Benign salivary gland tumors represent a diverse group of neoplasms with varied clinical behaviors. Successful management of these neoplasms relies on accurate clinical and diagnostic assessment, as well as appropriate therapeutic intervention. A strong understanding of the biologic behavior of the various types of lesions allows the development of an appropriate treatment plan tailored to each individual patient affected.
Tumors of the salivary glands account for only 2-4% of head and neck neoplasms. Most (~70%) salivary gland tumors originate in the parotid gland, with the bulk of the remainder arising in the submandibular gland (~8%) and in the minor salivary glands (~22%).[1, 2] Although 75% of parotid gland tumors are benign, slightly more than 50% of tumors of the submandibular gland and 60-80% of minor salivary gland tumors are found to be malignant.[3]
Minor salivary gland tumors thus are relatively uncommon neoplastic entities. Palatal minor salivary glands are the most common anatomic subsite affected by these tumors; most series identify a nearly equal distribution between benign and malignant tumors.[4]
The ubiquitous deposition of the minor salivary glands complicates the diagnosis and management of salivary gland tumors. The approach to a suspected tumor of the minor salivary glands begins with a thorough history and a physical examination. Radiographic imaging (computed tomography [CT] with or without magnetic resonance imaging [MRI]) and a histopathologic diagnosis (obtained via fine-needle aspiration [FNA] cytology) often provide useful diagnostic information prior to definitive surgical therapy.
The minor salivary glands consist of 600-1000 smaller, unnamed glands distributed throughout the upper aerodigestive tract (ie, the palate, lip, pharynx, nasopharynx, larynx, and parapharyngeal space). The majority (70-90%) are located in the oral cavity and oropharynx, including the lateral tongue, lips, buccal mucosa, palate, and retromolar pad. The greatest glandular densities are located within the hard (250) and soft (150) palates. The remaining glands are located in the nose, paranasal sinuses, pharynx, and larynx.
The minor salivary glands are commonly classified according to their anatomic location—for example, labial glands (upper and lower lips), buccal glands, and so forth.
As compared with the major salivary glands, the minor salivary glands are more numerous, are reduced in volume with regard to tissue size, have an abbreviated duct system, and have a paucity of capsular tissue. Overall, they contribute about 8-10% of the volume of unstimulated and stimulated whole saliva.
Most benign salivary gland tumors (95%) occur in adults, with the clear majority pathologically identified as pleomorphic adenomas. In children, the most common benign tumors of mesenchymal origin are hemangiomas, and the most common benign epithelial tumors are pleomorphic adenomas.[5]
Two major theories of salivary gland neoplastic pathogenesis have emerged: the multicellular theory and the bicellular (reserve cell) theory.[6] The histogenesis of salivary gland tumors is based on the salivary gland unit.
According to the multicellular theory, the origins of these lesions are as follows:
According to the bicellular theory, basal cells of the excretory duct and intercalated duct are stem cells from which the mature salivary gland unit arises. Tumors arise from one of these two stem cell populations. Warthin tumors, mixed tumors, oncocytomas, acinic cell carcinomas, adenoid cystic carcinomas, and oncocytic carcinomas arise from intercalated duct stem cells. Squamous cell carcinomas and mucoepidermoid carcinomas arise from stem cells of the excretory duct.[5]
View Image | Histologic architecture of the salivary gland unit. |
Etiologic factors for the development of benign salivary gland neoplasms are not well understood; however, both environmental and genetic factors have been proposed as potential causes.
Low-dose radiation has been implicated in the development of benign salivary gland tumors. The strongest evidence for this association is derived from analysis of the incidence of salivary gland neoplasms in atomic bomb survivors.[7] Supporting evidence is also provided by analysis of the relative risk conferred by exposure to early therapeutic external beam irradiation.
Exposure to diagnostic dental radiographs has also been found to confer an increased risk for salivary gland neoplasms, but this may be attributable to the greater radiation exposure inherent in older technology as compared with the reduced exposure characteristic of current low-dose diagnostic radiographs.[8]
The latency period for the development of a radiation-induced salivary gland tumor appears to be in the range of 15-20 years.
Although the molecular genetic basis for the development of benign salivary gland neoplasms is not well delineated, some preliminary observations have nonetheless been made. Initial studies demonstrated a high incidence of allelic loss of chromosomal arm 12q in pleomorphic adenoma.[9] Additional alterations, including cytogenetic abnormalities such as an 8q12 translocation involving PLAG1 (a zinc finger protein), have also been described.[10]
Finally, Epstein-Barr virus (EBV) may be a factor in the development of lymphoepithelial tumors of the salivary glands.
Between 60% and 80% of all minor salivary gland tumors are malignant. Overall, adenoid cystic carcinoma is the most common malignant tumor of all minor salivary glands.[11] In a study of 485 cases of minor salivary gland tumors from northeastern China, pleomorphic adenoma was found to be the most common type of benign tumor, and adenoid cystic carcinoma was the most common type of malignant tumor.[12]
With appropriate treatment of benign salivary gland tumors, the outcome is excellent, and the recurrence rate is very low.
Patients with salivary gland lesions require a thorough head and neck evaluation. Cranial nerve function is carefully noted and documented. Careful attention is given to findings that may indicate malignancy, such as the following:
Most patients who have benign minor salivary gland tumors present with a painless, progressive, enlarging mass in the affected minor salivary gland or oral cavity mucosal space. These masses can be firm to hard on palpation, mobile if within the salivary gland, and fixed in cases of local invasion.[13] Because of the multiple and varied locations of minor salivary glands, the presentation of benign tumors may be less specific.
Paranasal sinus minor salivary gland neoplasms may cause obstructive sinusitis, epistaxis, and nasal obstruction. Laryngotracheal salivary gland neoplasms may give rise to hoarseness, dysphagia, odynophonia, and cough. Parapharyngeal space salivary neoplasms often are diagnosed late in their evolution given lack of presenting symptoms until a large tumor size has been attained. Trismus, dysphagia, or dysphonia may be the first indication of a tumor in the parapharyngeal space.
Most sources cite the palate as the most common anatomic site for minor salivary gland tumors, of which 42-75% occur in the palatal mucosa. Other sites include the lips (4-21%), the buccal mucosa (5-16%), the tongue or floor of the mouth (4-12%), and the retromolar area (3-7%).[14]
Basal cell adenoma, first described by Kleinsasser and Klein in 1967, is an epithelial neoplasm composed of cells with a basaloid appearance and without a chondromyxoid matrix.[15] It accounts for 1-3% of all salivary neoplasms and typically occurs in adults, usually in the fourth to seventh decades. Most of these lesions (75-80%) occur in the parotid gland; the rest involve the submandibular and minor salivary glands, especially the upper lip and buccal mucosa. Basal cell adenoma typically presents as a slowly enlarging, asymptomatic mass.[16]
The membranous variant of basal cell adenoma, also known as a dermal analogue tumor, is associated in 25-38% of cases with Brooke-Spiegler syndrome, an autosomal dominant condition characterized by numerous dermal cylindromas, trichoepitheliomas, spiradenomas, or combinations thereof.[17]
Canalicular adenoma is defined as a tumor composed of columnar epithelial cells arranged in thin, anastomosing cords with a beaded pattern. It typically occurs in patients older than 50 years (range, 33-87 years), with a female-to-male ratio of 1:1 to 1.8:1.[18] It most commonly affects the upper lip (80% of cases) but has also been found to involve the buccal mucosa (10%), palate (3-10%), and parotid gland (< 4%).[19]
Canalicular adenoma typically presents as a painless, slowly enlarging submucosal mass covered by intact mucosa that ranges in color from normal to slightly blue, often mimicking a mucocele. Although it is typically a solitary lesion, multiple clinically apparent tumors have also been described.[20]
Cystadenomas constitute a rare category of benign cystic neoplasms. These tumors predominantly occur in the fifth decade, with a female-to-male ratio of 2:1 to 3:1.[16] They typically are found in the parotid gland and submandibular gland, though they may also be found in the lip. Oncocytic cystadenomas are common in the minor salivary tissue of the larynx as well.[21] Cystadenomas usually present as fluctuant painless masses on physical examination. In the oral cavity, they can also mimic the clinical presentation of mucoceles.
Lymphadenomas are rare benign tumors with prominent lymphoid stroma that does not consist of an oncocytic bilayer, as seen in Warthin tumor. This group of tumors usually occurs after the fifth decade, with no predilection for either sex.[22] Lymphadenoma is essentially a condition of the parotid gland, though rare cases involving the minor salivary glands have been reported. Lymphadenomas typically present as slow-growing painless masses; some degree of cystic change may result in a fluctuant appearance.[16]
Myoepitheliomas are uncommon tumors, comprising no more than 1-2% of all salivary neoplasms. The majority are benign (70-90%), but some are malignant (10-30%). Approximately 75% of all cases occur in the parotid gland and palate. They are uncommon in the submandibular gland and have been described infrequently in a variety of other sites, including the sinonasal tract, oral cavity, and larynx.
Myoepithelioma affects both sexes equally and most commonly occurs between the ages of 40 and 50 years (range, 9-95 years). The tumor often presents as a mass that enlarges slowly over a period of several months to years.[16]
Necrotizing sialometaplasia is a reactive nonneoplastic inflammatory process that usually affects the minor salivary glands of the palate; however, it may involve minor salivary glands in any location. It can easily be mistaken for a malignant tumor, in that it presents as a single unilateral painless (or only slightly painful) lesion of the hard palate.
Necrotizing sialometaplasia is of unclear origin but is thought to result from vascular infarction of salivary gland lobules. Potential causes of diminished blood flow include the following:
Necrotizing sialometaplasia affects patients between the ages of 23 and 66 years and is two to three times more common in males than in females. Lesions usually appear as large (1-4 cm), painless or painful, deeply ulcerated areas lateral to the palatal midline and near the junction of the hard and soft palates. They are usually unilateral but may be bilateral in some cases. A biopsy assists in ruling out a malignant process; otherwise, no additional treatment is indicated. [23]
Duplay first described an oncocytic tumor in 1875. Like other oncocytic neoplasms, oncocytoma is a tumor of the elderly, most commonly occurring in the seventh and eighth decades of life, with no predilection for either sex.[16] In 20% of cases, a prior history of irradiation may be present, giving rise to a subpopulation that presents at a younger age.[24]
More than 80% of oncocytomas occur in the parotid gland, though they can occur in the submandibular and minor salivary glands as well. These tumors are typically slow-growing painless masses; 7% of patients are found to have bilateral lesions. Oncocytomas may recur if excision is incomplete.[25]
Pleomorphic adenoma is the most common salivary gland tumor, accounting for 45-60% of all benign and malignant salivary neoplasms.[26] Approximately 80% occur in the parotid gland, 15% in the submandibular gland, and 10% in the minor salivary glands. In the oral cavity, the most commonly affected site is the palate, followed by the upper lip and the buccal mucosa.[27] These lesions are more frequent in women and occur in all age groups (mean age, 45 years).
The majority of pleomorphic adenomas grow slowly and are relatively asymptomatic, but they can reach an extremely large size if neglected. These tumors were termed pleomorphic because of the epithelial and connective-tissue components that compose them in varying degrees. Their gross appearance is that of a round, smooth mass with a thin, delicate, incomplete capsule. Notably, pleomorphic adenomas that arise in the minor salivary glands usually lack a capsule.
A sialolipoma is characterized as a well-circumscribed mass consisting of salivary gland and mature adipose tissue. It remains unclear whether the salivary tissue within the lesion is neoplastic tissue, hamartomatous tissue, or residual entrapped glandular tissue. Although sialolipomas are most commonly seen in the parotid gland, they can also involve the minor salivary glands and may affect the hard or soft palate. Such lesions should be distinguished from normal fatty replacement of salivary glands, which can occur with the aging process.[28]
A complete blood count (CBC) with differential may be elevated in cases with an underlying inflammatory process. This possibility must be excluded before definitive surgical intervention is initiated. For patients undergoing fine-needle aspiration (FNA), determination of prothrombin time (PT)/international normalized ratio (INR) may be indicated to assess for baseline coagulopathy.
Controversy exists regarding the routine use of imaging for small lesions of the minor salivary glands because radiographic imaging typically does not alter the management of these lesions.
Nevertheless, computed tomography (CT), magnetic resonance imaging (MRI), or both may be useful for suspected tumors of the parapharyngeal space. MRI and CT are also optimal for delineating the complete extent of the tumor and assessing for regional lymphadenopathy. In addition, these imaging modalities are useful for evaluating the possibility of invasion into surrounding tissues and facilitating the planning of definitive surgical resection.
When bony erosion is a concern (eg, in palatal minor salivary gland tumors), CT may be required to assess the extent of locoregional involvement, which will play a role in planning for definitive resection as well as subsequent reconstruction. Similarly, CT is indicated for minor salivary gland neoplasms involving the paranasal sinuses to delineate the extent of the tumor and differentiate tumor from obstructive inflammatory changes.
MRI (see the image below) is superior in soft-tissue differentiation and is particularly helpful in assessing tumor extent, marrow infiltration, and perineural spread. It can also detect signal changes and extracapsular spread within regional lymph nodes while simultaneously avoiding exposure to ionizing radiation. The disadvantages of MRI include its relatively high cost in comparison with CT, its susceptibility to motion artifact, and its poor cortical bone delineation.[31]
View Image | Coronal magnetic resonance imaging (MRI) scan demonstrating a large, benign lesion of the right parapharyngeal space. |
Minor salivary gland lesions in the mucosa of oral cavity, pharynx and tracheobronchial tree are not easily accessible or visualized via conventional ultrasonography. Accordingly, this imaging modality is rarely employed in the management of minor salivary gland lesions.
FNA cytology was first developed as a diagnostic tool at the Memorial Sloan-Kettering Cancer Center in the 1930s. However, it is only in the past two decades that it has become a widely applied technique in the management of salivary gland tumors.[32] In general, the histopathology of salivary gland tumors is extremely varied and complex; therefore, correct cytologic typing of a primary salivary gland neoplasm can be difficult to perform.[33]
The utility of FNA has been well established by Eneroth and others, who advocated its routine use and reported accuracy rates in the range of 74-90%.[34] Although the procedure is somewhat operator-dependent, it is generally regarded as safe, simple to perform, relatively inexpensive, and low in morbidity. When a needle of appropriate size is used, the risk of seeding of the needle tract is negligible (0.003% and 0.009%).[35] Open biopsy is rarely performed, because of the risk of tumor spillage, associated infection, and tumor recurrence.[5]
Currently, core needle biopsy (CNB) is not commonly employed in the management of salivary neoplasms, because of the risk of tumor spillage. The overall risk of tumor seeding with CNB is estimated to be in the range of 0-22%.[36] Factors implicated include needle size, use of a single vs coaxial needle, and tumor-related factors. There may, however, be a role for CNB in cases where prior FNA was nondiagnostic. Thus, surgeons must exercise discretion when considering CNB in the management of these lesions.
Basal cell adenomas comprise a mixture of basal, myoepithelial, and ductal cells. Basal cells are morphologically subdivided into the following two main categories:
The small dark cells usually form the periphery of tumor nests and demonstrate peripheral palisading, whereas the larger cells rest on top of this peripheral layer. Within the center, tumor nests are composed of small ductules lined by cuboidal epithelium.[16] Architecturally, basal cell adenomas are divided into the following six growth pattern subtypes[37] :
Canalicular adenomas may or may not be encapsulated and are composed of cuboidal to columnar cells with dark, often elongated nuclei with light eosinophilic to amphophilic cytoplasm. These cells are characteristically arranged in anastomosing cords that are two cells thick; this alternating pattern of abutment and separation has been referred to as beading.[16]
Cystadenomas may be lined by a variety of epithelial types. Most commonly, the luminal epithelium is cystic to cuboidal with pale eosinophilic cytoplasm. The outer layer is lined by an indistinct layer of basal cells with scant cytoplasm and small, ovoid nuclei. Oncocytic cystadenomas are a common variant, in which the lining is composed of columnar, oncocytic epithelium.[16]
Lymphadenomas are generally subcategorized as either sebaceous or nonsebaceous. Sebaceous lymphadenomas are more common and consist of solid-to-cystic proliferations of squamoid nests with varying degrees of sebaceous differentiation. One unique finding in sebaceous lymphadenomas is a granulomatous reaction to keratin and sebum in the surrounding lymphoid stroma. The epithelial component of nonsebaceous lymphadenomas is often basaloid in appearance, ranging from a solid to a tubulotrabecular growth pattern.[16]
Myoepitheliomas are composed primarily of spindle cells, plasmacytoid (hyaline) cells, or a combination of cells that grow in a solid, nodular, myxoid-mucinous, pseudoglandular, trabecular, or reticulated pattern. Epithelioid, clear cell, and oncocytic variants are less common pathologies.
The spindle cells are organized in sheets or swirls and have central oval to elongated nuclei with finely dispersed chromatin and blunt tapered ends. The plasmacytoid cells have glassy, dense eosinophilic cytoplasm and eccentric, round to oval nuclei. In comparison with other subsites, plasmacytoid variants are found more frequently in the palate.[16]
Oncocytomas are composed of polygonal oncocytes that may be arranged in a solid, a trabecular, and occasionally a compressed tubular growth pattern. Nuclei are round and vary from hyperchromatic to slightly vesicular with visible nucleoli. The periphery of tumor nests consists of darker cells with more scant cytoplasm. Squamous metaplasia may be seen in traumatized areas, particularly near an FNA tract.[16]
Pleomorphic adenomas have the following four components:
Most of these tumors are composed of approximately 50% epithelial-myoepithelial cells and 50% mesenchymal-stromal elements. Tumors in which the percentage of epithelial-myoepithelial cells is 80% or higher are referred to as cellular pleomorphic adenomas, whereas those in which the percentage of mesenchymal-stromal elements is 80% or higher are referred to as acellular pleomorphic adenomas.
The epithelial cells are cuboidal to polygonal and appear as small ducts and acini surrounded by a single layer of myoepithelial cells. Tumor cells have eosinophilic to amphophilic cytoplasm and central, mildly chromatic nuclei with absent or barely discernible nucleoli. Skin adnexal differentiation is frequently observed in palate pleomorphic adenoma.[38]
Myoepithelial cells exhibit remarkable phenotypic variation and may appear spindled, plasmacytoid, epithelioid, clear, or oncocytic. The mesenchymal-stromal components range from fibrous to myxoid to chondroid to osseous to lipomatous. Mitoses and necroses are sparse to absent and may be related to prior FNA cytology.[16]
Necrotizing sialometaplasia is similar in appearance to pseudoepitheliomatous hyperplasia, which appears as epithelial infiltration into underlying tissue, much like the visualized pattern of a carcinoma. Features distinguishing this condition from a malignant process include the following:
Histologically, lymphoepithelial hyperplasia is composed of diffuse, well-organized lymphoid tissue and lymphocytic interstitial infiltrate with obliteration of the acinar pattern.[23]
Sialolipomas are admixed with lipomatous and salivary tissue as well as lobules of mature adipocytes.
The general consensus is that definitive surgical therapy is indicated for most benign tumors of the minor salivary glands. Notable exceptions to this would be certain tumorlike conditions, such as lymphoepithelial cysts associated with AIDS, as well as small asymptomatic hemangiomas. Historically, physicians have advocated surgery without radiographic imaging or fine-needle aspiration (FNA) cytology; current recommendations include preoperative assessment with these diagnostic tools to assess for locoregional extent and concomitant lymphadenopathy.
The primary contraindication for surgical treatment of benign salivary gland tumors is the presence of associated medical comorbidities that preclude the use of general anesthesia.
In cases of inflammatory or infectious salivary masses (eg, acute bacterial sialadenitis or mycobacterial infection), administration of appropriate medical and supportive treatment is warranted. Salivary gland excision is sometimes indicated when chronic, symptomatic, recurrent sialadenitis proves refractory to conservative therapies. If lymphoma is diagnosed, appropriate treatment for the stage and subtype of lymphoma is indicated through consultation from a medical oncologist.
Management of benign salivary gland tumors includes complete removal with an adequate margin of peripheral tissue to avoid locoregional recurrence. This implies complete removal of the offending gland in whose native tissue the tumor has arisen. Excision is performed with the patient under general anesthesia without paralysis. The endotracheal tube is usually positioned in the corner of the mouth opposite the proposed surgical field.
Surgical treatment of minor salivary gland tumors depends on the site of origin and the extent of locoregional disease. For tumors of the lip or palate, this may simply involve wide local excision with primary closure. Benign minor salivary gland tumors of the upper lip and buccal mucosa are often managed with a mucosa-sparing wide local excision that sacrifices the etiologic minor salivary gland tissue with an intact tumor pseudocapsule.[39]
For more extensive palatal lesions, a bone-sparing, periosteal-sacrificing, wide local excision incorporating 5- to 10-mm linear margins within the palatal mucosa is recommended, with careful preservation of the tumor pseudocapsule. The periosteum and tumor pseudocapsule represent anatomic barrier margins on the deep surface of the tumor. In long-standing cases of benign palatal salivary gland tumors, the thin remaining bone is sacrificed on the deep surface of the tumor specimen; retention of thinned bone often is not technically possible or anatomically meaningful.
Immediate soft-tissue reconstruction of the resultant defect is possible and desirable; primary closure with adjunct locoregional flap reconstruction may be used if clinically indicated.
Larger tumors of the parapharyngeal space may necessitate a more complex surgical approach; intraoral resection typically is not recommended in such cases. The main options for external approaches to the parapharyngeal space are (1) a cervical-parotid approach and (2) a cervical-parotid approach with mandibulotomy.
Although this procedure does not require a full facial nerve dissection, the inferior divisions must be located and preserved. By retracting the sternocleidomastoid laterally, the surgeon can identify the internal jugular vein, the carotid artery, and the lower cranial nerves (IX-XII). For access to this space, the posterior belly of the digastric and stylohyoid muscles must be divided, followed by the external carotid artery and the stylomandibular ligament. In addition, the styloid process may be resected for delivery of larger tumors and greater visualization.
Often, in the treatment of benign lesions arising from the minor salivary glands, an attempt is made to avoid a mandibulotomy. However, in patients with tumors located in the superior aspect of the parapharyngeal space that are approaching the eustachian tube and skull base, a mandibulotomy may be necessary in order to provide optimal surgical access.[40]
Complications associated with definitive excision and reconstruction of palatal minor salivary gland tumors (both benign and malignant) include the following[41] :
Complications associated with definitive transcervical excision of parapharyngeal minor salivary gland tumors include the following[42] :
A regular diet may be resumed after excision of most benign salivary gland lesions. More extensive excisions may warrant adherence to a soft diet for 7 days. Patients are counseled to avoid spicy or acidic foods for 7 days while the reapproximated mucosa heals. Postoperative oral hygiene is also recommended, with routine saline rinses after meals.
Dietary alterations may be effective in preventing salivary gland tumors by increasing consumption of fruits and vegetables, particularly those high in vitamin C, and by limiting intake of food that is high in cholesterol.[43] A case-control study conducted in China revealed a significant protective effect of consumption of dark-yellow vegetables or liver, with a 70% reduction in the risk of salivary gland malignancy among the subjects with the highest intake of these particular types of foods.[44]
Patients should be followed at intervals of 1 week, 4 weeks, and 12 weeks postoperatively to monitor wound healing, as well as to look for any new symptoms related to the surgical resection or reconstruction. After this period, given the benign salivary pathology, patients may be monitored by their primary care provider at regular intervals until new symptoms or lesions develop for which repeat referral is warranted.