Ranula is a clinical term that includes mucus extravasation phenomenon and mucus retention cyst, but it occurs specifically in the floor of the mouth. Ranula is associated with the sublingual or submandibular glands and presents as a fluctuant, unilateral, soft tissue mass. It often exhibits a bluish color that has been compared with a frog’s belly, hence the term ranula. When it is significantly large, it can produce medial and superior deviation of the tongue. It may also cross the midline if the retained mucin dissects through the submucosa. A deep, plunging ranula develops if mucus herniates inferiorly through the mylohyoid muscle and along the fascial planes of the neck. On rare occasions, it may progress into the mediastinum.
The cause of mucus extravasation phenomenon is traumatic severance of a salivary gland excretory duct, resulting in escape of mucus, or extravasation, into the surrounding connective tissue (Figure 8-1). An inflammatory reaction of neutrophils followed by macrophages ensues. Granulation tissue forms a wall around the mucin pool, and the contributing salivary gland undergoes inflammatory change. Ultimately, scarring occurs in and around the gland.
The lower lip is the most common site of mucus extravasation phenomenon, but the buccal mucosa, anterior-ventral surface of the tongue (location of Blandin-Nuhn glands), floor of the mouth, and retromolar region are often affected (Figures 8-2 and 8-3). Lesions are uncommonly found in other intraoral regions where salivary glands are located, probably because of lower susceptibility to trauma.
Mucus extravasation phenomenon presents as a relatively painless mass of smooth surface ranging in size from a few millimeters to 2 cm in diameter. It has a bluish color when mucin is superficially located. Adolescents and children are more commonly affected than adults. Lesions may fluctuate in size because of mucosal rupture over the pooled mucin. Continued production of mucin leads to recurrence. The maximum size is usually reached within several days after injury, and a viscous material is found if aspiration is attempted.
Superficial mucocele is a variant of the extravasation-type mucocele. Rather than arising from traumatic duct rupture, this form of mucocele is believed to arise as a result of increased pressure in the outermost part of the excretory duct. These lesions are asymptomatic and numerous, occurring most commonly in the retromolar area, soft palate, and posterior buccal mucosa. Their clinical appearance suggests a vesiculobullous disease, but the lesions persist for an extended time. Other than being a diagnostic challenge, they are of little significance.
Extravasation of free mucin incites an inflammatory response that is followed by connective tissue repair. Neutrophils and macrophages are seen, and granulation tissue forms around the mucin pool (Figure 8-4). The adjacent salivary gland whose duct was transected shows ductal dilation, chronic inflammation, acinar degeneration, and interstitial fibrosis.
Although a history of a traumatic event followed by development of a bluish translucency of the lower lip is characteristic of the mucus extravasation phenomenon, other lesions might be considered when a typical history is absent. These include salivary gland neoplasm (especially mucoepidermoid carcinoma), vascular malformation, venous varix, and soft tissue neoplasm such as neurofibroma or lipoma. Rarely, a mucocele may appear in the alveolar gingival mucosa. When this occurs, an eruption cyst or gingival cyst should be included in the differential diagnosis.
Treatment for the mucus extravasation phenomenon consists of surgical excision. Aspiration of the fluid content provides no lasting clinical benefit. Removal of associated minor salivary glands along with the pooled mucus is necessary to prevent recurrence.
Mucus retention cysts usually result from obstruction of salivary flow caused by a sialolith (Box 8-1). The sialolith(s) may be found anywhere in the ductal system, from the gland parenchyma to the excretory duct orifice. A sialolith represents the precipitation of calcium salts (predominantly calcium carbonate and calcium phosphate) around a central nidus of cellular debris, inspissated mucin, and/or bacteria. Predisposition includes salivary stasis, chronic sialadenitis, and gout (uric acid calculi). Occasionally, periductal scar or an impinging tumor may cause the obstructive sialadenitis.
Obstructive sialadenitis due to stones is most commonly seen in submandibular glands (up to 80%) (Figures 8-5 and 8-6). About 20% are seen in the parotids, and a very small percentage is seen in sublingual and minor glands (especially upper lip). Adults are most commonly affected.
Recurrent swelling and pain are the primary presenting signs and symptoms, respectively, with worsening of either or both at mealtime. Infection may or may not be present. A purulent, cloudy-to-flocculent discharge at the duct orifice with massage, as well as limited flow from the gland at rest, is a common finding. Mucin in the floor-of-mouth lesions may penetrate the musculature and escape into the soft tissues of the neck, causing a plunging ranula.
Minor salivary gland lesions typically present as asymptomatic swellings without antecedent trauma. They vary in size from 3 to 10 mm and are mobile and nontender on palpation. The overlying mucosa is intact and has normal color.
Radiographically, nearly 90% of submandibular sialoliths are radiopaque, whereas most parotid calculi (90%) are radiolucent. The diagnosis may be suggested or confirmed by routine retrograde sialography or by cross-sectional imaging with intravenous contrast administration (computed tomographic [CT] sialogram).
The cystlike cavity of a mucus retention cyst is lined by normal but compressed ductal epithelium (Figure 8-7). The type of lining formed by the epithelial cells ranges from pseudostratified to stratified squamous. The cystlike lumen contains mucin obstructed by a sialolith. The connective tissue around the lesion is minimally inflamed, although the associated gland shows inflammatory-obstructive change.
Salivary gland neoplasms, the mucus extravasation phenomenon, and benign connective tissue neoplasms should be included in a clinical differential diagnosis. Dermoid cyst might also be included for lesions in the floor of the mouth. Differentiation from a calcified phlebolith may be necessary, depending on the clinical presentation. Phleboliths show a circular morphology, with multiple calcifications often present beyond the glandular drainage system.
For minor salivary glands, treatment consists of removal of both the mucus retention cyst and the associated gland to avoid postoperative mucus extravasation phenomenon, which may occur if only the cystic component is removed or decompressed. Lesions of the major salivary glands are treated in a similar way if the stone(s) resides in the hilum of the ductal system. If the stone is in the distal part of the ductal system, the sialolith may be surgically removed or may be milked through the duct orifice. If a duct is surgically entered, special precautions (marsupialization/cannula) are used to aid the healing process, so that duct scarring is minimized. Constriction of the duct through excessive scar formation could result in recurrence. Recurrence is noted in up to 20% of cases following routine treatment.
Retention cysts and pseudocysts involving the lining of the maxillary antrum are common findings on panoramic radiographs. These lesions are discovered incidentally and are of little clinical significance.
Retention cysts are thought to arise from blockage of an antral seromucous gland, resulting in a ductal epithelium-lined cystic structure filled with mucin. Pseudocysts are inflammatory in origin and result from fluid accumulation within the sinus membrane. They may be related to infection or allergy. Bacterial toxins, anoxia, and other factors presumably cause leakage of protein into surrounding soft tissue, thus raising the extravascular osmotic pressure with a subsequent fluid increase.
A great majority of these lesions are asymptomatic, although some slight tenderness may be noted in the mucobuccal fold or, more rarely, palpable buccal expansion in this region. On panoramic and periapical radiographs, retention cysts and pseudocysts of the maxillary sinus are hemispheric, homogeneously opaque, and well delineated (Figure 8-8). They usually demonstrate an attachment to the floor of the antrum, with size—rather than duration—being a function of the anatomic space. Uncommonly, these lesions may appear bilaterally.
The pathogenesis of the two forms of antral cysts is reflected in the histologic appearance. The retention cyst is lined by pseudostratified columnar epithelium with occasional interspersed mucous cells. The supportive elements are minimally inflamed. The pseudocyst shows no evidence of an epithelial lining but, rather, pools of mucoid material surrounded by slightly compressed connective tissue. A mixed inflammatory infiltrate is present within the granulation tissue wall, and numerous mucus-containing macrophages are present within the mucin pool.
A clinical differential diagnosis of cysts and pseudocysts arising within the mucosa of the maxillary sinus would include inflammatory polyps, hyperplasia of the sinus lining as a result of odontogenic infection, maxillary sinusitis, and neoplasms arising within the soft tissues of the antral lining.
Necrotizing sialometaplasia is a benign condition that typically affects the palate and rarely other sites containing salivary glands (Box 8-2). Recognition of this entity is important because it mimics malignancy both clinically and microscopically. Unnecessary surgery has been performed because of an erroneous preoperative diagnosis of squamous cell carcinoma or mucoepidermoid carcinoma.
The initiating event of necrotizing sialometaplasia is believed to be salivary gland ischemia precipitated by local trauma, surgical manipulation, or local anesthesia. Infarction of the gland follows, and squamous metaplasia of ductal remnants eventually appears.
This condition is believed to be due to local trauma or focal vascular compromise leading to discrete tissue necrosis in the area. Patients often have no history of a prior traumatic event, although some cases may be caused by local anesthetic placement in relation to a dental procedure with associated vascular compromise or direct vessel damage.
Intraorally, necrotizing sialometaplasia is characterized by a seemingly spontaneous appearance, most commonly at the junction of the hard and soft palates (Figure 8-9). Early in its evolution, the lesion may be noted as a tender swelling, often with a dusky erythema of the overlying mucosa. Subsequently the mucosa breaks down, and a sharply demarcated deep ulcer with a yellowish gray lobular base is formed. In the palate, the lesion may be unilateral or bilateral, with individual lesions ranging from 1 to 3 cm in diameter. Pain is generally disproportionately slight compared with the size of the lesion. Healing is generally protracted, taking from 6 to 10 weeks.
Submucosa adjacent to an ulcer shows necrosis of salivary glands and squamous metaplasia of salivary duct epithelium (Figure 8-10). Preservation of the lobular architecture of salivary glands serves to distinguish this process from neoplasia. The characteristic ductal squamous metaplasia shows no cytologic atypia, but the pattern may be misinterpreted as squamous cell carcinoma. When this metaplasia is seen in the presence of residual viable salivary gland, the lesion may be mistaken for mucoepidermoid carcinoma.
Clinically, squamous cell carcinoma and malignant minor salivary gland neoplasms must be ruled out, usually by a biopsy. Syphilitic gummas and deep fungal infections likewise must be ruled out because they may present as punched-out lesions of the palate. Findings from serology, biopsy, and/or culture are usually needed to exclude these entities. In medically compromised patients, such as those with poorly controlled diabetes, opportunistic fungal infections such as mucormycosis may cause a similar clinical picture.
The entity subacute necrotizing sialadenitis has been described as a nonspecific, inflammatory condition of minor salivary glands of unknown origin. It is characterized by abrupt onset of pain and localized swelling, usually of the hard or soft palate, but, unlike necrotizing sialometaplasia, it is self-limiting and has no ulcerative or metaplastic components.
This condition is a benign, self-limiting process that does not require surgical intervention. However, an incisional biopsy should be performed to establish a definitive diagnosis. Healing takes place over several weeks by secondary intention. Patient reassurance, wound irrigation using a bland baking soda-and-water mouth rinse, and occasional use of analgesics are the only necessary management steps.
The palate is the chief site of involvement of this salivary gland hyperplasia. A male predominance has been noted, and age ranges from 24 to 63 years. The clinical presentation is seen as a unilateral swelling of the hard and/or soft palate. This lesion is asymptomatic, broad-based, and covered with intact mucosa of normal color and quality.
Lobules of hyperplastic mucous glands extend beyond the submucosa and into the lamina propria. Individual acinar clusters are more numerous and larger than normal. Ducts exhibit a slight increase in relative prominence. The cytologic and morphologic features of acinar and ductal elements are within normal limits. Generally, no significant inflammatory cell infiltrate is found.
Mumps is an infectious, acute viral sialadenitis primarily affecting the parotid glands. Considered the most common of all salivary gland diseases before the advent of routine immunization, it has a year-round endemic pattern, although seasonal peaks are noted in the late winter and spring months. A rare noninfectious form of mumps or parotid enlargement is iodide mumps. This is seen most commonly in association with administration of iodine-containing radiographic contrast material. The condition is self-limiting and benign in nature with recurrence likely with repeat exposure to iodinated contrast material.
Patients develop fever, malaise, headache, and chills, in addition to preauricular pain. Salivary glands, usually the parotid, demonstrate a 70% incidence of bilateral infection. Parotid swelling tends to be asymmetric at the outset, reaching maximum proportions within 2 to 3 days. Severe local pain is often noted, especially on movement of the jaws in talking and chewing. Stensen’s duct may become partially occluded as the gland swells, with sharp pain resulting from stimulation of the secretory mechanism by food or drink. Perceptible diminution of swelling is noted approximately 10 days after the onset of symptoms. The disease affects males and females equally, especially young adults and children. Potentially serious complications (orchitis or oophoritis) can occur in adults. Mumps is a systemic infection, as evidenced by the widespread involvement of glandular and other tissues in the body, including the liver, pancreas, kidney, and nervous system.
Treatment is symptomatic and includes bed rest. Analgesics are prescribed, and corticosteroids may be used in severe cases. Complete recovery is generally the rule, although fatalities have been associated with viral encephalitis, myocarditis, and nephritis. Nerve deafness and bilateral testicular atrophy have been noted but are uncommon.
Prevention of the disease is possible using a live attenuated vaccine that induces a noncommunicable, subclinical infection. Antibody conversion occurs in approximately 90% of susceptible individuals, and immunity is lifelong.
Although mumps is the most common form of viral sialadenitis, parotitis may be caused by other viral agents, including Coxsackie A virus, echovirus, choriomeningitis virus, cytomegalovirus, and parainfluenza virus types 1 and 2.
Cytomegaloviral infection of the salivary glands, or cytomegalic inclusion disease, is a rare condition that affects neonates as a result of transplacental infection. Systemic disease may cause debilitation, developmental retardation, and premature birth.
When encountered in adults who are immunosuppressed (e.g., human immunodeficiency virus [HIV] infection, organ transplants), infection may cause fever, salivary gland enlargement, hepatosplenomegaly, pneumonitis, and lymphocytosis. Retinitis can be a serious complication of this infection. Cytomegalovirus can be demonstrated in biopsy material; with the use of in situ hybridization methods, its presence can be easily confirmed in tissue sections. Oral aphthous-like ulcers, particularly those arising in immunocompromised patients, may contain the virus, but its importance is undetermined. In severely infected immunocompromised patients, ganciclovir may be used to control cytomegaloviral infection.
Adults who are not immunosuppressed may also be infected with cytomegalovirus, as evidenced by demonstration of antibodies in serum. Symptoms may be nonexistent, or slight to debilitating fever and malaise may occur. The significance of cytomegaloviral infection in this population is poorly understood.
Bacterial infections of salivary glands generally are due to microbial overgrowth in association with a reduction in salivary flow. Such reduction in flow may be noted subsequent to dehydration, postoperative states, and debilitation. Traditionally, bacterial sialadenitis has been a common postoperative complication of surgery related to inadequate hydration. Numerous drugs associated with a decreased salivary flow rate likewise contribute to infections of the major salivary glands, especially the parotid. Submandibular gland sialadenitis is far less common than its parotid counterpart, in part because of the stated higher degree of bactericidal quality and the greater viscosity of submandibular saliva versus the serous and lower viscosity quality of parotid fluid. Other possible causes include trauma to the duct system and hematogenous spread of infection from other areas. The most commonly isolated organisms in parotitis are penicillin-resistant Staphylococcus aureus, Streptococcus viridans, Streptococcus pneumoniae, Escherichia coli, and Haemophilus influenzae. Anaerobic organisms may be cultured from acute cases and include Porphyromonans gingivalis. It is of interest to note the marked reduction in the overall incidence of acute parotitis after antibiotic preparations are introduced. As resistant strains of bacteria have appeared, the prevalence of acute parotitis has increased.
Clinical features of acute parotitis include the sudden onset of painful lateral facial swelling, low-grade fever, malaise, and headache. Laboratory studies disclose an elevated erythrocyte sedimentation rate (ESR) and leukocytosis, often with a characteristic shift to the left, where neutrophil counts are elevated, indicating acute infection. The involved gland is extremely tender, and the patient often demonstrates guarding during examination. Trismus is often noted, and purulence at the duct orifice may be produced by gentle pressure on the involved gland or duct.
If the infection is not eliminated early, suppuration may extend beyond the limiting capsule of the parotid gland. Extension into surrounding tissues along fascial planes in the neck or extension posteriorly into the external auditory canal may follow.
Management of bacterial sialadenitis is directed at elimination of the causative organism combined with rehydration of the patient and drainage of purulence, if present. Culture and sensitivity testing of the exudate at the orifice of the duct is the first step in antibiotic management. After a culture is obtained, all patients should empirically be placed on a regimen of a penicillinase-resistant antibiotic such as semisynthetic penicillin. Along with rehydration and attempts at establishing and encouraging salivary flow, moist warm compresses, analgesics, and rest are in order. Medications containing parasympathomimetic agents, which reduce salivary flow, should be reduced or eliminated.
Biopsy and retrograde sialography should be avoided, particularly in cases of acute and subacute infection. The former may cause sinus tract formation, and the latter may allow infection to proceed beyond the boundaries of the gland into surrounding soft tissues. With prompt and effective treatment of acute infection, recurrence is generally avoided. In cases of chronic recurrent parotitis with considerable destructive glandular changes, painful recurrent enlargement, and xerostomia, sialadenectomy—particularly in cases of submandibular gland involvement—may be considered, although duct ligation and parotidectomy remain treatment options.
In the juvenile variant of parotitis, intermittent unilateral or bilateral painful swelling is accompanied by fever and malaise. The initial attack usually occurs in individuals between ages 2 and 6 years, with numerous recurrences thereafter. A neonatal form of suppurative parotitis develops rarely, with S. aureus being the most common causative pathogen. Gross destruction of parenchymal and ductal elements may be noted on sialographic examination. Absence of secretory acinar components and a damaged ductal system with numerous punctate globular spaces may be noted. Spontaneous regeneration of parotid salivary tissue has been reported in this condition. Finally, the rare example of childhood- to adolescent-onset Sjögren’s syndrome may be heralded by recurrent bilateral parotitis.
Sarcoidosis is a granulomatous multisystemic disease of undetermined origin (Box 8-3). Although no specific cause has been identified, it has been suggested that this disease represents an infection or a hypersensitivity response to atypical mycobacteria. As many as 90% of sarcoidosis patients demonstrate significant titers of serum antibodies to these organisms. In some patients with sarcoidosis, a transmissible agent from human sarcoid tissue has been identified. With the use of molecular biological techniques, mycobacterial DNA and RNA have been identified in sarcoid tissues, raising the possibility of Mycobacterium tuberculosis or a related mycobacterial organism as a causative agent. Alternate microbial causes include Propionibacteria and Epstein-Barr and human herpesvirus 8 (HHV8) viruses.
Susceptibility related to human leukocyte antigens (HLAs) has been studied. Patients with some histocompatibility antigens (HLA-A1, HLA-B8, HLA-DR3, HLA-DRB1) may have a greater incidence of sarcoidosis than others. It has also been found that most patients with sarcoidosis are anergic, demonstrating decreased levels of cutaneous sensitization to dinitrochlorobenzene, as well as to tuberculin, mumps virus, Candida antigen, and pertussis antigen.
The protean manifestations of this disease are well known, and pulmonary symptoms are prime factors for evaluation, although the diagnosis generally is one of exclusion. Clinical courses range from spontaneous resolution to chronic progression. The disease may affect individuals at any age, although most are affected in the second through fourth decades. Females show a higher incidence than males, and blacks are more commonly affected than whites.
Sarcoidosis is usually a self-limiting, benign disease with an insidious onset and a protracted course. Patients may complain of lethargy, chronic fatigue, and anorexia, with specific signs and symptoms related to the organ involved.
Pulmonary manifestations are most characteristic of this disease. They are typified by bilateral, hilar, and, less commonly, paratracheal lymphadenopathy. The disease may stabilize at this point, or it may advance to pulmonary fibrosis and a more ominous prognosis. The most serious complications of sarcoidosis are pulmonary hypertension, respiratory failure, and cor pulmonale.
The skin may be involved in approximately 25% of cases; most commonly, an erythema nodosum of acute onset and short duration is seen. Skin plaques characterized by nontender, dark purple, elevated areas on the limbs, abdomen, and buttocks may appear. Another form of cutaneous pathology includes lesions known as lupus pernio, a term used to describe symmetric, infiltrative, violaceous plaques on the nose, cheeks, ears, forehead, and hands.
Ocular involvement is variable, with inflammation of the anterior uveal tract most commonly seen. This may be associated with parotid gland swelling and fever, referred to as uveoparotid fever or Heerfordt’s syndrome.
Hepatic involvement is common, with approximately 60% of patients showing granulomatous lesions on liver biopsy specimens. However, clinical evidence of hepatic involvement appears in less than 50% of patients, as demonstrated in abnormal liver function test results.
Osseous lesions are uncommonly noted, with a 5% occurrence rate in most studies. When present, punched-out lesions involving the distal phalanges with erosions of cancellous bone and an intact cortex are seen. Destruction of alveolar bone with tooth mobility may be evident within the maxilla and the mandible.
Oral soft tissue lesions of sarcoidosis are nodular and generally are indistinguishable from those seen in Crohn’s disease. Parotid swelling may occur unilaterally or bilaterally with about equal frequency (Box 8-4). This is often associated with lassitude, fever, gastrointestinal upset, joint pain, and night sweats, which may precede glandular involvement by several days to weeks. Other salivary glands may also be involved in the granulomatous inflammatory process, leading to xerostomia.
The upper aerodigestive tract may be involved, with lesions developing in the nasal mucosa, especially in the inferior turbinate and septal regions. Granulomas may occur in the nasal sinuses, pharynx, epiglottis, and larynx.
Serum chemistry, radiographic studies, and biopsy are useful laboratory tests. Serum chemistry studies should include calcium (for evidence of hypercalcemia) and angiotensin 1–converting enzyme, lysozyme, and adenosine deaminase levels (for evidence of macrophage activity within granulomas). Gallium scintiscanning and routine chest radiographs and intraoral films may be used to demonstrate bone involvement.
Consistent microscopic findings of sarcoidosis are seen as noncaseating granulomas (Figure 8-11). The granulomas may be well demarcated and discrete or confluent. Within the granulomas are epithelioid macrophages and multinucleated giant cells, which may contain stellate inclusions (asteroid bodies) and concentrically laminar calcifications (Schaumann bodies). A diffuse lymphocytic infiltrate may be seen around the periphery of the granulomas. The caseation-type necrosis that is typical of tuberculosis is absent. Microorganisms are also absent.
The Kveim test was traditionally used to establish the diagnosis of sarcoidosis; however, this test is no longer used. Of considerable value is a laboratory assay for angiotensin 1–converting enzyme. Elevation of this enzyme in conjunction with a positive chest radiograph has a high diagnostic reliability.
The histologic differential diagnosis includes tuberculosis, Crohn’s disease, leprosy, cat-scratch disease, fungal infection (blastomycosis, coccidioidomycosis, and histoplasmosis), and parasitic diseases such as toxoplasmosis. Granulomas seen in association with beryllium and talc exposure must also be considered.
Spontaneous resolution occurs in a significant number of patients (65% to 70%) with few to no signs of residua or chronic sequelae. Corticosteroids are generally considered beneficial in the acute phase and remain the drugs of choice in treating symptomatic pulmonary sarcoidosis. Other agents may be used in addition to or instead of corticosteroids. Chloroquine, given alone or in combination with corticosteroids, has been found useful in the management of this disease. Immunosuppressive drugs have been used with good results in individuals not responding to corticosteroid management. A management role for thalidomide and infliximab has been identified as well. Immunomodulators such as levamisole may be useful in the management of arthritic symptoms caused by sarcoidosis.
In general, the prognosis for sarcoidosis is good, but patients must be monitored periodically with chest radiographs and serum angiotensin 1–converting enzyme determinations. Clinical relapses are unusual in cases in which spontaneous resolution has occurred.
A generic term for a group of metabolic disorders that may cause salivary gland enlargement is sialadenosis, or sialosis. These conditions usually affect the parotid glands bilaterally, typically in the absence of inflammatory symptoms. Chronic alcoholism, dietary deficiency, obesity, diabetes mellitus, hypertension, bulimia, anorexia nervosa, and hyperlipidemia have been linked to this clinical salivary gland abnormality. Alterations in aquaporin water channel function have been implicated in the development of sialadenosis in recent years.
Asymptomatic enlargement of the parotid glands occur in 30% to 80% of patients with alcoholic cirrhosis or chronic alcoholism. Salivary gland enlargement has been attributed to chronic protein deficiency. Comparable parotid gland enlargement in individuals with liver cirrhosis resulting from other causes apparently does not occur. Nutritional or protein deprivation may lead to a similar salivary gland enlargement.
In diabetes mellitus, reduced flow rates have been reported in addition to bilateral parotid gland enlargement. The mechanism of acinar hypertrophy in this condition is unknown. Reduced flow rates from the parotid and other major salivary glands may lead to increased risk of bacterial sialadenitis.
In cases of type I hyperlipoproteinemia, a sicca-like syndrome has been described. This is characterized primarily by parotid enlargement with mild oral or ocular sicca symptoms; it is generally attributed to the presence of fatty replacement of functional salivary gland parenchyma.
Another endocrine-related salivary gland enlargement may be noted in acromegaly. This may merely be a reflection of a generalized organomegaly encountered in this endocrine-mediated disturbance. Apparent parotid enlargement (acinar hypertrophy) and increased levels of parotid flow have been noted in patients with chronic relapsing pancreatitis.
Sjögren’s syndrome is the expression of an autoimmune process that results principally in dry eyes (keratoconjunctivitis sicca) and dry mouth (xerostomia) owing to lymphocyte-mediated destruction of lacrimal and salivary gland parenchyma (Box 8-5). Other autoimmune conditions, particularly rheumatoid arthritis, lupus erythematosus, and scleroderma, may also be seen as a component of this syndrome. Lacrimal and salivary gland involvement is often one expression of this generalized exocrinopathy that is lymphocyte mediated.
Although the specific cause of this syndrome is unknown, it is considered a multifactorial process. Numerous immunologic alterations indicating a disease of great complexity characterized in part by environmental factors and a susceptible host results in a generalized immune dysregulation as noted by polyclonal B-cell hyperactivity reflecting lack of regulation by T-cell subpopulations. Specific immune system abnormalities include enhanced activity of the type 1 interferon system with subsequent upregulation of B-cell–activating factor. Other possible etiologic factors include altered autonomic activity of the affected glands and antimuscarinic receptor autoantibody production with resultant type 3 receptor dysfunction. As with the benign (salivary) lymphoepithelial lesion, the specific causes of this immunologic defect remain speculative.
This syndrome appears to be of autoimmune origin that may be limited to exocrine glands, or it may extend to include systemic connective tissue disorders. In instances of only exocrine glandular involvement, the syndrome is known as primary Sjögren’s syndrome. If an associated connective tissue disorder is present, in addition to the xerostomia and keratoconjunctivitis sicca, regardless of the specific type, it is known as secondary Sjögren’s syndrome; when associated with rheumatoid arthritis, it occurs on a different genetic background (HLA-DR4) and may represent a different pathogenetic process. Similarities and differences between primary and secondary forms of this condition have been noted, including a higher frequency of parotid gland enlargement and oral symptoms in the primary form with a more pronounced degree of B-cell activity. In both forms, extraglandular manifestations, with the exception of Raynaud’s phenomenon, and prevalence of local infiltration are similar. A third and distinct pattern of autoantibodies, genetic predisposition, clinical manifestations, and therapy is noted in the association of secondary Sjögren’s syndrome with progressive systemic sclerosis.
Viruses, particularly retroviruses and Epstein-Barr virus, have been implicated in the development of Sjögren’s syndrome, but none are proven causes. Evidence suggesting a role for retroviruses has come from the demonstration of antibodies against HIV-associated proteins in a subset of patients with Sjögren’s syndrome and from the clinical similarity of HIV-associated salivary gland disease to Sjögren’s syndrome. The significance of anti-HIV antibodies in some patients with Sjögren’s syndrome has not been determined. It has been suggested that these antibodies may be stimulated by another retrovirus that is related to HIV, or that they may represent cross-reacting autoantibodies.
Epstein-Barr virus has been demonstrated in the salivary gland tissue of patients with Sjögren’s syndrome. However, this virus has also been found in the salivary glands of normal individuals, thus weakening the contention that Epstein-Barr virus has a primary role in causing this condition. If Epstein-Barr virus is involved, its role is likely secondary in nature.
Initial steps in the development of disease involve parenchymal vascular endothelium, acinar cells, and mesenchymal elements, including dendritic cells, by way of type 1 interferon production, allowing homing and long-term retention and localization of organ-specific lymphocytes in the area. Alterations of out-in messaging between stroma and epithelial elements by way of stromal metalloproteinase activity are also believed to play an important role in the early phases of pathogenesis, as well as in apoptosis of acinar cells via FAS-FAS ligand interaction, granzyme A formation, elaboration of perforin, and engagement of Toll receptors and interferon production. The net result of cell surface and acinar cell perturbation may relate to membrane dysfunction by way of aquaporin transport alteration, whereby water channel transport may be permanently altered.
Sjögren’s syndrome occurs in all ethnic and racial groups. The peak age of onset is 50 years, and 90% of cases occur in women. Children and teenagers are rarely affected. Distinguishing between primary and secondary forms of the syndrome, especially those associated with rheumatoid arthritis, usually is not difficult. This may be important because of increased risk that lymphoreticular malignancy (low-grade CD20+ extranodal marginal zone B-cell non-Hodgkin’s lymphoma in 70% of cases, and other lymphoma variants in the remaining 30%) may develop in the primary form in approximately 5% of patients. The MALT1 gene demonstrates the specific translocations t(11;18)(q21;q21) and (t14;18)(q32;q21) in up to 26% of cases. Lymphoma is considered a late development during the course of the syndrome, occurring from 7.5 to 14 years after disease onset. Often presaging or predicting the development of malignancy are parotid enlargement, lymphadenopathy, inflammatory neuropathy, and vasculitis. Subsequent lymphoma is further characterized by the presence of cryoglobulinemia and serum or urinary monoclonal proteins.
The chief oral complaint in Sjögren’s syndrome is xerostomia, which may be the source of eating and speaking difficulties. These patients are also at greater risk for dental caries, periodontal disease, and oral candidiasis caused by dry mouth. Parotid gland enlargement, which is often recurrent and symmetric, occurs in approximately 50% of patients (Figure 8-12). A significant percentage of these patients also present with complaints of arthralgia, myalgia, and fatigue.
The salivary component of Sjögren’s syndrome may be assessed by sialochemical studies, nuclear imaging of the glands (scintigraphy), contrast sialography, flow rate analysis, and a minor salivary gland biopsy. The most commonly used and most reliable method of assessing salivary alteration in this syndrome is a labial salivary gland biopsy.
Nuclear medicine techniques using a technetium pertechnetate isotope and subsequent scintiscanning can yield functional information relative to uptake of the isotope by salivary gland tissue. Contrast sialography aids in detecting filling defects within the gland being examined. A punctate sialectasia is characteristic in individuals with Sjögren’s syndrome. This latter finding reflects significant ductal and acinar damage, with only the interlobular ducts remaining in cases of moderate to advanced disease. Over time, with further parenchymal and ductal damage, focal areas of narrowing or stenosis of larger ducts takes place and may be seen on a sialogram. Other forms of sialectasia, including globular and cavitary types, may be noted.
Other laboratory findings commonly found in primary and secondary Sjögren’s syndrome include mild anemia, leukopenia, eosinophilia, an elevated ESR, and diffuse elevation of serum immunoglobulin levels. In addition, numerous autoantibodies may be found, including rheumatoid factor, antinuclear antibodies, and precipitating antinuclear antibodies such as anti–Sjögren’s syndrome-A (SS-A) and anti–Sjögren’s syndrome-B (SS-B). Antibodies SS-A and SS-B may be seen in association with both primary and secondary Sjögren’s syndrome. Patients who have SS-B antibodies are more likely to develop extraglandular disease.
In the secondary form of Sjögren’s syndrome, rheumatoid arthritis is the most common systemic autoimmune disease, although systemic lupus erythematosus is not infrequently encountered (Box 8-6). Less commonly, diseases such as scleroderma, primary biliary cirrhosis, polymyositis, vasculitis, parotitis, and chronic active hepatitis may be associated with secondary Sjögren’s syndrome.
Immunogenetic typing studies have indicated statistically significant expression of various histocompatibility antigens in patients with primary and secondary forms of the syndrome. HLA-DR4 antigen is often identified in patients with secondary Sjögren’s syndrome; antigens found in patients with the primary form include HLA-B8 and HLA-DR3 types.
In individuals with Sjögren’s syndrome, a benign lymphocytic infiltrate replaces major salivary gland parenchyma. The initial lesion is focal periductal aggregation of lymphocytes and occasionally plasma cells. As inflammatory foci enlarge, a corresponding level of acinar degeneration is seen (Figures 8-13 and 8-14). With increasing lymphocytic infiltration, confluence of inflammatory foci occurs. Epimyoepithelial islands are present in major glands in approximately 40% of cases and are only rarely seen in minor glands. A positive correlation in the pattern and extent of infiltration between labial salivary glands and submandibular and parotid glands is noted in patients with Sjögren’s syndrome.
An objective grading system has been developed for assessing the salivary component (lymphocytic sialadenitis) of Sjögren’s syndrome in labial salivary gland biopsy specimens. A glandular area that contains 50 or more lymphocytes is designated as a focus. More than one focus in 4 mm2 is regarded as consistent with the salivary component of Sjögren’s syndrome. Interpretation of labial gland biopsy specimens should be done with the knowledge that infiltrates may be seen both in normal glands and in glands that are inflamed for other reasons, including myasthenia gravis, bone marrow transplantation, other connective tissue diseases, and obstructive phenomena.
Diagnosis depends on the correlation between patient history and laboratory data, clinical examination, and assessment of salivary function. An important consideration concerns the clinical manifestation of xerostomia. Although this is the main oral symptom and clinical sign in Sjögren’s syndrome, other considerations of dry mouth must be evaluated. In addition, major salivary gland enlargement is a feature of Sjögren’s syndrome, but it may be episodic in nature and may not be present at all in some patients. Sialographic and salivary scintigraphic findings generally are not specific and should be incorporated into other clinical and laboratory studies, including a minor salivary gland biopsy, as one considers the diagnosis of Sjögren’s syndrome.
Sjögren’s syndrome and the complication of the sicca component are best managed symptomatically. Artificial saliva and oral lubricants as well as artificial tears are available for this purpose. Preventive oral measures are extremely important relative to xerostomia. Scrupulous oral hygiene, dietary modification, topical fluoride therapy, and remineralizing solutions are important in maintaining oral and dental tissues. Use of sialagogues, such as pilocarpine and cevimeline, remains of limited value, especially in long-standing Sjögren’s syndrome. Dietary considerations also are important, whereby the patient must avoid intake of caffeine-containing drinks and foods and limit consumption of cariogenic foods and drinks.
The prognosis of Sjögren’s syndrome is complicated by an association with malignant transformation to lymphoma. This may occur in approximately 5% of cases, but it is more common in those with only the sicca component of the syndrome (primary Sjögren’s syndrom/>