Benign Tumors of Major Salivary Glands

Practice Essentials

Salivary gland tumors (SGTs) are uncommon and represent 2-3% of head and neck neoplasms.^[1]  

The salivary glands exist as larger named “major” glands and also as many widely dispersed “minor” glands that exist throughout the upper aerodigestive submucosa (ie, palate, lip, pharynx, nasopharynx, larynx, and parapharyngeal space). The paired major salivary glands include the following:

• Parotid
• Submandibular
• Sublingual

Approximately 80% of SGTs originate in the parotid gland; the remaining SGTs arise in the submandibular, sublingual, and minor salivary glands.  A good rule of thumb is that the likelihood of an SGT being malignant is inversely proportional to the size of the gland from which it originates.  Specifically, the odds of malignancy in the parotid, submandibular, and minor salivary glands are 20%, 50%, and 80%, respectively.

The approach to a suspected SGT begins with a thorough history and a meticulous physical examination. SGTs usually manifest as an enlargement or growth of the affected gland. Depending on the location of the gland, they can present with nerve compression symptoms when patients are seen later in the course with larger tumors. Clinicians may investigate and exclude a history of weight loss, underlying infectious processes (eg, fever, elevated white blood cell [WBC] count, and concomitant lymphadenopathy), and clinical indications of lymphoma type B symptoms (eg, night sweats, fever, and chills).

Additionally, clinical workup should aim to exclude malignant neoplasms originating from the salivary tissue or malignancies that originate in the mucosal or cutaneous lining of the head and neck region but may exhibit contiguous or metastatic involvement of salivary tissue. Features such as pain, rapid growth, cranial neuropathies, fixation to soft tissue or bone, and associated adenopathy should alert the clinician to the possibility of a malignant diagnosis.

Diagnostic imaging (eg, ultrasonography [US], computed tomography [CT], and magnetic resonance imaging [MRI]) often provides useful information before definitive surgical therapy. Cytopathologic evaluation using fine-needle aspiration (FNA) or core needle biopsy (CNB) may be performed in selected cases and may help dictate the extent of surgical management. However, for most patients presenting with salivary masses, the decision to intervene surgically is largely based on clinical assessment and imaging findings.^{[2, 3, 4, 5]}

From the infancy of surgical intervention, salivary gland surgery was limited to the treatment of ranulas and oral calculi, with the first recorded salivary surgery being a ranula excision performed by Guy de Chauliac of France in 1363.^[6]  The concept of surgical excision of a parotid tumor has been attributed to Bertrandi in 1802. The initial applications of this surgery included an extensive approach, causing serious disfiguration and disability.

By approximately 1850, the focus shifted toward dissection and the intimate relation between the facial nerve and the parotid gland. Attempts were made to perform the surgery with nerve preservation. John C Warren, MD, was the first to use ether inhalation anesthesia during his resection of a parotid tumor in Boston in 1846. In 1892, Codreanu (a Romanian native) performed the first total parotidectomy with facial nerve preservation. Grafting of the facial nerve after resection was attempted in the early 1950s.

In 1958, Beahrs and Adson eloquently described the relevant anatomy and surgical technique of current parotid gland surgery.^[7]  They stressed surgical landmarks for avoiding injury to the main trunk and branches of the facial nerve and advocated complete removal of the superficial portion of the parotid gland for noninvasive lesions confined to that portion of the gland.

For patient education resources, see the Cancer Center, as well as Cancer of the Mouth and Throat.

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Anatomy

The parotid gland is situated in the musculoskeletal recess formed by portions of the temporal bone, atlas, and mandible, along with their related muscles. The gland is divided into superficial and deep lobes on the basis of the plane in which the extratemporal portion of the facial nerve runs. The deep lobe can extend in the parapharyngeal space via the stylomandibular tunnel. The superficial layer of the deep cervical fascia surrounds the parotid gland. This fascia has an anteroinferior portion that becomes the stylomandibular ligament, separating the parotid gland from the submandibular gland.

The facial nerve exits the stylomastoid foramen just posterior to the base of the styloid, gives off small branches to the postauricular and posterior belly of the digastric muscles, and then turns anterolaterally. The main trunk then becomes embedded in parotid tissue and divides into temporofacial and cervicofacial branches just superficial to the retromandibular vein. Beyond this point, the nerve anatomy varies. In general, however, there are five peripheral nerve branches, as follows:

• Temporal or frontal
• Zygomatic
• Buccal
• Marginal mandibular
• Cervical

Multiple landmarks are used to identify the main trunk of the facial nerve during surgery. (See the image below.)

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Facial nerve (white arrow) and its divisions (green arrows) are shown. Retromandibular vein is visible (blue arrow).

The submandibular gland encompasses most of the submandibular or digastric triangle. Like the parotid gland, the submandibular gland can be divided into superficial and deep lobes on the basis of the relationship with the mylohyoid muscle. The marginal mandibular branch of the facial nerve courses between the deep surface of the platysma and the investing fascia that lies over the submandibular gland. The facial artery and vein are located just deep to this nerve, and ligation and superior traction of these vascular structures can prevent nerve injury during surgery.

Located along the posterior border of the mylohyoid are the lingual nerve, submandibular ganglion, and submandibular duct (Wharton duct). The hypoglossal nerve courses deep to the tendon of the digastric and thus lies medial to the superficial layer of the deep cervical fascia.

The sublingual gland is located between the mylohyoid and hyoglossus muscles. The gland is rather superficial and is covered by only a thin layer of oral mucosa; thus, it can often be palpated in the floor of the mouth.

The minor salivary glands are widely dispersed throughout the upper respiratory tract, including the palate, lip, pharynx, nasopharynx, larynx, and parapharyngeal space. The greatest densities of glands are located in the hard (250 glands) and soft (150 glands) palates.

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Pathophysiology

The histogenesis of SGTs is based on the salivary gland unit (see the image below). According to the multicellular theory of SGTs, pleomorphic adenomas originate from the intercalated duct cells and myoepithelial cells; oncocytic tumors originate from the striated duct cells; acinic cell tumors originate from the acinar cells; and mucoepidermoid and squamous cell tumors originate from the excretory duct cells.

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Histology of salivary gland unit.

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Etiology

Although the etiology of SGTs is unknown, associations with environmental or genetic factors have been suggested.^[8]

Smoking has been closely associated with Warthin tumors. Radiation exposure has been linked to the development of the benign Warthin tumor and to the malignant mucoepidermoid carcinoma. Epstein-Barr virus may be a factor in the development of lymphoepithelial tumors of the salivary glands. Genetic alterations (eg, allelic loss, monosomy and polysomy, and structural rearrangement) have been studied as factors in the development of SGTs, and many salivary neoplasms have been shown to possess tumor-specific genetic rearrangements.^[1]

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Epidemiology

SGTs represent 2-3% of head and neck neoplasms and are more common in women than in men. The peak incidence is in the third and fourth decades of life. Pleomorphic adenomas are the most common benign SGTs, followed by Warthin tumors (papillary cystadenoma lymphomatosum; see the image below). 

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Heterogeneous, predominantly low-density mass in tail of right parotid gland with minimal thin peripheral enhancement consistent with Warthin tumor.

In addition to these two most common entities, the updated 2022 classification by the World Health Organization (WHO) recognized 13 additional types of benign epithelial tumors of the salivary glands, with the addition of the following^{[1, 8]} :

• Sclerosing polycystic adenoma
• Keratocystoma
• Intercalated duct adenoma
• Striated duct adenoma

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Prognosis

Whereas surgical excision of benign SGTs can have specific consequences or complications, given the unique anatomic locations of these lesions, the overall outcome after removal is excellent.

Pleomorphic adenomas, in particular, have a very low rate of recurrence, which is presumed to be the result of incomplete surgical excision due to pseudopod extension of the tumor. If untreated, benign pleomorphic adenoma may, in rare cases, undergo transition to a malignant variant called carcinoma ex pleomorphic adenoma; the rate of such transformation is estimated at 10% over 10-15 years.

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History and Physical Examination

The classic presentation of a benign salivary gland tumor (SGT) is a painless, slow-growing mass on the face (parotid; see the first image below), the angle of the mandible (parotid tail, submandibular gland), the neck (submandibular gland; see the second and third images below), or the floor of the mouth (sublingual gland). One may also appreciate medialization of the palatine tonsil in cases of tumor originating in the deep lobe of the parotid and extending into the parapharyngeal space.

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Parotidectomy. Left parotid mass; preoperative marking of modified Blair incision on skin.

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Right submandibular benign salivary gland tumor in 42-year-old woman.

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Pictures before (above, left) and after (above, right) treatment for benign mandibular gland tumor. Specimen picture of gland (below).

A sudden increase in size may be indicative of infection, cystic degeneration, hemorrhage inside the mass, or malignant degeneration. In contrast to malignant SGTs, benign neoplasms are slow-growing, are almost always freely mobile and not fixed to the skin, and generally do not cause neural palsies (facial nerve dysfunction, pain, hoarseness, etc).^[9]

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Tumor Classification

Tumors of the salivary glands are classified on the basis of their cytologic, architectural, and biologic characteristics. The 2022 World Health Organization (WHO) classification of head and neck tumors (see Table 1 below) grouped SGTs into the following categories^[1] :

• Benign epithelial tumors
• Malignant epithelial tumors
• Mesenchymal tumors specific to the salivary glands

Table 1. World Health Organization Classification of Head and Neck Tumors (5th ed): Salivary Glands

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See Table

It should be noted that the 2022 WHO classification omitted several benign entities from the salivary gland section, on the grounds that they do not arise exclusively or even predominantly in salivary glands. These entities include lipomas, hemangiomas, hematolymphoid tumors, and nodular fasciitis.^[1]

Pleomorphic adenoma

Pleomorphic adenomas (benign mixed tumors) are the most common tumors of the salivary gland and are most often located in the tail of the parotid gland. When they are found in the minor salivary glands, the hard palate is the site most frequently involved, followed by the upper lip. (See the images below.)

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Note 12-mm right parotid, smoothly marginated, multilobulated, solid lesion, without focal calcification or necrosis. This was proven to be pleomorphi....

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Note 2- × 1.5-cm uniformly enhancing, smoothly marginated mass in superficial right parotid gland without necrosis or calcification, which is consiste....

These tumors were termed pleomorphic because of the epithelial and connective tissue components that compose them in varying degrees. Their gross appearance is a round, smooth mass with a thin, delicate, incomplete capsule. Notably, pleomorphic adenomas that arise in the minor salivary glands usually lack a capsule.

These tumors grow slowly, though they may become larger than other SGTs. The thin, delicate capsule may have pseudopod projections into the surrounding parotid tissue. This is of particular clinical significance because obtaining clean margins and avoiding spillage are mandatory to minimize recurrence.

Microscopically, benign mixed tumors are characterized by variable and diverse structural histologic patterns. Frequently, they have growth patterns of sheets, strands, or islands of spindle and stellate cells, with a myxoid configuration occasionally predominating. Treatment of benign neoplasms often involves the complete surgical excision of the affected gland. For neoplasms in the parotid gland, a partial parotidectomy, with a margin of normal salivary tissue and facial nerve dissection and preservation, is generally the procedure of choice.

Warthin tumor

Warthin tumor (papillary cystadenoma lymphomatosum or adenolymphoma) was first recognized by Albrecht in 1910 and later described by Warthin in 1929. In gross appearance, it is a smooth, soft parotid mass. It is well encapsulated when located in the parotid gland and contains multiple cysts.

Histologically, the Warthin tumor has a heavy lymphoid stroma and aciniform epithelial cells that line the cystic areas with papillary projections. Malignant transformation is exceedingly rare, and surgical excision is typically curative, with an excellent prognosis. The Warthin tumor tends to be bilateral in 10% of cases and is usually found in the major glands.

Oxyphilic adenoma (oncocytoma)

Oxyphilic adenoma (oncocytoma) was first described by Duplay in 1875. Oncocytomas of the salivary glands are very uncommon. Such neoplasms occur more often in women than in men, with a female-to-male ratio of 2:1. Patients are older than 50 years, and the superficial lobe of the parotid gland is the most commonly reported location. Oncocytomas rarely, if ever, occur in the minor salivary glands. They manifest as small (< 5 cm in diameter), firm, slow-growing, spherical masses. Bilateral oncocytomas of the parotid glands have been described.

Histologically, oncocytomas are large and spherical and have a distinct capsule. Uniform cells are arranged in solid sheets. These tumors recur if excision is incomplete; with complete excision, the prognosis is excellent.^[10]

Myoepithelioma

Myoepitheliomas are much less common benign tumors that originate as a monomorphic cell type. These tumors may display a spindle pattern of growth, a plasmacytoid pattern, or a combination of the two. Any recurrence after surgical excision is typically the result of incomplete resection, and the prognosis is generally very favorable.

Ductal papilloma

Ductal papilloma (DP) is a small, tan, fairly smooth lesion that is usually found in the submucosal layer. Microscopically, DP consists of a cystically dilated duct partially lined with a cuboidal epithelium with complex anastomosing papillary fronds of variable size filling the cystic area. DP of a minor salivary gland is a rare lesion that has been described only in various case reports.

Histologically, the differential diagnosis of DP includes papillary cystadenoma, which is commonly but erroneously diagnosed as DP. In papillary cystadenoma, intraductal hyperplasia occurs, and the dilated duct contains some papillary folds and projections. However, this occurs much less frequently than in DP.

Basal cell adenoma

Most basal cell adenomas arise in the major salivary glands and are composed of basaloid cells with scant cytoplasm. As with other benign monomorphic tumors of salivary gland origin, recurrence is uncommon after appropriate surgical excision, and malignant transformation is very rare.

Other benign salivary gland tumors

Additional, less common benign SGTs are detailed in Table 1 (see above).

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Laboratory Studies

A white blood cell (WBC) count should be performed to investigate for any evidence of leukocytosis and shift that might indicate a possible infectious process or lymphoproliferative disease.

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Imaging Studies

Imaging studies are most helpful in the diagnostic evaluation of salivary gland tumors (SGTs).^{[2, 11]}

Ultrasonography (US) is often the first-line modality for characterizing a neoplasm within the parotid or submandibular glands. In many cases, high-resolution US can adequately assess the size, evaluate the general morphology (cystic, solid, or complex), and define the type of borders (well-circumscribed vs poorly defined), thereby facilitating diagnosis and surgical management. Surgeon-performed US may serve as an extension of the physical examination or may be ordered as a separate standalone study, depending on institutional preferences.

Magnetic resonance imaging (MRI) and computed tomography (CT) may be used to further characterize larger tumors, those that extend beyond the depth that US can adequately assess, and those that raise concerns for malignant features on US or clinical assessment. (See the images below.) MRI is the most sensitive test for establishing the borders of soft-tissue tumor extension and perineural invasion or spread. 

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Heterogeneous, predominantly low-density mass in tail of right parotid gland with minimal thin peripheral enhancement consistent with Warthin tumor.

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Dense, small, solid lesions in parotid glands (more on left side than on right) in patient with lymphoma. This is representative of lymphomatous invol....

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Ill-defined masses in parotid glands bilaterally, proven to be large B-cell lymphoma in this patient with known Sjögren disease.

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Large B-cell lymphoma in patient with known Sjögren disease.

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Large B-cell lymphoma in patient with known Sjögren disease.

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Bilateral, solid, inhomogeneous parotid gland masses that are larger on left side than on right, with minimal necrosis. These were caused by lymphoma.....

Generally speaking, findings from CT and MRI cannot reliably be used to differentiate benign from malignant disease. However, with more advanced imaging techniques, such as diffusion-weighted imaging and quantitative perfusion MRI, progress is being made in the use of imaging modalities in the formulation of the differential diagnosis.^[12] Additionally, with the continued rise of artificial intelligence and machine learning, models specific to salivary neoplasms are being developed and utilized in attempts to increase the diagnostic utility of imaging.^[13]  

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Biopsy

In selected cases, fine-needle aspiration (FNA) biopsy (FNAB) may facilitate the management of a mass in the salivary gland by helping to distinguish a tumor from certain nonneoplastic or inflammatory processes that may respond better to medical management. 

In most patients who present with a salivary mass, the decision to offer surgical management is likely to be determined by clinical and imaging characteristics, and FNA may be considered as part of the workup on the basis of specific considerations of the case. Most benign tumors and low-grade malignancies without lymphadenopathy are treated with surgical extirpation of the primary tumor alone. Patients with high-grade salivary malignancies may require removal of the primary tumor and lymphadenectomy at the same time.

The reliability of FNA in making the diagnosis and determining the grade of malignancy remains a controversial issue. A meta-analysis by Schmidt et al showed that on average, FNA has a sensitivity of 80% and a specificity of 98% for parotid gland lesions.^[14] It should also be mentioned that the utility of FNA for distinguishing high-grade malignancies from low-grade malignancies and benign tumors may be limited by the local availability of expertise.

In the absence of the ability to differentiate the grade of malignancy, FNA may play a limited role in the decision to offer an operation; however, if the diagnosis of a high-grade salivary gland malignancy is made preoperatively, FNA may influence the extent of the operation. In contrast, there are some who advocate the use of core needle biopsy (CNB), which reportedly has higher sensitivity and specificity (92% and 100%, respectively) and provides more architectural information to the pathologist.^[15]  There are, however, some disadvantages and limitations to this method, including increased pain for the patient and a greater risk of nerve injury and hematoma formation.

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Approach Considerations

Experienced clinicians generally agree that surgical excision is indicated for all patients in whom a salivary gland mass develops, unless comorbid medical problems preclude such intervention. Ultimately, surgical excision permits definitive diagnosis and determines the need for any adjuvant therapy that may be indicated in malignant tumors.

Furthermore, surgery is recommended in view of the unique consequences that can arise from even a benign space-occupying mass or tumor in the head and neck region, specifically related to loss of function, disfigurement, and the psychosocial ramifications of such issues.

Indications for more urgent surgical treatment of salivary gland tumors (SGTs) include the following:

• Mass of the face, neck, and floor of the mouth
• Presence of clinical signs of malignancy (eg, a rapid growth on a slow-growing tumor, bleeding, airway compromise due to larger tumors, and nerve dysfunction such as paresthesia)

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Medical Therapy

Inflammatory infectious masses (eg, reactive or fungal) and lymphoma should be treated medically. When symptomatic recurrent chronic gland infection (eg, parotitis) proves refractory to conservative medical or endoscopic (ie, sialoendoscopic) treatments, salivary gland excision is sometimes indicated.

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Surgical Therapy

Management of benign SGTs includes complete removal of the neoplasm with an adequate margin of tissue to avoid recurrence. This usually involves either complete removal of the gland in which the tumor developed or extracapsular dissection of the tumor within the affected gland. Surgical excision of SGTs is performed in the operating room with the patient under general anesthesia, and it is done without using paralysis if intraoperative facial nerve monitoring is to be employed. The endotracheal tube is usually positioned in the corner of the mouth opposite to the surgical field.

Parotidectomy

The key to parotidectomy is safe localization of the facial nerve at the main trunk proximal to the gland. The possibility of total parotidectomy should be included in the preoperative plan. When a malignant diagnosis has not been ruled out, there should also be preoperative discussion of the potential need to sacrifice the facial nerve, with immediate grafting, cervical lymphadenectomy, and mandibulectomy.

Superficial parotidectomy remains the initial procedure of choice for benign parotid gland tumors. A modified Blair incision (see the image below) is often used. The incision usually starts just anterior to the ear helix, extends inferiorly below the ear lobe, and then continues onto the neck, paralleling—but staying at least 2 cm below—the body of the mandible. Other approaches, including a facelift incision, have been described.

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Parotidectomy. Left parotid mass; preoperative marking of modified Blair incision on skin.

To avoid injury to the facial nerve, the surgical field is exposed broadly, with the sternocleidomastoid muscle and the posterior belly of the digastric muscle serving as anatomic landmarks (see the images below). Additionally, the cartilage of the external auditory canal is exposed, and the tragal pointer and the tympanomastoid suture line (a palpatory landmark) are used to direct careful dissection so that the main extratemporal trunk of the facial nerve can be visualized.

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Parotidectomy. Wide plane maintaining thick vascularized skin flap is raised anteriorly. Note that greater auricular nerve is preserved, when possible....

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Parotidectomy. With wide plane of dissection maintained, sternocleidomastoid muscle and posterior belly of digastric muscle are exposed. Main trunk of....

Once the main trunk is exposed, dissection is performed to expose, while avoiding injury to, the individual branches of the nerve and, ultimately, to excise the tumor (see the image below).

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Facial nerve (white arrow) and its divisions (green arrows) are shown. Retromandibular vein is visible (blue arrow).

Extracapsular dissection may also be performed as an alternative to superficial parotidectomy so as to minimize associated morbidity and potentially reduce operating times. It is generally applied to small, superficial benign tumors of the parotid. In this technique, primary identification of the facial nerve is not performed; instead, parotid fascia overlying the tumor is incised, and blunt dissection to and around the tumor capsule is performed until the tumor can be safely extricated.

Depending on the tumor's location, facial nerve branches may be identified deep to the tumor; these should be dissected away and protected. For this reason, the use of facial nerve monitoring in this technique is still advocated. Several studies, including a 2021 meta-analysis by Mashrah et al,^[16] have shown extracapsular dissection to be not just a viable alternative but potentially the treatment of choice for many superficial parotid tumors, yielding reduced morbidity without oncologic compromise.

An optional electromyographic (EMG) facial nerve monitor may be used to permit stimulation of the nerve for confirmation of integrity as needed during dissection. Although this is an exceedingly rare scenario with dissection for benign tumors, if the tumor necessitates resection of a portion of the facial nerve, the nerve should be immediately repaired or reconstructed to afford the best chance of maintaining tone in the muscle or muscles being innervated.

Another potential complication is sacrifice of the greater auricular nerve causing loss of sensation to the ear lobule and surrounding skin. To avoid this, careful dissection through the subcutaneous plane is performed to permit identification and preservation of the nerve as the anatomy allows.

The facial hollowing and loss of facial symmetry that may result from tumor and gland removal can sometimes be addressed at the time of surgery by placing cadaveric human dermal matrix into the deficit or even by rotating a portion of the nearby sternocleidomastoid muscle into it. Other approaches using avascular fat graft (harvested from the patient’s abdominal wall) have also been described.

Whereas injury to the facial nerve and facial paralysis are the most feared complications of parotidectomy, there are other potential complications about which patients should be counseled. Postoperative sialocele or salivary fistula formation may occur, with an incidence as high as 5% for the former and as high as 3% for the latter; these figures are thought to be higher in less extensive surgical procedures.^[17]

Postoperative gustatory sweating (Frey syndrome) is reported with a widely variable incidence. It may occur as a consequence of aberrant innervation of cutaneous sweat glands with parasympathetic input originally meant for the saliva-producing cells after parotid surgery. Use of thick skin flaps, placement of cadaveric human dermal matrix, or autologous fat grafting may mitigate this complication.

Another, less frequently reported complication is first-bite syndrome, which is characterized by acute pain with initiation of mastication from the residual parotid gland. This is thought to be due to cholinergic sensitization and contraction of local residual myoepithelial cells secondary to damaged or aberrant sympathetic innervation in the operative bed.

Recurrence of a benign tumor can be avoided with complete excision of the lesion. Enucleation should be avoided so as to minimize the chance of tumor spillage and seeding recurrence.

Submandibular gland surgery

Submandibular gland surgery is performed with the patient under general anesthesia with endotracheal intubation. 

In classic transcervical approaches, an incision at least 2 cm below the body of the mandible is made through the platysma to permit identification of the superficial layer of the deep cervical fascia. To avoid injury to the marginal mandibular branch of the facial nerve, a technique of dividing the facial vein and raising a fascial flap/plane may be employed to ensure that dissection is deep to the nerve. Other approaches include direct identification of the nerve to avoid injury during dissection. Additionally, a transoral approach to submandibular gland excision has been shown to be viable and safe, with the added benefit of no external scarring.^[18]

Other significant potential complications during submandibular gland or tumor excision are injuries to the hypoglossal nerve, the lingual nerve, or both. This may result in disrupted motor function and decreased sensation to the ipsilateral tongue. Careful dissection with appropriate identification and preservation of these structures is recommended.

Although complete removal of the entire gland is the primary treatment of choice, some surgeons advocate partial sialadenectomy in the appropriate clinical setting. Studies that evaluated gland-preserving surgery in the setting of benign submandibular gland tumors showed decreased cosmetic deformity and higher rates of salivary flow, with no reported differences in recurrence rates.^{[19, 20]}

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