General Principles and Management
Daniel G. Deschler
Kevin S. Emerick
Lori J. Wirth
Paul M. Busse
ANATOMY
Parotid
The exocrine salivary gland system of the upper aerodigestive tract is composed of two distinct classes of salivary glands. The major salivary glands consist of paired structures in the head and neck region with consistent anatomic drainage patterns within the oral cavity. The largest of these is the parotid gland followed by the submandibular gland and finally the sublingual glands. The minor salivary gland system consists of between 500 to 1,000 small glands located throughout the upper aerodigestive tract. Great density is noted in the region of the lips and the anterior oral cavity but extension of these glands into the oropharynx, tongue, larynx, sinonasal passages as well as the trachea is also demonstrated.
The primary function of the salivary gland system is the production of saliva which is a complex fluid composed of electrolytes, mucopolysaccharides, mucoproteins, immunoglobulins, and lysozymes. The primary digestive enzymes of the salivary gland system are amylase and lipase. The quality of saliva produced by specific glands can be quite variable from the relatively serous saliva produced by the parotid glands to the thicker more mucoid secretion of the minor salivary glands. Saliva plays numerous critical functions within the oral cavity with primary focus on those affecting digestion. Saliva is critical for bolus formation and subsequent lubrication of the bolus to allow the various critically timed stages of deglutition. Enzymatic digestion of food begins with the interaction of the digestive enzymes contained within saliva. Adequate hydration from saliva allows successful speech and articulation. Similarly, saliva plays critical roles in the immune system as well as in the maintenance of dental hygiene. Treatment modalities, whether they be surgical, radiation therapy based, or chemotherapeutic, can have significant impact on salivary production and saliva quality and therefore significantly and negatively impact these critical functions.
The parotid glands are the largest of the major salivary glands weighing between 15 to 30 g each. The parotid gland is a lobulated gland that has its location based in the lateral aspect of the face, anterior and inferior to the auricle. The lateral aspect of the gland is covered by the facial skin. The posterior aspect of the gland rests against the ramus of the mandible. The superior extent of the gland is the zygomatic arch as it continues inferiorly to overlie the posterior belly of the digastric muscle. Laterally, a dense fascia will cover the parotid gland and this fascia will extend all the way from the zygomatic arch inferiorly toward the sternocleidomastoid muscle. Anteriorly, this fascia is contiguous with the fascia overlying the masseter muscle and is referred to as the parotidomasseteric fascia. At the superior and posterior aspect of the gland are several fascial attachments which are critical in the subsequent surgical intervention in and around the gland.1 Superiorly, thick fibrous attachments connect the gland to the zygoma. The fascia becomes thinner as the gland extends inferiorly in the pretragal region but then becomes quite dense again in the region of the tympanic bone and mastoid. This layer must meticulously be divided to allow access to the stylomastoid foramen and the identification of main trunk of the facial nerve. The most inferior aspect of the parotid gland is referred to as the tail of the parotid and overlies the angle of the ramus, extending down to the sternocleidomastoid muscle. This is the region in which the majority of benign tumors of the parotid gland are located. Final component of the parotid gland extends deeply behind the ramus of the mandible through the stylomandibular tunnel to enter the prestyloid component of the parapharyngeal space.
The primary arterial blood supply of the parotid gland is provided through branches of the extension of the external carotid artery as it continues under the digastric and stylohyoid muscles after giving off the facial artery branch which will course through the submandibular gland. The external carotid artery will then course through the deep parotid tissue to give off the superficial temporal artery. Further continuation of this vessel will give off the internal maxillary artery as it exits the gland. Of note is a
consistent arterial branch, the posterior auricular artery, which will be located approximately 2 mm lateral to the main trunk of the facial nerve and can be a useful landmark during facial nerve identification and subsequent dissection.
consistent arterial branch, the posterior auricular artery, which will be located approximately 2 mm lateral to the main trunk of the facial nerve and can be a useful landmark during facial nerve identification and subsequent dissection.
The venous system for the gland begins with the superficial temporal and the deep maxillary veins which combine within the gland to form the retromandibular vein. The retromandibular vein will exit the inferior-posterior aspect of the gland and usually be contiguous with the external jugular vein as it drains into the lower neck. If there is no external jugular vein of significance, the retromandibular vein will usually drain into a deep facial vein at the lower aspect of the gland and continue into the internal jugular vein. A critical anatomic relationship provided by the venous anatomy of the gland is that the facial nerve branches will standardly run in a plane just superficial to the retromandibular vein. Therefore, with axial imaging assessment of masses of the parotid gland, the orientation and displacement of the retromandibular vein can give useful information in potential facial nerve branch location.
The primary drainage pathway for the parotid gland is via the parotid duct. This structure is approximately 4 to 7 cm long and exits from the anterior aspect of the gland in the plane along the line from the oral commissure to the lobule of the ear. Upon leaving the gland, the parotid duct will course over the masseter muscle and then make a sharp turn medially as it pierces the buccinator muscle to exit in the oral cavity as the Stensen duct. The Stensen duct is visible as a small papule located in the buccal mucosa opposite the upper second molar. Accessory parotid glands are noted in between 21% and 56 % of patients and will be situated anterior to the gland along the course of the Stensen duct. In most cases, the accessory gland will have ancillary drainage into the parotid duct, but may also have independent drainage.
Critical to the management of any lesion within the parotid gland is a clear understanding of the motor neural supply to the face which is intimately related to the anatomy of the gland. The facial nerve (cranial nerve VII) provides the primary motor neural function to the muscles of facial expression. A thorough understanding of its anatomic course is critical to any surgical management of parotid gland lesions. Originating from the brain stem, the facial nerve has five distinct segments prior to exiting the temporal bone. These include the intracranial pontine segment, the meatal segment through the internal auditory canal, the labyrinthine segment, the tympanic segment, and finally the mastoid segment. The extratemporal component of the facial nerve begins upon its exit from the mastoid bone at the stylomastoid foramen. Familiarity with the intratemporal components of the facial nerve is critical as perineural involvement by tumor may extend proximally requiring resection of a nerve within these regions as well as grafting from the intratemporal nerve to its muscular branches.
The extratemporal facial nerve is directly addressed in most surgeries of the parotid gland, and a clear understanding of its anatomy is critical to successful treatment in this delicate anatomic region. The main trunk of the facial nerve will exit via the stylomastoid foramen which is located laterally and inferiorly to the styloid process at the intersection of the mastoid and the tympanic bones. The nerve will usually give off small branches just upon exiting the stylomastoid foramen to the stylohyoid muscle and the posterior belly of the digastric. At this point, the nerve will then enter the parotid gland and extend for a short course before beginning its branching pattern. The nerve is standardly identified in this region at the main trunk and then dissected in an antegrade fashion to expose its orientation to masses within the gland.
There are numerous critical landmarks which facilitate the location of the main trunk of the facial nerve as it exits the temporal bone (Table 25.1). The most consistent anatomic landmark is the tympanomastoid suture line. The main trunk of the facial nerve will standardly rest between 2 and 4 mm deep to this.2,3 The tragal pointer, the apex of the triangle forming the deepest part of the tragal cartilage, is another useful landmark and is defined as the triangular component of the deepest aspect of the tragal cartilage. This will rest approximately 1 cm superior and superficial to the nerve but is a less consistent landmark than the bony landmark of the tympanomastoid suture line.
TABLE 25.1 Anatomic Landmarks for Identification of the Facial Nerve during Parotid Surgery | ||||||||||||
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In the dissection of the facial nerve, it is critical that a wide and broad exposure is achieved. This involves freeing the fascial attachments in the pretragal and pretympanic components of the gland as well as broad inferior dissection which allows mobilization of the gland off the digastric muscle. Dissection is then done superiorly toward the digastric ridge where the muscle will enter the mastoid bone, and this similarly gives a good indication of the level at which the facial nerve will rest. With this broad superior and inferior dissection, meticulous dissection can then be done in the region of the tympanomastoid suture line to expose the stylomastoid foramen and the main trunk of the facial nerve. Once in the gland, the main trunk of the facial nerve will demonstrate one of numerous variations in branching pattern to innervate the various muscles of facial expression. The first major split in the nerve is at the pes anserinus. Here the nerve will usually break into two major branches, an upper temporofacial branch and a lower cervicofacial branch. Through various branching patterns described in Figure 25-1, five major branches will be given off. These include the frontotemporal branch, the orbitozygomatic branch, the buccal branch, the marginal mandibular branch, and the cervical branch.
As noted, clear identification of the facial nerve and its branches is critical to the surgical management of parotid masses, both benign and malignant. If there is an inability to adequately identify the main trunk of the facial nerve and proceed with a standard antegrade dissection, then alternative approaches can be undertaken. A retrograde means of dissection identifies specific branches of the facial nerve distally, once they leave the parotid gland, and then proceeds with dissection in a retrograde fashion as these branches coalesce to form the main branches and the main trunk of the facial nerve. The marginal mandibular branch can be identified inferiorly along the superior and posterior aspect of the submandibular gland and its fascia. The buccal branch will have a consistent location in the midface
as it crosses the masseter in close relation to the parotid duct. Similarly, the orbitozygomatic branch is in a consistent position located on the line between the tragus and the lateral canthus of the orbit. Whichever means of dissection is utilized, be it antegrade or retrograde or some combination, clear identification of the nerve and its anatomy is critical to surgical success.
as it crosses the masseter in close relation to the parotid duct. Similarly, the orbitozygomatic branch is in a consistent position located on the line between the tragus and the lateral canthus of the orbit. Whichever means of dissection is utilized, be it antegrade or retrograde or some combination, clear identification of the nerve and its anatomy is critical to surgical success.
 FIGURE 25-1. Anatomic variations of facial nerve branching. B, buccal; C, cervical; M, marginal mandibular; T, temporal; Z, zygomatic. Source: From Johns ME, Kapan MJ. Malignant neoplasms. In: Cummings CW, Frederickson JM, Harker LA, et al., eds. Otolaryngology—Head and Neck Surgery. 2nd ed. St. Louis, MO: Mosby-Year Book; 1993:1048, with permission. |
The sensory supply to the face and auricle surrounding the parotid gland is provided by the great auricular nerve which is formed from the cervical sensory plexus from rootlets C2 and C3. This nerve will course over the sternocleidomastoid muscle and then enter the parotid gland at a point that is usually 8 to 10 mm cephalad to the external jugular vein. The anterior branch of the great auricular nerve will course through the gland and supply the anterior facial skin whereas the posterior branch of the nerve will extend posterior to the lobule to innervate the ear. Preservation of the posterior branch of the great auricular nerve can be achieved with meticulous dissection of this branch through the posterolateral parotid parenchyma and maintenance of its course behind the lobule toward the ear, and studies have demonstrated potential benefit from the preservation of this nerve.
The secretomotor function of the parotid gland is controlled by the parasympathetic autoimmune system via the glossopharyngeal nerve (cranial nerve IX). Preganglionic parasympathetic fiber from the inferior salivary nucleus travel via cranial nerve IX through the jugular foramen where the tympanic branch will then turn back into the skull base via Jacobson nerve to enter the middle ear. These fibers will course along the roof of the middle ear becoming the lesser petrosal nerve which will then exit the skull base at the foramen ovale. The fibers then synapse at the otic ganglion located under the mandibular branch of cranial nerve V3. Postganglionic fibers exit the otic ganglion to join the auricular temporal branch of the trigeminal nerve in the inferotemporal fossa. These parasympathetic fibers supply the innervation for parotid salivary secretory function. Sympathetic innervation is modulated via the superior cervical ganglion sympathetic fibers, which travel along the external carotid system to innervate the gland.
The parotid gland is unique in its lymphatic anatomy. Through embryologic development, lymph nodes in the region of the parotid gland are incorporated into the gland itself and contained within the fascial borders. This is in distinction to the submandibular gland which contains no intraparenchymal lymph nodes. Ninety percent of the lymph nodes within the parotid gland will be located in the superficial lobe. The lymph nodes within the gland provide drainage from the scalp, face, ear, and orbit and primary tumors within these regions can lead to metastases within the parotid gland presenting as parotid masses. Similarly, lymphoma may occur within a lymph node in the parotid gland, presenting as a parotid mass.
Parapharyngeal Space
The parapharyngeal space is the deep-neck compartment oriented as an inverted pyramid in the parasagittal plane bilaterally. The base of this pyramid is situated at the skull base abutting the petrosal bone. The apex of the pyramid is the hyoid bone. The lateral borders are formed by the medial pterygoid muscle and the ramus of the mandible, whereas the medial border is constituted by the lateral pharyngeal wall with its associated fascia and musculature. The anterior limit is the pterygomandibular raphe whereas the posterior limit is the spine.
The parapharyngeal space is divided into two distinct compartments by the styloid process and the stylomandibular fascia. The poststyloid compartment of the parapharyngeal space contains the neurovascular structures of the carotid sheath whereas the primary components of the prestyloid compartment are elements of the deep lobe of the parotid gland. Parotid masses may involve the parapharyngeal spaces in two distinct fashions. Tumors can arise within the deep lobe of the parotid gland and then extend into the parapharyngeal space through the stylomandibular tunnel. These masses will have a dumbbell shape constituted by a component within the deep lobe of the gland as well as in the parapharyngeal space. Alternatively, tumors may arise from salivary gland tissue distinctly within the parapharyngeal space and therefore present as an isolated mass within the prestyloid parapharyngeal space. Masses of the parapharyngeal space are often incidentally noted on imaging of the head and neck region obtained for other reasons. Similarly, they may be asymptomatic but physical exam of the oral cavity can demonstrate a distinct
fullness of the lateral pharyngeal region with displacement of the soft palate, tonsil, and lateral pharyngeal wall. Physical exam can also demonstrate a diffuse fullness in the region of the parotid gland secondary to the lateral displacement of the gland by the deeply situated mass (Fig. 25-2).
fullness of the lateral pharyngeal region with displacement of the soft palate, tonsil, and lateral pharyngeal wall. Physical exam can also demonstrate a diffuse fullness in the region of the parotid gland secondary to the lateral displacement of the gland by the deeply situated mass (Fig. 25-2).
 FIGURE 25-2. T2-weighted MRI demonstrated extension pleomorphic adenoma of the left parapharyngeal space. |
Submandibular Gland
The second largest of the major salivary glands are the submandibular glands weighing 7 to 16 g each. These glands are located within the submandibular triangle that is bordered inferiorly by the anterior and posterior belly of the digastric muscle and superiorly by the lower border of the mandible. The majority of the submandibular gland is located below and posterior to the mylohyoid muscle with a smaller component anteriorly and superiorly, which extends deep to the mylohyoid muscle to abut the sublingual glands. This gives the gland a distinct horseshoe shape as it rests within the submandibular triangle. The submandibular gland is surrounded by the middle layer of the deep cervical fascia. This has importance as the marginal mandibular branch of the facial nerve runs in the plane immediately superficial to this fascia along the lateral and superior aspect of the submandibular gland. This becomes an important landmark in submandibular gland surgery designed to preserve the function of the lower branches of the facial nerve. As previously noted, there are no lymph nodes within the gland itself.4 The majority of lymph nodes associated with the submandibular gland rest superiorly along the facial vasculature as it exits the gland and crosses the mandible. These perifacial nodes deserve a distinct consideration in the setting of cutaneous malignancies as well as oral cavity cancers. Lymph nodes can also rest along the posterior component of the gland where it abuts level IIA.
The arterial supply to the submandibular gland is from the facial branch of the external carotid artery. The facial artery will branch from the ECA and course medially under the digastric and stylohyoid muscle to enter the posterior aspect of the gland. The facial artery will then give off two to four branches to supply the gland and then exit superiorly from the gland over the border of the mandible. Often a small notch can be palpable in the lower border of the mandible where this artery will cross.
The venous supply to the submandibular gland can be quite variable but primarily consist of the anterior facial vein, which travels over the mandible with the artery and then courses on the anterior surface of the gland lateral to its fascia. It then will join the common facial vein and empty into the internal jugular system. On rare occasions, the anterior facial vein may empty into a prominent anterior jugular vein or the external jugular system. The facial vein does have anatomic importance as the marginal mandibular branch of the facial nerve will run in the plane just superior to the nerve and therefore this relationship can be utilized in nerve-preserving maneuvers during submandibular gland surgery. If the vein is located in the lower to mid portion of the gland and then elevated superiorly, this will allow the nerve to be rotated superiorly and provide a protective effect. The posterior venous system of the submandibular gland drains via the posterior facial vein which can be quite prominent. Specific situations that lead to this increased size are if the posterior facial vein provides drainage of the retromandibular vein in the setting of an underdeveloped external jugular system.
The ductal drainage system of the submandibular gland coalesces to form the submandibular duct, which exits the gland and then travels deep to the lingual nerve and medial to the sublingual gland. The duct then enters the floor of the mouth as Wharton duct, which exits at either side of the lingual frenulum in the anterior floor of mouth. The submandibular gland maintains an intimate relationship with the lingual nerve because of its anatomic proximity as well as the attachment of the nerve to the gland via the submandibular ganglion. The lingual nerve enters the submandibular triangle from posteriorly and superiorly as an extension of the mandibular branch of cranial nerve V3. The lingual nerve will then give off a small branch to the mylohyoid muscle which is standardly sacrificed in the majority of submandibular gland surgeries. Parasympathetic secretory fibers from the facial nerve and chorda tympani travel along the lingual nerve to synapse in the submandibular ganglion. From here, the sensory fibers of the lingual nerve will continue anteriorly into the floor of mouth to supply the somatosensory and taste functions of the anterior two-thirds of the tongue. The lingual nerve and submandibular ganglion are readily exposed during surgical exploration with inferior retraction of the gland and superior retraction of the mylohyoid muscle. This allows the gland to be severed from the nerve while maintaining sensory function. This maneuver likewise allows assessment of potential direct neural involvement.
During the same maneuver, the hypoglossal nerve will be evident running in a separate plane deep into the gland. Surrounded by the venae comitantes, the nerve will continue anteromedially to supply motor function to the tongue. The hypoglossal nerve will originate from the skull base exiting at the hypoglossal canal and then travel medially to the internal jugular vein and superficially to the external carotid system as it turns medially to enter the submandibular triangle. The hypoglossal nerve will enter the submandibular triangle inferior and posterior to the junction of the anterior and posterior belly of the digastric muscle at the lesser cornu of the hyoid bone. The submandibular tumors do not routinely directly involve the 12th cranial nerve. Care must still be taken to avoid injury during gland resection with resultant hypoglossal paralysis.
Sublingual and Minor Salivary Glands
The smallest of the major salivary glands are the sublingual glands weighing between 2 and 4 g. The sublingual glands rest in the anterior floor of mouth superior to the mylohyoid muscle. Resting just lateral to the lingual frenulum and covered loosely by the oral cavity mucosa, the sublingual glands have a unique draining system via many small ductules (Rivinus ducts) which exit directly into the floor of mouth. Drainage may also occur via
connections to the submandibular ductal system. The sublingual glands are innervated by the parasympathetic fibers from the seventh cranial nerve.
connections to the submandibular ductal system. The sublingual glands are innervated by the parasympathetic fibers from the seventh cranial nerve.
The minor salivary gland system consists of between 500 and 1,000 variably sized small glands located throughout the upper digestive tract. Ranging in size from 1 to 5 mm, these glands are found throughout the lips, tongue, soft and hard palate, buccal mucosa, pharynx, larynx, upper trachea, nasopharynx, and paranasal sinuses. The majority of the minor salivary glands are concentrated in the region of the lips, tongue, soft and hard palate as well as the buccal mucosa. Postganglionic parasympathetic secretomotor innervation to the minor salivary glands depends on the anatomic region that primarily is via the lingual nerve and branches from the sphenopalatine ganglion.
EPIDEMIOLOGY
Salivary gland malignancies are not common. Considering that head and neck malignancies comprise only 5% to 6% of malignancies in the United States, the proportion of salivary malignancies overall is very small. They account for only 1 % to 6% of head and neck cancer and only 0.3% of all cancers. The relatively small number of patients with salivary gland malignancy has made it difficult to thoroughly describe the epidemiology and prevalence of these malignancies. Additionally, with >20 histologic subtypes, which have undergone an evolution of classifications and limited data on the etiology and risk factors for these tumors, accurately defining the true epidemiology of these tumors has been very difficult. Large population-based data from SEER provides some insight. An early study from SEER shows a mean incidence of 0.89 per 100,000 per year.5 A more recent SEER study using updated WHO histology classification found the incident rate to be 1.2 per 100,000 per year.6 Smaller series from institutional databases and national tumor registries in Europe have reported a similar incidence.7,8,9 The incidence appears to be very stable when compared over the last few decades.
There is a question of possible male predominance. The SEER data show a male predominance, with as much as a 51 % increase in incidence rate compared with females.9 However, other series have shown a much smaller difference in incidence rate which are effectively equal. Interestingly the SEER data identified a significant difference in the distribution of tumor histologies between men and women. For example, there are twice as many males with salivary ductal carcinoma, but there is no difference for adenoid cystic carcinoma (ACC). Depending on the makeup of tumor histology within a database, this could influence reported differences between males and females. There also appears to be a higher incidence rate among females <50; however, there is a higher rate among males >50.
Salivary glands malignancies typically present in the sixth decade of life. However, this too is likely impacted by histological subtype. Acinic cell carcinoma (AC), for example, has a mean age at diagnosis of 51 years, whereas squamous cell carcinoma has a mean age of >72 years of age. Some data have also suggested that more aggressive tumors tend to present at an older age, usually in the seventh decade.7 Describing differences in race among such a small population has been difficult. Early SEER data also found a 1.4 times greater incidence in white patients than in black patients.7,10 More recent data suggest this also may be histology driven.9 The incidence rates are equivalent among all races for the two most common histologies, mucoepidermoid and ACC. However, most other subtypes have a higher rate in white patients.
Another consideration is the distribution of malignant tumors among the different salivary glands. More than half occur in the parotid gland. Thirty percent arise in the submandibular gland and the remaining 10% to 15% arise in the sublingual and minor salivary glands. These overall numbers are important to consider when assessing a neoplasm in each of these different sites. However, the parotid gland is also the most common site for benign salivary gland tumors as well. Benign neoplasm predominates in the parotid gland with only 15% being malignant. On the other hand, 50% submandibular neoplasms are malignant and 70% to 80% of sublingual gland and minor salivary glands are malignant.11
There is limited knowledge available regarding the etiology of these tumors. There are data demonstrating variable expression and mutations related to epidermal growth factor receptor (EGFR), c-kit, Ki-67, MUC1, antiapoptotic proteins (BIM, BAX, Bcl 2), and her-2 to name a few, but these findings are far from universal. Viral etiologies including cytomegalo virus has recently been reported as a possible etiology.12 Altered p27/skp-2 expression has been reported as a key factor in differentiation and aggressiveness.13 However, it is unclear what induces these changes. The embryology and ultrastructure of the salivary gland can provide a framework for understanding how the different histologies of tumors develop (Fig. 25-3). Major salivary glands have
a ductal system through which both serous and mucinous cells drain. These are arranged into clusters called acini. The ducts are arranged in a series beginning with the acini, which drain into an intercalated duct which in turn drains into a striated duct and ultimately into the excretory duct.14 These ducts are lined with an epithelium, and a layer of myoepithelial cells are present deep into the epithelium. From this histologic framework, there are two theories on how malignant neoplasm arise.15 The multicellular theory suggests each type of neoplasm originates from a different cell type within the glandular unit, whereas the bi-cellular reserve cell theory suggests that all salivary neoplasm originate from either an excretory or intercalated duct cell which functions as a reserve cell with the ability to differentiate into different epithelial or epidermoid cells.
a ductal system through which both serous and mucinous cells drain. These are arranged into clusters called acini. The ducts are arranged in a series beginning with the acini, which drain into an intercalated duct which in turn drains into a striated duct and ultimately into the excretory duct.14 These ducts are lined with an epithelium, and a layer of myoepithelial cells are present deep into the epithelium. From this histologic framework, there are two theories on how malignant neoplasm arise.15 The multicellular theory suggests each type of neoplasm originates from a different cell type within the glandular unit, whereas the bi-cellular reserve cell theory suggests that all salivary neoplasm originate from either an excretory or intercalated duct cell which functions as a reserve cell with the ability to differentiate into different epithelial or epidermoid cells.
 FIGURE 25-3. Histologic structure of salivary gland tissue. |
PATHOLOGY
Although our understanding of histogenesis remains limited, there is a good descriptive knowledge of the different types of tumors classified as salivary gland malignancies. Additionally, this classification allows for tumors to be further subdivided into high grade and low grade (Table 25.2). The most common type overall is mucoepidermoid carcinoma (MEC) followed by adenoid cystic, acinic cell, adenocarcinoma, and carcinoma ex. However, the prevalence does vary based on age, gender, and anatomic location. The following is description of the key histologic subtypes.
Mucoepidermoid Carcinoma
MEC is the most common salivary gland malignancy overall, yet only accounts for 15% of all salivary tumors. However, MEC alone accounts for nearly a third of parotid malignancies. Greater than 80% of MEC occur in the parotid gland, 10% in the submandibular gland, and <5% in minor salivary glands.16 Palate is the most common minor salivary gland site for MEC, with rare occurrences on the retromolar trigone, floor of mouth, buccal mucosa, lip, and tongue. MEC is notably the most common malignant salivary gland tumor to arise in patients <20 years of age.
There is a variable composition of different cells in MEC: mucin-secreting, epidermoid, and intermediate. This variability has led to three distinct histological subtypes with different clinical courses.17 The initial descriptions of these tumors came from Stewart et al. in 1945. Shortly thereafter, Foote and Frazell established a two-tier grading system, one grade thought to be benign and the other malignant.16 However, it became clear to the authors that in fact all of these tumors were malignant, but in varying degrees of low, intermediate, and high grades. However, there has been a debate of the best way to consistently grade these tumors.
TABLE 25.2 Common Parotid Malignancies by Histologic Grade | ||||||||||||
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The two main grading systems were developed by Healey and modified by Batsakis17 and the system developed by Goode et al. at the AFIP.16 Each system grades tumors based on tumor architecture, pattern of invasion, cell type composition, histocytologic pleomorphism, and frequency of mitotic figures. Based on several studies using these grading systems, it has become clear there is a significant difference in the clinical behavior of these tumors depending on their grade. In addition to this focus on grade, there is also evidence for improved 5-year survival in stage I/II patients, 90%, compared with stage III/IV patients.18 Ultimately, specific genetic changes may be identified that better define these and help predict clinical outcome and guide treatment.14
Low-grade MEC (Fig. 25-4) has an excellent prognosis ranging from a reported 92% to 100% 5-year survival. Batsakis reported these tumors are found in a young population with a strong female predominance and present at an early stage.18,19 Surgical excision with negative margins yields an excellent local control rate, nearing 100%.16,18,19 These tumors rarely metastasize to regional lymph nodes or to distant sites. A recent report showed that surgery even with positive or close margins had an excellent control rate when adjuvant radiation was given.20
High-grade MEC behave very differently than their low-grade counterparts.21 Survival is very poor in this group, 22% to 43% 5-year survival. These tumors usually present in older patients, with a male predominance and present at stage III or IV16,17,18,19,22 with up to 85% of these tumors having regional metastasis. Of patients with MEC who present or develop distant metastasis, they are nearly all high grade. Histologically, these tumors frequently have poorly differentiated epidermoid cells and rare mucin-positive cells. They can be confused with other high-grade carcinomas such as squamous cell carcinoma, salivary ductal carcinoma, adenocarcinoma, and malignant mixed tumors.
Intermediate-grade tumors have an intermediate clinical course, both in terms of presentation and outcome. Patients present with smaller tumors than high-grade MEC, but neck metastasis is relatively common, occurring in almost 20% of patients.18
The local and regional/distant recurrence rates are 22% to 30% and 39%, respectively, which fall in between the incidence reported for high-grade and low-grade tumors. Five-year survival is approximately, 70% for the group as a whole.18,19 There appears to be a population of intermediate-grade MEC which does well, much like low-grade MEC, and a population which does quite poorly, behaving more like a high-grade MEC. Further studies into biochemical markers may help distinguish these tumors in the future. Not surprisingly, the variable clinical course has led to variable treatment among institutions. However, many favor an approach based on stage. Small, localized tumors with a benign clinical picture can be treated with wide local excision. However, large size, regional spread, and aggressive pathologic features should direct a more aggressive treatment course similar to a high-grade tumor.
The local and regional/distant recurrence rates are 22% to 30% and 39%, respectively, which fall in between the incidence reported for high-grade and low-grade tumors. Five-year survival is approximately, 70% for the group as a whole.18,19 There appears to be a population of intermediate-grade MEC which does well, much like low-grade MEC, and a population which does quite poorly, behaving more like a high-grade MEC. Further studies into biochemical markers may help distinguish these tumors in the future. Not surprisingly, the variable clinical course has led to variable treatment among institutions. However, many favor an approach based on stage. Small, localized tumors with a benign clinical picture can be treated with wide local excision. However, large size, regional spread, and aggressive pathologic features should direct a more aggressive treatment course similar to a high-grade tumor.
 FIGURE 25-4. Classic low-grade mucoepidermoid carcinoma with predominantly cystic component. The cysts are line with both epidermoid cells and mucinous cells. |
Adenoid Cystic Carcinoma
ACC is the second most common salivary gland malignancy. It was first recognized in 1854, but the term ACC was not used until 1953 by Foote and Frazell.23 They tend to present in the fifth and sixth decades of life without a clear sex predilection. It occurs most commonly in the minor salivary glands, with a predilection for the oral cavity and hard palate in particular. However, it is well known to occur in any salivary gland as well as other unexpected sites such as the lacrimal gland, esophagus, and tracheobronchial tree. Overall, these tumors are characterized by slow local growth with rare spread to regional lymphatics. However, they are well known for their propensity for perineural invasion (PNI) and distant metastasis.24,25,26 These tumors are also unique in that distant metastasis can also present in a very delayed fashion, years or decades later; therefore, long-term follow-up is important.27
The grading of ACC is much less controversial than other salivary gland malignancies. It is characterized by three histological subtypes: solid, tubular, and cribriform (Fig. 25-5). Most tumors possess components of two or three subtypes. The solid type demonstrates solid sheets and nests of atypical basaloid cells with an undifferentiated appearance and many mitoses.28 Several large series have demonstrated that the solid type histology imparts a worse prognosis with 5-year survival as low as 17% in some studies.24”26 Tubular histology has the best survival. The cribriform pattern is considered the classic ACC with a “Swisscheese” appearance and accounts for up to 64% of reported cases of ACC. It is considered an intermediate grade when comparing survival among all three of these subtypes.
 FIGURE 25-5. A: Cribriform type of adenoid cystic carcinoma with basaloid cells surrounding a myxoid matrix. B: Adenoid cystic carcinoma with extensive perineural spread. (See color insert.) |
Overall survival (OS) varies widely from different series and subsite. ACC is notable for its atypical survival curve. Unlike most head and neck malignancies, the survival for ACC does not plateau at 5 years. This is attributable to late local recurrences, late development of distant metastasis, and the slow growth of distant metastasis when they do occur. Clinical stage, solid histological subtype, and increased p53 expression are independent significant prognostic factors for poor survival.24 Age >45, paresthesias, pain, PNI and margin status also correlate with survival.25
ACC is usually treated with surgical resection followed by radiation therapy. Negative margins along nerves are a challenge to obtain because of extensive perineural spread and the presence of skip lesions along nerves. Despite the overall highgrade nature of this tumor, there is a low incidence of regional spread and elective neck dissection is not mandatory for the NO patient. However, more recent data have reported rates as high as 23% for occult regional metastasis including a 17% rate for early-stage tumors.29 Therefore, dissecting the first echelon of atrisk nodes may be considered. Given the margin issue discussed above, postoperative radiation is important for improving both local control and OS.24 Because of the slow-growing nature of this tumor, neutron beam therapy has been investigated.30 However, its overall benefit has yet to be determined in the postoperative setting and it is only available in a few sites worldwide.
Adenocarcinoma
Adenocarcinoma previously referred to a very heterogeneous group of tumors. However, today there are several well-described classifications of adenocarcinomas. These include tumors such as salivary duct carcinoma, polymorphous low-grade adenocarcinoma, and epithelial-myoepithelial carcinoma. These tumors are classified based on the different salivary subglandular units such as the different cells within the acini or different salivary ducts cells from which they arise. Those tumors that do not fall into recently described classifications are still collectively referred to as adenocarcinoma, not otherwise specified.
As more tumors are classified, the number of adenocarcinomas becomes much fewer, such that adenocarcinoma, not otherwise specified now represents the least common salivary gland tumor. This remaining group is still heterogenous with variable cytoarchitecture ranging from low grade to high grade in differentiation, solid or cystic, and papillary and nonpapillary features. They occur in older patients in their seventh decade of
life, with a 4:1 male predominance, and predominantly in major salivary glands.31 Poor prognostic features have previously been described and include advanced stage, high histological grade, infiltrative growth factor, and tumor DNA content.32
life, with a 4:1 male predominance, and predominantly in major salivary glands.31 Poor prognostic features have previously been described and include advanced stage, high histological grade, infiltrative growth factor, and tumor DNA content.32
Acinic Cell Carcinoma
ACs account for up 17% of all salivary malignancies. However, it appears to have a higher incidence among children, where it is second only to MEC in incidence. These tumors are thought to arise from progenitor reserve cells of the terminal tubules and intercalated ducts of salivary tissue.34 These tumors generally take the clinical course of a low-grade tumor. Batsakis did describe low- and high-grade histologic variants, with >90% of tumors considered histologically low grade.34
A recent National Cancer Data Base review of 1,353 cases has helped characterized this tumor.35 It arises at a younger age than other salivary gland malignancies based on a median age of 52. This study also found a female predilection. It has been reported to occur in all salivary glands but is predominantly a tumor of the parotid gland, 86% of cases. This is likely attributable to the predominance of serous-type acini in the parotid compared with other salivary glands. It is notable for an incidence of bilateral tumors in up to 3 % of cases, making it the second most common salivary neoplasm to occur bilaterally. Regional metastasis is not common. Studies report varying incidence from 0% to 17%, with most series reporting <10% and the National Cancer Data Base review identifying a 9.9% incidence.35,36,37
AC has an excellent 5-year disease-specific survival of >90%.35 Clinicopathologic factors that predict a poorer outcome include high-grade histology, regional or distant metastasis at presentation, primary tumor in the submandibular gland, and age >30 years.35 These patients likely have a 5-year survival around 30% to 40%. Interestingly, the overall recurrence rate from the Armed Forces Institute of Pathology series was 35%, yet within this group of recurrent disease only 16% died of this disease.38 Other reports have also highlighted that prolonged survival is possible despite persistent disease. This has led many surgeons to consider palliative surgery for patients with incurable disease.
Salivary Duct Carcinoma
Salivary duct carcinoma is best known histologically for its resemblance to ductal carcinoma of the breast, from which it is indistinct.39 Histologically, there are varying forms of cribriform, papillary, and solid growth patterns embedded in a sclerotic stroma. Comedonecrosis, PNI, and periglandular infiltration are common.
The clinical presentation is typical of a high-grade malignant tumor. It occurs most commonly in the parotid and is characterized by rapid onset, rapid progression, pain, and cranial nerve involvement. Advanced T and N stage are common as approximately half of patients present with stage IV disease, including up to 60% with regional metastasis.39,40 Regional metastasis is common even in small T1 tumors. The presence of regional metastasis is a particularly poor prognostic indicator as up to 50 % of patients with neck disease also had distant disease. Current treatment strategies provide good local regional control, unfortunately distant metastasis are not uncommon and make OS poor for these patients, 40% by 2 years and 20% by 5 years.39,40
All salivary duct tumors are treated as aggressive high-grade tumors. Aggressive surgical excision with facial nerve sacrifice, if clinically involved, and routine neck dissection are the standard first modality of treatment even for early T-stage tumors. Radiation to the primary and ipsilateral neck is also considered standard. Because of the poor survival and high incidence of distant metastasis, chemotherapy should also be considered. However, there is limited data on its efficacy, but a trial using cisplatin and 5-fluorouracil (5FU) is underway to investigate its use.40
Mixed Malignant Tumor and Carcinoma Ex-pleomorphic Adenoma
There is a pathological distinction between these two tumors. The first is a true mixed malignant carcinoma arising de novo and consists of a malignant epithelial component and a malignant mesenchymal component. The second is an epithelial malignancy which arises from a benign pleomorphic adenoma. True mixed malignant tumors are very rare and are therefore difficult to characterize clinically.
Carcinoma ex-pleomorphic adenoma is an aggressive tumor with variable histology. Typically, pleomorphic adenoma can still be identified within the mass, but >50 % of the mass shows malignant cells. This malignant component is most commonly adenocarcinoma (40%-44%), salivary duct carcinoma (25%-33%), adenoid cystic (14%), or adenosquamous cell carcinoma (7%).41,42 Unfortunately, the exact pathogenesis of these tumors remains unknown, but there are DNA studies which show increasing anaploidy over time, which indicates the potential for malignant transformation.43
These tumors usually arise in a long-standing mass. When a change in the long-standing mass occurs, patients usually present with rapid growth, pain, skin changes, and cranial nerve involvement. However, an asymptomatic neck mass is also a common presentation. Neck metastasis occurs in 20% to 30% of patients and distant spread eventually occurring in more than 40% of patients.40,41 As a group, survival is poor with 39% alive at 3 years and 30% at 5 years. There appears to be a subset which is particularly aggressive and progresses rapidly in the first year. These patients have approximately a 25% survival at 1 year.41 This group has a high T stage and N stage, >50% of the mass is carcinoma, and invasion into surrounding structures.41 Metastasis alone is a very poor prognostic factor. Spiro et al. reported only 1 of 31 patients with neck metastasis were alive at 10 years.44
Polymorphous Low-grade Adenocarcinoma
Polymorphous low-grade adenocarcinoma is an appropriate name as it has a very low-grade clinical course and is an accurate histologic description. Grossly, they are well circumscribed but not encapsulated. Microscopically, a mixture of growth patterns can be seen: solid islands, glandular profiles, tubules, trabeculae, cribriform nests, and single file lines of infiltration. They have a characteristic perineural targetoid pattern of growth. When the diagnosis is not clear, immunohistochemistry (IHC) can be helpful. Glial fibrillary acidic protein, S100, and SMA are nonspecific but can assist in the diagnosis.45
This subtype is notable for its propensity to arise in minor salivary glands, specifically those in the oral cavity.45 Within the oral cavity, the palate is the most common site, followed by the lip and the buccal mucosa. These tumors have a slow growth and
indolent biology, such that the typical presentation is that of an asymptomatic mass in the oral cavity, which has often been present for years. Metastasis is uncommon. In a series of 164 patients from the AFIP, there was no cervical or distant metastasis.45 Other series have reported up to a 12% neck metastasis incidence and 6% distant metastasis. The presence of a papillary component in these tumors may also be important. Some studies have shown a correlation with increased neck incidence of cervical metastasis when there is a prominent papillary component.46 This all leads to an excellent prognosis with a >90% survival.
indolent biology, such that the typical presentation is that of an asymptomatic mass in the oral cavity, which has often been present for years. Metastasis is uncommon. In a series of 164 patients from the AFIP, there was no cervical or distant metastasis.45 Other series have reported up to a 12% neck metastasis incidence and 6% distant metastasis. The presence of a papillary component in these tumors may also be important. Some studies have shown a correlation with increased neck incidence of cervical metastasis when there is a prominent papillary component.46 This all leads to an excellent prognosis with a >90% survival.
Primary Lymphoma
Primary lymphoma of the salivary glands is uncommon, comprising only 1.7% to 3.1% of salivary neoplasm and only 10% of head and neck lymphomas.47 Nearly all of them occur in the parotid gland. Greater than 85% are non-Hodgkin B-cell lymphomas, either nodular or diffuse. The remainder is nearly all Hodgkin disease. Parotid lymphomas can arise from intraglandular lymph nodes or can arise from the parenchyma itself. The latter is referred to as mucosa-associated lymphoid tissue and makes up the majority of cases. A previous history of underlying coexistent autoimmune disorder such as Sjogren syndrome or rheumatoid arthritis has been reported in up to 44% of patients. Approximately 5% of all Sjogrens patients will develop lymphoma. A mass occurring in a patient with a previous diagnosis of benign lymphoepithelial lesion, multiple masses in a unilateral parotid gland or bilateral parotid masses, or a mass associated with multiple, enlarged unilateral or bilateral cervical lymph nodes should all raise the suspicion of lymphoma.48 The surgeon’s role in this disease is to assist with diagnosis by providing adequate tissue in a safe manner. This can be accomplished with incisional or excisional biopsy, including parotidectomy, depending on the location and size.
NATURAL HISTORY
Because of the varied locations for salivary glands, the presentation and natural history of salivary gland malignancies can vary. However, size, pain, nerve symptoms, symptoms related to invasion of nearby structures and evidence of metastasis are the common points of the natural history regardless of location.
The major salivary glands are relatively superficial in their location and therefore masses are often recognized on selfpalpation by the patient and this is the most common initial presentation. These tumors will enlarge; however, the rate at which they grow is extremely variable based on histological subtype. Low-grade tumors as well as ACC tend to grow very slowly, similar to that observed for a benign pleomorphic adenoma. Patients may be aware of the mass for years before they seek medical attention because of this slow growth. However, high-grade tumors tend to rapidly grow. In the case of a carcinoma ex-pleomorphic, there may a long-standing slow-growing tumor that begins to rapidly change. However, a high-grade mucoepidermoid tumor may present initially with rapid growth.
Pain is an important component of the natural history. Up to a third of patients have pain on presentation. As the tumor grows into adjacent structures, other symptoms will develop such as trismus, fixation of mass, and overlying skin changes. Since all of the major salivary glands are adjacent to cranial nerves, tumors over time will ultimately involve these nerves either by direct invasion or perineural spread. In the parotid, this involves the facial nerve predominantly. The sublingual and submandibular glands are most likely to impact on the lingual and hypoglossal nerves. Trigeminal nerve involvement can be seen with tumors in any of these locations.
TABLE 25.3 Incidence of Cervical Lymph Node Metastasis by Histologic Tumor Type | ||||||||||||||||||||
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The natural history of metastasis is also quite varied based on histology (Table 25.3). Low-grade malignancies have a low risk of regional lymph node metastasis or distant spread.18 However, high-grade MEC, for example, has an 80 % incidence of regional metastasis in some series.22 ACC, which is considered a highgrade malignancy, does not follow this trend and actually has a very low risk of regional spread. However, it has a very high risk of distant metastasis and unresectable perineural spread along the trigeminal and facial nerves.24,26 AC and intermediate-grade MEC have a variable rate of regional spread, 10% to 20%. This can make lymph node management more challenging. Other clinical features may predict a higher risk of metastasis such as size and invasion of surrounding structures.
OS for salivary gland malignancies vary. Survival ranges from nearly 100% for low-grade MEC to as poor as 25% 1-year survival for carcinoma ex-pleomorphic. Other clinicopathologic features are likely important in the natural history as well such as margin status at resection and extracapsular spread.49
STAGING
Table 25.4 summarizes the American Joint Committee on Cancer 7th edition staging for salivary gland malignancies.50 Although much of the literature and discussion about treatment and prognosis of salivary gland malignancies focuses on histological grading, TNM staging remains an important and useful tool. Table 25.5 provides a review of survival based purely on histologic substype and Figure 25-6 highlights the impact of stage on survival. There is a clear incremental decrease in survival for each stage, such that at 5 years observed survival is 70 % for stage I compared with 30% survival for stage IV.50 This further demonstrates that stage and histology are important predictors of survival.
In the most recent update to the AJCC staging, there were a few changes. The most notable change to the staging in 2010 was the addition of stages IVA, B, and C. T4a tumors are now classified as stage IVA, T4b and N3 tumors are stage IVB, and patients with distant metastasis are stage IVC (Table 25.6).
TABLE 25.4 American Joint Committee on Cancer (AJCC) TNM Staging System: Salivary Gland Staging | ||||||||||||||||||||||||||||||||||||||
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TABLE 25.5 Estimate of 5-year Survival Based on Histologic Subtype | ||||||||||||||||||||
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EVALUATION
There are three key elements in the evaluation of a suspected salivary gland malignancy. Each has an important role in diagnosing a malignancy and helping direct treatment. These elements are the history and physical, imaging, and biopsy.
History and Physical
Because of the varied locations for salivary glands, the history and physical examination appropriate for each site can also be quite varied. The major salivary glands are relatively superficial in their location and therefore masses are often recognized on self-palpation by the patient. As with any neck mass, it is important to ascertain the key elements of the mass: size, nature of the progression, firmness, associated pain, overlying skin changes, and previous presence of masses. Because of the critical location of the cranial nerves with respect to the major salivary glands, it is important to ask about symptoms associated with the cranial nerves. Since minor salivary glands are distributed throughout the aerodigestive tract, these patients may have a completely different presentation. They are more likely to present with symptoms typical of classic squamous cell carcinoma of the head and neck such as throat discomfort, change in voice and speech, otalgia, and blood in the saliva. The history should also ascertain information about potential systemic manifestations such as unintentional weight loss, fatigue, pulmonary symptoms, bone pain, and focal neurological deficits.
The physical exam such as the history should characterize the mass based on location, size, mobility, and involvement of surrounding structures. Evaluation should assess for facial twitching or facial asymmetry, dysarthria, limited tongue mobility, dysphagia, facial dysesthesia or hypoesthesia, and changes in the sensation of the tongue and floor of mouth. Cranial nerves II through XII should be fully assessed on examination in all patients with a suspected salivary gland neoplasm.
Although the most common presentation is an asymptomatic mass, other signs and symptoms will help alert the clinician of a possible malignancy. Up to one-third of malignancies have pain associated with the mass. Twenty percent have some cranial nerve symptoms and 10% have overlying skin involvement.9
Imaging
Imaging studies are critical for evaluating and treatment planning for salivary gland malignancies in all sites. Computed tomography (CT) is most familiar to head and neck surgeons and is very useful for defining the presence of a mass as well as its relationship to boney structures such as the mandible and temporal bone. It is also an excellent modality for assessing lymph node statues. For minor salivary gland tumors or sublingual gland tumors, this remains an excellent first mode of imaging. However, in recent years MRI has become an important modality in salivary gland imaging.51 Greater experience with MRI has helped define classic features of benign and malignant tumors, which makes this potentially a more specific test and sensitive imaging modality.
There are several important potentially diagnostic features on MR imaging that can be used in the preoperative assessment. Malignant lesions are hypointense on T2 imaging, which is helpful in distinguishing between benign tumors such as a pleomorphic adenoma. High-grade malignant tumors usually have an irregular border and can be seen infiltrating surrounding structures. Low-grade malignancies are usually well circumscribed but they are not encapsulated.52,53 The hypointensity on T2 imaging and contrast enhancement should raise suspicion for
a malignancy. Additional findings can be indicative of specific histological subtypes. Mucoepidermoid tumors may demonstrate a significant cystic component that has high intensity on both T1 and T2 imaging due to the mucin content.53 Adenoid cystic tumors, which are predominantly solid type histology, have low signal intensity on T2 imaging whereas cribriform and tubular types have a higher intensity on T2 because of their lack of cellularity.53 Primary salivary lymphoma can be distinguished when it arises in a periparotid lymph node. There is typically a distinct plane separating the mass from the gland. This is more difficult to assess when the node is intraparotid; however, it is usually low signal intensity on both T1 and T2 imaging with limited enhancement with contrast.51,52
a malignancy. Additional findings can be indicative of specific histological subtypes. Mucoepidermoid tumors may demonstrate a significant cystic component that has high intensity on both T1 and T2 imaging due to the mucin content.53 Adenoid cystic tumors, which are predominantly solid type histology, have low signal intensity on T2 imaging whereas cribriform and tubular types have a higher intensity on T2 because of their lack of cellularity.53 Primary salivary lymphoma can be distinguished when it arises in a periparotid lymph node. There is typically a distinct plane separating the mass from the gland. This is more difficult to assess when the node is intraparotid; however, it is usually low signal intensity on both T1 and T2 imaging with limited enhancement with contrast.51,52
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