Physical Examination

The clinical presentation of malignant salivary gland neoplasms can range from indolent asymptomatic masses to rapidly growing painful masses with progressive facial nerve paralysis. In Spiro’s review of 2807 salivary gland tumors, pain was a symptom in only 10% of malignant cases¹ but was more frequently seen with malignant neoplasms than with benign ones. In general, episodic swelling and pain most often indicates salivary gland obstruction and inflammation, whereas constant pain is more worrisome for malignancy. However, sialadenitis can be secondary to obstruction by a salivary gland neoplasm; thus the latter must be considered in the evaluation of any salivary gland swelling with pain. Approximately 10% of parotid gland malignancies present with associated facial paralysis, and this portends a poor prognosis.^5,6

Radiologic Studies

Magnetic resonance imaging (MRI) is the radiologic modality most often recommended to assess salivary gland neoplasms if there are no contraindications. Benign and malignant neoplasms of the parotid gland are well visualized on T1-weighted images because they are easily distinguished from the fatty parenchyma of the gland, which appears hyperintense. In general, benign epithelial neoplasms (such as pleomorphic adenomas) and low-grade malignancies have low T1-weighted and high T2-weighted signal intensities (Fig. 88-1A and B). High-grade carcinomas tend to have low-to-intermediate signal intensities on both T1-weighted and T2-weighted imaging (discussed later). The use of contrast material such as gadolinium and fat saturation of T1-weighted imaging provides additional information regarding the extent of a salivary gland malignancy (Fig. 88-1C and D). This is particularly useful in terms of assessing bone involvement and perineural spread. Bone marrow and cortex appear hypointense on fat-saturated images, and infiltrating tumor tissue appears hyperintense when enhanced with gadolinium. Enlarged foramina at the skull base and the presence of hyperintense enhanced tumor tissue are suggestive of perineural spread.

Figure 88-1. Magnetic resonance imaging of salivary gland neoplasms. A, T1-weighted image of a pleomorphic adenoma in the parotid gland. B, T2-weighted image of the same pleomorphic adenoma. C, Axial T1-weighted, postgadolinium, fat-saturated image of an adenoid cystic carcinoma of the right sublingual gland. D, Coronal T1-weighted, postgadolinium, fat-saturated image of the same tumor in C.

(A and B from Som PM and Curtain HD. Head and Neck Imaging. 4th ed. Philadelphia: Mosby; 2002:2074, figure 39-102A and B).

Some have proposed that T2-weighted imaging is helpful in distinguishing benign from malignant salivary gland neoplasms. Som and Biller¹⁰ examined 35 parotid tumors by MRI and made the following observations. Benign tumors and low-grade malignancies had low T1-weighted and high T2-weighted signal intensities, and they had clearly defined margins. High-grade malignancies, on the other hand, had low T1- and T2-weighted signal intensities and poorly defined margins. Freling and colleagues,²⁰⁴ however, did not make the same observations. They examined 116 patients with parotid masses, 30 of which were malignant tumors, and found no correlation between malignancy and signal intensity, heterogeneity, or radiographic margins on MRI. Malignant lesions could be discriminated from benign ones only when there was infiltration into adjacent structures. Among the malignant lesions, there was no correlation between tumor grade and MRI features. Thus MRI provides useful information about the extent of the disease, but histopathologic diagnosis is still required to distinguish benign from malignant processes.

Computed tomography (CT) with intravenous contrast is also widely used in evaluating salivary gland masses primarily because of the speed with which images are acquired. CT is particularly useful for evaluating cortical bone erosion from adjacent tumors. CT is much better than MRI in visualizing small salivary duct calculi, and as such, it is particularly helpful in assessing salivary gland masses if sialolithiasis is considered to be a component of the etiology. Highly cellular tumors can be visualized in the parotid gland because the normal parotid tissue has a high fat content, which results in a lower radiodensity on CT imaging compared with neoplasms. However, in general, MRI is superior to CT for providing soft tissue detail and delineating the extent of salivary gland masses.

Biopsy

Pretreatment diagnosis has been made possible by the use of fine-needle aspiration (FNA) biopsies. This diagnostic tool was established in the mid-to-late 1960s^11–16 and has become a mainstay in the workup of salivary gland neoplasms. It is an extremely safe procedure that is well tolerated by patients and is considered to have no significant risk of tumor seeding to surrounding tissue.¹⁷

Although FNA biopsies of salivary neoplasms have proven to be extremely useful for preoperative planning, the interpretation of these biopsies can be difficult, resulting in diagnostic ambiguity and inaccuracy. A few entities have classic, pathognomonic features on needle aspiration. However, the variety of different tumor types and their widely overlapping histology usually necessitates the acquisition of biopsy or resection tissue for definitive diagnosis. Also, and most importantly, many malignant salivary gland tumors can only be diagnosable as such when the growth pattern (e.g., infiltration beyond the capsule into soft tissue, perineural invasion) is taken into consideration. In these cases, tumors can only be definitively diagnosed as malignant on surgical specimens, which adequately demonstrate the tumor architecture and its relationship to peripheral tissue. This is particularly true for low-grade malignant neoplasms such as polymorphous low-grade adenocarcinoma,¹⁸ myoepithelial carcinoma,^19,20 and basal cell adenocarcinoma,²¹ which usually have bland-looking tumor cells and lack necrosis or abundant mitoses. Among tumors of the head and neck, FNA biopsies of major salivary gland tumors are considered to have the highest rate of error.²² By most reports, the sensitivity of FNA biopsies to diagnose a malignant neoplasm is much lower than the specificity.^22–26 In other words, it is more common to misdiagnose a malignant tumor as benign than the reverse. A 5-year review of data from 6249 participant responses from the College of American Pathologists Interlaboratory Comparison Program in nongynecologic cytology revealed that FNA biopsies had a 68% sensitivity for diagnosing a salivary gland neoplasm as malignant, with an overall false-negative rate of 32%.²⁷ The greatest number of false-negative diagnoses occurred in cases of lymphoma (false-negative rate = 57%), followed by acinic cell carcinoma (false-negative rate = 49%), low-grade mucoepidermoid carcinoma (false-negative rate = 43%), and adenoid cystic carcinoma (false-negative rate = 33%). In cases of benign neoplasms from the same study, the specificity of FNA biopsies was 91%, with an overall false-positive rate of 8%. The greatest false-positive rate was in cases of monomorphic adenoma (53%), which were most often diagnosed as adenoid cystic carcinoma. Pleomorphic adenomas, when diagnosed as malignant, were most often misinterpreted as adenoid cystic carcinoma, and Warthin’s tumors as lymphoma.

Although the utility and ease of FNA biopsies have resulted in a decline in the use of frozen section analysis intraoperatively, there are still several indications for frozen section studies, as reviewed by Seethala and colleagues²⁸ and Westra.²² These include assessing the extent of tumor spread to local/regional tissues such as the nerves and lymph nodes, assessing surgical margins, and confirming/establishing the diagnosis in cases where the preoperative FNA biopsy was not diagnostic or was equivocal.

Staging

Clinical staging of salivary gland cancers is important for prognosis and treatment decisions. The 2003 TNM staging classification for major salivary gland cancers established by the American Joint Committee on Cancer (AJCC) is the classification most commonly used in the United States (Tables 88-3A and B). Minor salivary gland carcinomas are staged according to the anatomic site of origin (e.g., oral cavity, sinus, larynx). The staging guidelines are applicable to all forms of carcinoma; any nonepithelial tumor type is excluded.

Table 88-3A 2003 AJCC TNM Staging for Major Salivary Gland Cancer

AJCC, American Joint Committee on Cancer.

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

From Greene FL. AJCC Cancer Staging Manual. 6th ed. New York: Springer-Verlag, 2002.

Mucoepidermoid Carcinoma

Mucoepidermoid carcinoma is the most common salivary gland malignancy.^3,31–33 The majority of cases occur in the major salivary glands,³⁴ but mucoepidermoid carcinoma can also arise from minor salivary glands in the oral cavity, particularly in the hard palate, buccal mucosa, lip, and retromolar trigone.³⁵ Rarely, they can also arise intraosseously in the mandible and maxilla, but mucoepidermoid carcinomas of this location are considered odontogenic in origin and have a less aggressive clinical behavior.^36,37 Clinically, mucoepidermoid carcinomas are slightly more common in women and have a mean age of approximately 45 years, but they can also occur in children.³¹ In fact, they are the most common pediatric salivary gland carcinoma.³⁸ Patients usually present with a painless, slow-growing mass. Intraoral tumors may mimic a mucocele or vascular lesion clinically by presenting as a blue-red superficial nodule.³

Grossly, these tumors are not distinct. They usually have both solid and cystic components, often with mucinous material within the cysts.³⁹ This is what sometimes imparts a bluish color to them, which can mimic the appearance of a mucocele in the oral cavity. Microscopically, their hallmark is the presence of three cell types: mucous, squamoid (or epidermoid), and intermediate (Fig. 88-3A). The architecture is usually a mixture of cystic (see Fig. 88-3B) and solid elements, the latter with sheets (see Fig. 88-3C), nests, or ductlike structures. The mucous cells have abundant, light blue mucin in their cytoplasm and nuclei displaced to the periphery. The mucin is usually obvious, but, in cases where it is scant, special stains such as PAS, mucicarmine, or Alcian blue can be used to highlight it. The squamoid cells are large with abundant pink cytoplasm, and, although they look somewhat squamous in appearance, true keratinization in mucoepidermoid carcinoma is rare.⁴⁰ Intermediate cells typically have more modest amounts of pink or clear cytoplasm. The proportion of cell types varies quite a bit among tumors. Intermediate cells usually predominate and mucous cells usually line cystic spaces. Cytologic atypia varies from minimal to quite prominent.^41–43 Immunohistochemistry is of limited to no utility in the diagnosis.³⁹

Figure 88-3. Mucoepidermoid carcinoma (MEC). A, Different cell types shown in this tumor with abundant intermediate cells (I), intermixed mucous cells (M), and also squamoid or epidermoid cells (S) with slightly more prominent, pink cytoplasm (200×). B, Tumor with extensive cystic change (100×). C, High-grade MEC with solid sheets of intermediate cells, minimal mucous differentiation, and no cystic change (200×).

FNA yields a mixture of cell types. At a minimum, both glandular and squamoid components must be present to make the diagnosis. The mucous cells have abundant vacuolated cytoplasm, intermediate cells are relatively round and small with little cytoplasm and nuclei with open chromatin, and the squamoid cells have moderate amounts of dense, homogeneous cytoplasm. These typically appear orange on Papanicolaou staining.

The differential diagnosis, particularly in tumors arising along mucosal sites, includes necrotizing sialometaplasia, an uncommon non-neoplastic lesion of the hard palate with reactive changes in minor salivary glands⁴⁴ and, more importantly, adenosquamous carcinoma, which is an aggressive variant of squamous cell carcinoma. Adenosquamous carcinomas are high grade, have definitive squamous differentiation usually with keratinization (unlike mucoepidermoid carcinoma), and often have surface mucosal squamous dysplasia, a feature that mucoepidermoid carcinoma does not have.³⁹

Grading of mucoepidermoid carcinoma is important and correlates strongly with clinical behavior, although reproducibility and consistency are major issues, and no particular system has been universally accepted.^41–4345 Clinical staging is as important as histologic grade, so the two should be considered in tandem. In general, low-grade lesions have a prominent cystic component and abundant well-differentiated mucous cells with little cytologic atypia and low mitotic activity. High-grade lesions are more solid with squamoid and intermediate cells predominating. They also have cytologic atypia, mitotic activity, necrosis, and infiltrative growth. A number of different grading schemes (well reviewed by Luna³⁹) have been reported over the years. The most used grading system, originally designed by Auclair and colleagues,^41,43 uses a three-tiered score based on a number of histologic features (Table 88-5). The original grading system was initially criticized for a tendency to “under grade” the tumors when others demonstrated that a significant number of low-grade mucoepidermoid carcinomas developed progressive disease. The later modification by Brandwein and colleagues⁴² (see Table 88-5) refined the grading system such that none of the tumors classified as low grade in their study went on to have progressive disease. Low-grade mucoepidermoid carcinoma, as strictly defined by their criteria, rarely ever metastasizes or results in death of the patient.^41–43

Table 88-5 Grading Systems for Mucoepidermoid Carcinoma

From Auclair PL, Goode RK, Ellis GL. Mucoepidermoid of intraoral salivary glands. Cancer. 1992;69:2021-2030; Brandwein MS, Ivanov K, Wallace DI, et al. Mucoepidermoid carcinoma. A clinicopathologic study of 80 cases with special reference to histological grading. Am J Surg Pathol. 2001;25(7):835-845.

In addition to grade, location of the primary tumor is potentially important in predicting clinical behavior. Several studies have shown that low-grade mucoepidermoid carcinomas of the submandibular gland recur and metastasize much more frequently than those of the parotid or minor salivary glands.^40,43 Whether or not this represents truly different biology, it merits the aggressive and thorough resection of any submandibular gland primary malignancy, especially for known mucoepidermoid carcinoma.⁴²

Adenoid Cystic Carcinoma

Adenoid cystic carcinoma (ACC) is one of the more common,^3,32,33 and certainly more recognizable salivary gland tumors, being notorious for its infiltrative growth and slowly progressive behavior with recurrences and spread over a protracted course of many years.⁴⁶ These tumors essentially occur with an even distribution among all salivary gland sites,³² although the total number of minor salivary gland cases outnumber those of major salivary glands when all sites are considered together.^47–50 These malignancies occur with an equal incidence in men and women over a wide age range with the peak incidence between 50 and 60 years of age.^47–4951

Grossly, ACCs are solid, light tan, firm and well-circumscribed, but unencapsulated, tumors. Microscopically, there are three growth patterns: tubular, cribriform, and solid. The tubular form consists of small tubules sitting in a pink, hyalinized, and hypocellular stroma (Fig. 88-4A). The solid variant has only rounded lobules of tumor cells with no, or almost no, glandlike structures and without a defined architecture (see Fig. 88-4B). The classic and most easily recognized pattern, though, is the cribriform (“Swiss cheese”-appearing) variant. Nests of cells are arranged around glandlike spaces that consist of PAS-positive blue or pink material (see Fig. 88-4C). The central spaces look like glandular lumina but are actually extracellular cavities containing reduplicated basement membrane (or ground substance) material^52,53 and myxoid material that is produced by the tumor cells, rather than true epithelial mucin. The cells in ACC are markedly basaloid in appearance, with little cytoplasm and round-to-oval nuclei that are dark and hyperchromatic without nucleoli (see Fig. 88-4A).⁴⁸ They are quite uniform in size and show little mitotic activity, except for the solid type, where mitotic activity can range from barely to extremely prominent. A rim of inconspicuous myoepithelial cells with clear cytoplasm is also usually present.^29,54

Figure 88-4. Adenoid cystic carcinoma (ACC). A, Tubular (grade I) ACC consisting of small tubule-like structures with an epithelial lining of small tumor cells with dark chromatin and with central blue ground substance-type material (400×). B, Solid (grade III) ACC with rounded nests of basaloid cells with very little to no ground substance or glandlike formations (100×). C, Cribriform (grade II) ACC with basaloid cells arranged around multiple rounded collections of central basophilic material giving a “Swiss-cheese” appearance (200×). D, Classic fine-needle aspiration finding of ACC with rounded “cylinders” of basement-membrane/ground substance material (Diff-Quik; 600×).

FNA frequently yields characteristic results in ACC. Aspirates have tumor cells with scant cytoplasm and round, regular nuclei in sheets and clusters. These features by themselves are not characteristic and actually are so bland that they might suggest a benign lesion. However, the finding of well-defined, round “cylinders” and/or spheres of acellular stroma accompanying these cells is typical, but not 100% specific, for ACC. The cells often “cling” to these rounded structures (see Fig. 88-4D).

Histologic grading has yielded conflicting results in the literature for predicting prognosis. Clinical stage, on the other hand, holds a great deal of prognostic information and, as such, should be considered as much or more than grade in clinical management.⁵¹ Also, as with mucoepidermoid carcinoma, ACC of the submandibular gland has a much more aggressive clinical course than ACC of other sites.^49,51 The most accurate prognostic information has been garnered when tumors are not only graded by the predominant pattern (tubular, cribriform, or solid) but are more specifically graded as follows: tubular with or without some cribriform areas (grade I), cribriform with no tubular areas and with less than 30% solid areas (grade II), and cribriform with greater than 30% solid areas (grade III).^49,55 A frequent histologic feature of ACC is perineural invasion, which is identified in approximately 70% to 75% of cases.^49,56 Although somewhat inconsistent in the literature, many have correlated this finding with a worse prognosis, particularly when involving a major nerve trunk.^46,57–59

The diagnosis of ACC is generally straightforward from routine hematoxylin and eosin examination. However, it can be difficult on small biopsies because one may not be able to appreciate the architecture and infiltrative growth. The differential diagnosis includes other salivary gland neoplasms (such as polymorphous low-grade adenocarcinoma or pleomorphic adenoma), basaloid squamous cell carcinoma, or high-grade neuroendocrine carcinoma.⁵⁴ Although beyond the scope of this text, immunohistochemistry is not usually necessary but can occasionally be helpful in differentiating among these tumor types.^60,61

Polymorphous Low-Grade Adenocarcinoma

Polymorphous low-grade adenocarcinoma (PLGA) is a unique, low-grade neoplasm first recognized as a distinct entity in the mid 1980s.⁶² PLGAs arise almost exclusively from the minor salivary glands and, in most series, are the second most common minor salivary gland carcinoma.^35,46 The most common site for these neoplasms is the palate,⁶³ particularly at the junction of the hard and soft palates. Other sites include the upper lip, buccal mucosa, and posterior third of the tongue.¹⁸ There are only rare reports of PLGA arising in major salivary glands.³⁰ PLGA is twice as common in women and tends to present in the fourth to sixth decades as a slow-growing mass that may have been present for years.^18,63 They are often asymptomatic.¹⁸ On gross examination, they are circumscribed, unencapsulated, pale yellow or tan masses that range from 1 to 3 cm. Microscopically, the architectural features of this tumor are quite variable, as the name would suggest. They are well circumscribed but unencapsulated and may appear as solid nests in lobules, cribriform glandlike structures, or ductlike arrangements. A common appearance within the tumor is concentric whorling of the nests around each other in a single-file arrangement. This has been termed the “eye of the storm” pattern (Fig. 88-5A). Stromal hyalinization with a slate-gray coloration is also characteristic.¹⁸ Tumor cells are quite regular with moderate eosinophilic cytoplasm and characteristic round-to-oval, extremely regular nuclei with open chromatin (see Fig. 88-5B). There is little mitotic activity and no necrosis. The periphery of the tumor shows markedly infiltrative growth and most cases have perineural invasion (see Fig. 88-5C).^18,63,64

Figure 88-5. Polymorphous low-grade adenocarcinoma (PLGA). A, Hard palate PLGA showing an unencapsulated tumor with variable-sized tumor nests, different growth patterns from trabecular to tubular to cribriform, and infiltrating a myxoid and hyalinized stroma and growing around nerves (N; arrow) (100×). B, PLGA tumor cells with modest pink cytoplasm and oval nuclei with no significant variability in size or shape (400×). C, PLGA with infiltration of fat and foci of perineural invasion (200×).

The differential diagnosis includes pleomorphic adenoma and ACC. The myxochondroid areas of pleomorphic adenoma are not seen in PLGA, and, although minor salivary gland pleomorphic adenomas are unencapsulated, they will not show the infiltrative growth pattern of PLGA and will not have perineural invasion. One particular immunostain that may be useful in difficult cases is worth mentioning here. Curiously, it has been recognized that almost all pleomorphic adenomas will be positive for glial fibrillary acidic protein (GFAP), whereas almost all PLGA are negative.^65–68 ACC is important to differentiate from PLGA. This is done primarily by cytologic features because ACCs have basaloid cells with dark chromatin and little cytoplasm, whereas PLGA cells have moderate eosinophilic cytoplasm and nuclei with open chromatin.

PLGA is a low-grade malignancy, and histologic grading is not applicable. Conservative resection is the treatment of choice. Local recurrence occurs in 10% to 15% of patients.^18,63,69 Because lymph node metastases are distinctly uncommon (literature rates of around 10% or less), neck dissection is only recommended with significant clinical adenopathy or needle-proven metastasis. This likely overestimates the occurrence, however. With strict histologic criteria for PLGA, nodal metastases are extremely rare.¹⁸ Distant metastases are equally as uncommon,⁷⁰ and patients have an excellent long-term prognosis.^18,63,69 In fact, few patients have been documented to die from this tumor and only after prolonged periods.^18,63

Acinic Cell Carcinoma

Acinic cell carcinoma, as the name implies, is a tumor with cells showing differentiation toward cells of the normal salivary gland acini (see Fig. 88-2). However, these tumors also show evidence of ductal and myoepithelial differentiation, an important feature to keep in mind. They are uncommon, comprising 1% to 3% of all tumors and approximately 10% of all malignant ones.^3,32,33,71 More than 90% occur in the parotid,^72,73 with the rest scattered among minor salivary gland sites and rarely the submandibular gland.^71,74 Occurring over a wide age range from children to the elderly, they are relatively evenly distributed in the second through seventh decades⁷⁵ with a peak in the third decade.⁷³ Of note, these tumors are the second most common childhood salivary gland malignancy. They present as a slowly growing mass, which is only occasionally painful and rarely associated with a facial palsy.^71,73

Grossly, acinic cell carcinoma presents as a single, usually circumscribed, rubbery, solid mass with up to one third showing cystic degeneration.⁷⁵ Microscopically, they are highly variable, a feature of these tumors that has always led to angst in the diagnosing pathologist. The four principal histologic patterns are solid/lobular, microcystic, papillary-cystic, and follicular. Small tumors can be easily missed because the acinar cells are so well differentiated that they blend into the surrounding normal gland. Two features are classic, however. The first is the characteristic acinic cell, which has blue cytoplasm with abundant serous-type granules and a small, round, eccentrically placed nucleus (Fig. 88-6A). PAS stains will be strongly positive in these cells. A number of other cell types are seen including pink, clear, and vacuolated cells, such that most tumors are a mixture of different cell types (see Fig. 88-6A). The second classic feature is a dense lymphoid infiltrate with germinal centers (see Fig. 88-6B). The periphery of the tumors may or may not be infiltrative but are often “pushing” in nature (see Fig. 88-6C). Although one would assume that lack of an infiltrative border might signal a benign or low-grade lesion, there is no benign equivalent for this lesion (i.e., there is no known benign acinic cell neoplasm). “Dedifferentiation” has been described in a small subset of acinic cell carcinomas. This consists of tumors with areas of classic, “conventional” acinic cell carcinoma and an intermixed undifferentiated carcinoma in sheets with large, pleomorphic cells, brisk mitotic activity, and often necrosis.^76–78

Figure 88-6. Acinic cell carcinoma. A, Typical acinic cell carcinoma with round cells having abundant granular, blue cytoplasm (400×). B, Dense lymphoid infiltrate (left side) in and around the tumor (200×). C, Acinic cell carcinoma with pushing border with adjacent normal salivary gland tissue (100×).

The differential diagnosis includes normal parotid gland; however, acinic cell carcinoma will not have the exquisitely lobular architecture or the presence of ducts that normal salivary gland tissue will always have. For the pink and clear cell types, tumors such as oncocytic carcinoma or clear cell carcinoma not otherwise specified (NOS) must be considered, and the papillary variant of acinic cell carcinoma must be differentiated from cystadenocarcinoma. The finding of focal cells with blue, serous-type, cytoplasmic granules will confirm the diagnosis of acinic cell carcinoma. Immunohistochemistry has no significant utility in narrowing the differential diagnosis.

FNA biopsy of acinic cell carcinoma is fraught with difficulty because of the resemblance to normal tissue.²⁷ The diagnosis rests on finding a cellular specimen with sheets and clusters of large acinar cells with abundant granular cytoplasm and central round, regular nuclei. One should not see normal ductal epithelial cells or significant amounts of adipose tissue (both of these latter findings are from normal salivary gland tissue), but there is often a prominent background component of lymphocytes.

Surgical resection with negative margins is the most important therapy. These tumors will recur in approximately one third of cases.^71,73 Although classically regarded as low-grade malignancies, 10% to 15% of these tumors will metastasize locally to regional lymph nodes or distantly to the lung and bones. Acinic cell carcinomas are also notorious for recurrence and spread years beyond the primary presentation and for a protracted clinical course such that survival curves do not flatten out until after a decade.⁷⁹ Survival is approximately 80% at 5 years and 70% at 10 years.^71,75,79 Grading of these tumors has not correlated well with behavior, and there is not good agreement on histologic features within the proposed grading systems. Very bland, low-grade-appearing tumors can metastasize almost as frequently as tumors with more aggressive features. However, “dedifferentiation” (where there is a mixture of typical acinic cell carcinoma with a much higher-grade carcinoma) has consistently been associated with a poor outcome.^76–78

Malignant Mixed Tumors

“Malignant mixed tumor” is the broad term that is used to encompass three different salivary gland malignancies: true malignant mixed tumor (or carcinosarcoma), carcinoma ex pleomorphic adenoma, and metastasizing mixed tumor. As a group, these account for approximately 3% to 5% of all salivary gland malignancies,^3,32 and carcinoma ex pleomorphic adenoma is by far the most common of these.

True Salivary Gland Malignant Mixed Tumor (or Carcinosarcoma)

True salivary gland malignant mixed tumor (or carcinosarcoma) is a malignant neoplasm that consists of distinct carcinomatous and sarcomatous components. These tumors are rare,⁴⁶ comprising approximately 1% of all salivary gland malignancies.^32,35 The mean age of presentation is 58 years. Two thirds of cases arise in the parotid gland, approximately 15% in the submandibular gland, and 15% in the palate.^80–84 Grossly, the findings are not distinct. The mass may be circumscribed or ill defined. It is commonly firm and tan-white with hemorrhage and necrosis and, on occasion, grittiness or calcification. Microscopically, there is an intimate admixture of the two components (carcinoma and sarcoma), but the amounts of each can vary widely. The carcinoma component can have any type of differentiation but typically takes the form of high-grade salivary duct carcinoma or undifferentiated carcinoma (Fig. 88-7A).⁸⁰ The sarcomatous component is usually a chondrosarcoma (see Fig. 88-7B) or osteosarcoma,⁸⁰ but fibrosarcoma, leiomyosarcoma,⁸³ or even liposarcoma⁸⁵ is possible. Treatment consists of wide local excision combined with radiotherapy. The tumors are aggressive with up to two thirds of patients dying of either local recurrence or, commonly, distant metastasis to the lungs or bone, usually within a period of 30 months.⁸⁰

Figure 88-7. True malignant mixed tumor (carcinosarcoma). A, Biphasic tumor with a mixture of nests of poorly differentiated carcinoma (C) and a malignant spindle cell sarcoma in a myxoid stroma (S) (100×). B, Other areas of the same tumor show differentiation into chondrosarcoma with cells sitting in lacunae and a more blue, chondroid stroma (100×).

Carcinoma ex Pleomorphic Adenoma

Carcinoma ex pleomorphic adenoma is defined as a pleomorphic adenoma (or mixed tumor) in which, or with which, a carcinoma is present. It accounts for more than 95% of malignant mixed tumors but is still relatively uncommon. The critical thing to remember is that this term encompasses a heterogeneous group of tumors because the carcinoma component can be of any form, from very low grade to the highest grade types.⁸⁶ These tumors are most common in the parotid gland, followed by the submandibular gland, the minor salivary glands, and the sublingual gland.⁸⁷ Although there is a wide age range, most patients are in their sixth and seventh decades, approximately 1 decade later than the peak age for pleomorphic adenomas. The classic history is a patient with a longstanding mass that suddenly undergoes rapid growth over a period of several months.^87,88

Grossly, these tumors can reach up to 25 cm and the average is more than twice that for pleomorphic adenomas.⁸⁶ They usually consist of a tan-yellow, firm mass with ill-defined, infiltrative borders, and there may be a component of nodular, translucent blue or gray tumor representing the preexisting pleomorphic adenoma.⁸⁸ Microscopically, the proportions of the two components vary quite a bit from tumor to tumor. The pleomorphic adenoma component has typical features with myxoid, blue stromal areas, a variable proliferation of epithelial elements, including ductlike structures and sheets of myoepithelial cells, and chondroid areas reminiscent of cartilage (Fig. 88-8A). This may be replaced by scarring or be overgrown by the malignant component. The malignant component is often distinguished by its collagenous stromal hyalinization (see Fig. 88-8B). It most commonly takes the form of poorly differentiated adenocarcinoma NOS, salivary duct carcinoma, or undifferentiated carcinoma.⁸⁸ However, essentially any form of carcinoma can be found. As one can imagine, the prognosis and management are highly dependent on the type of carcinoma.⁸⁶

Figure 88-8. Carcinoma ex pleomorphic adenoma. A, Areas of otherwise typical pleomorphic adenoma in a carcinoma ex pleomorphic adenoma (200×). B, Another area showing nests of tubules of very atypical cells with nuclear pleomorphism, as well as mitotic activity. The cells sit in a hyalinized, pink stroma (400×). C, Carcinoma areas of a tumor that approach the periphery of the lesion but do not penetrate beyond it (carcinoma in situ) (40×).

The extent of invasion is a critical histologic feature for prognostication.^86,88–92 The malignant component should be classified as noninvasive (intracapsular), minimally invasive (≤1.5 mm beyond the capsule), or invasive (>1.5 mm). For those tumors where there is no invasion beyond the capsule/rounded edge of the tumor (so-called carcinoma ex pleomorphic adenoma “in-situ”) (see Fig. 88-8C) or where there is less than 1.5 mm invasion beyond it, there is essentially no risk of recurrence or metastasis from a completely resected tumor such that the behavior approaches that of benign pleomorphic adenoma.⁹² For invasive tumors, those with high-grade features do poorly, and those that are widely invasive have a survival ranging from 26% to 65% at 5 years and 0% to 38% at 20 years.^86,88,89 Wide resection with lymph node dissection and radiation therapy is the treatment of choice for widely invasive tumors or obvious cervical lymph node metastases.

Salivary Duct Carcinoma

Salivary duct carcinoma is a relatively recently described tumor that was separated from the generic category of salivary adenocarcinoma.⁹⁷ It is one of the most aggressive primary salivary gland tumors and has a similar histologic appearance to high-grade ductal carcinoma of the breast.^97–99 It accounts for less than 10% of salivary gland tumors. Males are more commonly affected at a rate of 4:1.^98,100–105 Patients generally present in the sixth decade with a rapidly growing parotid mass; a significant minority have facial nerve involvement and occasional facial skin ulceration.¹⁰⁵ Between 70% and 90% of cases arise in the parotid, with the remaining few occurring in the submandibular gland and oral minor salivary glands.^{98,101,104–106} Grossly, these tumors are ill defined, solid and white, with hemorrhage, necrosis, and occasionally cystic areas.^101,105 Infiltration of the surrounding tissue is usually quite obvious. Histologically, most salivary duct carcinomas have a large and prominent ductal carcinoma in-situ component with a cribriform pattern¹⁰¹ similar to what is seen in breast ductal carcinomas (Fig. 88-9A). This is the classic histologic finding. There is often central comedo-type necrosis. The invasive component consists of small nests, cords, and single large cells with abundant pink cytoplasm and large, round nuclei with vesicular chromatin and prominent nucleoli (see Fig. 88-9B).^101,105 There is marked tissue infiltration with stromal desmoplasia and brisk mitotic activity. Vascular and perineural invasion (see Fig. 88-9C) are common.^101,105,106 Immunohistochemistry is not particularly useful for diagnosis, but salivary duct carcinomas are positive for low- and high-molecular-weight cytokeratins, carcinoembryogenic antigen (CEA), androgen receptors, and, in a significant minority, Her2/neu,^99,107,108 with distinct membrane staining for the latter. A minority of the tumors have actual amplification of the Her2/neu gene. Unlike the histologically similar breast carcinoma, almost all salivary duct carcinomas are negative for estrogen and progesterone receptors.⁹⁹ The differential diagnosis includes metastatic breast carcinoma, poorly differentiated squamous cell carcinoma, and mucoepidermoid carcinoma. Intraductal cribriform carcinoma is the most important feature that argues for a diagnosis of primary salivary duct carcinoma and rules out these other possible lesions.

Figure 88-9. Salivary duct carcinoma (SDC). A, SDC showing cribriform carcinoma in situ in a large duct with large tumor cells with abundant pink cytoplasm (100×). B, Invasive component of SDC showing small nests and single cells with pink cytoplasm and large nuclei with pleomorphism and nucleoli (400×). C, Perineural invasion in SDC (200×).

Salivary duct carcinoma is high grade by definition. It is the most aggressive salivary gland carcinoma with 30% to 40% of patients developing local recurrence and between 50% and 75% developing distant metastases and dying of their disease, most within 4 years of diagnosis.^101,104,105 Wide local excision with neck dissection and postoperative radiotherapy is the treatment of choice.

Primary Squamous Cell Carcinoma

Squamous cell carcinomas are only rarely primary in the salivary gland, representing less than 1% of all malignancies in this site.¹⁰⁹ Metastases to intraparotid lymph nodes from primary skin cancers of the head and neck (particularly of the scalp, ear, and face) are much more common, as is direct invasion from adjacent tissues. Most patients are in their sixth through eighth decades, and sometimes there is a history of prior radiation therapy. By definition, the diagnosis of primary squamous cell carcinoma is restricted to the major salivary glands because those arising in the minor salivary glands cannot be distinguished from primary squamous carcinoma of the surrounding mucosa. Of these, 80% to 90% arise in the parotid gland, and 10% to 20% in the submandibular gland.^109,110 These tumors typically are high stage at the time of diagnosis.

Grossly, they appear as a firm, white, infiltrative, and nonencapsulated mass. Microscopically, they are identical to squamous cell carcinomas of the upper aerodigestive tract, although they tend to be better differentiated (most are moderately to well differentiated with abundant keratinization).^109–112 There is usually prominent desmoplasia and perineural invasion, with extension of the tumor into periglandular soft tissue.^109–112

Primary squamous cell carcinomas are aggressive tumors, with a 5-year survival of approximately 20% to 50%.¹¹² Histologic tumor grade does not correlate well with behavior. Treatment involves radical surgery, neck dissection, and radiotherapy.

Primary Small Cell Carcinoma

Small cell carcinoma (or high-grade neuroendocrine carcinoma) can occur as a primary tumor in the salivary glands, but this is quite uncommon, representing approximately 2% of salivary gland malignancies.^113,114 The majority occur in major salivary glands, particularly the parotid.^113,114 They present as a painless mass of several months, typically in patients in their sixth and seventh decades, many with associated cervical lymphadenopathy and/or facial nerve palsy.

Grossly, they are not distinct, being poorly circumscribed, infiltrative masses that are white or tan with frequent necrosis.¹¹⁴ Microscopically, they consist of large sheets or trabeculae of “small blue cells” (having moderate-sized nuclei and minimal cytoplasm). The nuclei characteristically have a punctate, granular (“salt and pepper”) chromatin without nucleoli.^113,114 There is nuclear molding where nuclei look pressed against each other due to the minimal amount of cytoplasm (Fig. 88-10A). There is brisk mitotic activity, frequent apoptosis, and often areas of necrosis.

Figure 88-10. Small cell carcinoma. A, Typical small cell carcinoma with cells with granular, punctuate chromatin and only small amounts of cytoplasm (400×). B, Cytokeratin 20 staining in small cell carcinoma of the salivary gland. Keratin stains in this tumor typically have a dotlike or punctuate staining pattern as is seen here (200×).

Immunohistochemistry shows staining for neuroendocrine markers such as synaptophysin, chromogranin-A, and CD56 (N-CAM).¹¹³ There is typically punctate or “dotlike” staining for pan-cytokeratin. In addition, specific cytokeratin staining patterns have been described including positive staining for cytokeratin 20 (see Fig. 88-10B) and absence of staining for cytokeratins 34βE12 and 5/6.⁶¹

The differential diagnosis includes the solid variant of ACC and poorly differentiated squamous cell carcinoma, both of which can be ruled out by neuroendocrine marker staining (synaptophysin, chromogranin-A, neural cell adhesion molecule or N-CAM). Importantly, for both the pathologist and clinician, one must rule out metastases from primary lung small cell carcinoma or skin Merkel’s cell carcinoma. Lung primary tumors should be detectable clinically and also would show positive staining for TTF-1 and lack of staining for cytokeratin 20. Metastatic Merkel’s cell carcinoma, on the other hand, is virtually indistinguishable from primary salivary small cell carcinoma^113,115,116; thus clinical findings are critical for these diagnoses.

The prognosis for small cell carcinomas is always relatively poor. However, for primary salivary small cell carcinoma, it may be slightly better than for pulmonary small cell, with reported 5-year survival rates between 13% and 50% and an average across studies of approximately 30% to 40%.^113,114,117 Lymph node metastases are frequent, as are distant metastases to the liver, lung, brain, and bones.¹¹³

Other Malignant Tumors

The salivary glands are the primary site of a large number of additional (and heterogeneous) tumors, only a few of which are discussed here. Most of the additional carcinomas are low grade, with relatively frequent local recurrences, but uncommon or rare metastases. These include epithelial-myoepithelial carcinoma,¹¹⁸ clear cell carcinoma, cystadenocarcinoma, basal cell adenocarcinoma,¹¹⁹ and myoepithelial carcinoma,^19,20 although the latter is somewhat more aggressive.

Epithelial-myoepithelial carcinomas are low-grade tumors that account for approximately 0.5% to 1% of salivary gland neoplasms. They occur in older patients, predominantly in the parotid gland (80%), and rarely in the larynx or paranasal sinuses. Microscopically, they are usually well demarcated and partially encapsulated, but there is invasion of tumor into adjacent parenchyma. The classic appearance is of duct structures with eosinophilic lining cells (the “epithelial” component), immediately overlying and surrounded by prominent clear cells (the “myoepithelial” component). Classically, the stroma between the tumor nests is pink and hyalinized, and the individual tumor cells are bland with minimal mitotic activity. By immunohistochemistry, the ductal lining cells are positive for low-molecular-weight cytokeratins, and the outer cells are positive for calponin, smooth muscle actin, and p63 (all markers of myoepithelial differentiation). The differential diagnosis includes pleomorphic adenoma and the tubular variant (grade I) of ACC. Epithelial-myoepithelial carcinoma is a moderately aggressive tumor with a recurrence rate of 40%, metastases to lymph nodes, lung, and liver of 15%, and a survival of 80% at 5 years. Treatment is wide local excision with or without radiotherapy.

Basal cell adenocarcinoma is the rare, malignant counterpart to basal cell adenoma. The vast majority arises in the parotid gland¹¹⁹ and has a typical morphology consisting of basaloid cells in tubular, trabecular, solid, or membranous patterns. The latter is called such because of the thick, hyalinized collagen that surrounds the nests of tumor cells. It is usually a low-grade carcinoma with histology showing a modest degree of cellular atypia and can only really be diagnosed as malignant on the basis of infiltrative growth into the surrounding tissue with or without perineural invasion.¹¹⁹ Local recurrence occurs in a minority of patients, and metastases to regional lymph nodes in less than 10%. The prognosis is thus excellent.

Myoepithelial carcinoma is the uncommon malignant counterpart to myoepithelioma. About 60% occur in the parotid gland.¹⁹ Like myoepitheliomas, these can have diverse cell types including epithelioid, spindled, plasmacytoid or hyaline, or clear cell. They have infiltrative peripheral borders, and one third of patients will die of metastatic disease, one third will have multiple local recurrences, and one third will be disease free after resection.

Adenocarcinoma NOS is a “salivary gland carcinoma that exhibits ductal differentiation but otherwise lacks the histologic features that define other types of salivary carcinoma.” This should not be considered a “wastebasket” diagnosis; it is simply a gland-forming carcinoma outside of the usual “herd.” There is an almost equal distribution between major and minor salivary glands.^120,121 They can range from bland but infiltrative tumors to pleomorphic and high-grade tumors with necrosis and wide infiltration. Thus given this heterogeneity, tumors should be graded into three categories: low grade, intermediate grade, and high grade.¹²¹ In general, the prognosis for adenocarcinoma NOS is worse than for most other salivary gland carcinoma with reported 10-year survival rates of 55%¹²⁰ and 15-year survival rates of 41%, 34%, and 28% for low, intermediate, and high grade tumors, respectively.¹²¹

Metastases

Metastasis to the salivary glands or, more commonly, to intraglandular or periglandular lymph nodes, is a frequent occurrence. The parotid gland contains an average of 20 intraparenchymal lymph nodes, whereas the submandibular and sublingual glands do not contain any.¹²² For this reason, the vast majority of metastases to the parotid gland are to intraparenchymal lymph nodes and thus from head and neck primaries,^123,124 while approximately 85% of those to the submandibular gland are from non–head and neck primaries. The parotid lymph nodes drain from the scalp, face, and ear skin and from the external auditory canal and tympanic membrane, so skin tumors such as squamous cell carcinoma and melanoma account for approximately 80% to 90% of metastases.^123,124 Merkel’s cell carcinomas also spread to this area but are uncommon. The remaining are from non–head and neck primary tumors, most commonly kidney, lung, and breast carcinomas.¹²⁵ The opposite distribution is seen for the submandibular gland, with 85% of metastases coming from infraclavicular primary tumors, most commonly breast, kidney, and lung carcinomas (small cell carcinoma of the lung in particular).^125–128

The histologic features of the tumors are identical to what is seen in the primary site lesions. In the parotid gland, when the tumors are smaller, they are seen as being “tropic” to the lymph nodes, a feature particularly important in identifying them as metastatic disease to the gland rather than emanating from it. They are focused within the lymph nodes, but they almost always have extracapsular extension with growth of the tumor into the adjacent normal salivary gland tissue. Many of them will obliterate the nodal tissue altogether (termed “soft tissue metastasis”) and so may just be seen as a nodule within the salivary tissue composed entirely of tumor. In these cases the pathologist cannot always be sure that the tumor is not a primary lesion. This is particularly important for two tumors: squamous cell carcinoma and high-grade neuroendocrine carcinoma. Both are rare primary lesions. For squamous cell carcinoma, the distinction between primary versus metastasis must be clinically ascertained. For high-grade neuroendocrine carcinomas, the differential diagnosis includes primary parotid gland small cell carcinoma, metastatic pulmonary small cell carcinoma, and Merkel’s cell carcinoma from the skin. As discussed earlier, immunohistochemistry can be helpful in this distinction.

Lymphoma

Primary lymphoma of the major salivary glands comprises approximately 5% of extranodal lymphomas and approximately 2% of all salivary gland tumors.^129,130 It is defined as arising in the salivary gland when there is absence of lymphoma in a noncontiguous site based on clinical evaluation.

Primary non-Hodgkin’s lymphoma (NHL) occurs either as a de novo process unrelated to other diseases or as a secondary process related to lymphoepithelial sialadenitis. De novo NHL can be large B-cell lymphoma (35%), follicular lymphoma (35%), or another low-grade lymphoma (30%), with half of the latter being secondary forms of the extranodal marginal zone B cell lymphomas of the mucosa-associated lymphoid tissue (MALT) type or just MALT lymphomas.^129,131 Most patients are older with the average age between 50 and 70¹³⁰ and present with a solitary, painless mass in de novo cases. In contrast, there is often a history of waxing and waning enlargement of several glands in the secondary forms.¹³² Most cases of salivary gland Hodgkin’s lymphoma occur in the parotid gland and probably just represent disease involvement of intraparotid lymph nodes.

Grossly, salivary glands involved with lymphoma usually have a tan-white to yellow-tan color and are diffusely and homogeneously involved (so-called “fish-flesh” appearance). The microscopic appearance depends a great deal on the type of lymphoma. Primary diffuse large B cell lymphoma consists of sheets of large lymphocytes diffusely effacing the normal gland and infiltrating (with little tissue reaction) into and around anything that is left (Fig. 88-11A). The cells have modest amounts of cytoplasm, round to oval nuclei with pale chromatin, one to three prominent nucleoli, and brisk mitotic activity (see Fig. 88-11B). Other primary lymphomas will have a similar growth pattern but with different cells depending on the type. MALT lymphomas occur in the setting of lymphoepithelial sialadenitis, with this being prominent in the background. There is a somewhat heterogeneous infiltrate of B cells with sheets of medium-sized lymphocytes with abundant pale cytoplasm, uniform nuclei, and distinct cell membranes. These form “halos” around the epithelial cell nests and extend away from them in broad strands (see Fig. 88-11C).¹²⁹ There is also a mixture of small cleaved lymphocytes, plasma cells, and lymphoplasmacytic cells that have cytologic features of both of the former two cell types (see Fig. 88-11D). The lymphoma cells markedly expand the spaces between the epithelial islands and also infiltrate into these islands along with the non-neoplastic lymphocytes from the background non-neoplastic sialadenitis. FNA is quite useful for diagnosing salivary gland lymphoma with high sensitivity and specificity for the diagnosis, as well as for providing material for flow cytometry.¹³³

Figure 88-11. Salivary gland lymphoma. A, Large B-cell lymphoma growing as a sheet with infiltration of salivary gland tissue without any stromal reaction or fibrosis (100×). B, Cells of large B-cell lymphoma have modest amounts of pink cytoplasm and large nuclei with clumped chromatin and one to three prominent nucleoli (400×). C, Mucosa-associated lymphoid tissue lymphoma showing diffuse involvement of the parotid gland by sheets of lymphocytes, which manifests as clearing around the epimyoepithelial islands (arrows) from the plasmacytoid B cells with clear cytoplasm that are accumulating there (40×). D, Central epimyoepithelial island (residual inflamed duct epithelium) surrounded by sheets of plasmacytoid lymphocytes with round nuclei, clumped chromatin, and pale to clear cytoplasm (400×).

Immunohistochemistry and molecular studies are critical to the diagnoses, particularly for MALT lymphoma, where the differential diagnosis includes inflammatory, non-neoplastic sialadenitis. In these cases, clonal immunoglobulin rearrangements by PCR combined with the light microscopic features makes the diagnosis of malignancy—both features are necessary.

Pediatric Salivary Gland Tumors

Pediatric salivary gland tumors are uncommon. The most common is the hemangioma followed by a long list of tumors, most of which are identical to adult forms such as mucoepidermoid carcinoma, acinic cell carcinoma, and ACC. Two are unique to the congenital period and bear mentioning here. Sialoblastoma is an extremely rare, potentially aggressive neoplasm that recapitulates the embryonic stage of salivary gland development and has been suggested to represent retained blastomatous cells. Local recurrence is relatively common, occurring in up to 30% of cases. Metastasis, however, is uncommon, and only one fatality has been reported. Salivary gland anlage tumor is a peculiar and unique hamartoma occurring in the perinatal period as a pedunculated mass attached to the wall of the nasopharynx.¹³⁴ These may obstruct the airway and, in this way, be clinically significant. Interestingly, they may be incidentally suctioned out of the newborn’s airway or spontaneously expelled.

Clinical Variables

In general, several clinical characteristics of the primary tumor have been proposed to be predictive of outcome. Not surprisingly, advanced tumor (T) stage, which takes into account both tumor size and the presence of extraglandular involvement, has been widely reported as being associated with the presence of metastases and poor survival.^138–146 The site of the primary tumor has also been proposed to have an association with poor survival. In particular, patients with malignant tumors of the submandibular and sublingual glands tend to have more frequent metastases and a worse outcome than patients with malignant tumors of the parotid gland.^{1,145,147,148} The relationship between the presence of metastatic disease and the tumor’s site and stage is reviewed later in “Surgery.”

The age and gender of the patient have also been suggested to be associated with prognosis. In a multivariate analysis by Terhaard and colleagues,¹³⁸ more advanced age was an independent predictor of poor overall survival and male gender was associated with a 17% increased risk for distant metastasis. Hocwald and colleagues¹⁴² also observed that patients older than the age of 50 years presented with more aggressive tumors and that men presented with higher T-stage tumors than women (53% vs. 26%). Similarly, O’Brien and colleagues¹⁴⁹ reported that patients 60 years or older had a significantly shorter survival but they did not find gender to be a significant factor for prognosis.

Presenting symptoms have also been examined for prognostic value. Specifically, facial nerve dysfunction and pain have been suggested in multiple studies to portend a poor prognosis. In the study by Terhaard and colleagues,¹³⁸ complete facial paralysis was an independent predictor of failed regional control, with a relative risk of 6.1. Likewise, in a multivariate analysis by North and colleagues,¹⁵⁰ facial nerve paresis was predictive of poor outcome with a 3-year, relapse-free survival of only 13%. In addition to its association with poor survival, facial nerve involvement has also been shown to be highly predictive of lymph node metastases.^146,151 Pain is another symptom that has been found to be associated with a poor clinical outcome in some studies¹⁵²; however, due in part to its subjective measurement, pain has not always been highly predictive.¹³⁸

Histologic Variables

It is generally accepted that certain histologic types of salivary gland malignancies can be placed into groups with either a favorable or poor clinical outcome. For example, patients with acinic cell carcinoma, low-grade mucoepidermoid carcinoma, PLGA, and basal cell adenocarcinoma tend to have better locoregional control rates and better disease-free survival following therapy compared with patients with other histologic types. Patients with high-grade mucoepidermoid carcinoma, undifferentiated carcinoma, squamous cell carcinoma, adenocarcinoma NOS, and salivary duct carcinoma tend to have a high incidence of nodal metastases and a poorer prognosis.

Tumor grade has been associated with prognosis for certain histologic types. Because the grading of salivary gland malignancies is subjective with variation between institutions and because there are many different histologic types, each with its own grading criteria, this variable has had mixed utility in predicting biologic behavior. Certain histologic types are inherently “high grade” or “low grade.” For instance, salivary duct carcinoma is a “high-grade” cancer, whereas polymorphous low-grade adenocarcinoma, as the name implies, is “low grade” (for more discussion, see the specific tumor types in “Histopathology” earlier). It is important to note that “high grade” is used in the literature to refer to both high-grade histologic types (generally referred to as “histologic grade”) and high-grade subtypes of certain specific malignancies, namely mucoepidermoid carcinoma and adenocarcinoma NOS.

When referring to histologic grade, high-grade malignant tumors are considered to include squamous cell carcinoma, undifferentiated carcinoma, high-grade mucoepidermoid carcinoma, and carcinoma ex-pleomorphic adenoma.^137,153 Low-grade malignancies include acinic cell carcinoma, low-grade mucoepidermoid carcinoma, low-grade adenocarcinoma (including basal cell and mucinous adenocarcinoma), and papillary cystadenocarcinoma. Intermediate-grade malignancies include adenoid cystic carcinoma and epithelial-myoepithelial carcinoma. In a multivariate analysis of 470 malignant tumors of the major salivary glands, Spiro and colleagues¹³⁷ found that histologic grade was an independent prognosticator of survival. This has been corroborated in another retrospective review by Chen and colleagues¹³⁹ of 207 patients with carcinomas of the major salivary glands that were treated with surgery alone. In this study, high histologic grade was also found to be an independent predictor of locoregional recurrence. Results such as these have led to the suggested role for postoperative radiation therapy in the treatment of high-grade salivary gland malignancies (discussed in “Radiation Therapy” later).

When considering a single histologic type of salivary gland malignancy, subtype grading of some malignancies is also highly correlated with clinical outcome. In general, grading seems to be most useful in predicting the clinical behavior of mucoepidermoid carcinoma and adenocarcinoma NOS.^1,154–157 In a review of 108 patients with mucoepidermoid carcinoma of the major and minor salivary glands by Guzzo and colleagues,¹⁵⁸ high-grade tumors were associated with a significantly reduced, 5-year, disease-free survival rate (22.5%) compared with low-grade tumors (97%, P <0.0001). Similarly, a recent review of 60 patients with mucoepidermoid carcinoma by Aro and colleagues¹⁵⁹ found patients with low-grade tumors to have a significantly better disease-free survival than those with either intermediate-grade or high-grade tumors. There was, however, no difference in disease-free survival between the intermediate and high-grade groups. Although adenoid cystic carcinoma has one of the more varied histologic phenotypes (tubular vs. cribriform vs. solid) allowing for easier grading classification, there is controversy over the utility of tumor grade in predicting the prognosis of patients with this malignancy. Some have strongly advocated its utility,^160,161 but studies by Spiro and colleagues^1,47,51 did not find grade to be predictive of clinical outcome in patients with this tumor type.

Local tissue invasion, regardless of histologic type, appears to portend a worse clinical outcome. In particular, perineural invasion and spread has been found to be a predictor of a more aggressive tumor behavior. In the multivariate analysis by Terhaard and colleagues,¹³⁸ perineural invasion was an independent prognostic factor associated with the risk of distant metastasis (relative risk = 2.2). Similarly, Hocwald and colleagues¹⁴² found perineural invasion to be an independent predictor of shorter disease-free survival in their multivariate analysis. Local bone invasion has also been shown to be independently associated with an increased risk of local recurrence and shorter overall survival.^138,162

Not surprisingly, the presence of positive surgical margins has also been shown to be associated with a worse clinical outcome. Therkildsen and colleagues¹³⁵ found this variable to be independently associated with both worse locoregional control and lower survival rates. Terhaard and colleagues¹³⁸ also found the status of the resection margin to be independently associated with poor local control with a relative risk of 3.5. These observations are consistent with other studies in which poor local control was associated with positive resection margins.^56,163,164

Molecular Markers

Markers of cell proliferation have been suggested to be prognostic for patients with salivary gland malignancy. Early studies looking at the proliferative fraction in salivary gland tumors using flow cytometry noted an association between proliferative activity and survival.¹⁶⁵ Two of the more commonly studied markers of proliferation are proliferating cell nuclear antigen (PCNA) and Ki-67. The expression of both PCNA and Ki-67 by tumor cells has been shown to correlate with higher-tumor grade and shorter, disease-free survival of patients with ACC and mucoepidermoid carcinoma.^166–171 In general Ki-67 is considered to be a more accurate marker of proliferating cells because it has a shorter half-life and hence more specific staining. In mucoepidermoid carcinoma, investigators have found that tumors with high expression of Ki-67 and low expression of p27 (a cyclin dependent kinase inhibitor, the action of which slows cell cycle progression) have a worse prognosis.^172,173

Another potential indicator of prognosis is a specific translocation, t(11;19), which brings together the MECT1 and MAML1 genes. This translocation has been identified in up to 70% of mucoepidermoid carcinomas.¹⁷⁴ Tumors with this translocation were found to be better differentiated and were shown to have a better prognosis. Although provocative, this has not garnered enough attention nor proven useful enough to be instituted in practice in the management of patients with these tumors. Whether or not it adds information beyond grade and clinical stage is unclear.

Another marker that has been investigated as a potential prognosticator is a receptor tyrosine kinase of the ErbB family. HER-2/neu (also known as ErbB2) is frequently expressed in a subset of salivary gland malignancies, salivary duct carcinoma in particular, and expression correlates significantly with prognosis.^104,175 This oncogene is also overexpressed in approximately one third of mucoepidermoid carcinomas, and its overexpression appears to correlate with poorer prognosis.^176,177 Prognostic data such as these have become the basis for targeted therapy against HER-2/neu, as discussed later in “Chemotherapy.”

Surgery

Parotidectomy

The parotid gland can be divided into a superficial (or lateral) and a deep “lobe” by a sagittal plane defined by branches of the facial nerve. The main trunk of the facial nerve, after it exits the stylomastoid foramen, gives off branches to the posterior belly of the digastric muscle and then runs through the parenchyma of the parotid tissue. It divides into an upper temporofacial division and a lower cervicofacial division at the pes anserinus, which is located approximately 1 to 2 cm from the stylomastoid foramen. The upper division divides further into the temporal, zygomatic, and buccal branches (Fig. 88-12). The lower division divides into the marginal mandibular and cervical branches. It is important to note that the parotid gland is actually unilobular and that the plane created by the fanning branches of the facial nerve is not a true anatomic separation of the gland into two discrete lobes. That being said, it is useful from a surgical standpoint to use the facial nerve as a plane of dissection.

Figure 88-12. Branches of the facial nerve. Variations of the facial nerve branching in the parotid gland are depicted.

(Adapted from Davis RA, Anson BJ, Budinger JM, et al. Surgical anatomy of the facial nerve and parotid gland based upon a study of 350 cervicofacial halves. Surg Gynecol Obstet. 1956;102:385-412).

When treating a salivary gland malignancy located in the lateral lobe, a superficial parotidectomy is generally adequate treatment for a small low-grade tumor that is well encapsulated, such as an acinic cell carcinoma. If the tumor is larger, a partial deep lobe resection can be performed to include an adequate margin of normal parotid tissue. A total parotidectomy, removing all of the lateral and deep tissue, is indicated for (1) high-grade malignant tumors with a high risk for metastasis, (2) any parotid malignancy with an indication of having metastasized to intraglandular or cervical lymph nodes, and (3) any primary malignancy originating within the deep lobe itself.

When performing a parotidectomy, one begins by making a modified version of the Blair incision typically used in rhytidectomies (Fig. 88-13). It begins at the root of the helix and extends inferiorly in the preauricular crease, curving posteriorly just below the lobule and then extending inferiorly and anteriorly to lie in a skin crease approximately two fingerbreadths below the inferior border of the mandible at the level of the hyoid bone. The inferior part of the incision can be extended to provide exposure for a lymph node dissection should one be indicated. An anteriorly based skin flap is then elevated in the subcutaneous plan immediately over the superficial musculoaponeurotic system (SMAS) layer. The greater auricular nerve is identified and traced inferiorly. It is divided superiorly and reflected inferiorly, preserving as much length as possible in the event that the facial nerve is resected and a cable graft is required. The tail of the parotid is elevated off of the sternocleidomastoid muscle, and the posterior belly of the digastric muscle is identified. The parotid gland tissue is then elevated off of the anterior aspect of the tragal cartilage, and the dissection is carried into the deeper aspects of the gland. The main trunk of the facial nerve is identified approximately 1 cm medial to the tragal pointer (Fig. 88-14). The nerve exits the stylomastoid foramen immediately posterior to the styloid process and enters the parotid gland immediately anterior to the insertion of the digastric muscle into the mastoid tip. In this region the posterior auricular artery coming from the external carotid artery is typically encountered and should be ligated once the facial nerve is identified. The main trunk of the nerve is traced anteriorly to the pes anserinus, and the branches of the upper and lower divisions are then followed, separating the lateral lobe of the gland from the nerve. Deep to the lower branches of the facial nerve, the retromandibular (posterior facial) vein may be encountered and should be ligated if a deep lobe parotidectomy is to be performed. If the location of the tumor prevents the identification of the main trunk of the facial nerve, one can identify a distal branch and trace the branch in a retrograde fashion back to the main trunk. The marginal mandibular branch is often used for this and can be found by following the posterior facial vein superiorly (Fig. 88-15).

Figure 88-13. Modified Blair incision for parotidectomy operations.

Figure 88-14. Identification of the main trunk of the facial nerve during a parotidectomy operation. The facial nerve exits the stylomastoid foramen and can be found approximately 1 cm medial and anteroinferior to the tragal pointer.

Figure 88-15. Identification of the marginal mandibular branch of the facial nerve. This branch can be found by carefully dissecting superiorly along the posterior facial vein. This can be useful when the location of the parotid tumor makes it difficult to identify the facial nerve at its main trunk. The marginal mandibular branch can be traced retrograde to the main trunk in these situations.

While performing a deep lobe parotidectomy, multiple intraglandular and periglandular vessels will be encountered. Specifically, branches of the external carotid artery must be identified and controlled, taking great care to identify and preserve the internal carotid artery. The external carotid artery is found just superior to the digastric muscle, and it should be controlled and/or ligated just before it enters the parotid gland. As mentioned earlier, the retromandibular (posterior facial) vein will often also need to be ligated to obtain access to the deep lobe. Once these vessels are controlled, the main trunk and branches of the facial nerve should be carefully elevated off of the deep lobe tumor (Fig. 88-16). Once this is accomplished, the gland can be dissected off of the deep musculature, mandible, and temporal bone. Intraglandular branches of the external carotid that will be encountered include the transverse facial artery and the internal maxillary artery. These should be ligated at the anterior aspect of the gland, at the posterior border of the mandibular ramus. If the tumor extends into the parapharyngeal space, it is dissected free using blunt dissection. Occasionally, the stylomandibular ligament will need to be divided so that the mandible can be retracted anteriorly to provide better access.

Figure 88-16. Dissection and removal of a deep lobe parotid tumor from the parapharyngeal space. The facial nerve has been dissected and mobilized over the tumor.

If the facial nerve is involved with tumor, it should be resected to negative margins. In general, if the preoperative facial nerve function is fully intact, the nerve is most likely not invaded, and all attempts should be made to preserve it. However, if the preoperative evaluation reveals a paretic or paralyzed facial nerve, it is likely invaded by the tumor and should be resected. The extent of the resection is dictated by intraoperative frozen section biopsies and should proceed until proximal and distal margins are deemed to be negative. This may require tracing the nerve into the mastoid region of the temporal bone by performing a mastoidectomy. The nerve is then reconstructed by primary neurorrhaphy or by placing an interposition graft, using either a segment of the greater auricular nerve or the sural nerve. Nerve mobilization after a mastoidectomy is often required in order to minimize tension on any reconstruction anastomosis. Facial nerve repair and facial paralysis rehabilitation is discussed in greater detail in another chapter within this textbook.

Advance parotid tumors may extend to adjacent structures including muscle (masseter, sternocleidomastoid, and pterygoid muscles), bone (mandible and mastoid tip), pharyngeal mucosa, and the overlying skin. In these situations the surgeon should be prepared to perform the type of operation that is necessary for complete extirpation of the tumor. This may require a partial mandibulectomy, a lateral or partial temporal bone resection, an extended resection of pharyngeal mucosa, or a resection of facial skin. Careful preoperative assessment of the extent of the tumor is essential to plan the extent of extirpation and reconstruction of the resulting defect.

Radiation Therapy

Chemotherapy

The use of systemic chemotherapy in the treatment of salivary gland malignancies is currently limited to palliative treatment of locally advanced unresectable, recurrent, and metastatic disease. A variety of agents have been explored; however, the studies that have been reported are nonrandomized and of small numbers of patients, making it difficult to assess the efficacy of these drugs. In addition, many of the reports are case series and retrospective reviews of heterogeneous types of malignancies and treatments. In order to circumvent the limitations of the available data, Rizk and colleagues¹⁹⁷ recently reported a meta-analysis of data from 205 patients obtained from 17 phase II or phase III trial studies. The chemotherapeutic agents used in these studies included cisplatin, carboplatin, epirubicin, cyclophosphamide, doxorubicin hydrochloride (Adriamycin), mitoxantrone, paclitaxel, 5-fluorouracil, vinorelbine, methotrexate, and bleomycin. All patients were treated for cancer of the major or minor salivary glands with either single-agent or multi-agent first-line palliative chemotherapy. Using meta-analysis linear regression, the authors found that patients treated with either platinum- or anthracycline (e.g., mitoxantrone)-based chemotherapy had an increase in their median survival. When looking at the data using a multivariate analysis, only platinum-based chemotherapy was found to be significantly associated with increased survival, but there appeared to be a positive interaction between platinum agents and anthracycline. Thus although the field is in need of prospective randomized trials, the available data suggest that these two agents may have a useful role, not only in palliative treatment, but also in definitive multimodality treatment of salivary gland malignancies prone to distant metastases.

Recently, attention has been directed to the possible role for directed therapy against biologic targets expressed in these cancers. These targets include receptor tyrosine kinases such as c-KIT and members of the ErbB family (the epidermal growth factor receptor (EGFR), Her2/neu). Adenoid cystic carcinoma has been shown to overexpress c-KIT in more than 90% of cases, and expression of c-KIT has been correlated with tumor grade.^198,199 EGFR (also known as ErbB1) is expressed in 79% of all parotid malignancies,¹⁹⁹ leading to the investigation of directed therapy against this target. Her2/neu (also known as ErbB2) is frequently expressed in a subset of salivary gland malignancies, namely salivary duct carcinoma, and expression correlates significantly with prognosis.^104,175 Observations such as these have established the rationale for investigating strategies to target these kinases in multiple phase II trials.^200–202 Unfortunately, no objective response was found when using either small molecule inhibitors or antibodies as monotherapy in patients with unresectable, recurrent, or metastatic disease. However, the therapeutics did appear to stabilize the disease in a substantial number of the patients in these trials, suggesting that inhibition of these targets was having some effect on the biology of these tumors. Indeed, there are promising data indicating that targeted therapy in combination with conventional chemotherapy may have a synergistic effect.²⁰³