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Salivary Gland Cancer Treatment (PDQ®)     
Last Modified: 07/11/2008
Health Professional Version
Table of Contents

Purpose of This PDQ Summary
General Information
Cellular Classification
Epithelial Neoplasms
Nonepithelial Neoplasms
Malignant Secondary Neoplasms
Stage Information
TNM Definitions
AJCC Stage Groupings
Treatment Option Overview
Stage I Major Salivary Gland Cancer
Low-grade Tumors
High-grade Tumors
Current Clinical Trials
Stage II Major Salivary Gland Cancer
Low-grade Tumors
High-grade Tumors
Current Clinical Trials
Stage III Major Salivary Gland Cancer
Low-grade Tumors
High-grade Tumors
Current Clinical Trials
Stage IV Major Salivary Gland Cancer
Current Clinical Trials
Recurrent Major Salivary Gland Cancer
Current Clinical Trials
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Changes to This Summary (07/11/2008)
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Purpose of This PDQ Summary

This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of salivary gland cancer. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board 1.

Information about the following is included in this summary:

  • Prognostic factors.
  • Histology.
  • Clinical presentation and prognosis.
  • Cellular classification.
  • Staging.
  • Treatment options by cancer stage.

This summary is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.

Some of the reference citations in the 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 2 in developing its level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for reimbursement determinations.

This summary is available in a patient version 3, written in less technical language, and in Spanish 4.

General Information

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence 2 for more information.)

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 cases to 3.0 cases per 100,000 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 the sixth or seventh decade of life.[3,4] 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]

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] (Refer to the PDQ summaries on Laryngeal Cancer Treatment 5, Lip and Oral Cavity Cancer Treatment 6, Nasopharyngeal Cancer Treatment 7, Hypopharyngeal Cancer Treatment 8, and Paranasal Sinus and Nasal Cavity Cancer Treatment 9 for more information.) 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% of all salivary gland neoplasms 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]

Histologically, salivary gland tumors represent the most heterogenous group of tumors of any tissue in the body.[10] Although almost 40 histologic 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 the pleomorphic adenoma, which comprises 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 the mucoepidermoid carcinoma, which comprises 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] This type and other histologic types of salivary gland neoplasms are reviewed in detail in the Cellular Classification 10 section.

Most patients with benign tumors of the major or minor salivary glands present with painless swelling of the parotid, submandibular, or the sublingual glands. Neurological signs, such as numbness or weakness caused by nerve involvement, typically indicate a malignancy.[2] Facial nerve weakness that is 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] The majority of parotid tumors, both benign and malignant, however, present as an asymptomatic mass in the gland.[2,8]

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, then 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:[16,17]

  • Gland in which they arise.
  • Histology.
  • Grade (i.e., degree of malignancy).
  • Extent of primary tumor (i.e., the 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.

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

Perineural invasion can also 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: 3iiiDii] Unresectable or recurrent tumors may respond to chemotherapy.[21-23] Fast neutron-beam radiation therapy or accelerated hyperfractionated photon-beam schedules have been shown to be effective in the treatment of inoperable, unresectable, and recurrent tumors.[24-26]

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

References

  1. Speight PM, Barrett AW: Salivary gland tumours. Oral Dis 8 (5): 229-40, 2002.  [PUBMED Abstract]

  2. Mendenhall WM, Riggs CE Jr, Cassisi NJ: Treatment of head and neck cancers. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2005, pp 662-732. 

  3. Ellis GL, Auclair PL: Tumors of the Salivary Glands. Washington, DC : 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.  [PUBMED Abstract]

  5. Scanlon EF, Sener SF: Head and neck neoplasia following irradiation for benign conditions. Head Neck Surg 4 (2): 139-45, 1981 Nov-Dec.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  9. Theriault C, Fitzpatrick PJ: Malignant parotid tumors. Prognostic factors and optimum treatment. Am J Clin Oncol 9 (6): 510-6, 1986.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  11. Seifert G, Sobin LH: Histological Typing of Salivary Gland Tumours. 2nd ed. Berlin, Germany: 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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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, UK: 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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  24. Wang CC, Goodman M: Photon irradiation of unresectable carcinomas of salivary glands. Int J Radiat Oncol Biol Phys 21 (3): 569-76, 1991.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  27. Naumann M, Zellner M, Toyka KV, et al.: Treatment of gustatory sweating with botulinum toxin. Ann Neurol 42 (6): 973-5, 1997.  [PUBMED Abstract]

  28. Arad-Cohen A, Blitzer A: Botulinum toxin treatment for symptomatic Frey's syndrome. Otolaryngol Head Neck Surg 122 (2): 237-40, 2000.  [PUBMED Abstract]

  29. von Lindern JJ, Niederhagen B, Bergé S, et al.: Frey syndrome: treatment with type A botulinum toxin. Cancer 89 (8): 1659-63, 2000.  [PUBMED Abstract]

Cellular Classification

Salivary gland neoplasms are remarkable for their histologic 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 primarily because of the complexity of the classification and the rarity of several entities, which may exhibit a broad spectrum of morphologic diversity in individual lesions, thus making differentiating benign from malignant tumors difficult.[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 because these neoplasms comprise a significant proportion of salivary gland neoplasms seen in the clinic. For completeness, malignant secondary tumors are also included.

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 shown below:[3]

  • Pleomorphic adenoma (i.e., mixed tumor) (see carcinoma ex pleomorphic adenoma).
  • Warthin tumor, also known as papillary cystadenoma lymphomatosum.
  • Monomorphic adenomas:
    • Basal cell adenoma (see basal cell adenocarcinoma 11).
    • Canalicular adenoma.
    • Oncocytoma (see oncocytic carcinoma).
    • Sebaceous adenoma.
    • Sebaceous lymphadenoma (see sebaceous lymphadenocarcinoma).
  • Myoepithelioma (see myoepithelial carcinoma).
  • Cystadenoma (see cystadenocarcinoma).
  • Ductal papillomas.
  • Sialoblastoma.

Histologic grading of salivary gland carcinomas is important to determine the proper treatment approach, though 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 histologic grade.[1] For example, stage I intermediate- 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 histologic grade as follows:[3,5-8]

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.

* [Note: 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 12.
  2. Adenoid cystic carcinoma 13.
  3. Adenocarcinomas 14.
    1. Acinic cell carcinoma 15.
    2. PLGA 16.
    3. Adenocarcinoma, NOS 17.
    4. Rare adenocarcinomas 11.
      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 18.
    1. Carcinoma ex pleomorphic adenoma 19.
    2. Carcinosarcoma 20.
    3. Metastasizing mixed tumor 21.
  5. Rare carcinomas 22.
    1. Primary squamous cell carcinoma 23.
    2. Epithelial-myoepithelial carcinoma 24.
    3. Anaplastic small cell carcinoma 25.
    4. Undifferentiated carcinomas 26.
      1. Small cell undifferentiated carcinoma.
      2. Large cell undifferentiated carcinoma.
      3. Lymphoepithelial carcinoma.
    5. Myoepithelial carcinoma 27.
    6. Adenosquamous carcinoma 28.
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 2 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, with an age range of 8 years to 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]

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 histologic 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.[17-19] 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.[3,23-25] 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, report 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] Regardless of histologic grade, adenoid cystic carcinomas, with their unusually slow biologic growth, tend to have a protracted course and ultimately a poor outcome, with a 10-year survival 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 histologic 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 towards 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] In these data, acinic cell carcinoma comprised 17% of primary malignant salivary gland tumors or about 6% of all salivary gland neoplasms; more than 80% 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 histologic 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 morphologic pattern nor cell composition was a predictive feature.[31]

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 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 (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, overall survival 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, not otherwise specified

Adenocarcinoma, NOS, is a salivary gland carcinoma that shows glandular or ductal differentiation but lacks the prominence of any of the morphologic 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. This tumor 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, also known as basaloid salivary carcinoma, carcinoma ex monomorphic adenoma, malignant basal cell adenoma, malignant basal cell tumor, and 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 comprised 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 is reported to be 60 years.[3]

Similar to most salivary gland neoplasms, swelling is typically the only sign or symptom experienced.[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, 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.[1,3,39-41] In the AFIP case files, the mean age of patients is 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 is known to have died as a result of this tumor.[3]

Cystadenocarcinoma—also known as malignant papillary cystadenoma, mucus-producing adenopapillary, or nonepidermoid, carcinoma; low-grade papillary adenocarcinoma of the palate; and papillary adenocarcinoma—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. 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; and approximately 65% of the tumors occurred in the major salivary glands, and primarily in the parotid.[3] Most patients present with a slowly 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 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. Tumor recurs in about 33% of cases.[43,44]

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, also known as oncocytic adenocarcinoma, is a rare, predominantly oncocytic neoplasm whose malignant nature is reflected both by its abnormal morphologic 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. Tumors smaller than 2 cm have a better prognosis than larger tumors.[6]

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 upon 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 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 to be low grade.[3]

Malignant mixed tumors

The classification of malignant mixed tumors, includes three distinct clinicopathologic entities: carcinoma ex pleomorphic adenoma, carcinosarcoma, and metastasizing mixed tumor. Carcinoma ex pleomorphic adenoma constitutes the vast majority of 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, is a carcinoma that shows histologic 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 carcinoma ex pleomorphic adenoma to comprise 8.8% of all mixed tumors and 4.6% of all malignant salivary gland tumors, ranking it 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 times 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, histologic grade and degree of invasion are important parameters 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] The majority of 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 histologic features are within the spectrum of features that typify pleomorphic adenoma.[3] The majority occur in the major salivary glands. The primary neoplasm is typically a single, well-defined mass. Recurrences, which may be multiple, have been reported to occur for 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 for 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 comprised 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.[3,11,57-59] This tumor is graded in a similar way to extrasalivary lesions according to the degree of differentiation, namely, low, intermediate, and high.[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 and 10 years were 24% and 18%, respectively.[57]

Epithelial-myoepithelial carcinoma

Epithelial-myoepithelial carcinoma, also known as adenomyoepithelioma, clear cell adenoma, tubular solid adenoma, monomorphic clear cell tumor, glycogen-rich adenoma, glycogen-rich adenocarcinoma, clear cell carcinoma, and salivary duct carcinoma, is an uncommon, low-grade epithelial neoplasm composed of variable proportions of ductal and large, clear-staining, differentiated myoepithelial cells. It comprises 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 is about 60 years and about 60% of the patients are 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.[60,62-64]

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 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 and have a better survival rate compared 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 morphologic 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, also known as extrapulmonary oat cell carcinoma, is a rare, primary malignant tumor that, with conventional light microscopy, 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 (see above).

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.[68-70] 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 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. Neoplasms 4 cm or larger may have a particularly poor outcome.[70,72]

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 Eskimo and Inuit populations.[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.[73,76-78]

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] To date, the largest series reported involves 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]

The majority of patients present with the primary complaint of a painless mass.[79] This is an intermediate-grade to high-grade carcinoma.[3,79] Histologic grade does not appear to correlate well with clinical behavior; tumors with a low-grade histologic 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 histopathologic features of both squamous cell carcinoma and adenocarcinoma. Only a handful of reports have discussed 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.[80-84] 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. The vast majority of the non-Hodgkin lymphomas arising in a background of benign lymphoepithelial lesions are marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT).[81-84] MALT lymphomas of the salivary glands, like their counterparts in other anatomic 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 histologic 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] Of importance is 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, histologic grade, tumor size, and stage.[93,94] (Refer to the PDQ summary on Adult Soft Tissue Sarcoma Treatment 29 for more information.) 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] The majority of 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.[97-99] The peak incidence for metastatic tumors in the salivary glands is reported to be in the seventh decade of life.[3]

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  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.  [PUBMED Abstract]

  77. Saw D, Lau WH, Ho JH, et al.: Malignant lymphoepithelial lesion of the salivary gland. Hum Pathol 17 (9): 914-23, 1986.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  80. Kassan SS, Thomas TL, Moutsopoulos HM, et al.: Increased risk of lymphoma in sicca syndrome. Ann Intern Med 89 (6): 888-92, 1978.  [PUBMED Abstract]

  81. Abbondanzo SL: Extranodal marginal-zone B-cell lymphoma of the salivary gland. Ann Diagn Pathol 5 (4): 246-54, 2001.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  83. Harris NL: Lymphoid proliferations of the salivary glands. Am J Clin Pathol 111 (1 Suppl 1): S94-103, 1999.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  85. Harris NL: Extranodal lymphoid infiltrates and mucosa-associated lymphoid tissue (MALT). A unifying concept. Am J Surg Pathol 15 (9): 879-84, 1991.  [PUBMED Abstract]

  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. Baltimore, Md: Williams & Wilkins, 1992, pp 1047-79. 

  87. Salhany KE, Pietra GG: Extranodal lymphoid disorders. Am J Clin Pathol 99 (4): 472-85, 1993.  [PUBMED Abstract]

  88. Schmid U, Helbron D, Lennert K: Primary malignant lymphomas localized in salivary glands. Histopathology 6 (6): 673-87, 1982.  [PUBMED Abstract]

  89. Gleeson MJ, Bennett MH, Cawson RA: Lymphomas of salivary glands. Cancer 58 (3): 699-704, 1986.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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. Philadelphia, Pa: 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. Philadelphia, Pa: 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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  95. Weiss SW, Goldblum JR: Enzinger and Weiss's Soft Tissue Tumors. 4th ed. St. Louis, Mo: 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.  [PUBMED Abstract]

  97. Gnepp DR: Metastatic disease to the major salivary glands. In: Ellis GL, Auclair PL, Gnepp DR, eds.: Surgical Pathology of the Salivary Glands. Philadelphia, Pa: 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.  [PUBMED Abstract]

  99. Batsakis JG, Bautina E: Metastases to major salivary glands. Ann Otol Rhinol Laryngol 99 (6 Pt 1): 501-3, 1990.  [PUBMED Abstract]

Stage Information

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.[1-4] Tumors arising in the minor salivary glands are staged according to the anatomic site of origin (e.g., oral cavity and sinuses). (Refer to the PDQ summaries on Laryngeal Cancer Treatment 5, Lip and Oral Cavity Cancer Treatment 6, Nasopharyngeal Cancer Treatment 7, Hypopharyngeal Cancer Treatment 8, and Paranasal Sinus and Nasal Cavity Cancer Treatment 9 for more information.)

Clinical stage, particularly tumor size, may be the critical factor to determine the outcome of salivary gland cancer and may be more important than histologic 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]

The American Joint Committee on Cancer (AJCC) has designated staging by TNM classification.[5]

TNM Definitions

Primary tumor (T)

  • TX: Primary tumor cannot be assessed
  • T0: No evidence of primary tumor
  • T1: Tumor 2 cm or less in greatest dimension without extraparenchymal extension*
  • T2: Tumor more than 2 cm but 4 cm or less in greatest dimension without extraparenchymal extension*
  • T3: Tumor more than 4 cm and/or tumor having extraparenchymal extension*
  • T4a: Tumor invades skin, mandible, ear canal, and/or facial nerve
  • T4b: Tumor invades skull base and/or pterygoid plates and/or encases carotid artery

* [Note: Extraparenchymal extension is clinical or macroscopic evidence of invasion of soft tissues. Microscopic evidence alone does not constitute extraparenchymal extension for classification purposes.]

Regional lymph nodes (N)

  • NX: Regional lymph nodes cannot be assessed
  • N0: No regional lymph node metastasis
  • N1: Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension
  • N2: Metastasis in a single ipsilateral lymph node, more than 3 cm but 6 cm or less in greatest dimension; or in multiple ipsilateral lymph nodes, 6 cm or less in greatest dimension; or in bilateral or contralateral lymph nodes, 6 cm or less in greatest dimension
    • N2a: Metastasis in a single ipsilateral lymph node, more than 3 cm but 6 cm or less in greatest dimension
    • N2b: Metastasis in multiple ipsilateral lymph nodes, 6 cm or less in greatest dimension
    • N2c: Metastasis in bilateral or contralateral lymph nodes, 6 cm or less in greatest dimension
  • N3: Metastasis in a lymph node more than 6 cm in greatest dimension

Distant metastasis (M)

  • MX: Distant metastasis cannot be assessed
  • M0: No distant metastasis
  • M1: Distant metastasis
AJCC Stage Groupings

Stage I

  • T1, N0, M0

Stage II

  • T2, N0, M0

Stage III

  • T3, N0, M0
  • T1, N1, M0
  • T2, N1, M0
  • T3, N1, M0

Stage IVA

  • T4a, N0, M0
  • T4a, N1, M0
  • T1, N2, M0
  • T2, N2, M0
  • T3, N2, M0
  • T4a, N2, M0

Stage IVB

  • T4b, any N, M0
  • Any T, N3, M0

Stage IVC

  • Any T, any N, M1

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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  5. Major salivary glands (parotid, submandibular, and sublingual). In: American Joint Committee on Cancer.: AJCC Cancer Staging Manual. 6th ed. New York, NY: Springer, 2002, pp 53-8. 

  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, UK: 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.  [PUBMED Abstract]

Treatment Option Overview

The minimum therapy for 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. Growing 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 histologic evidence of lymph node metastases is present.[1-8] Clinical trials, which have been completed in the United States and England, indicate that fast neutron-beam radiation improves disease-free and overall survival in patients with unresectable tumors or for patients with recurrent neoplasms.[9-12] Fast neutron-beam facilities 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.[15-19]

References

  1. Myers EN, Suen JY, eds.: Cancer of the Head and Neck. 3rd ed. Philadelphia, Pa: Saunders, 1996. 

  2. Freund HR: Principles of Head and Neck Surgery. 2nd ed. New York, NY: Appleton-Century-Crofts, 1979. 

  3. Lore JM: An Atlas of Head and Neck Surgery. 3rd ed. Philadelphia, Pa: Saunders, 1988. 

  4. Million RR, Cassisi NJ, eds.: Management of Head and Neck Cancer: A Multidisciplinary Approach. Philadelphia, Pa: Lippincott, 1994. 

  5. Wang CC, ed.: Radiation Therapy for Head and Neck Neoplasms. 3rd ed. New York: Wiley-Liss, 1997. 

  6. Cummings CW, Fredrickson JM, Harker LA, et al.: Otolaryngology - Head and Neck Surgery. Saint Louis, Mo: 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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  13. Wang CC, Goodman M: Photon irradiation of unresectable carcinomas of salivary glands. Int J Radiat Oncol Biol Phys 21 (3): 569-76, 1991.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  15. Kaplan MJ, Johns ME, Cantrell RW: Chemotherapy for salivary gland cancer. Otolaryngol Head Neck Surg 95 (2): 165-70, 1986.  [PUBMED Abstract]

  16. Eisenberger MA: Supporting evidence for an active treatment program for advanced salivary gland carcinomas. Cancer Treat Rep 69 (3): 319-21, 1985.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  18. Theriault C, Fitzpatrick PJ: Malignant parotid tumors. Prognostic factors and optimum treatment. Am J Clin Oncol 9 (6): 510-6, 1986.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

Stage I Major Salivary Gland Cancer

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence 2 for more information.)

Low-grade stage I tumors of the salivary gland are curable with surgery alone.[1-3] 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 poor-prognosis malignant salivary gland tumors.[5-7]

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

Low-grade Tumors

Standard treatment options:

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

Standard treatment options:

  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: 3iiiDii][9-11]

Treatment options under clinical evaluation:

  • Clinical trials exploring newer methods of local control. The role of chemotherapy remains under evaluation, though data suggest that some salivary gland tumors may be responsive to chemotherapy.[12,13]
Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage I salivary gland cancer 30. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site 31.

References

  1. Byers RM, Jesse RH, Guillamondegui OM, et al.: Malignant tumors of the submaxillary gland. Am J Surg 126 (4): 458-63, 1973.  [PUBMED Abstract]

  2. Mendenhall WM, Riggs CE Jr, Cassisi NJ: Treatment of head and neck cancers. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2005, pp 662-732. 

  3. Woods JE, Chong GC, Beahrs OH: Experience with 1,360 primary parotid tumors. Am J Surg 130 (4): 460-2, 1975.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  12. Kaplan MJ, Johns ME, Cantrell RW: Chemotherapy for salivary gland cancer. Otolaryngol Head Neck Surg 95 (2): 165-70, 1986.  [PUBMED Abstract]

  13. Eisenberger MA: Supporting evidence for an active treatment program for advanced salivary gland carcinomas. Cancer Treat Rep 69 (3): 319-21, 1985.  [PUBMED Abstract]

Stage II Major Salivary Gland Cancer

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence 2 for more information.)

Low-grade stage II tumors of the salivary gland may be cured with surgery alone.[1-3] Radiation therapy as primary treatment 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]

High-grade stage II salivary gland tumors that are confined to the gland in which they arise may be cured by surgery alone, though 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 has been shown to improve disease-free and overall survival in this clinical situation.[5-7]

Low-grade Tumors

Standard treatment options:

  1. Surgery alone or with postoperative radiation therapy, if indicated.[8,9]
  2. Chemotherapy should be considered in special circumstances, such as when radiation therapy or surgery are refused.
High-grade Tumors

Standard treatment options:

  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.[10][Level of evidence: 3iiiDii][11-13]
  3. Fast neutron-beam radiation or accelerated hyperfractionated photon beam schedules reportedly are more effective than conventional x-ray therapy in the treatment of inoperable, unresectable, or recurrent malignant salivary gland tumors.[5-7,14]

Treatment options under clinical evaluation:

  • Clinical trials exploring ways to improve local control with radiation therapy and/or radiosensitizers. The role of chemotherapy is also under study, as evidenced in the study.[15,16]
Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage II salivary gland cancer 32. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site 31.

References

  1. Byers RM, Jesse RH, Guillamondegui OM, et al.: Malignant tumors of the submaxillary gland. Am J Surg 126 (4): 458-63, 1973.  [PUBMED Abstract]

  2. Mendenhall WM, Riggs CE Jr, Cassisi NJ: Treatment of head and neck cancers. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2005, pp 662-732. 

  3. Woods JE, Chong GC, Beahrs OH: Experience with 1,360 primary parotid tumors. Am J Surg 130 (4): 460-2, 1975.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  8. Spiro RH: Salivary neoplasms: overview of a 35-year experience with 2,807 patients. Head Neck Surg 8 (3): 177-84, 1986 Jan-Feb.  [PUBMED Abstract]

  9. Theriault C, Fitzpatrick PJ: Malignant parotid tumors. Prognostic factors and optimum treatment. Am J Clin Oncol 9 (6): 510-6, 1986.  [PUBMED Abstract]

  10. Hosokawa Y, Shirato H, Kagei K, et al.: Role of radiotherapy for mucoepidermoid carcinoma of salivary gland. Oral Oncol 35 (1): 105-11, 1999.  [PUBMED Abstract]

  11. 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.  [PUBMED Abstract]

  12. Mendenhall WM, Morris CG, Amdur RJ, et al.: Radiotherapy alone or combined with surgery for salivary gland carcinoma. Cancer 103 (12): 2544-50, 2005.  [PUBMED Abstract]

  13. 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.  [PUBMED Abstract]

  14. Wang CC, Goodman M: Photon irradiation of unresectable carcinomas of salivary glands. Int J Radiat Oncol Biol Phys 21 (3): 569-76, 1991.  [PUBMED Abstract]

  15. Suen JY, Johns ME: Chemotherapy for salivary gland cancer. Laryngoscope 92 (3): 235-9, 1982.  [PUBMED Abstract]

  16. Posner MR, Ervin TJ, Weichselbaum RR, et al.: Chemotherapy of advanced salivary gland neoplasms. Cancer 50 (11): 2261-4, 1982.  [PUBMED Abstract]

Stage III Major Salivary Gland Cancer

Note: Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence 2 for more information.)

Patients with low-grade stage III tumors of the salivary gland may be cured with surgery alone.[1-3] 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.[4] 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 tumors that have spread to local lymph nodes.

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, though 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 and overall survival in this clinical situation.[5-7] 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.

Low-grade Tumors

Standard treatment options:

  1. Surgery alone or with postoperative radiation therapy when indicated.
  2. Chemotherapy should be considered in special circumstances, when radiation or surgery are refused or when tumors are recurrent or nonresponsive.

Treatment options under clinical evaluation:

  • Data with fast neutron-beam radiation have indicated superior results when compared with conventional radiation therapy using x-rays. The role of chemotherapy is under evaluation.[5,8-10]
High-grade Tumors

Standard treatment options:

  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.[11,12]
  2. Postoperative radiation therapy may improve local control and increase survival rates for patients with high-grade tumors, positive surgical margins, or perineural invasion.[13][Level of evidence: 3iiiDii][14-16]
  3. Fast neutron-beam radiation or accelerated hyperfractionated photon beam schedules have been reported to be more effective than conventional x-ray therapy in the treatment of inoperable, unresectable, or recurrent malignant salivary gland tumors.[5-7,17]

Treatment options under clinical evaluation:

  • Clinical trials exploring ways to improve local control with radiation therapy and/or radiosensitizers and with chemotherapy are under evaluation.[8-10,18,19]
Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage III salivary gland cancer 33. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site 31.

References

  1. Byers RM, Jesse RH, Guillamondegui OM, et al.: Malignant tumors of the submaxillary gland. Am J Surg 126 (4): 458-63, 1973.  [PUBMED Abstract]

  2. Mendenhall WM, Riggs CE Jr, Cassisi NJ: Treatment of head and neck cancers. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. 7th ed. Philadelphia, Pa: Lippincott Williams & Wilkins, 2005, pp 662-732. 

  3. Woods JE, Chong GC, Beahrs OH: Experience with 1,360 primary parotid tumors. Am J Surg 130 (4): 460-2, 1975.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  8. Kaplan MJ, Johns ME, Cantrell RW: Chemotherapy for salivary gland cancer. Otolaryngol Head Neck Surg 95 (2): 165-70, 1986.  [PUBMED Abstract]

  9. Eisenberger MA: Supporting evidence for an active treatment program for advanced salivary gland carcinomas. Cancer Treat Rep 69 (3): 319-21, 1985.  [PUBMED Abstract]

  10. 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.  [PUBMED Abstract]

  11. Spiro RH: Salivary neoplasms: overview of a 35-year experience with 2,807 patients. Head Neck Surg 8 (3): 177-84, 1986 Jan-Feb.  [PUBMED Abstract]

  12. Theriault C, Fitzpatrick PJ: Malignant parotid tumors. Prognostic factors and optimum treatment. Am J Clin Oncol 9 (6): 510-6, 1986.  [PUBMED Abstract]

  13. Hosokawa Y, Shirato H, Kagei K, et al.: Role of radiotherapy for mucoepidermoid carcinoma of salivary gland. Oral Oncol 35 (1): 105-11, 1999.  [PUBMED Abstract]

  14. 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.  [PUBMED Abstract]

  15. Mendenhall WM, Morris CG, Amdur RJ, et al.: Radiotherapy alone or combined with surgery for salivary gland carcinoma. Cancer 103 (12): 2544-50, 2005.  [PUBMED Abstract]

  16. 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.  [PUBMED Abstract]

  17. Wang CC, Goodman M: Photon irradiation of unresectable carcinomas of salivary glands. Int J Radiat Oncol Biol Phys 21 (3): 569-76, 1991.  [PUBMED Abstract]

  18. Suen JY, Johns ME: Chemotherapy for salivary gland cancer. Laryngoscope 92 (3): 235-9, 1982.  [PUBMED Abstract]

  19. Posner MR, Ervin TJ, Weichselbaum RR, et al.: Chemotherapy of advanced salivary gland neoplasms. Cancer 50 (11): 2261-4, 1982.  [PUBMED Abstract]

Stage IV Major Salivary Gland Cancer

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

Standard treatment options:

  • Fast neutron-beam radiation or accelerated hyperfractionated photon beam schedules have been reported to be more effective than conventional x-ray therapy in the treatment of inoperable, unresectable, or recurrent malignant salivary gland tumors.[1-5]

Treatment options under clinical evaluation:

  • Patients with stage IV salivary gland cancer should be considered candidates for clinical trials. Their cancer may be responsive to aggressive combinations of chemotherapy and radiation. Patients with any metastatic lesions could be considered for clinical trials. Chemotherapy using doxorubicin, cisplatin, cyclophosphamide, and fluorouracil as single agents or in various combinations is associated with modest response rates.[6-14]
Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with stage IV salivary gland cancer 34. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site 31.

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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  6. Eisenberger MA: Supporting evidence for an active treatment program for advanced salivary gland carcinomas. Cancer Treat Rep 69 (3): 319-21, 1985.  [PUBMED Abstract]

  7. Venook AP, Tseng A Jr, 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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  9. Posner MR, Ervin TJ, Weichselbaum RR, et al.: Chemotherapy of advanced salivary gland neoplasms. Cancer 50 (11): 2261-4, 1982.  [PUBMED Abstract]

  10. Suen JY, Johns ME: Chemotherapy for salivary gland cancer. Laryngoscope 92 (3): 235-9, 1982.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

Recurrent Major Salivary Gland Cancer

The prognosis for any treated cancer patient with progressing or relapsing disease 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-radiation therapy is superior to conventional radiation therapy using x-rays and may be curative in selected cases of recurrent disease.[1]

Disease-free and overall survival for patients with inoperable, unresectable, or recurrent malignant salivary gland tumors is superior in patients treated with fast neutron radiation as compared to those treated with conventional x-ray radiation therapy.[2-5] Clinical trials are appropriate and should be considered when possible.

Current Clinical Trials

Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with recurrent salivary gland cancer 35. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.

General information about clinical trials is also available from the NCI Web site 31.

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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

  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.  [PUBMED Abstract]

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Changes to This Summary (07/11/2008)

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.

Stage I Major Salivary Gland Cancer 39

Added Chen et al. as reference 11 40.

Stage II Major Salivary Gland Cancer 41

Added Mendenhall et al. as reference 12 42 and Chen et al. as reference 13 42.

Stage III Major Salivary Gland Cancer 43

Added Mendenall et al. as reference 15 44 and Chen et al. as reference 16 44.

More Information

About PDQ

Additional PDQ Summaries

Important:

This information is intended mainly for use by doctors and other health care professionals. If you have questions about this topic, you can ask your doctor, or call the Cancer Information Service at 1-800-4-CANCER (1-800-422-6237).


Glossary Terms

Level of evidence 3iiiDii
Nonconsecutive case series with total disease-free survival as an endpoint. See Levels of Evidence for Adult and Pediatric Cancer Treatment Studies (PDQ®) for more information.


Table of Links

1http://www.cancer.gov/cancerinfo/pdq/adult-treatment-board
2http://www.cancer.gov/cancertopics/pdq/levels-evidence-adult-treatment/HealthPr
ofessional
3http://www.cancer.gov/cancertopics/pdq/treatment/salivarygland/Patient
4http://www.cancer.gov/espanol/pdq/tratamiento/glandulasalival/HealthProfessional
5http://www.cancer.gov/cancertopics/pdq/treatment/laryngeal/HealthProfessional
6http://www.cancer.gov/cancertopics/pdq/treatment/lip-and-oral-cavity/HealthProf
essional
7http://www.cancer.gov/cancertopics/pdq/treatment/nasopharyngeal/HealthProfessio
nal
8http://www.cancer.gov/cancertopics/pdq/treatment/hypopharyngeal/HealthProfessio
nal
9http://www.cancer.gov/cancertopics/pdq/treatment/paranasalsinus/HealthProfessio
nal
10http://www.cancer.gov/cancertopics/pdq/treatment/salivarygland/HealthProfession
al/6.cdr#Section_6
11http://www.cancer.gov/cancertopics/pdq/treatment/salivarygland/HealthProfession
al/300.cdr#Section_300
12http://www.cancer.gov/cancertopics/pdq/treatment/salivarygland/HealthProfession
al/218.cdr#Section_218
13http://www.cancer.gov/cancertopics/pdq/treatment/salivarygland/HealthProfession
al/227.cdr#Section_227
14http://www.cancer.gov/cancertopics/pdq/treatment/salivarygland/HealthProfession
al/231.cdr#Section_231
15http://www.cancer.gov/cancertopics/pdq/treatment/salivarygland/HealthProfession
al/291.cdr#Section_291
16http://www.cancer.gov/cancertopics/pdq/treatment/salivarygland/HealthProfession
al/294.cdr#Section_294
17http://www.cancer.gov/cancertopics/pdq/treatment/salivarygland/HealthProfession
al/297.cdr#Section_297
18http://www.cancer.gov/cancertopics/pdq/treatment/salivarygland/HealthProfession
al/256.cdr#Section_256
19http://www.cancer.gov/cancertopics/pdq/treatment/salivarygland/HealthProfession
al/301.cdr#Section_301
20http://www.cancer.gov/cancertopics/pdq/treatment/salivarygland/HealthProfession
al/302.cdr#Section_302
21http://www.cancer.gov/cancertopics/pdq/treatment/salivarygland/HealthProfession
al/303.cdr#Section_303
22http://www.cancer.gov/cancertopics/pdq/treatment/salivarygland/HealthProfession
al/306.cdr#Section_306
23http://www.cancer.gov/cancertopics/pdq/treatment/salivarygland/HealthProfession
al/307.cdr#Section_307
24http://www.cancer.gov/cancertopics/pdq/treatment/salivarygland/HealthProfession
al/308.cdr#Section_308
25http://www.cancer.gov/cancertopics/pdq/treatment/salivarygland/HealthProfession
al/309.cdr#Section_309
26http://www.cancer.gov/cancertopics/pdq/treatment/salivarygland/HealthProfession
al/310.cdr#Section_310
27http://www.cancer.gov/cancertopics/pdq/treatment/salivarygland/HealthProfession
al/311.cdr#Section_311
28http://www.cancer.gov/cancertopics/pdq/treatment/salivarygland/HealthProfession
al/312.cdr#Section_312
29http://www.cancer.gov/cancertopics/pdq/treatment/adult-soft-tissue-sarcoma/Heal
thProfessional
30http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?diagnosis=38947&tt=1&a
mp;format=2&cn=1
31http://www.cancer.gov/clinicaltrials
32http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?diagnosis=38948&tt=1&a
mp;format=2&cn=1
33http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?diagnosis=38949&tt=1&a
mp;format=2&cn=1
34http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?diagnosis=38950&tt=1&a
mp;format=2&cn=1
35http://www.cancer.gov/Search/ClinicalTrialsLink.aspx?diagnosis=38951&tt=1&a
mp;format=2&cn=1
36https://cissecure.nci.nih.gov/livehelp/welcome.asp
37http://cancer.gov
38https://cissecure.nci.nih.gov/ncipubs
39http://www.cancer.gov/cancertopics/pdq/treatment/salivarygland/HealthProfession
al/45.cdr#Section_45
40http://www.cancer.gov/cancertopics/pdq/treatment/salivarygland/HealthProfession
al/100.cdr#Section_100
41http://www.cancer.gov/cancertopics/pdq/treatment/salivarygland/HealthProfession
al/58.cdr#Section_58
42http://www.cancer.gov/cancertopics/pdq/treatment/salivarygland/HealthProfession
al/103.cdr#Section_103
43http://www.cancer.gov/cancertopics/pdq/treatment/salivarygland/HealthProfession
al/73.cdr#Section_73
44http://www.cancer.gov/cancertopics/pdq/treatment/salivarygland/HealthProfession
al/107.cdr#Section_107
45http://cancer.gov/cancerinfo/pdq/cancerdatabase
46http://cancer.gov/cancerinfo/pdq/adulttreatment
47http://cancer.gov/cancerinfo/pdq/pediatrictreatment
48http://cancer.gov/cancerinfo/pdq/supportivecare
49http://cancer.gov/cancerinfo/pdq/screening
50http://cancer.gov/cancerinfo/pdq/prevention
51http://cancer.gov/cancerinfo/pdq/genetics
52http://cancer.gov/cancerinfo/pdq/cam