Malignant Salivary Gland Tumors

Allen Young; Oluwafunmilola Okuyemi

Malignant Salivary Gland Tumors

Author: Allen Young Editor: Oluwafunmilola T. Okuyemi Updated: 1/12/2023 5:53:17 PM

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

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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](B3)

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]

T Category	Tumor Size and Characteristics
Tx	Primary tumor cannot be assessed
Tis	Carcinoma in-situ
T0	No evidence of primary
T1	Tumor <2 cm without extra-parenchymal extension
T2	Tumor 2-4 cm without extra-parenchymal extension
T3	Tumor >4cm and or tumor has an extra-parenchymal extension
T4a	Tumor invades skin, mandible, external auditory canal, and/or facial nerve
T4b	Tumor invades the skull base, pterygoid plates, or encases the carotid artery
Clinical Node Category	Node Criteria
cNx	Regional lymph node cannot be assessed
cN0	No regional lymph node metastasis
cN1	Ipsilateral single metastatic lymph node <3 cm and Extra-nodal extension (ENE) negative
cN2a	Ipsilateral single metastatic node >3 cm but <6 cm, ENE negative
cN2b	Metastatic multiple ipsilateral nodes >6 cm, ENE negative
cN2c	Metastatic bilateral or contralateral lymph nodes <6 cm, ENE negative
cN3a	Metastatic lymph node <6 cm, ENE negative
cN3b	Metastasis in any lymph node with ENE positive
Metastasis Category	Metastasis Criteria
Mx	Metastasis cannot be assessed
M0	No distant metastasis
M1	Distant metastasis identified

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

Stage	Nodal Involvement	Extra-nodal Involvement
Stage 1	1 node or group of adjacent nodes	Single extra-nodal lesion without nodal involvement
Stage 2	2 or more nodal groups on the same side of the diaphragm	Stage 1 or 2 with limited contiguous extra-nodal spread
Stage 3	Nodes on both sides of the diaphragm, nodes above diaphragm with spleen involvement	N/A
Stage 4	Wide non-contiguous spread beyond lymph system to bone, liver, lung	N/A

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.

References

[1]

Boukheris H, Curtis RE, Land CE, Dores GM. Incidence of carcinoma of the major salivary glands according to the WHO classification, 1992 to 2006: a population-based study in the United States. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 2009 Nov:18(11):2899-906. doi: 10.1158/1055-9965.EPI-09-0638. Epub 2009 Oct 27 [PubMed PMID: 19861510]

[2]

Goldstein AM, Yuen J, Tucker MA. Second cancers after medulloblastoma: population-based results from the United States and Sweden. Cancer causes & control : CCC. 1997 Nov:8(6):865-71 [PubMed PMID: 9427429]

Level 2 (mid-level) evidence

[3]

Horn-Ross PL, Ljung BM, Morrow M. Environmental factors and the risk of salivary gland cancer. Epidemiology (Cambridge, Mass.). 1997 Jul:8(4):414-9 [PubMed PMID: 9209856]

Level 2 (mid-level) evidence

[4]

Milán T,Pukkala E,Verkasalo PK,Kaprio J,Jansén CT,Koskenvuo M,Teppo L, Subsequent primary cancers after basal-cell carcinoma: A nationwide study in Finland from 1953 to 1995. International journal of cancer. 2000 Jul 15; [PubMed PMID: 10861488]

Level 2 (mid-level) evidence

[5]

Fan CY, Wang J, Barnes EL. Expression of androgen receptor and prostatic specific markers in salivary duct carcinoma: an immunohistochemical analysis of 13 cases and review of the literature. The American journal of surgical pathology. 2000 Apr:24(4):579-86 [PubMed PMID: 10757407]

Level 3 (low-level) evidence

[6]

Nasser SM, Faquin WC, Dayal Y. Expression of androgen, estrogen, and progesterone receptors in salivary gland tumors. Frequent expression of androgen receptor in a subset of malignant salivary gland tumors. American journal of clinical pathology. 2003 Jun:119(6):801-6 [PubMed PMID: 12817426]

[7]

Schwarz-Furlan S, Brase C, Stockmann P, Furlan I, Hartmann A. [Hereditary head and neck tumors]. Der Pathologe. 2010 Oct:31(6):477-84. doi: 10.1007/s00292-010-1359-1. Epub [PubMed PMID: 20844882]

[8]

Ettl T, Schwarz-Furlan S, Haubner F, Müller S, Zenk J, Gosau M, Reichert TE, Zeitler K. The PI3K/AKT/mTOR signalling pathway is active in salivary gland cancer and implies different functions and prognoses depending on cell localisation. Oral oncology. 2012 Sep:48(9):822-30. doi: 10.1016/j.oraloncology.2012.02.021. Epub 2012 Mar 21 [PubMed PMID: 22445095]

[9]

Belsky JL, Tachikawa K, Cihak RW, Yamamoto T. Salivary gland tumors in atomic bomb survivors, Hiroshima-Nagasaki, 1957 to 1970. JAMA. 1972 Feb 14:219(7):864-8 [PubMed PMID: 5066669]

[10]

Schneider AB, Favus MJ, Stachura ME, Arnold MJ, Frohman LA. Salivary gland neoplasms as a late consequence of head and neck irradiation. Annals of internal medicine. 1977 Aug:87(2):160-4 [PubMed PMID: 889197]

[11]

Rice DH, Batsakis JG, McClatchey KD. Postirradiation malignant salivary gland tumor. Archives of otolaryngology (Chicago, Ill. : 1960). 1976 Nov:102(11):699-701 [PubMed PMID: 985205]

Level 3 (low-level) evidence

[12]

Boukheris H, Ron E, Dores GM, Stovall M, Smith SA, Curtis RE. Risk of radiation-related salivary gland carcinomas among survivors of Hodgkin lymphoma: a population-based analysis. Cancer. 2008 Dec 1:113(11):3153-9. doi: 10.1002/cncr.23918. Epub [PubMed PMID: 18823043]

[13]

Hayes RB,Bravo-Otero E,Kleinman DV,Brown LM,Fraumeni JF Jr,Harty LC,Winn DM, Tobacco and alcohol use and oral cancer in Puerto Rico. Cancer causes [PubMed PMID: 10334639]

Level 2 (mid-level) evidence

[14]

Sadetzki S, Oberman B, Mandelzweig L, Chetrit A, Ben-Tal T, Jarus-Hakak A, Duvdevani S, Cardis E, Wolf M. Smoking and risk of parotid gland tumors: a nationwide case-control study. Cancer. 2008 May 1:112(9):1974-82. doi: 10.1002/cncr.23393. Epub [PubMed PMID: 18361448]

Level 2 (mid-level) evidence

[15]

Licitra L, Grandi C, Prott FJ, Schornagel JH, Bruzzi P, Molinari R. Major and minor salivary glands tumours. Critical reviews in oncology/hematology. 2003 Feb:45(2):215-25 [PubMed PMID: 12604131]

[16]

Spitz MR, Tilley BC, Batsakis JG, Gibeau JM, Newell GR. Risk factors for major salivary gland carcinoma. A case-comparison study. Cancer. 1984 Nov 1:54(9):1854-9 [PubMed PMID: 6478421]

Level 3 (low-level) evidence

[17]

Muscat JE,Wynder EL, A case/control study of risk factors for major salivary gland cancer. Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery. 1998 Feb; [PubMed PMID: 9482552]

Level 2 (mid-level) evidence

[18]

Spitz MR, Fueger JJ, Goepfert H, Newell GR. Salivary gland cancer. A case-control investigation of risk factors. Archives of otolaryngology--head & neck surgery. 1990 Oct:116(10):1163-6 [PubMed PMID: 2206501]

Level 2 (mid-level) evidence

[19]

Taxy JB. Squamous carcinoma in a major salivary gland: a review of the diagnostic considerations. Archives of pathology & laboratory medicine. 2001 Jun:125(6):740-5 [PubMed PMID: 11371224]

Level 3 (low-level) evidence

[20]

Shemen LJ, Huvos AG, Spiro RH. Squamous cell carcinoma of salivary gland origin. Head & neck surgery. 1987 Mar-Apr:9(4):235-40 [PubMed PMID: 3667298]

Level 2 (mid-level) evidence

[21]

Spitz MR, Batsakis JG. Major salivary gland carcinoma. Descriptive epidemiology and survival of 498 patients. Archives of otolaryngology (Chicago, Ill. : 1960). 1984 Jan:110(1):45-9 [PubMed PMID: 6689907]

[22]

Wang BY, Lawson W, Robinson RA, Perez-Ordonez B, Brandwein M. Malignant melanomas of the parotid: comparison of survival for patients with metastases from known vs unknown primary tumor sites. Archives of otolaryngology--head & neck surgery. 1999 Jun:125(6):635-9 [PubMed PMID: 10367919]

Level 2 (mid-level) evidence

[23]

CONLEY J,ARENA S, PAROTID GLAND AS A FOCUS OF METASTASIS. Archives of surgery (Chicago, Ill. : 1960). 1963 Nov; [PubMed PMID: 14058839]

[24]

Prayson RA, Sebek BA. Parotid gland malignant melanomas. Archives of pathology & laboratory medicine. 2000 Dec:124(12):1780-4 [PubMed PMID: 11100057]

Level 2 (mid-level) evidence

[25]

Takeda Y. Melanocytes in the human parotid gland. Pathology international. 1997 Aug:47(8):581-3 [PubMed PMID: 9293542]

Level 3 (low-level) evidence

[26]

Voulgarelis M, Dafni UG, Isenberg DA, Moutsopoulos HM. Malignant lymphoma in primary Sjögren's syndrome: a multicenter, retrospective, clinical study by the European Concerted Action on Sjögren's Syndrome. Arthritis and rheumatism. 1999 Aug:42(8):1765-72 [PubMed PMID: 10446879]

Level 2 (mid-level) evidence

[27]

Turner MD. Salivary gland disease in Sjögren's syndrome: sialoadenitis to lymphoma. Oral and maxillofacial surgery clinics of North America. 2014 Feb:26(1):75-81. doi: 10.1016/j.coms.2013.09.006. Epub [PubMed PMID: 24287195]

[28]

Batsakis JG, Regezi JA. The pathology of head and neck tumors: salivary glands, part 1. Head & neck surgery. 1978 Sep-Oct:1(1):59-68 [PubMed PMID: 756396]

[29]

Speight PM,Barrett AW, Salivary gland tumours. Oral diseases. 2002 Sep; [PubMed PMID: 12363107]

[30]

Ettl T, Schwarz-Furlan S, Gosau M, Reichert TE. Salivary gland carcinomas. Oral and maxillofacial surgery. 2012 Sep:16(3):267-83. doi: 10.1007/s10006-012-0350-9. Epub 2012 Jul 29 [PubMed PMID: 22842859]

[31]

Al-Khateeb TH, Ababneh KT. Salivary tumors in north Jordanians: a descriptive study. Oral surgery, oral medicine, oral pathology, oral radiology, and endodontics. 2007 May:103(5):e53-9 [PubMed PMID: 17368055]

Level 2 (mid-level) evidence

[32]

de Oliveira FA, Duarte EC, Taveira CT, Máximo AA, de Aquino EC, Alencar Rde C, Vencio EF. Salivary gland tumor: a review of 599 cases in a Brazilian population. Head and neck pathology. 2009 Dec:3(4):271-5. doi: 10.1007/s12105-009-0139-9. Epub 2009 Sep 16 [PubMed PMID: 20596844]

Level 3 (low-level) evidence

[33]

Satko I,Stanko P,Longauerová I, Salivary gland tumours treated in the stomatological clinics in Bratislava. Journal of cranio-maxillo-facial surgery : official publication of the European Association for Cranio-Maxillo-Facial Surgery. 2000 Feb; [PubMed PMID: 10851675]

Level 2 (mid-level) evidence

[34]

Thomson DJ, Slevin NJ, Mendenhall WM. Indications for Salivary Gland Radiotherapy. Advances in oto-rhino-laryngology. 2016:78():141-7. doi: 10.1159/000442134. Epub 2016 Apr 12 [PubMed PMID: 27093301]

Level 3 (low-level) evidence

[35]

Spiro RH. Management of malignant tumors of the salivary glands. Oncology (Williston Park, N.Y.). 1998 May:12(5):671-80; discussion 683 [PubMed PMID: 9597678]

[36]

Bradley PJ. Frequency and Histopathology by Site, Major Pathologies, Symptoms and Signs of Salivary Gland Neoplasms. Advances in oto-rhino-laryngology. 2016:78():9-16. doi: 10.1159/000442120. Epub 2016 Apr 12 [PubMed PMID: 27092790]

Level 3 (low-level) evidence

[37]

Stevens E,Andreasen S,Bjørndal K,Homøe P, Tumors in the parotid are not relatively more often malignant in children than in adults. International journal of pediatric otorhinolaryngology. 2015 Aug; [PubMed PMID: 25953456]

[38]

Carlson ER, McCoy JM. Margins for Benign Salivary Gland Neoplasms of the Head and Neck. Oral and maxillofacial surgery clinics of North America. 2017 Aug:29(3):325-340. doi: 10.1016/j.coms.2017.03.009. Epub [PubMed PMID: 28709532]

[39]

Spiro RH. Salivary neoplasms: overview of a 35-year experience with 2,807 patients. Head & neck surgery. 1986 Jan-Feb:8(3):177-84 [PubMed PMID: 3744850]

Level 3 (low-level) evidence

[40]

Gallo O, Franchi A, Bottai GV, Fini-Storchi I, Tesi G, Boddi V. Risk factors for distant metastases from carcinoma of the parotid gland. Cancer. 1997 Sep 1:80(5):844-51 [PubMed PMID: 9307182]

Level 2 (mid-level) evidence

[41]

Ord RA, Ghazali N. Margin Analysis: Malignant Salivary Gland Neoplasms of the Head and Neck. Oral and maxillofacial surgery clinics of North America. 2017 Aug:29(3):315-324. doi: 10.1016/j.coms.2017.03.008. Epub 2017 May 24 [PubMed PMID: 28551337]

[42]

Camilleri IG, Malata CM, McLean NR, Kelly CG. Malignant tumours of the submandibular salivary gland: a 15-year review. British journal of plastic surgery. 1998 Apr:51(3):181-5 [PubMed PMID: 9664875]

Level 2 (mid-level) evidence

[43]

Eversole LR, Mucoepidermoid carcinoma: review of 815 reported cases. Journal of oral surgery (American Dental Association : 1965). 1970 Jul; [PubMed PMID: 5269211]

Level 3 (low-level) evidence

[44]

Krolls SO, Trodahl JN, Boyers RC. Salivary gland lesions in children. A survey of 430 cases. Cancer. 1972 Aug:30(2):459-69 [PubMed PMID: 4340661]

Level 3 (low-level) evidence

[45]

Martínez-Rodríguez N, Leco-Berrocal I, Rubio-Alonso L, Arias-Irimia O, Martínez-González JM. Epidemiology and treatment of adenoid cystic carcinoma of the minor salivary glands: a meta-analytic study. Medicina oral, patologia oral y cirugia bucal. 2011 Nov 1:16(7):e884-9 [PubMed PMID: 21743416]

Level 2 (mid-level) evidence

[46]

Bishop JA, Yonescu R, Batista D, Eisele DW, Westra WH. Most nonparotid "acinic cell carcinomas" represent mammary analog secretory carcinomas. The American journal of surgical pathology. 2013 Jul:37(7):1053-7. doi: 10.1097/PAS.0b013e3182841554. Epub [PubMed PMID: 23681074]

Level 2 (mid-level) evidence

[47]

Tuffin JR, Daniel F, Davies AS, Tyrrell CJ. Acinic cell carcinoma--Plymouth's experience with postoperative radical radiotherapy. The British journal of oral & maxillofacial surgery. 1989 Jun:27(3):186-91 [PubMed PMID: 2663052]

[48]

Lewis JE, Olsen KD, Sebo TJ. Carcinoma ex pleomorphic adenoma: pathologic analysis of 73 cases. Human pathology. 2001 Jun:32(6):596-604 [PubMed PMID: 11431714]

Level 2 (mid-level) evidence

[49]

Kimple AJ, Austin GK, Shah RN, Welch CM, Funkhouser WK, Zanation AM, Shockley WW. Polymorphous low-grade adenocarcinoma: a case series and determination of recurrence. The Laryngoscope. 2014 Dec:124(12):2714-9. doi: 10.1002/lary.24788. Epub 2014 Sep 17 [PubMed PMID: 25229805]

Level 2 (mid-level) evidence

[50]

Seethala RR, Johnson JT, Barnes EL, Myers EN. Polymorphous low-grade adenocarcinoma: the University of Pittsburgh experience. Archives of otolaryngology--head & neck surgery. 2010 Apr:136(4):385-92. doi: 10.1001/archoto.2010.39. Epub [PubMed PMID: 20403856]

Level 2 (mid-level) evidence

[51]

Gilbert MR, Sharma A, Schmitt NC, Johnson JT, Ferris RL, Duvvuri U, Kim S. A 20-Year Review of 75 Cases of Salivary Duct Carcinoma. JAMA otolaryngology-- head & neck surgery. 2016 May 1:142(5):489-95. doi: 10.1001/jamaoto.2015.3930. Epub [PubMed PMID: 26939990]

Level 3 (low-level) evidence

[52]

Edafe O,Hughes B,Tsirevelou P,Goswamy J,Kumar R, Understanding primary parotid squamous cell carcinoma - A systematic review. The surgeon : journal of the Royal Colleges of Surgeons of Edinburgh and Ireland. 2020 Feb; [PubMed PMID: 31040083]

Level 3 (low-level) evidence

[53]

Xu B, Wang L, Borsu L, Ghossein R, Katabi N, Ganly I, Dogan S. A proportion of primary squamous cell carcinomas of the parotid gland harbour high-risk human papillomavirus. Histopathology. 2016 Dec:69(6):921-929. doi: 10.1111/his.13027. Epub 2016 Aug 23 [PubMed PMID: 27374168]

[54]

Batsakis JG, McClatchey KD, Johns M, Regazi J. Primary squamous cell carcinoma of the parotid gland. Archives of otolaryngology (Chicago, Ill. : 1960). 1976 Jun:102(6):355-7 [PubMed PMID: 1275803]

Level 3 (low-level) evidence

[55]

Gaughan RK, Olsen KD, Lewis JE. Primary squamous cell carcinoma of the parotid gland. Archives of otolaryngology--head & neck surgery. 1992 Aug:118(8):798-801 [PubMed PMID: 1642829]

Level 2 (mid-level) evidence

[56]

Bahar M,Anavi Y,Abraham A,Ben-Bassat M, Primary malignant melanoma in the parotid gland. Oral surgery, oral medicine, and oral pathology. 1990 Nov; [PubMed PMID: 2234883]

Level 3 (low-level) evidence

[57]

Chang P, Knapper WH. Metastatic melanoma of unknown primary. Cancer. 1982 Mar 15:49(6):1106-11 [PubMed PMID: 7059936]

Level 2 (mid-level) evidence

[58]

Klausner JM, Gutman M, Inbar M, Rozin RR. Unknown primary melanoma. Journal of surgical oncology. 1983 Oct:24(2):129-31 [PubMed PMID: 6632893]

[59]

Gao N, Li LJ, Li Y, Wang L. Primary amelanotic malignant melanoma of the parotid gland: a case report. The Journal of international medical research. 2008 Nov-Dec:36(6):1435-9 [PubMed PMID: 19094455]

Level 3 (low-level) evidence

[60]

Yarington CT Jr. Metastatic malignant disease to the parotid gland. The Laryngoscope. 1981 Apr:91(4):517-9 [PubMed PMID: 6261053]

[61]

Travaglino A, Giordano C, Pace M, Varricchio S, Picardi M, Pane F, Staibano S, Mascolo M. Sjögren Syndrome in Primary Salivary Gland Lymphoma. American journal of clinical pathology. 2020 May 5:153(6):719-724. doi: 10.1093/ajcp/aqaa005. Epub [PubMed PMID: 32076706]

[62]

Takahashi H, Cheng J, Fujita S, Tsuda N, Tezuka F, Liu AR, Okabe H. Primary malignant lymphoma of the salivary gland: a tumor of mucosa-associated lymphoid tissue. Journal of oral pathology & medicine : official publication of the International Association of Oral Pathologists and the American Academy of Oral Pathology. 1992 Aug:21(7):318-25 [PubMed PMID: 1522534]

[63]

Zucca E, Roggero E, Bertoni F, Conconi A, Cavalli F. Primary extranodal non-Hodgkin's lymphomas. Part 2: Head and neck, central nervous system and other less common sites. Annals of oncology : official journal of the European Society for Medical Oncology. 1999 Sep:10(9):1023-33 [PubMed PMID: 10572599]

[64]

Rzepakowska A,Zwierzyńska K,Osuch-Wójcikiewicz E,Niemczyk K, Lymphoid tissue neoplasms in the neck region - epidemiological and clinical analysis over 15 years. Otolaryngologia polska = The Polish otolaryngology. 2017 Jun 30 [PubMed PMID: 28541247]

Level 2 (mid-level) evidence

[65]

Abbondanzo SL. Extranodal marginal-zone B-cell lymphoma of the salivary gland. Annals of diagnostic pathology. 2001 Aug:5(4):246-54 [PubMed PMID: 11510008]

[66]

Delli K, Vissink A, Spijkervet FK. Salivary gland biopsy for Sjögren's syndrome. Oral and maxillofacial surgery clinics of North America. 2014 Feb:26(1):23-33. doi: 10.1016/j.coms.2013.09.005. Epub [PubMed PMID: 24287191]

[67]

Kassan SS, Thomas TL, Moutsopoulos HM, Hoover R, Kimberly RP, Budman DR, Costa J, Decker JL, Chused TM. Increased risk of lymphoma in sicca syndrome. Annals of internal medicine. 1978 Dec:89(6):888-92 [PubMed PMID: 102228]

Level 3 (low-level) evidence

[68]

Update on Peer Review., D'Eustachio R,Clinton WJ,, Journal of the New Jersey Dental Association, 1977 Spring [PubMed PMID: 8639173]

Level 3 (low-level) evidence

[69]

O'Neill ID. t(11;19) translocation and CRTC1-MAML2 fusion oncogene in mucoepidermoid carcinoma. Oral oncology. 2009 Jan:45(1):2-9. doi: 10.1016/j.oraloncology.2008.03.012. Epub 2008 May 16 [PubMed PMID: 18486532]

[70]

Tonon G, Modi S, Wu L, Kubo A, Coxon AB, Komiya T, O'Neil K, Stover K, El-Naggar A, Griffin JD, Kirsch IR, Kaye FJ. t(11;19)(q21;p13) translocation in mucoepidermoid carcinoma creates a novel fusion product that disrupts a Notch signaling pathway. Nature genetics. 2003 Feb:33(2):208-13 [PubMed PMID: 12539049]

Level 3 (low-level) evidence

[71]

Bell RB, Dierks EJ, Homer L, Potter BE. Management and outcome of patients with malignant salivary gland tumors. Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons. 2005 Jul:63(7):917-28 [PubMed PMID: 16003616]

Level 2 (mid-level) evidence

[72]

El-Naggar AK, Lovell M, Killary AM, Clayman GL, Batsakis JG. A mucoepidermoid carcinoma of minor salivary gland with t(11;19)(q21;p13.1) as the only karyotypic abnormality. Cancer genetics and cytogenetics. 1996 Mar:87(1):29-33 [PubMed PMID: 8646736]

Level 3 (low-level) evidence

[73]

Mitani Y, Li J, Rao PH, Zhao YJ, Bell D, Lippman SM, Weber RS, Caulin C, El-Naggar AK. Comprehensive analysis of the MYB-NFIB gene fusion in salivary adenoid cystic carcinoma: Incidence, variability, and clinicopathologic significance. Clinical cancer research : an official journal of the American Association for Cancer Research. 2010 Oct 1:16(19):4722-31. doi: 10.1158/1078-0432.CCR-10-0463. Epub 2010 Aug 11 [PubMed PMID: 20702610]

[74]

Brill LB 2nd, Kanner WA, Fehr A, Andrén Y, Moskaluk CA, Löning T, Stenman G, Frierson HF Jr. Analysis of MYB expression and MYB-NFIB gene fusions in adenoid cystic carcinoma and other salivary neoplasms. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 2011 Sep:24(9):1169-76. doi: 10.1038/modpathol.2011.86. Epub 2011 May 13 [PubMed PMID: 21572406]

[75]

Brayer KJ, Frerich CA, Kang H, Ness SA. Recurrent Fusions in MYB and MYBL1 Define a Common, Transcription Factor-Driven Oncogenic Pathway in Salivary Gland Adenoid Cystic Carcinoma. Cancer discovery. 2016 Feb:6(2):176-87. doi: 10.1158/2159-8290.CD-15-0859. Epub 2015 Dec 2 [PubMed PMID: 26631070]

[76]

Diegel CR,Cho KR,El-Naggar AK,Williams BO,Lindvall C, Mammalian target of rapamycin-dependent acinar cell neoplasia after inactivation of Apc and Pten in the mouse salivary gland: implications for human acinic cell carcinoma. Cancer research. 2010 Nov 15; [PubMed PMID: 21062985]

Level 3 (low-level) evidence

[77]

Locati LD, Perrone F, Losa M, Mela M, Casieri P, Orsenigo M, Cortelazzi B, Negri T, Tamborini E, Quattrone P, Bossi P, Rinaldi G, Bergamini C, Calderone RG, Liberatoscioli C, Licitra L. Treatment relevant target immunophenotyping of 139 salivary gland carcinomas (SGCs). Oral oncology. 2009 Nov:45(11):986-90. doi: 10.1016/j.oraloncology.2009.05.635. Epub 2009 Jul 1 [PubMed PMID: 19574086]

Level 2 (mid-level) evidence

[78]

Skálová A, Stárek I, Vanecek T, Kucerová V, Plank L, Szépe P, Di Palma S, Leivo I. Expression of HER-2/neu gene and protein in salivary duct carcinomas of parotid gland as revealed by fluorescence in-situ hybridization and immunohistochemistry. Histopathology. 2003 Apr:42(4):348-56 [PubMed PMID: 12653946]

[79]

Andreadis D, Epivatianos A, Poulopoulos A, Nomikos A, Papazoglou G, Antoniades D, Barbatis C. Detection of C-KIT (CD117) molecule in benign and malignant salivary gland tumours. Oral oncology. 2006 Jan:42(1):57-65 [PubMed PMID: 16140564]

[80]

Glas AS,Hollema H,Nap RE,Plukker JT, Expression of estrogen receptor, progesterone receptor, and insulin-like growth factor receptor-1 and of MIB-1 in patients with recurrent pleomorphic adenoma of the parotid gland. Cancer. 2002 Apr 15; [PubMed PMID: 12001119]

[81]

Sugano S, Mukai K, Tsuda H, Hirohashi S, Furuya S, Shimosato Y, Ebihara S, Takeyama I. Immunohistochemical study of c-erbB-2 oncoprotein overexpression in human major salivary gland carcinoma: an indicator of aggressiveness. The Laryngoscope. 1992 Aug:102(8):923-7 [PubMed PMID: 1353853]

[82]

Felix A, El-Naggar AK, Press MF, Ordonez NG, Fonseca I, Tucker SL, Luna MA, Batsakis JG. Prognostic significance of biomarkers (c-erbB-2, p53, proliferating cell nuclear antigen, and DNA content) in salivary duct carcinoma. Human pathology. 1996 Jun:27(6):561-6 [PubMed PMID: 8666365]

[83]

Durr ML, Mydlarz WK, Shao C, Zahurak ML, Chuang AY, Hoque MO, Westra WH, Liegeois NJ, Califano JA, Sidransky D, Ha PK. Quantitative methylation profiles for multiple tumor suppressor gene promoters in salivary gland tumors. PloS one. 2010 May 26:5(5):e10828. doi: 10.1371/journal.pone.0010828. Epub 2010 May 26 [PubMed PMID: 20520817]

[84]

Schache AG,Hall G,Woolgar JA,Nikolaidis G,Triantafyllou A,Lowe D,Risk JM,Shaw RJ,Liloglou T, Quantitative promoter methylation differentiates carcinoma ex pleomorphic adenoma from pleomorphic salivary adenoma. British journal of cancer. 2010 Dec 7; [PubMed PMID: 21063414]

[85]

Travis LW, Rice DH, McClatchey KD, Wallace SW. Malignant melanoma of conjunctiva metastatic to parotid gland. Reports of cases and discussion of surgical management. The Laryngoscope. 1977 Dec:87(12):2000-7 [PubMed PMID: 926964]

Level 3 (low-level) evidence

[86]

Santini H, Byers RM, Wolf PF. Melanoma metastatic to cervical and parotid nodes from an unknown primary site. American journal of surgery. 1985 Oct:150(4):510-2 [PubMed PMID: 4051118]

[87]

GREENE GW Jr, BERNIER JL. Primary malignant melanomas of the parotid gland. Oral surgery, oral medicine, and oral pathology. 1961 Jan:14():108-16 [PubMed PMID: 13708292]

Level 3 (low-level) evidence

[88]

Wildenberg ME, van Helden-Meeuwsen CG, van de Merwe JP, Drexhage HA, Versnel MA. Systemic increase in type I interferon activity in Sjögren's syndrome: a putative role for plasmacytoid dendritic cells. European journal of immunology. 2008 Jul:38(7):2024-33. doi: 10.1002/eji.200738008. Epub [PubMed PMID: 18581327]

[89]

Gottenberg JE, Cagnard N, Lucchesi C, Letourneur F, Mistou S, Lazure T, Jacques S, Ba N, Ittah M, Lepajolec C, Labetoulle M, Ardizzone M, Sibilia J, Fournier C, Chiocchia G, Mariette X. Activation of IFN pathways and plasmacytoid dendritic cell recruitment in target organs of primary Sjögren's syndrome. Proceedings of the National Academy of Sciences of the United States of America. 2006 Feb 21:103(8):2770-5 [PubMed PMID: 16477017]

[90]

Mariette X. Lymphomas complicating Sjögren's syndrome and hepatitis C virus infection may share a common pathogenesis: chronic stimulation of rheumatoid factor B cells. Annals of the rheumatic diseases. 2001 Nov:60(11):1007-10 [PubMed PMID: 11602464]

[91]

Jakobsson PA, Blanck C, Eneroth CM. Mucoepidermoid carcinoma of the parotid gland. Cancer. 1968 Jul:22(1):111-24 [PubMed PMID: 4298176]

[92]

Batsakis JG, Chinn E, Regezi JA, Repola DA. The pathology of head and neck tumors: salivary glands, part 2. Head & neck surgery. 1978 Nov-Dec:1(2):167-80 [PubMed PMID: 755809]

[93]

FOOTE FW Jr, FRAZELL EL. Tumors of the major salivary glands. Cancer. 1953 Nov:6(6):1065-133 [PubMed PMID: 13106826]

[94]

Healey WV, Perzin KH, Smith L. Mucoepidermoid carcinoma of salivary gland origin. Classification, clinical-pathologic correlation, and results of treatment. Cancer. 1970 Aug:26(2):368-88 [PubMed PMID: 5451215]

[95]

Yaga US, Gollamudi N, Mengji AK, Besta R, Panta P, Prakash B, Rajashekar E. Adenoid cystic carcinoma of the palate: case report and review of literature. The Pan African medical journal. 2016:24():106. doi: 10.11604/pamj.2016.24.106.8596. Epub 2016 May 31 [PubMed PMID: 27642445]

Level 3 (low-level) evidence

[96]

DeAngelis AF, Tsui A, Wiesenfeld D, Chandu A. Outcomes of patients with adenoid cystic carcinoma of the minor salivary glands. International journal of oral and maxillofacial surgery. 2011 Jul:40(7):710-4. doi: 10.1016/j.ijom.2011.02.010. Epub 2011 Mar 10 [PubMed PMID: 21396798]

Level 2 (mid-level) evidence

[97]

Shimamoto H, Chindasombatjaroen J, Kakimoto N, Kishino M, Murakami S, Furukawa S. Perineural spread of adenoid cystic carcinoma in the oral and maxillofacial regions: evaluation with contrast-enhanced CT and MRI. Dento maxillo facial radiology. 2012 Feb:41(2):143-51. doi: 10.1259/dmfr/21825064. Epub [PubMed PMID: 22301639]

Level 2 (mid-level) evidence

[98]

ABRAMS AM, CORNYN J, SCOFIELD HH, HANSEN LS. ACINIC CELL ADENOCARCINOMA OF THE MAJOR SALIVARY GLANDS. A CLINICOPATHOLOGIC STUDY OF 77 CASES. Cancer. 1965 Sep:18():1145-62 [PubMed PMID: 14332544]

Level 3 (low-level) evidence

[99]

Eneroth CM, Jakobsson PA, Blanck C. Acinic cell carcinoma of the parotid gland. Cancer. 1966 Dec:19(12):1761-72 [PubMed PMID: 5927935]

[100]

Lewis JE, Olsen KD, Weiland LH. Acinic cell carcinoma. Clinicopathologic review. Cancer. 1991 Jan 1:67(1):172-9 [PubMed PMID: 1985714]

[101]

Gomez DR, Katabi N, Zhung J, Wolden SL, Zelefsky MJ, Kraus DH, Shah JP, Wong RJ, Ghossein RA, Lee NY. Clinical and pathologic prognostic features in acinic cell carcinoma of the parotid gland. Cancer. 2009 May 15:115(10):2128-37. doi: 10.1002/cncr.24259. Epub [PubMed PMID: 19309749]

[102]

Skálová A, Sima R, Vanecek T, Muller S, Korabecna M, Nemcova J, Elmberger G, Leivo I, Passador-Santos F, Walter J, Rousarova M, Jedlickova K, Curik R, Geierova M, Michal M. Acinic cell carcinoma with high-grade transformation: a report of 9 cases with immunohistochemical study and analysis of TP53 and HER-2/neu genes. The American journal of surgical pathology. 2009 Aug:33(8):1137-45. doi: 10.1097/PAS.0b013e3181a38e1c. Epub [PubMed PMID: 19461506]

Level 3 (low-level) evidence

[103]

Weiler C,Zengel P,van der Wal JE,Guntinas-Lichius O,Schwarz S,Harrison JD,Kirchner T,Ihrler S, Carcinoma ex pleomorphic adenoma with special reference to the prognostic significance of histological progression: a clinicopathological investigation of 41 cases. Histopathology. 2011 Oct; [PubMed PMID: 22014054]

Level 3 (low-level) evidence

[104]

Schwarz S, Müller M, Ettl T, Stockmann P, Zenk J, Agaimy A. Morphological heterogeneity of oral salivary gland carcinomas: a clinicopathologic study of 41 cases with long term follow-up emphasizing the overlapping spectrum of adenoid cystic carcinoma and polymorphous low-grade adenocarcinoma. International journal of clinical and experimental pathology. 2011 Apr:4(4):336-48 [PubMed PMID: 21577319]

Level 3 (low-level) evidence

[105]

Darling MR, Schneider JW, Phillips VM. Polymorphous low-grade adenocarcinoma and adenoid cystic carcinoma: a review and comparison of immunohistochemical markers. Oral oncology. 2002 Oct:38(7):641-5 [PubMed PMID: 12167416]

[106]

Gibbons D, Saboorian MH, Vuitch F, Gokaslan ST, Ashfaq R. Fine-needle aspiration findings in patients with polymorphous low grade adenocarcinoma of the salivary glands. Cancer. 1999 Feb 25:87(1):31-6 [PubMed PMID: 10096357]

[107]

Huang AT,Tang C,Bell D,Yener M,Izquierdo L,Frank SJ,El-Naggar AK,Hanna EY,Weber RS,Kupferman ME, Prognostic factors in adenocarcinoma of the salivary glands. Oral oncology. 2015 Jun; [PubMed PMID: 25843792]

[108]

Patel SG, Prasad ML, Escrig M, Singh B, Shaha AR, Kraus DH, Boyle JO, Huvos AG, Busam K, Shah JP. Primary mucosal malignant melanoma of the head and neck. Head & neck. 2002 Mar:24(3):247-57 [PubMed PMID: 11891956]

Level 2 (mid-level) evidence

[109]

Woodwards RT, Shepherd NA, Hensher R. Malignant melanoma of the parotid gland: a case report and literature review. The British journal of oral & maxillofacial surgery. 1993 Oct:31(5):313-5 [PubMed PMID: 8218087]

Level 3 (low-level) evidence

[110]

Hwang JH, Kim DW, Kim KS, Lee SY. Mucosa-associated lymphoid tissue lymphoma of the accessory parotid gland presenting as a simple cheek mass: A case report. Medicine. 2019 Sep:98(36):e17042. doi: 10.1097/MD.0000000000017042. Epub [PubMed PMID: 31490395]

Level 3 (low-level) evidence

[111]

Kroese FGM,Haacke EA,Bombardieri M, The role of salivary gland histopathology in primary Sjögren's syndrome: promises and pitfalls. Clinical and experimental rheumatology. 2018 May-Jun [PubMed PMID: 30156550]

[112]

Nagao T. "Dedifferentiation" and high-grade transformation in salivary gland carcinomas. Head and neck pathology. 2013 Jul:7 Suppl 1(Suppl 1):S37-47. doi: 10.1007/s12105-013-0458-8. Epub 2013 Jul 3 [PubMed PMID: 23821210]

[113]

Guzzo M, Locati LD, Prott FJ, Gatta G, McGurk M, Licitra L. Major and minor salivary gland tumors. Critical reviews in oncology/hematology. 2010 May:74(2):134-48. doi: 10.1016/j.critrevonc.2009.10.004. Epub 2009 Nov 24 [PubMed PMID: 19939701]

Level 3 (low-level) evidence

[114]

Wierzbicka M, Kopeć T, Szyfter W, Kereiakes T, Bem G. The presence of facial nerve weakness on diagnosis of a parotid gland malignant process. European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery. 2012 Apr:269(4):1177-82. doi: 10.1007/s00405-011-1882-6. Epub 2011 Dec 18 [PubMed PMID: 22179671]

Level 2 (mid-level) evidence

[115]

Weber RS,Byers RM,Petit B,Wolf P,Ang K,Luna M, Submandibular gland tumors. Adverse histologic factors and therapeutic implications. Archives of otolaryngology--head [PubMed PMID: 2166537]

Level 2 (mid-level) evidence

[116]

Sun G, Yang X, Tang E, Wen J, Lu M, Hu Q. The treatment of sublingual gland tumours. International journal of oral and maxillofacial surgery. 2010 Sep:39(9):863-8. doi: 10.1016/j.ijom.2010.04.051. Epub [PubMed PMID: 20605409]

[117]

Diercks GR, Rosow DE, Prasad M, Kuhel WI. A case of preoperative "first-bite syndrome" associated with mucoepidermoid carcinoma of the parotid gland. The Laryngoscope. 2011 Apr:121(4):760-2. doi: 10.1002/lary.21282. Epub 2011 Feb 22 [PubMed PMID: 21344454]

Level 3 (low-level) evidence

[118]

Eneroth CM, Zetterberg A. A cytochemical method of grading the malignancy of salivary gland tumours preoperatively. Acta oto-laryngologica. 1976 May-Jun:81(5-6):489-95 [PubMed PMID: 1274560]

[119]

Magaki SD, Bhuta S, Abemayor E, Nabili V, Sepahdari AR, Lai CK. Carcinoma ex-pleomorphic adenoma of the parotid gland consisting of high-grade salivary duct carcinoma and keratinizing squamous cell carcinoma. Oral surgery, oral medicine, oral pathology and oral radiology. 2015 Sep:120(3):e169-73. doi: 10.1016/j.oooo.2015.01.014. Epub 2015 Feb 3 [PubMed PMID: 25782724]

Level 3 (low-level) evidence

[120]

Kılıçkaya MM,Aynali G,Ceyhan AM,Çiriş M, Metastatic Malignant Melanoma of Parotid Gland with a Regressed Primary Tumor. Case reports in otolaryngology. 2016; [PubMed PMID: 27478668]

Level 3 (low-level) evidence

[121]

Lee YY, Wong KT, King AD, Ahuja AT. Imaging of salivary gland tumours. European journal of radiology. 2008 Jun:66(3):419-36. doi: 10.1016/j.ejrad.2008.01.027. Epub 2008 Mar 11 [PubMed PMID: 18337041]

[122]

Kovacević DO, Fabijanić I. Sonographic diagnosis of parotid gland lesions: correlation with the results of sonographically guided fine-needle aspiration biopsy. Journal of clinical ultrasound : JCU. 2010 Jul:38(6):294-8. doi: 10.1002/jcu.20704. Epub [PubMed PMID: 20544864]

Level 2 (mid-level) evidence

[123]

Hanna E, Vural E, Prokopakis E, Carrau R, Snyderman C, Weissman J. The sensitivity and specificity of high-resolution imaging in evaluating perineural spread of adenoid cystic carcinoma to the skull base. Archives of otolaryngology--head & neck surgery. 2007 Jun:133(6):541-5 [PubMed PMID: 17576903]

Level 2 (mid-level) evidence

[124]

Burke CJ,Thomas RH,Howlett D, Imaging the major salivary glands. The British journal of oral [PubMed PMID: 20381221]

[125]

Wittekindt C, Burmeister HP, Guntinas-Lichius O. [Diagnostic and therapy of salivary gland diseases: relevant aspects for the pathologist from the clinical perspective]. Der Pathologe. 2009 Nov:30(6):424-31. doi: 10.1007/s00292-009-1202-8. Epub [PubMed PMID: 19756611]

Level 3 (low-level) evidence

[126]

Habermann CR, Arndt C, Graessner J, Diestel L, Petersen KU, Reitmeier F, Ussmueller JO, Adam G, Jaehne M. Diffusion-weighted echo-planar MR imaging of primary parotid gland tumors: is a prediction of different histologic subtypes possible? AJNR. American journal of neuroradiology. 2009 Mar:30(3):591-6. doi: 10.3174/ajnr.A1412. Epub 2009 Jan 8 [PubMed PMID: 19131405]

[127]

Roh JL, Ryu CH, Choi SH, Kim JS, Lee JH, Cho KJ, Nam SY, Kim SY. Clinical utility of 18F-FDG PET for patients with salivary gland malignancies. Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2007 Feb:48(2):240-6 [PubMed PMID: 17268021]

[128]

Jeong HS,Chung MK,Son YI,Choi JY,Kim HJ,Ko YH,Baek CH, Role of 18F-FDG PET/CT in management of high-grade salivary gland malignancies. Journal of nuclear medicine : official publication, Society of Nuclear Medicine. 2007 Aug; [PubMed PMID: 17631549]

[129]

Uchida Y, Minoshima S, Kawata T, Motoori K, Nakano K, Kazama T, Uno T, Okamoto Y, Ito H. Diagnostic value of FDG PET and salivary gland scintigraphy for parotid tumors. Clinical nuclear medicine. 2005 Mar:30(3):170-6 [PubMed PMID: 15722820]

[130]

Keyes JW Jr, Harkness BA, Greven KM, Williams DW 3rd, Watson NE Jr, McGuirt WF. Salivary gland tumors: pretherapy evaluation with PET. Radiology. 1994 Jul:192(1):99-102 [PubMed PMID: 8208973]

[131]

Kechagias N, Ntomouchtsis A, Valeri R, Patrikidou A, Kitikidou K, Xirou P, Destouni C, Vahtsevanos K, Antoniades K. Fine-needle aspiration cytology of salivary gland tumours: a 10-year retrospective analysis. Oral and maxillofacial surgery. 2012 Mar:16(1):35-40. doi: 10.1007/s10006-011-0291-8. Epub 2011 Sep 6 [PubMed PMID: 21894513]

Level 2 (mid-level) evidence

[132]

Schmidt RL,Hall BJ,Wilson AR,Layfield LJ, A systematic review and meta-analysis of the diagnostic accuracy of fine-needle aspiration cytology for parotid gland lesions. American journal of clinical pathology. 2011 Jul; [PubMed PMID: 21685031]

Level 1 (high-level) evidence

[133]

Colella G, Cannavale R, Flamminio F, Foschini MP. Fine-needle aspiration cytology of salivary gland lesions: a systematic review. Journal of oral and maxillofacial surgery : official journal of the American Association of Oral and Maxillofacial Surgeons. 2010 Sep:68(9):2146-53. doi: 10.1016/j.joms.2009.09.064. Epub 2010 Jul 1 [PubMed PMID: 20580145]

Level 1 (high-level) evidence

[134]

Routsias JG, Goules JD, Charalampakis G, Tzima S, Papageorgiou A, Voulgarelis M. Malignant lymphoma in primary Sjögren's syndrome: an update on the pathogenesis and treatment. Seminars in arthritis and rheumatism. 2013 Oct:43(2):178-86. doi: 10.1016/j.semarthrit.2013.04.004. Epub 2013 Jun 29 [PubMed PMID: 23816048]

[135]

Schmidt RL, Hall BJ, Layfield LJ. A systematic review and meta-analysis of the diagnostic accuracy of ultrasound-guided core needle biopsy for salivary gland lesions. American journal of clinical pathology. 2011 Oct:136(4):516-26. doi: 10.1309/AJCP5LTQ4RVOQAIT. Epub [PubMed PMID: 21917673]

Level 1 (high-level) evidence

[136]

Schmidt RL,Hunt JP,Hall BJ,Wilson AR,Layfield LJ, A systematic review and meta-analysis of the diagnostic accuracy of frozen section for parotid gland lesions. American journal of clinical pathology. 2011 Nov; [PubMed PMID: 22031311]

Level 1 (high-level) evidence

[137]

Fu KK, Leibel SA, Levine ML, Friedlander LM, Boles R, Phillips TL. Carcinoma of the major and minor salivary glands: analysis of treatment results and sites and causes of failures. Cancer. 1977 Dec:40(6):2882-90 [PubMed PMID: 201357]

[138]

Armstrong JG, Harrison LB, Spiro RH, Fass DE, Strong EW, Fuks ZY. Malignant tumors of major salivary gland origin. A matched-pair analysis of the role of combined surgery and postoperative radiotherapy. Archives of otolaryngology--head & neck surgery. 1990 Mar:116(3):290-3 [PubMed PMID: 2306346]

[139]

Terhaard CH, Lubsen H, Rasch CR, Levendag PC, Kaanders HH, Tjho-Heslinga RE, van Den Ende PL, Burlage F, Dutch Head and Neck Oncology Cooperative Group. The role of radiotherapy in the treatment of malignant salivary gland tumors. International journal of radiation oncology, biology, physics. 2005 Jan 1:61(1):103-11 [PubMed PMID: 15629600]

[140]

Lewis AG, Tong T, Maghami E. Diagnosis and Management of Malignant Salivary Gland Tumors of the Parotid Gland. Otolaryngologic clinics of North America. 2016 Apr:49(2):343-80. doi: 10.1016/j.otc.2015.11.001. Epub [PubMed PMID: 27040585]

[141]

Lin HH, Limesand KH, Ann DK. Current State of Knowledge on Salivary Gland Cancers. Critical reviews in oncogenesis. 2018:23(3-4):139-151. doi: 10.1615/CritRevOncog.2018027598. Epub [PubMed PMID: 30311570]

[142]

Terhaard CH, Postoperative and primary radiotherapy for salivary gland carcinomas: indications, techniques, and results. International journal of radiation oncology, biology, physics. 2007; [PubMed PMID: 17848295]

[143]

Mendenhall WM, Morris CG, Amdur RJ, Werning JW, Villaret DB. Radiotherapy alone or combined with surgery for salivary gland carcinoma. Cancer. 2005 Jun 15:103(12):2544-50 [PubMed PMID: 15880750]

[144]

Spiro JD, Spiro RH. Cancer of the parotid gland: role of 7th nerve preservation. World journal of surgery. 2003 Jul:27(7):863-7 [PubMed PMID: 14509520]

Level 3 (low-level) evidence

[145]

Harish K. Management of primary malignant epithelial parotid tumors. Surgical oncology. 2004 Jul:13(1):7-16 [PubMed PMID: 15145029]

[146]

Lim YC,Lee SY,Kim K,Lee JS,Koo BS,Shin HA,Choi EC, Conservative parotidectomy for the treatment of parotid cancers. Oral oncology. 2005 Nov; [PubMed PMID: 16129655]

Level 2 (mid-level) evidence

[147]

Domenick NA, Johnson JT. Parotid tumor size predicts proximity to the facial nerve. The Laryngoscope. 2011 Nov:121(11):2366-70. doi: 10.1002/lary.22335. Epub [PubMed PMID: 22020887]

Level 2 (mid-level) evidence

[148]

Roh JL, Kim HS, Park CI. Randomized clinical trial comparing partial parotidectomy versus superficial or total parotidectomy. The British journal of surgery. 2007 Sep:94(9):1081-7 [PubMed PMID: 17701949]

Level 1 (high-level) evidence

[149]

Salama AR, Ord RA. Clinical implications of the neck in salivary gland disease. Oral and maxillofacial surgery clinics of North America. 2008 Aug:20(3):445-58. doi: 10.1016/j.coms.2008.03.002. Epub [PubMed PMID: 18603202]

[150]

Spiro RH,Armstrong J,Harrison L,Geller NL,Lin SY,Strong EW, Carcinoma of major salivary glands. Recent trends. Archives of otolaryngology--head [PubMed PMID: 2537093]

Level 2 (mid-level) evidence

[151]

Armstrong JG, Harrison LB, Thaler HT, Friedlander-Klar H, Fass DE, Zelefsky MJ, Shah JP, Strong EW, Spiro RH. The indications for elective treatment of the neck in cancer of the major salivary glands. Cancer. 1992 Feb 1:69(3):615-9 [PubMed PMID: 1730113]

Level 2 (mid-level) evidence

[152]

Rodríguez-Cuevas S, Labastida S, Baena L, Gallegos F. Risk of nodal metastases from malignant salivary gland tumors related to tumor size and grade of malignancy. European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery. 1995:252(3):139-42 [PubMed PMID: 7662346]

[153]

Lloyd S, Yu JB, Ross DA, Wilson LD, Decker RH. A prognostic index for predicting lymph node metastasis in minor salivary gland cancer. International journal of radiation oncology, biology, physics. 2010 Jan 1:76(1):169-75. doi: 10.1016/j.ijrobp.2009.01.021. Epub [PubMed PMID: 19386433]

[154]

Schramm VL Jr, Imola MJ. Management of nasopharyngeal salivary gland malignancy. The Laryngoscope. 2001 Sep:111(9):1533-44 [PubMed PMID: 11568602]

Level 2 (mid-level) evidence

[155]

Ettl T,Schwarz S,Kleinsasser N,Hartmann A,Reichert TE,Driemel O, Overexpression of EGFR and absence of C-KIT expression correlate with poor prognosis in salivary gland carcinomas. Histopathology. 2008 Nov; [PubMed PMID: 18983466]

[156]

Jaehne M, Roeser K, Jaekel T, Schepers JD, Albert N, Löning T. Clinical and immunohistologic typing of salivary duct carcinoma: a report of 50 cases. Cancer. 2005 Jun 15:103(12):2526-33 [PubMed PMID: 15900577]

Level 3 (low-level) evidence

[157]

Stennert E, Kisner D, Jungehuelsing M, Guntinas-Lichius O, Schröder U, Eckel HE, Klussmann JP. High incidence of lymph node metastasis in major salivary gland cancer. Archives of otolaryngology--head & neck surgery. 2003 Jul:129(7):720-3 [PubMed PMID: 12874071]

Level 2 (mid-level) evidence

[158]

Frankenthaler RA, Byers RM, Luna MA, Callender DL, Wolf P, Goepfert H. Predicting occult lymph node metastasis in parotid cancer. Archives of otolaryngology--head & neck surgery. 1993 May:119(5):517-20 [PubMed PMID: 8484940]

Level 2 (mid-level) evidence

[159]

Chisholm EJ, Elmiyeh B, Dwivedi RC, Fisher C, Thway K, Kerawala C, Clarke PM, Rhys-Evans PH. Anatomic distribution of cervical lymph node spread in parotid carcinoma. Head & neck. 2011 Apr:33(4):513-5. doi: 10.1002/hed.21479. Epub [PubMed PMID: 20652975]

[160]

Ferlito A, Shaha AR, Rinaldo A, Mondin V. Management of clinically negative cervical lymph nodes in patients with malignant neoplasms of the parotid gland. ORL; journal for oto-rhino-laryngology and its related specialties. 2001 May-Jun:63(3):123-6 [PubMed PMID: 11359087]

[161]

Medina JE. Neck dissection in the treatment of cancer of major salivary glands. Otolaryngologic clinics of North America. 1998 Oct:31(5):815-22 [PubMed PMID: 9735109]

[162]

Ziglinas P, Arnold A, Arnold M, Zbären P. Primary tumors of the submandibular glands: a retrospective study based on 41 cases. Oral oncology. 2010 Apr:46(4):287-91. doi: 10.1016/j.oraloncology.2010.01.011. Epub 2010 Feb 26 [PubMed PMID: 20189445]

Level 2 (mid-level) evidence

[163]

Salgado LR, Spratt DE, Riaz N, Romesser PB, Wolden S, Rao S, Chin C, Hong JC, Wong R, Lee NY. Radiation therapy in the treatment of minor salivary gland tumors. American journal of clinical oncology. 2014 Oct:37(5):492-7. doi: 10.1097/COC.0b013e31827e54e5. Epub [PubMed PMID: 23428950]

Level 2 (mid-level) evidence

[164]

Garden AS, el-Naggar AK, Morrison WH, Callender DL, Ang KK, Peters LJ. Postoperative radiotherapy for malignant tumors of the parotid gland. International journal of radiation oncology, biology, physics. 1997 Jan 1:37(1):79-85 [PubMed PMID: 9054880]

Level 2 (mid-level) evidence

[165]

Laramore GE, Krall JM, Griffin TW, Duncan W, Richter MP, Saroja KR, Maor MH, Davis LW. Neutron versus photon irradiation for unresectable salivary gland tumors: final report of an RTOG-MRC randomized clinical trial. Radiation Therapy Oncology Group. Medical Research Council. International journal of radiation oncology, biology, physics. 1993 Sep 30:27(2):235-40 [PubMed PMID: 8407397]

Level 1 (high-level) evidence

[166]

Voulgarelis M, Ziakas PD, Papageorgiou A, Baimpa E, Tzioufas AG, Moutsopoulos HM. Prognosis and outcome of non-Hodgkin lymphoma in primary Sjögren syndrome. Medicine. 2012 Jan:91(1):1-9. doi: 10.1097/MD.0b013e31824125e4. Epub [PubMed PMID: 22198497]

Level 2 (mid-level) evidence

[167]

Schoenfeld JD, Sher DJ, Norris CM Jr, Haddad RI, Posner MR, Balboni TA, Tishler RB. Salivary gland tumors treated with adjuvant intensity-modulated radiotherapy with or without concurrent chemotherapy. International journal of radiation oncology, biology, physics. 2012 Jan 1:82(1):308-14. doi: 10.1016/j.ijrobp.2010.09.042. Epub 2010 Nov 13 [PubMed PMID: 21075557]

Level 2 (mid-level) evidence

[168]

Cooper JS,Pajak TF,Forastiere AA,Jacobs J,Campbell BH,Saxman SB,Kish JA,Kim HE,Cmelak AJ,Rotman M,Machtay M,Ensley JF,Chao KS,Schultz CJ,Lee N,Fu KK, Postoperative concurrent radiotherapy and chemotherapy for high-risk squamous-cell carcinoma of the head and neck. The New England journal of medicine. 2004 May 6; [PubMed PMID: 15128893]

Level 1 (high-level) evidence

[169]

Pederson AW, Salama JK, Haraf DJ, Witt ME, Stenson KM, Portugal L, Seiwert T, Villaflor VM, Cohen EE, Vokes EE, Blair EA. Adjuvant chemoradiotherapy for locoregionally advanced and high-risk salivary gland malignancies. Head & neck oncology. 2011 Jul 26:3():31. doi: 10.1186/1758-3284-3-31. Epub 2011 Jul 26 [PubMed PMID: 21791072]

[170]

Cerda T, Sun XS, Vignot S, Marcy PY, Baujat B, Baglin AC, Ali AM, Testelin S, Reyt E, Janot F, Thariat J. A rationale for chemoradiation (vs radiotherapy) in salivary gland cancers? On behalf of the REFCOR (French rare head and neck cancer network). Critical reviews in oncology/hematology. 2014 Aug:91(2):142-58. doi: 10.1016/j.critrevonc.2014.02.002. Epub 2014 Feb 16 [PubMed PMID: 24636481]

[171]

Nakano K, Sato Y, Sasaki T, Shimbashi W, Fukushima H, Yonekawa H, Mitani H, Kawabata K, Takahashi S. Combination chemotherapy of carboplatin and paclitaxel for advanced/metastatic salivary gland carcinoma patients: differences in responses by different pathological diagnoses. Acta oto-laryngologica. 2016 Sep:136(9):948-51. doi: 10.3109/00016489.2016.1170876. Epub 2016 Apr 20 [PubMed PMID: 27094013]

[172]

Papaspyrou G,Hoch S,Rinaldo A,Rodrigo JP,Takes RP,van Herpen C,Werner JA,Ferlito A, Chemotherapy and targeted therapy in adenoid cystic carcinoma of the head and neck: a review. Head [PubMed PMID: 20652885]

[173]

Laurie SA, Siu LL, Winquist E, Maksymiuk A, Harnett EL, Walsh W, Tu D, Parulekar WR. A phase 2 study of platinum and gemcitabine in patients with advanced salivary gland cancer: a trial of the NCIC Clinical Trials Group. Cancer. 2010 Jan 15:116(2):362-8. doi: 10.1002/cncr.24745. Epub [PubMed PMID: 19924794]

Level 1 (high-level) evidence

[174]

Williams MD, Roberts DB, Kies MS, Mao L, Weber RS, El-Naggar AK. Genetic and expression analysis of HER-2 and EGFR genes in salivary duct carcinoma: empirical and therapeutic significance. Clinical cancer research : an official journal of the American Association for Cancer Research. 2010 Apr 15:16(8):2266-74. doi: 10.1158/1078-0432.CCR-09-0238. Epub 2010 Apr 6 [PubMed PMID: 20371674]

[175]

Holst VA, Marshall CE, Moskaluk CA, Frierson HF Jr. KIT protein expression and analysis of c-kit gene mutation in adenoid cystic carcinoma. Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc. 1999 Oct:12(10):956-60 [PubMed PMID: 10530560]

[176]

Frattini M,Saletti P,Romagnani E,Martin V,Molinari F,Ghisletta M,Camponovo A,Etienne LL,Cavalli F,Mazzucchelli L, PTEN loss of expression predicts cetuximab efficacy in metastatic colorectal cancer patients. British journal of cancer. 2007 Oct 22; [PubMed PMID: 17940504]

[177]

Haddad R, Colevas AD, Krane JF, Cooper D, Glisson B, Amrein PC, Weeks L, Costello R, Posner M. Herceptin in patients with advanced or metastatic salivary gland carcinomas. A phase II study. Oral oncology. 2003 Oct:39(7):724-7 [PubMed PMID: 12907212]

[178]

Vidal L, Tsao MS, Pond GR, Cohen EE, Cohen RB, Chen EX, Agulnik M, Hotte S, Winquist E, Laurie S, Hayes DN, Ho J, Dancey J, Siu LL. Fluorescence in situ hybridization gene amplification analysis of EGFR and HER2 in patients with malignant salivary gland tumors treated with lapatinib. Head & neck. 2009 Aug:31(8):1006-12. doi: 10.1002/hed.21052. Epub [PubMed PMID: 19309723]

[179]

Ciardiello F, Tortora G. EGFR antagonists in cancer treatment. The New England journal of medicine. 2008 Mar 13:358(11):1160-74. doi: 10.1056/NEJMra0707704. Epub [PubMed PMID: 18337605]

[180]

Edge SB, Compton CC. The American Joint Committee on Cancer: the 7th edition of the AJCC cancer staging manual and the future of TNM. Annals of surgical oncology. 2010 Jun:17(6):1471-4. doi: 10.1245/s10434-010-0985-4. Epub [PubMed PMID: 20180029]

[181]

Lydiatt WM, Patel SG, O'Sullivan B, Brandwein MS, Ridge JA, Migliacci JC, Loomis AM, Shah JP. Head and Neck cancers-major changes in the American Joint Committee on cancer eighth edition cancer staging manual. CA: a cancer journal for clinicians. 2017 Mar:67(2):122-137. doi: 10.3322/caac.21389. Epub 2017 Jan 27 [PubMed PMID: 28128848]

[182]

Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, Lister TA, Alliance, Australasian Leukaemia and Lymphoma Group, Eastern Cooperative Oncology Group, European Mantle Cell Lymphoma Consortium, Italian Lymphoma Foundation, European Organisation for Research, Treatment of Cancer/Dutch Hemato-Oncology Group, Grupo Español de Médula Ósea, German High-Grade Lymphoma Study Group, German Hodgkin's Study Group, Japanese Lymphorra Study Group, Lymphoma Study Association, NCIC Clinical Trials Group, Nordic Lymphoma Study Group, Southwest Oncology Group, United Kingdom National Cancer Research Institute. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2014 Sep 20:32(27):3059-68 [PubMed PMID: 25113753]

[183]

Sultan I, Rodriguez-Galindo C, Al-Sharabati S, Guzzo M, Casanova M, Ferrari A. Salivary gland carcinomas in children and adolescents: a population-based study, with comparison to adult cases. Head & neck. 2011 Oct:33(10):1476-81. doi: 10.1002/hed.21629. Epub 2010 Nov 10 [PubMed PMID: 21928420]

Level 3 (low-level) evidence

[184]

Kupferman ME, de la Garza GO, Santillan AA, Williams MD, Varghese BT, Huh W, Roberts D, Weber RS. Outcomes of pediatric patients with malignancies of the major salivary glands. Annals of surgical oncology. 2010 Dec:17(12):3301-7. doi: 10.1245/s10434-010-1165-2. Epub 2010 Jun 29 [PubMed PMID: 20585877]

Level 2 (mid-level) evidence

[185]

Renehan AG,Gleave EN,Slevin NJ,McGurk M, Clinico-pathological and treatment-related factors influencing survival in parotid cancer. British journal of cancer. 1999 Jun; [PubMed PMID: 10376987]

[186]

Therkildsen MH, Christensen M, Andersen LJ, Schiødt T, Hansen HS. Salivary gland carcinomas--prognostic factors. Acta oncologica (Stockholm, Sweden). 1998:37(7-8):701-13 [PubMed PMID: 10050991]

Level 2 (mid-level) evidence

[187]

Schwarz S, Stiegler C, Müller M, Ettl T, Brockhoff G, Zenk J, Agaimy A. Salivary gland mucoepidermoid carcinoma is a clinically, morphologically and genetically heterogeneous entity: a clinicopathological study of 40 cases with emphasis on grading, histological variants and presence of the t(11;19) translocation. Histopathology. 2011 Mar:58(4):557-70. doi: 10.1111/j.1365-2559.2011.03777.x. Epub 2011 Mar 3 [PubMed PMID: 21371076]

Level 3 (low-level) evidence

[188]

Bhattacharyya N, Fried MP. Determinants of survival in parotid gland carcinoma: a population-based study. American journal of otolaryngology. 2005 Jan-Feb:26(1):39-44 [PubMed PMID: 15635580]

[189]

Speight PM,Barrett AW, Prognostic factors in malignant tumours of the salivary glands. The British journal of oral [PubMed PMID: 19409681]

[190]

Hocwald E, Korkmaz H, Yoo GH, Adsay V, Shibuya TY, Abrams J, Jacobs JR. Prognostic factors in major salivary gland cancer. The Laryngoscope. 2001 Aug:111(8):1434-9 [PubMed PMID: 11568581]

Level 2 (mid-level) evidence

[191]

Kelley DJ, Spiro RH. Management of the neck in parotid carcinoma. American journal of surgery. 1996 Dec:172(6):695-7 [PubMed PMID: 8988681]

Level 2 (mid-level) evidence

[192]

Oliveira LR, Soave DF, Oliveira-Costa JP, Zorgetto VA, Ribeiro-Silva A. Prognostic factors in patients with malignant salivary gland neoplasms in a Brazilian population. Asian Pacific journal of cancer prevention : APJCP. 2011:12(2):363-8 [PubMed PMID: 21545195]

Level 2 (mid-level) evidence

[193]

Becker C,Dahlem KKK,Pfeiffer J, Prognostic value of comorbidities in patients with carcinoma of the major salivary glands. European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery. 2017 Mar; [PubMed PMID: 27888340]

[194]

Glazer TA, Shuman AG. Distant Metastases and Palliative Care. Advances in oto-rhino-laryngology. 2016:78():182-8. doi: 10.1159/000442139. Epub 2016 Apr 12 [PubMed PMID: 27092552]

Level 3 (low-level) evidence

[195]

Thorvaldsson SE, Beahrs OH, Woolner LB, Simons JN. Mucoepidermoid tumors of the major salivary glands. American journal of surgery. 1970 Oct:120(4):432-8 [PubMed PMID: 5507327]

[196]

Brandwein MS, Ivanov K, Wallace DI, Hille JJ, Wang B, Fahmy A, Bodian C, Urken ML, Gnepp DR, Huvos A, Lumerman H, Mills SE. Mucoepidermoid carcinoma: a clinicopathologic study of 80 patients with special reference to histological grading. The American journal of surgical pathology. 2001 Jul:25(7):835-45 [PubMed PMID: 11420454]

[197]

Guzzo M, Andreola S, Sirizzotti G, Cantu G. Mucoepidermoid carcinoma of the salivary glands: clinicopathologic review of 108 patients treated at the National Cancer Institute of Milan. Annals of surgical oncology. 2002 Aug:9(7):688-95 [PubMed PMID: 12167584]

[198]

Clode AL,Fonseca I,Santos JR,Soares J, Mucoepidermoid carcinoma of the salivary glands: a reappraisal of the influence of tumor differentiation on prognosis. Journal of surgical oncology. 1991 Feb; [PubMed PMID: 1992215]

[199]

Witt RL. Major salivary gland cancer. Surgical oncology clinics of North America. 2004 Jan:13(1):113-27 [PubMed PMID: 15062365]

[200]

Rinaldo A, Ferlito A, Pellitteri PK, Robbins KT, Shaha AR, Bradley PJ, Kowalski LP, Wei WI. Management of malignant submandibular gland tumors. Acta oto-laryngologica. 2003 Oct:123(8):896-904 [PubMed PMID: 14606589]

[201]

Cohen AN, Damrose EJ, Huang RY, Nelson SD, Blackwell KE, Calcaterra TC. Adenoid cystic carcinoma of the submandibular gland: a 35-year review. Otolaryngology--head and neck surgery : official journal of American Academy of Otolaryngology-Head and Neck Surgery. 2004 Dec:131(6):994-1000 [PubMed PMID: 15577803]

Level 2 (mid-level) evidence

[202]

Hamper K,Lazar F,Dietel M,Caselitz J,Berger J,Arps H,Falkmer U,Auer G,Seifert G, Prognostic factors for adenoid cystic carcinoma of the head and neck: a retrospective evaluation of 96 cases. Journal of oral pathology [PubMed PMID: 2160530]

Level 2 (mid-level) evidence

[203]

Perzin KH, Gullane P, Clairmont AC. Adenoid cystic carcinomas arising in salivary glands: a correlation of histologic features and clinical course. Cancer. 1978 Jul:42(1):265-82 [PubMed PMID: 208752]

[204]

Neskey DM, Klein JD, Hicks S, Garden AS, Bell DM, El-Naggar AK, Kies MS, Weber RS, Kupferman ME. Prognostic factors associated with decreased survival in patients with acinic cell carcinoma. JAMA otolaryngology-- head & neck surgery. 2013 Nov:139(11):1195-202. doi: 10.1001/jamaoto.2013.4728. Epub [PubMed PMID: 24076756]

Level 2 (mid-level) evidence

[205]

Chong GC, Beahrs OH, Woolner LB. Surgical management of acinic cell carcinoma of the parotid gland. Surgery, gynecology & obstetrics. 1974 Jan:138(1):65-8 [PubMed PMID: 4809004]

[206]

Spiro RH,Huvos AG,Strong EW, Cancer of the parotid gland. A clinicopathologic study of 288 primary cases. American journal of surgery. 1975 Oct; [PubMed PMID: 170839]

Level 3 (low-level) evidence

[207]

Moon P, Tusty M, Divi V, Megwalu UC. Significance of Nodal Metastasis in Parotid Gland Acinar Cell Carcinoma. The Laryngoscope. 2021 Apr:131(4):E1125-E1129. doi: 10.1002/lary.28966. Epub 2020 Aug 8 [PubMed PMID: 32770798]

[208]

Wang Y, Wang S, Zhou X, Zhou H, Cui Y, Li Q, Zhang L. Acinar cell carcinoma: a report of 19 cases with a brief review of the literature. World journal of surgical oncology. 2016 Jun 28:14(1):172. doi: 10.1186/s12957-016-0919-0. Epub 2016 Jun 28 [PubMed PMID: 27352960]

Level 3 (low-level) evidence

[209]

Hickman RE, Cawson RA, Duffy SW. The prognosis of specific types of salivary gland tumors. Cancer. 1984 Oct 15:54(8):1620-4 [PubMed PMID: 6089994]

[210]

Chen AM, Garcia J, Bucci MK, Quivey JM, Eisele DW. The role of postoperative radiation therapy in carcinoma ex pleomorphic adenoma of the parotid gland. International journal of radiation oncology, biology, physics. 2007 Jan 1:67(1):138-43 [PubMed PMID: 17049183]

[211]

Olsen KD, Lewis JE. Carcinoma ex pleomorphic adenoma: a clinicopathologic review. Head & neck. 2001 Sep:23(9):705-12 [PubMed PMID: 11505478]

Level 2 (mid-level) evidence

[212]

Tortoledo ME, Luna MA, Batsakis JG. Carcinomas ex pleomorphic adenoma and malignant mixed tumors. Histomorphologic indexes. Archives of otolaryngology (Chicago, Ill. : 1960). 1984 Mar:110(3):172-6 [PubMed PMID: 6322732]

[213]

Kumar M, Stivaros N, Barrett AW, Thomas GJ, Bounds G, Newman L. Polymorphous low-grade adenocarcinoma--a rare and aggressive entity in adolescence. The British journal of oral & maxillofacial surgery. 2004 Jun:42(3):195-9 [PubMed PMID: 15121262]

Level 3 (low-level) evidence

[214]

Castle JT, Thompson LD, Frommelt RA, Wenig BM, Kessler HP. Polymorphous low grade adenocarcinoma: a clinicopathologic study of 164 cases. Cancer. 1999 Jul 15:86(2):207-19 [PubMed PMID: 10421256]

Level 3 (low-level) evidence

[215]

Evans HL, Luna MA. Polymorphous low-grade adenocarcinoma: a study of 40 cases with long-term follow up and an evaluation of the importance of papillary areas. The American journal of surgical pathology. 2000 Oct:24(10):1319-28 [PubMed PMID: 11023093]

Level 3 (low-level) evidence

[216]

Barnes L,Rao U,Krause J,Contis L,Schwartz A,Scalamogna P, Salivary duct carcinoma. Part I. A clinicopathologic evaluation and DNA image analysis of 13 cases with review of the literature. Oral surgery, oral medicine, and oral pathology. 1994 Jul; [PubMed PMID: 8078666]

Level 3 (low-level) evidence

[217]

Guzzo M, Di Palma S, Grandi C, Molinari R. Salivary duct carcinoma: clinical characteristics and treatment strategies. Head & neck. 1997 Mar:19(2):126-33 [PubMed PMID: 9059870]

[218]

Lee S, Kim GE, Park CS, Choi EC, Yang WI, Lee CG, Keum KC, Kim YB, Suh CO. Primary squamous cell carcinoma of the parotid gland. American journal of otolaryngology. 2001 Nov-Dec:22(6):400-6 [PubMed PMID: 11713725]

Level 2 (mid-level) evidence

[219]

International Non-Hodgkin's Lymphoma Prognostic Factors Project. A predictive model for aggressive non-Hodgkin's lymphoma. The New England journal of medicine. 1993 Sep 30:329(14):987-94 [PubMed PMID: 8141877]

[220]

Guntinas-Lichius O,Klussmann JP,Schroeder U,Quante G,Jungehuelsing M,Stennert E, Primary parotid malignoma surgery in patients with normal preoperative facial nerve function: outcome and long-term postoperative facial nerve function. The Laryngoscope. 2004 May; [PubMed PMID: 15126763]

Level 2 (mid-level) evidence

[221]

Eisele DW, Wang SJ, Orloff LA. Electrophysiologic facial nerve monitoring during parotidectomy. Head & neck. 2010 Mar:32(3):399-405. doi: 10.1002/hed.21190. Epub [PubMed PMID: 19672866]

[222]

Sanabria A, Kowalski LP, Bradley PJ, Hartl DM, Bradford CR, de Bree R, Rinaldo A, Ferlito A. Sternocleidomastoid muscle flap in preventing Frey's syndrome after parotidectomy: a systematic review. Head & neck. 2012 Apr:34(4):589-98. doi: 10.1002/hed.21722. Epub 2011 Apr 5 [PubMed PMID: 21472880]

Level 1 (high-level) evidence

[223]

Curry JM, Fisher KW, Heffelfinger RN, Rosen MR, Keane WM, Pribitkin EA. Superficial musculoaponeurotic system elevation and fat graft reconstruction after superficial parotidectomy. The Laryngoscope. 2008 Feb:118(2):210-5 [PubMed PMID: 18030169]

Level 2 (mid-level) evidence

[224]

Filho WQ,Dedivitis RA,Rapoport A,Guimarães AV, Sternocleidomastoid muscle flap preventing Frey syndrome following parotidectomy. World journal of surgery. 2004 Apr; [PubMed PMID: 15022023]

[225]

de Bree R, van der Waal I, Leemans CR. Management of Frey syndrome. Head & neck. 2007 Aug:29(8):773-8 [PubMed PMID: 17230557]

[226]

Kolokythas A. Long-term surgical complications in the oral cancer patient: a comprehensive review. Part I. Journal of oral & maxillofacial research. 2010:1(3):e1. doi: 10.5037/jomr.2010.1301. Epub 2010 Oct 1 [PubMed PMID: 24421971]

[227]

Kim DD, Ord RA. Complications in the treatment of head and neck cancer. Oral and maxillofacial surgery clinics of North America. 2003 May:15(2):213-27 [PubMed PMID: 18088676]

[228]

Schauber MD, Fontenelle LJ, Solomon JW, Hanson TL. Cranial/cervical nerve dysfunction after carotid endarterectomy. Journal of vascular surgery. 1997 Mar:25(3):481-7 [PubMed PMID: 9081129]

[229]

Raaijmakers E, Engelen AM. Is sensorineural hearing loss a possible side effect of nasopharyngeal and parotid irradiation? A systematic review of the literature. Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology. 2002 Oct:65(1):1-7 [PubMed PMID: 12413668]

Level 1 (high-level) evidence

[230]

Dawson AK, Orr JA. Long-term results of local excision and radiotherapy in pleomorphic adenoma of the parotid. International journal of radiation oncology, biology, physics. 1985 Mar:11(3):451-5 [PubMed PMID: 2982770]

[231]

Barton J, Slevin NJ, Gleave EN. Radiotherapy for pleomorphic adenoma of the parotid gland. International journal of radiation oncology, biology, physics. 1992:22(5):925-8 [PubMed PMID: 1313407]

Level 2 (mid-level) evidence

[232]

Leonetti JP, Marzo SJ, Zender CA, Porter RG, Melian E. Temporal bone osteoradionecrosis after surgery and radiotherapy for malignant parotid tumors. Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology. 2010 Jun:31(4):656-9 [PubMed PMID: 20964249]

Level 2 (mid-level) evidence

[233]

Pauloski BR, Logemann JA, Rademaker AW, McConnel FM, Heiser MA, Cardinale S, Shedd D, Lewin J, Baker SR, Graner D. Speech and swallowing function after anterior tongue and floor of mouth resection with distal flap reconstruction. Journal of speech and hearing research. 1993 Apr:36(2):267-76 [PubMed PMID: 8487519]

[234]

Rentschler GJ, Mann MB. The effects of glossectomy on intelligibility of speech and oral perceptual discrimination. Journal of oral surgery (American Dental Association : 1965). 1980 May:38(5):348-54 [PubMed PMID: 6928933]

[235]

Brands MT, Brennan PA, Verbeek ALM, Merkx MAW, Geurts SME. Follow-up after curative treatment for oral squamous cell carcinoma. A critical appraisal of the guidelines and a review of the literature. European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. 2018 May:44(5):559-565. doi: 10.1016/j.ejso.2018.01.004. Epub 2018 Jan 12 [PubMed PMID: 29433990]