Cellular Classification of Salivary Gland Cancer
Salivary gland neoplasms are remarkable for their histological diversity. These neoplasms include benign and malignant tumors of epithelial, mesenchymal, and lymphoid origin. Salivary gland tumors pose a particular challenge to the surgical pathologist. Differentiating benign from malignant tumors may be difficult, primarily because of the complexity of the classification and the rarity of several entities, which may exhibit a broad spectrum of morphological diversity in individual lesions.[1] In some cases, hybrid lesions may be seen.[2] The key guiding principle to establish the malignant nature of a salivary gland tumor is the demonstration of an infiltrative margin.[1]
The following cellular classification scheme draws heavily from a scheme published by the Armed Forces Institute of Pathology (AFIP).[3] Malignant nonepithelial neoplasms are included in the scheme because these neoplasms comprise a significant proportion of salivary gland neoplasms seen in the clinical setting. For completeness, malignant secondary tumors are also included in the scheme.
Where AFIP statistics regarding the incidence, or relative frequency, of particular histopathologies are cited, some bias may exist because of the AFIP methods of case accrual as a pathology reference service. When possible, other sources are cited for incidence data. Notwithstanding the AFIP data, the incidence of a particular histopathology has been found to vary considerably depending upon the study cited. This variability in reporting may be partially caused by the rare incidence of many salivary gland neoplasms.
Epithelial Neoplasms
The clinician should be aware that several benign epithelial salivary gland neoplasms have malignant counterparts, which are discussed below:[3]
- Pleomorphic adenoma (i.e., mixed tumor). For more information, see the Carcinoma ex pleomorphic adenoma section.
- Warthin tumor, also known as papillary cystadenoma lymphomatosum.
- Monomorphic adenomas:
- Basal cell adenoma. For more information, see the Basal cell adenocarcinoma section.
- Canalicular adenoma.
- Oncocytoma. For more information, see the Oncocytic carcinoma section.
- Sebaceous adenoma.
- Sebaceous lymphadenoma. For more information, see the Sebaceous lymphadenocarcinoma section.
- Myoepithelioma. For more information, see the Myoepithelial carcinoma section.
- Cystadenoma. For more information, see the Cystadenocarcinoma section.
- Ductal papillomas.
- Sialoblastoma.
Histological grading of salivary gland carcinomas is important to determine the proper treatment approach, although it is not an independent indicator of the clinical course and must be considered in the context of the clinical stage. Clinical stage, particularly tumor size, may be the critical factor to determine the outcome of salivary gland cancer and may be more important than histological grade.[1] For example, stage I intermediate-grade or high-grade mucoepidermoid carcinomas can be successfully treated, whereas low-grade mucoepidermoid carcinomas that present as stage III disease may have a very aggressive clinical course.[4]
Grading is used primarily for mucoepidermoid carcinomas, adenocarcinomas, not otherwise specified (NOS), adenoid cystic carcinomas, and squamous cell carcinomas.[1,3] Various other salivary gland carcinomas can also be categorized according to histological grade as follows:[3,5,6,7,8]
Low grade
- Acinic cell carcinoma.
- Basal cell adenocarcinoma.
- Clear cell carcinoma.
- Cystadenocarcinoma.
- Epithelial-myoepithelial carcinoma.
- Mucinous adenocarcinoma.
- Polymorphous low-grade adenocarcinoma (PLGA).
Low grade, intermediate grade, and high grade
- Adenocarcinoma, NOS.
- Mucoepidermoid carcinoma.*
- Squamous cell carcinoma.
Intermediate grade and high grade
High grade
- Anaplastic small cell carcinoma.
- Carcinosarcoma.
- Large cell undifferentiated carcinoma.
- Small cell undifferentiated carcinoma.
- Salivary duct carcinoma.
*Some investigators consider mucoepidermoid carcinoma to be of only two grades: low grade and high grade.[5]
Salivary gland carcinomas and mixed tumors
- Mucoepidermoid carcinoma.
- Adenoid cystic carcinoma.
- Adenocarcinomas.
- Acinic cell carcinoma.
- PLGA.
- Adenocarcinoma, NOS.
- Rare adenocarcinomas.
- Basal cell adenocarcinoma.
- Clear cell carcinoma.
- Cystadenocarcinoma.
- Sebaceous adenocarcinoma.
- Sebaceous lymphadenocarcinoma.
- Oncocytic carcinoma.
- Salivary duct carcinoma.
- Mucinous adenocarcinoma.
- Malignant mixed tumors.
- Carcinoma ex pleomorphic adenoma.
- Carcinosarcoma.
- Metastasizing mixed tumor.
- Rare carcinomas.
- Primary squamous cell carcinoma.
- Epithelial-myoepithelial carcinoma.
- Anaplastic small cell carcinoma.
- Undifferentiated carcinomas.
- Small cell undifferentiated carcinoma.
- Large cell undifferentiated carcinoma.
- Lymphoepithelial carcinoma.
- Myoepithelial carcinoma.
- Adenosquamous carcinoma.
Mucoepidermoid carcinoma
Mucoepidermoid carcinoma is a malignant epithelial tumor that is composed of various proportions of mucous, epidermoid (e.g., squamous), intermediate, columnar, and clear cells and often demonstrates prominent cystic growth. It is the most common malignant neoplasm observed in the major and minor salivary glands.[1,9] Mucoepidermoid carcinoma represents 29% to 34% of malignant tumors originating in both major and minor salivary glands.[3,5,10,11] In two large retrospective series, 84% to 93% of cases originated in the parotid gland.[12,13] With regard to malignant tumors of the minor salivary glands, mucoepidermoid carcinoma shows a strong predilection for the lower lip.[3,14] In an AFIP review of civilian cases, the mean age of patients was 47 years (range, 8–92 years).[3] Prior exposure to ionizing radiation appears to substantially increase the risk of developing malignant neoplasms of the major salivary glands, particularly mucoepidermoid carcinoma.[3,13]
Most patients are asymptomatic and present with solitary, painless masses. Symptoms include pain, drainage from the ipsilateral ear, dysphagia, trismus, and facial paralysis.[3] For more information, see Cancer Pain.
Microscopic grading of mucoepidermoid carcinoma is important to determine the prognosis.[1,12,15] Mucoepidermoid carcinomas are graded as low grade, intermediate grade, and high grade. Grading parameters with point values include the following:
- Intracystic component (+2).
- Neural invasion present (+2).
- Necrosis present (+3).
- Mitosis (≥4 per 10 high-power field [+3]).
- Anaplasia present (+4).
Total point scores are 0 to 4 for low grade, 5 to 6 for intermediate grade, and 7 to 14 for high grade.
In a retrospective review of 243 cases of mucoepidermoid carcinoma of the major salivary glands, a statistically significant correlation was shown between this point-based grading system and outcome for parotid tumors but not for submandibular tumors.[12] Another retrospective study that used this histological grading system indicated that tumor grade correlated well with prognosis for mucoepidermoid carcinoma of the major salivary glands, excluding submandibular tumors, and minor salivary glands.[13] A modification of this grading system placed more emphasis on features of tumor invasion.[16] Nonetheless, though tumor grade may be useful, stage appears to be a better indicator of prognosis.[3,16]
Cytogenetically, mucoepidermoid carcinoma is characterized by a t(11;19)(q14–21;p12–13) translocation, which is occasionally the sole cytogenetic alteration.[17,18,19] This translocation creates a novel fusion product, MECT1::MAML2, which disrupts a Notch signaling pathway.[20] Notch signaling plays a key role in the normal development of many tissues and cell types, through diverse effects on cellular differentiation, survival, and/or proliferation, and may be involved in a wide variety of human neoplasms.[21]
Rarely, mucoepidermoid carcinoma may originate within the jaws. This tumor type is known as central mucoepidermoid carcinoma.[3] The mandibular to maxillary predilection is approximately 3:1.[22]
Adenoid cystic carcinoma
Adenoid cystic carcinoma, formerly known as cylindroma, is a slow growing but aggressive neoplasm with a remarkable capacity for recurrence.[23] Morphologically, three growth patterns have been described: cribriform, or classic pattern; tubular; and solid, or basaloid pattern. The tumors are categorized according to the predominant pattern.[3,23,24,25] The cribriform pattern shows epithelial cell nests that form cylindrical patterns. The lumina of these spaces contain periodic acid-Schiff (PAS)-positive mucopolysaccharide secretions. The tubular pattern reveals tubular structures that are lined by stratified cuboidal epithelium. The solid pattern shows solid groups of cuboidal cells. The cribriform pattern is the most common, and the solid pattern is the least common.[26] Solid adenoid cystic carcinoma is a high-grade lesion with reported recurrence rates of as much as 100%, compared with 50% to 80% for the tubular and cribriform variants.[25]
In a review of its case files, the AFIP found adenoid cystic carcinoma to be the fifth most common malignant epithelial tumor of the salivary glands after mucoepidermoid carcinomas; adenocarcinomas, NOS; acinic cell carcinomas; and PLGA.[3] Other series, however, reported adenoid cystic carcinoma to be the second most common malignant tumor, with an incidence or relative frequency of approximately 20%.[1] In the AFIP data, this neoplasm constitutes approximately 7.5% of all epithelial malignancies and 4% of all benign and malignant epithelial salivary gland tumors. The peak incidence for this tumor is reported to be in the fourth through sixth decades of life.[3]
This neoplasm typically develops as a slow-growing swelling in the preauricular or submandibular region. Pain and facial paralysis develop frequently during the course of the disease and are likely related to the associated high incidence of nerve invasion.[3] For more information, see Cancer Pain. Regardless of histological grade, adenoid cystic carcinomas, with their unusually slow biological growth, tend to have a protracted course and ultimately a poor outcome, with 10-year survival rates reported to be less than 50% for all grades.[1,27] These carcinomas typically show frequent recurrences and late distant metastases.[1,28] Clinical stage may be a better prognostic indicator than histological grade.[28,29] In a retrospective review of 92 cases, a tumor size larger than 4 cm was associated with an unfavorable clinical course in all cases.[30]
Adenocarcinomas
Acinic cell carcinoma
Acinic cell carcinoma, also known as acinic cell adenocarcinoma, is a malignant epithelial neoplasm in which the neoplastic cells express acinar differentiation. By conventional use, the term acinic cell carcinoma is defined by cytologic differentiation toward serous acinar cells, as opposed to mucous acinar cells, whose characteristic feature is cytoplasmic PAS-positive zymogen-type secretory granules.[3] In AFIP data of salivary gland neoplasms, acinic cell carcinoma is the third most common salivary gland epithelial neoplasm after mucoepidermoid carcinoma and adenocarcinoma, NOS.[3] Acinic cell carcinoma accounted for 17% of primary malignant salivary gland tumors or about 6% of all salivary gland neoplasms. More than 80% of these tumors occur in the parotid gland, women were affected more than men, and the mean age was 44 years. Other studies have reported a relative frequency of acinic cell carcinoma from 0% to 19% of malignant salivary gland neoplasms.[3]
Clinically, patients typically present with a slowly enlarging mass in the parotid region. Pain is a symptom in more than 33% of patients. For acinic cell carcinoma, staging is likely a better predictor of outcome than histological grading.[3] In a retrospective review of 90 cases, poor prognostic features included pain or fixation; gross invasion; and microscopic features of desmoplasia, atypia, or increased mitotic activity. Neither morphological pattern nor cell composition was a predictive feature.[31] For more information, see Cancer Pain.
PLGA
PLGA is a malignant epithelial tumor that is essentially limited to occurrence in minor salivary gland sites and is characterized by bland, uniform nuclear features; diverse but characteristic architecture; infiltrative growth; and perineural infiltration.[3] In a series of 426 patients with minor salivary gland tumors, PLGA represented 11% of all tumors and 26% of those that were malignant.[32] In minor gland sites, PLGA is twice as frequent as adenoid cystic carcinoma, and among all benign and malignant salivary gland neoplasms, only pleomorphic adenoma and mucoepidermoid carcinoma are more common.[3] In the AFIP case files, more than 60% of tumors occurred in the mucosa of either the soft or hard palates, approximately 16% occurred in the buccal mucosa, and 12% occurred in the upper lip. The average age of patients is reported to be 59 years, with 70% of patients between the ages of 50 and 79 years.[3] The female-to-male ratio is about 2:1, a proportion greater than for malignant salivary gland tumors in general.[3,33]
PLGA typically presents as a firm, nontender swelling involving the mucosa of the hard and soft palates (i.e., it is often found at their junction), the cheek, or the upper lip. Discomfort, bleeding, telangiectasia, or ulceration of the overlying mucosa may occasionally occur.[3] This salivary gland neoplasm typically runs a moderately indolent course. In a study of 40 cases with long-term follow-up, the overall survival rate was 80% at 25 years.[34] Because of the unpredictable behavior of the tumor, some investigators consider the qualifying term, low grade, to be misleading and instead prefer the term polymorphous adenocarcinoma.[1]
Adenocarcinoma, NOS
Adenocarcinoma, NOS, is a salivary gland carcinoma that shows glandular or ductal differentiation but lacks the prominence of any of the morphological features that characterize the other, more specific carcinoma types. The diagnosis of adenocarcinoma, NOS, is essentially one of exclusion. In an AFIP review of cases, adenocarcinoma, NOS, was second only to mucoepidermoid carcinoma in frequency among malignant salivary gland neoplasms.[3] Other series have reported an incidence of 4% to 10%.[1] In AFIP files, the mean patient age was 58 years.[3] Approximately 40% and 60% of tumors occurred in the major and minor salivary glands, respectively. Among the major salivary gland tumors, 90% occurred in the parotid gland. Adenocarcinoma, NOS is graded in a similar way to extrasalivary lesions according to the degree of differentiation.[1] Tumor grades include low-grade, intermediate-grade, and high-grade categories.[3]
Patients with tumors in the major salivary glands typically present with solitary, painless masses.[35] Two retrospective studies indicate that survival is better for patients with tumors of the oral cavity than for those with tumors of the parotid and submandibular glands.[35,36] These studies differ regarding the prognostic significance of tumor grade.
Rare adenocarcinomas
Basal cell adenocarcinoma
Basal cell adenocarcinoma, also known as basaloid salivary carcinoma, carcinoma ex monomorphic adenoma, malignant basal cell adenoma, malignant basal cell tumor, or basal cell carcinoma, is an epithelial neoplasm that is cytologically similar to basal cell adenoma but is infiltrative and has a small potential for metastasis.[3] In AFIP case files spanning almost 11 years, basal cell carcinoma made up 1.6% of all salivary gland neoplasms and 2.9% of salivary gland malignancies.[3] Nearly 90% of tumors occurred in the parotid gland.[3,37] The average age of patients was 60 years.[3]
Similar to most salivary gland neoplasms, swelling is typically the only sign or symptom.[37] A sudden increase in size may occur in a few patients.[38] Basal cell carcinomas are low-grade carcinomas that are infiltrative, locally destructive, and tend to recur. The carcinomas occasionally metastasize. In a retrospective series that included 29 patients, there were recurrences in 7 patients and metastases in 3 patients.[37] In another retrospective review that included 72 patients, 37% of the patients experienced local recurrences.[38] The overall prognosis for patients with this tumor is good.[37,38]
Clear cell carcinoma
Clear cell carcinoma, also known as clear cell adenocarcinoma, is a very rare malignant epithelial neoplasm composed of a monomorphous population of cells that have optically clear cytoplasm with standard hematoxylin and eosin stains and lack features of other specific neoplasms. Because of inconsistencies in the methods of reporting salivary gland neoplasms, meaningful incidence rates for this tumor are difficult to derive from the literature.[3] Most cases involve the minor salivary glands.[1,3,39,40,41] In the AFIP case files, the mean age of patients was approximately 58 years.[3]
In most patients, swelling is the only symptom. Clear cell adenocarcinoma is a low-grade neoplasm. As of 1996, the AFIP reported that no patient had died of this tumor.[3]
Cystadenocarcinoma
Cystadenocarcinoma is a rare malignant epithelial tumor characterized histologically by prominent cystic and, frequently, papillary growth but lacking features that characterize cystic variants of several more common salivary gland neoplasms. It is also known as malignant papillary cystadenoma, mucus-producing adenopapillary, or nonepidermoid, carcinoma; low-grade papillary adenocarcinoma of the palate; or papillary adenocarcinoma. Cystadenocarcinoma is the malignant counterpart of cystadenoma.[3]
In a review that included 57 patients, the AFIP found that men and women are affected equally. The average patient age was approximately 59 years. Approximately 65% of the tumors occurred in the major salivary glands, primarily in the parotid.[3] Most patients present with a slow-growing asymptomatic mass. Clinically, this neoplasm is rarely associated with pain or facial paralysis. Cystadenocarcinoma is considered to be a low-grade neoplasm.[3]
Sebaceous adenocarcinoma
Sebaceous adenocarcinoma is a rare malignant epithelial tumor composed of islands and sheets of cells that have morphologically atypical nuclei, an infiltrative growth pattern, and focal sebaceous differentiation. This is a very rare tumor, as few cases have been reported in the literature.[3] Almost all cases occur in the parotid gland.[3] The average age of patients is reported to be 69 years.[42]
An equal number of patients present with a painless, slow-growing, asymptomatic swelling or pain. A few experience facial paralysis.[3] Most sebaceous adenocarcinomas are probably intermediate-grade malignancies. The tumor recurs in about 33% of cases.[43,44]
Sebaceous lymphadenocarcinoma
Sebaceous lymphadenocarcinoma is an extremely rare malignant tumor that represents carcinomatous transformation of sebaceous lymphadenoma. The carcinoma element may be sebaceous adenocarcinoma or some other specific or nonspecific form of salivary gland cancer.[3] Only three cases have been reported in the literature.[43,45] The three cases occurred in or around the parotid gland. All patients were in their seventh decade of life. Two of the three patients were asymptomatic. One had tenderness on palpation. Case reports suggest that this is a low-grade malignancy with a good prognosis.[44,45]
Oncocytic carcinoma
Oncocytic carcinoma, also known as oncocytic adenocarcinoma, is a rare, predominantly oncocytic neoplasm whose malignant nature is reflected both by its abnormal morphological features and infiltrative growth. Oncocytic carcinoma represents less than 1% of almost 3,100 salivary gland tumors accessioned to the AFIP files during a 10-year period.[3] Most cases occur in the parotid gland. The average age of patients in the AFIP series was 63 years.[3]
Approximately 33% of the patients usually develop parotid masses that cause pain or paralysis.[46] Oncocytic carcinoma is a high-grade carcinoma. Patients with tumors smaller than 2 cm have a better prognosis than patients with larger tumors.[6]
Salivary duct carcinoma
Salivary duct carcinoma, also known as salivary duct adenocarcinoma, is a rare, typically high-grade malignant epithelial neoplasm composed of structures that resemble expanded salivary gland ducts. A low-grade variant exists.[47] Incidence rates vary depending on the study cited.[3] In the AFIP files, salivary duct carcinomas represent only 0.2% of all epithelial salivary gland neoplasms. More than 85% of cases involve the parotid gland, and approximately 75% of patients are men. The peak incidence is reported to be in the seventh and eighth decades of life.[3]
Clinically, parotid swelling is the most common sign. Facial nerve dysfunction or paralysis occur in more than 25% of patients and may be the initial manifestation.[3] The high-grade variant of this neoplasm is one of the most aggressive types of salivary gland carcinoma and is typified by local invasion, lymphatic and hematogenous spread, and poor prognosis.[3,7] In a retrospective review of 104 cases, 33% of patients developed local recurrence, and 46% of patients developed distant metastasis.[48]
Mucinous adenocarcinoma
Mucinous adenocarcinoma is a rare malignant neoplasm characterized by large amounts of extracellular epithelial mucin that contains cords, nests, and solitary epithelial cells. The incidence is unknown. Limited data indicate that most, if not all, occur in the major salivary glands, with the submandibular gland as the predominant site.[3,49] These tumors may be associated with dull pain and tenderness.[3,49] This neoplasm may be considered low grade.[3]
Malignant mixed tumors
The classification of malignant mixed tumors includes three distinct clinicopathological entities: carcinoma ex pleomorphic adenoma, carcinosarcoma, and metastasizing mixed tumor. Carcinoma ex pleomorphic adenoma accounts for most cases, whereas carcinosarcoma, a true malignant mixed tumor, and metastasizing mixed tumor are extremely rare.[3]
Carcinoma ex pleomorphic adenoma
Carcinoma ex pleomorphic adenoma, also known as carcinoma ex mixed tumor, shows histological evidence of arising from or in a benign pleomorphic adenoma.[50] Diagnosis requires the identification of benign tumor in the tissue sample.[51] The incidence or relative frequency of this tumor varies considerably depending on the study cited.[1] A review of material at the AFIP showed that carcinoma ex pleomorphic adenoma makes up 8.8% of all mixed tumors and 4.6% of all malignant salivary gland tumors. It is ranked as the sixth most common malignant salivary gland tumor after mucoepidermoid carcinoma; adenocarcinoma, NOS; acinic cell carcinoma; polymorphous low-grade adenocarcinoma; and adenoid cystic carcinoma.[3] The neoplasm occurs primarily in the major salivary glands.[52]
The most common clinical presentation is a painless mass.[3] Approximately 33% of patients may experience facial paralysis.[53] Depending on the series cited, survival rates vary significantly: 25% to 65% at 5 years, 24% to 50% at 10 years, 10% to 35% at 15 years, and 0% to 38% at 20 years.[3] In addition to tumor stage, histological grade and degree of invasion help to determine prognosis.[54]
Carcinosarcoma
Carcinosarcoma, also known as true malignant mixed tumor, is a rare malignant salivary gland neoplasm that contains both carcinoma and sarcoma components. Either or both components are expressed in metastatic foci. Some carcinosarcomas develop de novo, while others develop in association with benign mixed tumor. This neoplasm is rare; only eight cases exist in the AFIP case files.[3] At one facility, only 11 cases were recorded over a 32-year period.[8] Most of these tumors occur in the major salivary glands.
Swelling, pain, nerve palsy, and ulceration have been frequent clinical findings. Carcinosarcoma is an aggressive, high-grade malignancy. In the largest series reported, which consisted of 12 cases, the average survival period was 3.6 years.[8]
Metastasizing mixed tumor
Metastasizing mixed tumor is a very rare, histologically benign salivary gland neoplasm that inexplicably metastasizes. Often, a long interval occurs between the diagnosis of the primary tumor and the metastases. The histological features are within the spectrum of features that typify pleomorphic adenoma.[3] Most of these tumors occur in the major salivary glands. The primary neoplasm is typically a single, well-defined mass. Recurrences, which may be multiple, have occurred as many as 26 years after excision of the primary neoplasm.[55]
Rare carcinomas
Primary squamous cell carcinoma
Primary squamous cell carcinoma, also known as primary epidermoid carcinoma, is a malignant epithelial neoplasm of the major salivary glands that is composed of squamous (i.e., epidermoid) cells. Diagnosis requires the exclusion of primary disease located in some other head and neck site; indeed, most squamous cell carcinomas of the major salivary glands represent metastatic disease.[3] This diagnosis is not made in minor salivary glands because distinction from the more common mucosal squamous cell carcinoma is not possible.[3] Previous exposure to ionizing radiation appears to increase the risk of developing this neoplasm.[11,56,57] The median time between radiation therapy and diagnosis of the neoplasm is approximately 15.5 years.[11] The reported frequency of this tumor among all major salivary gland tumors has varied from 0.9% to 4.7%.[3,10] In AFIP major salivary gland accessions from 1985 to 1996, primary squamous cell carcinoma accounted for 2.7% of all tumors; 5.4% of malignant tumors; and 2.5% and 2.8%, respectively, of all parotid and submandibular tumors.[3] The average age in the AFIP registry was 64 years.[3] This neoplasm occurs in the parotid gland almost nine times more often than in the submandibular gland.[3,57] There is a strong male predilection.[3,11,57,58,59] This tumor is graded in a similar way to extrasalivary lesions according to the degree of differentiation, namely, low grade, intermediate grade, and high grade.[1]
Most patients present with an asymptomatic mass in the parotid region. Other symptoms may include a painful mass and facial nerve palsy.[57] The prognosis for this neoplasm is poor. In a 30-year retrospective analysis of 50 cases of squamous cell carcinoma of the salivary glands, survival rates at 5 years and 10 years were 24% and 18%, respectively.[57]
Epithelial-myoepithelial carcinoma
Epithelial-myoepithelial carcinoma is an uncommon, low-grade epithelial neoplasm composed of variable proportions of ductal and large, clear-staining, differentiated myoepithelial cells. It is also known as adenomyoepithelioma, clear cell adenoma, tubular solid adenoma, monomorphic clear cell tumor, glycogen-rich adenoma, glycogen-rich adenocarcinoma, clear cell carcinoma, or salivary duct carcinoma. The tumor represents approximately 1% of all epithelial salivary gland neoplasms.[3,60] It is predominantly a tumor of the parotid gland. In the AFIP case files, the mean age of patients was about 60 years, and about 60% of the patients were female.[3]
Localized swelling is commonly the only symptom, but occasionally patients experience facial weakness or pain.[61,62] Overall, epithelial-myoepithelial carcinoma is a low-grade carcinoma that recurs frequently, has a tendency to metastasize to periparotid and cervical lymph nodes, and occasionally results in distant metastasis and death.[60,62,63,64]
Anaplastic small cell carcinoma
Anaplastic small cell carcinoma of the salivary glands was first described in 1972.[65] Subsequent histochemical and electron microscopic studies have supported the neuroendocrine nature of this tumor.[66,67] Microscopically, the tumor cells have oval, hyperchromatic nuclei and a scant amount of cytoplasm and are organized in sheets, strands, and nests. The mitotic rate is high. Neuroendocrine carcinomas are more frequently found in the minor salivary glands. These patients have a better survival rate than patients with small cell carcinomas of the lung.[68] The undifferentiated counterpart of this neoplasm is the small cell undifferentiated carcinoma.
Undifferentiated carcinomas
Undifferentiated carcinomas of salivary glands are a group of uncommon malignant epithelial neoplasms that lack the specific light-microscopic morphological features of other types of salivary gland carcinomas. These carcinomas are histologically similar to undifferentiated carcinomas that arise in other organs and tissues. Accordingly, metastatic carcinoma is a primary concern in the differential diagnosis of these neoplasms.[3]
Small cell undifferentiated carcinoma
Small cell undifferentiated carcinoma, also known as extrapulmonary oat cell carcinoma, is a rare, primary malignant tumor. With conventional light microscopy, it is composed of undifferentiated cells and, with ultrastructural or immunohistochemical studies, does not demonstrate neuroendocrine differentiation. This is the undifferentiated counterpart of anaplastic small cell carcinoma. For more information, see the Anaplastic small cell carcinoma section.
In an AFIP review of case files, small cell carcinoma represented 1.8% of all major salivary gland malignancies; the mean age of patients was 56 years.[3] In 50% of the cases, patients present with an asymptomatic parotid mass of 3 months' or less duration.[68,69,70] This is a high-grade neoplasm. In a retrospective review of 12 cases, a tumor size of more than 4 cm was found to be the most important predictor of behavior. In another small retrospective series, estimated survival rates at 2 and 5 years were 70% and 46%, respectively.[68]
Large cell undifferentiated carcinoma
Large cell undifferentiated carcinoma is a tumor in which features of acinar, ductal, epidermoid, or myoepithelial differentiation are absent under light microscopy, though occasionally, poorly formed duct-like structures are found. This neoplasm accounts for approximately 1% of all epithelial salivary gland neoplasms.[3,53,71,72] Most of these tumors occur in the parotid gland.[70,72] In AFIP data, the peak incidence is in the seventh to eighth decades of life.[3]
Rapid growth of a parotid swelling is a common clinical presentation.[59] This is a high-grade neoplasm that frequently metastasizes and has a poor prognosis. Patients with neoplasms of 4 cm or larger may have a particularly poor outcome.[70,72]
Lymphoepithelial carcinoma
Lymphoepithelial carcinoma, also known as undifferentiated carcinoma with lymphoid stroma and carcinoma ex lymphoepithelial lesion, is an undifferentiated tumor that is associated with a dense lymphoid stroma. An exceptionally high incidence of this tumor is found in the Inuit population.[3,73] This neoplasm has been associated with Epstein-Barr virus infection.[74,75] Of the occurrences, 80% are in the parotid gland.[3]
In addition to the presence of a parotid or submandibular mass, pain is a frequent symptom, and facial nerve palsy occurs in as many as 20% of patients.[76] Of the patients, more than 40% have metastases to cervical lymph nodes at initial presentation, 20% develop local recurrences or lymph node metastases, and 20% develop distant metastases within 3 years following therapy.[73,76,77,78] For more information, see Cancer Pain.
Myoepithelial carcinoma
Myoepithelioma carcinoma is a rare, malignant salivary gland neoplasm in which the tumor cells almost exclusively manifest myoepithelial differentiation. This neoplasm represents the malignant counterpart of benign myoepithelioma.[3] The largest series reported involved 25 cases.[79] Approximately 66% of the tumors occur in the parotid gland.[3,74] The mean age of patients is reported to be 55 years.[79]
Most patients present with the primary complaint of a painless mass.[79] This is an intermediate grade to high-grade carcinoma.[3,79] Histological grade does not appear to correlate well with clinical behavior; tumors with a low-grade histological appearance may behave aggressively.[79]
Adenosquamous carcinoma
Adenosquamous carcinoma is an extremely rare malignant neoplasm that simultaneously arises from surface mucosal epithelium and salivary gland ductal epithelium. The carcinoma shows histopathological features of both squamous cell carcinoma and adenocarcinoma. Only a handful of reports describe this tumor.[3]
In addition to swelling, adenosquamous carcinoma produces visible changes in the mucosa, including erythema, ulceration, and induration. Pain frequently accompanies ulceration. Limited data indicate that this is a highly aggressive neoplasm with a poor prognosis.[3]
Nonepithelial Neoplasms
Lymphomas and benign lymphoepithelial lesion
Lymphomas of the major salivary glands are characteristically of the non-Hodgkin type. In an AFIP review of case files, non-Hodgkin lymphoma accounted for 16.3% of all malignant tumors that occurred in the major salivary glands; disease in the parotid gland accounted for about 80% of all cases.[3]
Patients with benign lymphoepithelial lesion (e.g., Mikulicz disease), which is a manifestation of the autoimmune disease Sjögren syndrome, are at an increased risk for development of non-Hodgkin lymphoma.[80,81,82,83,84] Benign lymphoepithelial lesion is clinically characterized by diffuse and bilateral enlargement of the salivary and lacrimal glands.[23] Morphologically, a salivary gland lesion is composed of prominent myoepithelial islands surrounded by a lymphocytic infiltrate. Germinal centers are often present in the lymphocytic infiltrate.[23] Immunophenotypically and genotypically, the lymphocytic infiltrate is composed of B-lymphocytes and T-lymphocytes, which are polyclonal. In some instances, the B-cell lymphocytic infiltrate can undergo clonal expansion and evolve into frank non-Hodgkin lymphoma. Most of the non-Hodgkin lymphomas arising in a background of benign lymphoepithelial lesions are marginal zone lymphomas of mucosa-associated lymphoid tissue (MALT).[81,82,83,84] MALT lymphomas of the salivary glands, like their counterparts in other anatomical sites, typically display relatively indolent clinical behavior.[3,85]
Primary non-MALT lymphomas of the salivary glands may also occur and appear to have a prognosis similar to those in patients who have histologically identical nodal lymphomas.[86,87] Unlike non-Hodgkin lymphoma, involvement of the major salivary glands by Hodgkin lymphoma is rare. Most tumors occur in the parotid gland.[3] The most common histological types encountered are the nodular sclerosing and lymphocyte-predominant variants.[88,89]
Mesenchymal neoplasms
Mesenchymal neoplasms account for 1.9% to 5% of all neoplasms that occur within the major salivary glands.[90,91] These cellular classifications pertain to major salivary gland tumors. Because the minor salivary glands are small and embedded within fibrous connective tissue, fat, and skeletal muscle, the origin of a mesenchymal neoplasm from stroma cannot be determined.[3] The types of benign mesenchymal salivary gland neoplasms include hemangiomas, lipomas, and lymphangiomas.
Malignant mesenchymal salivary gland neoplasms include malignant schwannomas, hemangiopericytomas, malignant fibrous histiocytomas, rhabdomyosarcomas, and fibrosarcomas, among others. In the major salivary glands, these neoplasms represent approximately 0.5% of all benign and malignant salivary gland tumors and approximately 1.5% of all malignant tumors.[90,92,93] It is important to establish a primary salivary gland origin for these tumors by excluding the possibilities of metastasis and direct extension from other sites. In addition, the diagnosis of salivary gland carcinosarcoma should be excluded.[3] Primary salivary gland sarcomas behave like their soft tissue counterparts, in which prognosis is related to sarcoma type, histological grade, tumor size, and stage.[93,94] For more information, see Soft Tissue Sarcoma Treatment. A comprehensive review of salivary gland mesenchymal neoplasms can be found elsewhere.[95]
Malignant Secondary Neoplasms
Malignant neoplasms whose origins lie outside the salivary glands may involve the major salivary glands by:[3]
- Direct invasion from cancers that lie adjacent to the salivary glands.
- Hematogenous metastases from distant primary tumors.
- Lymphatic metastases to lymph nodes within the salivary gland.
Direct invasion of nonsalivary gland tumors into the major salivary glands is principally from squamous cell and basal cell carcinomas of the overlying skin.
Approximately 80% of metastases to the major salivary glands may be from primary tumors elsewhere in the head and neck; the remaining 20% may be from infraclavicular sites.[96,97] The parotid gland is the site of 80% to 90% of the metastases, and the remainder involve the submandibular gland.[97,98] In a decade-long AFIP experience, metastatic tumors constituted approximately 10% of malignant neoplasms in the major salivary glands, exclusive of malignant lymphomas.[3] Most metastatic primary tumors to the major salivary glands are squamous cell carcinomas and melanomas from the head and neck that presumably reach the parotid gland via the lymphatic system; infraclavicular primary tumors, such as the lung, kidney, and breast, reach the salivary glands by a hematogenous route.[97,98,99] The peak incidence for metastatic tumors in the salivary glands is reported to be in the seventh decade of life.[3]
References:
-
Speight PM, Barrett AW: Salivary gland tumours. Oral Dis 8 (5): 229-40, 2002.
-
Seifert G, Donath K: Hybrid tumours of salivary glands. Definition and classification of five rare cases. Eur J Cancer B Oral Oncol 32B (4): 251-9, 1996.
-
Ellis GL, Auclair PL: Tumors of the Salivary Glands. Armed Forces Institute of Pathology, 1996. Atlas of Tumor Pathology, 3.
-
Cheuk W, Chan JKC: Salivary gland tumors. In: Fletcher CDM, ed.: Diagnostic Histopathology of Tumors. 3rd ed. Churchill Livingstone, 2007, pp 239-326.
-
Spiro RH, Huvos AG, Berk R, et al.: Mucoepidermoid carcinoma of salivary gland origin. A clinicopathologic study of 367 cases. Am J Surg 136 (4): 461-8, 1978.
-
Goode RK, Corio RL: Oncocytic adenocarcinoma of salivary glands. Oral Surg Oral Med Oral Pathol 65 (1): 61-6, 1988.
-
Guzzo M, Di Palma S, Grandi C, et al.: Salivary duct carcinoma: clinical characteristics and treatment strategies. Head Neck 19 (2): 126-33, 1997.
-
Stephen J, Batsakis JG, Luna MA, et al.: True malignant mixed tumors (carcinosarcoma) of salivary glands. Oral Surg Oral Med Oral Pathol 61 (6): 597-602, 1986.
-
Auclair PL, Ellis GL, Gnepp DR, et al.: Salivary gland neoplasms: general considerations. In: Ellis GL, Auclair PL, Gnepp DR, eds.: Surgical Pathology of the Salivary Glands. Saunders, 1991, pp 135-64.
-
Eveson JW, Cawson RA: Salivary gland tumours. A review of 2410 cases with particular reference to histological types, site, age and sex distribution. J Pathol 146 (1): 51-8, 1985.
-
Spitz MR, Batsakis JG: Major salivary gland carcinoma. Descriptive epidemiology and survival of 498 patients. Arch Otolaryngol 110 (1): 45-9, 1984.
-
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.
-
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.
-
Neville BW, Damm DD, Weir JC, et al.: Labial salivary gland tumors. Cancer 61 (10): 2113-6, 1988.
-
Auclair PL, Goode RK, Ellis GL: Mucoepidermoid carcinoma of intraoral salivary glands. Evaluation and application of grading criteria in 143 cases. Cancer 69 (8): 2021-30, 1992.
-
Brandwein MS, Ivanov K, Wallace DI, et al.: Mucoepidermoid carcinoma: a clinicopathologic study of 80 patients with special reference to histological grading. Am J Surg Pathol 25 (7): 835-45, 2001.
-
Nordkvist A, Gustafsson H, Juberg-Ode M, et al.: Recurrent rearrangements of 11q14-22 in mucoepidermoid carcinoma. Cancer Genet Cytogenet 74 (2): 77-83, 1994.
-
Horsman DE, Berean K, Durham JS: Translocation (11;19)(q21;p13.1) in mucoepidermoid carcinoma of salivary gland. Cancer Genet Cytogenet 80 (2): 165-6, 1995.
-
El-Naggar AK, Lovell M, Killary AM, et al.: A mucoepidermoid carcinoma of minor salivary gland with t(11;19)(q21;p13.1) as the only karyotypic abnormality. Cancer Genet Cytogenet 87 (1): 29-33, 1996.
-
Tonon G, Modi S, Wu L, et al.: t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma creates a novel fusion product that disrupts a Notch signaling pathway. Nat Genet 33 (2): 208-13, 2003.
-
Allenspach EJ, Maillard I, Aster JC, et al.: Notch signaling in cancer. Cancer Biol Ther 1 (5): 466-76, 2002 Sep-Oct.
-
Brookstone MS, Huvos AG: Central salivary gland tumors of the maxilla and mandible: a clinicopathologic study of 11 cases with an analysis of the literature. J Oral Maxillofac Surg 50 (3): 229-36, 1992.
-
Major and minor salivary glands. In: Rosai J, ed.: Ackerman's Surgical Pathology. 8th ed. Mosby, 1996, pp 815-56.
-
Batsakis JG, Luna MA, el-Naggar A: Histopathologic grading of salivary gland neoplasms: III. Adenoid cystic carcinomas. Ann Otol Rhinol Laryngol 99 (12): 1007-9, 1990.
-
Tomich CE: Adenoid cystic carcinoma. In: Ellis GL, Auclair PL, Gnepp DR, eds.: Surgical Pathology of the Salivary Glands. Saunders, 1991, pp 333-49.
-
Perzin KH, Gullane P, Clairmont AC: Adenoid cystic carcinomas arising in salivary glands: a correlation of histologic features and clinical course. Cancer 42 (1): 265-82, 1978.
-
Spiro RH: The controversial adenoid cystic carcinoma. Clinical considerations. In: McGurk M, Renehan AG, eds.: Controversies in the Management of Salivary Gland Disease. Oxford University Press, 2001, pp 207-11.
-
Friedrich RE, Bleckmann V: Adenoid cystic carcinoma of salivary and lacrimal gland origin: localization, classification, clinical pathological correlation, treatment results and long-term follow-up control in 84 patients. Anticancer Res 23 (2A): 931-40, 2003 Mar-Apr.
-
Spiro RH, Huvos AG: Stage means more than grade in adenoid cystic carcinoma. Am J Surg 164 (6): 623-8, 1992.
-
Hamper K, Lazar F, Dietel M, et al.: Prognostic factors for adenoid cystic carcinoma of the head and neck: a retrospective evaluation of 96 cases. J Oral Pathol Med 19 (3): 101-7, 1990.
-
Lewis JE, Olsen KD, Weiland LH: Acinic cell carcinoma. Clinicopathologic review. Cancer 67 (1): 172-9, 1991.
-
Waldron CA, el-Mofty SK, Gnepp DR: Tumors of the intraoral minor salivary glands: a demographic and histologic study of 426 cases. Oral Surg Oral Med Oral Pathol 66 (3): 323-33, 1988.
-
Vincent SD, Hammond HL, Finkelstein MW: Clinical and therapeutic features of polymorphous low-grade adenocarcinoma. Oral Surg Oral Med Oral Pathol 77 (1): 41-7, 1994.
-
Evans HL, Luna MA: Polymorphous low-grade adenocarcinoma: a study of 40 cases with long-term follow up and an evaluation of the importance of papillary areas. Am J Surg Pathol 24 (10): 1319-28, 2000.
-
Spiro RH, Huvos AG, Strong EW: Adenocarcinoma of salivary origin. Clinicopathologic study of 204 patients. Am J Surg 144 (4): 423-31, 1982.
-
Matsuba HM, Mauney M, Simpson JR, et al.: Adenocarcinomas of major and minor salivary gland origin: a histopathologic review of treatment failure patterns. Laryngoscope 98 (7): 784-8, 1988.
-
Muller S, Barnes L: Basal cell adenocarcinoma of the salivary glands. Report of seven cases and review of the literature. Cancer 78 (12): 2471-7, 1996.
-
Ellis GL, Wiscovitch JG: Basal cell adenocarcinomas of the major salivary glands. Oral Surg Oral Med Oral Pathol 69 (4): 461-9, 1990.
-
Simpson RH, Sarsfield PT, Clarke T, et al.: Clear cell carcinoma of minor salivary glands. Histopathology 17 (5): 433-8, 1990.
-
Ogawa I, Nikai H, Takata T, et al.: Clear cell tumors of minor salivary gland origin. An immunohistochemical and ultrastructural analysis. Oral Surg Oral Med Oral Pathol 72 (2): 200-7, 1991.
-
Milchgrub S, Gnepp DR, Vuitch F, et al.: Hyalinizing clear cell carcinoma of salivary gland. Am J Surg Pathol 18 (1): 74-82, 1994.
-
Ellis GL, Auclair PL, Gnepp DR, et al.: Other malignant epithelial neoplasms. In: Ellis GL, Auclair PL, Gnepp DR, eds.: Surgical Pathology of the Salivary Glands. Saunders, 1991, pp 455-88.
-
Gnepp DR: Sebaceous neoplasms of salivary gland origin: a review. Pathol Annu 18 Pt 1: 71-102, 1983.
-
Gnepp DR, Brannon R: Sebaceous neoplasms of salivary gland origin. Report of 21 cases. Cancer 53 (10): 2155-70, 1984.
-
Linhartová A: Sebaceous glands in salivary gland tissue. Arch Pathol 98 (5): 320-4, 1974.
-
Sugimoto T, Wakizono S, Uemura T, et al.: Malignant oncocytoma of the parotid gland: a case report with an immunohistochemical and ultrastructural study. J Laryngol Otol 107 (1): 69-74, 1993.
-
Delgado R, Klimstra D, Albores-Saavedra J: Low grade salivary duct carcinoma. A distinctive variant with a low grade histology and a predominant intraductal growth pattern. Cancer 78 (5): 958-67, 1996.
-
Barnes L, Rao U, Krause J, et al.: Salivary duct carcinoma. Part I. A clinicopathologic evaluation and DNA image analysis of 13 cases with review of the literature. Oral Surg Oral Med Oral Pathol 78 (1): 64-73, 1994.
-
Osaki T, Hirota J, Ohno A, et al.: Mucinous adenocarcinoma of the submandibular gland. Cancer 66 (8): 1796-801, 1990.
-
Röijer E, Nordkvist A, Ström AK, et al.: Translocation, deletion/amplification, and expression of HMGIC and MDM2 in a carcinoma ex pleomorphic adenoma. Am J Pathol 160 (2): 433-40, 2002.
-
LiVolsi VA, Perzin KH: Malignant mixed tumors arising in salivary glands. I. Carcinomas arising in benign mixed tumors: a clinicopathologic study. Cancer 39 (5): 2209-30, 1977.
-
Gnepp DR: Malignant mixed tumors of the salivary glands: a review. Pathol Annu 28 Pt 1: 279-328, 1993.
-
Seifert G: [Diseases of the Salivary Glands: Pathology, Diagnosis, Treatment, Facial Nerve Surgery]; translated by Philip M. Stell. Thieme, 1986.
-
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.
-
Wenig BM, Hitchcock CL, Ellis GL, et al.: Metastasizing mixed tumor of salivary glands. A clinicopathologic and flow cytometric analysis. Am J Surg Pathol 16 (9): 845-58, 1992.
-
Schneider AB, Favus MJ, Stachura ME, et al.: Salivary gland neoplasms as a late consequence of head and neck irradiation. Ann Intern Med 87 (2): 160-4, 1977.
-
Shemen LJ, Huvos AG, Spiro RH: Squamous cell carcinoma of salivary gland origin. Head Neck Surg 9 (4): 235-40, 1987 Mar-Apr.
-
Sterman BM, Kraus DH, Sebek BA, et al.: Primary squamous cell carcinoma of the parotid gland. Laryngoscope 100 (2 Pt 1): 146-8, 1990.
-
Gaughan RK, Olsen KD, Lewis JE: Primary squamous cell carcinoma of the parotid gland. Arch Otolaryngol Head Neck Surg 118 (8): 798-801, 1992.
-
Batsakis JG, el-Naggar AK, Luna MA: Epithelial-myoepithelial carcinoma of salivary glands. Ann Otol Rhinol Laryngol 101 (6): 540-2, 1992.
-
Daley TD, Wysocki GP, Smout MS, et al.: Epithelial-myoepithelial carcinoma of salivary glands. Oral Surg Oral Med Oral Pathol 57 (5): 512-9, 1984.
-
Collina G, Gale N, Visonà A, et al.: Epithelial-myoepithelial carcinoma of the parotid gland: a clinico-pathologic and immunohistochemical study of seven cases. Tumori 77 (3): 257-63, 1991.
-
Simpson RH, Clarke TJ, Sarsfield PT, et al.: Epithelial-myoepithelial carcinoma of salivary glands. J Clin Pathol 44 (5): 419-23, 1991.
-
Noel S, Brozna JP: Epithelial-myoepithelial carcinoma of salivary gland with metastasis to lung: report of a case and review of the literature. Head Neck 14 (5): 401-6, 1992 Sep-Oct.
-
Koss LG, Spiro RH, Hajdu S: Small cell (oat cell) carcinoma of minor salivary gland origin. Cancer 30 (3): 737-41, 1972.
-
Gnepp DR, Wick MR: Small cell carcinoma of the major salivary glands. An immunohistochemical study. Cancer 66 (1): 185-92, 1990.
-
Perez-Ordonez B, Caruana SM, Huvos AG, et al.: Small cell neuroendocrine carcinoma of the nasal cavity and paranasal sinuses. Hum Pathol 29 (8): 826-32, 1998.
-
Gnepp DR, Corio RL, Brannon RB: Small cell carcinoma of the major salivary glands. Cancer 58 (3): 705-14, 1986.
-
Scher RL, Feldman PS, Levine PA: Small-cell carcinoma of the parotid gland with neuroendocrine features. Arch Otolaryngol Head Neck Surg 114 (3): 319-21, 1988.
-
Hui KK, Luna MA, Batsakis JG, et al.: Undifferentiated carcinomas of the major salivary glands. Oral Surg Oral Med Oral Pathol 69 (1): 76-83, 1990.
-
Spiro RH: Salivary neoplasms: overview of a 35-year experience with 2,807 patients. Head Neck Surg 8 (3): 177-84, 1986 Jan-Feb.
-
Batsakis JG, Luna MA: Undifferentiated carcinomas of salivary glands. Ann Otol Rhinol Laryngol 100 (1): 82-4, 1991.
-
Bosch JD, Kudryk WH, Johnson GH: The malignant lymphoepithelial lesion of the salivary glands. J Otolaryngol 17 (4): 187-90, 1988.
-
Hamilton-Dutoit SJ, Therkildsen MH, Neilsen NH, et al.: Undifferentiated carcinoma of the salivary gland in Greenlandic Eskimos: demonstration of Epstein-Barr virus DNA by in situ nucleic acid hybridization. Hum Pathol 22 (8): 811-5, 1991.
-
Leung SY, Chung LP, Yuen ST, et al.: Lymphoepithelial carcinoma of the salivary gland: in situ detection of Epstein-Barr virus. J Clin Pathol 48 (11): 1022-7, 1995.
-
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.
-
Saw D, Lau WH, Ho JH, et al.: Malignant lymphoepithelial lesion of the salivary gland. Hum Pathol 17 (9): 914-23, 1986.
-
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.
-
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.
-
Kassan SS, Thomas TL, Moutsopoulos HM, et al.: Increased risk of lymphoma in sicca syndrome. Ann Intern Med 89 (6): 888-92, 1978.
-
Abbondanzo SL: Extranodal marginal-zone B-cell lymphoma of the salivary gland. Ann Diagn Pathol 5 (4): 246-54, 2001.
-
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.
-
Harris NL: Lymphoid proliferations of the salivary glands. Am J Clin Pathol 111 (1 Suppl 1): S94-103, 1999.
-
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.
-
Harris NL: Extranodal lymphoid infiltrates and mucosa-associated lymphoid tissue (MALT). A unifying concept. Am J Surg Pathol 15 (9): 879-84, 1991.
-
Burke JS: Waldeyer's ring, sinonasal region, salivary gland, thyroid gland, central nervous system, and other extranodal lymphomas and lymphoid hyperplasias. In: Knowles DM, ed.: Neoplastic Hematopathology. Williams & Wilkins, 1992, pp 1047-79.
-
Salhany KE, Pietra GG: Extranodal lymphoid disorders. Am J Clin Pathol 99 (4): 472-85, 1993.
-
Schmid U, Helbron D, Lennert K: Primary malignant lymphomas localized in salivary glands. Histopathology 6 (6): 673-87, 1982.
-
Gleeson MJ, Bennett MH, Cawson RA: Lymphomas of salivary glands. Cancer 58 (3): 699-704, 1986.
-
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.
-
Auclair PL, Ellis GL, Gnepp DR, et al.: Salivary gland neoplasms: general considerations. In: Ellis GL, Auclair PL, Gnepp DR, eds.: Surgical Pathology of the Salivary Glands. Saunders, 1991, pp 135-64.
-
Auclair PL, Ellis GL: Nonlymphoid sarcomas of the major salivary glands. In: Ellis GL, Auclair PL, Gnepp DR, eds.: Surgical Pathology of the Salivary Glands. Saunders, 1991, pp 514-27.
-
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.
-
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.
-
Weiss SW, Goldblum JR: Enzinger and Weiss's Soft Tissue Tumors. 4th ed. Mosby, 2001.
-
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.
-
Gnepp DR: Metastatic disease to the major salivary glands. In: Ellis GL, Auclair PL, Gnepp DR, eds.: Surgical Pathology of the Salivary Glands. Saunders, 1991, pp 560-9.
-
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.
-
Batsakis JG, Bautina E: Metastases to major salivary glands. Ann Otol Rhinol Laryngol 99 (6 Pt 1): 501-3, 1990.