37.2.1 Risk Factors

Etiologic risk factors for salivary gland malignancies are not well understood due to paucity of robust studies, but several risk factors have been suggested. Some occupational exposures ^{15 , 16} and dietary factors have been implicated. ¹⁷ A history of radiation to the head and neck, for example, exposure to nuclear fallout among atomic bomb survivors, has been associated with increased risk of mucoepidermoid carcinoma in particular. ^{16 , 18 , 19} Radioiodine for the treatment of well-differentiated thyroid carcinoma ²⁰ and chemotherapy for childhood cancers have also been suggested to increase the risk of mucoepidermoid carcinoma. ¹ Despite these reported associations, most salivary gland malignancies cannot be attributed to a specific etiology.

37.2.2 Patient Population

Most minor salivary gland malignant neoplasms affect individuals in their fifth and sixth decades of life and have a slight female predominance with female-to-male ratios of approximately 1.5 to 1. ^{1 , 7 , 8 , 11 , 12} Minor salivary gland malignancies can also rarely affect children, with mucoepidermoid carcinoma the most common subtype, followed by adenoid cystic carcinoma, and adenocarcinoma. Similar to adults, the most common anatomic location for malignancies in children is the oral cavity, in particular the hard palate. ²¹ Pediatric malignancies are rarely high-grade, and often require only complete surgical resection. ²¹ Most series report favorable long-term outcomes with a low risk of recurrence. ^{21 – 23}

37.2.3 Classification

There are a number of different histopathologic tumor types observed among malignancies of the minor salivary glands. The World Health Organization recently released a new classification schema in its 2017 4th edition guideline which identifies 22 malignant and 11 benign entities (▶ Table 37.1). ¹ The two most frequently encountered malignancies in the oral cavity are mucoepidermoid carcinoma (15-59%) and adenoid cystic carcinoma (26-60%), with a lower prevalence of polymorphous adenocarcinoma (previously known as polymorphous low-grade adenocarcinoma) (15-26%), ^{1 , 2} adenocarcinoma, NOS (7-22%), and acinic cell carcinoma (2-3%). ^{7 , 8 , 24 – 27}

37.2.4 Clinical Presentation

Minor salivary gland malignancies typically present as a slow-growing firm or soft mass (▶ Fig. 37.2), often on the hard palate. The mass is usually covered with intact mucosa but sometimes may exhibit bleeding or ulceration. Most masses are asymptomatic. In edentulous patients, difficulty wearing dentures may be the initial presenting symptom. A small subset of tumors present with pain, which is more commonly associated with malignant compared with benign tumors. ^{5 , 28} Adenoid cystic carcinoma in particular has a propensity for perineural invasion, and thus may present with nerve-related symptoms such as numbness or weakness in addition to pain. ²⁹ It is generally not possible to definitively distinguish malignant from benign tumors on physical examination alone.

37.3.1 Differential Diagnosis

The differential diagnosis for oral cavity lesions includes a wide array of benign and inflammatory processes such as mucoceles, fibromas, granulomas, etc. as well as benign minor salivary gland lesions, the most common of which is pleomorphic adenoma (▶ Table 37.1). ³ Other malignant neoplasms include the more common mucosal squamous cell carcinoma, and rarely, lymphoma, metastases from other primary tumors, or mesenchymal malignant tumors, such as malignant schwannoma, malignant fibrous histiocytoma, and rhabdomyosarcoma. ³⁰

37.3.2 Considerations for Biopsy of Suspected Malignancy

The role of biopsy in the workup of intraoral salivary gland neoplasms is to (1) establish the tissue of origin (e.g., salivary gland versus mucosal lesion or lymphoma), and (2) determine whether the tumor is benign or malignant in order to guide surgical planning and patient counseling. Although it is useful for the surgeon to know the histologic subtype and grade of malignancy, this is not always possible if tissue sampling is limited. A small biopsy specimen may preclude evaluation of important pathological features such as infiltrative growth and tissue architecture that are necessary to differentiate tumor types. ³¹ Many salivary gland tumors have heterogenous growth patterns, and histologic features may be shared amongst several tumor types, thus increasing diagnostic complexity. A possible exception is mucoepidermoid carcinoma, which can often be diagnosed even with a scant tissue sample. ³¹

Core needle, punch, and incisional biopsies provide more tissue for pathologic evaluation than fine-needle aspiration cytology (FNAC), ³² and for salivary gland neoplasms arising in the oral cavity, these biopsies are often readily attainable. Whereas incisional biopsy is rarely recommended for major salivary gland tumors given their proximity to important neural structures, and risk of tumor spillage for pleomorphic adenomas in particular; there is typically less risk associated with such biopsies for intraoral minor salivary gland neoplasms due to their location. Ultrasound guidance, which is often useful for major gland masses, is rarely necessary for oral cavity neoplasms. Although there is a concern for tumor seeding in cases of pleomorphic adenoma that may give pause to clinicians considering biopsy of a suspected salivary gland neoplasm, there are very few such reported cases attributed to FNAC or core needle biopsies. ^{32 , 33} Excisional biopsy is not recommended due to high rates of positive margins and increased difficulty of planning or undertaking the definitive resection. ⁷

37.3.3 Imaging Studies and Extent of Disease Evaluation

Imaging studies are indicated to evaluate the local extent of the tumor with regard to surgical resectability, and for extent of disease evaluation, for example, to assess for cervical lymphadenopathy and/or distant metastases.

Magnetic resonance imaging (MRI) with gadolinium contrast enhancement is the imaging modality of choice for evaluation of salivary gland tumors and provides valuable information regarding local tumor spread and perineural invasion (▶ Fig. 37.2). Characteristics that suggest a high-grade salivary malignancy include invasion of adjacent structures, irregular or poorly defined borders, low signal on T2 images, heterogeneous enhancement, and central tumor necrosis. ³⁰

In addition to tumor characteristics observable on standard MRI, evolving MRI techniques have allowed for increasingly accurate prediction of tumor biology. Apparent diffusion coefficients (ADC) on diffusion-weighted imaging (DWI) can give valuable clues as to whether a tumor is benign or malignant, and it can even suggest a specific histology and grade. Multiple studies have reported a lower ADC for malignant tumors compared with benign tumors. Lower ADC is attributed to the restricted diffusion of water protons through tumors with cytotoxic edema and high cellularity compared with normal tissues and vasogenic edema. ^{34 , 35} The sensitivity, specificity, and positive and negative predictive values of DWI for identifying malignant versus benign salivary gland tumors have been reported at 91 to 100%. ^{34 , 36} Dynamic contrast-enhanced (DCE) MRI is another technique that measures tumor enhancement over time and gives additional parameters that can help distinguish malignant from benign tumors. ³⁰ It is recommended that DWI and DCE be added to MRI with contrast in the workup of intraoral minor salivary gland tumors whenever possible.

A limitation of MRI is its ability to evaluate bony detail. Computed tomography (CT) scanning provides excellent bony resolution, therefore a CT scan can be a valuable adjunct to MRI in cases of questionable bone involvement (▶ Fig. 37.3a). Contrast-enhanced CT scan can also provide soft tissue evaluation in patients with contraindications to MRI, such as those with pacemakers or other implants. ¹⁸fluorodeoxyglucose (FDG) positron emission tomography (PET)-CT is not always useful for distinguishing benign versus malignant salivary gland diseases because some benign tumors may demonstrate PET avidity. ³⁰

Approximately 15% of patients with minor salivary gland malignancies have cervical lymph node metastases. ^{11 , 26 , 37} The cervical lymph nodes should be included in any head and neck imaging study so that the neck is evaluated for possible regional nodal involvement. Distant metastases are not uncommon in certain minor salivary gland malignancies and develop in 15 to 30% of patients, with the highest risk among those with high-grade tumors and with clinically positive cervical lymph nodes. ^{38 , 39} The lungs are the most common site for distant metastasis, and should be evaluated as part of the initial workup with a noncontrast chest CT scan or chest radiograph, or other imaging modality. ³⁰ Adenoid cystic carcinoma, in particular, has a well-described propensity for lung metastases that may develop in > 50% of patients ¹ even in the absence of involved neck lymph nodes. ^{38 , 40}

Other less common sites of distant metastases are the liver, bone, and distant lymph nodes. ³⁸ Additional evaluation for distant metastatic disease outside of the lungs and in the absence of symptoms, however, is not standard. ¹⁸FDG PET-CT has been shown in recent studies to change management for a subset of patients (15-40% of reported cohorts) with salivary gland malignancies in whom distant metastatic disease is identified using this imaging modality. Most of these cases represented a transition in the goals of management from curative to palliative intent with the discovery of distant metastases (see later discussion of distant metastases). ^{18 , 41 – 44} FDG PET-CT is not yet routinely recommended as part of initial staging, but may become so in the future if it is consistently shown both to change management and be cost-effective.

37.3.4 Molecular Alterations

Recent advances in molecular testing offer an unprecedented understanding of the genetic alterations that underlie salivary gland malignancies, holding promise for increased diagnostic accuracy as well as therapeutic targeting and improved prognostic information. In particular, a number of salivary gland malignancies harbor specific genetic translocations (▶ Table 37.2). Up to 80% of adenoid cystic carcinomas have a t?(6;9)(q22-23;p23-24) rearrangement resulting in a MYB-NFIB fusion gene, which is a useful ancillary diagnostic test. Approximately 40 to 80% of mucoepidermoid carcinomas have t(11;19)(q21;p13) rearrangement resulting in CRTC1-MAML2 fusion gene that may be associated with less aggressive disease and improved prognosis in both low- and high-grade mucoepidermoid carcinomas. Nearly all mammary analogue secretory carcinomas harbor t(12;15)(p13;q25) rearrangement with ETV6-NTRK3 fusion. Although these genetic alterations are currently useful primarily for diagnostic purposes, future research may shed light on their potential roles as therapeutic targets. ⁴⁵