Salivary Gland Neoplasms
- Author: Steve C Lee, MD, PhD; Chief Editor: Arlen D Meyers, MD, MBA more...
Neoplasms that arise in the salivary glands are relatively rare, yet they represent a wide variety of both benign and malignant histologic subtypes as seen in the image below. Although researchers have learned much from the study of this diverse group of tumors over the years, the diagnosis and treatment of salivary gland neoplasms remain complex and challenging problems for the head and neck surgeon. Some common salivary gland neoplasms are listed in the image below.
Salivary gland neoplasms make up 6% of all head and neck tumors. The incidence of salivary gland neoplasms as a whole is approximately 1.5 cases per 100,000 individuals in the United States. An estimated 700 deaths (0.4 per 100,000 for males and 0.2 per 100,000 for females) related to salivary gland tumors occur annually.
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 when older than 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 the following 3 pairs of glands: 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 arise 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, as seen in the image below.
Almost 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 the image below.
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 require a thorough understanding of tumor etiology, biologic behavior of each tumor type, and salivary gland anatomy.
The etiology of salivary gland neoplasms is not fully understood. Two theories predominate: the bicellular stem cell theory and the 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.
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 arise 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.
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). Although smoking is highly associated with head and neck squamous cell carcinoma, it does not appear to be associated with salivary gland malignancies. However some studies have indicated a relationship between salivary gland malignancies and occupational exposure to silica dust and nitrosamines.[2, 3]
As with most cancers, the exact molecular mechanism by which tumorigenesis occurs in salivary gland neoplasms is incompletely understood. Multiple pathways and oncogenes have been implicated, including oncogenes that are known to be associated with a wide variety of human cancers. These include p53, Bcl-2, PI3K/Akt, MDM2, and ras.
Mutation in p53 have been found in both benign and malignant salivary gland neoplasms and some evidence suggests that the presence of p53 mutations correlates with a higher rate of tumor recurrence. RAS is a G protein involved in growth signal transduction, and derangements in ras signalling are implicated in a wide variety of solid tumors. H-Ras mutations have been shown in a significant proportion of pleomorphic adenomas, adenocarcinomas, and mucoepidermoid carcinomas.
Studies that look at the neovascularization in salivary gland neoplasms have revealed factors that increase angiogenesis and are important in the progression of salivary gland neoplasms. Vascular endothelial growth factor (VEGF) is expressed by over half of salivary gland carcinomas tested and is correlated with clinical stage, recurrence, metastasis, and survival.
Seventy percent of pleomorphic adenomas have associated chromosomal rearrangements. The most common is a rearrangement of 8q12, occurring in 39% of pleomorphic adenomas. The target gene at this locus is PLAG1, which encodes a zinc finger transcription factor. The other target gene is HMGA2, which encodes a nonhistone chromosomal high mobility group protein that is involved in structural regulation of the chromosome and transcription. This gene is located at 12q13-15. Because these rearrangements are unique to pleomorphic adenomas amongst salivary gland neoplasms, interrogation of these rearrangements by RT-PCR or FISH may aid in diagnosis.
In mucoepidermoid carcinoma, the t(11;19)(q21;p13) chromosomal translocation has be identified in up to 70% of cases. This translocation creates a MECT1-MAML2 fusion protein that disrupts the Notch signaling pathway. This fusion protein is expressed by all cell types of mucoepidermoid when the translocation is present. Interestingly, fusion-positive tumors appear to be much less aggressive than fusion-negative tumors. Fusion-positive patients have significantly longer median survival and lower rates of local recurrence and distant metastasis.
CD117 or c-kit is a tyrosine kinase receptor that is found in adenoid cystic carcinoma, myoepithelial carcinoma, and lymphoepitheliomalike carcinoma. CD117 expression is able to reliably differentiate ACC from polymorphous low-grade adenocarcinoma, and small molecule inhibitors of this receptor are currently being studied as a potential therapeutic agent.
Other salivary gland neoplasms have been associated with overexpressed beta-catenin through abnormal Wnt signaling. Adenoid cystic carcinoma with mutations in CTNNB1 (b-catenin gene), AXIN1 (axis inhibition protein 1), and APC (adenomatosis polyposis coli tumor suppressor) show tumorigenesis via this process. Promoter methylation is known to develop tumors by inactivating tumor suppressor genes. Mutations that cause hypermethylation and downregulation of 14-3-3ó, a target gene for p53 in the Gap2/mitosis (G2/M) cell cycle checkpoint, was found to be extensive in adenoid cystic carcinoma (ACC). The methylation of genes that control apoptosis and DNA repair were also found in ACC, especially in high-grade tumors.
Chromosomal loss has been found to be an important cause of mutations and tumorigenesis in salivary gland tumors. Allelic loss of chromosomal arm 19q has been reported to occur commonly in adenoid cystic carcinoma. Mucoepidermoid carcinomas also show the loss of chromosomal arms 2q, 5p, 12p, and 16q more than 50% of the time.
Multiple other genes are being investigated in the tumorigenesis of salivary gland neoplasms. Hepatocyte growth factor (HGF), a protein that causes morphogenesis and dispersion of epithelial cells, has been found to increase adenoid cystic carcinoma scattering and perhaps invasiveness. Expression of proliferating cell nuclear antigen (PCNA) was found in the 2 most common malignant salivary tumors, mucoepidermoid carcinomas and adenoid cystic carcinomas, with higher expression in submandibular gland—derived malignancies. Overexpression of fibroblast growth factor 8b has been shown to lead to salivary gland tumors in transgenic mice.
Newer research in salivary gland neoplasms is focusing on factors that increase tumor invasion and spread. Matrix metalloproteinase-1, tenascin-C, and beta-6 integrin have been found to be associated with benign tumor expansion and tissue invasion by malignant tumors. In adenoid cystic carcinoma, increased immunoreactivity for nerve growth factor and tyrosine kinase A has been correlated with perineural invasion.
Taking 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. Although 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 manifest 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 of salivary gland masses should occur in the context 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. Bimanual palpation for submandibular and sublingual masses also 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 manifest as salivary gland masses. Also, the cervical lymph node basin should be palpated to assess for metastatic disease from a primary lesion of the salivary glands.
CN VII should be assessed carefully to identify any weakness or paralysis. Facial nerve palsy usually indicates a malignant lesion with infiltration into the nerve.
The salivary glands begin to form at 6-9 weeks’ gestation. The major salivary glands arise from ectodermal tissue. The minor salivary glands arise from either ectodermal or endodermal tissue, depending on 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 its 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 manifest within the substance of the 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 mucus, serum, or both. 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 along the salivary gland unit 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.
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 manifest 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 that pass posterior to the stylomandibular ligament into the parapharyngeal space, forming unrestricted round masses, are called round tumors.
The parotid is a unilobular gland through which the facial nerve passes. No true superficial and deep lobes exist. 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 that innervate 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 that leads to the deep jugular lymphatic chain.
The gland receives parasympathetic secretomotor innervation from preganglionic fibers that arise 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.
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.
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 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, 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 a 10-fold increase in flow 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. Saliva forms a protective film for the teeth and prevents dental caries and enamel breakdown, which occur 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.
Stenner M, Klussmann JP. Current update on established and novel biomarkers in salivary gland carcinoma pathology and the molecular pathways involved. Eur Arch Otorhinolaryngol. 2009 Mar. 266(3):333-41. [Medline].
Straif K, Weiland SK, Bungers M, Holthenrich D, Keil U. Exposure to nitrosamines and mortality from salivary gland cancer among rubber workers. Epidemiology. 1999 Nov. 10(6):786-7. [Medline].
Zheng W, Shu XO, Ji BT, Gao YT. Diet and other risk factors for cancer of the salivary glands:a population-based case-control study. Int J Cancer. 1996 Jul 17. 67(2):194-8. [Medline].
Elledge R. Current concepts in research related to oncogenes implicated in salivary gland tumourigenesis: a review of the literature. Oral Dis. 2009 May. 15(4):249-54. [Medline].
Cheuk W, Chan JK. Advances in salivary gland pathology. Histopathology. 2007 Jul. 51(1):1-20. [Medline].
Mamlouk MD, Rosbe KW, Glastonbury CM. Paediatric parotid neoplasms: a 10 year retrospective imaging and pathology review of these rare tumours. Clin Radiol. 2015 Mar. 70(3):270-7. [Medline].
Yuan WH, Hsu HC, Chou YH, Hsueh HC, Tseng TK, Tiu CM. Gray-scale and color Doppler ultrasonographic features of pleomorphic adenoma and Warthin's tumor in major salivary glands. Clin Imaging. 2009 Sep-Oct. 33(5):348-53. [Medline].
Rong X, Zhu Q, Ji H, et al. Differentiation of pleomorphic adenoma and Warthin's tumor of the parotid gland: ultrasonographic features. Acta Radiol. 2014 Dec. 55(10):1203-9. [Medline].
Adeyemi BF, Kolude BM, Akang EE, Lawoyin JO. A study of the utility of silver nucleolar organizer regions in categorization and prognosis of salivary gland tumors. Oral Surg Oral Med Oral Pathol Oral Radiol Endod. 2006 Oct. 102(4):513-20. [Medline].
Skalova A, Sima R, Kaspirkova-Nemcova J, et al. Cribriform Adenocarcinoma of Minor Salivary Gland Origin Principally Affecting the Tongue: Characterization of New Entity. Am J Surg Pathol. 2011 Aug. 35(8):1168-1176. [Medline].
Jaehne M, Roeser K, Jaekel T, Schepers JD, Albert N, Loning T. Clinical and immunohistologic typing of salivary duct carcinoma: a report of 50 cases. Cancer. 2005 Jun 15. 103(12):2526-33. [Medline].
Johnson JT, Ferlito A, Fagan JJ, Bradley PJ, Rinaldo A. Role of limited parotidectomy in management of pleomorphic adenoma. J Laryngol Otol. 2007 Dec. 121(12):1126-8. [Medline].
Kim WS, Lee HS, Park YM, et al. Surgical Outcomes of Parotid Cancer: A 10-Year Experience. Otolaryngol Head Neck Surg. 2012 Aug. 147(2 suppl):P180-P181. [Medline].
Eneroth CM, Hamberger CA. Principles of treatment of different types of parotid tumors. Laryngoscope. 1974 Oct. 84(10):1732-40. [Medline].
Terhaard CH, Lubsen H, Van der Tweel I, et al. Salivary gland carcinoma: independent prognostic factors for locoregional control, distant metastases, and overall survival: results of the Dutch head and neck oncology cooperative group. Head Neck. 2004 Aug. 26(8):681-92; discussion 692-3. [Medline].
Wax MK, Kaylie DM. Does a positive neural margin affect outcome in facial nerve grafting?. Head Neck. 2007 Jun. 29(6):546-9. [Medline].
Magnano M, gervasio CF, Cravero L, et al. Treatment of malignant neoplasms of the parotid gland. Otolaryngol Head Neck Surg. 1999 Nov. 121(5):627-32. [Medline].
Iseli TA, Karnell LH, Preston TW, et al. Facial nerve sacrifice and radiotherapy in parotid adenoid cystic carcinoma. Laryngoscope. 2008 Oct. 118(10):1781-6. [Medline].
Casler JD, Conley JJ. Surgical management of adenoid cystic carcinoma in the parotid gland. Otolaryngol Head Neck Surg. 1992 Apr. 106(4):332-8. [Medline].
Airoldi M, Pedani F, Succo G, et al. Phase II randomized trial comparing vinorelbine versus vinorelbine plus cisplatin in patients with recurrent salivary gland malignancies. Cancer. 2001 Feb 1. 91(3):541-7. [Medline].
Alves FA, Pires FR, De Almeida OP, Lopes MA, Kowalski LP. PCNA, Ki-67 and p53 expressions in submandibular salivary gland tumours. Int J Oral Maxillofac Surg. 2004 Sep. 33(6):593-7. [Medline].
Arabi Mianroodi AA, Sigston EA, Vallance NA. Frozen section for parotid surgery: should it become routine?. ANZ J Surg. 2006 Aug. 76(8):736-9. [Medline].
Aversa S, Ondolo C, Bollito E, Fadda G, Conticello S. Preoperative cytology in the management of parotid neoplasms. Am J Otolaryngol. 2006 Mar-Apr. 27(2):96-100. [Medline].
Bahar G, Dudkiewicz M, Feinmesser R, et al. Acute parotitis as a complication of fine-needle aspiration in Warthin's tumor. A unique finding of a 3-year experience with parotid tumor aspiration. Otolaryngol Head Neck Surg. 2006 Apr. 134(4):646-9. [Medline].
Bajaj Y, Singh S, Cozens N, Sharp J. Critical clinical appraisal of the role of ultrasound guided fine needle aspiration cytology in the management of parotid tumours. J Laryngol Otol. 2005 Apr. 119(4):289-92. [Medline].
Balakrishnan K, Castling B, McMahon J, et al. Fine needle aspiration cytology in the management of a parotid mass: a two centre retrospective study. Surgeon. 2005 Apr. 3(2):67-72. [Medline].
Balakrishnan K, Castling B, McMahon J, et al. Fine needle aspiration cytology in the management of a parotid mass: a two centre retrospective study. Surgeon. 2005 Apr. 3(2):67-72. [Medline].
Batsakis JG, Chinn E, Regezi JA, Repola DA. The pathology of head and neck tumors: salivary glands, part 2. Head Neck Surg. 1978 Nov-Dec. 1(2):167-80. [Medline].
Batsakis JG, Regezi JA. The pathology of head and neck tumors: salivary glands, part 1. Head Neck Surg. 1978 Sep-Oct. 1(1):59-68. [Medline].
Batsakis JG, Regezi JA. The pathology of head and neck tumors: salivary glands, part 4. Head Neck Surg. 1979 Mar-Apr. 1(4):340-9. [Medline].
Bell RB, Dierks EJ, Homer L, Potter BE. Management and outcome of patients with malignant salivary gland tumors. J Oral Maxillofac Surg. 2005 Jul. 63(7):917-28. [Medline].
Bialek EJ, Jakubowski W, Karpinska G. Role of ultrasonography in diagnosis and differentiation of pleomorphic adenomas: work in progress. Arch Otolaryngol Head Neck Surg. 2003 Sep. 129(9):929-33. [Medline].
Boahene DK, Olsen KD, Lewis JE, Pinheiro AD, Pankratz VS, Bagniewski SM. Mucoepidermoid carcinoma of the parotid gland: the Mayo clinic experience. Arch Otolaryngol Head Neck Surg. 2004 Jul. 130(7):849-56. [Medline].
Brackrock S, Krull A, Roser K, Schwarz R, Riethdorf L, Alberti W. Neutron therapy, prognostic factors and dedifferentiation of adenoid cystic carcinomas (ACC) of salivary glands. Anticancer Res. 2005 Mar-Apr. 25(2B):1321-6. [Medline].
Brennan PA, Umar T, Smith GI, McCauley P, Peters WJ, Langdon JD. Expression of type 2 nitric oxide synthase and p53 in Warthin's tumour of the parotid. J Oral Pathol Med. 2002 Sep. 31(8):458-62. [Medline].
Bullerdiek J, Wobst G, Meyer-Bolte K, et al. Cytogenetic subtyping of 220 salivary gland pleomorphic adenomas: correlation to occurrence, histological subtype, and in vitro cellular behavior. Cancer Genet Cytogenet. 1993 Jan. 65(1):27-31. [Medline].
Califano J, Eisele DW. Benign salivary gland neoplasms. Otolaryngol Clin North Am. 1999 Oct. 32(5):861-73. [Medline].
Castle JT, Thompson LD, Frommelt RA, Wenig BM, Kessler HP. Polymorphous low grade adenocarcinoma: a clinicopathologic study of 164 cases. Cancer. 1999 Jul 15. 86(2):207-19. [Medline].
Cesteleyn L, Helman J, King S, Van de Vyvere G. Temporoparietal fascia flaps and superficial musculoaponeurotic system plication in parotid surgery reduces Frey's syndrome. J Oral Maxillofac Surg. 2002 Nov. 60(11):1284-97; discussion 1297-8. [Medline].
Chavez-Delgado ME, Gomez-Pinedo U, Feria-Velasco A, et al. Ultrastructural analysis of guided nerve regeneration using progesterone- and pregnenolone-loaded chitosan prostheses. J Biomed Mater Res B Appl Biomater. 2005 Jul. 74(1):589-600. [Medline].
Chavez-Delgado ME, Mora-Galindo J, Gomez-Pinedo U, et al. Facial nerve regeneration through progesterone-loaded chitosan prosthesis. A preliminary report. J Biomed Mater Res B Appl Biomater. 2003 Nov 15. 67(2):702-11. [Medline].
Chen AM, Garcia J, Bucci MK, Quivey JM, Eisele DW. The role of postoperative radiation therapy in carcinoma ex pleomorphic adenoma of the parotid gland. Int J Radiat Oncol Biol Phys. 2007 Jan 1. 67(1):138-43. [Medline].
Cohen EG, Patel SG, Lin O, et al. Fine-needle aspiration biopsy of salivary gland lesions in a selected patient population. Arch Otolaryngol Head Neck Surg. 2004 Jun. 130(6):773-8. [Medline].
Daa T, Kashima K, Kaku N, Suzuki M, Yokoyama S. Mutations in components of the Wnt signaling pathway in adenoid cystic carcinoma. Mod Pathol. 2004 Dec. 17(12):1475-82. [Medline].
Daphna-Iken D, Shankar DB, Lawshe A, Ornitz DM, Shackleford GM, MacArthur CA. MMTV-Fgf8 transgenic mice develop mammary and salivary gland neoplasia and ovarian stromal hyperplasia. Oncogene. 1998 Nov 26. 17(21):2711-7. [Medline].
Douglas JG, Einck J, Austin-Seymour M, Koh WJ, Laramore GE. Neutron radiotherapy for recurrent pleomorphic adenomas of major salivary glands. Head Neck. 2001 Dec. 23(12):1037-42. [Medline].
Douglas JG, Koh WJ, Austin-Seymour M, Laramore GE. Treatment of salivary gland neoplasms with fast neutron radiotherapy. Arch Otolaryngol Head Neck Surg. 2003 Sep. 129(9):944-8. [Medline].
Douglas JG, Silbergeld DL, Laramore GE. Gamma knife stereotactic radiosurgical boost for patients treated primarily with neutron radiotherapy for salivary gland neoplasms. Stereotact Funct Neurosurg. 2004. 82(2-3):84-9. [Medline].
Driemel O, Maier H, Kraft K, Haase S, Hemmer J. Flow cytometric DNA ploidy in salivary gland tumours. Oncol Rep. 2005 Jan. 13(1):161-5. [Medline].
Ellis GL, Auclair PL. Tumors of the Salivary Glands. Center for Medical Education Technologies. Rockville, MD; 1996.
Enamorado I, Lakhani R, Korkmaz H, et al. Correlation of histopathological variants, cellular DNA content, and clinical outcome in adenoid cystic carcinoma of the salivary glands. Otolaryngol Head Neck Surg. 2004 Nov. 131(5):646-50. [Medline].
Enlund F, Nordkvist A, Sahlin P, Mark J, Stenman G. Expression of PLAG1 and HMGIC proteins and fusion transcripts in radiation-associated pleomorphic adenomas. Int J Oncol. 2002 Apr. 20(4):713-6. [Medline].
Foschini MP, Gaiba A, Cocchi R, Pennesi MG, Pession A. p63 expression in salivary gland tumors: role of DeltaNp73L in neoplastic transformation. Int J Surg Pathol. 2005 Oct. 13(4):329-35. [Medline].
Gaillard C, Perie S, Susini B, St Guily JL. Facial nerve dysfunction after parotidectomy: the role of local factors. Laryngoscope. 2005 Feb. 115(2):287-91. [Medline].
Gallipoli A, Manganella G, De Lutiodi di et al. Ultrasound contrast media in the study of salivary gland tumors. Anticancer Res. 2005 May-Jun. 25(3c):2477-82. [Medline].
Gedlicka C, Schüll B, Formanek M, et al. Mitoxantrone and cisplatin in recurrent and/or metastatic salivary gland malignancies. Anticancer Drugs. 2002 Jun. 13(5):491-5. [Medline].
Genelhu MC, Gobbi H, Soares FA, Campos AH, Ribeiro CA, Cassali GD. Immunohistochemical expression of p63 in pleomorphic adenomas and carcinomas ex-pleomorphic adenomas of salivary glands. Oral Oncol. 2006 Feb. 42(2):154-60. [Medline].
Gilbert J, Li Y, Pinto HA, et al. Phase II trial of taxol in salivary gland malignancies (E1394): a trial of the Eastern Cooperative Oncology Group. Head Neck. 2006 Mar. 28(3):197-204. [Medline].
Govindaraj S, Cohen M, Genden EM, Costantino PD, Urken ML. The use of acellular dermis in the prevention of Frey's syndrome. Laryngoscope. 2001 Nov. 111(11 Pt 1):1993-8. [Medline].
Handra-Luca A, Ruhin B, Lesty C, Fouret P. P27, SKP2, and extra-cellular signal-related kinase signalling in human salivary gland mucoepidermoid carcinoma. Oral Oncol. 2006 Nov. 42(10):1005-10. [Medline].
Harada K, Kawaguchi S, Supriatno, Onoue T, Yoshida H, Sato M. Enhancement of apoptosis in salivary gland cancer cells by the combination of oral fluoropyrimidine anticancer agent (S-1) and radiation. Int J Oncol. 2004 Oct. 25(4):905-11. [Medline].
Heller KS, Attie JN, Dubner S. Accuracy of frozen section in the evaluation of salivary tumors. Am J Surg. 1993 Oct. 166(4):424-7. [Medline].
Heller KS, Attie JN, Dubner S. Accuracy of frozen section in the evaluation of salivary tumors. Am J Surg. 1993 Oct. 166(4):424-7. [Medline].
Huber PE, Debus J, Latz D, et al. Radiotherapy for advanced adenoid cystic carcinoma: neutrons, photons or mixed beam?. Radiother Oncol. 2001 May. 59(2):161-7. [Medline].
Johns ME. The salivary glands: anatomy and embryology. Otolaryngol Clin North Am. 1977 Jun. 10(2):261-71. [Medline].
Johns ME, Goldsmith MM. Current management of salivary gland tumors. Part 2. Oncology (Williston Park). 1989 Mar. 3(3):85-91; discussion 94, 99. [Medline].
Johns ME, Goldsmith MM. Incidence, diagnosis, and classification of salivary gland tumors. Part 1. Oncology (Williston Park). 1989 Feb. 3(2):47-56; discussion 56, 58, 62. [Medline].
Johns MM 3rd, Westra WH, Califano JA, Eisele D, Koch WM, Sidransky D. Allelotype of salivary gland tumors. Cancer Res. 1996 Mar 1. 56(5):1151-4. [Medline].
Kerawala CJ, McAloney N, Stassen LF. Prospective randomised trial of the benefits of a sternocleidomastoid flap after superficial parotidectomy. Br J Oral Maxillofac Surg. 2002 Dec. 40(6):468-72. [Medline].
Koyuncu M, Sesen T, Akan H, et al. Comparison of computed tomography and magnetic resonance imaging in the diagnosis of parotid tumors. Otolaryngol Head Neck Surg. 2003 Dec. 129(6):726-32. [Medline].
Kyrmizakis DE, Pangalos A, Papadakis CE, Logothetis J, Maroudias NJ, Helidonis ES. The use of botulinum toxin type A in the treatment of Frey and crocodile tears syndromes. J Oral Maxillofac Surg. 2004 Jul. 62(7):840-4. [Medline].
Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics, 1998. CA Cancer J Clin. 1998 Jan-Feb. 48(1):6-29. [Medline].
Lee JH, Lee JH, Kim A, Kim I, Chae YS. Unique expression of MUC3, MUC5AC and cytokeratins in salivary gland carcinomas. Pathol Int. 2005 Jul. 55(7):386-90. [Medline].
Li J, El-Naggar A, Mao L. Promoter methylation of p16INK4a, RASSF1A, and DAPK is frequent in salivary adenoid cystic carcinoma. Cancer. 2005 Aug 15. 104(4):771-6. [Medline].
Lim JJ, Kang S, Lee MR, et al. Expression of vascular endothelial growth factor in salivary gland carcinomas and its relation to p53, Ki-67 and prognosis. J Oral Pathol Med. 2003 Oct. 32(9):552-61. [Medline].
Luukkaa H, Klemi P, Leivo I, Vahlberg T, Grenman R. Prognostic significance of Ki-67 and p53 as tumor markers in salivary gland malignancies in Finland: an evaluation of 212 cases. Acta Oncol. 2006. 45(6):669-75. [Medline].
MacLusky NJ, Chalmers-Redman R, Kay G, Ju W, Nethrapalli IS, Tatton WG. Ovarian steroids reduce apoptosis induced by trophic insufficiency in nerve growth factor-differentiated PC12 cells and axotomized rat facial motoneurons. Neuroscience. 2003. 118(3):741-54. [Medline].
Mantesso A, Loducca SV, Bendit I, Garicochea B, Nunes FD, de Araujo VC. Mdm2 mRNA expression in salivary gland tumour cell lines. J Oral Pathol Med. 2004 Feb. 33(2):96-101. [Medline].
Marchese-Ragona R, Marioni G, Restivo DA, Staffieri A. The role of botulinum toxin in postparotidectomy fistula treatment. A technical note. Am J Otolaryngol. 2006 May-Jun. 27(3):221-4. [Medline].
Maruya S, Namba A, Matsubara A, et al. Salivary gland carcinoma treated with concomitant chemoradiation with intraarterial cisplatin and docetaxel. Int J Clin Oncol. 2006 Oct. 11(5):403-6. [Medline].
Matizonkas-Antonio LF, de Mesquita RA, de Souza SC, Nunes FD. TP53 mutations in salivary gland neoplasms. Braz Dent J. 2005. 16(2):162-6. [Medline].
Mendenhall WM, Morris CG, Amdur RJ, Werning JW, Villaret DB. Radiotherapy alone or combined with surgery for salivary gland carcinoma. Cancer. 2005 Jun 15. 103(12):2544-50. [Medline].
Miyake H, Matsumoto A, Hori Y, et al. Warthin's tumor of parotid gland on Tc-99m pertechnetate scintigraphy with lemon juice stimulation: Tc-99m uptake, size, and pathologic correlation. Eur Radiol. 2001. 11(12):2472-8. [Medline].
Moreira JM, Ohlsson G, Rank FE, Celis JE. Down-regulation of the tumor suppressor protein 14-3-3sigma is a sporadic event in cancer of the breast. Mol Cell Proteomics. 2005 Apr. 4(4):555-69. [Medline].
Motoori K, Yamamoto S, Ueda T, et al. Inter- and intratumoral variability in magnetic resonance imaging of pleomorphic adenoma: an attempt to interpret the variable magnetic resonance findings. J Comput Assist Tomogr. 2004 Mar-Apr. 28(2):233-46. [Medline].
North CA, Lee DJ, Piantadosi S, Zahurak M, Johns ME. Carcinoma of the major salivary glands treated by surgery or surgery plus postoperative radiotherapy. Int J Radiat Oncol Biol Phys. 1990 Jun. 18(6):1319-26. [Medline].
Otsuka H, Graham MM, Kogame M, Nishitani H. The impact of FDG-PET in the management of patients with salivary gland malignancy. Ann Nucl Med. 2005 Dec. 19(8):691-4. [Medline].
Petit T, Bearss DJ, Troyer DA, Munoz RM, Windle JJ. p53-independent response to cisplatin and oxaliplatin in MMTV-ras mouse salivary tumors. Mol Cancer Ther. 2003 Feb. 2(2):165-71. [Medline].
Raimondi AR, Vitale-Cross L, Amornphimoltham P, Gutkind JS, Molinolo A. Rapid development of salivary gland carcinomas upon conditional expression of K-ras driven by the cytokeratin 5 promoter. Am J Pathol. 2006 May. 168(5):1654-65. [Medline].
Raine C, Saliba K, Chippindale AJ, McLean NR. Radiological imaging in primary parotid malignancy. Br J Plast Surg. 2003 Oct. 56(7):637-43. [Medline].
Rau AR, Kini H, Pai RR. Tissue effects of fine needle aspiration on salivary gland tumours. Indian J Pathol Microbiol. 2006 Apr. 49(2):226-8. [Medline].
Raymond MR, Yoo JH, Heathcote JG, McLachlin CM, Lampe HB. Accuracy of fine-needle aspiration biopsy for Warthin's tumours. J Otolaryngol. 2002 Oct. 31(5):263-70. [Medline].
Rohen C, Rogalla P, Meyer-Bolte K, Bartnitzke S, Chilla R, Bullerdiek J. Pleomorphic adenomas of the salivary glands: absence of HMGIY rearrangements. Cancer Genet Cytogenet. 1999 Jun. 111(2):178-81. [Medline].
Roijer E, Nordkvist A, Strom AK, et al. Translocation, deletion/amplification, and expression of HMGIC and MDM2 in a carcinoma ex pleomorphic adenoma. Am J Pathol. 2002 Feb. 160(2):433-40. [Medline].
Roob G, Fazekas F, Hartung HP. Peripheral facial palsy: etiology, diagnosis and treatment. Eur Neurol. 1999 Jan. 41(1):3-9. [Medline].
Russo G, Zamparelli A, Howard CM, et al. Expression of cell cycle-regulated proteins pRB2/p130, p107, E2F4, p27, and pCNA in salivary gland tumors: prognostic and diagnostic implications. Clin Cancer Res. 2005 May 1. 11(9):3265-73. [Medline].
Sakamoto M, Sasano T, Higano S, Takahashi S, Iikubo M, Kakehata S. Usefulness of heavily T(2) weighted magnetic resonance images for the differential diagnosis of parotid tumours. Dentomaxillofac Radiol. 2003 Sep. 32(5):295-9. [Medline].
Schuller DE, McCabe BF. Salivary gland neoplasms in children. Otolaryngol Clin North Am. 1977 Jun. 10(2):399-412. [Medline].
Shikhani AH, Johns ME. Tumors of the major salivary glands in children. Head Neck Surg. 1988 Mar-Apr. 10(4):257-63. [Medline].
Shirasaka T, Shimamato Y, Ohshimo H, et al. Development of a novel form of an oral 5-fluorouracil derivative (S-1) directed to the potentiation of the tumor selective cytotoxicity of 5-fluorouracil by two biochemical modulators. Anticancer Drugs. 1996 Jul. 7(5):548-57. [Medline].
Spiro RH. Changing trends in the management of salivary tumors. Semin Surg Oncol. 1995 May-Jun. 11(3):240-5. [Medline].
Spiro RH. Management of malignant tumors of the salivary glands. Oncology (Williston Park). 1998 May. 12(5):671-80; discussion 683. [Medline].
Spiro RH, Huvos AG, Strong EW. Cancer of the parotid gland. A clinicopathologic study of 288 primary cases. Am J Surg. 1975 Oct. 130(4):452-9. [Medline].
Stannard CE, Hering E, Hough J, Knowles R, Munro R, Hille J. Post-operative treatment of malignant salivary gland tumours of the palate with iodine-125 brachytherapy. Radiother Oncol. 2004 Dec. 73(3):307-11. [Medline].
Stern SJ, Suen JY. Salivary gland tumors. Curr Opin Oncol. 1993 May. 5(3):518-25. [Medline].
Stow N, Veivers D, Poole A. Fine-needle aspiration cytology in the management of salivary gland tumors: an Australian experience. Ear Nose Throat J. 2004 Feb. 83(2):128-31. [Medline].
Stárek I, Koranda P, Zboøil V, Mrzena L. Sentinel lymph node biopsy in parotid gland carcinoma. Clin Nucl Med. 2006 Apr. 31(4):203-4. [Medline].
Suzuki K, Cheng J, Watanabe Y. Hepatocyte growth factor and c-Met (HGF/c-Met) in adenoid cystic carcinoma of the human salivary gland. J Oral Pathol Med. 2003 Feb. 32(2):84-9. [Medline].
Taki S, Yamamoto T, Kawai A, Terahata S, Kinuya K, Tonami H. Sonographically guided core biopsy of the salivary gland masses: safety and efficacy. Clin Imaging. 2005 May-Jun. 29(3):189-94. [Medline].
Tan LG, Khoo ML. Accuracy of fine needle aspiration cytology and frozen section histopathology for lesions of the major salivary glands. Ann Acad Med Singapore. 2006 Apr. 35(4):242-8. [Medline].
Terhaard CH, Lubsen H, Rasch CR, et al. The role of radiotherapy in the treatment of malignant salivary gland tumors. Int J Radiat Oncol Biol Phys. 2005 Jan 1. 61(1):103-11. [Medline].
Tsang YT, Chang YM, Lu X, Rao PH, Lau CC, Wong KK. Amplification of MGC2177, PLAG1, PSMC6P, and LYN in a malignant mixed tumor of salivary gland detected by cDNA microarray with tyramide signal amplification. Cancer Genet Cytogenet. 2004 Jul 15. 152(2):124-8. [Medline].
Tugnoli V, Marchese Ragona R, Eleopra R, De Grandis D, Montecucco C. Treatment of Frey syndrome with botulinum toxin type F. Arch Otolaryngol Head Neck Surg. 2001 Mar. 127(3):339-40. [Medline].
U.S. Cancer Statistics Working Group. United States Cancer Statistics: 2001 Incidence and Mortality. Atlanta (GA): Department of Health and Human Services, Centers for Disease Contr. 2004.
Urquhart A, Hutchins LG, Berg RL. Preoperative computed tomography scans for parotid tumor evaluation. Laryngoscope. 2001 Nov. 111(11 Pt 1):1984-8. [Medline].
van der Putten L, de Bree R, Plukker JT, et al. Permanent unilateral hearing loss after radiotherapy for parotid gland tumors. Head Neck. 2006 Oct. 28(10):902-8. [Medline].
Van Heerden WF, Raubenheimer EJ, Dreyer L. The role of DNA ploidy and Ki-67 in the grading of mucoepidermoid carcinomas. Anticancer Res. 2005 May-Jun. 25(3c):2589-92. [Medline].
Vargas H, Galati LT, Parnes SM. A pilot study evaluating the treatment of postparotidectomy sialoceles with botulinum toxin type A. Arch Otolaryngol Head Neck Surg. 2000 Mar. 126(3):421-4. [Medline].
Voz ML, Astrom AK, Kas K, Mark J, Stenman G, Van de Ven WJ. The recurrent translocation t(5;8)(p13;q12) in pleomorphic adenomas results in upregulation of PLAG1 gene expression under control of the LIFR promoter. Oncogene. 1998 Mar. 16(11):1409-16. [Medline].
Wan YL, Chan SC, Chen YL, et al. Ultrasonography-guided core-needle biopsy of parotid gland masses. AJNR Am J Neuroradiol. 2004 Oct. 25(9):1608-12. [Medline].
Wang L, Sun M, Jiang Y, et al. Nerve growth factor and tyrosine kinase A in human salivary adenoid cystic carcinoma: expression patterns and effects on in vitro invasive behavior. J Oral Maxillofac Surg. 2006 Apr. 64(4):636-41. [Medline].
Waterman M, Ben-Izhak O, Eliakim R, Groisman G, Vlodavsky I, Ilan N. Heparanase upregulation by colonic epithelium in inflammatory bowel disease. Mod Pathol. 2007 Jan. 20(1):8-14. [Medline].
Weber A, Langhanki L, Schutz A, Gerstner A, Bootz F, Wittekind C. Expression profiles of p53, p63, and p73 in benign salivary gland tumors. Virchows Arch. 2002 Nov. 441(5):428-36. [Medline].
Westernoff TH, Jordan RC, Regezi JA, Ramos DM, Schmidt BL. Beta-6 Integrin, tenascin-C, and MMP-1 expression in salivary gland neoplasms. Oral Oncol. 2005 Feb. 41(2):170-4. [Medline].
Yabuuchi H, Fukuya T, Tajima T, Hachitanda Y, Tomita K, Koga M. Salivary gland tumors: diagnostic value of gadolinium-enhanced dynamic MR imaging with histopathologic correlation. Radiology. 2003 Feb. 226(2):345-54. [Medline].
Yamamoto Y, Kishimoto Y, Wistuba II, et al. DNA analysis at p53 locus in carcinomas arising from pleomorphic adenomas of salivary glands: comparison of molecular study and p53 immunostaining. Pathol Int. 1998 Apr. 48(4):265-72. [Medline].
Yih WY, Kratochvil FJ, Stewart JC. Intraoral minor salivary gland neoplasms: review of 213 cases. J Oral Maxillofac Surg. 2005 Jun. 63(6):805-10. [Medline].
Zbaren P, Schar C, Hotz MA, Loosli H. Value of fine-needle aspiration cytology of parotid gland masses. Laryngoscope. 2001 Nov. 111(11 Pt 1):1989-92. [Medline].
Zbaren P, Schupbach J, Nuyens M, Stauffer E. Elective neck dissection versus observation in primary parotid carcinoma. Otolaryngol Head Neck Surg. 2005 Mar. 132(3):387-91. [Medline].
Zhang J, Peng B, Chen X. Expressions of nuclear factor kappaB, inducible nitric oxide synthase, and vascular endothelial growth factor in adenoid cystic carcinoma of salivary glands: correlations with the angiogenesis and clinical outcome. Clin Cancer Res. 2005 Oct 15. 11(20):7334-43. [Medline].
Zhao X, Ren W, Yang W, et al. Wnt pathway is involved in pleomorphic adenomas induced by overexpression of PLAG1 in transgenic mice. Int J Cancer. 2006 Feb 1. 118(3):643-8. [Medline].