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Major and minor salivary gland tumours – 2016

UPDATED AUGUST 2016

1. GENERAL INFORMATION

1.1 Definition

According to the International Classification of Diseases for Oncology (ICD-O-3), we defined “major and minor salivary glands” all epithelial neoplasm arisen in parotids, submandibular, and sublingual glands  (ICD-O-3 code: C07-08; major salivary gland cancers). However, the minor salivary gland neoplasms are specific type of adenocarcinoma which arise in many head-and-neck sites. The RARECAREnet website provide topographic and morphologic ICD-O codes and definition for both major and minor glands cancers definition (RARECAREnet).

1.2 Epidemiological data

1.2.1 Incidence

Minor salivary gland cancers are salivary gland type cancers of the head and neck (H&N). These malignancies are very rare with an annual incidence rates of 1.4 per 100,000, calculated in the European cases diagnosed between 2000 and 2007, based on 21,794 cases (RARECAREnet).
Incidence was higher for the major glands (1.0) than the salivary gland type tumours of H&N (0.4) carcinoma. In 2013, about 7,800 new cases were estimated in Europe (EU28), 8.5% of all H&N cancers.
Incidence was more frequent in males than in females, with a male-female ratio of 1.5, and highest in the elderly. The annual rates raised from 0.15 in <25 years to 1.2 in 25-64 years, then increased markedly to 4.3 per 100,000 in the >65 years old population. In Europe, standardised incidence rates remained stable from 1995 to 2007 (RARECAREnet).

1.2.2 Survival

In Europe, according to the RARECAREnet project (RARECAREnet), survival was calculated from 21,364 cases diagnosed between 2000 and 2007. One-, 3-, and 5-year survival was 83%, 69%, and 63%, respectively.
Five years survival was significantly better for the salivary gland type tumours of H&N (67%) than for major salivary glands cancers cases (61%).
Survival was significantly better in female than in male (72% vs. 55%).
Five-year survival was highest (95%) in children and young patients (<25 years), then decreased to 70% in 25-64-year-old cases. In the elderly (>65 years) survival was markedly low (53%: 50% for major and 60% for salivary gland type tumours of H&N cases). In Europe, during the period 1999-2007, 5-year survival remained stable.

1.2.3 Risk factors

Irradiation is one cause of malignant salivary gland tumours. This was found in Japanese survivors of the atomic bomb and in patients who had been receiving irradiation to head and neck during childhood for benign conditions, e.g., to reduce the size of tonsils and adenoids (Schneider 1998).  Several studies associated a history of prior cancer (especially those related with ultraviolet radiation, immunosuppression, and Epstain-Barr virus) with salivary gland cancers.
Among more than 5,000 Swedish patients with Hodgkin disease, there was an over 4-fold significant increase in cancer of the salivary glands (Dong 2001). A US and Swedish study revealed an increased risk of second cancer, salivary glands included, in more than 1,000 children with a diagnosis of medulloblastoma (Goldstein 1997). On a total of about 70,000 Finnish cases of skin basal-cell carcinoma diagnosed between 1953 and 1995, the incidence rate to have a subsequent salivary glands carcinoma was 3.3 fold higher than in the general population (Milan 2000). A more recent study based on 20 survivors from childhood cancer diagnosed at the St. Jude Children’s Research Hospital from 1963 to 2003 reported that they developed a salivary gland neoplasm after the completion of their treatment. The authors concluded that radiation and chemotherapy used to treat patients with childhood malignancies increase the risk of developing a second neoplasm of salivary gland origin (Whatley 2006).
Diet may be effective in preventing salivary glands cancer, especially increasing consumption of fruits and vegetables, particularly those high in vitamin C, and limiting food high in cholesterol (Horn-Ross 1997a). A case-control study conducted in the Chinese population revealed significant protective effect of consumption of dark-yellow vegetables or liver, with about 70% reduced risk of salivary glands cancer among people in the highest intake group of these foods (Zheng 1996). A following study conducted in a different population confirm the protective role of vegetable, even if not statistically significant, and found an increased risk for high intake of alcohol, sweets, starchy foods and a protective role of meats (all non significant).
Among non-diet factors, male sex, a high BMI (obesity), exposure to occupational radiation, family history of cancer, and household income were suggestive of increased disease risk (Forrest 2008).
In a large cohort of Southern European, men with or at high risk of HIV infection was found to be at a very high risk to have a cancer of salivary glands (SIR: 33.6) (Serraino 2000).
An increased incidence of salivary gland carcinoma was shown in workers of a variety of industries, including rubber manufacturing, exposure to nickel compound (Horn-Ross 1997b), and to be employed in hair dressing and beauty shops (Swanson 1997). Occupational exposure to either ionizing radiation or formaldehyde has been linked to this cancer type, as well (Wilson 2004).

2. PATHOLOGY AND BIOLOGY

2.1 Histologic types

The salivary gland tumours are epithelial neoplasms; they are currently classified according to the WHO histological classification published in 2005 (Barnes 2005). This classification includes 24 malignant histotypes. Soft tissue tumours, haematological neoplasms and secondary tumours will be not described in this chapter. Histological classification of salivary gland tumours is evolving and a new WHO classification is under preparation. The importance of tumour grading has become widely accepted, although this may be difficult even for an experienced pathologist.

  • Haematolymphoma tumours
    • Hodgkin lymphoma
    • Diffuse large B cell lymphoma (9680/3)
    • Extranodal marginal zone B cell lymphoma (9699/3)
  • Soft tissue tumours
    • Haemangioma (9120/0)
  • Malignant epithelial tumours
    • Acinic cell carcinoma (8550/3)
    • Mucoepidermoid carcinoma (8430/3)
    • Adenoid cystic carcinoma (8200/3)
    • Polymorphous low-grade adenocarcinoma (8525/3)
    • Epithelial-myoepithelial carcinoma (8562/3)
    • Clear cell carcinoma, not otherwise specified (8310/3)
    • Basal cell adenocarcinoma (8147/3)
    • Sebaceous carcinoma (8410/3)
    • Sebaceus lymphadenocarcinoma (8410/3)
    • Cystadenocarcinoma (8440/3)
    • Low grade cribriform cystadenocarcinoma
    • Mucinous adenocarcinoma (8480/3)
    • Oncocytic carcinoma (8290/3)
    • Salivary duct carcinoma (8500/3)
    • Adenocarcinoma, not otherwise specified (8140/3)
    • Myoepithelial carcinoma (8982/3)
    • Carcinoma ex pleomorphic adenoma (8941/3)
    • Carcinosarcoma (8980/3)
    • Metastasizing pleomorphic adenoma (8940/1)
    • Squamous cell carcinoma (8070/3)
    • Small cell carcinoma (8041/3)
    • Large cell carcinoma (8012/3)
    • Lymphoepithelial carcinoma (8082/3)
    • Sialoblastoma (8974/1)
  • Sebaceous adenoma (8410/0)
    • Lymphadenoma
      • Sebaceous _(8410/0)
      • Non-sebaceus (8410/0)
    • Ductal papilloma
      • Inverted ductal papilloma (8503/0)
      • Intraductal papilloma (8503/0)
      • Sialadenoma papilliferum (8406/0)
    • Cystadenoma (8440/0)
  • Benign epithelial tumours
    • Pleomorphic adenoma (8940/0)*
    • Myoepithelioma (8982/0)
    • Basal cell adenoma (8147/0)
    • Whartin tumour (adenolymphoma) (8561/0)
    • Oncocytoma (oncocytic adenoma) (8290/0)
    • Canalicular adenoma (8149/0)
  • Secondary tumours

*Morphology code of the International Classification of Disease for Oncology (ICD-0) [821] and the Systematized Nomenclature of Medicine. Behaviour is code /0 for benign tumours, /3 for malignant tumours and/1 for borderline or uncertain behaviour.

2.2 Grading

The grade of a tumour (high, intermediate, and low) is supposed to reflect the inherent biological nature of a tumour (aggressive, intermediate or indolent). The term has been used loosely so confusing the attempt to identify the probable biological nature of the tumour. Salivary carcinomas are classified into histological types or families. The majority of the tumours in a family (adenocarcinoma, adenoid cystic carcinoma) have a similar biological nature (but not all). So certain families are known to be high grade or biologically aggressive (anaplastic, carcinoma in pleomorphic adenoma, SCC, high grade mucoepidermoid), some low grade (acinic cell, low-grade adenocarcinoma, polymorphus low grade) and intermediate (adenoidcystic carcinoma). But in addition it is possible in some tumour families to use histological features to identify a subgroup of tumours with indolent or aggressive nature. Adenoid cystic carcinoma and mucoepidermoid carcinoma are the only named tumour graded. Adenoid cystic carcinoma derives from the combination of three distinct histological patterns: tubular, cribriform and solid. The solid variant is associated with the worse outcome (Vander Poorten 1999) and two grading schemes based on the amount of solid pattern in the tumour (>30% (Perzin 1978; Szanto 1984) or >50% (Spiro 1974) are currently in use to define high-grade cases. Recently a new grading system has been proposed, based on the presence or not of solid pattern independently of the amount (van Weert 2015). The grading system for mucoepidermoid carcinoma distinguishes low-, intermediate-, and high-grade tumours based on several morphological parameters (Coca-Pelaz 2015). It is relevant for management and prognosis.
The last method of determining the biological nature of the tumour and the most reliable are clinical features of aggression, size, infiltration, metastasis and they are incorporated in the staging system for salivary gland cancer. The later has taken over from histological type as the main factor directing management. The prognosis of salivary gland tumours appears to correlate mainly with histological subtype. A group of neoplasms exists (e.g., salivary duct carcinoma, oncocytic carcinoma, squamous cell carcinoma, large cell carcinoma), which are considered as high-grade tumours with poor prognosis. These showed a high tendency to recur locally and frequent distant metastases (Seethala 2011).

2.3 Chromosomal rearrangements

Chromosomal rearrangements are uncommon in salivary glands carcinomas. In adenoid cystic carcinoma, MYB activation is the most relevant oncogenic event, being present in at least 80% of the cases. MYB can be activated by MYB-NFIB gene fusion that derives from the t(6;9) translocation, involving the MYB oncogene and the transcription factor gene NFIB; copy number gain or insertion of the 3’-part of NFIB near the MYB locus are other mechanisms activating MYB (Ho 2013a; Stephens 2013). MYB represents a useful hallmark in doubtful adenoid cystic cases as well as a potential new target for novel therapies.
The fusion of MALM2 and the CRTC1 genes was reported in mucoepidermoid carcinomas. This is a tumour specific translocation t(11,19), almost found in low and in intermediate-grade mucoepidermoid carcinoma and correlates with a favourable prognosis (Stenman 2014). The oncoprotein deriving from the fusion acts disrupting a NOTCH signalling pathway (Tonon 2003). Although high-grade MEC might harbour the fusion gene, most of them are generally fusion negative.
EWSR1rearrangements have been reported in hyalinising clear cell carcinoma and in myoepithelial carcinoma. EWS1 rearrangements have been described also in soft tissue myoepithelial tumour (SMET) where different genes can be pattern of rearrangements, resulting in several fusion transcripts (i.e., EWSR1-ZNF444, EWSR1-PBX1 or EWSR1-POU5F1). Only EWSR1-ATF1 fusion product has been described in hyalinising clear cell carcinoma, becoming a useful diagnostic tool of this rare subtype (Weinreb 2013).
The mammary analogue secretory carcinoma (MASC) is a new pathology entity described for the first time few years ago. MASC shares with the secretory carcinoma of the breast several histological and immunohistochemical characteristics including a chromosomal translocation t(12,15) (p13;q25) which leads to a fusion gene between the ETV6 gene on chromosome 12 and the NTRK3 gene on chromosome 15 (Skalova 2013; Fehr 2011). ETV6-NTRK3 fusion gene has not been described in any other salivary glands carcinomas although it has been reported in other malignant tumours as congenital fibrosarcoma, congenital cellular mesoblastic nephroma, and acute myeloid leukaemia. The fusion protein promotes cell proliferation and survival.

2.4 Biological targets

Tyrosine kinase (TK) and hormonal receptors are the most investigated targets. EGFR is the most expressed TK receptor (70%) in salivary gland carcinomas and its expression is detected in almost all malignant histotypes (Locati 2009). No correlation has been found between EGFR expression and gene amplification analysis (Locati 2009). HER2 is present in particular in histotypes derived from the excretory duct, such as salivary duct cancer. A correlation between HER2 3+ and gene amplification is found in at least 57 to 73% of cases (Skalova 2003; Dagrada 2004). Both HER2 overexpression and gene amplification seems to correlate with a worse prognosis (Press 1994). Mutation in PIK3CA (20%-33%) and deletions of PTEN (50%-59%) have been described in HER2 negative salivary duct carcinoma (Piha-Paul 2011; Nardi 2013); BRAF activating mutations have been reported in 7% of the cases (Griffith 2013). C-kit is expressed mostly in histotypes originated from intercalated duct as adenoid cystic carcinoma, as well as in other malignant histotypes and benign tumours (Andreadis 2006; Chandan 2004). None genetic mutations at exons 11 and 17 have been found and an autocrine/paracrine loop seems to be the most likely c-kit activation mechanism (Holst 1999; Jeng 2000; Sorensen 2006). TrkC/NTRK3 signalling pathway has been reported to be activated in preclinical experiments in adenoid cystic carcinomas (Ivanov 2013). Mutation in RAS pathway (BRAF and HRAS) have been described (Wetterskog 2013) as well as in the NOTCH pathway (13%) and in the FGF-IGF-PI3K signalling pathway (30%) (Ho 2013a; Stephens 2013).
Neurotrophic tyrosine kinase receptor, type 1 (TRK-A) is commonly present in normal salivary gland tissue but it is also overexpressed and activated in 66% of salivary duct carcinomas and in 25% of adenoid cystic carcinomas, respectively (Negri 2008). Oestrogen and progesterone expression is very rare and it has been found both in benign and malignant salivary gland tumours (Glas 2002). Androgen receptor (AR) expression is uncommon and it is mainly restricted to salivary duct carcinoma (70% of the cases). AR activation is not sustained by gene amplification; gene copy number gain, alternative AR isoform (AR-V7/AR3) equal to those reported in hormone resistant prostate cancer and AR mutations have been identified (Mitani 2014).

3. DIAGNOSIS

3.1 Signs and symptoms

3.1.1 Major salivary gland tumours

The rate of malignant tumours is inversely correlated to the glandular size: 15-32% in parotid gland, 41-45% in submandibular gland and 70-90% in sublingual gland. Every painless swelling of a salivary gland must arouse suspicion, especially if there are no signs of inflammation. These tumours have a range of biological behaviours. About 40% of tumours are indolent (especially in young people <40y) and present as slow growing lumps; a similar percentage is aggressive (especially in the elderly) and facial palsy may be a presenting feature. Clinical indicators suggesting a malignant salivary gland tumour are: rapid growth rate, pain, facial nerve involvement, and neck nodes. Every sign of facial nerve palsy, complete or partial, is always a sign of a locally infiltrating parotid cancer. Clinical presentation may also be characterised by parapharyngeal or palatal or palatal fullness. Trismus, skin ulceration and fistulas can be present in very advanced malignancies. On the other hand, a slow growth of an asymptomatic mass does not exclude a malignant nature.

3.1.2 Minor salivary gland tumours

There are between 450 and 750 minor salivary glands distributed in the upper aerodigestive tract, in the palate, paranasal sinuses and nasal cavity, tongue, floor of mouth, gingiva, pharynx, larynx and trachea. About one half of the tumours that arise in these glands are malignant. The incidence of malignancy depends on the site of occurrence. In the palate the rate is similar to the submandibular gland, 40%-60%. But as you go from the tongue to FOM, the incidence increases till to 90%. The signs and symptoms depend on size and position of the tumour. They may vary because of their diverse locations. More than 50% of them are intraoral and usually cause a painless submucosal swelling. The mucosal layer is frequently adherent to the mass; a small ulcer could be also present. Tumours arising in the oropharyngeal area can cause a painless lump. If the nasopharynx or the nasal cavity is infiltrated this may cause facial pain, nasal obstruction or bleeding. If the tumour occurs in the larynx, trachea or bronchus it can cause hoarseness, voice change, dyspnoea or cough.

3.2 Diagnostic strategy

Physical examination is the most important tool for diagnosis. Since approximately 80% of salivary gland tumours arise in the parotid and approximately 80% of them are benign, the initial diagnostic strategy should include differential diagnosis with other benign conditions, such as cysts, inflammatory processes and lymph node hyperplasia. When a malignant lesion is suspected, pathological diagnosis is needed. Ultrasonography is a low cost modality with high sensitivity (approximately 100% – similar to CT scan) and it is always recommended as preoperative examination, since approximately 90% of tumours arise in the superficial lobe. Ultrasound proves excellent for differentiating intraglandular from extraglandular lesions. It is not able to show part of the deeper parotid lobe that could be investigated by CT or MRI. This latter is recommended in demonstrating the interface of tumour and surrounding tissues for a correct surgical planning, especially for larger tumours (more than 4 cm) and for those tumours arising in deep structures and/or involving them. The advantages of MRI over CT include also the elimination of dental artifacts and the ability to distinguish between a tumour and an obstructed secretion. MRI imaging is also recommended in minor salivary gland cancers arising in oral and nasal cavity, paranasal sinuses where the full extent of the neoplasm usually cannot be defined by clinical examination alone.

3.3 Pathological diagnosis

If there is frank evidence of malignancy and destructive surgery in the form of neck dissection and total parotidectomy is considered then some form of tissue biopsy is indicated. Open or true cut- spillage is not a problem because all the tissues around the biopsy will be resected. The penalty of using such radical surgery to treat a parotid tuberculosis or a lymphoma is obvious. The dilemma arises in the presence of an indolent cancer masquerading as a benign tumour. In this circumstance the clinician is reliant principally on clinical skill. An experienced clinician should be able to distinguish between the two in 90% of cases (Renehan 1996) (660 apparently benign lumps of which 30 were malignant) and with the additional benefit of fine needle aspiration cytology (FNAC) the risk of treating a malignant tumour inadvertently is reduced even further. FNA has a high sensitivity and specificity with the accuracy ranging from 87% to 96% (Gal 1996) but the technique is operator sensitive. Sensitivity ranges between 73% and 86.6% both in malignant and in benign tumours while specificity was noted to be usually better in benign than in malignant tumours (97% vs. 85%) (Riley 2005). False negative diagnoses due to inadequate sampling appear to be the most frequent error. It enables to discriminate between a primary salivary tumour and a pathological lymph node in the case of a periglandular nodule. Unnecessary surgery can be avoided in about one third of cases (Ellis 1996). Repeated aspirations may be useful in order to diagnose a tumour with cystic degeneration, which is relatively frequent in mucoepidermoid carcinoma. The risk of seeding along the needle route has been demonstrated to be negligible. In spite of these observations, FNAC should be left to clinical discretion. It is cheap, simple to perform and in appropriate hands is quite accurate. Morbidity is very low and seeding has not been reported. FNA has a particular role in cases where the suspected pathological diagnosis would change the therapeutic strategy. It is strongly recommended when a salivary tumour is not suspected such as tuberculosis, lymphoma, or an enlarged lymph node as is frequently the case in children or those with autoimmune disease. In children there is a second reason for considering FNAC. The ratio of malignant to benign tumours is higher than in adults even though these cancers are normally indolent in nature. If mistaken for a benign tumour and inadequately excised then either further surgery may be required placing the facial nerve at risk or adjuvant RT may be considered. Radiotherapy has significant adverse effects on facial growth that can lead to subsequent facial deformity. FNAC may help the surgeon to avoid this situation. Salivary gland enlargement is normally of inflammatory origin mainly represented by inflammatory neoplasm or benign cyst while epithelial tumours are very uncommon, particularly in the submandibular gland (Guzzo 2006). Open biopsy is not usually recommended due to the risk of seeding. In the presence of small masses in minor salivary glands (palate, tongue) punch biopsy (dermatological punch) may be preferable to direct excision, unless the latter provides adequate margins, should the lesion prove to be malignant. The accuracy of frozen section diagnosis is quite controversial. False-positive rates account for 1.1 %, false-negative rates were 2.6%. The accuracy rate is better for benign tumours than for malignant lesions (98.7% vs. 85.9%) (Gnepp 2001). Examination of frozen sections of the removed specimen, including periglandular lymph nodes, is used by several surgeons to plan immediate neck dissection. This procedure has several limitations since it may be difficult to differentiate between various histotypes.

4. STAGING

4.1 TNM classification 7.0 (Sobin 2009)

This classification is applied only to major salivary glands tumours. Tumours arising in minor salivary glands are included in the classification of their anatomic site of origin (Table 1).

Table 1. TNM Classification, 7th edition.
Primary Tumour (T)
TX Primary tumour cannot be assessed
T0 No evidence of primary tumour
T1 Tumour 2 cm or less in greatest dimension without extraparenchymal extension*
T2 Tumour more than 2 cm but not more than 4 cm in greatest dimension without extraparenchymal extension*
T3 Tumour more than 4 cm and /or tumour with extraparenchymal extension*
T4a Tumour invades skin, mandible, ear canal, or facial nerve
T4b Tumour invades base of skull pterygoid plates or encases carotid artery.
Note: * Extraparenchymal extension is clinical or macroscopic evidence of invasion of soft tissue or nerve, except those listed under T4a and T4b. Microscopic evidence alone does not constitute extraparenchymal extension for classification purposes.
Regional Lymph Nodes (N)
NX Regional lymph nodes cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension
N2 Metastasis as specified below
N2a Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension
N2b Metastases in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension
N2c Metastases in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension
N3 Metastasis in a lymph node more than 6 cm in greatest dimension
Note: Midline nodes are considered ipsilateral nodes.
Distant Metastases (M)
M0 No distant metastases
M1 Distant metastases
Table 2. Stage grouping.
Stage Anatomic sites
I T1; N0; M0
II T2; N0; M0
III T3; N0; M0
T1,T2,T3; N1; M0
IVA T4a,T4b; N0,N1; M0
T1,T2,T3,T4a; N2; M0
IVB T4b, Any N, M0
Any T, N3, M0
IVC Any T, Any N, M1

4.2 Staging procedures

Physical examination with consideration of facial nerve function and good clinical judgment represents the most important factors in clinical decision making ultrasonography can compliment these investigations and has the advantage of being less expensive alternative and can be used to aid in core biopsy of the glands. Head and neck CT scan and/or MRI are recommended in the presence of malignant disease, although the latter is the preferred imaging for staging the primary tumour. MRI (slice thickness ≤3 mm) with contrast is able to accurately assess the perineural spread as well as the extension of disease in the soft tissue. Contrast CT scan (slice thickness 0.6-1 mm) has some advantages over MRI: it takes less time, it is extendible to lung and abdomen if necessary, and it is more accurate in the study of bone. Chest-x-ray is considered enough to exclude lung metastases, second level examinations (i.e., Thorax CT) will be carried out in case of clinical suspicious. While the use of 18-FDG PET/CT in primary tumour staging is controversial, it seems to have a role in selected advanced or recurrent high-grade cases to exclude distant metastases. 18-FDG PET/CT is not routinely recommend in low-grade tumours. 11-C-methionine PET/CT seems to be advantageous to individualize the treatment strategy in patients with adenoid cystic carcinoma where a high residual uptake post-carbon ions RT correlates with a poor outcome (Toubaru 2013).

5. PROGNOSIS

5.1 Natural history

Malignant tumours of the salivary glands show widely different patterns of growth. The most common ones (adenoid cystic, low-grade mucoepidermoid carcinoma, acinic cell carcinomas) frequently grow slowly, sometimes so slowly that they are mistaken for benign or non-neoplastic lesions, especially in the major salivary glands. In other cases they can be locally aggressive in all of their primary sites, with invasion of surrounding tissues (fasciae, muscles, nerves, bone, and skin). Invasiveness usually extends parallel to the grading, which accounts for both local recurrences and spreading. Lymphatic spread is generally less frequent than that of epidermoid carcinoma arising from digestive and respiratory mucosae, but it can be very frequent in some particular histotypes, such as salivary ductal carcinomas, high-grade mucoepidermoid carcinomas, carcinomas ex pleomorphic adenoma squamous cell carcinomas. Lymphatic spread is not frequent in polymorphous low-grade adenocarcinoma (range 9-15%), it is rare in low-grade mucoepidermoid carcinoma and in adenoid cystic carcinoma, in which the prevalent spread follows the perineural sheets. An exception is adenoid cystic carcinomas with high-grade transformation where the risk of neck node metastasis ranges from 43% to 57%. A prophylactic neck dissection or adjuvant radiotherapy is advisable in this specific clinical situation (Hellquist 2016). Distant haematogenous metastases are the main cause of death in malignant salivary gland tumours. Their frequency varies with histology and it mainly depends on the grading, but their clinical course can be very different. Distant metastases are located with the highest frequency in the lungs (80% of distant location), followed by bone (15%), liver, and other sites (5%). Adenoid cystic carcinoma, adenocarcinoma NOS, carcinoma ex-mixed tumour, small cell carcinoma and salivary ductal carcinoma show the highest distant metastases rate (up to 50%). Distant metastases from adenoid cystic carcinoma show a particularly slow evolution with survivals reaching up to 20 years. Metastasizing pleomorphic adenoma is a rare histologically benign adenoma that inexplicably manifests local or distant metastases. This tumour is characterized by multiple local recurrences and a long interval between development of primary tumour and its metastases. Metastases usually occur to bone (50%) followed by lung and lymph nodes (30% both) (Chen 2000). All these remarks should be taken into consideration for treatment planning. Survival strongly correlates with clinical stage and grade (Table 3).

Table 3. Survival of the most common major salivary gland malignancies.
Histology (WHO 2005) 5-year survival (%)
References
Polymorphous low-grade adenocarcioma 95-100 (Castle 1999; Evans 2000)
Acinic cell carcinoma 75-96 (Witt 2004; Hickman 1984)
Mucoepidermoid carcinoma (low grade) 75 – 89 (Witt 2004; Guzzo 2002; Clode 1991)
Myoepitelial carcinoma
67 (Nagao 1998; Di Palma 1993)
Mucoepidermoid carcinoma (high grade) 23-50 (Witt 2004; Guzzo 2002; Clode 1991)
Adenoid cystic carcinoma
35-70 – (10-years DFS 10-20) (Hamper 1990; Perzin 1978)
Carcinoma ex pleomorphic adenoma 40 (30-96 correlated with histology) (Witt 2004; Tortoledo 1984; Lewis 2001)
Salivary duct carcinoma
4-years DFS 20-35 (Guzzo 1997; Barnes 1994)

5.2 Prognostic factors

Tumour stage, histology, grading, linfovascular invasion, facial nerve paralysis, extraparotid tumours extension, and cervical node involvement are the most important tumours-related predictors of survival and all are able to influence treatment outcomes (Hocwald 2001; Bhattacharyya 2002; Frankenthaler 1991; Spiro 1992; Hosni 2016). Patient’s age and positive surgical margins along with the prognostic factors reported above have to be considered as the main issues for loco-regional control in parotid gland cancer (Carrillo 2007; Chen 2007). Neural spread is commonly reported in adenoid cystic carcinoma also in early stage and it correlates with a worse outcome. Very recently intraneural invasion has been reported to be independently associated to a poor prognosis (Amit 2014a). Solid histological feature correlates with worse prognosis, advanced stage and distant metastases (Vander Poorten 1999). High-expression of Ki-67 and VEGF are independent prognostic factors of poor overall survival (Park 2016). The site of the disease seems to influence the outcome of patients with adenoid cystic carcinoma, having nasal cavity, pharynx and larynx a worse 5-yr survival rate than major salivary glands and oral cavity (Ciccolallo 2009). In case of epithelial-myoepithelial carcinoma, margin status, angiolymphatic invasion, tumour necrosis and myoepithelial anaplasia seem the most important predictors of recurrence (Seethala 2007). The presence of CRTC1-MAML2 gene fusion in low-grade and intermediate-grade of mucoepidermoid carcinoma correlates with a good prognosis (Seethala 2010; Jee 2013). Among the minor salivary glands carcinomas, site of occurrence (e.g., larynx, nasal cavity, paranasal sinus); age >75 years; histotype (adenoid cystic carcinoma, adenocarcinoma, mucoepidermoid carcinoma and other rare tumours), stage at diagnosis, grade, and treatment (no surgery vs. surgery) also seem effective in predicting prognosis (Amit 2014b; Baddour 2016).

5.3 Predictive factors

The factors predicting the response to treatment are probably growth rate (short interval between primary treatment and occurrence of distant metastases) and high malignancy grade, although this has not been substantiated in the literature.

6. TREATMENT

6.1 Treatment strategy

The standard treatment of resectable carcinomas of the major and minor salivary glands is surgical excision, on a type C basis. A routine prophylactic neck dissection is not recommended. However, it is standard in selected cases. Postoperative radiotherapy is recommended on a type R basis in selected patients. Primary radiotherapy is recommended, on a type R basis, for patients who refuse surgery or who are suffering from an inoperable/unresectable tumour. For both major and minor salivary gland tumours chemotherapy is only suitable for individual clinical use, on a type 3 level of evidence, in a palliative fashion for unresectable relapsing disease, for patients not amenable to radiotherapy, and for patients with metastatic disease.

6.2 Major salivary gland tumours

6.2.1 Local and locoregional disease

The treatment of salivary gland tumours, more than most other neoplasms, has to be individualised to each patient. It is for this reason that experience is important. In malignant disease, many clinical decisions are dictated by practical issues. If the tumour is stage III or IV then it is highly likely that a wide resection is envisaged and the neck will be entered for purposes of access. The old adage that has stood the test of time is that «if one enters the neck for any reason one should proceed to some form of neck dissection». So the option of an elective neck dissection tends to arise in stage-I and stage-II disease.
The standard treatment, on a type C basis, of resectable carcinomas of the major salivary glands is a well planned and carefully executed surgical excision. This is particularly so in the submandibular gland where wide excision in continuity with some form of neck dissection as the primary procedure has been shown to have a survival advantage. In general lymph node metastases are low (14% to 20%) (Stennert 2003) and more frequently in high-grade and advanced T-stage tumours and (or) in presence of extracapsular extension or facial paralysis irrespective of histology (Scianna 2007; Bell 2005; Bhattacharyya 2002; Armstrong 1992). In such patients a selective prophylactic neck dissection may be appropriate on a type R basis. Conventional neck dissection is standard treatment in each patient with nodal involvement. Selective neck dissection should include levels I, II, and III in cancer of the submaxillary-sublingual glands, and levels IB, II, III, IV, and VA in parotid cancer. Modified radical neck dissection is an acceptable treatment for N1 neck, if the node is mobile and for selected N2b necks (3 cm, mobile) on a type 3 level of evidence (Ferlito 2001; Gavilan 1989; Lingeman 1977; Molinari 1980).
Superficial parotidectomy with facial nerve dissection is considered the primary diagnostic procedure of choice for all parotid neoplasms as well as the therapeutic procedure for malignant tumours that occur in the superficial lobe of the gland. Conversely, enucleation will result in higher rates of recurrence and facial nerve dysfunction. Partial superficial parotidectomy, as described by Leverstein, seems to be safe and effective in treating benign tumours (Leverstein 1997).
In the case of large extension into the parapharyngeal space, the surgical exposure of the deep lobe may be achieved also by cervical approach and/or may require mandibulotomy. A balance between eradicating the tumour and preserving the facial nerve is warranted. Radical parotidectomy including the facial nerve is the standard option, on a type C basis, if the tumour is adherent or infiltrative to other structures (preoperative facial palsy, skin involvement). Immediate nerve grafting is recommended in patients under 65 years. For older patients only rehabilitative local procedures are recommended.
Extraparotid tumour extensions may need skin excision, mandibulectomy or partial resection of maxilla and temporal bone. Retromandibular parotid gland tumours need a transcervical approach, only a few may need a mandibulectomy for access. Reconstruction is dependent on the kind of defect. For submandibular tumours excision of the whole gland alone is occasionally adequate treatment when the lesion is small and well confined to the parenchyma and of low-grade histology.
In every other case, an adequate resection is recommended, including the bed of the gland and any adjacent structure in contact with it, up to a real suprahyoid dissection (removal of levels I, II and III lymph nodes). This procedure provides tissue for diagnosis and it also removes the primary echelon lymph nodes at risk for metastasis (Weber 1990). In all locations, postoperative radiotherapy is recommended, on a type R basis, for patients with residual disease after surgery (e.g., R1, R2), in the presence of extensive nodal involvement (e.g., more than 3 metastatic nodes) and extracapsular spread. Postoperative radiotherapy is suitable for individual clinical use, on a type 3 level of evidence for high-grade tumours, and/or in the presence of vascular/perineural invasion, and/or in the presence of advanced disease (facial nerve involvement, deep lobe involvement (Borthne 1986; Elkon 1978; Fitzpatrick 1986; Harrison 1990; McNaney 1983; North 1990).
Adjuvant RT could be omitted for patients with grade-1 adenoid cystic carcinoma, pT1N0 R0 and no perineural invasion (Mendenhall 2004).
If in the past two-dimensional or conformal RT techniques were the standard, nowadays new techniques as intensity modulated RT (IMRT) are currently employed. IMRT is recommended for irradiation of named nerves to the skull base in cases of perineural diffusion (Hosni 2016). Local control was significantly improved with doses to tumour bed/original tumour volume of 60 Gy with standard fractionation (1.8-2 Gy per fraction). Doses of at least 56-63 Gy should be administered to the skull base if consistently included. For patients with minimal residual disease after surgery (R1-resection) a minimum dose of 66 Gy photons in daily fractions of 1.8-2 Gy with conventional fractionation is advisable. Patients with postsurgical macroscopic disease (R2-resection), with unresectable primary tumours or with inoperable recurrent tumours should be given doses of >65 Gy photons (70 Gy photons for gross residual disease). Irradiation of the adjacent neck lymph nodes should be given with 50-60 Gy photons if there is tumour involvement.
After a neck dissection, irradiation of the neck is optional. Elective neck irradiation in case of clinically negative necks reduced the 10-year nodal failure rate from 26% to 0% (Chen 2007).
There is a rationale in the use of particle beam radiotherapy in SGCs. Advantages in comparison to photons are the capability to overcome radioresistance of SGCs and the higher ability to spare organs at risk. No comparison data with photons are available, thus the use of particles RT in an adjuvant setting after an R0 or R1 resection is not supported, whilst it has to be considered in case of unresectable and R2 disease (see paragraph 6.3). The same considerations apply for minor salivary glands carcinomas.
The role of postoperative chemo-radiation is currently under investigation in a randomized RTOG trial. In two retrospective studies, postoperative chemo-radiotherapy obtained a better local control over radiotherapy alone (Schoenfeld 2012; Tanvetyanon 2009).

6.3 Minor salivary gland tumours

6.3.1 Local disease and locoregional disease

Minor salivary gland tumours may arise anywhere in the head and neck. Local and loco-regional surgical excision is the recommended treatment. In general, the treatment of these tumours follows the pattern adopted for squamous cell carcinomas arising in the upper aerodigestive tract. A low rate of cervical lymph nodes metastases has been reported (Terhaard 2004; Strick 2004). Therefore, there is probably little benefit from elective neck dissection for patients with small and low-grade tumours of the minor salivary glands. Postoperative radiotherapy is recommended, on a type R basis, in patients with advanced disease.

6.4 Unresectable/inoperable locoregional disease

In cases of unresectable/inoperable loco-regional disease definitive radiotherapy is recommended, on a type 2 level of evidence. Photons or particle radiotherapy can be employed. Long-term loco-regional control rates with photons are lower than 50% and 20% for adenoid cystic carcinoma and non-adenoid cystic carcinoma, respectively. Most of the data on particle therapy derive from patients with adenoid cystic carcinoma. Although neutrons obtained a significant improvement in 2-year loco-regional control over photons (67% vs. 17%), they are not routinely employed due to the high rate of late severe toxicities and a doubtful benefit over photons in terms of therapeutic index as well as the lack of direct comparison with modern photons RT such as IMRT. Carbon ions seem to have more biological advantages over protons; however, both these particles were able to obtain a better 5-yr local-control (66-68%) and overall survival over photons alone, supporting their use in advanced adenoid cystic carcinomas.

6.5 Local relapse

Surgery, irradiation and re-irradiation are suitable for individual clinical use, on a type R basis for local relapse. Endpoints of treatment are frequently palliative. If reirradiation is possible, highly conformal techniques such as IMRT or stereotactic RT with a sufficiently high dose to the gross tumour volume (at least 60 Gy with conventional fractionation) should be used (Sulman 2009). Re-irradiation with carbon ions was reported in 58 patients with adenoid cystic carcinoma with weak toxicities and encouraging response rate (Jensen 2015).
If surgery and irradiation are not feasible, then palliative chemotherapy (see paragraph 6.6) may be considered.

6.6 Regionally relapsing disease

The standard treatment for late regional lymph-node metastases is modified radical or classic radical neck dissection, according to the extension of the disease. Postoperative radiotherapy is recommended for patients with massive involvement of the neck nodes (more than 3 nodes) or in the presence of capsular rupture. Recurrence within the field of a previous neck dissection can be treated with radiotherapy or surgical excision, if possible, but the prognosis is dismal.

6.7 Metastatic disease

Carcinomas of the salivary glands may metastasize to lymph nodes, lung, liver and bone. Distant metastases develop with wide variably according to the histology. Metastases are rare in low-grade tumour (i.e., low-grade mucoepidermoid carcinoma, polymorphous low-grade adenocarcinoma or clear cell carcinoma). High-grade salivary duct carcinoma shows distant metastases in about 46% of the cases. High-grade mucoepidermoid and acinic cell carcinomas develop themselves in 5% to 16% of cases. Metastases from adenoid cystic carcinoma range from 25%-55% and usually show an indolent asymptomatic course. Solitary metastases of lung and liver can be resected. Lung metastasectomy in a highly selected subset of patients provides a prolonged freedom from progression but whether this could be translated into a survival benefit, is still a matter of debate (Locati 2005).
Bone metastases are rare, but if there is the risk of fracture or drug-resistant pain, radiotherapy is recommended. Palliative chemotherapy is suitable for individual clinical use, on a type 3 level of evidence. In adenoid cystic carcinoma, chemotherapy is generally deserved in case of progressive and/or symptomatic disease, while in the other circumstances a watchful waiting is generally suggested.
The most studied regimen, consisting of cyclophosphamide plus doxorubicin plus cisplatin (CAP), produced response rates ranging from 22% to 100%, and complete responses in up to 40% depending on sample size. Data derived from the combination of carboplatin with paclitaxel have not gained better results (Airoldi 2000). The best single-agent activity has been reported for cisplatin, 5-fluorouracil (5-FU) or doxorubicin, albeit in small series of patients. Is still not clear whether combination chemotherapy has any advantage over single agent chemotherapy (Airoldi 1994; Alberts 1981; Belani 1988; Creagan 1988; Dimery 1990; Douglas 1996; Jones 1993; Licitra 1991; Licitra 1996; Posner 1982; Schramm 1981; Triozzi 1987; Venook 1987).
Chemotherapy activity seems to be histotype driven. It has been suggested that patients with adenocarcinoma, adenoid cystic carcinoma, acinar cell carcinoma, and malignant mixed tumours are similarly sensitive to the CAP regimen. Patients with mucoepidermoid and undifferentiated tumours, however, appear to respond better to those drugs active against squamous cell carcinomas (e.g., cisplatin, 5-FU, methotrexate) (Kaplan 1986). Paclitaxel seems to be active in histotypes other than adenoid cystic carcinoma (Gilbert 2006); gemcitabine also resulted in none activity in ACC.
Patients responding to chemotherapy have not been documented to have a survival benefit over non-responding patients. However, the palliative effect of chemotherapy was often pronounced. The employment of anti-androgen blockade is suitable for individual clinical use in selected AR-expressing advanced salivary gland tumours (van der Hulst 1994; Jaspers 2011; Locati 2016). An international randomized trial to assess the efficacy of androgen blockade over chemotherapy is currently ongoing as well as a phase II trial to test the activity of abiraterone (Locati 2014) after progression under androgen-deprivation therapy. The employment of target therapies is not recommended out of clinical trials. Among phase II trials on biological treatment, there are no activities verified for imatinib, trastuzumab, gefitinib, cetuximab, lapatinib, bortezomib (Hotte 2005; Glisson 2005; Licitra 2006; Agulnik 2007). A very modest response rate has been reported for dovitinib, dasatinib and vorinostat in adenoid cystic carcinoma (4.5%, 2.5%, and 7%, respectively) (Keam 2015; Wong 2016; Argiris 2011). Antiangiogenic agents in adenoid cystic carcinoma showed no activity in case of sunitinib (Chau 2012) and a weak response rate with axitinib (9%) (Ho 2013b) and sorafenib (11%) (Locati 2013; Thomson 2015). A remarkable activity of sorafenib has been reported in two high-grade mucoepidermoid carcinomas (Locati 2013).

7. LATE SEQUELAE

7.1 Treatment late effects and sequelae

Facial nerve morbidity is more likely to occur as a complication of treatment of malignant tumours. Temporary postoperative paresis is quite common (range 8%-38%). Conversely, definitive facial nerve paralysis is rare and it strictly depends on whether surgical intervention is performed on a primary tumour or on a local recurrence. In fact, in the former it occurs in about 1% of cases, while in the latter it occurs in 15%-40% of patients (Helmus 1997; Stevens 1982; Myssiorek 1990).
It has been shown that nerve sacrifice is rarely necessary, unless the nerve is directly involved in the tumour area. Furthermore, radical resection is often not necessary if postoperative radiotherapy is given (Witt 2004). Additional postoperative sequelae are salivary fistulae and neuromas of the greater auricular nerve.
Minor complications are more common after parotidectomy: Frey’s syndrome (local facial sweating and flushing during meals) occurs in varying degrees in 20% to 40% of cases; anaesthesia in the periauricular skin is almost constant (Simpson 1987).
Sequelae due to radiotherapy should be divided into acute and late side-effects. Mild acute side effects consist of skin erythema, mucositis, and dysphagia. Severe acute side effects manifest as desquamation and mucosal ulcers. Late side-effects consist of telangiectasia, permanent taste impairment, subcutaneous fibrosis, xerostomia, and otitis externa or media associated with partial hearing loss and pain (McNeese 1989; Moss 1994). Bone necrosis rarely occurs.

7.2 Related and secondary tumours

Second tumours may occasionally arise in irradiated areas. The latent period for development of the irradiation-induced cancers varies from 10 to 25 years.

8. FOLLOW-UP

8.1 General principles and objectives

The aims of follow-up in disease-free patients are early recognition of loco-regional relapse, to allow for effective salvage treatment and early recognition of treatment complications (i.e., xerostomia and trismus) and their treatment. As for other malignancies, there are no evidence-based strategies to perform follow-up in SGCs.
Follow-up appointments are scheduled on an individual basis determined by risk of occurrence. Periodical examinations should be carried out by head-and-neck surgeons along with radiation or medical oncologists and dentists, when the patient received RT/CT.
Distant metastases represents the main cause of treatment failure (33%), followed by neck metastasis (22%), and local relapse (13%) (Terhaard 2004).
The relative risk depends on tumour grade and stage, positive nodal disease, facial nerve involvement, and extraparenchimal extension. 70% of local recurrences are observed within three years, except in cases of low-grade tumours and adenoid cystic carcinoma. Consequently, during this period patients should be strictly followed-up.
According to the individual patient’s characteristics a proper schedule could be as follows:

  • 1st year post treatment: every 3 months;
  • 2nd year: every 4 months;
  • 3rd, 4th, and 5th year: every 6 months;
  • after 5 years: every 12 months.

Salivary gland malignancies require a prolonged follow-up period for true measures of clinical outcome, in particular in the case of low-grade tumours and adenoid cystic carcinomas. Yearly chest X-ray can be considered in high-grade tumours, in submandibular and minor salivary gland cancers, on a type R basis, as these are associated with frequent occurrence of pulmonary metastases. Chest CT scan should be performed in cases of local relapse, when salvage treatment is planned. Head and neck MRI could be planned each 6 months for the first three years, than yearly.

INDEX

 

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Dr. Gemma Gatta (Consultant)
Italian National Cancer Institute – Milan, Italy
mail: gemma.gatta@istitutotumori.mi.it

Dr. Marco Guzzo (Author)
Italian National Cancer Institute – Milan, Italy
mail: marco.guzzo@istitutotumori.mi.it

Dr. Laura Locati (Author)
Italian National Cancer Institute – Milan, Italy
mail: laura.locati@istitutotumori.mi.it

Dr. Mark McGurk (Reviewer)
King’s College – London, United Kingdom
mail: mark.mcgurk@kcl.ac.uk

Prof. Franz Josef Prott (Author)
St. Josefs-Hospital – Wiesbaden, Germany
mail: prott@stahlentherapie-wiesbaden.de