Salivary Gland Cancer Treatment (PDQ®): Treatment - Health Professional Information [NCI]

General Information About Salivary Gland Cancer

Incidence and Mortality

Salivary gland tumors are a morphologically and clinically diverse group of neoplasms, which may present significant diagnostic and management challenges. These tumors are rare, with an overall incidence in the Western world of approximately 2.5 to 3.0 cases per 100,000 people per year.[1] Malignant salivary gland neoplasms account for more than 0.5% of all malignancies and approximately 3% to 5% of all head and neck cancers.[1,2] Most patients with malignant salivary gland tumors are in their sixth or seventh decade of life.[3,4]

Carcinogenesis and Risk Factors

Although exposure to ionizing radiation has been implicated as a cause of salivary gland cancer, the etiology of most salivary gland cancers cannot be determined.[2,3,5,6] Occupations associated with an increased risk for salivary gland cancers include rubber products manufacturing, asbestos mining, plumbing, and some types of woodworking.[3]

Anatomy

Tumors of the salivary glands comprise those in the major glands (e.g., parotid, submandibular, and sublingual) and the minor glands (e.g., oral mucosa, palate, uvula, floor of mouth, posterior tongue, retromolar area and peritonsillar area, pharynx, larynx, and paranasal sinuses).[2,7] Minor salivary gland lesions are most frequently seen in the oral cavity.[2]

Of salivary gland neoplasms, more than 50% are benign, and approximately 70% to 80% originate in the parotid gland.[1,2,8] The palate is the most common site of minor salivary gland tumors. The frequency of malignant lesions varies by site. Approximately 20% to 25% of parotid tumors, 35% to 40% of submandibular tumors, 50% of palate tumors, and more than 90% of sublingual gland tumors are malignant.[1,9]

Histopathology

Histologically, salivary gland tumors represent the most heterogenous group of tumors of any tissue in the body.[10] Although almost 40 histological types of epithelial tumors of the salivary glands exist, some are exceedingly rare and may be the subject of only a few case reports.[1,11] The most common benign major and minor salivary gland tumor is pleomorphic adenoma, which makes up about 50% of all salivary gland tumors and 65% of parotid gland tumors.[1] The most common malignant major and minor salivary gland tumor is mucoepidermoid carcinoma, which represents about 10% of all salivary gland neoplasms and approximately 35% of malignant salivary gland neoplasms.[1,12] This neoplasm occurs most often in the parotid gland.[2,12,13] For more information about this type and other histological types of salivary gland neoplasms, see the Cellular Classification of Salivary Gland Cancer section.

Clinical Presentation

Most patients with benign tumors of the major or minor salivary glands present with painless swelling of the parotid, submandibular, or sublingual glands. Neurological signs, such as numbness or weakness caused by nerve involvement, typically indicate a malignancy.[2] Facial nerve weakness associated with a parotid or submandibular tumor is an ominous sign. Persistent facial pain is highly suggestive of malignancy. Approximately 10% to 15% of malignant parotid neoplasms present with pain.[8,14] However, most parotid tumors, both benign and malignant, present as an asymptomatic mass in the gland.[2,8] For more information, see Cancer Pain.

Prognostic Factors

Early-stage, low-grade, malignant salivary gland tumors are usually curable by adequate surgical resection alone. The prognosis is more favorable when the tumor is in a major salivary gland. The parotid gland is most favorable followed by the submandibular gland. The least favorable primary sites are the sublingual and minor salivary glands. Large bulky tumors or high-grade tumors carry a poorer prognosis and may best be treated by surgical resection combined with postoperative radiation therapy.[15] The prognosis also depends on the following factors:[16,17]

• Gland in which the tumor arises.
• Histology.
• Grade (i.e., degree of malignancy).
• Extent of primary tumor (i.e., stage).
• Whether the tumor involves the facial nerve, has fixation to the skin or deep structures, or has spread to lymph nodes or distant sites.

Follow-Up and Survivorship

Overall, clinical stage, particularly tumor size, may be the crucial factor that determines the outcome of salivary gland cancer and may be more important than histological grade.[18]

Treatment management

Perineural invasion can occur, particularly in high-grade adenoid cystic carcinoma, and should be specifically identified and treated.[19] Radiation therapy may increase the chance of local control and increase the survival of patients when adequate margins cannot be achieved.[20][Level of evidence C2] Unresectable or recurrent tumors may respond to chemotherapy.[21,22,23] Fast neutron-beam radiation therapy or accelerated hyperfractionated photon-beam schedules have been effective in the treatment of inoperable, unresectable, and recurrent tumors.[24,25,26]

Follow-up after treatment

Complications of surgical treatment for parotid neoplasms include facial nerve dysfunction and Frey syndrome (also known as gustatory flushing and sweating and auriculotemporal syndrome).[8] Frey syndrome has been successfully treated with injections of botulinum toxin A.[27,28,29]

References:

1. Speight PM, Barrett AW: Salivary gland tumours. Oral Dis 8 (5): 229-40, 2002.
2. Mendenhall WM, Werning JW, Pfister DG: Treatment of head and neck cancer. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Lippincott Williams & Wilkins, 2011, pp 729-80.
3. Ellis GL, Auclair PL: Tumors of the Salivary Glands. Armed Forces Institute of Pathology, 1996. Atlas of Tumor Pathology, 3.
4. Wahlberg P, Anderson H, Biörklund A, et al.: Carcinoma of the parotid and submandibular glands--a study of survival in 2465 patients. Oral Oncol 38 (7): 706-13, 2002.
5. Scanlon EF, Sener SF: Head and neck neoplasia following irradiation for benign conditions. Head Neck Surg 4 (2): 139-45, 1981 Nov-Dec.
6. van der Laan BF, Baris G, Gregor RT, et al.: Radiation-induced tumours of the head and neck. J Laryngol Otol 109 (4): 346-9, 1995.
7. Spiro RH, Thaler HT, Hicks WF, et al.: The importance of clinical staging of minor salivary gland carcinoma. Am J Surg 162 (4): 330-6, 1991.
8. Gooden E, Witterick IJ, Hacker D, et al.: Parotid gland tumours in 255 consecutive patients: Mount Sinai Hospital's quality assurance review. J Otolaryngol 31 (6): 351-4, 2002.
9. Theriault C, Fitzpatrick PJ: Malignant parotid tumors. Prognostic factors and optimum treatment. Am J Clin Oncol 9 (6): 510-6, 1986.
10. Brandwein MS, Ferlito A, Bradley PJ, et al.: Diagnosis and classification of salivary neoplasms: pathologic challenges and relevance to clinical outcomes. Acta Otolaryngol 122 (7): 758-64, 2002.
11. Seifert G, Sobin LH: Histological Typing of Salivary Gland Tumours. 2nd ed. Springer-Verlag, 1991.
12. Guzzo M, Andreola S, Sirizzotti G, et al.: Mucoepidermoid carcinoma of the salivary glands: clinicopathologic review of 108 patients treated at the National Cancer Institute of Milan. Ann Surg Oncol 9 (7): 688-95, 2002.
13. Goode RK, Auclair PL, Ellis GL: Mucoepidermoid carcinoma of the major salivary glands: clinical and histopathologic analysis of 234 cases with evaluation of grading criteria. Cancer 82 (7): 1217-24, 1998.
14. Spiro RH, Huvos AG, Strong EW: Cancer of the parotid gland. A clinicopathologic study of 288 primary cases. Am J Surg 130 (4): 452-9, 1975.
15. Parsons JT, Mendenhall WM, Stringer SP, et al.: Management of minor salivary gland carcinomas. Int J Radiat Oncol Biol Phys 35 (3): 443-54, 1996.
16. Vander Poorten VL, Balm AJ, Hilgers FJ, et al.: The development of a prognostic score for patients with parotid carcinoma. Cancer 85 (9): 2057-67, 1999.
17. 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 26 (8): 681-92; discussion 692-3, 2004.
18. Spiro RH: Factors affecting survival in salivary gland cancers. In: McGurk M, Renehan AG, eds.: Controversies in the Management of Salivary Gland Disease. Oxford University Press, 2001, pp 143-50.
19. Gormley WB, Sekhar LN, Wright DC, et al.: Management and long-term outcome of adenoid cystic carcinoma with intracranial extension: a neurosurgical perspective. Neurosurgery 38 (6): 1105-12; discussion 1112-3, 1996.
20. Hosokawa Y, Shirato H, Kagei K, et al.: Role of radiotherapy for mucoepidermoid carcinoma of salivary gland. Oral Oncol 35 (1): 105-11, 1999.
21. Borthne A, Kjellevold K, Kaalhus O, et al.: Salivary gland malignant neoplasms: treatment and prognosis. Int J Radiat Oncol Biol Phys 12 (5): 747-54, 1986.
22. Spiro RH: Salivary neoplasms: overview of a 35-year experience with 2,807 patients. Head Neck Surg 8 (3): 177-84, 1986 Jan-Feb.
23. Licitra L, Cavina R, Grandi C, et al.: Cisplatin, doxorubicin and cyclophosphamide in advanced salivary gland carcinoma. A phase II trial of 22 patients. Ann Oncol 7 (6): 640-2, 1996.
24. Wang CC, Goodman M: Photon irradiation of unresectable carcinomas of salivary glands. Int J Radiat Oncol Biol Phys 21 (3): 569-76, 1991.
25. Buchholz TA, Laramore GE, Griffin BR, et al.: The role of fast neutron radiation therapy in the management of advanced salivary gland malignant neoplasms. Cancer 69 (11): 2779-88, 1992.
26. Krüll A, Schwarz R, Engenhart R, et al.: European results in neutron therapy of malignant salivary gland tumors. Bull Cancer Radiother 83 (Suppl): 125-9s, 1996.
27. Naumann M, Zellner M, Toyka KV, et al.: Treatment of gustatory sweating with botulinum toxin. Ann Neurol 42 (6): 973-5, 1997.
28. Arad-Cohen A, Blitzer A: Botulinum toxin treatment for symptomatic Frey's syndrome. Otolaryngol Head Neck Surg 122 (2): 237-40, 2000.
29. von Lindern JJ, Niederhagen B, Bergé S, et al.: Frey syndrome: treatment with type A botulinum toxin. Cancer 89 (8): 1659-63, 2000.

Cellular Classification of Salivary Gland Cancer

Salivary gland neoplasms are remarkable for their histological diversity. These neoplasms include benign and malignant tumors of epithelial, mesenchymal, and lymphoid origin. Salivary gland tumors pose a particular challenge to the surgical pathologist. Differentiating benign from malignant tumors may be difficult, primarily because of the complexity of the classification and the rarity of several entities, which may exhibit a broad spectrum of morphological diversity in individual lesions.[1] In some cases, hybrid lesions may be seen.[2] The key guiding principle to establish the malignant nature of a salivary gland tumor is the demonstration of an infiltrative margin.[1]

The following cellular classification scheme draws heavily from a scheme published by the Armed Forces Institute of Pathology (AFIP).[3] Malignant nonepithelial neoplasms are included in the scheme because these neoplasms comprise a significant proportion of salivary gland neoplasms seen in the clinical setting. For completeness, malignant secondary tumors are also included in the scheme.

Where AFIP statistics regarding the incidence, or relative frequency, of particular histopathologies are cited, some bias may exist because of the AFIP methods of case accrual as a pathology reference service. When possible, other sources are cited for incidence data. Notwithstanding the AFIP data, the incidence of a particular histopathology has been found to vary considerably depending upon the study cited. This variability in reporting may be partially caused by the rare incidence of many salivary gland neoplasms.

Epithelial Neoplasms

The clinician should be aware that several benign epithelial salivary gland neoplasms have malignant counterparts, which are discussed below:[3]

• Pleomorphic adenoma (i.e., mixed tumor). For more information, see the Carcinoma ex pleomorphic adenoma section.
• Warthin tumor, also known as papillary cystadenoma lymphomatosum.
• Monomorphic adenomas:
  • Basal cell adenoma. For more information, see the Basal cell adenocarcinoma section.
  • Canalicular adenoma.
  • Oncocytoma. For more information, see the Oncocytic carcinoma section.
  • Sebaceous adenoma.
  • Sebaceous lymphadenoma. For more information, see the Sebaceous lymphadenocarcinoma section.
• Myoepithelioma. For more information, see the Myoepithelial carcinoma section.
• Cystadenoma. For more information, see the Cystadenocarcinoma section.
• Ductal papillomas.
• Sialoblastoma.

Histological grading of salivary gland carcinomas is important to determine the proper treatment approach, although it is not an independent indicator of the clinical course and must be considered in the context of the clinical stage. Clinical stage, particularly tumor size, may be the critical factor to determine the outcome of salivary gland cancer and may be more important than histological grade.[1] For example, stage I intermediate-grade or high-grade mucoepidermoid carcinomas can be successfully treated, whereas low-grade mucoepidermoid carcinomas that present as stage III disease may have a very aggressive clinical course.[4]

Grading is used primarily for mucoepidermoid carcinomas, adenocarcinomas, not otherwise specified (NOS), adenoid cystic carcinomas, and squamous cell carcinomas.[1,3] Various other salivary gland carcinomas can also be categorized according to histological grade as follows:[3,5,6,7,8]

Low grade

• Acinic cell carcinoma.
• Basal cell adenocarcinoma.
• Clear cell carcinoma.
• Cystadenocarcinoma.
• Epithelial-myoepithelial carcinoma.
• Mucinous adenocarcinoma.
• Polymorphous low-grade adenocarcinoma (PLGA).

Low grade, intermediate grade, and high grade

• Adenocarcinoma, NOS.
• Mucoepidermoid carcinoma.*
• Squamous cell carcinoma.

Intermediate grade and high grade

• Myoepithelial carcinoma.

High grade

• Anaplastic small cell carcinoma.
• Carcinosarcoma.
• Large cell undifferentiated carcinoma.
• Small cell undifferentiated carcinoma.
• Salivary duct carcinoma.

*Some investigators consider mucoepidermoid carcinoma to be of only two grades: low grade and high grade.[5]

Salivary gland carcinomas and mixed tumors

1. Mucoepidermoid carcinoma.
2. Adenoid cystic carcinoma.
3. Adenocarcinomas.
   1. Acinic cell carcinoma.
   2. PLGA.
   3. Adenocarcinoma, NOS.
   4. Rare adenocarcinomas.
      1. Basal cell adenocarcinoma.
      2. Clear cell carcinoma.
      3. Cystadenocarcinoma.
      4. Sebaceous adenocarcinoma.
      5. Sebaceous lymphadenocarcinoma.
      6. Oncocytic carcinoma.
      7. Salivary duct carcinoma.
      8. Mucinous adenocarcinoma.
4. Malignant mixed tumors.
   1. Carcinoma ex pleomorphic adenoma.
   2. Carcinosarcoma.
   3. Metastasizing mixed tumor.
5. Rare carcinomas.
   1. Primary squamous cell carcinoma.
   2. Epithelial-myoepithelial carcinoma.
   3. Anaplastic small cell carcinoma.
   4. Undifferentiated carcinomas.
      1. Small cell undifferentiated carcinoma.
      2. Large cell undifferentiated carcinoma.
      3. Lymphoepithelial carcinoma.
   5. Myoepithelial carcinoma.
   6. Adenosquamous carcinoma.

Mucoepidermoid carcinoma

Mucoepidermoid carcinoma is a malignant epithelial tumor that is composed of various proportions of mucous, epidermoid (e.g., squamous), intermediate, columnar, and clear cells and often demonstrates prominent cystic growth. It is the most common malignant neoplasm observed in the major and minor salivary glands.[1,9] Mucoepidermoid carcinoma represents 29% to 34% of malignant tumors originating in both major and minor salivary glands.[3,5,10,11] In two large retrospective series, 84% to 93% of cases originated in the parotid gland.[12,13] With regard to malignant tumors of the minor salivary glands, mucoepidermoid carcinoma shows a strong predilection for the lower lip.[3,14] In an AFIP review of civilian cases, the mean age of patients was 47 years (range, 8–92 years).[3] Prior exposure to ionizing radiation appears to substantially increase the risk of developing malignant neoplasms of the major salivary glands, particularly mucoepidermoid carcinoma.[3,13]

Most patients are asymptomatic and present with solitary, painless masses. Symptoms include pain, drainage from the ipsilateral ear, dysphagia, trismus, and facial paralysis.[3] For more information, see Cancer Pain.

Microscopic grading of mucoepidermoid carcinoma is important to determine the prognosis.[1,12,15] Mucoepidermoid carcinomas are graded as low grade, intermediate grade, and high grade. Grading parameters with point values include the following:

• Intracystic component (+2).
• Neural invasion present (+2).
• Necrosis present (+3).
• Mitosis (≥4 per 10 high-power field [+3]).
• Anaplasia present (+4).

Total point scores are 0 to 4 for low grade, 5 to 6 for intermediate grade, and 7 to 14 for high grade.

In a retrospective review of 243 cases of mucoepidermoid carcinoma of the major salivary glands, a statistically significant correlation was shown between this point-based grading system and outcome for parotid tumors but not for submandibular tumors.[12] Another retrospective study that used this histological grading system indicated that tumor grade correlated well with prognosis for mucoepidermoid carcinoma of the major salivary glands, excluding submandibular tumors, and minor salivary glands.[13] A modification of this grading system placed more emphasis on features of tumor invasion.[16] Nonetheless, though tumor grade may be useful, stage appears to be a better indicator of prognosis.[3,16]

Cytogenetically, mucoepidermoid carcinoma is characterized by a t(11;19)(q14–21;p12–13) translocation, which is occasionally the sole cytogenetic alteration.[17,18,19] This translocation creates a novel fusion product, MECT1::MAML2, which disrupts a Notch signaling pathway.[20] Notch signaling plays a key role in the normal development of many tissues and cell types, through diverse effects on cellular differentiation, survival, and/or proliferation, and may be involved in a wide variety of human neoplasms.[21]

Rarely, mucoepidermoid carcinoma may originate within the jaws. This tumor type is known as central mucoepidermoid carcinoma.[3] The mandibular to maxillary predilection is approximately 3:1.[22]

Adenoid cystic carcinoma

Adenoid cystic carcinoma, formerly known as cylindroma, is a slow growing but aggressive neoplasm with a remarkable capacity for recurrence.[23] Morphologically, three growth patterns have been described: cribriform, or classic pattern; tubular; and solid, or basaloid pattern. The tumors are categorized according to the predominant pattern.[3,23,24,25] The cribriform pattern shows epithelial cell nests that form cylindrical patterns. The lumina of these spaces contain periodic acid-Schiff (PAS)-positive mucopolysaccharide secretions. The tubular pattern reveals tubular structures that are lined by stratified cuboidal epithelium. The solid pattern shows solid groups of cuboidal cells. The cribriform pattern is the most common, and the solid pattern is the least common.[26] Solid adenoid cystic carcinoma is a high-grade lesion with reported recurrence rates of as much as 100%, compared with 50% to 80% for the tubular and cribriform variants.[25]

In a review of its case files, the AFIP found adenoid cystic carcinoma to be the fifth most common malignant epithelial tumor of the salivary glands after mucoepidermoid carcinomas; adenocarcinomas, NOS; acinic cell carcinomas; and PLGA.[3] Other series, however, reported adenoid cystic carcinoma to be the second most common malignant tumor, with an incidence or relative frequency of approximately 20%.[1] In the AFIP data, this neoplasm constitutes approximately 7.5% of all epithelial malignancies and 4% of all benign and malignant epithelial salivary gland tumors. The peak incidence for this tumor is reported to be in the fourth through sixth decades of life.[3]

This neoplasm typically develops as a slow-growing swelling in the preauricular or submandibular region. Pain and facial paralysis develop frequently during the course of the disease and are likely related to the associated high incidence of nerve invasion.[3] For more information, see Cancer Pain. Regardless of histological grade, adenoid cystic carcinomas, with their unusually slow biological growth, tend to have a protracted course and ultimately a poor outcome, with 10-year survival rates reported to be less than 50% for all grades.[1,27] These carcinomas typically show frequent recurrences and late distant metastases.[1,28] Clinical stage may be a better prognostic indicator than histological grade.[28,29] In a retrospective review of 92 cases, a tumor size larger than 4 cm was associated with an unfavorable clinical course in all cases.[30]

Adenocarcinomas

Acinic cell carcinoma

Acinic cell carcinoma, also known as acinic cell adenocarcinoma, is a malignant epithelial neoplasm in which the neoplastic cells express acinar differentiation. By conventional use, the term acinic cell carcinoma is defined by cytologic differentiation toward serous acinar cells, as opposed to mucous acinar cells, whose characteristic feature is cytoplasmic PAS-positive zymogen-type secretory granules.[3] In AFIP data of salivary gland neoplasms, acinic cell carcinoma is the third most common salivary gland epithelial neoplasm after mucoepidermoid carcinoma and adenocarcinoma, NOS.[3] Acinic cell carcinoma accounted for 17% of primary malignant salivary gland tumors or about 6% of all salivary gland neoplasms. More than 80% of these tumors occur in the parotid gland, women were affected more than men, and the mean age was 44 years. Other studies have reported a relative frequency of acinic cell carcinoma from 0% to 19% of malignant salivary gland neoplasms.[3]

Clinically, patients typically present with a slowly enlarging mass in the parotid region. Pain is a symptom in more than 33% of patients. For acinic cell carcinoma, staging is likely a better predictor of outcome than histological grading.[3] In a retrospective review of 90 cases, poor prognostic features included pain or fixation; gross invasion; and microscopic features of desmoplasia, atypia, or increased mitotic activity. Neither morphological pattern nor cell composition was a predictive feature.[31] For more information, see Cancer Pain.

PLGA

PLGA is a malignant epithelial tumor that is essentially limited to occurrence in minor salivary gland sites and is characterized by bland, uniform nuclear features; diverse but characteristic architecture; infiltrative growth; and perineural infiltration.[3] In a series of 426 patients with minor salivary gland tumors, PLGA represented 11% of all tumors and 26% of those that were malignant.[32] In minor gland sites, PLGA is twice as frequent as adenoid cystic carcinoma, and among all benign and malignant salivary gland neoplasms, only pleomorphic adenoma and mucoepidermoid carcinoma are more common.[3] In the AFIP case files, more than 60% of tumors occurred in the mucosa of either the soft or hard palates, approximately 16% occurred in the buccal mucosa, and 12% occurred in the upper lip. The average age of patients is reported to be 59 years, with 70% of patients between the ages of 50 and 79 years.[3] The female-to-male ratio is about 2:1, a proportion greater than for malignant salivary gland tumors in general.[3,33]

PLGA typically presents as a firm, nontender swelling involving the mucosa of the hard and soft palates (i.e., it is often found at their junction), the cheek, or the upper lip. Discomfort, bleeding, telangiectasia, or ulceration of the overlying mucosa may occasionally occur.[3] This salivary gland neoplasm typically runs a moderately indolent course. In a study of 40 cases with long-term follow-up, the overall survival rate was 80% at 25 years.[34] Because of the unpredictable behavior of the tumor, some investigators consider the qualifying term, low grade, to be misleading and instead prefer the term polymorphous adenocarcinoma.[1]

Adenocarcinoma, NOS

Adenocarcinoma, NOS, is a salivary gland carcinoma that shows glandular or ductal differentiation but lacks the prominence of any of the morphological features that characterize the other, more specific carcinoma types. The diagnosis of adenocarcinoma, NOS, is essentially one of exclusion. In an AFIP review of cases, adenocarcinoma, NOS, was second only to mucoepidermoid carcinoma in frequency among malignant salivary gland neoplasms.[3] Other series have reported an incidence of 4% to 10%.[1] In AFIP files, the mean patient age was 58 years.[3] Approximately 40% and 60% of tumors occurred in the major and minor salivary glands, respectively. Among the major salivary gland tumors, 90% occurred in the parotid gland. Adenocarcinoma, NOS is graded in a similar way to extrasalivary lesions according to the degree of differentiation.[1] Tumor grades include low-grade, intermediate-grade, and high-grade categories.[3]

Patients with tumors in the major salivary glands typically present with solitary, painless masses.[35] Two retrospective studies indicate that survival is better for patients with tumors of the oral cavity than for those with tumors of the parotid and submandibular glands.[35,36] These studies differ regarding the prognostic significance of tumor grade.

Rare adenocarcinomas

Basal cell adenocarcinoma

Basal cell adenocarcinoma, also known as basaloid salivary carcinoma, carcinoma ex monomorphic adenoma, malignant basal cell adenoma, malignant basal cell tumor, or basal cell carcinoma, is an epithelial neoplasm that is cytologically similar to basal cell adenoma but is infiltrative and has a small potential for metastasis.[3] In AFIP case files spanning almost 11 years, basal cell carcinoma made up 1.6% of all salivary gland neoplasms and 2.9% of salivary gland malignancies.[3] Nearly 90% of tumors occurred in the parotid gland.[3,37] The average age of patients was 60 years.[3]

Similar to most salivary gland neoplasms, swelling is typically the only sign or symptom.[37] A sudden increase in size may occur in a few patients.[38] Basal cell carcinomas are low-grade carcinomas that are infiltrative, locally destructive, and tend to recur. The carcinomas occasionally metastasize. In a retrospective series that included 29 patients, there were recurrences in 7 patients and metastases in 3 patients.[37] In another retrospective review that included 72 patients, 37% of the patients experienced local recurrences.[38] The overall prognosis for patients with this tumor is good.[37,38]

Clear cell carcinoma

Clear cell carcinoma, also known as clear cell adenocarcinoma, is a very rare malignant epithelial neoplasm composed of a monomorphous population of cells that have optically clear cytoplasm with standard hematoxylin and eosin stains and lack features of other specific neoplasms. Because of inconsistencies in the methods of reporting salivary gland neoplasms, meaningful incidence rates for this tumor are difficult to derive from the literature.[3] Most cases involve the minor salivary glands.[1,3,39,40,41] In the AFIP case files, the mean age of patients was approximately 58 years.[3]

In most patients, swelling is the only symptom. Clear cell adenocarcinoma is a low-grade neoplasm. As of 1996, the AFIP reported that no patient had died of this tumor.[3]

Cystadenocarcinoma

Cystadenocarcinoma is a rare malignant epithelial tumor characterized histologically by prominent cystic and, frequently, papillary growth but lacking features that characterize cystic variants of several more common salivary gland neoplasms. It is also known as malignant papillary cystadenoma, mucus-producing adenopapillary, or nonepidermoid, carcinoma; low-grade papillary adenocarcinoma of the palate; or papillary adenocarcinoma. Cystadenocarcinoma is the malignant counterpart of cystadenoma.[3]

In a review that included 57 patients, the AFIP found that men and women are affected equally. The average patient age was approximately 59 years. Approximately 65% of the tumors occurred in the major salivary glands, primarily in the parotid.[3] Most patients present with a slow-growing asymptomatic mass. Clinically, this neoplasm is rarely associated with pain or facial paralysis. Cystadenocarcinoma is considered to be a low-grade neoplasm.[3]

Sebaceous adenocarcinoma

Sebaceous adenocarcinoma is a rare malignant epithelial tumor composed of islands and sheets of cells that have morphologically atypical nuclei, an infiltrative growth pattern, and focal sebaceous differentiation. This is a very rare tumor, as few cases have been reported in the literature.[3] Almost all cases occur in the parotid gland.[3] The average age of patients is reported to be 69 years.[42]

An equal number of patients present with a painless, slow-growing, asymptomatic swelling or pain. A few experience facial paralysis.[3] Most sebaceous adenocarcinomas are probably intermediate-grade malignancies. The tumor recurs in about 33% of cases.[43,44]

Sebaceous lymphadenocarcinoma

Sebaceous lymphadenocarcinoma is an extremely rare malignant tumor that represents carcinomatous transformation of sebaceous lymphadenoma. The carcinoma element may be sebaceous adenocarcinoma or some other specific or nonspecific form of salivary gland cancer.[3] Only three cases have been reported in the literature.[43,45] The three cases occurred in or around the parotid gland. All patients were in their seventh decade of life. Two of the three patients were asymptomatic. One had tenderness on palpation. Case reports suggest that this is a low-grade malignancy with a good prognosis.[44,45]

Oncocytic carcinoma

Oncocytic carcinoma, also known as oncocytic adenocarcinoma, is a rare, predominantly oncocytic neoplasm whose malignant nature is reflected both by its abnormal morphological features and infiltrative growth. Oncocytic carcinoma represents less than 1% of almost 3,100 salivary gland tumors accessioned to the AFIP files during a 10-year period.[3] Most cases occur in the parotid gland. The average age of patients in the AFIP series was 63 years.[3]

Approximately 33% of the patients usually develop parotid masses that cause pain or paralysis.[46] Oncocytic carcinoma is a high-grade carcinoma. Patients with tumors smaller than 2 cm have a better prognosis than patients with larger tumors.[6]

Salivary duct carcinoma

Salivary duct carcinoma, also known as salivary duct adenocarcinoma, is a rare, typically high-grade malignant epithelial neoplasm composed of structures that resemble expanded salivary gland ducts. A low-grade variant exists.[47] Incidence rates vary depending on the study cited.[3] In the AFIP files, salivary duct carcinomas represent only 0.2% of all epithelial salivary gland neoplasms. More than 85% of cases involve the parotid gland, and approximately 75% of patients are men. The peak incidence is reported to be in the seventh and eighth decades of life.[3]

Clinically, parotid swelling is the most common sign. Facial nerve dysfunction or paralysis occur in more than 25% of patients and may be the initial manifestation.[3] The high-grade variant of this neoplasm is one of the most aggressive types of salivary gland carcinoma and is typified by local invasion, lymphatic and hematogenous spread, and poor prognosis.[3,7] In a retrospective review of 104 cases, 33% of patients developed local recurrence, and 46% of patients developed distant metastasis.[48]

Mucinous adenocarcinoma

Mucinous adenocarcinoma is a rare malignant neoplasm characterized by large amounts of extracellular epithelial mucin that contains cords, nests, and solitary epithelial cells. The incidence is unknown. Limited data indicate that most, if not all, occur in the major salivary glands, with the submandibular gland as the predominant site.[3,49] These tumors may be associated with dull pain and tenderness.[3,49] This neoplasm may be considered low grade.[3]

Malignant mixed tumors

The classification of malignant mixed tumors includes three distinct clinicopathological entities: carcinoma ex pleomorphic adenoma, carcinosarcoma, and metastasizing mixed tumor. Carcinoma ex pleomorphic adenoma accounts for most cases, whereas carcinosarcoma, a true malignant mixed tumor, and metastasizing mixed tumor are extremely rare.[3]

Carcinoma ex pleomorphic adenoma

Carcinoma ex pleomorphic adenoma, also known as carcinoma ex mixed tumor, shows histological evidence of arising from or in a benign pleomorphic adenoma.[50] Diagnosis requires the identification of benign tumor in the tissue sample.[51] The incidence or relative frequency of this tumor varies considerably depending on the study cited.[1] A review of material at the AFIP showed that carcinoma ex pleomorphic adenoma makes up 8.8% of all mixed tumors and 4.6% of all malignant salivary gland tumors. It is ranked as the sixth most common malignant salivary gland tumor after mucoepidermoid carcinoma; adenocarcinoma, NOS; acinic cell carcinoma; polymorphous low-grade adenocarcinoma; and adenoid cystic carcinoma.[3] The neoplasm occurs primarily in the major salivary glands.[52]

The most common clinical presentation is a painless mass.[3] Approximately 33% of patients may experience facial paralysis.[53] Depending on the series cited, survival rates vary significantly: 25% to 65% at 5 years, 24% to 50% at 10 years, 10% to 35% at 15 years, and 0% to 38% at 20 years.[3] In addition to tumor stage, histological grade and degree of invasion help to determine prognosis.[54]

Carcinosarcoma

Carcinosarcoma, also known as true malignant mixed tumor, is a rare malignant salivary gland neoplasm that contains both carcinoma and sarcoma components. Either or both components are expressed in metastatic foci. Some carcinosarcomas develop de novo, while others develop in association with benign mixed tumor. This neoplasm is rare; only eight cases exist in the AFIP case files.[3] At one facility, only 11 cases were recorded over a 32-year period.[8] Most of these tumors occur in the major salivary glands.

Swelling, pain, nerve palsy, and ulceration have been frequent clinical findings. Carcinosarcoma is an aggressive, high-grade malignancy. In the largest series reported, which consisted of 12 cases, the average survival period was 3.6 years.[8]

Metastasizing mixed tumor

Metastasizing mixed tumor is a very rare, histologically benign salivary gland neoplasm that inexplicably metastasizes. Often, a long interval occurs between the diagnosis of the primary tumor and the metastases. The histological features are within the spectrum of features that typify pleomorphic adenoma.[3] Most of these tumors occur in the major salivary glands. The primary neoplasm is typically a single, well-defined mass. Recurrences, which may be multiple, have occurred as many as 26 years after excision of the primary neoplasm.[55]

Rare carcinomas

Primary squamous cell carcinoma

Primary squamous cell carcinoma, also known as primary epidermoid carcinoma, is a malignant epithelial neoplasm of the major salivary glands that is composed of squamous (i.e., epidermoid) cells. Diagnosis requires the exclusion of primary disease located in some other head and neck site; indeed, most squamous cell carcinomas of the major salivary glands represent metastatic disease.[3] This diagnosis is not made in minor salivary glands because distinction from the more common mucosal squamous cell carcinoma is not possible.[3] Previous exposure to ionizing radiation appears to increase the risk of developing this neoplasm.[11,56,57] The median time between radiation therapy and diagnosis of the neoplasm is approximately 15.5 years.[11] The reported frequency of this tumor among all major salivary gland tumors has varied from 0.9% to 4.7%.[3,10] In AFIP major salivary gland accessions from 1985 to 1996, primary squamous cell carcinoma accounted for 2.7% of all tumors; 5.4% of malignant tumors; and 2.5% and 2.8%, respectively, of all parotid and submandibular tumors.[3] The average age in the AFIP registry was 64 years.[3] This neoplasm occurs in the parotid gland almost nine times more often than in the submandibular gland.[3,57] There is a strong male predilection.[3,11,57,58,59] This tumor is graded in a similar way to extrasalivary lesions according to the degree of differentiation, namely, low grade, intermediate grade, and high grade.[1]

Most patients present with an asymptomatic mass in the parotid region. Other symptoms may include a painful mass and facial nerve palsy.[57] The prognosis for this neoplasm is poor. In a 30-year retrospective analysis of 50 cases of squamous cell carcinoma of the salivary glands, survival rates at 5 years and 10 years were 24% and 18%, respectively.[57]

Epithelial-myoepithelial carcinoma

Epithelial-myoepithelial carcinoma is an uncommon, low-grade epithelial neoplasm composed of variable proportions of ductal and large, clear-staining, differentiated myoepithelial cells. It is also known as adenomyoepithelioma, clear cell adenoma, tubular solid adenoma, monomorphic clear cell tumor, glycogen-rich adenoma, glycogen-rich adenocarcinoma, clear cell carcinoma, or salivary duct carcinoma. The tumor represents approximately 1% of all epithelial salivary gland neoplasms.[3,60] It is predominantly a tumor of the parotid gland. In the AFIP case files, the mean age of patients was about 60 years, and about 60% of the patients were female.[3]

Localized swelling is commonly the only symptom, but occasionally patients experience facial weakness or pain.[61,62] Overall, epithelial-myoepithelial carcinoma is a low-grade carcinoma that recurs frequently, has a tendency to metastasize to periparotid and cervical lymph nodes, and occasionally results in distant metastasis and death.[60,62,63,64]

Anaplastic small cell carcinoma

Anaplastic small cell carcinoma of the salivary glands was first described in 1972.[65] Subsequent histochemical and electron microscopic studies have supported the neuroendocrine nature of this tumor.[66,67] Microscopically, the tumor cells have oval, hyperchromatic nuclei and a scant amount of cytoplasm and are organized in sheets, strands, and nests. The mitotic rate is high. Neuroendocrine carcinomas are more frequently found in the minor salivary glands. These patients have a better survival rate than patients with small cell carcinomas of the lung.[68] The undifferentiated counterpart of this neoplasm is the small cell undifferentiated carcinoma.

Undifferentiated carcinomas

Undifferentiated carcinomas of salivary glands are a group of uncommon malignant epithelial neoplasms that lack the specific light-microscopic morphological features of other types of salivary gland carcinomas. These carcinomas are histologically similar to undifferentiated carcinomas that arise in other organs and tissues. Accordingly, metastatic carcinoma is a primary concern in the differential diagnosis of these neoplasms.[3]

Small cell undifferentiated carcinoma

Small cell undifferentiated carcinoma, also known as extrapulmonary oat cell carcinoma, is a rare, primary malignant tumor. With conventional light microscopy, it is composed of undifferentiated cells and, with ultrastructural or immunohistochemical studies, does not demonstrate neuroendocrine differentiation. This is the undifferentiated counterpart of anaplastic small cell carcinoma. For more information, see the Anaplastic small cell carcinoma section.

In an AFIP review of case files, small cell carcinoma represented 1.8% of all major salivary gland malignancies; the mean age of patients was 56 years.[3] In 50% of the cases, patients present with an asymptomatic parotid mass of 3 months' or less duration.[68,69,70] This is a high-grade neoplasm. In a retrospective review of 12 cases, a tumor size of more than 4 cm was found to be the most important predictor of behavior. In another small retrospective series, estimated survival rates at 2 and 5 years were 70% and 46%, respectively.[68]

Large cell undifferentiated carcinoma

Large cell undifferentiated carcinoma is a tumor in which features of acinar, ductal, epidermoid, or myoepithelial differentiation are absent under light microscopy, though occasionally, poorly formed duct-like structures are found. This neoplasm accounts for approximately 1% of all epithelial salivary gland neoplasms.[3,53,71,72] Most of these tumors occur in the parotid gland.[70,72] In AFIP data, the peak incidence is in the seventh to eighth decades of life.[3]

Rapid growth of a parotid swelling is a common clinical presentation.[59] This is a high-grade neoplasm that frequently metastasizes and has a poor prognosis. Patients with neoplasms of 4 cm or larger may have a particularly poor outcome.[70,72]

Lymphoepithelial carcinoma

Lymphoepithelial carcinoma, also known as undifferentiated carcinoma with lymphoid stroma and carcinoma ex lymphoepithelial lesion, is an undifferentiated tumor that is associated with a dense lymphoid stroma. An exceptionally high incidence of this tumor is found in the Inuit population.[3,73] This neoplasm has been associated with Epstein-Barr virus infection.[74,75] Of the occurrences, 80% are in the parotid gland.[3]

In addition to the presence of a parotid or submandibular mass, pain is a frequent symptom, and facial nerve palsy occurs in as many as 20% of patients.[76] Of the patients, more than 40% have metastases to cervical lymph nodes at initial presentation, 20% develop local recurrences or lymph node metastases, and 20% develop distant metastases within 3 years following therapy.[73,76,77,78] For more information, see Cancer Pain.

Myoepithelial carcinoma

Myoepithelioma carcinoma is a rare, malignant salivary gland neoplasm in which the tumor cells almost exclusively manifest myoepithelial differentiation. This neoplasm represents the malignant counterpart of benign myoepithelioma.[3] The largest series reported involved 25 cases.[79] Approximately 66% of the tumors occur in the parotid gland.[3,74] The mean age of patients is reported to be 55 years.[79]

Most patients present with the primary complaint of a painless mass.[79] This is an intermediate grade to high-grade carcinoma.[3,79] Histological grade does not appear to correlate well with clinical behavior; tumors with a low-grade histological appearance may behave aggressively.[79]

Adenosquamous carcinoma

Adenosquamous carcinoma is an extremely rare malignant neoplasm that simultaneously arises from surface mucosal epithelium and salivary gland ductal epithelium. The carcinoma shows histopathological features of both squamous cell carcinoma and adenocarcinoma. Only a handful of reports describe this tumor.[3]

In addition to swelling, adenosquamous carcinoma produces visible changes in the mucosa, including erythema, ulceration, and induration. Pain frequently accompanies ulceration. Limited data indicate that this is a highly aggressive neoplasm with a poor prognosis.[3]

Nonepithelial Neoplasms

Lymphomas and benign lymphoepithelial lesion

Lymphomas of the major salivary glands are characteristically of the non-Hodgkin type. In an AFIP review of case files, non-Hodgkin lymphoma accounted for 16.3% of all malignant tumors that occurred in the major salivary glands; disease in the parotid gland accounted for about 80% of all cases.[3]

Patients with benign lymphoepithelial lesion (e.g., Mikulicz disease), which is a manifestation of the autoimmune disease Sjögren syndrome, are at an increased risk for development of non-Hodgkin lymphoma.[80,81,82,83,84] Benign lymphoepithelial lesion is clinically characterized by diffuse and bilateral enlargement of the salivary and lacrimal glands.[23] Morphologically, a salivary gland lesion is composed of prominent myoepithelial islands surrounded by a lymphocytic infiltrate. Germinal centers are often present in the lymphocytic infiltrate.[23] Immunophenotypically and genotypically, the lymphocytic infiltrate is composed of B-lymphocytes and T-lymphocytes, which are polyclonal. In some instances, the B-cell lymphocytic infiltrate can undergo clonal expansion and evolve into frank non-Hodgkin lymphoma. Most of the non-Hodgkin lymphomas arising in a background of benign lymphoepithelial lesions are marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT).[81,82,83,84] MALT lymphomas of the salivary glands, like their counterparts in other anatomical sites, typically display relatively indolent clinical behavior.[3,85]

Primary non-MALT lymphomas of the salivary glands may also occur and appear to have a prognosis similar to those in patients who have histologically identical nodal lymphomas.[86,87] Unlike non-Hodgkin lymphoma, involvement of the major salivary glands by Hodgkin lymphoma is rare. Most tumors occur in the parotid gland.[3] The most common histological types encountered are the nodular sclerosing and lymphocyte-predominant variants.[88,89]

Mesenchymal neoplasms

Mesenchymal neoplasms account for 1.9% to 5% of all neoplasms that occur within the major salivary glands.[90,91] These cellular classifications pertain to major salivary gland tumors. Because the minor salivary glands are small and embedded within fibrous connective tissue, fat, and skeletal muscle, the origin of a mesenchymal neoplasm from stroma cannot be determined.[3] The types of benign mesenchymal salivary gland neoplasms include hemangiomas, lipomas, and lymphangiomas.

Malignant mesenchymal salivary gland neoplasms include malignant schwannomas, hemangiopericytomas, malignant fibrous histiocytomas, rhabdomyosarcomas, and fibrosarcomas, among others. In the major salivary glands, these neoplasms represent approximately 0.5% of all benign and malignant salivary gland tumors and approximately 1.5% of all malignant tumors.[90,92,93] It is important to establish a primary salivary gland origin for these tumors by excluding the possibilities of metastasis and direct extension from other sites. In addition, the diagnosis of salivary gland carcinosarcoma should be excluded.[3] Primary salivary gland sarcomas behave like their soft tissue counterparts, in which prognosis is related to sarcoma type, histological grade, tumor size, and stage.[93,94] For more information, see Soft Tissue Sarcoma Treatment. A comprehensive review of salivary gland mesenchymal neoplasms can be found elsewhere.[95]

Malignant Secondary Neoplasms

Malignant neoplasms whose origins lie outside the salivary glands may involve the major salivary glands by:[3]

1. Direct invasion from cancers that lie adjacent to the salivary glands.
2. Hematogenous metastases from distant primary tumors.
3. Lymphatic metastases to lymph nodes within the salivary gland.

Direct invasion of nonsalivary gland tumors into the major salivary glands is principally from squamous cell and basal cell carcinomas of the overlying skin.

Approximately 80% of metastases to the major salivary glands may be from primary tumors elsewhere in the head and neck; the remaining 20% may be from infraclavicular sites.[96,97] The parotid gland is the site of 80% to 90% of the metastases, and the remainder involve the submandibular gland.[97,98] In a decade-long AFIP experience, metastatic tumors constituted approximately 10% of malignant neoplasms in the major salivary glands, exclusive of malignant lymphomas.[3] Most metastatic primary tumors to the major salivary glands are squamous cell carcinomas and melanomas from the head and neck that presumably reach the parotid gland via the lymphatic system; infraclavicular primary tumors, such as the lung, kidney, and breast, reach the salivary glands by a hematogenous route.[97,98,99] The peak incidence for metastatic tumors in the salivary glands is reported to be in the seventh decade of life.[3]

References:

1. Speight PM, Barrett AW: Salivary gland tumours. Oral Dis 8 (5): 229-40, 2002.
2. Seifert G, Donath K: Hybrid tumours of salivary glands. Definition and classification of five rare cases. Eur J Cancer B Oral Oncol 32B (4): 251-9, 1996.
3. Ellis GL, Auclair PL: Tumors of the Salivary Glands. Armed Forces Institute of Pathology, 1996. Atlas of Tumor Pathology, 3.
4. Cheuk W, Chan JKC: Salivary gland tumors. In: Fletcher CDM, ed.: Diagnostic Histopathology of Tumors. 3rd ed. Churchill Livingstone, 2007, pp 239-326.
5. Spiro RH, Huvos AG, Berk R, et al.: Mucoepidermoid carcinoma of salivary gland origin. A clinicopathologic study of 367 cases. Am J Surg 136 (4): 461-8, 1978.
6. Goode RK, Corio RL: Oncocytic adenocarcinoma of salivary glands. Oral Surg Oral Med Oral Pathol 65 (1): 61-6, 1988.
7. Guzzo M, Di Palma S, Grandi C, et al.: Salivary duct carcinoma: clinical characteristics and treatment strategies. Head Neck 19 (2): 126-33, 1997.
8. Stephen J, Batsakis JG, Luna MA, et al.: True malignant mixed tumors (carcinosarcoma) of salivary glands. Oral Surg Oral Med Oral Pathol 61 (6): 597-602, 1986.
9. Auclair PL, Ellis GL, Gnepp DR, et al.: Salivary gland neoplasms: general considerations. In: Ellis GL, Auclair PL, Gnepp DR, eds.: Surgical Pathology of the Salivary Glands. Saunders, 1991, pp 135-64.
10. Eveson JW, Cawson RA: Salivary gland tumours. A review of 2410 cases with particular reference to histological types, site, age and sex distribution. J Pathol 146 (1): 51-8, 1985.
11. Spitz MR, Batsakis JG: Major salivary gland carcinoma. Descriptive epidemiology and survival of 498 patients. Arch Otolaryngol 110 (1): 45-9, 1984.
12. Goode RK, Auclair PL, Ellis GL: Mucoepidermoid carcinoma of the major salivary glands: clinical and histopathologic analysis of 234 cases with evaluation of grading criteria. Cancer 82 (7): 1217-24, 1998.
13. Guzzo M, Andreola S, Sirizzotti G, et al.: Mucoepidermoid carcinoma of the salivary glands: clinicopathologic review of 108 patients treated at the National Cancer Institute of Milan. Ann Surg Oncol 9 (7): 688-95, 2002.
14. Neville BW, Damm DD, Weir JC, et al.: Labial salivary gland tumors. Cancer 61 (10): 2113-6, 1988.
15. Auclair PL, Goode RK, Ellis GL: Mucoepidermoid carcinoma of intraoral salivary glands. Evaluation and application of grading criteria in 143 cases. Cancer 69 (8): 2021-30, 1992.
16. Brandwein MS, Ivanov K, Wallace DI, et al.: Mucoepidermoid carcinoma: a clinicopathologic study of 80 patients with special reference to histological grading. Am J Surg Pathol 25 (7): 835-45, 2001.
17. Nordkvist A, Gustafsson H, Juberg-Ode M, et al.: Recurrent rearrangements of 11q14-22 in mucoepidermoid carcinoma. Cancer Genet Cytogenet 74 (2): 77-83, 1994.
18. Horsman DE, Berean K, Durham JS: Translocation (11;19)(q21;p13.1) in mucoepidermoid carcinoma of salivary gland. Cancer Genet Cytogenet 80 (2): 165-6, 1995.
19. El-Naggar AK, Lovell M, Killary AM, et al.: A mucoepidermoid carcinoma of minor salivary gland with t(11;19)(q21;p13.1) as the only karyotypic abnormality. Cancer Genet Cytogenet 87 (1): 29-33, 1996.
20. Tonon G, Modi S, Wu L, et al.: t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma creates a novel fusion product that disrupts a Notch signaling pathway. Nat Genet 33 (2): 208-13, 2003.
21. Allenspach EJ, Maillard I, Aster JC, et al.: Notch signaling in cancer. Cancer Biol Ther 1 (5): 466-76, 2002 Sep-Oct.
22. Brookstone MS, Huvos AG: Central salivary gland tumors of the maxilla and mandible: a clinicopathologic study of 11 cases with an analysis of the literature. J Oral Maxillofac Surg 50 (3): 229-36, 1992.
23. Major and minor salivary glands. In: Rosai J, ed.: Ackerman's Surgical Pathology. 8th ed. Mosby, 1996, pp 815-56.
24. Batsakis JG, Luna MA, el-Naggar A: Histopathologic grading of salivary gland neoplasms: III. Adenoid cystic carcinomas. Ann Otol Rhinol Laryngol 99 (12): 1007-9, 1990.
25. Tomich CE: Adenoid cystic carcinoma. In: Ellis GL, Auclair PL, Gnepp DR, eds.: Surgical Pathology of the Salivary Glands. Saunders, 1991, pp 333-49.
26. Perzin KH, Gullane P, Clairmont AC: Adenoid cystic carcinomas arising in salivary glands: a correlation of histologic features and clinical course. Cancer 42 (1): 265-82, 1978.
27. Spiro RH: The controversial adenoid cystic carcinoma. Clinical considerations. In: McGurk M, Renehan AG, eds.: Controversies in the Management of Salivary Gland Disease. Oxford University Press, 2001, pp 207-11.
28. Friedrich RE, Bleckmann V: Adenoid cystic carcinoma of salivary and lacrimal gland origin: localization, classification, clinical pathological correlation, treatment results and long-term follow-up control in 84 patients. Anticancer Res 23 (2A): 931-40, 2003 Mar-Apr.
29. Spiro RH, Huvos AG: Stage means more than grade in adenoid cystic carcinoma. Am J Surg 164 (6): 623-8, 1992.
30. Hamper K, Lazar F, Dietel M, et al.: Prognostic factors for adenoid cystic carcinoma of the head and neck: a retrospective evaluation of 96 cases. J Oral Pathol Med 19 (3): 101-7, 1990.
31. Lewis JE, Olsen KD, Weiland LH: Acinic cell carcinoma. Clinicopathologic review. Cancer 67 (1): 172-9, 1991.
32. Waldron CA, el-Mofty SK, Gnepp DR: Tumors of the intraoral minor salivary glands: a demographic and histologic study of 426 cases. Oral Surg Oral Med Oral Pathol 66 (3): 323-33, 1988.
33. Vincent SD, Hammond HL, Finkelstein MW: Clinical and therapeutic features of polymorphous low-grade adenocarcinoma. Oral Surg Oral Med Oral Pathol 77 (1): 41-7, 1994.
34. Evans HL, Luna MA: Polymorphous low-grade adenocarcinoma: a study of 40 cases with long-term follow up and an evaluation of the importance of papillary areas. Am J Surg Pathol 24 (10): 1319-28, 2000.
35. Spiro RH, Huvos AG, Strong EW: Adenocarcinoma of salivary origin. Clinicopathologic study of 204 patients. Am J Surg 144 (4): 423-31, 1982.
36. Matsuba HM, Mauney M, Simpson JR, et al.: Adenocarcinomas of major and minor salivary gland origin: a histopathologic review of treatment failure patterns. Laryngoscope 98 (7): 784-8, 1988.
37. Muller S, Barnes L: Basal cell adenocarcinoma of the salivary glands. Report of seven cases and review of the literature. Cancer 78 (12): 2471-7, 1996.
38. Ellis GL, Wiscovitch JG: Basal cell adenocarcinomas of the major salivary glands. Oral Surg Oral Med Oral Pathol 69 (4): 461-9, 1990.
39. Simpson RH, Sarsfield PT, Clarke T, et al.: Clear cell carcinoma of minor salivary glands. Histopathology 17 (5): 433-8, 1990.
40. Ogawa I, Nikai H, Takata T, et al.: Clear cell tumors of minor salivary gland origin. An immunohistochemical and ultrastructural analysis. Oral Surg Oral Med Oral Pathol 72 (2): 200-7, 1991.
41. Milchgrub S, Gnepp DR, Vuitch F, et al.: Hyalinizing clear cell carcinoma of salivary gland. Am J Surg Pathol 18 (1): 74-82, 1994.
42. Ellis GL, Auclair PL, Gnepp DR, et al.: Other malignant epithelial neoplasms. In: Ellis GL, Auclair PL, Gnepp DR, eds.: Surgical Pathology of the Salivary Glands. Saunders, 1991, pp 455-88.
43. Gnepp DR: Sebaceous neoplasms of salivary gland origin: a review. Pathol Annu 18 Pt 1: 71-102, 1983.
44. Gnepp DR, Brannon R: Sebaceous neoplasms of salivary gland origin. Report of 21 cases. Cancer 53 (10): 2155-70, 1984.
45. Linhartová A: Sebaceous glands in salivary gland tissue. Arch Pathol 98 (5): 320-4, 1974.
46. Sugimoto T, Wakizono S, Uemura T, et al.: Malignant oncocytoma of the parotid gland: a case report with an immunohistochemical and ultrastructural study. J Laryngol Otol 107 (1): 69-74, 1993.
47. Delgado R, Klimstra D, Albores-Saavedra J: Low grade salivary duct carcinoma. A distinctive variant with a low grade histology and a predominant intraductal growth pattern. Cancer 78 (5): 958-67, 1996.
48. Barnes L, Rao U, Krause J, et al.: Salivary duct carcinoma. Part I. A clinicopathologic evaluation and DNA image analysis of 13 cases with review of the literature. Oral Surg Oral Med Oral Pathol 78 (1): 64-73, 1994.
49. Osaki T, Hirota J, Ohno A, et al.: Mucinous adenocarcinoma of the submandibular gland. Cancer 66 (8): 1796-801, 1990.
50. Röijer E, Nordkvist A, Ström AK, et al.: Translocation, deletion/amplification, and expression of HMGIC and MDM2 in a carcinoma ex pleomorphic adenoma. Am J Pathol 160 (2): 433-40, 2002.
51. LiVolsi VA, Perzin KH: Malignant mixed tumors arising in salivary glands. I. Carcinomas arising in benign mixed tumors: a clinicopathologic study. Cancer 39 (5): 2209-30, 1977.
52. Gnepp DR: Malignant mixed tumors of the salivary glands: a review. Pathol Annu 28 Pt 1: 279-328, 1993.
53. Seifert G: [Diseases of the Salivary Glands: Pathology, Diagnosis, Treatment, Facial Nerve Surgery]; translated by Philip M. Stell. Thieme, 1986.
54. Brandwein MS, Ferlito A, Bradley PJ, et al.: Diagnosis and classification of salivary neoplasms: pathologic challenges and relevance to clinical outcomes. Acta Otolaryngol 122 (7): 758-64, 2002.
55. Wenig BM, Hitchcock CL, Ellis GL, et al.: Metastasizing mixed tumor of salivary glands. A clinicopathologic and flow cytometric analysis. Am J Surg Pathol 16 (9): 845-58, 1992.
56. Schneider AB, Favus MJ, Stachura ME, et al.: Salivary gland neoplasms as a late consequence of head and neck irradiation. Ann Intern Med 87 (2): 160-4, 1977.
57. Shemen LJ, Huvos AG, Spiro RH: Squamous cell carcinoma of salivary gland origin. Head Neck Surg 9 (4): 235-40, 1987 Mar-Apr.
58. Sterman BM, Kraus DH, Sebek BA, et al.: Primary squamous cell carcinoma of the parotid gland. Laryngoscope 100 (2 Pt 1): 146-8, 1990.
59. Gaughan RK, Olsen KD, Lewis JE: Primary squamous cell carcinoma of the parotid gland. Arch Otolaryngol Head Neck Surg 118 (8): 798-801, 1992.
60. Batsakis JG, el-Naggar AK, Luna MA: Epithelial-myoepithelial carcinoma of salivary glands. Ann Otol Rhinol Laryngol 101 (6): 540-2, 1992.
61. Daley TD, Wysocki GP, Smout MS, et al.: Epithelial-myoepithelial carcinoma of salivary glands. Oral Surg Oral Med Oral Pathol 57 (5): 512-9, 1984.
62. Collina G, Gale N, Visonà A, et al.: Epithelial-myoepithelial carcinoma of the parotid gland: a clinico-pathologic and immunohistochemical study of seven cases. Tumori 77 (3): 257-63, 1991.
63. Simpson RH, Clarke TJ, Sarsfield PT, et al.: Epithelial-myoepithelial carcinoma of salivary glands. J Clin Pathol 44 (5): 419-23, 1991.
64. Noel S, Brozna JP: Epithelial-myoepithelial carcinoma of salivary gland with metastasis to lung: report of a case and review of the literature. Head Neck 14 (5): 401-6, 1992 Sep-Oct.
65. Koss LG, Spiro RH, Hajdu S: Small cell (oat cell) carcinoma of minor salivary gland origin. Cancer 30 (3): 737-41, 1972.
66. Gnepp DR, Wick MR: Small cell carcinoma of the major salivary glands. An immunohistochemical study. Cancer 66 (1): 185-92, 1990.
67. Perez-Ordonez B, Caruana SM, Huvos AG, et al.: Small cell neuroendocrine carcinoma of the nasal cavity and paranasal sinuses. Hum Pathol 29 (8): 826-32, 1998.
68. Gnepp DR, Corio RL, Brannon RB: Small cell carcinoma of the major salivary glands. Cancer 58 (3): 705-14, 1986.
69. Scher RL, Feldman PS, Levine PA: Small-cell carcinoma of the parotid gland with neuroendocrine features. Arch Otolaryngol Head Neck Surg 114 (3): 319-21, 1988.
70. Hui KK, Luna MA, Batsakis JG, et al.: Undifferentiated carcinomas of the major salivary glands. Oral Surg Oral Med Oral Pathol 69 (1): 76-83, 1990.
71. Spiro RH: Salivary neoplasms: overview of a 35-year experience with 2,807 patients. Head Neck Surg 8 (3): 177-84, 1986 Jan-Feb.
72. Batsakis JG, Luna MA: Undifferentiated carcinomas of salivary glands. Ann Otol Rhinol Laryngol 100 (1): 82-4, 1991.
73. Bosch JD, Kudryk WH, Johnson GH: The malignant lymphoepithelial lesion of the salivary glands. J Otolaryngol 17 (4): 187-90, 1988.
74. Hamilton-Dutoit SJ, Therkildsen MH, Neilsen NH, et al.: Undifferentiated carcinoma of the salivary gland in Greenlandic Eskimos: demonstration of Epstein-Barr virus DNA by in situ nucleic acid hybridization. Hum Pathol 22 (8): 811-5, 1991.
75. Leung SY, Chung LP, Yuen ST, et al.: Lymphoepithelial carcinoma of the salivary gland: in situ detection of Epstein-Barr virus. J Clin Pathol 48 (11): 1022-7, 1995.
76. Borg MF, Benjamin CS, Morton RP, et al.: Malignant lympho-epithelial lesion of the salivary gland: a case report and review of the literature. Australas Radiol 37 (3): 288-91, 1993.
77. Saw D, Lau WH, Ho JH, et al.: Malignant lymphoepithelial lesion of the salivary gland. Hum Pathol 17 (9): 914-23, 1986.
78. Cleary KR, Batsakis JG: Undifferentiated carcinoma with lymphoid stroma of the major salivary glands. Ann Otol Rhinol Laryngol 99 (3 Pt 1): 236-8, 1990.
79. Savera AT, Sloman A, Huvos AG, et al.: Myoepithelial carcinoma of the salivary glands: a clinicopathologic study of 25 patients. Am J Surg Pathol 24 (6): 761-74, 2000.
80. Kassan SS, Thomas TL, Moutsopoulos HM, et al.: Increased risk of lymphoma in sicca syndrome. Ann Intern Med 89 (6): 888-92, 1978.
81. Abbondanzo SL: Extranodal marginal-zone B-cell lymphoma of the salivary gland. Ann Diagn Pathol 5 (4): 246-54, 2001.
82. Ihrler S, Baretton GB, Menauer F, et al.: Sjögren's syndrome and MALT lymphomas of salivary glands: a DNA-cytometric and interphase-cytogenetic study. Mod Pathol 13 (1): 4-12, 2000.
83. Harris NL: Lymphoid proliferations of the salivary glands. Am J Clin Pathol 111 (1 Suppl 1): S94-103, 1999.
84. DiGiuseppe JA, Corio RL, Westra WH: Lymphoid infiltrates of the salivary glands: pathology, biology and clinical significance. Curr Opin Oncol 8 (3): 232-7, 1996.
85. Harris NL: Extranodal lymphoid infiltrates and mucosa-associated lymphoid tissue (MALT). A unifying concept. Am J Surg Pathol 15 (9): 879-84, 1991.
86. Burke JS: Waldeyer's ring, sinonasal region, salivary gland, thyroid gland, central nervous system, and other extranodal lymphomas and lymphoid hyperplasias. In: Knowles DM, ed.: Neoplastic Hematopathology. Williams & Wilkins, 1992, pp 1047-79.
87. Salhany KE, Pietra GG: Extranodal lymphoid disorders. Am J Clin Pathol 99 (4): 472-85, 1993.
88. Schmid U, Helbron D, Lennert K: Primary malignant lymphomas localized in salivary glands. Histopathology 6 (6): 673-87, 1982.
89. Gleeson MJ, Bennett MH, Cawson RA: Lymphomas of salivary glands. Cancer 58 (3): 699-704, 1986.
90. Seifert G, Oehne H: [Mesenchymal (non-epithelial) salivary gland tumors. Analysis of 167 tumor cases of the salivary gland register] Laryngol Rhinol Otol (Stuttg) 65 (9): 485-91, 1986.
91. Auclair PL, Ellis GL, Gnepp DR, et al.: Salivary gland neoplasms: general considerations. In: Ellis GL, Auclair PL, Gnepp DR, eds.: Surgical Pathology of the Salivary Glands. Saunders, 1991, pp 135-64.
92. Auclair PL, Ellis GL: Nonlymphoid sarcomas of the major salivary glands. In: Ellis GL, Auclair PL, Gnepp DR, eds.: Surgical Pathology of the Salivary Glands. Saunders, 1991, pp 514-27.
93. Luna MA, Tortoledo ME, Ordóñez NG, et al.: Primary sarcomas of the major salivary glands. Arch Otolaryngol Head Neck Surg 117 (3): 302-6, 1991.
94. Auclair PL, Langloss JM, Weiss SW, et al.: Sarcomas and sarcomatoid neoplasms of the major salivary gland regions. A clinicopathologic and immunohistochemical study of 67 cases and review of the literature. Cancer 58 (6): 1305-15, 1986.
95. Weiss SW, Goldblum JR: Enzinger and Weiss's Soft Tissue Tumors. 4th ed. Mosby, 2001.
96. Cantera JM, Hernandez AV: Bilateral parotid gland metastasis as the initial presentation of a small cell lung carcinoma. J Oral Maxillofac Surg 47 (11): 1199-201, 1989.
97. Gnepp DR: Metastatic disease to the major salivary glands. In: Ellis GL, Auclair PL, Gnepp DR, eds.: Surgical Pathology of the Salivary Glands. Saunders, 1991, pp 560-9.
98. Seifert G, Hennings K, Caselitz J: Metastatic tumors to the parotid and submandibular glands--analysis and differential diagnosis of 108 cases. Pathol Res Pract 181 (6): 684-92, 1986.
99. Batsakis JG, Bautina E: Metastases to major salivary glands. Ann Otol Rhinol Laryngol 99 (6 Pt 1): 501-3, 1990.

Stage Information for Salivary Gland Cancer

In general, tumors of the major salivary glands are staged according to size, extraparenchymal extension, lymph node involvement (in parotid tumors, whether or not the facial nerve is involved), and presence of metastases.[1,2,3,4] Tumors arising in the minor salivary glands are staged according to the anatomical site of origin (e.g., oral cavity and sinuses).

Clinical stage, particularly tumor size, may be the critical factor in determining the outcome of salivary gland cancer and may be more important than histological grade.[5,6] Diagnostic imaging studies may be used in staging. With excellent spatial resolution and superior soft tissue contrast, magnetic resonance imaging (MRI) offers advantages over computed tomographic scanning in the detection and localization of head and neck tumors. Overall, MRI is the preferred modality for evaluation of suspected neoplasms of the salivary glands.[7]

American Joint Committee on Cancer (AJCC) Stage Groupings and TNM Definitions

The AJCC has designated staging by TNM (tumor, node, metastasis) classification to define salivary gland cancer.[5]

References:

1. Spiro RH, Huvos AG, Strong EW: Cancer of the parotid gland. A clinicopathologic study of 288 primary cases. Am J Surg 130 (4): 452-9, 1975.
2. Fu KK, Leibel SA, Levine ML, et al.: Carcinoma of the major and minor salivary glands: analysis of treatment results and sites and causes of failures. Cancer 40 (6): 2882-90, 1977.
3. Levitt SH, McHugh RB, Gómez-Marin O, et al.: Clinical staging system for cancer of the salivary gland: a retrospective study. Cancer 47 (11): 2712-24, 1981.
4. Kuhel W, Goepfert H, Luna M, et al.: Adenoid cystic carcinoma of the palate. Arch Otolaryngol Head Neck Surg 118 (3): 243-7, 1992.
5. Major salivary glands. In: Amin MB, Edge SB, Greene FL, et al., eds.: AJCC Cancer Staging Manual. 8th ed. Springer; 2017, pp. 95–101.
6. Spiro RH: Factors affecting survival in salivary gland cancers. In: McGurk M, Renehan AG, eds.: Controversies in the Management of Salivary Gland Disease. Oxford University Press, 2001, pp 143-50.
7. Shah GV: MR imaging of salivary glands. Magn Reson Imaging Clin N Am 10 (4): 631-62, 2002.

Treatment Option Overview for Salivary Gland Cancer

The minimum therapy for patients with low-grade malignancies of the superficial portion of the parotid gland is a superficial parotidectomy. For all other lesions, a total parotidectomy is often indicated. The facial nerve or its branches should be resected if involved by tumor; repair can be done simultaneously. Evidence suggests that postoperative radiation therapy augments surgical resection, particularly for the high-grade neoplasms, when margins are close or involved, when tumors are large, or when histological evidence of lymph node metastases is present.[1,2,3,4,5,6,7,8] Clinical trials in the United States and England indicated that fast neutron-beam radiation therapy improves disease-free survival and overall survival in patients with unresectable tumors or for patients with recurrent neoplasms.[9,10,11,12] Facilities with fast neutron-beam radiation therapy are of limited availability in the United States. Accelerated hyperfractionated photon-beam radiation therapy has also resulted in high rates of long-term local regional controls.[13,14] The use of chemotherapy for malignant salivary gland tumors remains under evaluation.[15,16,17,18,19]

References:

1. Myers EN, Suen JY, eds.: Cancer of the Head and Neck. 3rd ed. Saunders, 1996.
2. Freund HR: Principles of Head and Neck Surgery. 2nd ed. Appleton-Century-Crofts, 1979.
3. Lore JM: An Atlas of Head and Neck Surgery. 3rd ed. Saunders, 1988.
4. Million RR, Cassisi NJ, eds.: Management of Head and Neck Cancer: A Multidisciplinary Approach. Lippincott, 1994.
5. Wang CC, ed.: Radiation Therapy for Head and Neck Neoplasms. 3rd ed. Wiley-Liss, 1997.
6. Cummings CW, Fredrickson JM, Harker LA, et al.: Otolaryngology - Head and Neck Surgery. Mosby-Year Book, Inc., 1998.
7. Garden AS, el-Naggar AK, Morrison WH, et al.: Postoperative radiotherapy for malignant tumors of the parotid gland. Int J Radiat Oncol Biol Phys 37 (1): 79-85, 1997.
8. Chen AM, Granchi PJ, Garcia J, et al.: Local-regional recurrence after surgery without postoperative irradiation for carcinomas of the major salivary glands: implications for adjuvant therapy. Int J Radiat Oncol Biol Phys 67 (4): 982-7, 2007.
9. Buchholz TA, Laramore GE, Griffin BR, et al.: The role of fast neutron radiation therapy in the management of advanced salivary gland malignant neoplasms. Cancer 69 (11): 2779-88, 1992.
10. Krüll A, Schwarz R, Engenhart R, et al.: European results in neutron therapy of malignant salivary gland tumors. Bull Cancer Radiother 83 (Suppl): 125-9s, 1996.
11. Douglas JG, Lee S, Laramore GE, et al.: Neutron radiotherapy for the treatment of locally advanced major salivary gland tumors. Head Neck 21 (3): 255-63, 1999.
12. Douglas JG, Laramore GE, Austin-Seymour M, et al.: Treatment of locally advanced adenoid cystic carcinoma of the head and neck with neutron radiotherapy. Int J Radiat Oncol Biol Phys 46 (3): 551-7, 2000.
13. Wang CC, Goodman M: Photon irradiation of unresectable carcinomas of salivary glands. Int J Radiat Oncol Biol Phys 21 (3): 569-76, 1991.
14. Douglas JG, Koh WJ, Austin-Seymour M, et al.: Treatment of salivary gland neoplasms with fast neutron radiotherapy. Arch Otolaryngol Head Neck Surg 129 (9): 944-8, 2003.
15. Kaplan MJ, Johns ME, Cantrell RW: Chemotherapy for salivary gland cancer. Otolaryngol Head Neck Surg 95 (2): 165-70, 1986.
16. Eisenberger MA: Supporting evidence for an active treatment program for advanced salivary gland carcinomas. Cancer Treat Rep 69 (3): 319-21, 1985.
17. Spiro RH: Salivary neoplasms: overview of a 35-year experience with 2,807 patients. Head Neck Surg 8 (3): 177-84, 1986 Jan-Feb.
18. Theriault C, Fitzpatrick PJ: Malignant parotid tumors. Prognostic factors and optimum treatment. Am J Clin Oncol 9 (6): 510-6, 1986.
19. Licitra L, Cavina R, Grandi C, et al.: Cisplatin, doxorubicin and cyclophosphamide in advanced salivary gland carcinoma. A phase II trial of 22 patients. Ann Oncol 7 (6): 640-2, 1996.

Treatment of Stage I Major Salivary Gland Cancer

Treatment Options for Low-Grade Stage I Major Salivary Gland Tumors

Treatment options for low-grade stage I major salivary gland tumors include the following:

1. Surgery alone.
2. Postoperative radiation therapy should be considered when the resection margins are positive.

Low-grade stage I tumors of the salivary gland are curable with surgery alone.[1,2,3] Radiation therapy may be used for tumors for which resection involves a significant cosmetic or functional deficit or as an adjuvant to surgery when positive margins are present.[4] Neutron-beam therapy is effective in the treatment of patients with malignant salivary gland tumors with a poor prognosis.[5,6,7]

Treatment Options for High-Grade Stage I Major Salivary Gland Tumors

Treatment options for high-grade stage I major salivary gland tumors include the following:

1. Localized high-grade salivary gland tumors that are confined to the gland in which they arise may be cured by radical surgery alone.
2. Postoperative radiation therapy may improve local control and increase survival rates for patients with high-grade tumors, positive surgical margins, or perineural invasion.[8][Level of evidence C2]; [9,10,11]
3. Chemotherapy (under clinical evaluation).[12,13]

Clinical trials exploring newer methods of local control are appropriate.

High-grade stage I salivary gland tumors that are confined to the gland in which they arise may be cured by surgery alone. Adjuvant radiation therapy may be used, especially with the presence of positive margins.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Byers RM, Jesse RH, Guillamondegui OM, et al.: Malignant tumors of the submaxillary gland. Am J Surg 126 (4): 458-63, 1973.
2. Mendenhall WM, Werning JW, Pfister DG: Treatment of head and neck cancer. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Lippincott Williams & Wilkins, 2011, pp 729-80.
3. Woods JE, Chong GC, Beahrs OH: Experience with 1,360 primary parotid tumors. Am J Surg 130 (4): 460-2, 1975.
4. Guillamondegui OM, Byers RM, Luna MA, et al.: Aggressive surgery in treatment for parotid cancer: the role of adjunctive postoperative radiotherapy. Am J Roentgenol Radium Ther Nucl Med 123 (1): 49-54, 1975.
5. Krüll A, Schwarz R, Engenhart R, et al.: European results in neutron therapy of malignant salivary gland tumors. Bull Cancer Radiother 83 (Suppl): 125-9s, 1996.
6. Douglas JG, Lee S, Laramore GE, et al.: Neutron radiotherapy for the treatment of locally advanced major salivary gland tumors. Head Neck 21 (3): 255-63, 1999.
7. Douglas JG, Laramore GE, Austin-Seymour M, et al.: Treatment of locally advanced adenoid cystic carcinoma of the head and neck with neutron radiotherapy. Int J Radiat Oncol Biol Phys 46 (3): 551-7, 2000.
8. Hosokawa Y, Shirato H, Kagei K, et al.: Role of radiotherapy for mucoepidermoid carcinoma of salivary gland. Oral Oncol 35 (1): 105-11, 1999.
9. Garden AS, el-Naggar AK, Morrison WH, et al.: Postoperative radiotherapy for malignant tumors of the parotid gland. Int J Radiat Oncol Biol Phys 37 (1): 79-85, 1997.
10. Mendenhall WM, Morris CG, Amdur RJ, et al.: Radiotherapy alone or combined with surgery for salivary gland carcinoma. Cancer 103 (12): 2544-50, 2005.
11. Chen AM, Granchi PJ, Garcia J, et al.: Local-regional recurrence after surgery without postoperative irradiation for carcinomas of the major salivary glands: implications for adjuvant therapy. Int J Radiat Oncol Biol Phys 67 (4): 982-7, 2007.
12. Kaplan MJ, Johns ME, Cantrell RW: Chemotherapy for salivary gland cancer. Otolaryngol Head Neck Surg 95 (2): 165-70, 1986.
13. Eisenberger MA: Supporting evidence for an active treatment program for advanced salivary gland carcinomas. Cancer Treat Rep 69 (3): 319-21, 1985.

Treatment of Stage II Major Salivary Gland Cancer

Treatment Options for Low-Grade Stage II Major Salivary Gland Tumors

Treatment options for low-grade stage II major salivary gland tumors include the following:

1. Surgery alone or with postoperative radiation therapy, if indicated, is appropriate.[1,2]
2. Chemotherapy should be considered in special circumstances, such as when radiation therapy or surgery is refused.

Low-grade stage II tumors of the salivary gland may be cured with surgery alone.[3,4,5] Radiation therapy may be used as primary treatment for tumors for in which resection involves a significant cosmetic or functional deficit or as an adjuvant to surgery when positive margins are present.[6]

Treatment Options for High-Grade Stage II Major Salivary Gland Tumors

Treatment options for high-grade stage II major salivary gland tumors include the following:

1. Localized high-grade salivary gland tumors that are confined to the gland in which they arise may be cured by radical surgery alone.
2. Postoperative radiation therapy may improve local control and increase survival rates for patients with high-grade tumors, positive surgical margins, or perineural invasion.[7][Level of evidence C2]; [8,9,10]
3. Fast neutron-beam radiation therapy or accelerated hyperfractionated photon-beam schedules reportedly are more effective than conventional x-ray therapy in the treatment of patients with inoperable, unresectable, or recurrent malignant salivary gland tumors.[11,12,13,14]
4. Chemotherapy (under clinical evaluation).[15,16]

Clinical trials exploring ways to improve local control with radiation therapy and/or radiosensitizers are appropriate.

High-grade stage II salivary gland tumors that are confined to the gland in which they arise may be cured by surgery alone, although adjuvant radiation therapy may be used, especially if positive margins are present. Primary radiation therapy may be given for tumors that are inoperable, unresectable, or recurrent. Fast neutron-beam radiation therapy has been shown to improve disease-free survival and overall survival in this clinical situation.[11,13,14]

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Spiro RH: Salivary neoplasms: overview of a 35-year experience with 2,807 patients. Head Neck Surg 8 (3): 177-84, 1986 Jan-Feb.
2. Theriault C, Fitzpatrick PJ: Malignant parotid tumors. Prognostic factors and optimum treatment. Am J Clin Oncol 9 (6): 510-6, 1986.
3. Byers RM, Jesse RH, Guillamondegui OM, et al.: Malignant tumors of the submaxillary gland. Am J Surg 126 (4): 458-63, 1973.
4. Mendenhall WM, Werning JW, Pfister DG: Treatment of head and neck cancer. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Lippincott Williams & Wilkins, 2011, pp 729-80.
5. Woods JE, Chong GC, Beahrs OH: Experience with 1,360 primary parotid tumors. Am J Surg 130 (4): 460-2, 1975.
6. Guillamondegui OM, Byers RM, Luna MA, et al.: Aggressive surgery in treatment for parotid cancer: the role of adjunctive postoperative radiotherapy. Am J Roentgenol Radium Ther Nucl Med 123 (1): 49-54, 1975.
7. Hosokawa Y, Shirato H, Kagei K, et al.: Role of radiotherapy for mucoepidermoid carcinoma of salivary gland. Oral Oncol 35 (1): 105-11, 1999.
8. Garden AS, el-Naggar AK, Morrison WH, et al.: Postoperative radiotherapy for malignant tumors of the parotid gland. Int J Radiat Oncol Biol Phys 37 (1): 79-85, 1997.
9. Mendenhall WM, Morris CG, Amdur RJ, et al.: Radiotherapy alone or combined with surgery for salivary gland carcinoma. Cancer 103 (12): 2544-50, 2005.
10. Chen AM, Granchi PJ, Garcia J, et al.: Local-regional recurrence after surgery without postoperative irradiation for carcinomas of the major salivary glands: implications for adjuvant therapy. Int J Radiat Oncol Biol Phys 67 (4): 982-7, 2007.
11. Krüll A, Schwarz R, Engenhart R, et al.: European results in neutron therapy of malignant salivary gland tumors. Bull Cancer Radiother 83 (Suppl): 125-9s, 1996.
12. Wang CC, Goodman M: Photon irradiation of unresectable carcinomas of salivary glands. Int J Radiat Oncol Biol Phys 21 (3): 569-76, 1991.
13. Douglas JG, Lee S, Laramore GE, et al.: Neutron radiotherapy for the treatment of locally advanced major salivary gland tumors. Head Neck 21 (3): 255-63, 1999.
14. Douglas JG, Laramore GE, Austin-Seymour M, et al.: Treatment of locally advanced adenoid cystic carcinoma of the head and neck with neutron radiotherapy. Int J Radiat Oncol Biol Phys 46 (3): 551-7, 2000.
15. Suen JY, Johns ME: Chemotherapy for salivary gland cancer. Laryngoscope 92 (3): 235-9, 1982.
16. Posner MR, Ervin TJ, Weichselbaum RR, et al.: Chemotherapy of advanced salivary gland neoplasms. Cancer 50 (11): 2261-4, 1982.

Treatment of Stage III Major Salivary Gland Cancer

Treatment Options for Low-Grade Stage III Major Salivary Gland Tumors

Treatment options for low-grade stage III major salivary gland tumors include the following:

1. Surgery alone or with postoperative radiation therapy, if indicated, is appropriate.
2. Chemotherapy should be considered in special circumstances, such as when radiation or surgery is refused or when tumors are recurrent or nonresponsive.
3. Fast neutron-beam radiation therapy (under clinical evaluation). Data in which fast neutron-beam radiation therapy has been used have indicated superior results when compared with conventional radiation therapy using x-rays.[1,2]
4. Chemotherapy (under clinical evaluation).[3,4]

Patients with low-grade stage III tumors of the salivary gland may be cured with surgery alone.[5,6,7] Radiation therapy as primary treatment is not often required but may be used for tumors for which resection involves a significant cosmetic or functional deficit, or as an adjuvant to surgery when positive margins are present.[8] Patients with low-grade tumors that have spread to lymph nodes may be cured with resection of the primary tumor and the involved lymph nodes, with or without radiation therapy. Neutron-beam therapy is effective in the treatment of patients with tumors that have spread to local lymph nodes.

Treatment Options for High-Grade Stage III Major Salivary Gland Tumors

Treatment options for high-grade stage III major salivary gland tumors include the following:

1. Patients with localized high-grade salivary gland tumors that are confined to the gland in which they arise may be cured by radical surgery alone.[9,10]
2. Postoperative radiation therapy may improve local control and increase survival rates for patients with high-grade tumors, positive surgical margins, or perineural invasion.[11][Level of evidence C2]; [12,13,14]
3. Fast neutron-beam radiation therapy or accelerated hyperfractionated photon-beam schedules have been reported to be more effective than conventional x-ray therapy in the treatment of patients with inoperable, unresectable, or recurrent malignant salivary gland tumors.[1,15,16,17]
4. Radiation therapy, radiosensitizers, and chemotherapy (under clinical evaluation). Clinical trials are exploring ways to improve local control with these modalities.[2,3,4,18,19]

Patients with high-grade stage III salivary gland tumors that are confined to the gland in which they arise may be cured by surgery alone, although adjuvant postoperative radiation therapy may be used, especially if positive margins are present. Primary conventional x-ray radiation therapy may provide palliation for patients with unresectable tumors. Fast neutron beams, however, have been reported to improve disease-free survival and overall survival in this clinical situation.[1,16,17] Patients with tumors that have spread to regional lymph nodes should have a regional lymphadenectomy as part of the initial surgical procedure. Adjuvant radiation therapy for these tumors may reduce the local recurrence rate.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Krüll A, Schwarz R, Engenhart R, et al.: European results in neutron therapy of malignant salivary gland tumors. Bull Cancer Radiother 83 (Suppl): 125-9s, 1996.
2. Catterall M, Errington RD: The implications of improved treatment of malignant salivary gland tumors by fast neutron radiotherapy. Int J Radiat Oncol Biol Phys 13 (9): 1313-8, 1987.
3. Kaplan MJ, Johns ME, Cantrell RW: Chemotherapy for salivary gland cancer. Otolaryngol Head Neck Surg 95 (2): 165-70, 1986.
4. Eisenberger MA: Supporting evidence for an active treatment program for advanced salivary gland carcinomas. Cancer Treat Rep 69 (3): 319-21, 1985.
5. Byers RM, Jesse RH, Guillamondegui OM, et al.: Malignant tumors of the submaxillary gland. Am J Surg 126 (4): 458-63, 1973.
6. Mendenhall WM, Werning JW, Pfister DG: Treatment of head and neck cancer. In: DeVita VT Jr, Lawrence TS, Rosenberg SA: Cancer: Principles and Practice of Oncology. 9th ed. Lippincott Williams & Wilkins, 2011, pp 729-80.
7. Woods JE, Chong GC, Beahrs OH: Experience with 1,360 primary parotid tumors. Am J Surg 130 (4): 460-2, 1975.
8. Guillamondegui OM, Byers RM, Luna MA, et al.: Aggressive surgery in treatment for parotid cancer: the role of adjunctive postoperative radiotherapy. Am J Roentgenol Radium Ther Nucl Med 123 (1): 49-54, 1975.
9. Spiro RH: Salivary neoplasms: overview of a 35-year experience with 2,807 patients. Head Neck Surg 8 (3): 177-84, 1986 Jan-Feb.
10. Theriault C, Fitzpatrick PJ: Malignant parotid tumors. Prognostic factors and optimum treatment. Am J Clin Oncol 9 (6): 510-6, 1986.
11. Hosokawa Y, Shirato H, Kagei K, et al.: Role of radiotherapy for mucoepidermoid carcinoma of salivary gland. Oral Oncol 35 (1): 105-11, 1999.
12. Garden AS, el-Naggar AK, Morrison WH, et al.: Postoperative radiotherapy for malignant tumors of the parotid gland. Int J Radiat Oncol Biol Phys 37 (1): 79-85, 1997.
13. Mendenhall WM, Morris CG, Amdur RJ, et al.: Radiotherapy alone or combined with surgery for salivary gland carcinoma. Cancer 103 (12): 2544-50, 2005.
14. Chen AM, Granchi PJ, Garcia J, et al.: Local-regional recurrence after surgery without postoperative irradiation for carcinomas of the major salivary glands: implications for adjuvant therapy. Int J Radiat Oncol Biol Phys 67 (4): 982-7, 2007.
15. Wang CC, Goodman M: Photon irradiation of unresectable carcinomas of salivary glands. Int J Radiat Oncol Biol Phys 21 (3): 569-76, 1991.
16. Douglas JG, Lee S, Laramore GE, et al.: Neutron radiotherapy for the treatment of locally advanced major salivary gland tumors. Head Neck 21 (3): 255-63, 1999.
17. Douglas JG, Laramore GE, Austin-Seymour M, et al.: Treatment of locally advanced adenoid cystic carcinoma of the head and neck with neutron radiotherapy. Int J Radiat Oncol Biol Phys 46 (3): 551-7, 2000.
18. Suen JY, Johns ME: Chemotherapy for salivary gland cancer. Laryngoscope 92 (3): 235-9, 1982.
19. Posner MR, Ervin TJ, Weichselbaum RR, et al.: Chemotherapy of advanced salivary gland neoplasms. Cancer 50 (11): 2261-4, 1982.

Treatment of Stage IV Major Salivary Gland Cancer

Treatment Options for Stage IV Major Salivary Gland Tumors

Standard therapy for patients with tumors that have spread to distant sites is not curative.

Treatment options for high-grade stage IV major salivary gland tumors include the following:

1. Fast neutron-beam radiation therapy or accelerated hyperfractionated photon-beam schedules have been reported to be more effective than conventional x-ray therapy in the treatment of patients with inoperable, unresectable, or recurrent malignant salivary gland tumors.[1,2,3,4,5]
2. Aggressive combinations of chemotherapy and radiation (under clinical evaluation).

Patients with stage IV salivary gland cancer and patients with any metastatic lesions should consider enrollment in clinical trials. Their cancer may be responsive to aggressive combinations of chemotherapy and radiation. Patients with any metastatic lesions could consider clinical trials. Chemotherapy using doxorubicin, cisplatin, cyclophosphamide, and fluorouracil as single agents or in various combinations is associated with modest response rates.[6,7,8,9,10,11,12,13,14]

Fluorouracil dosing

The DPYD gene encodes an enzyme that catabolizes pyrimidines and fluoropyrimidines, like capecitabine and fluorouracil. An estimated 1% to 2% of the population has germline pathogenic variants in DPYD, which lead to reduced DPD protein function and an accumulation of pyrimidines and fluoropyrimidines in the body.[15,16] Patients with the DPYD*2A variant who receive fluoropyrimidines may experience severe, life-threatening toxicities that are sometimes fatal. Many other DPYD variants have been identified, with a range of clinical effects.[15,16,17] Fluoropyrimidine avoidance or a dose reduction of 50% may be recommended based on the patient's DPYD genotype and number of functioning DPYD alleles.[18,19,20]DPYD genetic testing costs less than $200, but insurance coverage varies due to a lack of national guidelines.[21] In addition, testing may delay therapy by 2 weeks, which would not be advisable in urgent situations. This controversial issue requires further evaluation.[22]

References:

1. Wang CC, Goodman M: Photon irradiation of unresectable carcinomas of salivary glands. Int J Radiat Oncol Biol Phys 21 (3): 569-76, 1991.
2. Laramore GE, Krall JM, Griffin TW, et al.: Neutron versus photon irradiation for unresectable salivary gland tumors: final report of an RTOG-MRC randomized clinical trial. Radiation Therapy Oncology Group. Medical Research Council. Int J Radiat Oncol Biol Phys 27 (2): 235-40, 1993.
3. Krüll A, Schwarz R, Engenhart R, et al.: European results in neutron therapy of malignant salivary gland tumors. Bull Cancer Radiother 83 (Suppl): 125-9s, 1996.
4. Douglas JG, Lee S, Laramore GE, et al.: Neutron radiotherapy for the treatment of locally advanced major salivary gland tumors. Head Neck 21 (3): 255-63, 1999.
5. Douglas JG, Laramore GE, Austin-Seymour M, et al.: Treatment of locally advanced adenoid cystic carcinoma of the head and neck with neutron radiotherapy. Int J Radiat Oncol Biol Phys 46 (3): 551-7, 2000.
6. Eisenberger MA: Supporting evidence for an active treatment program for advanced salivary gland carcinomas. Cancer Treat Rep 69 (3): 319-21, 1985.
7. Venook AP, Tseng A, Meyers FJ, et al.: Cisplatin, doxorubicin, and 5-fluorouracil chemotherapy for salivary gland malignancies: a pilot study of the Northern California Oncology Group. J Clin Oncol 5 (6): 951-5, 1987.
8. Rentschler R, Burgess MA, Byers R: Chemotherapy of malignant major salivary gland neoplasms: a 25-year review of M. D. Anderson Hospital experience. Cancer 40 (2): 619-24, 1977.
9. Posner MR, Ervin TJ, Weichselbaum RR, et al.: Chemotherapy of advanced salivary gland neoplasms. Cancer 50 (11): 2261-4, 1982.
10. Suen JY, Johns ME: Chemotherapy for salivary gland cancer. Laryngoscope 92 (3): 235-9, 1982.
11. Catterall M, Errington RD: The implications of improved treatment of malignant salivary gland tumors by fast neutron radiotherapy. Int J Radiat Oncol Biol Phys 13 (9): 1313-8, 1987.
12. Ono M, Watanabe A, Matsumoto Y, et al.: Methamphetamine modifies the photic entraining responses in the rodent suprachiasmatic nucleus via serotonin release. Neuroscience 72 (1): 213-24, 1996.
13. Saroja KR, Mansell J, Hendrickson FR, et al.: An update on malignant salivary gland tumors treated with neutrons at Fermilab. Int J Radiat Oncol Biol Phys 13 (9): 1319-25, 1987.
14. Licitra L, Cavina R, Grandi C, et al.: Cisplatin, doxorubicin and cyclophosphamide in advanced salivary gland carcinoma. A phase II trial of 22 patients. Ann Oncol 7 (6): 640-2, 1996.
15. Sharma BB, Rai K, Blunt H, et al.: Pathogenic DPYD Variants and Treatment-Related Mortality in Patients Receiving Fluoropyrimidine Chemotherapy: A Systematic Review and Meta-Analysis. Oncologist 26 (12): 1008-1016, 2021.
16. Lam SW, Guchelaar HJ, Boven E: The role of pharmacogenetics in capecitabine efficacy and toxicity. Cancer Treat Rev 50: 9-22, 2016.
17. Shakeel F, Fang F, Kwon JW, et al.: Patients carrying DPYD variant alleles have increased risk of severe toxicity and related treatment modifications during fluoropyrimidine chemotherapy. Pharmacogenomics 22 (3): 145-155, 2021.
18. Amstutz U, Henricks LM, Offer SM, et al.: Clinical Pharmacogenetics Implementation Consortium (CPIC) Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing: 2017 Update. Clin Pharmacol Ther 103 (2): 210-216, 2018.
19. Henricks LM, Lunenburg CATC, de Man FM, et al.: DPYD genotype-guided dose individualisation of fluoropyrimidine therapy in patients with cancer: a prospective safety analysis. Lancet Oncol 19 (11): 1459-1467, 2018.
20. Lau-Min KS, Varughese LA, Nelson MN, et al.: Preemptive pharmacogenetic testing to guide chemotherapy dosing in patients with gastrointestinal malignancies: a qualitative study of barriers to implementation. BMC Cancer 22 (1): 47, 2022.
21. Brooks GA, Tapp S, Daly AT, et al.: Cost-effectiveness of DPYD Genotyping Prior to Fluoropyrimidine-based Adjuvant Chemotherapy for Colon Cancer. Clin Colorectal Cancer 21 (3): e189-e195, 2022.
22. Baker SD, Bates SE, Brooks GA, et al.: DPYD Testing: Time to Put Patient Safety First. J Clin Oncol 41 (15): 2701-2705, 2023.

Treatment of Recurrent Major Salivary Gland Cancer

The prognosis for any patient with progressing or relapsing salivary gland cancer is poor, regardless of cell type or stage. Selecting further treatment depends on many factors, including the specific cancer, prior treatment, site of recurrence, and individual patient considerations. Fast neutron-beam radiation therapy is superior to conventional radiation therapy using x-rays and may be curative in selected patients with recurrent disease.[1]

Patients with inoperable, unresectable, or recurrent malignant salivary gland tumors treated with fast neutron-beam radiation therapy have better disease-free survival and overall survival than patients treated with conventional x-ray radiation therapy.[2,3,4,5] Clinical trials are appropriate and should be considered when possible.

Current Clinical Trials

Use our advanced clinical trial search to find NCI-supported cancer clinical trials that are now enrolling patients. The search can be narrowed by location of the trial, type of treatment, name of the drug, and other criteria. General information about clinical trials is also available.

References:

1. Laramore GE, Krall JM, Griffin TW, et al.: Neutron versus photon irradiation for unresectable salivary gland tumors: final report of an RTOG-MRC randomized clinical trial. Radiation Therapy Oncology Group. Medical Research Council. Int J Radiat Oncol Biol Phys 27 (2): 235-40, 1993.
2. Laramore GE: Fast neutron radiotherapy for inoperable salivary gland tumors: is it the treatment of choice? Int J Radiat Oncol Biol Phys 13 (9): 1421-3, 1987.
3. Saroja KR, Mansell J, Hendrickson FR, et al.: An update on malignant salivary gland tumors treated with neutrons at Fermilab. Int J Radiat Oncol Biol Phys 13 (9): 1319-25, 1987.
4. Buchholz TA, Laramore GE, Griffin BR, et al.: The role of fast neutron radiation therapy in the management of advanced salivary gland malignant neoplasms. Cancer 69 (11): 2779-88, 1992.
5. Krüll A, Schwarz R, Engenhart R, et al.: European results in neutron therapy of malignant salivary gland tumors. Bull Cancer Radiother 83 (Suppl): 125-9s, 1996.

Latest Updates to This Summary (08 / 16 / 2024)

The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.

Treatment of Stage IV Major Salivary Gland Cancer

Added Fluorouracil dosing as a new subsection.

This summary is written and maintained by the PDQ Adult Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.

About This PDQ Summary

Purpose of This Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of adult salivary gland cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.

Reviewers and Updates

This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).

Board members review recently published articles each month to determine whether an article should:

• be discussed at a meeting,
• be cited with text, or
• replace or update an existing article that is already cited.

Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.

The lead reviewers for Salivary Gland Cancer Treatment are:

• Andrea Bonetti, MD (Azienda ULSS 9 of the Veneto Region)
• Monaliben Patel, MD (University of Rochester Medical Center)
• Minh Tam Truong, MD (Boston University Medical Center)

Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.

Levels of Evidence

Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system in developing its level-of-evidence designations.

Permission to Use This Summary

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The preferred citation for this PDQ summary is:

PDQ® Adult Treatment Editorial Board. PDQ Salivary Gland Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at: https://www.cancer.gov/types/head-and-neck/hp/adult/salivary-gland-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389389]

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Last Revised: 2024-08-16