Salivary Gland Neoplasms

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http://www.emedicine.com/ent/topic679.htm
Last Updated: July 25, 2003

Synonyms and related keywords: parotid cancer, salivary gland cancer, salivary gland malignancy, pleomorphic adenoma, Warthin tumor, Warthin’s tumor, mucoepidermoid carcinoma, adenoid cystic carcinoma

Contents
Introduction
Relevant Anatomy And Contraindications
Workup
Treatment
Complications
Outcome And Prognosis
Pictures
Bibliography

Author: Michael M Johns, MD, Lecturer, Department of Otolaryngology-Head and Neck Surgery, Vanderbilt University; Vice President of Health Affairs, Director of Health Sciences Center, Professor, Department of Otolaryngology, Emory University School of Medicine

Michael M Johns, MD, is a member of the following medical societies: American Academy of Otolaryngology-Head and Neck Surgery, American Head and Neck Society, American Laryngological Association, and American Laryngological Rhinological and Otological Society

Editor(s): David J Terris, MD, Fellowship Codirector, Associate Professor, Department of Surgery, Division of Otolaryngology, Stanford University Medical Center; Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, Pharmacy, eMedicine; Erik Kass, MD, Chief, Department of Clinical Otolaryngology, NIH National Institute On Deafness and Other Communication Disorders; Christopher L Slack, MD, Consulting Staff, Otolaryngology-Facial Plastic Surgery, Lawnwood Regional Medical Center; and Arlen D Meyers, MD, MBA, Professor, Department of Otolaryngology-Head and Neck Surgery, University of Colorado School of Medicine

Introduction
Neoplasms arising in the salivary glands are relatively rare, yet represent a wide variety of benign and malignant histologic subtypes (see Image 1). While researchers have learned much from the study of this diverse group of tumors over the years, diagnosis and treatment of salivary gland neoplasms remains a complex and challenging problem for the head and neck surgeon.
The incidence of salivary gland neoplasms as a whole is approximately 1-2 cases per 100,000 individuals in the US. An estimated 750 deaths related to salivary gland tumors occur annually. Salivary gland neoplasms make up 1% of all head and neck tumors.

Salivary gland neoplasms most commonly appear in the sixth decade of life. Patients with malignant lesions typically present after age 60 years, whereas those with benign lesions usually present after age 40 years. Benign neoplasms occur more frequently in women than in men, but malignant tumors are distributed equally between the sexes.

The salivary glands are divided into 2 groups: the major salivary glands and the minor salivary glands. The major salivary glands consist of 3 pairs of glands, ie, the parotid glands, the submandibular glands, and the sublingual glands. The minor salivary glands comprise 600-1000 small glands distributed throughout the upper aerodigestive tract.

Among salivary gland neoplasms, 80% arise in the parotid glands, 10-15% arise in the submandibular glands, and the remainder occur in the sublingual and minor salivary glands.

Most series report that about 80% of parotid neoplasms are benign, with the relative proportion of malignancy increasing in the smaller glands. A useful rule of thumb is the 25/50/75 rule. That is, as the size of the gland decreases, the incidence of malignancy of a tumor in the gland increases, in approximately these proportions. The most common tumor of the parotid gland is the pleomorphic adenoma, which represents about 60% of all parotid neoplasms (see Image 2). Almost one half of all submandibular gland neoplasms and most sublingual and minor salivary gland tumors are malignant. The relative proportion of submandibular tumors is shown in Image 3.

Salivary gland neoplasms are rare in children. Most tumors (65%) are benign, with hemangiomas being the most common, followed by pleomorphic adenomas. In children, 35% of salivary gland neoplasms are malignant. Mucoepidermoid carcinoma is the most common salivary gland malignancy in children.

Successful diagnosis and treatment of patients with salivary gland tumors requires a thorough understanding of tumor etiology, biologic behavior of each tumor type, and salivary gland anatomy.

Problem: See the Introduction.
Frequency: See the Introduction.

Etiology: The etiology of salivary gland neoplasms is not fully understood. Two theories predominate: Bicellular stem cell theory and multicellular theory.

Bicellular stem cell theory
This theory holds that tumors arise from 1 of 2 undifferentiated stem cells, the excretory duct reserve cell or the intercalated duct reserve cell. Excretory stem cells give rise to squamous cell and mucoepidermoid carcinomas, while intercalated stem cells give rise to pleomorphic adenomas, oncocytomas, adenoid cystic carcinomas, adenocarcinomas, and acinic cell carcinomas.

Multicellular theory
In the multicellular theory, each tumor type is associated with a specific differentiated cell of origin within the salivary gland unit. Squamous cell carcinomas arise from excretory duct cells, pleomorphic adenomas arise from the intercalated duct cells, oncocytomas arise from the striated duct cells, and acinic cell carcinomas originate from acinar cells.

Recent evidence suggests that the bicellular stem cell theory is the more probable etiology of salivary gland neoplasms. This theory more logically explains neoplasms that contain multiple discrete cell types, such as pleomorphic adenomas and Warthin tumors.

Associated factors
Radiation therapy in low doses has been associated with the development of parotid neoplasms 15-20 years after treatment. After therapy, the incidence of pleomorphic adenomas, mucoepidermoid carcinomas, and squamous cell carcinomas is increased.

Tobacco and alcohol, which are highly associated with head and neck squamous cell carcinoma, have not been shown to play a role in the development of malignancies of the salivary glands. However, tobacco smoking has been associated with the development of Warthin tumors (papillary cystadenoma lymphomatosum). While smoking is highly associated with head and neck squamous cell carcinoma, it does not appear to be associated with salivary gland malignancies.

Pathophysiology: The molecular events that lead to the formation of salivary gland neoplasms are not well understood. Some preliminary observations have been published, however. Pleomorphic adenomas have been shown to have a high incidence of allelic loss on chromosomal arm 12q. The high-mobility group protein gene (HMGIC) is a transcriptional activator located in this region, and recurrent translocations have been discovered involving this gene in pleomorphic adenomas.

Additionally, recurrent translocations involving PLAG1, a zinc-finger gene located on chromosomal arm 8q, have been reported in pleomorphic adenomas. Overexpression of p53 has been identified in a high proportion of carcinomas arising from pleomorphic adenomas, while few p53 mutations have been described in other salivary gland tumors.

Allelic loss of chromosomal arm 19q has been reported to occur commonly in adenoid cystic carcinoma, and loss of chromosomal arms 2q, 5p, 12p, and 16q is reported to occur in more than 50% of mucoepidermoid carcinomas. In addition, overexpression of fibroblast growth factor 8b has been shown to lead to salivary gland tumors in transgenic mice.


Clinical:
History
A thorough history is important in treating patients with suspected salivary gland neoplasms. A diverse variety of pathologic processes, including infectious, autoimmune, and inflammatory diseases, can affect the salivary glands and may masquerade as neoplasms. While most masses of the parotid gland are ultimately diagnosed as true neoplasms, submandibular gland enlargement is most commonly secondary to chronic inflammation and calculi.

Initial history taking should focus on the presentation of the mass, growth rate, changes in size or symptoms with meals, facial weakness or asymmetry, and associated pain. A thorough general history provides insight into possible inflammatory, infectious, or autoimmune etiologies.

Most patients with salivary gland neoplasms present with a slowly enlarging painless mass. A discrete mass in an otherwise normal-appearing gland is the norm for parotid gland neoplasms. Parotid neoplasms most commonly occur in the tail of the gland. Submandibular neoplasms often appear with diffuse enlargement of the gland, whereas sublingual tumors produce a palpable fullness in the floor of the mouth.

Minor salivary gland tumors have a varied presentation depending on the site of origin. Painless masses on the palate or floor of mouth are the most common presentation of minor salivary neoplasm. Laryngeal salivary gland neoplasms may produce airway obstruction, dysphagia, or hoarseness. Minor salivary tumors of the nasal cavity or paranasal sinus can present with nasal obstruction or sinusitis. Lateral pharyngeal wall protrusions with resultant dysphagia and muffled voice should raise suspicion of a parapharyngeal space neoplasm.

Facial paralysis or other neurologic deficit associated with a salivary gland mass indicates malignancy. The significance of painful salivary gland masses is not entirely clear. Pain may be a feature associated with both benign and malignant tumors. Pain may arise from suppuration or hemorrhage into a mass or from infiltration of a malignancy into adjacent tissue.

Physical examination
Physical examination of salivary gland masses should occur in the setting of a thorough general head and neck examination.

Note the size, mobility, and extent of the mass, as well as its fixation to surrounding structures and any tenderness. Perform bimanual palpation of the lateral pharyngeal wall for deep lobe parotid tumors to assess for parapharyngeal space extension. Similarly, bimanual palpation for submandibular and sublingual masses reveals the extent of the mass and its fixation to surrounding structures.

Pay attention to surrounding skin and mucosal sites, which drain to the parotid and submandibular lymphatics. Regional metastases from skin or mucosal malignancies may present as salivary gland masses.

A careful neurologic examination focusing on the cranial nerves reveals clues regarding neural infiltration and the extent of malignant lesions.


Relevant Anatomy and Contraindications

Relevant Anatomy:

Embryogenesis
The salivary glands begin to form in the sixth to ninth weeks of gestation. The major salivary glands arise from ectodermal tissue. The minor salivary glands arise from either ectodermal or endodermal tissue, depending of their location. Development of each salivary gland begins with ingrowth of tissue from oral epithelium, initially forming solid nests. Later differentiation leads to tubule formation with 2 layers of epithelial cells, which differentiate to form ducts, acini, and myoepithelial cells. Embryologically, the submandibular gland forms earlier than does the parotid gland. The resulting associated lymph nodes are outside the gland.

The parotid gland becomes encapsulated later in embryology. This leads to lymph nodes, which are trapped within the gland. Most of the nodes, 11 on average, are located in the superficial portion of the gland, and the rest, 2 on average, are in the deep portion. This embryologic difference explains why lymphatic metastases may present within the substance of parotid gland and not the submandibular gland.

Salivary-gland secretory unit
Salivary glands are made up of acini and ducts. The acini contain cells that secrete mucous and/or serous. These cells drain first into the intercalated duct, followed by the striated duct, and finally into the excretory duct. Myoepithelial cells surround the acini and intercalated duct and serve to expel secretory products into the ductal system. Basal cells exist along the salivary gland unit and replace damaged or turned-over elements.

The parotid gland acini contain predominately serous cells, while the submandibular gland acini are mixed, containing both mucous and serous cells, and the sublingual and minor salivary glands have predominately mucous acini.

Parotid gland
The parotid gland is the largest of the salivary glands. It is located in a compartment anterior to the ear and is invested by fascia that suspends the gland from the zygomatic arch. The parotid compartment contains the parotid gland, nerves, blood vessels, and lymphatic vessels, along with the gland itself.

The compartment may be divided into superficial, middle, and deep portions for describing the contents, but the space has no discrete anatomic divisions. The superficial portion contains the facial nerve, great auricular nerve, and auriculotemporal nerve. The middle portion contains the superficial temporal vein, which unites with the internal maxillary vein to form the posterior facial vein. The deep portion contains the external carotid artery, the internal maxillary artery, and the superficial temporal artery.

The parotid compartment is a wedge-shaped 3-dimensional area with superior, anterior diagonal, posterior diagonal, and deep borders. It is bounded superiorly by the zygomatic arch; anteriorly by the masseter muscle, lateral pterygoid muscle, and mandibular ramus; and inferiorly by the sternocleidomastoid muscle, and the posterior belly of the digastric muscle. The deep portion lies lateral to the parapharyngeal space, styloid process, stylomandibular ligament, and carotid sheath.

The deep anatomic relationship is important because tumors may arise in the deep portion and grow into the parapharyngeal space and may present as intraoral masses. These tumors are termed dumbbell tumors when they grow between the posterior aspect of the mandibular ramus and the stylomandibular ligament. This position causes a narrow constricted portion with larger unrestricted portions on either side forming a dumbbell shape. Tumors are called round tumors when they pass posterior to the stylomandibular ligament into the parapharyngeal space, forming unrestricted round masses.

The parotid is a unilobular gland through which the facial nerve passes. There are no true superficial and deep lobes. The term superficial parotidectomy or parotid lobectomy refers only to the surgically created boundary from facial nerve dissection.

The Stensen duct drains the parotid gland. Initially, it is located approximately 1 cm below the zygoma and runs horizontally. It passes anteriorly to the masseter muscle and then penetrates the buccinator muscle to open intraorally opposite the second maxillary molar.

The facial nerve exits the skull via the stylomastoid foramen located immediately posterior to the base of the styloid process and anterior to the attachment of the digastric muscle to the mastoid tip at the digastric ridge. The nerve travels anteriorly and laterally to enter the parotid gland. Branches of the facial nerve innervating the posterior auricular muscle, posterior digastric muscle, and stylohyoid muscle arise before the nerve enters the parotid gland. Just after entering the parotid gland, it divides into 2 major divisions: the upper and lower divisions. This branch point is referred to as the pes anserinus. Subsequent branching is variable, but the nerve generally forms 5 branches. The buccal, marginal mandibular, and cervical branches arise from the lower division. The zygomatic and temporal branches arise from the upper division.

Branches of the external carotid artery provide arterial supply to the parotid gland. The posterior facial vein provides venous drainage, and lymphatic drainage is from lymph nodes within and external to the gland leading to the deep jugular lymphatic chain.

The gland receives parasympathetic secretomotor innervation from preganglionic fibers arising in the inferior salivatory nucleus. These fibers travel with the glossopharyngeal nerve to exit the skull via the jugular foramen. They then leave the glossopharyngeal nerve as the Jacobson nerve and reenter the skull via the inferior tympanic canaliculus. The fibers traverse the middle ear space broadly over the promontory of the cochlea (tympanic plexus) and exit the temporal bone superiorly as the lesser petrosal nerve. The lesser petrosal nerve exits the middle cranial fossa through the foramen ovale, where the preganglionic fibers synapse in the otic ganglion. The postganglionic fibers travel with the auriculotemporal nerve to supply the parotid gland.

Submandibular gland
The submandibular glands are the second-largest salivary glands, after the parotid. They are encapsulated glands located anterior and inferior to the angle of the mandible in the submandibular triangle formed from the anterior and posterior bellies of the digastric muscle and the inferior border of the mandible.

The submandibular gland has a superficial portion located lateral to the mylohyoid and a deep portion located between the mylohyoid and the hyoglossus. The marginal mandibular branch of the facial nerve and the anterior facial vein pass superficially to the gland. Posteriorly, the gland is separated from the parotid gland by the stylomandibular ligament. The facial artery crosses the deep portion of the gland.

The Wharton duct drains the gland. It passes between the mylohyoid and hyoglossus muscles and along the genioglossus muscle to enter the oral cavity lateral to the lingual frenulum.

The lingual nerve and submandibular ganglion are located superior to the submandibular gland and deep to the mylohyoid muscle. The hypoglossal nerve lies deep to the gland and inferior to the Wharton duct.

Arterial blood supply is from the lingual and facial arteries. The anterior facial vein provides venous drainage. The lymphatic drainage is to the submandibular nodes and then to the deep jugular chain.

The submandibular and sublingual glands receive parasympathetic secretomotor innervation from preganglionic fibers, which originate in the superior salivatory nucleus. These fibers leave the brainstem as the nervus intermedius to join with the facial nerve. They then leave the facial nerve with the chorda tympani to synapse in the submandibular ganglion. Postganglionic fibers innervate the submandibular and sublingual glands.

Sublingual glands
The sublingual glands are the smallest of the major salivary glands. Unlike the parotid and submandibular gland, the sublingual gland is unencapsulated. Each gland lies medial to the mandibular body, just above the mylohyoid muscle and deep to the mucosa of the mouth floor.

Rather than 1 major duct, the sublingual glands have from 8-20 small ducts, which penetrate the floor of mouth mucosa to enter the oral cavity laterally and posteriorly to the Wharton duct. Arterial supply is from the lingual artery. Lymphatic drainage is to the submental and submandibular lymph nodes, then to the deep cervical lymph nodes. Innervation is via the same pathway as the submandibular gland.

Minor salivary glands
Approximately 600-1000 minor salivary glands are located throughout the paranasal sinuses, nasal cavity, oral mucosa, hard palate and soft palate, pharynx, and larynx. Each gland is a discrete unit with its own duct opening into the oral cavity.

Together, the salivary glands produce 1-1.5 L of saliva per day. About 45% is produced by the parotid gland: 45% by the submandibular glands, and 5% each by the sublingual and minor salivary glands. Saliva is produced at a low basal rate throughout the day, with flow increasing 10-fold during meals. Saliva functions to maintain lubrication of the mucous membranes and to clear food, cellular debris, and bacteria from the oral cavity. Saliva contains salivary amylase, which assists in initial digestion of food. It forms a protective film for the teeth and prevents dental caries and enamel breakdown, which occurs in the absence of saliva. Also, by virtue of production of lysozyme and immunoglobulin A in the salivary glands, saliva plays an antimicrobial role against bacteria and viruses in the oral cavity.

Imaging Studies:

* CT scanning and MRI

* Imaging studies of the salivary glands are usually unnecessary for the assessment of small tumors within the parotid or submandibular gland. CT or MRI is useful for determining the extent of large tumors and for evaluating extraglandular extension. Additionally, CT or MRI is helpful in distinguishing an intraparotid deep-lobe tumor from a parapharyngeal space tumor and for evaluation of cervical lymph nodes for metastasis.

* Minor salivary gland neoplasms are often difficult to assess on examination, and the use of preoperative CT or MRI is important for determining the extent of tumor, which otherwise is not clinically appreciable. This imaging is particularly valuable for salivary gland neoplasms in the paranasal sinus, where skull-base or intracranial extension may alter resectability of the tumors.

* CT-guided needle biopsy guided can be used to evaluate for difficult-to-reach tumors, such as neoplasms in the parapharyngeal space.

* Though often used in the past, CT sialography does not offer imaging superior to that of high-resolution CT or MRI alone, and the results rarely alter management.

* For most small parotid neoplasms without clinical evidence of facial nerve involvement, no pretreatment imaging studies are required.


Diagnostic Procedures:

* Fine-needle aspiration biopsy

* Fine-needle aspiration biopsy (FNAB) is a valuable diagnostic adjunct in evaluation of head and neck masses. Its role in evaluation of salivary gland tumors is controversial.

* Overall sensitivity of FNAB in distinguishing between benign and malignant salivary gland tumors is approximately 95%. Its specificity is approximately 98%.

* It is generally agreed that FNAB is useful in evaluation of submandibular masses. Relatively few submandibular triangle masses represent primary submandibular gland neoplasms. Most of these masses are due to either inflammatory diseases or neoplasms involving the lymph nodes in this region. FNAB is helpful for differentiating between these possibilities and for directing therapy.

* Value of routine FNAB for parotid masses is less clear. Opponents state that FNAB results rarely alter the management of parotid masses, which is carefully planned and executed surgical excision. Proponents believe that obtaining a preoperative histologic diagnosis is valuable for several reasons: Knowledge of the histologic type may be helpful in preparing patients and surgeons for the more extensive surgery required for high-grade malignancies, and some nonneoplastic causes of parotid masses may be ruled out without surgical intervention.


Histologic Findings:
A variety of benign and malignant neoplasms can arise in the salivary glands. An accurate histopathologic diagnosis is essential for the rational treatment of patients with salivary gland neoplasms. Batsakis et al have reported the classification system most commonly used in epithelial salivary gland tumors (see Image 3).


Benign salivary gland neoplasms

Pleomorphic adenoma, or benign mixed tumor
Pleomorphic adenomas are the most common salivary gland tumor. They represent 60% of parotid tumors and 36% of submandibular tumors. They affect men and women equally and usually appear in the fifth decade. The tumors are typically slow growing and asymptomatic.

On gross evaluation, the tumors are smooth, multilobular, and encapsulated. The capsule, however, is incomplete microscopically, and tumor pseudopodia may extend beyond the margin of the apparent capsule. The contents of the tumor appear varied depending on the cellularity and the myxoid content.

Microscopically, the characteristic feature is the morphologic diversity of the tumor, with presence of both epithelial and mesenchymal-like elements. Two cells are responsible for the varied appearance, the epithelial cell and the myoepithelial cells. The epithelial cells make up the majority of the cellular regions, and the myoepithelial cells make up the stromal areas. The ratio of cellular elements to stromal elements can vary widely. The stromal component may have a myxoid, fibroid, or chondroid appearance.

Presence of pseudopodia that extend beyond the apparent margin of the tumor is responsible for the significant rate of recurrence with simple enucleation of pleomorphic adenomas. The treatment of choice for pleomorphic adenomas of the parotid gland is superficial lobectomy (described in Treatment), taking a cuff of normal glandular tissue with the tumors. Submandibular and minor salivary gland pleomorphic adenomas should likewise be removed with a cuff of normal tissue. Abiding by this principle has led to low rates of recurrence, typically lower than 5%.

A premium is placed on initial excision of pleomorphic adenomas, because management of recurrent disease is difficult and often frustrating. Recurrent pleomorphic adenomas often occur in a multifocal fashion and can present 10-15 years after initial resection. Repeat operation puts the facial nerve at increased risk for permanent injury, and facial nerve monitoring is helpful to diminish this risk. Cure rates are reported to be 25% or lower when repeat operation for recurrent pleomorphic adenomas are performed.

Radiation therapy may be helpful in treating multiply recurrent disease and is decided on a case-by-case basis. The facial nerve should not be sacrificed in the removal of pleomorphic adenomas. Tumor grossly adherent to the nerve should be removed by using microdissection techniques.

Warthin tumor, or papillary cystadenoma lymphomatosum
Warthin tumors represent the second-most common benign salivary gland neoplasm, comprising approximately 6-10% of all parotid tumors. Warthin tumors rarely occur in the submandibular or minor salivary glands. Warthin tumors affect men more commonly than women, a ratio of 5:1, and they typically appear between the fourth and seventh decades. The incidence is increased among tobacco smokers. Warthin tumors are bilateral in 12% of cases.

Warthin tumors have a smooth capsule. When incised, multiple cystic spaces containing mucinous material are appreciated. On microscopic evaluation, multiple papillae are present, projecting into the cystic spaces. The papillae consist of a double-layered epithelium. The outer layer consists of granular oncocytes with apically located nuclei. The inner layer contains round-to-cuboidal eosinophilic cells. The stroma beneath the epithelium is lymphoid, often containing germinal centers.

Warthin tumors are best treated by means of superficial parotidectomy that spares the facial nerve.

Oncocytoma
Oncocytomas are unusual benign neoplasms that arise from the granular oncocytes within the salivary glands. These tumors account for less than 1% of all salivary gland tumors. They occur more commonly in older patients and affect men and women equally. Malignant oncocytomas do occur, but they are extremely rare.

Benign oncocytomas are smooth and firm with a rubbery consistency. The tumors are cellular, containing round eosinophilic cells with a granular cytoplasm. The nuclei are small and have indentations. The granular appearance of these cells is the result of the high number of mitochondria present in the cytoplasm. Electron microscopy is used to identify this ultrastructural feature, which can be diagnostically helpful.

These tumors most commonly arise in the superficial portion of the parotid gland. They are best treated by superficial parotidectomy with preservation of the facial nerve. Tumors occurring outside the parotid gland should be excised with a cuff of normal tissue.

Monomorphic adenoma
Monomorphic adenomas often are grouped with pleomorphic adenomas. These are distinct tumors histologically, however, and lack pleomorphic features. Basal cell adenomas and clear cell adenomas are included in this group of tumors. Monomorphic adenomas are benign, slow growing, and are the least aggressive of the salivary gland tumors. They probably represent less than 2% of salivary gland neoplasms.

The most common variety of monomorphic adenomas is the basal cell adenoma. Basal cell adenomas most commonly occur in the minor salivary glands, usually the upper lip. The parotid gland is the usual location when they occur in the major salivary glands.

Grossly, the tumors are encapsulated and are smooth. Microscopically, the tumors contain epithelial parenchyma, which is sharply demarcated from the scant stroma by a thick prominent basement membrane. The epithelial cells have a palisading appearance at the periphery of the tumor parenchyma. The appearance can be confused with adenoid cystic carcinoma, but the distinction is clearly important, as the biologic behavior of the 2 tumors is vastly different.

Treatment consists of surgical excision with a margin of normal tissue for these benign and nonaggressive tumors.

Malignant salivary gland neoplasms

Mucoepidermoid carcinoma
Mucoepidermoid carcinoma is the most commonly occurring malignant neoplasm of the parotid gland and is the second-most common malignant neoplasm of the submandibular gland after adenoid cystic carcinoma. It represents about 8% of all parotid tumors.

Mucoepidermoid carcinomas are divided into low, intermediate, and high grades. These tumors contain 2 types of cells, as the name implies, mucous and epidermoid cells. The grade of tumor is determined by the relative proportion of these 2 cells. Low-grade tumors have a higher preponderance of mucous cells than epidermoid cells. The ratio of epidermoid cells rises in higher grades, and high-grade mucoepidermoid carcinomas may even resemble squamous cell carcinomas.

Low-grade tumors usually are small and appear partially encapsulated on gross examination. They may have some cystic components. High-grade tumors usually are larger and are more infiltrative. A capsule usually is not recognizable, and the tumors are more solid with a grayish-white appearance.

On microscopic examination, low-grade tumors contain sheets of mucoid cells separated by bands of epidermoid cells. Mucous cells are clear and plump with small nuclei. Epidermoid components resemble squamous cell carcinoma. High-grade mucoepidermoid carcinomas are composed nearly entirely of nests of malignant epidermoid cells. Few mucous cells or none at all are present, although when specially stained, cells containing mucous are apparent. This differentiates high-grade mucoepidermoid carcinoma from squamous cell carcinoma.

The biologic behavior of mucoepidermoid carcinoma is dependent on the grade of tumor. Low-grade lesions are fairly nonaggressive, and appropriate treatment imparts a good prognosis. High-grade neoplasms are much more aggressive, with high rates of regional lymph node metastases. Appropriate management of mucoepidermoid carcinoma is discussed below under Treatment of malignant salivary gland tumors.

Adenoid cystic carcinoma
Adenoid cystic carcinoma is the second-most common malignant salivary gland tumor, representing approximately 6% of all salivary gland neoplasms. It is the most common malignancy in the submandibular gland. It usually appears as a slow-growing painless mass.

Metastasis to regional lymph nodes is uncommon, but distant metastasis (usually to lung) is more common. Adenoid cystic carcinoma is unique in that survival at 5 years is approximately 65%, but 15-year survival is only 12%. Because of the slow growth of this tumor, patients may remain free of disease after initial treatment for 10 years or longer, only to develop metastases. Local recurrence is also common. The tendency for this tumor to grow along perineural and perivascular planes, often with skip lesions, helps explain the generally poor success of treatment.

Grossly, adenoid cystic carcinomas are usually monolobular and nonencapsulated. They have a gray-pink color and infiltrate the surrounding normal tissue. Microscopically, the tumors consist of basaloid epithelial elements that form cylindrical structures. Tumors are classified by the general architecture into 3 types, cribriform, tubular, and solid. The cribriform pattern has the classic Swiss cheese appearance with basophilic mucinous substance filling the cystic spaces. In the tubular pattern, the cells are arranged in smaller ducts and tubules with less prominent cystic spaces. The solid type is characterized by sheets of neoplastic cells with few cystic spaces. Any given tumor may contain all 3 patterns, but common to all types is the propensity for perineural invasion. Perineural extension accounts for the difficulty in eradicating adenoid cystic carcinoma despite extent of excision. Treatment is discussed below.

Acinic cell carcinoma
Acinic cell carcinoma is a low-grade neoplasm that represents 1% of all salivary gland neoplasms. Almost all (95%) arise in the parotid gland, and the majority of the remainder arise in the submandibular gland.

The tumors are formed of serous cells, explaining the propensity for the parotid gland. Grossly, they are encapsulated, hard, gray-white tumors. The tumors consist of lobules of round uniform-appearing cells with abundant cytoplasm arranged in nests. The cells most commonly resemble the serous acinar cells of the parotid gland, but they may have a clear cytoplasm as well.
Treatment is discussed below.


Carcinoma ex-pleomorphic adenoma
Carcinoma ex-pleomorphic adenoma refers to an epithelial carcinoma that arises from a preexisting pleomorphic adenoma. This tumor contains only malignant epithelial elements. This finding is in contrast to the malignant mixed tumor, which is a malignant neoplasm containing both epithelial and mesenchymal-like elements. This rare tumor is not related to pleomorphic adenoma.

Carcinoma ex-pleomorphic adenoma represents about 2-4% of salivary gland malignancies. Malignant degeneration of a pleomorphic adenoma seldom occurs, but the rate increases with long-term observation (ie, longer than 10 years) of the benign tumor. The characteristic clinical feature is sudden rapid growth of an otherwise slow-growing or stable mass.

Gross tumors appear firm, unencapsulated, and nodular with areas of central necrosis and hemorrhage. Microscopically, the diagnosis is based upon identifying a malignant process infiltrating a neoplasm, which has the histologic features of a pleomorphic adenoma. The malignant component may appear as an adenocarcinoma, squamous cell carcinoma, or undifferentiated carcinoma.

Carcinoma ex-pleomorphic adenomas have an aggressive natural history and a poor prognosis. Regional and distant metastases are common. Treatment is discussed below.


Squamous cell carcinoma
Primary squamous cell carcinoma of the salivary glands is rare. It is important to rule out a high-grade mucoepidermoid carcinoma, which may appear similar to a squamous cell carcinoma. Similarly, the differential diagnosis must exclude a primary squamous cell carcinoma of the skin or upper respiratory squamous mucosa with regional metastasis to the salivary glands. Excluding these 2 possibilities, true primary squamous cell carcinomas likely represent 0.3-1.5% of salivary gland tumors.
As in other head and neck squamous cell carcinomas, local and regional recurrences occur frequently. Treatment is discussed below.


Adenocarcinoma
Adenocarcinomas of the salivary gland represent those malignancies that cannot otherwise be easily classified. Collectively, they are rare, making up about 2-3% of salivary gland tumors. Some pathologists classify them as low- or high-grade, although all generally have an aggressive biologic behavior. They are treated and staged as described below.


Medical therapy:

Chemotherapy
In general, salivary gland malignancies respond poorly to chemotherapy, and adjuvant chemotherapy currently is indicated only for palliation. Doxorubicin- and platinum-based agents are most commonly used.

Neutron therapy
Recent reports have shown that neutron-based radiation therapy may be more effective than photon-based radiation therapy for the treatment of malignant salivary gland neoplasms. Neutron therapy causes significant morbidity, although it may increase local-regional control after resection of tumor with microscopic or clear margins.

Surgical therapy
The mainstay for treatment of all primary salivary gland tumors is carefully planned and executed surgical excision. Principles of surgery vary with the site of origin and are discussed as such.

Superficial parotidectomy with identification and dissection of the facial nerve is the minimum operation for diagnosis and treatment of parotid masses. Neither incisional biopsy nor enucleation should be performed for parotid masses.


Treatment of malignant salivary gland neoplasms

Parotid gland
The histopathologic diagnosis of parotid masses is often unknown prior to surgery. Thus, the minimum procedure that should be performed for masses in the parotid gland is a superficial parotidectomy with identification and preservation of the facial nerve. The shift from enucleation, which was popular prior to 1950, to superficial parotidectomy as the minimal procedure for parotid tumors has substantially reduced recurrence rates for both benign and malignant disease. For benign pathology, this procedure is curative. By today’s standards, enucleation and incisional biopsies should never be performed.

The specimen removed with superficial parotidectomy may be sent to pathology for frozen section analysis to intraoperatively determine whether a lesion is benign or malignant. Malignant diagnoses deserve special consideration and are discussed in Treatment of malignant salivary gland neoplasms below.

The facial nerve should not be sacrificed for benign tumors.

Submandibular gland
Routine FNAB for submandibular masses is helpful to rule out inflammatory disease of the submandibular gland, which is treated nonoperatively, and to rule out metastatic disease to the submandibular region, which is treated on the basis of the primary neoplasm.
Benign neoplasms of the submandibular gland require complete excision of the gland. Malignant neoplasms at a minimum require complete excision of the gland plus extended surgery depending on the specific tumor factors. Malignancies are discussed in the next section. Treatment of malignant salivary gland neoplasms

Primary treatment of malignant tumors of the salivary glands is surgery. This is often combined with postoperative radiation therapy, depending on specific tumor characteristics and stage. Extent of surgery is based on the size of the tumor, local extension, and neck metastases. The facial nerve is spared unless it is directly involved. Radiation therapy is recommended for all but small low-grade tumors.

Parotid gland
On the basis of the histologic classification and clinical stage, a useful management schema has been developed and is shown in Image 5. Four groups are identified. (Tumor, nodes, and metastases [TNM] stages are described in the Stage section.)

Group 1 includes T1 and T2 low-grade tumors (eg, low-grade mucoepidermoid carcinoma, acinic cell carcinoma). For these tumors, perform parotidectomy (superficial or total) with an adequate margin of normal tissue with preservation of the facial nerve. Inspect first-echelon nodes at the time of surgery and send suspicious nodes to pathology for evaluation. For complete excision without tumor spillage and no evidence of cervical metastases, radiation therapy is not performed.

Group 2 includes T1 and T2 tumors with high-grade features (eg, high-grade mucoepidermoid carcinoma, adenoid cystic carcinoma, squamous cell carcinoma, adenocarcinoma, carcinoma ex-pleomorphic adenoma). For these tumors, perform total parotidectomy, including first-echelon lymph nodes. Perform further neck dissection (modified radical neck dissection or selective neck dissection) for upper nodes confirmed to be positive on frozen sections or for clinically palpable cervical disease. Preserve the facial nerve unless it is directly infiltrated by tumor. In this case, the nerve is resected until the frozen section shows clear margins, and it is immediately reconstructed with cable grafting. Administer postoperative radiation therapy to the parotid region and the neck.

Group 3 includes any T3 tumor, any N+, and any recurrent tumors not in group 4. Tumors in this group generally require radical parotidectomy with sacrifice of the facial nerve in order to obtain sufficient tumor-free margins. Perform frozen sectioning of the facial nerve stump with continued excision until the margin is free. Immediately reconstruct the facial nerve with a cable graft. Perform neck dissection for positive nodal disease and treat the parotid bed and neck with postoperative radiation therapy.

Group 4 includes T4 tumors. Direct excision based on tumor size and location. Perform radical parotidectomy with excision of the involved structures (eg, facial nerve, mandible, mastoid tip, skin) as required to obtain tumor-free margins. Complex reconstruction, including free tissue transfer, is usually required to maximize functional restoration. Perform neck dissection for N+ disease and administer postoperative radiation therapy.

Submandibular gland
Submandibular salivary gland malignancies may be treated by a similar approach (see Image 5). For small, low-grade tumors (group 1), submandibular triangle excision is adequate without resection of cranial nerves.

For group 2 tumors, a wider resection of the submandibular triangle is required for clear margins. Sacrifice nerves only if they are directly involved with tumor. Frozen-section sampling of the epineurium of cranial nerves near the tumor mass may be performed, with the results directing further excision. Perform neck dissection for clinically positive disease. Postoperative radiation therapy is given.

Group 3 tumors commonly require sacrifice of the lingual and hypoglossal nerves to obtain clear margins. Perform selective or modified radical neck dissection and administer postoperative radiation therapy.

Group 4 tumors require wide surgical extirpation to fit the tumor extent. This may include mandible, floor of mouth, tongue, skin, and cranial nerves with appropriate reconstruction. Neck dissection and postoperative radiation therapy are added for these tumors.


Intraoperative details:

Superficial parotidectomy
Perform surgery with the patient under general anesthesia without paralysis. The face and neck are exposed and covered with a transparent adhesive drape for visualization of facial motion throughout the case. A properly designed incision allows adequate exposure and will yield a good cosmetic result. An incision is made in the preauricular crease. It may be taken posterior to the tragus. It is extended to the attachment of the lobule and carried over the mastoid tip. The incision is then extended into the neck in a skin crease. Alternatively, a facelift incision may be used for hidden scar placement in the hairline.

A Shaw hemostatic scalpel may be used to maintain hemostasis of the incision. Alternatively, a vasoconstrictive agent may be infiltrated into the skin. Take care not to inject deeply if an anesthetic agent, such as lidocaine or bupivacaine, is used. Some surgeons do not recommend the use of a local anesthetic because of the risk of facial paralysis.

Elevate a skin flap from the underlying parotid fascia, which has silvery sheen. Carry the flap anteriorly to the posterior border of the masseter muscle. Take care anteriorly so as not to disrupt the peripheral branches of the facial nerve.

The next step is to identify the main trunk of the facial nerve. Successful and rapid identification is achieved by taking advantage of known anatomic landmarks and wide exposure. Dissect the tail of the parotid gland anteriorly off the sternocleidomastoid muscle. Take care to preserve the greater auricular nerve if possible. Dissect the tail medially until the posterior belly of the digastric muscle is identified. The posterior belly of the digastric muscle is an important landmark for identifying the facial nerve, as the nerve may be identified just superior the muscle at approximately the same depth.

Next, perform dissection along the anterior aspect of the tragus along the perichondrium. Maintain a wide plane and retract the parotid gland medially. The cartilage will form a point medially, termed the tragal pointer. The facial nerve lies approximately 1 cm deep to this landmark, slightly anterior and inferior. A more reliable landmark is palpation of the tympanomastoid suture line in this region, which separates the mastoid tip from the tympanic portion of the temporal bone. The main trunk of the facial nerve lies at approximately this level or slightly medial. The styloid process may be palpated, and the facial nerve will lie between the styloid process and the posterior belly of the digastric muscle as it inserts on the mastoid tip.

The bridge of tissue created between the preauricular dissection and the dissection to the digastric muscle is divided superficially, and then blunt separation of soft tissues is performed in the direction of the facial nerve to identify the main trunk. A nerve stimulator may be helpful in locating the main trunk and branches, but use it sparingly.

In tissue beds previously operated on or in situations in which bulk tumor causes obstruction, this classic method of identifying the facial nerve may be impractical. In these situations, a peripheral branch of the facial nerve may be identified and traced posteriorly to the main trunk. Alternatively, the mastoid tip may be removed with a drill and the facial nerve identified intratemporally as it exits the stylomastoid foramen.

Once the main trunk of the facial nerve is located, use a fine-tipped hemostat to create a tunnel along the nerve and divide the parotid tissue superficially. This method of dissection involves 4 steps using the dissecting hemostat: push, lift, spread, and cut. If the facial nerve is constantly maintained in view, this method eliminates inadvertent injury.

Identify the pes anserinus (the point of main division of the facial nerve) and dissect each branch of the facial nerve out to the periphery. Depending on tumor location, the surgeon may start with either the inferior or the superior division. Once one division is dissected, a tunnel over the next division superiorly or inferiorly is created and connected to the previous dissection. This is repeated for each branch of the facial nerve, reflecting the parotid gland and tumor away from the facial nerve, then dissecting the final soft tissue attachments after each branch of the nerve has been identified. Low-level stimulation of the facial nerve at the conclusion of the operation is performed to confirm that all branches are intact.

This technique yields an intact superficial portion of the parotid gland that contains the tumor. Careful hemostasis is achieved by using a bipolar cautery. Do not use monopolar cautery in vicinity of the facial nerve. Insert a closed suction drain through a separate stab incision in the hairline and close the wound in layers. Antibiotic ointment and a gauze dressing may be applied.

Total parotidectomy
Strictly speaking, total parotidectomy is a misnomer. The procedure, by definition, involves removal of as much parotid tissue medial and lateral to the facial nerve as possible, along with the accompanying tumor. Exact approach varies depending on tumor location, but it usually involves a superficial parotidectomy to identify and preserve the facial nerve, followed by removal of parotid tissue and tumor deep to the facial nerve.

Attempt to preserve the facial nerve at all times. The nerve is never sacrificed for benign disease and sacrificed only if malignancy is found to be directly infiltrating the nerve. In these situations, remove the involved branch with the specimen and obtain frozen sections to ensure clearance of tumor.

Removal of dumbbell-shaped tumors and parapharyngeal space tumors requires additional exposure. This may be accomplished either transcervically after removal of the submandibular gland or via an extended approach with mandibulotomy and/or lip-splitting incision. This is discussed in a separate article on Parapharyngeal Space Tumors.

For cases of recurrent tumor and in cases where difficult dissection is anticipated, intraoperative facial nerve monitoring may be helpful in identifying and preserving the facial nerve.

Submandibular gland excision
Submandibular excision is generally performed with the patient under general anesthesia without paralysis. Make a 5-cm incision in a skin crease of the neck approximately 2-3 cm below the inferior border of the mandible. Carry the incision through the platysma and create small subplatysmal flaps inferiorly and superiorly. The surgeon must take care to avoid injuring the marginal mandibular branch of the facial nerve. The procedure may be accomplished by direct identification and dissection superiorly or by incision of the fascia overlying the gland and ligation of the posterior facial vein. The vein and fascia are reflected superiorly, protecting the marginal mandibular nerve.

In managing bulky tumors or malignancy, positive identification and dissection of the marginal mandibular branch not only provides wider exposure but also allows complete excision of the level I perifacial lymph nodes with the surgical specimen.

The gland and surrounding tissues are then freed from the undersurface of the mandible. The facial artery is usually divided as it approaches the mandible. Dissect the inferior portion of the gland from the digastric muscle. The facial artery is encountered again inferiorly near its origin from the external carotid artery and ligated. Retract the specimen laterally to expose the mylohyoid muscle. The mylohyoid muscle is dissected free and retracted medially. This maneuver exposes the hypoglossal nerve inferiorly, the lingual nerve superiorly, and the submandibular duct (Wharton duct). Retract the specimen inferiorly and identify the submandibular ganglion along the lingual nerve. The hypoglossal nerve is identified inferiorly. Once the lingual nerve, hypoglossal nerve, and submandibular duct are positively confirmed, ligate and transect the submandibular duct and ganglion. Final soft-tissue attachments are divided, and the specimen is removed.

If a neck dissection is indicated, this dissection is performed in continuity. Again, nerves are preserved unless directly involved with tumor. With neurotrophic tumors (adenoid cystic carcinoma,) frozen sections may be taken from the epineurium with excision of involved nerves.

Achieve careful hemostasis, insert a closed suction drain or Penrose drain, and close the wound in layers. Antibiotic ointment and a gauze dressing may be applied.


Postoperative details:
Examination of the facial nerve should be performed in the recovery room as soon as possible. If there is any uncertainty regarding the surgical integrity of the nerve, and paralysis of 1 or more branches is discovered, repeat exploration with cable grafting of injured segments should be performed.

Patients are usually admitted for one night. Closed drains are placed to bulb or wall suction and removed once output diminishes to approximately 30 mL/d (usually on postoperative day 1).
Patients should be monitored for the development of hematomas in the wound, which should be drained if discovered.

Facial nerve injury
This is an immediate postoperative complication that can be partial or complete. The surgeon must be confident at termination of the procedure that no branch has been inadvertently divided. If any doubt exists, repeat exploration is indicated to explore the nerve and repair divided branches. If the nerve is intact, monitor the patient for recovery. The use of steroids in this circumstance is controversial.

For incomplete eye closure, initiate an eye-care program consisting of lubricating drops and ointment to prevent exposure keratopathy. It may be useful to tape the eyelid closed at night. Consultation with an ophthalmologist is helpful for monitoring the eye, and reanimation procedures are considered at a later date. If facial nerve resection is required, simultaneous insertion of a gold weight into the upper eyelid may be helpful to prevent postoperative exposure keratopathy.

Hematoma
Careful hemostasis prevents this complication, but repeat exploration is occasionally required in cases involving hematoma formation.

Sialocele, or salivary fistula
This is a relatively common complication following parotid surgery. It may be treated by aspiration and compressive dressings. Fluid should be sent for amylase testing to confirm the diagnosis of sialocele. Anticholinergic medications, such as glycopyrrolate, may be helpful to reduce salivary flow.

Frey syndrome, or gustatory sweating
This is the most common long-term complication of parotid surgery. It occurs as a result of inappropriate autonomic reinnervation of sweat glands in the skin from parotid parasympathetics. The patient experiences facial sweating and flushing with meals. This complication commonly is not problematic. For significant symptoms, treatment with glycopyrrolate or topical scopolamine may be considered. A variety of measures to prevent this complication have been suggested, including dermal grafting, fat grafting, Alloderm placement, sub–superficial musculoaponeurotic system (SMAS) dissection, and maintenance of a thick skin flap.

Outcome and Prognosis

Understanding the factors that influence survival allows surgeons to develop a rational and well thought-out treatment plan.

Stage
Staging of malignant salivary gland tumors is important for predicting prognosis and for accurate comparison of treatment results. The American Joint Committee for Cancer Staging and End Result Reporting (AJCC) has published a TNM-based staging system for major salivary gland malignancies. The most recent edition, published in 1997, is summarized in Image 4.

This staging system has been developed on the basis of retrospective studies performed by Spiro, who correlated various tumor factors with the prognosis. The system includes tumor size, local extension of tumor, cervical lymph node metastases, and distant metastases. This method of staging has been shown to be correlated with survival. The 10-year determinant survival rate is 83% for stage I tumors, 76% for stage II tumors, and 32% for stage III tumors.

Histology
It is not surprising that the histologic diagnosis is correlated with biologic behavior. For this reason, dividing tumors into low-grade and high-grade categories is useful. Low-grade tumors include acinic cell carcinoma and low-grade mucoepidermoid carcinoma. High-grade tumors include adenoid cystic carcinoma, high-grade mucoepidermoid carcinoma, carcinoma ex-pleomorphic adenoma, squamous cell carcinoma, and adenocarcinoma. Low-grade tumors have 10-year survival rates of 80-95%, while 10-year survival rates for high-grade tumors range from 25-50%.

Histopathologic diagnosis is often unavailable at the time of initial surgery, and grading usually cannot be performed with frozen-section analysis. Thus, histologic information is typically not available before surgery. However, histopathologic diagnosis and grade should be considered because they may affect the decision regarding further surgery, elective neck dissection, or adjuvant radiation therapy (see Image 5).

Lymph node metastases
The ocurrence of regional lymph node metastases is related to tumor histopathology and size. The highest rates of lymph node metastases occur with high-grade mucoepidermoid carcinoma (44% of cases), squamous cell carcinoma (36% of cases), adenocarcinoma (26% of cases), undifferentiated carcinoma (23% of cases), and carcinoma ex-pleomorphic adenoma (21% of cases). High-grade mucoepidermoid carcinoma and squamous cell carcinoma have high rates of occult lymph node metastases (16% and 40%, respectively).

Modified radical neck dissection is indicated in any patient with clinically positive neck nodes. First-echelon lymph nodes, which are exposed during parotidectomy, should be sampled if they appear suspicious, with further treatment based on pathology. Elective neck dissection generally is not required because of the low rate of regional failure with salivary gland malignancy. Limited neck dissection for the N0 neck may be appropriate in patients with a high probability of occult cervical metastases (eg, those with high-grade mucoepidermoid carcinoma, squamous cell carcinoma, or tumors larger than 4 cm).

Pain
The significance of pain as a presenting symptom with salivary gland masses is not clear, because both malignant and benign disease may cause pain. However, among patients who are known to have a malignancy, those complaining of pain have a lower 5-year survival rate (35% vs 68% for those without pain). Thus, although pain is not a criterion of malignancy, it has poor prognostic significance for patients with malignancy and likely represents invasion of a nerve by tumor.

Facial nerve paralysis
Parotid masses associated with facial paralysis are nearly universally malignant, and this finding portends a poor prognosis. In a review of 1029 cases of parotid malignancy, Enroth and coworkers found that 14% of these cases are associated with facial nerve paralysis. Their patient had a 5-year survival of 9%.

Distant metastases
Distant metastases clearly portend a poor prognosis. Parotid tumors result in distant metastasis in 21% of cases. The incidence of distant metastases among high-grade tumors is 32%. For adenoid cystic carcinoma, the rate of distant metastases is nearly 50%. The most common sites are lung and bone. Although patients with metastases from adenoid cystic carcinoma may survive longer than 10 years because of the slow growth of these tumors, their survival with metastatic disease is short.

Note: The following images are not available here, but may be viewed on the emedicine.com website at: http://www.emedicine.com/ent/topic679.htm


PICTURES 
Caption: Picture 1. Salivary gland neoplasms. Common salivary gland neoplasms.
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Caption: Picture 2. Salivary gland neoplasms. Common parotid neoplasms.
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Caption: Picture 3. Salivary gland neoplasms. Common submandibular neoplasms.
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Caption: Picture 4. Salivary gland neoplasms. American Joint Committee for Cancer Staging and End Result Reporting (AJCC) classification of major salivary gland malignancies.
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Caption: Picture 5. Salivary gland neoplasms. Management algorithm for salivary gland malignancies.
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