Continuing Education Activity

Salivary gland tumors are a rare group of complex, heterogeneous histologies located in the parotid gland, submandibular gland, sublingual gland, and minor salivary glands of the upper aerodigestive tract. This diverse group of malignant tumors has a wide range of etiology, pathophysiology, treatment, and prognosis. This activity reviews the evaluation and treatment of malignant salivary gland tumors and highlights the role of the interprofessional team in evaluating and treating patients with this condition.

Objectives:

• Identify the etiology of malignant salivary gland tumors and associated conditions.
• Assess the physical examination of patients with malignant salivary gland tumors.
• Evaluate the treatment options available for malignant salivary gland tumors.

Introduction

Salivary gland tumors are a rare group of complex, heterogeneous histologies located in the parotid, submandibular, sublingual, and minor salivary glands of the upper aerodigestive tract. The wide variety of tumor etiology, microscopic histology, growth patterns, and tumor characteristics can make diagnosis and treatment challenging for clinicians. The World Health Organization in 2005 recognized 24 different malignant salivary gland cancers; the most common histologies include mucoepidermoid carcinoma (MEC), acinic cell carcinoma (ACC), adenoid cystic carcinoma (AdCC), carcinoma ex-pleomorphic adenoma (CExPA), and adenocarcinoma.[1]

Etiology

The exact etiology of salivary gland cancer is unknown. Still, various mechanisms have been proposed, including radiation, viruses (EBV and HIV), immunosuppression, ultraviolet light exposure, occupational exposures in rubber or nickel industries, prior diagnosis of medulloblastoma, prior diagnosis of basal cell carcinoma, androgen receptor expression, and genetics.[2][3][4][5][6][7][8] In studies involving Japanese survivors of the atomic bomb and patients who received radiation treatment during childhood for benign conditions, radiation exposure was identified as a significant risk factor for the development of salivary malignancies.[9][10] MEC appears to be the most common salivary gland malignancy associated with radiation exposure.[11][12] Compared to other head and neck cancers, the risk of developing malignant salivary gland tumors from exposure to tobacco and alcohol has been controversial, with several studies noting both positive association and no appreciable association. Sawabe et al found no significant association between cigarette smoking and MEC but did show a positive correlation between tobacco smoking and other malignant salivary histologies.[13][14] Chronic inflammation of the salivary glands has not been established as a risk factor. However, autoimmune conditions such as Sjogren syndrome may predispose an individual to develop a salivary gland malignancy such as lymphoma.[15][16][17][18] Although squamous cell carcinoma (SCC) of the head and neck has been linked to tobacco, alcohol, and UV exposure, the presence of primary SCC in the salivary glands is rare and does not retain the same risk factors.[19] The most significant risk factor for primary SCC of the salivary glands appears to be prior gland radiation.[20][21] 

Most melanoma cases of the major salivary glands are attributed to metastasis from cutaneous sources of the upper face and scalp.[22] However, the presence of melanoma in the parotid without any other primary sites has been reported in the literature.[23] Although the exact etiology is unknown, melanocytes have been found in the intralobular duct of the parotid gland and have been postulated to serve as the cells of origin for primary melanoma of the salivary glands.[24][25] The development of non-Hodgkin lymphoma (NHL) of the salivary glands has been associated with a prior diagnosis of the autoimmune disease, Sjogren syndrome (SS). Studies have shown that 4.3% of patients with Sjogren syndrome develop NHL within 5-10 years.[26][27]

Epidemiology

Salivary gland malignancies comprise 0.5 to 1.2% of all cancers and 5% of head and neck cancers.[28][29][30] They more commonly affect women with a male-to-female ratio of 1 to 1.5.[31] Malignant lesions are found in about 21.7% of all salivary gland neoplasms.[32][33] Most malignant cases occur in the parotid, followed by the submandibular, sublingual, and minor salivary glands.[34] The probability of malignancy in a parotid mass ranges from 15% to 32%, compared to 41% to 50% in a submandibular mass, 70% to 90% in minor salivary gland masses, and almost 100% in sublingual masses.[35] Salivary gland tumors in children are more likely to be malignant. Malignant tumors in children under 10 years old tend to be of a higher grade with poorer prognosis.[36] Salivary tumors in children older than 10 were benign in 85% of cases, similar to that of the adult population.[37] The most common pediatric malignant salivary gland tumors include MEC, adenocarcinoma, and ACC.[28][30]

The parotid gland harbors 60 to 75% of all salivary gland tumors.[38] The most common malignant tumors are MEC, AdCC, CExPA, adenocarcinoma, and SCC.[39][40] The submandibular gland harbors 10-15% of all salivary gland tumors with an equal distribution of benign and malignant neoplasms.[41] AdCC is the most common malignant neoplasm in the submandibular gland, followed by MEC and CExPA. Less common tumors include ACC, salivary duct carcinoma, epi-myoepithelial carcinoma, carcinosarcoma, oncocytic carcinoma, and SCC.[41] Malignant submandibular tumors are more common in the 6th decade with a predilection for men.[42] In the minor salivary glands, as many as 50% of tumors are malignant, most often located in the palate.[38]

Epidemiology of Specific Salivary Gland Malignancies

• MEC is the most common salivary gland malignancy in adults and children.[36] About 89% of cases are found in the parotid, followed by 8.4% in the submandibular gland and 0.4% in the sublingual gland.[43] There is an equal distribution between the sexes with a predilection for the 4th to 5th decade.[44]
• AdCC accounts for about 10% of all salivary gland neoplasms and 30% of all minor salivary gland tumors. It has a predilection for patients in the 5th to 6th decade with no difference in gender, although it tends to be more common in the submandibular gland in women.[36][45][46]
• ACC is located in the parotid gland in more than 80% of all cases, submandibular glands in 4%, and intraoral minor salivary glands in 17%. Bilateral parotid involvement is seen in 3-5% of cases.[47] It has a predilection for women and more commonly occurs in the 5th decade.[36][44][46]
• CExPA accounts for 5% to 15% of all salivary gland malignancies and can arise in up to 25% of untreated pleomorphic adenomas.[48] Malignant transformation is often seen in recurrent pleomorphic adenoma (PA), with the risk of transformation ranging from 5% to 10% for untreated pleomorphic adenomas over 15 years.[41] About 82% of cases occur in the parotid and submandibular glands, followed by 18% in the intraoral minor salivary glands.[41]
• Polymorphous Low-Grade Adenocarcinoma (PLGA) occurs almost exclusively in the minor salivary glands, with rare reports of it in the major salivary glands.[49] It is the second most common intraoral minor salivary gland malignancy after MEC.[49][50]
• Salivary Duct Carcinoma accounts for 7 to 10% of all salivary gland tumors and is often found in the parotid in older men in the 6th to 7th decades.[30][36][51] It is a very aggressive malignancy of the salivary glands.
• SCC has a predilection for men and is usually found in the parotid. They are considered rare due to the infrequent occurrence of squamous metaplasia of ductal epithelium, which is thought to be responsible for the malignant transformation.[52] The specific etiology of the malignant transformation is not known, although there is evidence implicating high-risk HPV viruses.[53] High-grade MEC and extension from an extra-parotid source are often misdiagnosed as primary SCC of the parotid. The true incidence of primary squamous cell carcinoma of the parotid is unknown due to its rarity and its frequency of being a misclassification of metastatic SCC. Evidence from the literature suggests the true incidence may be around 0.75-1%.[54] Although a range of 0.3% to 4.3% has also been cited, these higher frequencies are thought to be due to misrepresentations or misclassification of these tumors.[52][55][52]
• Primary melanoma of the salivary gland is extremely rare and accounts for 0.68% of malignant parotid neoplasms.[56] There is a predilection for males in the 6th to 7th decade.[19][57][58] Most melanoma in the parotid is due to cutaneous and mucosal metastasis from the head and neck.[59][60]
• NHL of the salivary gland accounts for less than 10% of malignant salivary gland tumors.[61][62][63] Although it encompasses less than 5% of all extranodal NHL, it is the most common extranodal lymphoma at the neck, comprising two-thirds of all cases.[64] It preferentially occurs in women and patients over 50 years old.[65] The most common variant of lymphoma associated with Sjogren Syndrome is mucosa-associated lymphoid tissue lymphoma (MALT), with 48% to 75% of all cases followed by diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma.[27][61][66] The majority of cases occur in the parotid gland.[26][67][68]

Pathophysiology

MEC arises from the epithelium of the interlobular and intralobular salivary ducts. The most common genetic finding is the chromosomal translocation t(11;19)(q21:p13), leading to the fusion of MECT1 and MAML2 genes, which is responsible for disrupting the NOTCH signaling pathway.[69][70] This translocation is found in 50% to 70% of patients with MEC and is more often seen in low-grade tumors associated with a better prognosis.[71][72] Over 50% of AdCC tumors contain the t(6;9)(q22-23;p23-24) translocation, which fuses the MYB protooncogene on chromosome 6q to the NFIB gene on chromosome 9p, resulting in an overexpression of MYB-NFIB fusion oncogene and worse prognosis.[73][74][75] ACC develops from tumorigenesis of cells responsible for acinar development, namely the reserve cells of the intercalated ducts and terminal tubules. In mice studies, inactivation of PTEN and Apc led to an upregulation of mTOR and Wnt signaling, which increased the incidence of ACC.[76] ACC in humans has also been found to have a higher mTOR expression than other salivary malignancies.[8]

The presence of biological receptors in salivary gland malignancies has recently come under investigation. Tyrosine kinase receptors such as the epidermal growth factor receptor (EGFR) are present in up to 71% of all salivary gland cancers.[77] Epidermal growth factor receptor 2 (HER2) is present in cancers derived from excretory ducts such as the salivary ducts.[78] C-kit is expressed in malignancies derived from the intercalated ducts of salivary glands such as AdCC.[79] Androgen receptor expression has been found in salivary duct carcinoma and adenocarcinoma.[77] Gonadal hormone receptors such as the estrogen and progesterone receptors have been found in benign and malignant salivary gland neoplasms.[80] Salivary duct carcinoma tends to overexpress erb-B2, which has been associated with a worse prognosis.[81][82] Epigenetic mutations involving DNA promoter methylation of tumor suppressor genes can lead to transcriptional inactivation and increase both the risk of salivary duct carcinoma and the transformation of pleomorphic adenoma into carcinoma ex pleomorphic adenoma.[83][84] The presence of SCC in the salivary glands is suspected to arise from several sources, including 1) malignant squamous portion of MEC, 2) metastasis from a cutaneous or mucosal head and neck source, 3) metastasis from distant primary carcinoma, or 4) primary squamous cell carcinoma.[19]

Approximately 4.4% to 5.2% of malignant melanoma of the parotid cases do not have a primary source.[57][58] They are suspected to be due to a metastatic cutaneous source that has subsequently regressed or metastases from an unusual mucosal site such as the sclera, nasal cavity, paranasal sinuses, or throat.[85][22][86][85] In addition, although rare, primary melanoma can develop in the parotid gland. Melanoblasts can migrate into the gland during the invagination of oral epithelium during parotid gland development.[87] In an autopsy case, Takeda et al discovered the presence of melanocytes in the basal and suprabasal layers of the interlobular ducts, which can serve as the cells of origin for primary melanoma of the parotid.[25] The development of lymphoma from Sjogren syndrome is theorized to be due to prolonged B-cell activity and survival. Sjogren syndrome is associated with excessive expression of cytokines, chemokines, and inflammatory factors such as interferon (IFN) and B-cell activating factor.[88][89] The B-cell activating factor induces the migration of T and B lymphocytes into the salivary glands to create an autoimmune reaction. The B cells start producing SS-A and SS-B antibodies, which are used to diagnose Sjogren syndrome.[27] Although the exact pathway is unknown, the constant activity of these B cells is believed to be the inciting event of lymphomagenesis in Sjogren syndrome.[90]

Histopathology

MEC is a non-encapsulated, poorly circumscribed mass with cystic components that can often be mistaken for mucoceles.[91] MEC can comprise up to 6 different types of cells, including maternal, intermediate, epidermoid, clear, columnar, and mucous. Maternal cells are the progenitors for the other cell types and have small, round nuclei with scant, basophilic cytoplasm. Intermediate cells can develop into either glandular or epidermoid cells. Epidermoid cells present with homogenous cytoplasm and occasional keratin pearls and intracellular bridges. Clear cells have watery cytoplasm with small, central nuclei. Columnar cells resemble the secretory duct cells of the salivary gland and transform into mucous cells. Mucous cells have small nuclei at the periphery with foamy, reticular cytoplasm and can occasionally develop a signet-ring appearance.[91][92] MEC can occur as low, intermediate, or high-grade disease depending on the quantity of aggressive epidermoid tissue. Low-grade MEC has well-formed cystic spaces with high glandular composition. The intermediate grade tends to have more solid nests of epidermoid and intermediate cells with less prominent cystic spaces. High-grade MEC has limited mucous cells with large amounts of solid, squamous cells that can often be misdiagnosed as squamous cell carcinoma.[93][94] When MEC arises in the submandibular gland, it behaves aggressively regardless of its histologic grading.[36] 

AdCC presents as a non-encapsulated, well-circumscribed mass with biphasic ductal and myoepithelial components and 3 distinct patterns: tubular, cribriform, and solid.[36][30] The cribriform variant presents a “Swiss-cheese” appearance, containing cylindrical pseudocysts lined with epithelial cells and hyaline material. The tubular variant consists of ducts lined by 1 to 2 layers of myoepithelial-like cells. The solid variant has solid epithelial islands with central areas of necrosis.[28][95] The solid variant is the most aggressive of the 3 and tends to hematogenous metastasis in 40-60% of cases with perineural invasion along the palatine branches, through which it can extend into the pterygopalatine fossa and cavernous sinus.[95][96][97]

ACC presents several growth patterns, including solid (most common), papillary-cystic, follicular, and microcystic.[98] Microscopically, it appears well-circumscribed by a lymphoid stroma or a capsule. Individual cells can be granulated serous-type cells, primitive tubule cells, or undifferentiated polymorphous cells.[98][99] Although ACC is usually considered a low-grade malignancy, it can undergo high-grade transformation into high-grade adenocarcinoma or undifferentiated carcinoma and present with complete loss of acinar differentiation, desmoplasia, tumor necrosis, frequent mitosis, and cervical or distant metastasis.[100][101][102]

CExPA arises from an existing pleomorphic adenoma and can histologically resemble salivary duct carcinoma, adenocarcinoma, or undifferentiated carcinoma.[48][103] Microscopically, it can present with varying extents of invasion, including intracapsular, minor extracapsular (<5 mm beyond the capsule), and wide extracapsular (>5 mm beyond the capsule). The wide extracapsular variant presents a high risk of recurrence and distant metastasis.[30][48][103]

PLGA presents as an unencapsulated mass predominantly seen on the palate, with a high concentration of minor salivary glands. Histologically, it can resemble AdCC and has an infiltrative growth pattern with a mixture of solid, cribriform, tubular, and cystic patterns.[104][105][106]

Salivary Duct Carcinoma is similar in histology to high-grade duct carcinoma of the breast.[107] It can present with cribriform, solid, cystic, or papillary growth patterns.[30]

SCC presents with intracellular keratinization, intercellular bridging, and keratin-pearl formation without any intracellular mucin.[92]

Melanoma of the parotid presents with large, rounded eosinophilic cells with a pleomorphic nucleus and prominent nuclei.[24][108] To be considered a primary melanoma of the parotid, the melanoma tumor must be intra-parotid with no lymph node tissue present and no prior excisions or evidence of malignant lesions elsewhere in the body.[109] 

NHL of the major salivary gland presents with atypical lymphocytes with invasion into the adjacent ductal epithelium, lymphoepithelial lesions, and lymphoid follicles or germinal centers.[66][110][111]

A high-grade transformation is a rare event involving a well-differentiated tumor's transformation into an aggressive, poorly differentiated, high-grade morphology that lacks any original histologic characteristics. It can be seen in AdCC, ACC, PLGA, and MEC.[112]

History and Physical

Patients often present with a history of a palpable mass that localizes to the region of the salivary glands. A detailed history should be obtained, including pain symptoms, onset and duration of the mass, growth rate, associated swallowing difficulties, and occurrence of facial weakness. Past medical history, including a history of previous skin cancers of the head and neck, surgical history, family history of malignancies, and social risk factors such as smoking, past radiation exposure, and occupational exposures, should be elicited. Physical exam should include a comprehensive head and neck exam focused on the salivary glands, cranial nerves, and cervical nodes. Malignant tumors can present as painless, fixed, or mobile masses, so distinguishing from benign tumors may be hard to distinguish. Advanced malignancies may present with pain, palatal fullness, parapharyngeal fullness, trismus, overlying skin ulceration, or fistulas. Minor salivary gland tumors can present as submucosal oral swelling with ulceration or with nasal obstruction and bleeding if they occur in the nasal cavity or nasopharynx. Minor salivary gland tumors in the pharynx or larynx can cause dysphagia, odynophagia, airway obstruction, vocal hoarseness, and dyspnea on exertion.[113] Rapid growth, pain, facial nerve paresis, and cervical lymphadenopathy are concerning signs of malignancy.[38]

Parotid malignancies presenting as large, fixed preauricular masses can be associated with cervical lymph node metastasis. Facial nerve paralysis can be seen in up to 12 to 15% of cases and is often associated with AdCC, MEC, and salivary duct carcinoma.[114] Submandibular malignancies often present as painless neck masses in the submandibular triangle of the neck. Malignant lesions here are often firm and lobulated, may be fixed to skin or deeper tissues, and may exhibit associated paralysis of the facial nerve's lingual nerve, hypoglossal nerve, or marginal mandibular branch.[115] Sublingual gland malignancies can present as painless, non-ulcerated masses on the floor of the mouth, although about 50% of cases can present with pain and numbness.[116] As previously mentioned, minor salivary gland malignant tumors tend to present along the upper aerodigestive tract as asymptomatic submucosal masses, rare ulceration, and occasional upper airway narrowing.[36]

Specific presentations peculiar to the salivary malignancies include:

• MEC often presents as an asymptomatic, firm mass with occasional pain and facial paralysis.[36] First-bite syndrome has been associated with MEC.[114]
• AdCC presents as a slow-growing, solid mass with pain secondary to perineural and extra-parenchymal invasion. Cervical lymph node metastasis occurs at a rate of 20% at presentation and is more common with submandibular tumors.[36] First-bite syndrome has also been associated with AdCC.[117]
• ACC presents as a slow-growing, solitary mass with occasional pain.[36]
• PLGA presents as a well-circumscribed mass with pain; ulceration is present in 8% of cases.[36]
• CExPA commonly presents in a patient with a history of a long-standing parotid mass characterized by a sudden increase in size. It can be associated with pain and nerve palsy in up to 30% of cases.[118]
• Salivary duct carcinoma presents as a firm, poorly defined mass with the invasion of the surrounding glandular and soft tissue, resulting in associated pain and facial nerve palsy. More than 50% of patients display cervical metastasis at initial presentation.[36]
• SCC can present as a long-standing mass with sudden rapid growth, pain, facial nerve palsy, or overlying skin ulceration.[119]
• Melanoma of the parotid gland can present as an indolent and firm preauricular mass with infiltrative growth resulting in pain, facial nerve palsy, and overlying dermal changes such as ulceration and erythema.[19][120] 
• NHL of the salivary gland can present with unilateral or bilateral swelling of the parotid gland, cervical lymphadenopathy, splenomegaly, vasculitis, and palpable purpura.[27]

Evaluation

Evaluation Options Include

Ultrasound is the first non-invasive option for evaluating major salivary gland tumors, especially superficial parotid lesions. It can help localize tumors, distinguish solid masses from cystic collections, and help guide fine-needle aspiration biopsy. Heterogenous echogenicity, local invasion, poorly defined margins, and lymphadenopathy are sonographic signs of malignancy.[121][122]

Computerized tomography (CT). Conventional CT can evaluate tumor extent, bony infiltration, and lymphadenopathy. However, it is limited by the dental artifact and has a poor soft-tissue resolution, especially for MEC, AdCC, and ACC, leading to underestimating the lesion.[30]

Magnetic resonance imaging (MRI). MRI is recommended to assess tumor extent, soft tissue invasion, and nerve involvement for lesions in the deep parotid lobe, sublingual glands, and minor salivary glands. MRI can be performed to detect the facial nerve branches and their interface with surrounding soft tissue for surgical planning. MRI has a higher sensitivity and specificity than CT in detecting perineural spread, especially for AdCC.[123] Heterogenous contrast enhancement, local soft tissue invasion, poorly defined margins, hypointensity on T2-weighted imaging, and lymphadenopathy are characteristics of malignancy.[121][124] Diffusion-weighted MRI can quantify the diffusion properties of water in tumor tissue into the apparent diffusion coefficient (ADC) that can help distinguish malignant tumors from benign tumors. Salivary gland malignancies have significantly smaller ADC than benign tumors, although the ADC of Warthin’s tumor is even smaller than that of malignancies due to excessive lymphoid tissue resembling lymphoma.[125][126]

Positron emission tomography (PET). The role of PET is to detect locoregional and distant metastasis. Compared with conventional CT, PET is more accurate in demonstrating tumor extension, nodal involvement, local recurrence, and distant metastasis due to the tissues’ higher standardized uptake values.[127][128] However, PET cannot differentiate between benign and malignant tumors because benign tumors (such as pleomorphic adenoma and Warthin’s tumor) exhibit high glucose uptake values due to cells with high mitochondrial content.[129][130]

Biopsy. Imaging is unable to completely distinguish between benign and malignant lesions. Therefore, obtaining histological samples is key to determining the next steps in management. An incisional biopsy can be used for minor salivary glands in the oral cavity but is not recommended for parotid lesions due to the risk of damage to the facial nerve and the possibility of tumor seeding. Hence, ultrasound-guided fine-needle aspiration (FNA) is preferred.[131] FNA's sensitivity and specificity in differentiating between benign and malignant lesions are 80% and 97%, respectively.[132] However, FNA may falter in determining the specific malignant subtype and tumor grade.[133] 

An ultrasound-guided core needle biopsy can obtain larger tissue specimens with histologic architecture, improving tumor grade recognition to allow further subtyping. The diagnosis and classification of the specific type of lymphoma of the salivary glands require histological cellular architecture.[134] Disadvantages of core biopsy include more pain, increased risk of facial nerve injury, and hematoma.[135] The intraoperative frozen section has a sensitivity and specificity of 90% and 99%, distinguishing between benign and malignant lesions.[136]

Treatment / Management

Surgical excision with negative margins is the mainstay of treatment for all salivary gland malignancies. Despite preoperative attempts to obtain a diagnosis through a needle biopsy, histological diagnosis may sometimes not be available until surgery, when frozen specimens can be analyzed. The extent of surgery and the need for neck dissection or adjuvant radiotherapy depend on the malignancy's subtype, grade, and stage.[30] Adjuvant radiation therapy is recommended after surgical excision to improve locoregional control in cases with positive margins, cervical metastases, advanced cancer stage, aggressive histology or grade, perineural invasion, lymphovascular invasion, or extra-glandular extension.[137][138][139][140][141] Primary radiation therapy is usually reserved for patients with unresectable disease, metastatic disease, or poor surgical candidacy.[142][143] Chemotherapy and biologically targeted therapy are the standard of care for lymphoma but have limited roles in the other malignancies, often utilized in the palliative setting with partial response.[27][34] More prospective research and clinical trials are needed before chemotherapy and targeted therapies become routine clinical tools in managing salivary malignancies.[34][113]

Differential Diagnosis

The differential diagnosis for malignant salivary gland tumors are as follows:

• Benign salivary lesions (pleomorphic adenoma, myoepithelioma, basal cell adenoma, Warthin's tumor, oncocytoma, canalicular adenoma, sebaceous adenoma, lymphadenoma, inverted ductal papilloma, intraductal papilloma, cystadenoma)
• Benign salivary cysts
• Sialadenitis
• Sialoliths
• Lymphadenopathy (from infectious or inflammatory causes)
• Tuberculosis
• Mononucleosis
• Chronic Sclerosing Sialadenitis (Küttner tumor, which is more common in the submandibular gland)
• First Branchial cleft cysts
• Lymphoepithelial cysts (especially in immunocompromised patients such as HIV patients)
• Metastases from tumors of other body sites

Surgical Oncology

Wide local excision is the first-line treatment for all malignant salivary gland tumors. Superficial parotidectomy is the standard treatment of choice for the removal of benign and malignant parotid tumors in the superficial lobe with preservation of the facial nerve.[38] The procedure involves elevating a skin flap over the parotid capsule, identifying the facial nerve trunk and dissecting along all its branches, with preservation of the facial nerve branches that are uninvolved by malignancy, and subsequent removal of the superficial lobe of the parotid while maintaining the integrity of the tumor pseudocapsule.[38] A total parotidectomy is required for advanced or deep lobe lesions. If the facial nerve is infiltrated, a radical total parotidectomy with facial nerve sacrifice and reconstruction is required.[144] For tumors abutting the facial nerve, the tumor can be peeled off and followed with adjuvant radiotherapy to clear microscopic disease.[144][145]

The disadvantages of superficial parotidectomy include excessive resection of parotid tissue, leading to loss of parotid function, and the risk of facial nerve paralysis due to complete facial nerve dissection. For low-grade or smaller lesions located in the lateral or latero-inferior part of the superficial lobe, the partial superficial parotidectomy, where the tumor is resected with a normal margin of parotid tissue with the facial nerve dissected only in the vicinity of the tumor, has been proposed.[146][147] A comparison of the 2 techniques was studied by Roh et al who found partial superficial parotidectomy to have better cosmesis, improved sensory and salivary functions, less facial nerve weakness, and no difference in recurrence rate.[148] Excision of the entire submandibular gland should be performed for any submandibular malignant lesions or if the final diagnosis cannot be confirmed.[149] The procedure involves elevating subplatysmal flaps over the submandibular gland, identifying and ligating the facial vessels and submandibular duct, preserving the lingual and hypoglossal nerves, and removing the gland while maintaining the integrity of the tumor.

Cervical (neck) metastases in salivary gland malignancies range from 10% to 40%, depending on tumor grade, location, histologic subtype, and size.[150][151] Cervical metastasis is present in 35% to 62% of high-grade tumors and 0% to 15% of low-grade tumors.[152] Minor salivary gland tumors in the pharynx or larynx present with neck metastases in 30 to 47% of cases.[153][154] Histologies such as salivary duct carcinoma, adenocarcinoma, or high-grade MEC have a rate of neck metastasis ranging from 40% to 80%.[150][153][155][156] In patients with a clinically negative neck, occult metastasis has been identified in 12% to 50% of cases.[151][157] The presence of occult metastasis has been associated with tumor grade, advanced patient age, lymphatic invasion, and extra-parotid tumor extension.[158]

Chisholm et al analyzed the anatomical distributions of positive nodal metastasis in parotid cancers showing only ipsilateral involvement. They found up to 28% in level I, 59% in level II, 52% in level II, 38% in level IV, and 42% in level IV. About 33% of cases displayed skip metastasis to level V, which led to the recommendation of a complete ipsilateral neck dissection from level I-V for parotid malignancies with positive neck disease.[159][152][160] In malignancies with clinically negative neck disease, elective neck dissection is recommended for high-grade T3/T4 tumors, facial nerve paralysis, age >54 years, extra-glandular extension, and lymphatic invasion.[71][161]

For submandibular and minor salivary gland carcinomas, clinical cervical metastasis is present in 8 to 20% of cases. It increases to 41% after neck dissection, with the most frequently involved nodes occurring in levels I-III for submandibular gland malignancies.[42][139][151] Thus, a supra-omohyoid neck dissection (level I to III) is recommended.[115][153][162] Minor salivary gland carcinomas from the pharynx or larynx should undergo neck dissection from levels II to IV.[154]

Radiation Oncology

Radiation therapy (RT) to the primary site is recommended in the postoperative or adjuvant setting to improve locoregional control and survival, especially in high-grade histology, advanced stage of the disease, positive or close margins, perineural invasion, lymphovascular invasion, cervical lymph node metastases, or extra-glandular extension.[137][138][139][140][141] A total dose of 60-66 Gy divided into daily fractions of 2 Gy over 6 weeks has been recommended. Elective neck radiation for clinically negative neck disease is optional. Positive neck disease can be irradiated with 50-60 Gy.[113] Studies show 10-year local control rates ranging from 83% to 91% for combining surgery and adjuvant radiation therapy in advanced-stage disease.[139][163][164]

Primary radiation therapy is advised only in selective scenarios, including unresectable disease, poor surgical candidacy, unacceptable functional and cosmetic comorbidities from surgery, and palliation.[139][143] Mendenhall et al. showed that the 10-year locoregional control rate in the setting of primary radiation therapy was dependent on the disease stage, ranging from 70% for stage I-III down to 24% for stage IV. Less than 20% of patients with stage IV disease are cured with radiation therapy alone.[143] Neutron therapy has better locoregional control rates than photon therapy in unresectable cases, but there appears to be no difference in long-term survival.[165]

Medical Oncology

Chemotherapy is the mainstay of treatment for lymphoma of the salivary gland. Patients with MALT lymphoma are commonly treated with rituximab, 2-chlorodeoxyadenosine, fludarabine, and chlorambucil-cyclophosphamide.[134]  Rituximab is a chimeric monoclonal antibody that binds to the surface CD20 proteins of B cells, triggering cellular death.[27] For cases of DLBCL transformation, the standard chemotherapeutic regimen is cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) with rituximab.[166]

The benefit of chemotherapy is limited for other salivary gland malignancies. Combining chemotherapeutic agents (such as carboplatin, paclitaxel, fluorouracil, and hydroxyurea) with adjuvant radiation has shown moderate benefit with 5-year locoregional control rates of 90% to 95% reported in some studies. However, there was no overall survival benefit compared with non-responding patients.[167][168][169] Other studies have failed to demonstrate any significant locoregional control or survival benefit in incorporating chemotherapy into primary or adjuvant RT.[34][170][171] In patients who are not surgical or radiation candidates, palliative chemotherapy involving cisplatin, paclitaxel, and gemcitabine has been shown to have a partial response in 20 to 25% of non-AdCC cases and <10% of AdCC cases.[172][173]

Targeted therapies against C-Kit (Imatinib), HER2 (Trastuzumab), EGFR (Cetuximab), and mTOR (Temsirolimus) have gained popularity due to the expression of biological receptors in several malignant salivary tumors. However, response rates have not been superior. This is likely due to a discrepancy between protein overexpression and gene mutation and loss of tumor suppressor PTEN that interferes with target therapy responsiveness.[174][175][176][177][178][179]

Staging

Clinical Staging 

Major salivary gland carcinomas are staged according to the TNM system of the American Joint Committee on Cancer (AJCC) 8 edition.[113][180][181]

Table

T Category Tumor Size and Characteristics

Staging for NHL based on the Lugano classification.[182]

Table

Stage Nodal Involvement

Prognosis

Salivary gland malignancies have a wide spectrum of prognoses due to the heterogeneous array of histologies. In general, the prognosis of salivary malignancies is better for children and adolescents than adults due to lower frequencies of cervical metastasis, absence of local soft tissue invasion, and more differentiated histologies. The 5-year overall survival for children after surgical treatment is 85% compared with 60% for adults.[183][184] Regardless of malignant subtype, negative prognostic factors for survival include advanced age, high-stage disease, high-grade histology, cervical metastasis, male gender, presence of pain, facial nerve involvement, perineural invasion, local soft tissue invasion, positive or close margins, distant metastasis, and comorbidities.[143][185][186][187][188][189][190][191] Smoking and alcohol statuses were controversial, with some studies showing no significant influence on overall survival or disease-free survival [192][193], whereas other studies found them to be poor prognostic factors.[3][13] Distant metastasis most commonly involves the lungs (40% to 91%) followed by bone (13% to 40%), liver (4% to 19%), soft tissue (9%), distant nodal basins (8%), and the brain (4% to 7%).[194] Distant metastasis is the main cause of mortality for malignant salivary glands.[113]

Overexpression of epidermal growth factor receptor (EGRF) and human epidermal growth factor receptor 2 (HER2) have been identified in several salivary gland malignancies, such as salivary duct carcinoma. They tend to predict a higher incidence of cervical metastasis and worse survival.[30] The absence of c-kit expression in AdCC is correlated with poorer prognosis.[155]

• MEC: Low-grade MEC, especially cases with the MECT1-MAML2 gene fusion, have a good prognosis with a 5-year survival rate of more than 90%. However, the high-grade squamous variant of MEC has a high tendency for recurrence, cervical metastasis, and distant metastasis, with 5-year survival as low as 30% to 41.6%.[187][195] About 33% of patients with MEC were found to have regional metastasis, of which 85% exhibited a high-grade primary tumor.[196] The 5-year survival has been shown to range from 75% to 96%.[197][198][199] The overall 10-year survival rate for MEC is about 53%.[200]

• AdCC: Distant metastasis in AdCC takes a prolonged course and is often more common than cervical metastasis.[41] The rate of distant metastasis ranges from 25% to 55%, whereas the local recurrence rate ranges from 15% to 85%. Distant metastasis from submandibular AdCC most commonly involves the lungs, and regional metastasis from submandibular AdCC is more common than other major salivary glands due to the proximity of the draining lymph nodes.[200][201] The 5-year survival rate cited in the literature is unreliably optimistic at 60% to 90% due to the prolonged, indolent growth pattern of AdCC that can ultimately result in poor disease-free survival of 10% to 20% at 10 to 15 years. The solid pattern histology has the worst prognosis.[36][200][202][203]

• ACC: Overall survival is influenced by male gender, age >45 years, tumor size larger than 3 cm, and presence of distant metastasis.[204] Cervical neck metastasis occurs in 6-10% and distant metastasis in 12% to 15% of cases.[205][206][207][208] The survival rate at 5-years is 75% to 96% and at 20-years is 56%.[99][206][209]

• CExPA: CExPA can display a wide range of recurrence and survival rates depending on the extent of differentiation and invasion. Tumors with wide extracapsular invasion beyond 5 mm of the capsule present a high risk of recurrence and distant metastasis.[30][48][103]. Regional metastasis in CExPA reduces the 5-year survival rate from 67% to 16%.[210] Clinical neck metastasis is present in 33% of patients with CExPA, and occult neck metastasis in 16% of patients.[211] The 5-year survival ranges from 30% to 96%, depending on the histology variant.[48][212] The overall 10-year survival rate for CExPA is 62%.[200]

• PLGA: Local recurrence is reported in 9-33% of cases, with cervical lymph node metastasis present in 6% to 35% of cases and distant metastasis at 1%.[213] PLGA has an indolent growth pattern known to recur for decades after initial treatment.[49] The 5-year survival rate ranges from 75% to 100%.[213][214][215]

• Salivary duct carcinoma: Salivary duct carcinoma presents with perineural and lymphovascular invasion in 60% and 30% of cases, respectively.[30] Cervical lymph node metastasis is seen in up to 60% of cases, with 50% of patients already having distant metastasis at the time of presentation.[155][216] The 5-year overall survival ranges from 20% to 50%.[51][113][216][113][217] The majority of patients die within 3 years of diagnosis.[51]

• SCC: The overall 5-year survival of primary SCC of the salivary glands is influenced based on tumor staging and ranges from 50% to 80% for early-stage tumors and 15% for advanced-stage tumors.[20][21][55] Advanced age, facial palsy, and regional nodal metastasis were poor prognostic factors.[55][218]

• Melanoma: The prognosis of melanoma of unknown primary is controversial, with some studies stating no difference compared with typical melanoma at the same stage.[58][86] However, Wang et al showed patients with salivary melanoma of unknown primary had improved 5-year survival at 38.5% compared with 14.2% for patients with known primary tumor sites.[22] Furthermore, melanoma patients with unknown primary sites were found to have a longer disease-free survival period (4.2 years vs. 2.6 years).[22]

• NHL: Patients with MALT have a 3-year overall survival of 80%.[134] Patients with more aggressive DLBCL transformation have a 3-year overall survival ranging from 37% to 100%.[166] Poor prognostic factors include age over 60, elevated serum lactate dehydrogenase level, more than 1 extranodal site, and stage III or IV disease.[219]

Complications

The incidence of temporary facial nerve palsy after parotidectomy ranges from 10% to 65%, with permanent paralysis seen in less than 5%.[146][220][221] The incidence of Frey syndrome after parotidectomy varies widely from 2% to 80% due to the time interval since surgery as well as the surveillance criteria from the surgeons.[222] Treatment for Frey syndrome includes antiperspirant ointment, botulinum toxin A injections, and barrier flaps such as superficial musculoaponeurotic system flap, temporoparietal flap, sternocleidomastoid flap, anterolateral thigh flap, or thick skin flaps.[222][223][224][225] Additional complications from surgical resection include sialocele, salivary fistula, neuromas of the great auricular nerve, and preauricular skin anesthesia.[113] Patients who undergo submandibular gland resection or neck dissection for cervical lymph node metastasis have a risk of neurological damage to the spinal accessory, phrenic, hypoglossal, lingual, vagus, sympathetic trunk, and the marginal mandibular branch of the facial nerve.[226][227][228] Complications from radiation include sensorineural hearing loss, chronic otitis media/externa, otalgia, skin erythema, mucositis, dysphagia, dysgeusia, xerostomia, soft tissue fibrosis, osteoradionecrosis, and radiation-induced malignancy.[34][113] In a study, approximately 36% of patients were found to develop hearing loss of 10 dB or higher at 4kHz.[229] Mandibular osteoradionecrosis (<2%) and radiation-induced malignancy (1%) at 10 to 25 years are rare complications.[113][230][231][232]

Postoperative and Rehabilitation Care

Postoperative surveillance aims to detect locoregional recurrence and manage any treatment complications that may arise. Surgery and radiation can result in long-term swallowing difficulties (xerostomia, mucositis, trismus), as well as cosmetic defects from facial nerve paralysis. Early intervention for facial nerve reconstruction and rehabilitation and consultation with speech pathologists for swallowing difficulties is vital for allowing the patient to re-integrate as much as possible into their pre-treatment functional status and improve their quality of life.[226][233][234] Over 70% of recurrences occur within the first 3 years of treatment, except for low-grade malignancies and AdCC. According to the National Comprehensive Cancer Network (NCCN) guidelines for post-treatment surveillance, patients should receive regular follow up every 1 to 3 months in the 1 year after treatment, every 2-6 months in the 2 years, every 4-8 months in the 3 to 5 years, and every 12 months after the 5 years.[235] All salivary gland malignancies require post-treatment surveillance for up to 20 years (especially AdCC due to its propensity for delayed recurrences or metastases). Annual chest imaging should be performed for high-grade lesions and submandibular gland tumors due to the high risk of pulmonary metastasis. Thyroid hormones should be monitored every 6-12 months for neck radiation patients.[113]

Consultations

An interprofessional team would need to diagnose and manage salivary malignancies, including an otolaryngologist, general surgeon, plastic or reconstructive surgeon, radiation oncologist, medical oncologist, speech-language pathologist, psychologist, and primary care physician.

Deterrence and Patient Education

Patients should be educated on the risk factors for developing salivary gland tumors and counseled to avoid exposure to these risks as much as possible. Patients and their families should be educated on the different treatment options and timelines, including surgical resection, radiation therapy, and chemotherapy. Patients and parents should be counseled on the possible risks and complications of all treatment modalities, and their comorbidities should be fully assessed by their primary care physicians to determine if they are candidates for surgical resection. Long-term follow-up is crucial for salivary malignancies and must be emphasized to patients, given the indolent growth pattern of certain pathologies such as AdCC.

Enhancing Healthcare Team Outcomes

Patients with salivary malignancies should be managed by a multidisciplinary team of otolaryngologists, plastic surgeons, general surgeons, pathologists, radiation oncologists, medical oncologists, speech-language pathologists, psychologists, and primary care physicians. Salivary malignancies present with varying histologies and severities and often require multimodal therapy involving surgery, radiation, and chemotherapy. Close communication and collaboration between the surgeons, radiation oncologists, and medical oncologists can provide a tailored approach for each patient. Difficulties in swallowing can occur from acute radiation toxicity. Patients may need a consultation with general surgery for gastric tube placement to ensure optimal nutrition perioperatively and for the duration of any adjuvant therapy. The speech-language pathologist's early post-treatment intervention can help patients regain pre-treatment function to prevent malnutrition and dependence on enteral feeding. Recurrence of salivary malignancies can occur several years, even decades, after initial treatment. Thus, the otolaryngologist, medical and radiation oncologists, and primary care physician's routine close follow-up is strongly recommended. Finally, patients may develop visible surgical scarring and facial nerve paralysis associated with depression, social anxiety, and social avoidance. Formal peer support groups and consultation with a psychologist can aid patients in addressing these latter concerns.

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Disclosure: Allen Young declares no relevant financial relationships with ineligible companies.

Disclosure: Oluwafunmilola Okuyemi declares no relevant financial relationships with ineligible companies.