Sciences, Bangalore



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Sialolithiasis, Salivary Duct Stone, Salivary Calculi

Clinical features

Sialoliths are calcified bodies that develop within the sali-vary gland or ductal system. These are one of the most common salivary gland conditions. These are believed to develop from deposition of calcium salts around a focus of material within the duct lumen. Solitary or multiple sialo-liths can form. The initiating focus may consist of desqua-mated epithelial cells, bacteria, foreign bodies, or mucus. Sialoliths most commonly occur in the submandibular gland (80–90%), but may develop in the parotid and sub-lingual gland as well. Multiple stones are more common in the parotid glands than other major glands. Minor gland calculi are occasionally seen in labial glands and buccal mucosa. These usually form in young and middle-aged adults, but may develop at any age. The classic presenta-tion is an intermittent postprandial salivary gland swell-ing that gradually subsides over the next 2–3 hours. Patients report moderately severe pain, just before, during and after meals due to stimulation of salivary flow and the pressure produced against the occluded duct. Recurrent and chronic obstruction causes stasis, inflammation, and infection, which can result in persistent enlargement. Sialoliths may be round or elongated and measure from 2 mm to 2 or more centimeters in diameter. The involved duct may contain a single stone or multiple stones. Upon excision and gross examination, these appear yellow in color. The cause is uncertain, but sialolith formation can be promoted by chronic sialadenitis and partial duct obstruction.

Diagnostic procedures

Conventional radiographs can successfully image most sialoliths as they appear as radiopaque masses. Smaller sialoliths that are not fully calcified pose a diagnostic chal-lenge. Underexposed radiographs can sometimes demon-strate the presence of the sialolith. Occlusal films help identify stones in the submandibular gland as shown in Figures 15 and 16. If a panoramic film is generated, multi-ple calcifications may be identified as shown in Figure 17. It is possible for multiple calcifications to appear superim-posed on the mandible and mimic a bony lesion. A sialo-graph of Wharton’s duct depicts ductal enlargement proximal to the sialolith in Figure 18. However, Rabinov and Weber report that up to 20% of salivary calculi are radiolucent. If not calcified, the stones may not be evident on these films. Non-contrast CT is often considered the best single modality for the diagnosis of calculi. Most stones not seen on conventional radiographs can be detected by CT. Sialographs are useful in detecting non-calcified sialo-liths, but sialography is an invasive procedure with poten-tial to dislodge the stone deeper into the gland, as well as

Figure 15

Occlusal radiograph of sialolith in submandibular gland. Courtesy: Dr Carol Stewart

Figure 16

Occlusal radiograph of sialolith in submandibular gland. Courtesy: Dr James Pettigrew

facilitate retrograde spread of any existing bacterial infec-tion as a result of stasis. In addition, sialography can cause increased pain when acute sialadenitis exists. Dormant infections can get worse after sialography; thus necessi-tating the use of antibiotics. Con trast CT examination, on the other hand, can image non-calcified sialoliths if these are larger. In Asia and Europe, ultrasound imaging is the mainstay of imaging.



281

Figure 17

Panoramic film of multiple sialoliths in parotid gland. Courtesy: Dr James Pettigrew

Figure 18

Sialograph of submandibular gland showing dilatation of Wharton’s duct proximal to sialolith. Courtesy:

Dr Ajit Auluck and Dr Chandrakant Shetty

Histopathology

The histopathologic features include a calcified mass that exhibits concentric laminations surrounding a central focus of amorphous debris. The associated duct will demonstrate squamous, oncocytic or mucous cell metaplasia.

Treatment

Small stones may be removed by massaging and manipula-tion to move the stones toward the duct orifice or peripheral/transoral ductotomy. Large stones may require excison of gland and/or associated duct. Lithotripsy has been tried with limited success. Sialoendoscopy provides a new minimally

invasive treatment modality that does not require removal of the gland for sialolithiasis. Commonly associated with sial-olithiasis is acute or chronic sialadenitis, which is described in the next section.

Sialadenitis

Sialadenitis or an inflammation of the salivary glands may arise from a variety of infectious and non-infectious conditions. Non-infectious causes of salivary gland dys-function include disorders such as SS, sarcoidosis, radia-tion therapy, medications, and congenital anomalies were discussed in the previous sections. The infectious causes, which will be discussed in the following sections, com-monly include bacterial and viral infections. Salivary stones or sialoliths are also associated with salivary gland dysfunction of the major and minor glands. Conditions that predominately affect the minor salivary glands, such as cheilitis glandularis and necrotizing sialometaplasia will be reviewed as well.

Non-specific Sialadenitis

Non-specific sialadenitis may manifest as chronic paroti-tis, also called chronic recurrent parotitis. The cause of the parotid gland enlargement may be multifactorial and include decreased salivation either from decreased pro-duction or decreased secretion, stasis and an ascending retrograde infection. Sometimes, no predisposing factor is identified. This entity is usually unilateral, painful (mild to severe), and characterized by intermittent exacerbations of swelling and remission. Massaging or milking the gland will reveal cloudy or purulent secretions. In a large series, Bhatty et al reported that the mean age was 46 years, with mean duration of symptoms of 4.6 years. The swell-ing may last for several hours or several weeks. The condi-tion establishes a cycle of blockage and infection, which becomes self-perpetuating. Fever and malaise may be present. Remissions last from weeks to years. The extent of the gland destruction may increase over time with each episode as does the pain intensity. The disease tends to progress and may lead to the formation of a fibrous mass in the affected gland.

Diagnostic imaging

Sialography will demonstrate the parotid duct system. A ‘sausage-like’ pattern reflects areas of duct wall dilatations and stricturing that result from the effects of the ascend-ing bacterial infection. Because sialography may result in retrograde spread of infection into the gland, other imag-ing modalities are preferred. CT scan may show increased density due to the normal parotid gland fat being replaced by inflammation and fibrosis. Contrast CT will show enlargement of the gland and its duct in the absence of



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a causative agent such as a sialolith. Figure 19 shows uni-lateral gland and duct enlargement of the right subman-dibular gland. Figure 20A–C show non-specific sialadenitis in the right parotid and submandibular glands.

Histopathology

The histopathology is consistent with non-specific sialad-enitis with marked infiltrate of inflammatory cells. The histology may show mild chronic sialadenitis or widespread

involvement of the gland with areas of destruction. Acinar loss and fibrosis will be present in varying amounts.

Treatment

Treatments include antibiotic therapy during an acute attack, sialogogues, increased fluid intake and parotid gland massage. When surgical intervention is appropriate, a superficial parotidectomy has a high success rate with minimal long-term complications.

Bacterial Sialadenitis

Bacterial sialadenitis may arise from a bacterial infection involving any of the salivary glands. Acute bacterial sia-ladenitis most commonly occurs in children younger than 2 months and in elderly persons who are debilitated by systemic illness, or who have had surgical procedures. How-ever, persons of all ages may be affected. The most com-mon pathogens are Staphylococcus aureus and anaerobic bacteria.

Clinical features

Acute sialadenitis is seen in the parotid gland and is bilateral in 10–25% of case. The affected gland is swollen and painful, and the overlying skin may be erythematous. The patient may present with a low-grade fever and tris-mus. Milking the gland may reveal a purulent discharge. Acute suppurative sialadenitis is most frequently due to S. aureus, but also may arise from streptococci, including Streptococcus pneumoniae and Streptococcus pyogenes and gram-negative aerobic bacilli including Escherichia coli.A study of acute sialadenitis from all three major glands

Figure 19

Unilateral enlargement of the right submandibular gland and duct, consistent with low-grade sialadenitis.

Courtesy: Dr Madhu Nair

Figure 20

BA C

Non-specific sialadenitis noted in the right parotid and submandibular glands. Courtesy: Dr Madhu Nair



283

with 47 specimens as reported by Brook revealed a broad spectrum of microbes present in the purulent fluid. The pre-dominant aerobes were S. aureus and Hemophilus influen-zae, while anaerobes were gram-negative bacilli, including Prevotella, Porphyromonas, Fuso bacterium and Peptostrepto-coccus species.

Histopathology

The diagnostic features of acute sialadenitis will include neutrophils within the ductal system and acini.

Diagnosis

A history of preceding events may aid in making the diag-nosis. Predisposing factors can include dehydration, malnu-trition, immunosuppression, dental infection, anticholinergic medications, tracheotomy, sialectasis, ductal obstruction, neurosurgical, and abdominal surgical procedures.

Treatment

Treatment for acute sialadenitis includes appropriate anti-biotic therapy based on culture and sensitivity findings. Rehydration is important to improve salivary flow. If an abscess has formed, surgical drainage may be required. If the condition is severe, surgical removal of the gland may be necessary. In debilitated patients, the condition may be fatal due to spread of infection and sepsis. Prompt recog-nition by the dentist with appropriate referral otorhino-laryngologist for definitive treatment is essential for a good outcome.

Subacute Necrotizing Sialadenitis

Clinical features

Subacute necrotizing sialadenitis (SANS) is a form of sali-vary inflammation that occurs most commonly in young adults and teens. The lesion involves minor salivary glands of the hard and soft palate, and presents as a localized palatal swelling covered by erythematous, intact mucosa. The nodule may be accompanied by abrupt onset of pain. An infectious or allergic origin has been suggested. Some diagnosticians have questioned whether SANS represents a separate entity or part of the spectrum of necrotizing sialometaplasia. Unlike necrotizing sialometaplasia, SANS does not ulcerate or slough necrotic tissue.

Histopathology

Subacute necrotizing sialadenitis is characterized by a heavy mixed inflammatory infiltrate consisting of neutro-phils, lymphocytes, histiocytes, and eosinophils. There is an absence of acinar cells and those present may exhibit

necrosis. The ducts tend to be atrophic and do not show squamous metaplasia characteristic of necrotizing sialo-metaplasia. Based on the clinical and histopathologic fea-tures, some prefer to consider SANS a separate non-specific inflammatory condition of the minor salivary glands with unknown etiology.

Treatment

Subacute necrotizing sialadenitis is self-limiting and heals within 2–3 weeks. It generally requires no treatment.

Cheilitis Glandularis

The term ‘cheilitis glandularis’ was first used by Volkmann in 1870 to describe a disorder that presented with a chronic, suppurative inflammation of the lower lip charac-terized by swelling of the mucous glands, dilated open-ings, and mucopurulent discharge. Cheilitis glandularis is an uncommon inflammatory condition of the minor sali-vary glands, and most commonly affects the lower lip of adult males. The etiology is unknown, however associated factors have been suggested. These factors include tobacco, poor oral hygiene, bacterial infections, possibly heredity, and actinic damage.

Clinical features

Cheilitis glandularis most commonly affects the lower lip, but it has been reported in the upper lip, palate, and buccal mucosa. Affected individuals experience swelling and eversion of the lower lip as a result of hypertrophy and inflammation of the glands as seen in Figure 21. The open-ings of the minor salivary ducts are inflamed and dilated, and pressure on the glands may produce mucopurulent secretions emanating from the ductal openings. The con-dition most frequently occurs in middle-aged men, but women and children have been reported as well.

Historically, cheilitis glandularis has been classifi ed into three types, based on the severity of the disease. These are (i) simple, (ii) superfi cial suppurative (Baelz’s disease), and (iii) deep suppurative (cheilitis glandularis apostematosa). The superfi cial suppurative type demonstrates painless crusting, swelling, and induration of the lip with superfi -cial and deep ulceration. This type seems to be the result of secondary infection of the simple type. The deep suppura-tive type, also known as cheilitis glandularis apostematosa, myxadenitis labialis, or cheilitis glandularis suppuritiva profunda, is a deep-seated infection associated with abscess formation and spontaneous expression of suppurative mate-rial from the ducts. The latter two types represent prog-ressive stages of the diseases with bacterial involvement and demonstrate increased infl ammation, suppuration, and ulceration of the lip.



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Figure 21

Cheilitis glandularis. Courtesy: Department of Oral Medicine, MCODS, Mangalore

Figure 22

Necrotizing sialometaplasia of the palate. A well-defined ulcer that began after 1 week of seating porcelain fused to metal

(PFM) crown on tooth number 3. Patient reported mild discomfort and that the lesion was progressively getting

larger. Courtesy: Dr Indraneel Bhattacharyya

Histopathology

Histopathologic features consist of non-specific chronic inflammation, dilated secretory ducts, dilated ducts con-taining mucin, areas of fibrosis, and areas of chronic scle-rosing sialadenitis. The ductal lining may show oncocytic metaplasia and atrophy of the acini. Concomitant dysplas-tic changes may be seen in the surface epithelium.

Diagnosis

The differential diagnosis for cheilitis glandularis would include orofacial granulomatosis and multiple mucoceles. Orofacial granulomatosis, which will be described in the next section, is a non-tender, persistent swelling of the lips usually with oral ulcerations. Histologic findings would include non-caseating giant cell granulomas. Definitive diagnosis of cheilitis glandularis requires a biopsy along with the clinical picture.

Treatment

The treatment for cheilitis glandularis may vary depend-ing on the severity of the condition. It may be treated with lip balms, sunscreens, topical steroids, intralesional ste-roids, systemic antihistamines, and/or antibiotics. If conser-vative therapy fails, surgical resection or vermillionectomy may be indicated. A significant percentage of cases of deep suppurative type have been associated with the development of squamous cell carcinoma of the overlying epithelium. Because actinic damage has been implicated in many cases of cheilitis glandularis, malignant degeneration could be asso-ciated with susceptibility to environmental factors, espe-cially sun damage versus considering cheilitis glandularis

as a true malignant condition. Radiation therapy was used in the past, but is no longer recommended due to associ-ated complications.

Necrotizing Sialometaplasia

Clinical features

Necrotizing sialometaplasia is an uncommon, benign, but locally aggressive inflammatory lesion of salivary gland tissue which both clinically and histologically may mimic a salivary gland malignancy. In 1973, it was described by Abrams and colleagues as a reactive necrotizing inflam-matory process of the minor salivary glands of the hard palate. While the etiology is unknown, the prevailing the-ory is that local ischemia of the salivary tissue leads to local infarction. Most patients are in the 4th or 5th decade, but the lesion has been reported in all ages, except chil-dren. In a large series as reported by Brannon et al, males were affected more often than females, and whites were affected more commonly than African-Americans by a ratio of 5:1. Most lesions occur in the posterior hard pal-ate, usually unilateral (Figure 22). Bilateral and midline lesions may occur as well. Other intraoral sites such as the retromolar pad, buccal mucosa, lower lip, and tongue have been affected. Early lesions may present as a non-ulcerated swelling in the posterior palate with or without pain. Within 2–3 weeks, the necrotic tissue sloughs and leaves a crater-like ulcer ranging from 1 cm to more than 5 cm. Commonly, patients do not seek treatment until the ulcer occurs. They may report a feeling of fullness in the area, prior to the ulceration. Pain may or may not be a complaint even though the ulcer may be quite large.



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Diagnostic imaging

A palatal soft tissue attenuation focus with no character-istic appearance may be noted on CT and MRI. Osseous changes are not noted. Lesions in the parotid are also some-times seen. Ultrasonography may detect multiple foci of hypoechoic nature within the parotids. Contrast CT dem-onstrates high attenuation areas within the parotids while MRI can clearly show well-delineated masses that are hypo-intense on T1 and isointense on T2 weighted contrasted images. Findings could resemble those of benign tumors such as pleomorphic adenomas. Alternatively, a more dif-fuse margin on CT can be misconstrued for a malignant tumor. The condition can also appear in other locations within the sinonasal and upper aerodigestive tracts.

Histopathology

Biopsy is necessary to confirm the diagnosis and rule out malignant disease. The histopathology includes ulcerated mucosa, pseudoepitheliomatous hyperplasia of the epithe-lium, acinar necrosis, and squamous metaplasia of salivary ducts. Coagulation necrosis has been seen in early lesions. Inflammatory cells may be found with fibrosis and granu-lation tissue. While mucous cells are necrotic, the lobular architecture of involved glands is preserved. The lesion can be misdiagnosed as squamous cell carcinoma or muco epidermoid carcinoma in the absence of an adequate representative section of the lesion.

Treatment

Once the diagnosis has been established, no specific treat-ment is indicated. The lesion will heal by secondary inten-tion with no intervention within 4–10 weeks.

Chronic Sclerosing Sialadenitis (Kuttner Tumor)

Clinical features

The Kuttner tumor, a chronic inflammatory condition of the salivary glands, was first described by Kuttner in 1896. Clinically, the condition cannot be distinguished from a true neoplasm. The submandibular gland is affected more commonly than any other salivary gland. It is usually localized to the superficial aspect of the submandibular gland, but may involve the deep aspect. It manifests as a firm, enlarged gland. Etiology may be sialolithiasis (about one-third of all cases), autoimmune sialadenitis or idio-pathic. Recent reports suggest that pathogenesis probably has an immunologic background.

Histopathology

The histolopathologic features consist of chronic sclerosing sialadenitis, specifically chronic inflammation and fibro-sis. It may be seen with sialolithiasis.

Diagnostic imaging

Ultrasound imaging results in the gland appearing enlarged and lobular with a cirrhotic pattern of numerous hypoechoic regions against a heterogeneous background. The presence of lymph node enlargement is sometimes noted on CT/MRI. Diffuse enlargement of the gland with enhancement may be noted on CT.

Treatment

The treatment is surgical removal.

VIRAL-INDUCED SALIVARY GLAND PATHOLOGY

Mumps

Clinical features

Epidemic parotitis or mumps is a moderately infectious disease caused by a virus of the paramyxovirus group. Generally, mumps is a disease of childhood with an incu-bation period of 2–3 weeks. The virus may be in the saliva of affected persons and dissemination through droplets is common. The patient will complain of fever, fatigue, and present with a painful unilateral, or more commonly, bilat-eral parotid enlargement. The infection may also involve the submandibular gland. Clinical features include a flu-like illness with fever, headache, vomiting, and pain below the ear. This is followed by firm, somewhat rubbery swell-ing of the salivary glands, sometimes elevating the ears. The glands are extremely tender to palpation and milking them may produce a thick white secretion from Stensen’s ducts. The swelling may last approximately 1 week. Other organs may be involved which include the testes, ovaries, pancreas, and mammary glands.

Prognosis and treatment

When the disease affects the adult male, orchitis, inflam-mation of the testicles, is a complication approximately 20% of the time. The orchitis is usually unilateral, but can occur bilaterally. Even with involvement of both testicles, sterility is only a rare complication of orchitis. In adults, dyspnea secondary to severe swelling of the salivary gland which required a tracheostomy, has been reported by Ishida et al. The mumps vaccine has been available since 1968, which has resulted in a marked decline in the inci-dence of the disease.

Human Immunodeficiency Virus (HIV)

Clinical features

Benign lymphoepithelial lesions (BLEL) in AIDS or AIDS-related parotid cysts (ARPC) are frequently reported in HIV


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