Salivary Gland Pathology

CLINICAL AND RADIOGRAPHIC FEATURES: Salivary gland aplasia has been reported more frequently in men than women by a 2:1 ratio. Some individuals are affected by agenesis of all four of the largest glands (both parotids and submandibular glands), but others may be missing only one to three of the four glands. In spite of the absence of the glands, the face still has a normal appearance because the sites are filled in by fat or connective tissue. Intraorally, the orifices of the missing glands are absent.

As would be anticipated, the most significant symptom associated with salivary gland aplasia is severe xerostomia with its attendant problems (see page 464). The tongue may appear leathery, and the patient is at greater risk for developing dental caries and erosion (Fig. 11-1). However, some degree of moisture still may be present because of the continued activity of the minor salivary glands. Absence of the major glands can be confirmed by technetium-99m pertechnetate scintiscan, computed tomography (CT), or magnetic resonance imaging (MRI).

LADD syndrome is an autosomal dominant disorder that is caused by mutations in the fibroblast growth factor 10 (FGF10) gene. It is characterized by aplasia or hypoplasia of the lacrimal and salivary glands, cup-shaped ears, and dental and digital anomalies. Dental features may include hypodontia, microdontia, and mild enamel hypoplasia.

TREATMENT AND PROGNOSIS: Patient management is directed toward compensating for the saliva deficiency, and saliva substitutes are often necessary. If any residual functional salivary gland tissue is present, then sialagogue medications such as pilocarpine or cevimeline may be used to increase saliva production. Salivary flow also may be stimulated via the use of sugarless gum or sour candy. Regular preventive dental care is important to avoid xero-stomia-related caries and enamel breakdown.

CLINICAL FEATURES: Mucoceles typically appear as dome-shaped mucosal swellings that can range from 1 or 2 mm to several centimeters in size (Figs. 11-2 to 11-4). They are most common in children and young adults, perhaps because younger people are more likely to experience trauma that induces mucin spillage. However, mucoceles have been reported in patients of all ages, including infants and older adults. The spilled mucin below the mucosal surface often imparts a bluish translucent hue to the swelling, although deeper mucoceles may be normal in color. The lesion characteristically is fluctuant, but some mucoceles feel firmer to palpation. The reported duration of the lesion can vary from a few days to several years; most patients report that the lesion has been present for several weeks. Many patients relate a history of a recurrent swelling that periodically may rupture and release its fluid contents.

The lower lip is by far the most common site for the mucocele; a recent large study of 1824 cases found that 81% occurred at this one site (Table 11-1). Lower lip mucoceles usually are found lateral to the midline. Less common sites include the floor of mouth (ranulas: 5.8%), anterior ventral tongue (from the glands of Blandin-Nuhn: 5.7%), buccal mucosa (4.7%), palate (1.4%), and retromolar pad (0.5%). Mucoceles rarely develop on the upper lip. In the large series summarized in Table 11-1, not a single example was identified from the upper lip. This is in contrast to salivary gland tumors, which are not unusual in the upper lip but are distinctly uncommon in the lower lip.

As noted, the soft palate and retromolar area are uncommon sites for mucoceles. However, one interesting variant, the superficial mucocele, does develop in these areas and along the posterior buccal mucosa. Superficial mucoceles present as single or multiple tense vesicles that measure 1 to 4 mm in diameter (Fig. 11-5). The lesions often burst, leaving shallow, painful ulcers that heal within a few days. Repeated episodes at the same location are not unusual. Some patients relate the development of the lesions to mealtimes. Superficial mucoceles also have been reported to occur in association with lichenoid disorders, such as lichen planus, lichenoid drug eruptions, and chronic graft-versus-host disease (GVHD). The vesicular appearance is created by the superficial nature of the mucin spillage, which causes a separation of the epithelium from the connective tissue. The pathologist must be aware of this lesion and should not mistake it microscopically for a vesiculobullous disorder, especially mucous membrane (cicatricial) pemphigoid.

HISTOPATHOLOGIC FEATURES: On microscopic examination, the mucocele shows an area of spilled mucin surrounded by a granulation tissue response (Figs. 11-6 and 11-7). The inflammation usually includes numerous foamy histiocytes (macrophages). In some cases a ruptured salivary duct may be identified feeding into the area. The adjacent minor salivary glands often contain a chronic inflammatory cell infiltrate and dilated ducts.

TREATMENT AND PROGNOSIS: Some mucoceles are short-lived lesions that rupture and heal by themselves. Many lesions, however, are chronic in nature, and local surgical excision is necessary. To minimize the risk of recurrence, the surgeon should remove any adjacent minor salivary glands that may be feeding into the lesion when the area is excised. The excised tissue should be submitted for microscopic examination to confirm the diagnosis and rule out the possibility of a salivary gland tumor. The prognosis is excellent, although occasional mucoceles will recur, necessitating reexcision, especially if the feeding glands are not removed.

RANULA: Ranula is a term used for mucoceles that occur in the floor of the mouth. The name is derived from the Latin word rana, which means “frog,” because the swelling may resemble a frog’s translucent underbelly. The term ranula also has been used to describe other similar swellings in the floor of the mouth, including true salivary duct cysts, dermoid cysts, and cystic hygromas. However, the term is best used for mucus escape reactions (mucoceles). The source of mucin spillage is usually from the sublingual gland, but ranulas also may arise from the submandibular duct or, possibly, from minor salivary glands in the floor of the mouth. Larger ranulas usually arise from the body of the sublingual gland, although smaller lesions can develop along the sublingual plica from the superficial ducts of Rivini of this gland.

CLINICAL FEATURES: The ranula usually appears as a blue, dome-shaped, fluctuant swelling in the floor of the mouth (Fig. 11-8), but deeper lesions may be normal in color. Ranulas are seen most frequently in children and young adults. They tend to be larger than mucoceles in other oral locations, often developing into large masses that fill the floor of the mouth and elevate the tongue. The ranula usually is located lateral to the midline, a feature that may help to distinguish it from a midline dermoid cyst (see page 33). Like other mucoceles, ranulas may rupture and release their mucin contents, only to re-form.

An unusual clinical variant, the plunging or cervical ranula, occurs when the spilled mucin dissects through the mylohyoid muscle and produces swelling within the neck (Fig. 11-9). A concomitant swelling in the floor of the mouth may or may not be present. If no lesion is produced in the mouth, then the clinical diagnosis of ranula may not be suspected. Imaging studies can be helpful in supporting a diagnosis of plunging ranula and in determining the origin of the lesion. CT and MRI images of plunging ranulas that arise from the sublingual gland often exhibit a slight extension of the lesion into the sublingual space (“tail sign”)—an imaging feature not observed in lesions that develop from the submandibular gland.

HISTOPATHOLOGIC FEATURES: The microscopic appearance of a ranula is similar to that of a mucocele in other locations. The spilled mucin elicits a granulation tissue response that typically contains foamy histiocytes.

TREATMENT AND PROGNOSIS: Treatment of the ranula consists of removal of the feeding sublingual gland and/or marsupialization. Marsupialization (exteriorization) entails removal of the roof of the intraoral lesion, which often can be successful for small, superficial ranulas associated with the ducts of Rivini. However, marsupialization is often unsuccessful for larger ranulas developing from the body of the sublingual gland, and most authors emphasize that removal of the offending gland is the most important consideration in preventing a recurrence of the lesion. If the gland is removed, then meticulous dissection of the lining of the lesion may not be necessary for the lesion to resolve, even for the plunging ranula.

CLINICAL FEATURES: Salivary duct cysts usually occur in adults and can arise within either the major or minor glands. Cysts of the major glands are most common within the parotid gland, presenting as slowly growing, asymptomatic swellings. Intraoral cysts can occur at any minor gland site, but most frequently they develop in the floor of the mouth, buccal mucosa, and lips (Fig. 11-10). They often look like mucoceles and are characterized by a soft, fluctuant swelling that may appear bluish, depending on the depth of the cyst below the surface. Some cysts may feel relatively firm to palpation. Cysts in the floor of the mouth often arise adjacent to the submandibular duct and sometimes have an amber color.

On rare occasions, patients have been observed to develop prominent ectasia of the excretory ducts of many of the minor salivary glands throughout the mouth. Such lesions have been termed “mucus retention cysts,” although they probably represent multi-focal ductal dilatation. The individual lesions often present as painful nodules that demonstrate dilated ductal orifices on the mucosal surface. Mucus or pus may be expressed from these dilated ducts.

HISTOPATHOLOGIC FEATURES: The lining of the salivary duct cyst is variable and may consist of cuboidal, columnar, or atrophic squamous epithelium surrounding thin or mucoid secretions in the lumen (Fig. 11-11). In contrast, ductal ectasia secondary to salivary obstruction is characterized by oncocytic metaplasia of the epithelial lining. This epithelium often demonstrates papillary folds into the cystic lumen, somewhat reminiscent of a small Warthin tumor (see page 482) but without the prominent lymphoid stroma (Fig. 11-12). If this proliferation is extensive enough, then these lesions sometimes are diagnosed as papillary cystadenoma, although it seems likely that most are not true neoplasms. The individual lesions of patients with multiple “mucus retention cysts” also show prominent oncocytic metaplasia of the epithelial lining.

TREATMENT AND PROGNOSIS: Isolated salivary duct cysts are treated by conservative surgical excision. For cysts in the major glands, partial or total removal of the gland may be necessary. The lesion should not recur.

For rare patients who develop multifocal salivary ductal ectasia (“mucus retention cysts”), local excision may be performed for the more problematic swellings; however, surgical management does not appear feasible or advisable for all of the lesions, which may number as many as 100. In one reported case, systemic erythromycin and chlorhexidine mouth rinses were helpful in relieving pain and reducing drainage of pus. Sialagogue medications also may be helpful in stimulating salivary flow, thereby preventing the accumulation of inspissated mucus within the dilated excretory ducts.

CLINICAL AND RADIOGRAPHIC FEATURES: Sialoliths most often develop within the ductal system of the submandibular gland; the formation of stones within the parotid gland system is distinctly less frequent. The long, tortuous, upward path of the submandibular (Wharton’s) duct and the thicker, mucoid secretions of this gland may be responsible for its greater tendency to form salivary calculi. Sialoliths also can form within the minor salivary glands, most often within the glands of the upper lip or buccal mucosa. Salivary stones can occur at almost any age, but they are most common in young and middle-aged adults.

Major gland sialoliths most frequently cause episodic pain or swelling of the affected gland, especially at mealtime. The severity of the symptoms varies, depending on the degree of obstruction and the amount of resultant backpressure produced within the gland. If the stone is located toward the terminal portion of the duct, then a hard mass may be palpated beneath the mucosa (Fig. 11-13).

Sialoliths typically appear as radiopaque masses on radiographic examination. However, not all stones are visible on standard radiographs (perhaps because of the degree of calcification of some lesions). They may be discovered anywhere along the length of the duct or within the gland itself (Fig. 11-14). Stones in the terminal portion of the submandibular duct are best demonstrated with an occlusal radiograph. On panoramic or periapical radiographs, the calcification may appear superimposed on the mandible and care must be exercised not to confuse it with an intrabony lesion (Fig. 11-15). Multiple parotid stones radiographically can mimic calcified parotid lymph nodes, such as might occur in tuberculosis. Sialography, ultrasound, and CT scanning may be helpful additional imaging studies for sialoliths.

Minor gland sialoliths often are asymptomatic but may produce local swelling or tenderness of the affected gland (Fig. 11-16). A small radiopacity often can be demonstrated with a soft tissue radiograph.

HISTOPATHOLOGIC FEATURES: On gross examination, sialoliths appear as hard masses that are round, oval, or cylindrical. They are typically yellow, although they may be a white or yellow-brown color. Submandibular stones tend to be larger than those of the parotid or minor glands. Sialoliths are usually solitary, although occasionally two or more stones may be discovered at surgery.

Microscopically, the calcified mass exhibits concentric laminations that may surround a nidus of amorphous debris (Fig. 11-17). If the associated duct also is removed, then it often demonstrates squamous, oncocytic, or mucous cell metaplasia. Periductal inflammation is also evident. The ductal obstruction frequently is associated with an acute or chronic sialadenitis of the feeding gland.

TREATMENT AND PROGNOSIS: Small sialoliths of the major glands sometimes can be treated conservatively by gentle massage of the gland in an effort to milk the stone toward the duct orifice. Sialagogues (drugs that stimulate salivary flow), moist heat, and increased fluid intake also may promote passage of the stone. Larger sialoliths usually need to be removed surgically. If significant inflammatory damage has occurred within the feeding gland, then the gland may need to be removed. Minor gland sialoliths are best treated by surgical removal, including the associated gland.

Shock wave lithotripsy (extracorporeal or intracorporeal), salivary gland endoscopy, and radiologically guided basket retrieval are newer techniques that have been shown to be effective in the removal of sialoliths from the major glands. These minimally invasive techniques have low morbidity and may preclude the necessity of gland removal.

CLINICAL AND RADIOGRAPHIC FEATURES: Acute bacterial sialadenitis is most common in the parotid gland and is bilateral in 10% to 25% of cases. The affected gland is swollen and painful, and the overlying skin may be warm and erythematous (Fig. 11-18). An associated low-grade fever and trismus may be present. A purulent discharge often is observed from the duct orifice when the gland is massaged (Fig. 11-19).

Recurrent or persistent ductal obstruction (most commonly caused by sialoliths) can lead to a chronic sialadenitis. Periodic swelling and pain occur within the affected gland, usually developing at mealtime when salivary flow is stimulated. In the submandibular gland, persistent enlargement may develop (Küttner tumor), which is difficult to distinguish from a true neoplasm. Sialography often demonstrates sialectasia (ductal dilatation) proximal to the area of obstruction (Fig. 11-20). In chronic parotitis, Stensen’s duct may show a characteristic sialographic pattern known as “sausaging,” which reflects a combination of dilatation plus ductal strictures from scar formation. Chronic sialadenitis also can occur in the minor glands, possibly as a result of blockage of ductal flow or local trauma.

Subacute necrotizing sialadenitis is a form of salivary inflammation that occurs most commonly in teenagers and young adults. The lesion usually involves the minor salivary glands of the hard or soft palate, presenting as a painful nodule that is covered by intact, erythematous mucosa. Unlike necrotizing sialometaplasia (see page 471), the lesion does not ulcerate or slough necrotic tissue. An infectious or allergic cause has been hypothesized.

HISTOPATHOLOGIC FEATURES: In patients with acute sialadenitis, accumulation of neutrophils is observed within the ductal system and acini. Chronic sialadenitis is characterized by scattered or patchy infiltration of the salivary parenchyma by lymphocytes and plasma cells. Atrophy of the acini is common, as is ductal dilatation. If associated fibrosis is present, then the term chronic sclerosing sialadenitis is used (Fig. 11-21).

Subacute necrotizing sialadenitis is characterized by a heavy mixed inflammatory infiltrate consisting of neutrophils, lymphocytes, histiocytes, and eosinophils. There is loss of most of the acinar cells, and many of the remaining ones exhibit necrosis. The ducts tend to be atrophic and do not show hyperplasia or squamous metaplasia.

TREATMENT AND PROGNOSIS: The treatment of acute sialadenitis includes appropriate antibiotic therapy and rehydration of the patient to stimulate salivary flow. Surgical drainage may be needed if there is abscess formation. Although this regimen is usually sufficient, a 20% to 50% mortality rate has been reported in debilitated patients because of the spread of the infection and sepsis.

The management of chronic sialadenitis depends on the severity of the condition and ranges from conservative therapy to surgical intervention. Initial management often includes antibiotics, analgesics, sialagogues, and glandular massage. Early cases that develop secondary to ductal blockage may respond to removal of the sialolith or other obstruction. However, if sialectasia is present, then the dilated ducts can lead to stasis of secretions and predispose the gland to further sialolith formation. Sialadenoscopy and ductal irrigation are newer techniques that can be used to dilate ductal strictures and to eliminate sialoliths and mucus plugs. Second-line treatment options for chronic parotitis have included ligation of Stensen’s duct, but this method has a high failure rate. Tympanic neurectomy, which results in decreased secretion by the parotid gland via transection of the parasympathetic secretory fibers at the tympanic plexus, produces improvement in 75% of patients with chronic parotitis. If conservative methods cannot control chronic sialadenitis, then surgical removal of the affected gland may be necessary.

Subacute necrotizing sialadenitis is a self-limiting condition that usually resolves within 2 weeks of diagnosis without treatment.

CLINICAL FEATURES: Cheilitis glandularis characteristically occurs on the lower lip, although there are also purported cases involving the upper lip and palate. Affected individuals experience swelling and eversion of the lower lip as a result of hypertrophy and inflammation of the glands (Fig. 11-22). The openings of the minor salivary ducts are inflamed and dilated, and pressure on the glands may produce mucopurulent secretions from the ductal openings. The condition most often has been reported in middle-aged and older men, although cases also have been described in women and children. However, some of the childhood cases may represent other entities, such as exfoliative cheilitis (see page 304).

Historically, cheilitis glandularis has been classified into three types, based on the severity of the disease:

The latter two types represent progressive stages of the disease with bacterial involvement; they are characterized by increasing inflammation, suppuration, ulceration, and swelling of the lip.

HISTOPATHOLOGIC FEATURES: The microscopic findings of cheilitis glandularis are not specific and usually consist of chronic sialadenitis and ductal dilatation. Concomitant dysplastic changes may be observed in the overlying surface epithelium in some cases.

TREATMENT AND PROGNOSIS: The treatment of choice for most cases of persistent cheilitis glandularis associated with actinic damage is vermilionectomy (lip shave), which usually produces a satisfactory cosmetic result. A significant percentage of cases (18% to 35%) have been associated with the development of squamous cell carcinoma of the overlying epithelium of the lip. Because actinic damage has been implicated in many cases of cheilitis glandularis, it is likely that this same solar radiation is responsible for the malignant degeneration.

CLINICAL FEATURES: The excess saliva production typically produces drooling and choking, which may cause social embarrassment. In children with mental retardation or cerebral palsy, the uncontrolled salivary flow may lead to macerated sores around the mouth, chin, and neck that can become secondarily infected. The constant soiling of clothes and bed linens can be a significant problem for the parents and caretakers of these patients.

An interesting type of supersalivation of unknown cause has been termed idiopathic paroxysmal sialorrhea. Individuals with this condition experience short episodes of excessive salivation lasting from 2 to 5 minutes. These episodes are associated with a prodrome of nausea or epigastric pain.

TREATMENT AND PROGNOSIS: Some causes of sialorrhea are transitory or mild, and no treatment is needed. For individuals with increased salivation associated with gastroesophageal reflux disease, medical management of their reflux problem may be beneficial.

For persistent severe drooling, therapeutic intervention may be indicated. Speech therapy can be used to improve neuromuscular control, but patient cooperation is necessary. Anticholinergic medications can decrease saliva production but may produce unacceptable side effects. Transdermal scopolamine has been tried with some success, but it should not be used in children younger than age 10. Intraglandular injection of botulinum toxin has been shown to be successful in reducing salivary secretions, with a duration of action that varies from 6 weeks to 6 months.

Several surgical techniques have been used successfully to control severe drooling in individuals with poor neuromuscular control:

In ductal relocation, the ducts are repositioned posteriorly to the tonsillar fossa, thereby redirecting salivary flow and minimizing drooling. The use of bilateral tympanic neurectomy and sectioning of the chorda tympani destroys parasympathetic innervation to the glands, reducing salivary secretions and possibly inducing xerostomia. However, this procedure also produces a loss of taste to the anterior two thirds of the tongue.

CLINICAL FEATURES: Examination of the patient typically demonstrates a reduction in salivary secretions, and the residual saliva appears either foamy or thick and “ropey.” The mucosa appears dry, and the clinician may notice that the examining gloves stick to the mucosal surfaces. The dorsal tongue often is fissured with atrophy of the filiform papillae (see Fig. 11-1). The patient may complain of difficulty with mastication and swallowing, and they may even indicate that food adheres to the oral membranes during eating. The clinical findings, however, do not always correspond to the patient’s symptoms. Some patients who complain of dry mouth may appear to have adequate salivary flow and oral moistness. Conversely, some patients who clinically appear to have a dry mouth have no complaints. The degree of saliva production can be assessed by measuring both resting and stimulated salivary flow.

There is an increased prevalence of oral candidiasis in patients with xerostomia because of the reduction in the cleansing and antimicrobial activity normally provided by saliva. In addition, these patients are more prone to dental decay, especially cervical and root caries. This problem has been associated more often with radiation therapy, and it is sometimes called radiation-induced caries but more appropriately should be called xerostomia-related caries (see page 296).

TREATMENT AND PROGNOSIS: The treatment of xerostomia is difficult and often unsatisfactory. Artificial salivas are available and may help make the patient more comfortable, as may continuous sips of water throughout the day. In addition, sugarless candy can be used in an effort to stimulate salivary flow. One of the better patient-accepted management approaches includes the use of oral hygiene products that contain lactoperoxidase, lysozyme, and lactoferrin (e.g., Biotene toothpaste and mouth rinse, Oralbalance gel). If the dryness is secondary to the patient’s medication, then discontinuation or dose modification in consultation with the patient’s physician may be considered; a substitute drug can also be tried.

Systemic pilocarpine is a parasympathomimetic agonist that can be used as a sialagogue. At doses of 5 to 10 mg, three to four times daily, it can be an effective promoter of salivary secretion. Excess sweating is a common side effect, but more serious problems, such as increased heart rate and blood pressure, are uncommon. The U.S. Food and Drug Administration (FDA) has also approved cevimeline hydrochloride, an acetylcholine derivative, for use as a sialagogue. Both pilocarpine and cevimeline are contraindicated in patients with narrow-angle glaucoma.

Because of the increased potential for dental caries in patients with xerostomia, frequent dental visits are recommended. Office and daily home fluoride applications can be used to help prevent decay, and chlorhexidine mouth rinses minimize plaque buildup.

BENIGN LYMPHOEPITHELIAL LESION (MYOEPITHELIAL SIALADENITIS): In the late 1800s, Johann von Mikulicz-Radecki described the case of a patient with an unusual bilateral painless swelling of the lacrimal glands and all of the salivary glands. Histopathologic examination of the involved glands showed an intense lymphocytic infiltrate, with features that today are recognized microscopically as the benign lymphoepithelial lesion. This clinical presentation became known as Mikulicz disease, and clinicians began using this term to describe a variety of cases of bilateral parotid and lacrimal enlargement. However, many of these cases were not examples of benign lymphoepithelial lesions microscopically; instead, they represented salivary and lacrimal involvement by other disease processes, such as tuberculosis, sarcoidosis, and lymphoma. These cases of parotid and lacrimal enlargement secondary to other diseases were later recognized as being different and termed Mikulicz syndrome, with the term Mikulicz disease reserved for cases associated with benign lymphoepithelial lesions. However, these two terms have become so confusing and ambiguous that they should no longer be used.

Many cases of so-called Mikulicz disease may be examples of what is now more commonly known as Sjögren syndrome (see page 466). Sjögren syndrome is an autoimmune disease that may produce bilateral salivary and lacrimal enlargement, with microscopic features of benign lymphoepithelial lesion. However, not all benign lymphoepithelial lesions are necessarily associated with the clinical disease complex of Sjögren syndrome.

CLINICAL FEATURES: Most benign lymphoepithelial lesions develop as a component of Sjögren syndrome. Those not associated with Sjögren syndrome are usually unilateral, although occasional bilateral examples are seen. On occasion, benign lymphoepithelial lesions occur in association with other salivary gland pathologic conditions, such as sialoliths and benign or malignant epithelial tumors.

The benign lymphoepithelial lesion most often develops in adults, with a mean age of 50. From 60% to 80% of cases occur in women. Eighty-five percent of cases occur in the parotid gland, with infrequent examples also reported in the submandibular gland and minor salivary glands. The lesion usually appears as a firm, diffuse swelling of the affected gland that sometimes is dramatic in size. It may be asymptomatic or associated with mild pain.

HISTOPATHOLOGIC FEATURES: Microscopic examination of the benign lymphoepithelial lesion shows a heavy lymphocytic infiltrate associated with the destruction of the salivary acini (Fig. 11-23). Germinal centers may or may not be seen. Although the acini are destroyed, the ductal epithelium persists. The ductal cells and surrounding myoepithelial cells become hyperplastic, forming highly characteristic groups of cells, known as epimyoepithelial islands, throughout the lymphoid proliferation. The presence of epimyoepithelial islands once was considered indicative of a benign process, but now it is recognized that these islands also can be found in low-grade salivary lymphomas of the mucosa-associated lymphoid tissue (MALT lymphomas, marginal zone B-cell lymphomas).

TREATMENT AND PROGNOSIS: Although the benign lymphoepithelial lesion fre-quently necessitates surgical removal of the involved gland, the prognosis in most cases is good. However, individuals with benign lymphoepithelial lesions have an increased risk for lymphoma, either within the affected gland or in an extrasalivary site. Although the exact risk is uncertain, one study showed the risk in patients with Sjögren syndrome to be more than 40 times higher than expected in the general population. (The management of patients with Sjögren syndrome is discussed on page 470.)

With the development of modern molecular techniques to assess for gene rearrangements and monoclonality within lymphoid infiltrates, it is now recognized that some lesions originally believed to represent benign lymphoepithelial lesions are actually early-stage MALT lymphomas. Many experts now recognize a spectrum of salivary lymphoid proliferations, which range from benign lymphoepithelial lesions to borderline lesions to frank lymphomas. Because of this, some authors have dropped the term benign from this spectrum and refer to these proliferations only as lymphoepithelial lesions. Fortunately, most MALT lymphomas are low-grade tumors that tend to remain localized with good survival rates. However, occasional tumors transform to higher-grade lymphomas with more aggressive behavior.

In addition, a rare malignant counterpart of this lesion, called a malignant lymphoepithelial lesion or lymphoepithelial carcinoma, represents a poorly differentiated salivary carcinoma with a prominent lymphoid stroma. Most of these lesions have occurred in Inuit and Asian populations and appear to have arisen de novo as carcinomas; however, some cases (especially in non-Inuits) have been reported to develop from a prior benign lymphoepithelial lesion. The Epstein-Barr virus (EBV) has been strongly associated in the cause of malignant lymphoepithelial lesions, especially those cases arising in Inuit and Asian populations. The 5-year survival rate has been reported to range from 70% to 85%.

CLINICAL AND RADIOGRAPHIC FEATURES: Sjögren syndrome is not a rare condition. Although the exact prevalence depends on the clinical criteria used, current estimates place the population prevalence at 0.5%, with a 9:1 female-to-male ratio. It is seen predominantly in middle-aged adults, but rare examples have been described in children. The revised classification criteria suggested by the American-European Consensus Group are shown in Box 11-2.

When the condition is associated with another connective tissue disease, it is called secondary Sjögren syndrome. It can be associated with almost any other autoimmune disease, but the most common associated disorder is rheumatoid arthritis. About 15% of patients with rheumatoid arthritis have Sjögren syndrome. In addition, secondary Sjögren syndrome may develop in 30% of patients with systemic lupus erythematosus (SLE).

The principal oral symptom is xerostomia, which is caused by decreased salivary secretions; however, the severity of this dryness can vary widely from patient to patient. The saliva may appear frothy, with a lack of the usual pooling saliva in the floor of the mouth. Affected patients may complain of difficulty in swallowing, altered taste, or difficulty in wearing dentures. The tongue often becomes fissured and exhibits atrophy of the papillae (Fig. 11-24). The oral mucosa may be red and tender, usually as a result of secondary candidiasis. Related denture sore mouth and angular cheilitis are common. The lack of salivary cleansing action predisposes the patient to dental decay, especially cervical caries.

From one third to one half of patients have diffuse, firm enlargement of the major salivary glands during the course of their disease (Fig. 11-25). This swelling is usually bilateral, may be nonpainful or slightly tender, and may be intermittent or persistent in nature. The greater the severity of the disease, the greater the likelihood of this salivary enlargement. In addition, the reduced salivary flow places these individuals at increased risk for retrograde bacterial sialadenitis.

Although it is not diagnostic, sialographic examination often reveals punctate sialectasia and lack of normal arborization of the ductal system, typically demonstrating a “fruit-laden, branchless tree” pattern (Fig. 11-26). Scintigraphy with radioactive technetium-99m pertechnetate characteristically shows decreased uptake and delayed emptying of the isotope.

The term keratoconjunctivitis sicca describes not only the reduced tear production by the lacrimal glands but also the pathologic effect on the epithelial cells of the ocular surface. As in xerostomia, the severity of xerophthalmia can vary widely from one patient to the next. The lacrimal inflammation causes a decrease of the aqueous layer of the tear film; however, mucin production is normal and may result in a mucoid discharge. Patients often complain of a scratchy, gritty sensation or the perceived presence of a foreign body in the eye. Defects of the ocular surface epithelium develop and can be demonstrated with rose bengal dye. Vision may become blurred, and sometimes there is an aching pain. The ocular manifestations are least severe in the morning on wakening and become more pronounced as the day progresses.

A simple means to confirm the decreased tear secretion is the Schirmer test. A standardized strip of sterile filter paper is placed over the margin of the lower eyelid, between the medial and lateral third of the lid of the unanesthetized eye, so that the tabbed end rests just inside the lower lid. By measuring the length of wetting of the filter paper, tear production can be assessed. Values less than 5 mm (after a 5-minute period) are considered diagnostic of keratoconjunctivitis sicca.

Sjögren syndrome is a systemic disease, and the inflammatory process also can affect various other body tissues. The skin is often dry, as are the nasal and vaginal mucosae. Fatigue is fairly common, and depression sometimes can occur. Other possible associated problems include lymphadenopathy, primary biliary cirrhosis, Raynaud’s phenomenon, interstitial nephritis, interstitial lung fibrosis, vasculitis, and peripheral neuropathies.

LABORATORY VALUES: In patients with Sjögren syndrome, the erythrocyte sedimentation rate is high and serum immunoglobulin (Ig) levels, especially IgG, typically are elevated. A variety of autoantibodies can be produced, and although none of these is specifically diagnostic, their presence can be another helpful clue to the diagnosis. A positive rheumatoid factor (RF) is found in approximately 60% of cases, regardless of whether the patient has rheumatoid arthritis. Antinuclear antibodies (ANAs) are also present in 75% to 85% of patients. Two particular nuclear autoantibodies—anti-SS-A (anti-Ro) and anti-SS-B (anti-La)—may be found, especially in patients with primary Sjögren syndrome. Anti-SS-A antibodies have been detected in approximately 40% of patients, whereas anti-SS-B antibodies have been discovered in about 25% of these individuals. Occasionally, salivary duct autoantibodies also can be demonstrated, usually in secondary Sjögren syndrome. However, because these are infrequent in primary cases, they are believed to occur as a secondary phenomenon (rather than playing a primary role in pathogenesis).

HISTOPATHOLOGIC FEATURES: The basic microscopic finding in Sjögren syndrome is a lymphocytic infiltration of the salivary glands, with destruction of the acinar units. If the major glands are enlarged, then microscopic examination usually shows progression to a lymphoepithelial lesion (see page 466), with characteristic epimyoepithelial islands in a background lymphoid stroma. Lymphocytic infiltration of the minor glands also occurs, although epimyoepithelial islands are rarely seen in this location.

Biopsy of the minor salivary glands of the lower lip has become a useful test in the diagnosis of Sjögren syndrome. A 1.5- to 2.0-cm incision is made on clinically normal lower labial mucosa, parallel to the vermilion border and lateral to the midline, allowing the harvest of five or more accessory glands. These glands then are examined histopathologically for the presence of focal chronic inflammatory aggregates (50 or more lymphocytes and plasma cells). These aggregates should be adjacent to normal-appearing acini and should be found consistently in most of the glands in the specimen. The finding of more than one focus of 50 or more cells within a 4-mm² area of glandular tissue is considered supportive of the diagnosis of Sjögren syndrome (Fig. 11-27). The greater the number of foci (up to 10 or confluent foci) is, the greater is the correlation with this diagnosis. The focal nature of this chronic inflammation among otherwise normal acini is a highly suggestive pattern; in contrast, the finding of scattered inflammation with ductal dilatation and fibrosis (chronic sclerosing sialadenitis) does not support the diagnosis of Sjögren syndrome.

Although labial salivary gland biopsy has become a widely used test in the diagnosis of Sjögren syndrome, it is not 100% reliable. Some patients diagnosed with Sjögren syndrome will show no significant labial gland inflammation; conversely, examination of labial glands removed incidentally from non-Sjögren patients sometimes will show focal lymphocytic infiltrates. Sjögren syndrome patients who smoke have been shown to have a significantly lower frequency of abnormal lymphocytic foci scores in their labial gland specimens. It also is important that a pathologist experienced in the analysis of these specimens examines the labial gland biopsies. One study showed that slightly more than half of labial gland specimens required a revised diagnosis after being reviewed by a second pathologist.

Other authors have advocated incisional biopsy of the parotid gland through a posterior auricular approach instead of a labial salivary gland biopsy. One study has shown this technique to be more sensitive in demonstrating inflammatory changes that support the diagnosis of Sjögren syndrome; however, other authors think that this technique confers no increased benefit over labial gland biopsy. Parotid biopsy may enable the clinician to evaluate an enlarged gland for the development of lymphoma and rule out the possibility of sialadenosis or sarcoidosis.

TREATMENT AND PROGNOSIS: The treatment of the patient with Sjögren syndrome is mostly supportive. The dry eyes are best managed by periodic use of artificial tears. In addition, attempts can be made to conserve the tear film through the use of sealed glasses to prevent evaporation. Sealing the lacrimal punctum at the inner margin of the eyelids also can be helpful by blocking the normal drainage of any lacrimal secretions into the nose.

Artificial salivas are available for the treatment of xerostomia; sugarless candy or gum can help to keep the mouth moist. Symptoms often can be relieved by the use of oral hygiene products that contain lactoperoxidase, lysozyme, and lactoferrin (e.g., Biotene toothpaste and mouth rinse, Oralbalance gel). Sialagogue medications, such as pilocarpine and cevimeline, can be useful to stimulate salivary flow if enough functional salivary tissue still remains. Medications known to diminish secretions should be avoided, if at all possible. Because of the increased risk of dental caries, daily fluoride applications may be indicated in dentulous patients. Antifungal therapy often is needed to treat secondary candidiasis.

Patients with Sjögren syndrome have an increased risk for lymphoma, up to 40 times higher than the normal population. These tumors may arise initially within the salivary glands or within lymph nodes. With the advent of modern molecular pathology techniques to detect B-cell monoclonality (e.g., in situ hybridization, polymerase chain reaction [PCR]), many salivary gland infiltrates formerly thought to represent benign lymphoepithelial lesions are now being diagnosed as lymphomas. These tumors are predominantly low-grade non-Hodgkin’s B-cell lymphomas of the mucosa-associated lymphoid tissue (i.e., MALT lymphomas), although occasionally, high-grade MALT lymphomas can develop that demonstrate more aggressive behavior. The detection of immunoglobulin gene rearrangements in labial salivary gland biopsies may prove to be a useful marker for predicting the development of lymphoma.

CLINICAL AND RADIOGRAPHIC FEATURES: Sialadenosis usually appears as a slowly evolving swelling of the parotid glands, which may or may not be painful (Fig. 11-28). The condition is usually bilateral, but it also can be unilateral. In some patients, the submandibular glands may be affected, but involvement of minor salivary glands is distinctly rare. Decreased salivary secretion may occur. Sialography demon-strates a “leafless tree” pattern, which is thought to be caused by compression of the finer ducts by hypertrophic acinar cells.

HISTOPATHOLOGIC FEATURES: Microscopic examination reveals hypertrophy of the acinar cells, sometimes two to three times greater than normal size. The nuclei are displaced to the cell base, and the cytoplasm is engorged with zymogen granules. In cases associated with long-standing diabetes or alcoholism, there may be acinar atrophy and fatty infiltration. Significant inflammation is not observed.

TREATMENT AND PROGNOSIS: The clinical management of sialadenosis is often unsatisfactory because it is closely related to the control of the underlying cause. Mild examples may cause few pro-blems. If the swelling becomes a cosmetic concern, then partial parotidectomy can be performed. Pilocarpine recently has been reported to be beneficial in reducing salivary gland enlargement in bulimic patients.

CLINICAL FEATURES: Adenomatoid hyperplasia is a rare lesion of the minor salivary glands characterized by localized swelling that mimics a neoplasm. This pseudotumor most often occurs on the hard or soft palate, although it also has been reported in other oral minor salivary gland sites. The pathogenesis of adenomatoid hyperplasia is uncertain, but it has been speculated that local trauma may play a role. It is most common in the fourth to sixth decades of life. Most examples present as sessile, painless masses that may be soft or firm to palpation. They usually are normal in color, although a few lesions are red or bluish.

HISTOPATHOLOGIC FEATURES: Microscopic examination demonstrates lobular aggregates of relatively normal-appearing mucous acini that are greater in number than normally would be found in the area. These glands also sometimes appear to be increased in size. In some instances, the glands are situated close to the mucosal surface. Chronic inflammation occasionally is seen, but it usually is mild and localized.

TREATMENT AND PROGNOSIS: Because the clinical presentation of adenomatoid hyperplasia mimics a tumor, biopsy is necessary to establish the diagnosis. Once the diagnosis has been established, no further treatment is indicated and the lesion should not recur.

CLINICAL FEATURES: Necrotizing sialometaplasia most frequently develops in the palatal salivary glands; more than 75% of all cases occur on the posterior palate. The hard palate is affected more often than the soft palate. About two thirds of palatal cases are unilateral, with the rest being bilateral or midline in location. Necrotizing sialometaplasia also has been reported in other minor salivary gland sites and, occasionally, in the parotid gland. The submandibular and sublingual glands are rarely affected. Although it can occur at almost any age, necrotizing sialometaplasia is most common in adults; the mean age of onset is 46 years. Males are affected nearly twice as often as females.

The condition appears initially as a nonulcerated swelling, often associated with pain or paresthesia (Fig. 11-29). Within 2 to 3 weeks, necrotic tissue sloughs out, leaving a craterlike ulcer that can range from less than 1 cm to more than 5 cm in diameter (Fig. 11-30). The patient may report that “a part of my palate fell out.” At this point, the pain often subsides. In rare instances, there can be destruction of the underlying palatal bone.

HISTOPATHOLOGIC FEATURES: The microscopic appearance of necrotizing sialometaplasia is characterized by acinar necrosis in early lesions, followed by associated squamous metaplasia of the salivary ducts (Fig. 11-31). Although the mucous acinar cells are necrotic, the overall lobular architecture of the involved glands is still preserved—a helpful histopathologic clue. There may be liberation of mucin, with an associated inflammatory response. The squamous metaplasia of the salivary ducts can be striking and produce a pattern that is easily misdiagnosed as squamous cell carcinoma or mucoepidermoid carcinoma. The frequent association of pseudoepitheliomatous hyperplasia of the overlying epithelium may further compound this mistaken impression. In most cases, however, the squamous proliferation has a bland cytologic appearance.

TREATMENT AND PROGNOSIS: Because of the worrisome clinical presentation of necrotizing sialometaplasia, biopsy usually is indicated to rule out the possibility of malignant disease. Once the diagnosis has been established, no specific treatment is indicated or necessary. The lesion typically resolves on its own accord, with an average healing time of 5 to 6 weeks.

CLINICAL AND RADIOGRAPHIC FEATURES: Regardless of the site of origin, the pleomorphic adenoma typically appears as a painless, slowly growing, firm mass (Figs. 11-32 to 11-34). The patient may be aware of the lesion for many months or years before seeking a diagnosis. The tumor can occur at any age but is most common in young and middle-aged adults between the ages of 30 and 60. Pleomorphic adenoma is also the most common primary salivary gland tumor to develop during childhood. There is a slight female predilection.

Most pleomorphic adenomas of the parotid gland occur in the superficial lobe and present as a swelling overlying the mandibular ramus in front of the ear. Facial nerve palsy and pain are rare. Initially, the tumor is movable but becomes less mobile as it grows larger. If neglected, then the lesion can grow to grotesque proportions. About 10% of parotid mixed tumors develop within the deep lobe of the gland beneath the facial nerve (Fig. 11-35). Sometimes these lesions grow in a medial direction between the ascending ramus and stylomandibular ligament, resulting in a dumbbell-shaped tumor that appears as a mass of the lateral pharyngeal wall or soft palate. On rare occasions, bilateral pleomorphic adenomas of the parotid glands have been reported, developing in either a synchronous or metachronous fashion.

The palate is the most common site for minor gland mixed tumors, accounting for approximately 50% of intraoral examples. This is followed by the upper lip (27%) and buccal mucosa (17%). Palatal tumors almost always are found on the posterior lateral aspect of the palate, presenting as smooth-surfaced, dome-shaped masses (Figs. 11-36 and 11-37). If the tumor is traumatized, then secondary ulceration may occur. Because of the tightly bound nature of the hard palate mucosa, tumors in this location are not movable, although those in the lip or buccal mucosa frequently are mobile.

HISTOPATHOLOGIC FEATURES: The pleomorphic adenoma is typically a well-circumscribed, encapsulated tumor (Fig. 11-38). However, the capsule may be incomplete or show infiltration by tumor cells. This lack of complete encapsulation is more common for minor gland tumors, especially along the superficial aspect of palatal tumors beneath the epithelial surface.

The tumor is composed of a mixture of glan-dular epithelium and myoepithelial cells within a mesenchyme-like background. The ratio of the epithelial elements and the mesenchyme-like component is highly variable among different tumors. Some tumors may consist almost entirely of background “stroma.” Others are highly cellular with little background alteration.

The epithelium often forms ducts and cystic structures or may occur as islands or sheets of cells. Keratinizing squamous cells and mucus-producing cells also can be seen. Myoepithelial cells often make up a large percentage of the tumor cells and have a variable morphology, sometimes appearing angular or spindled. Some myoepithelial cells are rounded and demonstrate an eccentric nucleus and eosinophilic hyalinized cytoplasm, thus resembling plasma cells (Fig. 11-39). These characteristic plasmacytoid myoepithelial cells are more prominent in tumors arising in the minor glands.

The highly characteristic “stromal” changes are believed to be produced by the myoepithelial cells. Extensive accumulation of mucoid material may occur between the tumor cells, resulting in a myxomatous background (Fig. 11-40). Vacuolar degeneration of cells in these areas can produce a chondroid appearance (Fig. 11-41). In many tumors, the stroma exhibits areas of an eosinophilic, hyalinized change (Fig. 11-42). At times, fat or osteoid also is seen.

Occasionally, salivary tumors are seen that are composed almost entirely of myoepithelial cells with no ductal elements. Such tumors often are called myoepitheliomas, although they probably represent one end of the spectrum of mixed tumors.

TREATMENT AND PROGNOSIS: Pleomorphic adenomas are best treated by surgical excision. For lesions in the superficial lobe of the parotid gland, superficial parotidectomy with identification and preservation of the facial nerve is recommended. Local enucleation should be avoided because the entire tumor may not be removed or the capsule may be violated, resulting in seeding of the tumor bed. For tumors of the deep lobe of the parotid, total parotidectomy is usually necessary, also with preservation of the facial nerve, if possible. Submandibular tumors are best treated by total removal of the gland with the tumor. Tumors of the hard palate usually are excised down to periosteum, including the overlying mucosa. In other oral sites the lesion often enucleates easily through the incision site.

With adequate surgery the prognosis is excellent, with a cure rate of more than 95%. The risk of recurrence appears to be lower for tumors of the minor glands. Conservative enucleation of parotid tumors often results in recurrence, with management of these cases made difficult as a result of multifocal seeding of the primary tumor bed. In such cases, multiple recurrences are not unusual. Tumors with a predominantly myxoid appearance are more susceptible to recur than those with other microscopic patterns.

Malignant degeneration is a potential complication, resulting in a carcinoma ex pleomorphic adenoma (see page 492). The risk of malignant transformation is probably small, but it may occur in as many as 5% of all cases.

CLINICAL FEATURES: The oncocytoma is predominantly a tumor of older adults, with a peak prevalence in the eighth decade of life. A slight female predilection has been observed but may not be significant. Oncocytomas occur primarily in the major salivary glands, especially the parotid gland, which accounts for about 85% to 90% of all cases. Oncocytomas of the minor salivary glands are exceedingly rare.

The tumor appears as a firm, slowly growing, painless mass that rarely exceeds 4 cm in diameter. Parotid oncocytomas usually are found in the superficial lobe and are clinically indistinguishable from other benign tumors. On occasion, bilateral tumors can occur, although these may represent examples of multinodular oncocytic hyperplasia (oncocytosis).

HISTOPATHOLOGIC FEATURES: The oncocytoma is usually a well-circumscribed tumor that is composed of sheets of large polyhedral cells (oncocytes), with abundant granular, eosinophilic cytoplasm (Fig. 11-43). Sometimes these cells form an alveolar or glandular pattern. The cells have centrally located nuclei that can vary from small and hyperchromatic to large and vesicular. Little stroma is present, usually in the form of thin fibrovascular septa. An associated lymphocytic infiltrate may be noted.

The granularity of the cells corresponds to an overabundance of mitochondria, which can be demonstrated by electron microscopy. These granules also can be identified on light microscopic examination with a phosphotungstic acid hematoxylin (PTAH) stain. The cells also contain glycogen, as evidenced by their positive staining with the periodic acid-Schiff (PAS) technique but by negative PAS staining after digestion with diastase.

Oncocytomas may contain variable numbers of cells with a clear cytoplasm. In rare instances, these clear cells may compose most of the lesion and create difficulty in distinguishing the tumor from low-grade salivary clear cell adenocarcinoma or metastatic renal cell carcinoma.

TREATMENT AND PROGNOSIS: Oncocytomas are best treated by surgical excision. In the parotid gland, this usually entails partial parotidectomy (lobectomy) to avoid violation of the tumor capsule. The facial nerve should be preserved whenever possible. For tumors in the submandibular gland, treatment consists of total removal of the gland. Oncocytomas of the oral minor salivary glands should be removed with a small margin of normal surrounding tissue.

The prognosis after removal is good, with a low rate of recurrence. However, oncocytomas of the sinonasal glands can be locally aggressive and have been considered to be low-grade malignancies. Rare examples of histopathologically malignant oncocytomas (oncocytic carcinoma) also have been reported. These carcinomas have a relatively poor prognosis.

CLINICAL FEATURES: Oncocytosis is found primarily in the parotid gland; however, in rare instances, it may involve the submandibular or minor salivary glands. It can be an incidental finding in otherwise normal salivary gland tissue, but it may be extensive enough to produce clinical swelling. Usually the proliferation is multifocal and nodular, but sometimes the entire gland can be replaced by oncocytes (diffuse hyperplastic oncocytosis). As with other oncocytic proliferations, oncocytosis occurs most frequently in older adults.

HISTOPATHOLOGIC FEATURES: Microscopic examination usually reveals focal nodular collections of oncocytes within the salivary gland tissue. These enlarged cells are polyhedral and demonstrate abundant granular, eosinophilic cytoplasm as a result of the proliferation of mitochondria. On occasion, these cells may have a clear cytoplasm from the accumulation of glycogen (Fig. 11-44). The multifocal nature of the proliferation may be confused with that of a metastatic tumor, especially when the oncocytes are clear in appearance.

TREATMENT AND PROGNOSIS: Oncocytosis is a benign condition and often is discovered only as an incidental finding. No further treatment is necessary, and the prognosis is excellent.

CLINICAL FEATURES: The Warthin tumor usually appears as a slowly growing, painless, nodular mass of the parotid gland (Fig. 11-45). It may be firm or fluctuant to palpation. The tumor most frequently occurs in the tail of the parotid near the angle of the mandible, and it may be noted for many months before the patient seeks a diagnosis. One unique feature is the tendency of Warthin tumor to occur bilaterally, which has been noted in 5% to 17% of reported cases. Most of these bilateral tumors do not occur simultaneously but are metachronous (occurring at different times).

In rare instances, the Warthin tumor has been reported within the submandibular gland or minor salivary glands. However, because the lymphoid component is often less pronounced in these extraparotid sites, the pathologist should exercise caution to avoid overdiagnosis of a lesion better classified as a papillary cystadenoma or a salivary duct cyst with oncocytic ductal metaplasia.

Warthin tumor most often occurs in older adults, with a peak prevalence in the sixth and seventh decades of life. The observed frequency of this tumor is much lower in blacks than in whites. Most studies show a decided male predilection, with some early studies demonstrating a male-to-female ratio up to 10:1. However, more recent investigations show a more balanced sex ratio. Because Warthin tumors have been associated with cigarette smoking, this changing sex ratio may be a reflection of the increased prevalence of smoking in women over the past few decades. This association with smoking also may help explain the frequent bilaterality of the tumor, because any tumorigenic effects of smoking might be manifested in both parotids.

HISTOPATHOLOGIC FEATURES: The Warthin tumor has one of the most distinctive histopathologic patterns of any tumor in the body. Although the term papillary cystadenoma lymphomatosum is cumbersome, it accurately describes the salient microscopic features.

The tumor is composed of a mixture of ductal epithelium and a lymphoid stroma (Figs. 11-46 and 11-47). The epithelium is oncocytic in nature, forming uniform rows of cells surrounding cystic spaces. The cells have abundant, finely granular eosinophilic cytoplasm and are arranged in two layers. The inner luminal layer consists of tall columnar cells with centrally placed, palisaded, and slightly hyperchromatic nuclei. Beneath this is a second layer of cuboidal or polygonal cells with more vesicular nuclei. The lining epithelium demonstrates multiple papillary infoldings that protrude into the cystic spaces. Focal areas of squamous metaplasia or mucous cell prosoplasia may be seen. The epithelium is supported by a lymphoid stroma that frequently shows germinal center formation.

TREATMENT AND PROGNOSIS: Surgical removal is the treatment of choice for patients with Warthin tumor. The procedure usually is easily accomplished because of the superficial location of the tumor. Some surgeons prefer local resection with minimal surrounding tissue; others opt for superficial parotidectomy to avoid violating the tumor capsule and because a tentative diagnosis may not be known preoperatively. A 6% to 12% recurrence rate has been reported. Many authors, however, believe that the tumor is frequently multicentric in nature; therefore, it is difficult to determine whether these are true recurrences or secondary tumor sites. Malignant Warthin tumors (carcinoma ex papillary cystadenoma lymphomatosum) have been reported but are exceedingly rare.

CLINICAL FEATURES: The canalicular adenoma shows a striking predilection for the upper lip, with nearly 75% occurring in this location. It represents the first or second most common tumor (along with pleomorphic adenoma) of the upper lip. The buccal mucosa is the second most common site. Occurrence in other minor salivary glands is uncommon, and canalicular adenomas of the parotid gland are rare.

The tumor nearly always occurs in older adults, with a peak prevalence in the seventh decade of life. There is a definite female predominance, ranging from 1.2 to 1.8 females for each male.

The canalicular adenoma appears as a slowly growing, painless mass that usually ranges from several millimeters to 2 cm (Fig. 11-48). It may be firm or somewhat fluctuant to palpation. The overlying mucosa may be normal in color or bluish and can be mistaken for a mucocele. However, mucoceles of the upper lip are rare. In some instances, the lesion has been noted to be multifocal, with multiple separate tumors discovered in the upper lip or buccal mucosa.

HISTOPATHOLOGIC FEATURES: The microscopic pattern of canalicular adenoma is monomorphic in nature. This pattern is characterized by single-layered cords of columnar or cuboidal epithelial cells with deeply basophilic nuclei (Fig. 11-49). In some areas, adjacent parallel rows of cells may be seen, resulting in a bilayered appearance of the tumor cords. These cells enclose ductal structures, sometimes in the form of long canals. Larger cystic spaces often are created, and the epithelium may demonstrate papillary projections into the cystic lumina. The tumor cells are supported by a loose connective tissue stroma with prominent vascularity. Unlike the appearance in pleomorphic adenomas, stromal alterations, such as chondroid metaplasia, do not occur. A thin, fibrous capsule often surrounds the tumor, although satellite islands are observed in the surrounding salivary gland tissue in approximately 22% to 24% of cases, which explains the tendency for multifocal tumors.

TREATMENT AND PROGNOSIS: The canalicular adenoma is best treated by local surgical excision. Recurrence is uncommon and actually may represent cases that are multifocal in nature.

CLINICAL FEATURES: Unlike the canalicular adenoma, the basal cell adenoma is primarily a tumor of the parotid gland, with around 75% of all cases occurring there. However, the minor glands represent the second most common site, specifically the glands of the upper lip and buccal mucosa. The tumor can occur at any age but is most common in middle-aged and older adults, with a peak prevalence in the seventh decade of life. The tumor appears to be more common in women, with some studies showing as high as a 2:1 female-to-male ratio.

Clinically, the basal cell adenoma appears as a slowly growing, freely movable mass similar to a pleomorphic adenoma. Most tumors are less than 3 cm in diameter. Parotid tumors usually are located within the superficial lobe of the gland.

One subtype, the membranous basal cell adenoma, deserves separate mention. This form of the tumor appears to be hereditary, often occurring in combination with skin appendage tumors, such as dermal cylindromas and trichoepitheliomas. Multiple bilateral tumors may develop within the parotids. Because these tumors often bear a histopathologic resemblance to the skin tumors, they also have been called dermal analogue tumors.

HISTOPATHOLOGIC FEATURES: The basal cell adenoma is usually encapsulated or well circumscribed. The most common subtype is the solid variant, which consists of multiple islands and cords of epithelial cells that are supported by a small amount of fibrous stroma. The peripheral cells of these islands are palisaded and cuboidal to columnar in shape, similar to the microscopic appearance of basal cell carcinoma. These peripheral cells are frequently hyperchromatic; the central cells of the islands tend to have paler staining nuclei. The central cells occasionally form eddies or keratin pearls.

The trabecular subtype demonstrates narrow cordlike epithelial strands (Fig. 11-50). The tubular subtype is characterized by the formation of small, round, ductlike structures. Frequently, a mixture of histopathologic subtypes is seen.

The membranous basal cell adenoma exhibits multiple large lobular islands of tumor that are molded together in a jigsaw puzzle fashion. These islands are surrounded by a thick layer of hyaline material, which represents reduplicated basement membrane. Similar hyaline droplets also are often found among the epithelial cells. The microscopic appearance is similar to that of a dermal cylindroma, one of the skin tumors with which it is often associated.

TREATMENT AND PROGNOSIS: The treatment of basal cell adenoma is similar to that of pleomorphic adenoma and consists of complete surgical removal. Recurrence is rare for most histopathologic subtypes. However, the membranous subtype has a 25% to 37% recurrence rate, possibly related to its multifocal nature.

The malignant counterpart of the basal cell adenoma is the basal cell adenocarcinoma. Most basal cell adenocarcinomas arise de novo, but some examples develop from malignant degeneration of a preexisting basal cell adenoma. Fortunately, these tumors have a relatively good prognosis; although local recurrence is common, the tumor rarely metastasizes or results in death.

CLINICAL FEATURES: The sialadenoma papilliferum most commonly arises from the minor salivary glands, especially on the palate, although it also has been reported in the parotid gland. It usually is seen in older adults and has a 1.5:1.0 male-to-female ratio. The tumor appears as an exophytic, papillary surface growth that is clinically similar to the common squamous papilloma (Fig. 11-51).

The intraductal papilloma is an ill-defined lesion that often has been confused with other salivary gland lesions, such as the papillary cystadenoma. It usually occurs in adults and is most common in the minor salivary glands, where it appears as a submucosal swelling.

The inverted ductal papilloma is a rare tumor that has been described only in the minor salivary glands of adults. The lower lip and mandibular vestibule are the most common locations. The lesion usually ap-pears as an asymptomatic nodule, which sometimes may show a pit or indentation in the overlying surface mucosa (Fig. 11-52).

HISTOPATHOLOGIC FEATURES: At low-power magnification, the sialadenoma papilli-ferum is somewhat similar to the squamous papilloma, exhibiting multiple exophytic papillary projections that are covered by stratified squamous epithelium. This epithelium is contiguous with a proliferation of papillomatous ductal epithelium found below the surface and extending downward into the deeper connective tissues (Fig. 11-53). Multiple ductal lumina are formed, which characteristically are lined by a double-rowed layer of cells consisting of a luminal layer of tall columnar cells and a basilar layer of smaller cuboidal cells. These ductal cells often have an oncocytic appearance. An inflammatory infiltrate of plasma cells, lymphocytes, and neutrophils is characteristically present. Because of their microscopic similarity, this tumor has been considered to be an analogue of the cutaneous syringocystadenoma papilliferum.

The intraductal papilloma exhibits a dilated, unicystic structure that is located below the mucosal surface. It is lined by a single or double row of cuboidal or columnar epithelium, which has multiple arborizing papillary projections into the cystic lumen. In contrast, the inverted ductal papilloma is composed primarily of a proliferation of squamoid epithelium with multiple thick, bulbous papillary projections that fill the ductal lumen (Fig. 11-54). This epithelium may be contiguous with the overlying mucosal epithelium, communicating with the surface through a small porelike opening. Although the tumor is primarily squamous in nature, the luminal lining cells of the papillary projections are often cuboidal or columnar in shape, with scattered mucus-producing cells.

TREATMENT AND PROGNOSIS: All three forms of ductal papilloma are best treated by conservative surgical excision. Recurrence is rare.

CLINICAL FEATURES: Most studies show that the mucoepidermoid carcinoma is the most common malignant salivary gland neoplasm. In the United States, it makes up 10% of all major gland tumors and 15% to 23% of minor gland tumors. However, British studies have shown a much lower relative frequency, with mucoepidermoid carcinoma accounting for only 1% to 2% of major gland neoplasms and 9% of minor gland tumors. Perhaps a true geographic difference exists in the prevalence of this lesion.

The tumor occurs fairly evenly over a wide age range, extending from the second to seventh decades of life. Rarely is it seen in the first decade of life. However, mucoepidermoid carcinoma is the most common malignant salivary gland tumor in children. Some tumors have been associated with a previous history of radiation therapy to the head and neck region.

The mucoepidermoid carcinoma is most common in the parotid gland and usually appears as an asymptomatic swelling. Most patients are aware of the lesion for 1 year or less, although some report a mass of many years’ duration. Pain or facial nerve palsy may develop, usually in association with high-grade tumors. The minor glands constitute the second most common site, especially the palate (Fig. 11-55). Minor gland tumors also typically appear as asymptomatic swellings, which are sometimes fluctuant and have a blue or red color that can be mistaken clinically for a mucocele. Although the lower lip, floor of mouth, tongue, and retromolar pad areas are uncommon locations for salivary gland neoplasia, the mucoepidermoid carcinoma is the most common salivary tumor in each of these sites (Fig. 11-56). Intraosseous tumors also may develop in the jaws (see page 490).

HISTOPATHOLOGIC FEATURES: As its name implies, the mucoepidermoid carcinoma is composed of a mixture of mucus-producing cells and squamous (epidermoid) cells (Figs. 11-57 to 11-59). The mucous cells vary in shape but contain abundant foamy cytoplasm that stains positively with mucin stains. The epidermoid cells are characterized by squamoid features, often demonstrating a polygonal shape, intercellular bridges, and, rarely, keratinization. In addition, a third type of cell—the intermediate cell—is typically present and is believed to be a progenitor of both the mucous and the epidermoid cells. Intermediate cells vary in appearance from small, basaloid (“maternal”) cells to slightly larger ovoid cells with scant, pale eosinophilic cytoplasm. Some tumors also show variable numbers of clear cells, which sometimes can predominate the microscopic picture (Fig. 11-60). An associated lymphoid infiltrate is not unusual and may be so prominent in some cases that the lesion can be mistaken for a metastatic tumor within a lymph node.

Traditionally, mucoepidermoid carcinomas have been categorized into one of three histopathologic grades based on the following:

Low-grade tumors show prominent cyst formation, minimal cellular atypia, and a relatively high proportion of mucous cells. High-grade tumors consist of solid islands of squamous and intermediate cells, which can demonstrate considerable pleomorphism and mitotic activity (Fig. 11-61). Mucus-producing cells may be infrequent, and the tumor sometimes can be difficult to distinguish from squamous cell carcinoma.

Intermediate-grade tumors show features that fall between those of the low-grade and high-grade neoplasms. Cyst formation occurs but is less prominent than that observed in low-grade tumors. All three major cell types are present, but the intermediate cells usually predominate. Cellular atypia may or may not be observed.

However, some authors have found that the relative proportion of the three different cell types does not necessarily correlate with prognosis. To overcome this, two expert groups have proposed evaluation schemes based on significant microscopic parameters, to which relative point values have been assigned to determine the grade of the tumor (Table 11-12).

TREATMENT AND PROGNOSIS: The treatment of mucoepidermoid carcinoma is predicated by the location, histopathologic grade, and clinical stage of the tumor. Early-stage tumors of the parotid often can be treated by subtotal parotidectomy with preservation of the facial nerve. Advanced tumors may necessitate total removal of the parotid gland, with sacrifice of the facial nerve. Submandibular gland tumors are treated by total removal of the gland. Mucoepidermoid carcinomas of the minor glands usually are treated by assured surgical excision. For low-grade neoplasms, only a modest margin of surrounding normal tissue may need to be removed, but high-grade or large tumors warrant wider resection, similar to that required for squamous cell carcinomas. If there is underlying bone destruction, then the involved bone must be excised.

Radical neck dissection is indicated for patients with clinical evidence of metastatic disease and also may be considered for patients with larger or high-grade tumors. Postoperative radiation therapy also may be used for more aggressive tumors.

The prognosis depends on the grade and stage of the tumor. Patients with low-grade tumors generally have a good prognosis. For most primary sites, local recurrences or regional metastases are uncommon, and around 90% to 98% of patients are cured. The prognosis for those with intermediate-grade tumors is slightly worse than that for low-grade tumors. The outlook for patients with high-grade tumors is guarded, with only 30% to 54% of patients surviving.

For unknown reasons, submandibular gland tumors are associated with a poorer outlook than those in the parotid gland. Mucoepidermoid carcinomas of the oral minor salivary glands generally have a good prognosis, probably because they are mostly low- to intermediate-grade tumors. However, tumors of the tongue and floor of the mouth are less predictable and may exhibit more aggressive behavior.

CLINICAL AND RADIOGRAPHIC FEATURES: Intraosseous mucoepidermoid carcinomas are most common in middle-aged adults and demonstrate a slight female predilection. They are three times more common in the mandible than in the maxilla and are most often seen in the molar-ramus area. The most frequent presenting symptom is cortical swelling, although some lesions may be discovered as incidental findings on radiographs. Pain, trismus, and paresthesia are reported less frequently.

Radiographs usually reveal either a unilocular or multilocular radiolucency with well-defined borders (Fig. 11-62). However, some examples are characterized by a more irregular and ill-defined area of bone destruction. Some cases are associated with an unerupted tooth and, therefore, clinically may suggest an odontogenic cyst or tumor.

HISTOPATHOLOGIC FEATURES: The microscopic appearance of intraosseous mucoepidermoid carcinoma is similar to that of its soft tissue counterpart. Most tumors are low-grade lesions, although high-grade mucoepidermoid carcinomas also have been reported within the jaws.

TREATMENT AND PROGNOSIS: The primary treatment modality for patients with intraosseous mucoepidermoid carcinoma is surgery; adjunctive radiation therapy also sometimes is used. Radical surgical resection offers a better chance for cure than do more conservative procedures, such as enucleation or curettage. The local recurrence rate with conservative treatment is 40%, in contrast to 13% for more radical treatment. Metastasis has been reported in about 12% of cases. The overall prognosis is fairly good; around 10% of patients die, usually as a result of local recurrence of the tumor.

CLINICAL FEATURES: Around 85% of all acinic cell adenocarcinomas occur in the parotid gland, a logical finding because this is the largest gland and one that is composed entirely of serous elements (Fig. 11-63). Most surveys have shown that this neoplasm makes up 1% to 3% of all parotid tumors, although one study showed it represented 8.6% of all parotid tumors (see Table 11-4). It is much less common in the submandibular gland, which is the site for only 2.7% to 4% of these tumors. About 9% of all acinic cell adenocarcinomas develop in the oral minor salivary glands, with the buccal mucosa, lips, and palate being the most common sites (Fig. 11-64). Overall, around 2% to 6.5% of all minor salivary gland tumors are acinic cell adenocarcinomas.

The tumor occurs over a broad age range, with a relatively even peak prevalence stretching from the second to the seventh decades of life; the mean age is in the middle 40s. Approximately 60% of cases occur in women. The tumor usually appears as a slowly growing mass, and the lesion often is present for many months or years before a diagnosis is made. The tumor may be otherwise asymptomatic, although associated pain or tenderness sometimes is reported. Facial nerve paralysis is an infrequent but ominous sign for parotid tumors.

HISTOPATHOLOGIC FEATURES: Acinic cell adenocarcinomas are highly variable in their microscopic appearance. The tumor often is well circumscribed and sometimes may even appear encapsulated; however, some tumors exhibit an infiltrative growth pattern. The most characteristic cell is one with features of the serous acinar cell, with abundant granular basophilic cytoplasm and a round, darkly stained eccentric nucleus. These cells are fairly uniform in appearance, and mitotic activity is uncommon. Other cells may resemble intercalated duct cells, and some tumors also have cells with a clear, vacuolated cytoplasm.

Several growth patterns may be seen. The solid variety consists of numerous well-differentiated acinar cells arranged in a pattern that resembles normal parotid gland tissue (Figs. 11-65 and 11-66). In the microcystic variety, multiple small cystic spaces are created that may contain some mucinous or eosinophilic material. In the papillary-cystic variety, larger cystic areas are formed that are lined by epithelium having papillary projections into the cystic spaces (Fig. 11-67). The follicular variety has an appearance similar to that of thyroid tissue. A lymphoid infiltrate, sometimes with germinal center formation, is not unusual.

TREATMENT AND PROGNOSIS: Acinic cell adenocarcinomas confined to the superficial lobe of the parotid gland are best treated by lobectomy; for those in the deep lobe, total parotidectomy is usually necessary. The facial nerve may need to be sacrificed if it is involved by tumor. Submandibular tumors are managed by total removal of the gland, and minor gland tumors are treated with assured surgical excision. Lymph node dissection is not indicated unless there is clinical evidence of metastatic disease. Adjunctive radiation therapy may be considered for uncontrolled local disease.

The acinic cell adenocarcinoma is associated with one of the better prognoses of any of the malignant salivary gland tumors. Approximately one third of patients have recurrences locally, and metastases develop in 10% to 15% of patients. From 6% to 26% of patients die of their disease. The prognosis for minor gland tumors is better than that for tumors arising in the major glands.

CLINICAL FEATURES:

HISTOPATHOLOGIC FEATURES:

TREATMENT AND PROGNOSIS:

CLINICAL AND RADIOGRAPHIC FEATURES: The adenoid cystic carcinoma can occur in any salivary gland site, but approximately 50% to 60% develop within the minor salivary glands. The palate is the most common site for minor gland tumors (Fig. 11-71). The remaining tumors are found mostly in the parotid and submandibular glands, with a fairly even distribution between these two sites. On an individual basis, however, a striking difference can be seen among the various glands. In the parotid gland, the adenoid cystic carcinoma is relatively rare, constituting only 2% to 3% of all tumors. In the submandibular gland, this tumor accounts for 12% to 17% of all tumors and is the most common malignancy. It is also relatively common among palatal salivary neoplasms; it represents 8% to 15% of all such tumors. The lesion is most common in middle-aged adults and is rare in people younger than age 20. There is a fairly equal sex distribution, although some studies have shown a slight female predilection.

The adenoid cystic carcinoma usually appears as a slowly growing mass. Pain is a common and important finding, occasionally occurring early in the course of the disease before there is a noticeable swelling. Patients often complain of a constant, low-grade, dull ache, which gradually increases in intensity. Facial nerve paralysis may develop with parotid tumors. Palatal tumors can be smooth surfaced or ulcerated. Tumors arising in the palate or maxillary sinus often show radiographic evidence of bone destruction (Fig. 11-72).

HISTOPATHOLOGIC FEATURES: The adenoid cystic carcinoma is composed of a mixture of myoepithelial cells and ductal cells that can have a varied arrangement (Fig. 11-73). Three major patterns are recognized: (1) cribriform, (2) tubular, and (3) solid. Usually a combination of these is seen, and the tumor is classified based on the predominant pattern.

The cribriform pattern is the most classic and best-recognized appearance, characterized by islands of basaloid epithelial cells that contain multiple cylindrical, cystlike spaces resembling Swiss cheese. These spaces often contain a mildly basophilic mucoid material, a hyalinized eosinophilic product, or a combined mucoid-hyalinized appearance. Sometimes the hyalinized material also surrounds these cribriform islands (Fig. 11-74), or small strands of tumor are found embedded within this hyalinized “stroma.” The tumor cells are small and cuboidal, exhibiting deeply basophilic nuclei and little cytoplasm. These cells are fairly uniform in appearance, and mitotic activity is rarely seen. The pathologist should be mindful that other salivary tumors, especially polymorphous low-grade adenocarcinoma, also may exhibit areas with a cribriform pattern.

In the tubular pattern, the tumor cells are similar but occur as multiple small ducts or tubules within a hyalinized stroma. The tubular lumina can be lined by one to several layers of cells, and sometimes both a layer of ductal cells and myoepithelial cells can be discerned.

The solid variant consists of larger islands or sheets of tumor cells that demonstrate little tendency toward duct or cyst formation. Unlike the cribriform and tubular patterns, cellular pleomorphism and mitotic activity, as well as focal necrosis in the center of the tumor islands, may be observed.

A highly characteristic feature of adenoid cystic carcinoma is its tendency to show perineural invasion (Fig. 11-75), which probably corresponds to the common clinical finding of pain in these patients. Sometimes the cells appear to have a swirling arrangement around nerve bundles. However, perineural invasion is not pathognomonic for adenoid cystic carcinoma; it also may be seen in other salivary malignancies, especially polymorphous low-grade adenocarcinomas.

Positive immunostaining reactions for CD43 and c-kit (CD117) in adenoid cystic carcinoma have been reported to be useful diagnostic features that can help to distinguish this tumor from polymorphous low-grade adenocarcinoma, basal cell adenoma, and canalicular adenoma. In addition, the patterns of expression of a variety of other immunohistochemical markers have been suggested to be diagnostically relevant, including stains for vimentin, collagen IV, laminin, integrins, Ki-67, smooth muscle actin, and various cytokeratins.

TREATMENT AND PROGNOSIS: Adenoid cystic carcinoma is a relentless tumor that is prone to local recurrence and eventual distant metas-tasis. Surgical excision is usually the treatment of choice, and adjunct radiation therapy may slightly improve patient survival in some cases. Because metastasis to regional lymph nodes is uncommon, neck dissection typically is not indicated. Because of the poor overall prognosis, regardless of treatment, clinicians should be cautioned against needlessly aggressive and mutilating surgical procedures for large tumors or cases already showing metastases.

Because the tumor is prone to late recurrence and metastasis, the 5-year survival rate has little significance and does not equate to a cure. The 5-year survival rate may be as high as 70%, but this rate continues to decrease over time. The 10-year survival is approximately 50%, and by 20 years, only 25% of patients are still alive. Tumors with a solid histopathologic pattern are associated with a worse outlook than those with a cribriform or tubular arrangement. With respect to site, the prognosis is poorest for tumors arising in the maxillary sinus and submandibular gland. Most studies have shown that microscopic identification of perineural invasion has little effect on the prognosis. Tumor DNA ploidy analysis may help to predict the prognosis of adenoid cystic carcinoma; patients with diploid tumors have been shown to have a significantly better outcome than patients with aneuploid tumors.

Death usually results from local recurrence or distant metastases. Tumors of the palate or maxillary sinus eventually may invade upward to the base of the brain. Metastases occur in approximately 35% of patients, most frequently involving the lungs and bones.

CLINICAL FEATURES: The polymorphous low-grade adenocarcinoma is almost exclusively a tumor of the minor salivary glands. However, rare examples also have been reported in the major glands, either arising de novo or as the malignant component of a carcinoma ex pleomorphic adenoma. Sixty-five percent occur on the hard or soft palate (Fig. 11-76), with the upper lip and buccal mucosa being the next most common locations. It is most common in older adults, having a peak prevalence in the sixth to eighth decades of life. Two thirds of all cases occur in females.

The tumor most often appears as a painless mass that may have been present for a long time with slow growth. Occasionally, it is associated with bleeding or discomfort. Tumor can erode or infiltrate the underlying bone.

HISTOPATHOLOGIC FEATURES: The tumor cells of polymorphous low-grade adenocarcinomas have a deceptively uniform appearance. They are round to polygonal in shape, with indistinct cell borders and pale to eosinophilic cytoplasm. The nuclei may be round, ovoid, or spindled; these nuclei usually are pale staining, although they can be more basophilic in some areas. The cells can exhibit different growth patterns, hence, the polymorphous term. The cells may grow in a solid pattern or form cords, ducts, or larger cystic spaces. In some tumors, a cribriform pattern can be produced that mimics adenoid cystic carcinoma (Fig. 11-77). Mitotic figures are uncommon.

At low power, the tumor sometimes appears well circumscribed. However, the peripheral cells are usually infiltrative, invading the adjacent tissue in a single-file fashion (Fig. 11-78). Extension into underlying bone or skeletal muscle may be observed. The stroma is often mucoid in nature, or it may demonstrate hyalinization. Perineural invasion is common—another feature that may cause the tumor to be mistaken for adenoid cystic carcinoma (Fig. 11-79). However, a distinction between these two tumors is important because of their vastly different prognoses.

Immunohistochemical staining can be helpful in distinguishing polymorphous low-grade adenocarcinoma from other salivary gland tumors that it may mimic. When compared with adenoid cystic carcinoma, polymorphous low-grade adenocarcinoma exhibits significantly weaker expression of CD43 and c-kit (CD117). Likewise, lack of staining for glial fibrillary acidic protein (GFAP) can help to differentiate this tumor from pleomorphic adenoma, which is almost always strongly positive for GFAP.

TREATMENT AND PROGNOSIS: The polymorphous low-grade adenocarcinoma is best treated by wide surgical excision, sometimes including resection of the underlying bone. Metastasis to regional lymph nodes is relatively uncommon, occurring in just under 10% of patients. Therefore, neck dissection seems unwarranted unless there is clinical evidence of cervical metastases. Distant metastasis is rare.

The overall prognosis is relatively good. Recurrent disease has been reported in 9% to 17% of all patients, but this usually can be controlled with reexcision. Death from tumor is rare but may occur secondary to direct extension into vital structures. Microscopic identification of perineural invasion does not appear to affect the prognosis.

CLINICAL AND HISTOPATHOLOGIC FEATURES: Because these adenocarcinomas represent such a diverse group of neoplasms, it is difficult to generalize about their clinical and microscopic features. Like most salivary tumors, they appear to be most common in the parotid gland, followed by the minor glands and the submandibular gland (Figs. 11-80 and 11-81). They may present as asymptomatic masses or cause pain or facial nerve paralysis. The microscopic appearance is highly variable but demonstrates features of a glandular malignancy with evidence of cellular pleomorphism, an infiltrative growth pattern, or both. These tumors exhibit a wide spectrum of differentiation, ranging from well-differentiated, low-grade neoplasms to poorly differentiated, high-grade malignancies.

As these tumors are studied more, it should be possible to classify some of them into separate, specific categories and allow more definitive analyses of their clinical and microscopic features.

TREATMENT AND PROGNOSIS: Because of their diversity, it is difficult to predict the prognosis for salivary adenocarcinoma (NOS), but patients with early-stage, well-differentiated tumors appear to have a better outcome. The survival rate is better for tumors of the oral cavity than for those in the major salivary glands. The reported 10-year survival rate for parotid tumors ranges from 26% to 55%; in contrast, one study reported a 10-year survival rate of 76% for intraoral tumors.