Salivary Gland Neoplasms Workup

Updated: Apr 28, 2017
  • Author: Steve C Lee, MD, PhD; Chief Editor: Arlen D Meyers, MD, MBA  more...
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Workup

Imaging Studies

CT scanning and MRI

Imaging studies of the salivary glands are usually unnecessary for the assessment of small tumors within the parotid or submandibular gland. Computed tomography (CT) scanning or magnetic resonance imaging (MRI) is useful for determining the extent of large tumors, for evaluating extraglandular extension, for determining the actual depth of parotid tumors, and for discovering other tumors in one gland or in the contralateral gland. Additionally, CT scanning and MRI are helpful in distinguishing an intraparotid deep-lobe tumor from a parapharyngeal space tumor and for evaluation of cervical lymph nodes for metastasis.

CT scanning and MRI can be used to predict possible malignancy based on observation of poorly defined tumor margins; MRI is the better of the 2 for this purpose. Indeed, a study by Mamlouk et al of pediatric patients with parotid neoplasms indicated that on MRI scans, the presence not only of poorly defined borders but also of a hypointense T2 signal, restricted diffusion, and focal necrosis are suggestive of malignancy, although not specific for it. The study involved 17 patients, including 11 with malignant tumors and six with benign neoplasms. [10]

However, no difference exists between the specificities and sensitivities of CT scanning and MRI for the location or amount of infiltration of tumors in the parotid gland.

Minor salivary gland neoplasms are often difficult to assess on examination, and the use of preoperative CT scanning or MRI is important for determining the extent of tumor, which is otherwise not clinically appreciable. This imaging is particularly valuable for salivary gland neoplasms in the paranasal sinus, where skull-base or intracranial extension may alter the resectability of the tumors.

CT-guided needle biopsy can be used to evaluate difficult-to-reach tumors, such as neoplasms in the parapharyngeal space.

For most small parotid neoplasms without clinical evidence of facial nerve involvement, no pretreatment imaging studies are required.

Gadolinium-enhanced dynamic MRI can be used to possibly differentiate pleomorphic adenomas from malignant salivary gland tumors using peak time of enhancement at 120 seconds and to differentiate between malignancies and Warthin tumors using washout ratios of 30% with a sensitivity of 100% and specificity of 80%. However, MRI can only suggest a diagnosis; definitive diagnosis requires pathologic examination.

Ultrasonography

New technologies, including high-resolution probes and harmonic imaging, can delineate location, homogeneity or heterogeneity, shape, vascularity, and margins of salivary tumors in the periauricular, buccal, and submandibular area.

Ultrasonography may be able to reveal the type of tumor, [5] and new ultrasonographic contrast mediums can now demonstrate the vascularity of the tumor before surgery.

A study by Rong et al identified differences between the ultrasonographic characteristics of Warthin tumors and those of pleomorphic adenomas, including with regard to shape, vascularity, and the prevalence of cystic areas. The study involved 93 Warthin tumors (61 patients) and 77 pleomorphic adenomas (70 patients), with lobulated lesions representing 38.7% of Warthin tumors and 63.6% of pleomorphic adenomas. Grade 2 or 3 vascularity was identified in the majority of Warthin tumors (73.1%), while grade 0 or 1 vascularity was present in most of the pleomorphic adenomas (77.9%); vessel distribution also varied significantly between the two types of tumors. In addition, cystic areas were identified in 45.2% of the Warthin tumors but in only 20.8% of the pleomorphic adenomas. [11]

Ultrasonography can guide fine-needle aspiration to increase the likelihood of getting a good sample, and it can precisely guide core needle biopsies 97% of the time in an outpatient setting, lessening the need for intraoperative biopsies.

Ultrasonography can also guide automated core biopsy systems with a sensitivity of 75%, specificity of 96.6%, and accuracy of 91.9%.

Nuclear imaging

F-18 fluorodeoxyglucose positron emission tomography (FDG-PET) scanning can be used to plan treatment of salivary gland malignancies by detecting lymph node metastases that require a neck dissection or by finding distant metastases that may not have caused abnormalities in routine blood work. This is most useful when combined with CT scanning.

Technetium-99m (Tc-99m) pertechnetate scintigraphy with lemon juice stimulation can be used to diagnose Warthin tumors with correlation between tumor size and Tc-99m uptake.

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Diagnostic Procedures

See the list below:

  • Fine-needle aspiration biopsy (FNAB)
    • FNAB is a valuable diagnostic adjunct in evaluation of head and neck masses. Its role in evaluation of salivary gland tumors is controversial.
    • Overall sensitivity of FNAB in distinguishing between benign and malignant salivary gland tumors is approximately 95%. Its specificity is approximately 98%.
    • FNAB has a positive predictive value of approximately 84% and a negative predictive value of approximately 77%.
    • Results that include a predominating lymphocyte indicate the need for further workup for lymphoma, but salivary neoplasms should still be considered. Even if an FNAB result is negative, the test does not replace the clinical judgment in the management of a suspected salivary gland neoplasm.
    • Most experts generally agree that FNAB is useful in the evaluation of submandibular masses. Relatively few submandibular triangle masses represent primary submandibular gland neoplasms. Most of these masses are due to either inflammatory diseases or neoplasms that involve the lymph nodes in this region. FNAB is helpful for differentiating between these possibilities and for directing therapy.
    • The value of routine FNAB for parotid masses is less clear. Opponents state that FNAB results rarely alter the management of parotid masses, which is carefully planned and executed surgical excision. Proponents believe that obtaining a preoperative histologic diagnosis is valuable for the following reasons:
      • Knowledge of the histologic type may be helpful in preparing patients and surgeons for the more extensive surgery required for high-grade malignancies.
      • Some nonneoplastic causes of parotid masses may be ruled out without surgical intervention.
      • Recent studies have found parotid gland FNAB to have an accuracy of 94-97%, a sensitivity of 83-84%, and specificity of 96-100%. Positive and negative predictive values for malignancy were 84.6% and 96.4%, respectively.
    • FNAB for Warthin tumors can have false-positive results, leading to misdiagnosing more dangerous tumors such as pleomorphic adenomas and acinic cell carcinomas. Also, FNAB results have revealed a higher rate of parotitis in patients with Warthin tumors because of susceptibility to infarction and inflammation.
    • Complications of FNAB are nondiagnostic biopsies and tissue changes found after excision that may interfere with histological evaluation, including needle tracts and infarction.
  • Flow cytometry
    • The value of flow cytometry in salivary gland neoplasms is supporting histopathology by detecting possibly malignant tumors.
    • Flow cytometry has also been shown to help in prognosis in adenoid cystic carcinoma by determining the DNA ploidy of tumor cells. This information has been shown to correlate with overall prognosis and long-term disease-free survival periods.
  • Determining aneuploidy versus diploidy by flow cytometry has been found to help grade mucoepidermoid carcinomas by one study, which found that high grade cancers are aneuploidy 89% of the time and diploid cancers are low or intermittent grade 88% of the time.
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Histologic Findings

A variety of benign and malignant neoplasms can arise in the salivary glands. An accurate histopathologic diagnosis is essential for the rational treatment of patients with salivary gland neoplasms. Batsakis et al have reported the classification system most commonly used in epithelial salivary gland tumors.

Benign salivary gland neoplasms

See the list below:

  • Pleomorphic adenoma, or benign mixed tumor
    • Pleomorphic adenomas are the most common salivary gland tumor. They represent 60% of parotid tumors and 36% of submandibular tumors. They affect men and women equally and usually appear in the fifth decade of life. The tumors are typically slow growing and produce no symptoms.
    • On gross evaluation, the tumors are smooth, multilobular, and encapsulated. The capsule, however, is incomplete microscopically, and tumor pseudopodia may extend beyond the margin of the apparent capsule. The contents of the tumor appear varied depending on the cellularity and the myxoid content.
    • Microscopically, the characteristic feature is the morphologic diversity of the tumor, with presence of both epithelial and mesenchymal-like elements. Two cells are responsible for the varied appearance: the epithelial cell and the myoepithelial cells. The epithelial cells make up most the cellular regions, and the myoepithelial cells make up the stromal areas. The ratio of cellular elements to stromal elements can vary widely. The stromal component may have a myxoid, fibroid, or chondroid appearance.
    • The presence of pseudopodia that extend beyond the apparent margin of the tumor is responsible for the significant rate of recurrence with simple enucleation of pleomorphic adenomas. The management of choice for pleomorphic adenomas of the parotid gland is superficial lobectomy (described in Treatment), taking a cuff of normal glandular tissue with the tumors. Submandibular and minor salivary gland pleomorphic adenomas should likewise be removed with a cuff of normal tissue. Abiding by this principle has led to low rates of recurrence, typically lower than 5%.
    • A premium is placed on initial excision of pleomorphic adenomas because management of recurrent disease is difficult and often frustrating. Recurrent pleomorphic adenomas often occur in a multifocal fashion and can manifest 10-15 years after initial resection. Repeat operation puts the facial nerve at increased risk for permanent injury, and facial nerve monitoring is helpful to diminish this risk. Cure rates are reported to be 25% or lower when a repeat operation for recurrent pleomorphic adenomas is performed.
    • Radiation therapy may be helpful in treating multiple recurrent disease and is decided on a case-by-case basis. The facial nerve should not be sacrificed in the removal of pleomorphic adenomas. Tumor grossly adherent to the nerve should be removed by using microdissection techniques.
  • Warthin tumor or papillary cystadenoma lymphomatosum
    • Warthin tumors represent the second-most common benign salivary gland neoplasm, comprising approximately 6-10% of all parotid tumors. Warthin tumors rarely occur in the submandibular or minor salivary glands. Warthin tumors affect men more commonly than women, with a male-to-female ratio of 5:1, and they typically appear between the fourth and seventh decades of life. The prevalence is increased among tobacco smokers. Warthin tumors are bilateral in 12% of cases.
    • Warthin tumors have a smooth capsule. When incised, multiple cystic spaces that contain mucinous material are appreciated. On microscopic evaluation, multiple papillae are present, projecting into the cystic spaces. The papillae consist of a double-layered epithelium. The outer layer consists of granular oncocytes with apically located nuclei. The inner layer contains round-to-cuboidal eosinophilic cells. The stroma beneath the epithelium is lymphoid, often containing germinal centers.
    • Warthin tumors are best treated by means of superficial parotidectomy that spares the facial nerve.
  • Oncocytoma
    • Oncocytomas are unusual benign neoplasms that arise from the granular oncocytes within the salivary glands. These tumors account for less than 1% of all salivary gland tumors. They occur more commonly in older patients and affect men and women equally. Malignant oncocytomas do occur, but they are extremely rare.
    • Benign oncocytomas are smooth and firm, with a rubbery consistency. The tumors are cellular, containing round eosinophilic cells with a granular cytoplasm. The nuclei are small and have indentations. The granular appearance of these cells is the result of the high number of mitochondria present in the cytoplasm. Electron microscopy is used to identify this ultrastructural feature, which can be diagnostically helpful.
    • These tumors most commonly arise in the superficial portion of the parotid gland. They are best treated with superficial parotidectomy with preservation of the facial nerve. Tumors that occur outside the parotid gland should be excised with a cuff of normal tissue.
  • Monomorphic adenoma
    • Monomorphic adenomas are often grouped with pleomorphic adenomas. These are distinct tumors histologically, however, and lack pleomorphic features. Basal cell adenomas and clear cell adenomas are included in this group of tumors. Monomorphic adenomas are benign, slow growing, and are the least aggressive of the salivary gland tumors. They probably represent fewer than 2% of salivary gland neoplasms.
    • The most common variety of monomorphic adenomas is the basal cell adenoma. Basal cell adenomas occur most commonly in the minor salivary glands, usually the upper lip. Of the major salivary glands, the parotid gland is the usual location of occurrence.
    • Grossly, the tumors are encapsulated and are smooth. Microscopically, the tumors contain epithelial parenchyma, which is sharply demarcated from the scant stroma by a thick, prominent basement membrane. The epithelial cells have a palisading appearance at the periphery of the tumor parenchyma. The appearance can be confused with adenoid cystic carcinoma, but the distinction is clearly important, as the biologic behavior of the 2 tumors is vastly different.
    • Treatment consists of surgical excision with a margin of normal tissue for these benign and nonaggressive tumors.

Malignant salivary gland neoplasms

See the list below:

  • Mucoepidermoid carcinoma
    • Mucoepidermoid carcinoma is the most commonly occurring malignant neoplasm of the parotid gland and is the second most common malignant neoplasm of the submandibular gland after adenoid cystic carcinoma. It represents approximately 8% of all parotid tumors.
    • Mucoepidermoid carcinomas are divided into low, intermediate, and high grades. These tumors contain two types of cells, as the name implies, mucous and epidermoid cells. The grade of tumor is determined by the relative proportion of these two cells. Low-grade tumors have a higher preponderance of mucous cells than epidermoid cells do. The ratio of epidermoid cells rises in higher grades, and high-grade mucoepidermoid carcinomas may even resemble squamous cell carcinomas.
    • Low-grade tumors are usually small and appear partially encapsulated upon gross examination. They may have some cystic components. High-grade tumors are usually larger and are more infiltrative. A capsule is usually not recognizable, and the tumors are more solid with a grayish-white appearance.
    • Upon microscopic examination, low-grade tumors contain sheets of mucoid cells separated by bands of epidermoid cells. Mucous cells are clear and plump with small nuclei. Epidermoid components resemble squamous cell carcinoma. High-grade mucoepidermoid carcinomas are nearly entirely composed of nests of malignant epidermoid cells. Few mucous cells or none at all are present, although when specially stained, cells that contain mucus are apparent. This differentiates high-grade mucoepidermoid carcinoma from squamous cell carcinoma.
    • The biologic behavior of mucoepidermoid carcinoma is dependent on the grade of tumor. Low-grade lesions are fairly nonaggressive, and appropriate treatment imparts a good prognosis. High-grade neoplasms are much more aggressive, with high rates of regional lymph node metastases. Appropriate management of mucoepidermoid carcinoma is discussed below under Treatment for malignant salivary gland tumors.
  • Adenoid cystic carcinoma
    • Adenoid cystic carcinoma is the second most common malignant salivary gland tumor, representing approximately 6% of all salivary gland neoplasms. It is the most common malignancy in the submandibular gland and usually appears as a slow-growing painless mass.
    • Metastasis to regional lymph nodes is uncommon, but distant metastasis (usually to the lung) is more common. Adenoid cystic carcinoma is unique in that survival at 5 years is approximately 65%, but 15-year survival is only 12%. Because of the slow growth of this tumor, patients may remain free of disease after initial treatment for 10 years or longer, only to develop metastases. Local recurrence is also common. The tendency for this tumor to grow along perineural and perivascular planes, often with skip lesions, helps explain the generally poor success of treatment.
    • Grossly, adenoid cystic carcinomas are usually monolobular and nonencapsulated. They have a gray-pink color and infiltrate the surrounding normal tissue. Microscopically, the tumors consist of basaloid epithelial elements that form cylindrical structures. Tumors are classified by the general architecture into the following 3 types: cribriform, tubular, and solid. The cribriform pattern has the classic Swiss cheese appearance with basophilic mucinous substance filling the cystic spaces. In the tubular pattern, the cells are arranged in smaller ducts and tubules with less prominent cystic spaces. The solid type is characterized by sheets of neoplastic cells with few cystic spaces. Any given tumor may contain all 3 patterns, but common to all types is the propensity for perineural invasion. Perineural extension accounts for the difficulty in eradicating adenoid cystic carcinoma despite extent of excision.
    • Treatment is discussed below.
  • Acinic cell carcinoma
    • Acinic cell carcinoma is a low-grade neoplasm that represents 1% of all salivary gland neoplasms. Almost all (95%) arise in the parotid gland, and most of the remainder arise in the submandibular gland.
    • The tumors are formed of serous cells, explaining the propensity for the parotid gland. Grossly, they are encapsulated, hard, gray-white tumors. The tumors consist of lobules of round uniform-appearing cells with abundant cytoplasm arranged in nests. The cells most commonly resemble the serous acinar cells of the parotid gland, but they may have a clear cytoplasm as well.
    • Treatment is discussed below.
  • Carcinoma ex-pleomorphic adenoma
    • Carcinoma ex-pleomorphic adenoma refers to an epithelial carcinoma that arises from a preexisting pleomorphic adenoma. This tumor contains only malignant epithelial elements. This finding is in contrast to the malignant mixed tumor, which is a malignant neoplasm that contains both epithelial and mesenchymal-like elements. This rare tumor is not related to pleomorphic adenoma.
    • Carcinoma ex-pleomorphic adenoma represents approximately 2-4% of salivary gland malignancies. Malignant degeneration of a pleomorphic adenoma seldom occurs, but the rate increases with long-term observation (ie, >10 y) of the benign tumor. The characteristic clinical feature is sudden rapid growth of an otherwise slow growing or stable mass.
    • Gross tumors appear firm, unencapsulated, and nodular, with areas of central necrosis and hemorrhage. Microscopically, the diagnosis is based on a malignant process that infiltrates a neoplasm, which has the histologic features of a pleomorphic adenoma. The malignant component may appear as an adenocarcinoma, squamous cell carcinoma, or undifferentiated carcinoma.
    • Carcinoma ex-pleomorphic adenomas have an aggressive natural history and a poor prognosis. Regional and distant metastases are common. Treatment is discussed below.
  • Squamous cell carcinoma
    • Primary squamous cell carcinoma of the salivary glands is rare. Ruling out a high-grade mucoepidermoid carcinoma, which may appear similar to a squamous cell carcinoma, is important. Similarly, the differential diagnosis must exclude a primary squamous cell carcinoma of the skin or upper respiratory squamous mucosa with regional metastasis to the salivary glands. Excluding these 2 possibilities, true primary squamous cell carcinomas likely represent 0.3-1.5% of salivary gland tumors.
    • As in other head and neck squamous cell carcinomas, local and regional recurrences occur frequently. Treatment is discussed below.
  • Adenocarcinoma
    • Adenocarcinomas of the salivary gland represent those malignancies that cannot otherwise be easily classified. Collectively, they are rare, making up approximately 2-3% of salivary gland tumors. Some pathologists classify them as low- or high-grade, although all generally have an aggressive biologic behavior. They are treated and staged as described below.
    • As a result of investigations into the microcellular processes of salivary neoplasms, several immunostaining and histologic studies can be performed on biopsied or sectioned tissue to assist in the workup. Staining for silver nucleolar organizer region (AgNOR) can help differentiate benign or inflammatory lesions from malignant ones. However, the AgNOR cannot distinguish between histological types or grades. [12]
    • Cytoplasmic immunostaining for pRb or p130, a member of the Rb family of tumor suppressor genes, has been directly correlated with increased tumor grade in salivary gland malignancies.
    • The loss of immunostaining for p63 in myoepithelial cells has been associated with malignancy and loss of differentiation. This technique can be used to look for malignant cells to distinguish pleomorphic adenomas from carcinoma ex-pleomorphic adenomas.
    • Immunostaining of mucin expression can help differentiate mucoepidermoid carcinoma (MEC) and acinic cell carcinoma (ACC). A recent study found that MEC uniquely expresses MUC5AC but not MUC3; ACC usually expresses MUC3 and not MUC5AC.
  • Polymorphous low-grade adenocarcinoma
    • Polymorphous low-grade adenocarcinoma (PLGA) is an indolent tumor that can be confused on pathology with adenoid cystic carcinoma and has been previously recognized as lobular carcinoma, trabecular adenocarcinoma, and terminal duct carcinoma. PLGA has a predilection for perineural invasion and is predominantly a tumor of minor salivary glands. PLGA has a low rate of cervical metastasis (4-12%), and postoperative radiation does not appear to improve survival. Prognosis is very good for this tumor, with 10-year survival in excess of 90%.
    • Recently, a rare low-grade adenocarcinoma with a predilection for the tongue and good prognosis despite a relatively high rate of cervical metastasis has been described. This entity, named cribiform adenocarcinoma of minor salivary gland origin, is similar to polymorphous low-grade adenocarcinoma in histology and prognosis, but differs in metastatic potential and most common site of origin. [13]
  • Salivary duct carcinoma: Salivary duct carcinoma is a rare aggressive tumor that usually arises from the parotid gland. It represents 1-3% of all salivary gland malignancies and predominantly affects males in the seventh decade of life. It has a high rate of cervical metastasis, with greater than 50% of patients having nodal metastasis at the time of diagnosis. Prognosis is poor, with 5-year survival estimated at 42% for stage I disease and 23% for stage IV disease. Patterns of failure are evenly split between local and distant failure. Current treatment recommendations are total versus radical parotidectomy and ipsilateral neck dissection. The efficacy of postoperative radiation therapy is unclear; however, in view of the poor prognosis of this tumor, most patients are given adjuvant radiation therapy. The role of chemotherapy in this disease is also unknown. [14]
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Staging

AJCC staging is described in the image below.

American Joint Committee for Cancer Staging and En American Joint Committee for Cancer Staging and End Result Reporting (AJCC) classification of major salivary gland malignancies.
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