Epithelial Neoplasms
Nonepithelial Neoplasms
Malignant Secondary Neoplasms

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.

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

Mucoepidermoid carcinoma 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, 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]

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 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, 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.

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]

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, 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, 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 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]

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, 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 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 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]

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 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]

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 for more information.) A comprehensive review of salivary gland mesenchymal neoplasms can be found elsewhere.[95]

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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