## Incidence and epidemiology
Major salivary gland cancers (SGCs) comprise 5% of head and neck cancers in Europe. The worldwide crude and ageadjusted incidence rates are 0.69 and 0.57 cases per 100 000 people per year, respectively, with 53 583 new patients in 2020. In Europe, crude and age-adjusted incidence rates are 1.3 and 0.67 cases per 100 000 people per year, respectively, with 9917 new patients in 2020.Data for minor SGCs are limited, but the RARECARENet project estimated the crude incidence of minor salivary gland-type cancers of the head and neck to be 0.4 cases per 100 000 people in the 2000-2007 diagnosis period; minor SGCs have a slight predominance in males and incidence is highest in the elderly (>65 years).History of head and neck cancer and cervicofacial radiotherapy (RT) have both been associated with an increased risk of major SGC [odds ratio (OR) 17.06, 95% confidence interval (CI) 4.34-67.05 and OR 31.74, 95% CI 2.48-405. [bib_ref] Management of salivary gland tumours: United Kingdom National Multidisciplinary Guidelines, Sood [/bib_ref] , respectively]. [bib_ref] Risk factors for salivary gland cancers in France: results from a case-control..., Radoi [/bib_ref] [bib_ref] Current state of knowledge on salivary gland cancers, Lin [/bib_ref] Industries such as cereal and other crop production, furniture manufacturing, interurban road transport and industrial cleaning have also been associated with an increased risk of major SGC. [bib_ref] Risk factors for salivary gland cancers in France: results from a case-control..., Radoi [/bib_ref] [bib_ref] Current state of knowledge on salivary gland cancers, Lin [/bib_ref] [bib_ref] Air pollution from industrial waste gas emissions is associated with cancer incidences..., Cong [/bib_ref] Smoking only seems to increase the risk of developing major SGCs other than mucoepidermoid carcinoma (MEC) (OR 5.15, 95% CI 2.06-12.87) [bib_ref] Heterogeneous impact of smoking on major salivary gland cancer according to histopathological..., Sawabe [/bib_ref] ; however, ionising radiation is the only wellestablished risk factor. [bib_ref] Incidence of carcinoma of the major salivary glands according to the WHO..., Boukheris [/bib_ref] SGCs include >20 distinct histological subtypes. Given their rarity and heterogeneity, population-based epidemiological studies providing incidence rates according to histology are limited.
SGC typically occurs in the sixth and seventh decades of life and has a male predominance 2 ; however, age at diagnosis and gender predominance vary by histology. MEC, adenoid cystic carcinoma (AdCC) and acinic cell carcinoma (AcCC) tend to occur at an earlier age than adenocarcinoma and squamous cell carcinoma (SCC). MEC, AdCC and AcCC are more common in females up to w50 years of age; however, incidence of AdCC and AcCC is similar for females and males at older ages, whereas MEC has a higher incidence rate among older males. [bib_ref] Incidence of carcinoma of the major salivary glands according to the WHO..., Boukheris [/bib_ref] The ratio of tumour diagnoses in parotid, submandibular, minor and sublingual subsites is 100:10:10:1, and the proportion of malignant tumours at these sites is 20%, 50%, 50% and 80%, respectively. [bib_ref] Incidence of salivary gland neoplasms in a defined UK population, Bradley [/bib_ref] SGC incidence has not increased between 1995 and 2007 in Europe 10 or between 1995 and 2010 in the United States. [bib_ref] Incidence of carcinoma of the major salivary glands according to the WHO..., Boukheris [/bib_ref] The 5-year relative survival rate (estimated as the ratio of observed to expected survival in the general population, matched by age, sex, calendar year and geographical area) for patients with major SGC is 63% (95% CI 62% to 63.7%) in Europe. [bib_ref] Burden and centralised treatment in Europe of rare tumours: results of RARECAREnet..., Gatta [/bib_ref] This decreases with age, from w90% (95% CI 91% to 97%) in patients aged <25 years, to 70% (95% CI 69% to 71%) in patients aged 25-64 years and 53% (95% CI 52% to 55%) in those aged >65 years. Five-year relative survival is higher in females (72%, 95% CI 71% to 74%) than in males (55%, 95% CI 54% to 56%). Furthermore, 5-year relative survival differs across European regions, with the highest rate of 74% (95% CI 71% to 78%) reported in Nordic countries (Finland, Iceland, Norway) and the lowest rate of 52% (95% CI 50% to 54%) reported in Eastern European countries (Bulgaria, Czech Republic, Estonia, Latvia, Lithuania, Poland, Slovakia). SGC relative survival has not improved in Europe between 1999 and 2007.The 5-year relative survival rate for minor salivary glandtype cancers of the head and neck is 67% and is higher in females than in males. Five-year survival rates are highest in children (>90%) and patients aged <25 years, and then decrease to 60% in patients aged >65 years. In Europe during the period 1999-2007, 5-year survival remained stable and was highest in Nordic countries (84%) and lowest in Eastern European countries (55%).

## Diagnosis, pathology and molecular biology
SGC should be classified according to the World Health Organization (WHO) Classification of Head and Neck Tumours.Including both benign and malignant tumours, there are over 30 distinct salivary gland tumour types in the latest WHO classification system (see , available at https://doi.org/10.1016/j.esmoop. 2022.100602, for classification of the malignant tumour types).

## Diagnostic work-up
The symptoms of SGC depend on tumour location. Symptoms that should prompt consideration of SGC include pain in the face or mouth, an externally or submucosally growing lump or (facial) nerve paralysis.
Cytology or histology is mandatory. Ultrasound-guided salivary gland fine-needle aspiration (FNA) cytology has become the accepted minimally invasive method for evaluating parotid and submandibular gland tumours preoperatively. This can distinguish malignant from benign disease in 90% of cases if examined by a pathologist experienced in salivary gland disease.The Milan system for reporting salivary gland cytopathology is recommended. It facilitates standardised reporting and links each diagnostic category to a risk of malignancy (ROM); risks were recently confirmed in a large meta-analysis. [bib_ref] Retrospective assessment of the effectiveness of the Milan system for reporting salivary..., Farahani [/bib_ref] The Milan system facilitates ROMassociated therapeutic approaches, e.g. initial treatment can be intensified when high-grade malignancy is suspected (one study reported 99% diagnostic accuracy 14 ) (see , available at https://doi.org/10. 1016/j.esmoop.2022.100602).If FNA is non-diagnostic or if the clinical situation requires more information on histotype, core needle biopsy, while more demanding and with a slightly increased risk of complications, [bib_ref] Evaluation: fine needle aspiration cytology, ultrasound-guided core biopsy and open biopsy techniques, Howlett [/bib_ref] has less inadequate sampling (risk ratio 0.85) and a higher diagnostic yield than FNA. [bib_ref] Comparison of core needle biopsy and fineneedle aspiration in diagnosis of malignant..., Cho [/bib_ref] It is thus an accepted next step in the diagnostic work-up. [bib_ref] Fine-needle aspiration with selective use of core needle biopsy of major salivary..., Romano [/bib_ref] Open biopsies should be avoided in major salivary gland lesions due to the risk of complicating definitive surgical treatment and the risk of spillage, with the exception of skin ulcerating tumours. For minor salivary gland tumours, an experienced surgeon should take a biopsy of the tumour and surrounding stroma. [bib_ref] Why is the histomorphological diagnosis of tumours of minor salivary glands much..., Ihrler [/bib_ref] Incisional biopsy is recommended for submucosally extending tumours, and an incisional or forceps biopsy should be taken for ulcerating lesions.
Ultrasound, computed tomography (CT), magnetic resonance imaging (MRI) and [ 18 F]2-fluoro-2-deoxy-D-glucosee positron emission tomography (FDGePET) are the imaging techniques most commonly used to assess lesions in the major salivary glands, with MRI being the preferred modality (see [fig_ref] Figure 1: Work-up of major salivary gland nodules [/fig_ref]. Diagnostic imaging techniques are described in Section 1 of the Supplementary Material, available at https://doi.org/10.1016/j.esmoop.2022.100602.

## Histological tumour type and molecular biology
The SGC histological type essentially defines its biological behaviour, which influences prognosis and patterns of recurrence, and thus clinical management.
Some SGC types, such as basal cell adenocarcinoma, lowgrade MEC, intraductal carcinoma and conventional AcCC, are indolent, with high risk of locoregional recurrence but low rates of nodal involvement and distant metastases. [bib_ref] An update on grading of salivary gland carcinomas, Seethala [/bib_ref] Immunohistochemistry (IHC) on the surgical specimen provides supplementary visualisation of cell compartments and cell populations, thus improving SGC taxonomy. The role of molecular diagnostics in SGC is evolving. Many monomorphic SGCs are now known to harbour defining balanced translocations, some of which are readily evaluable on paraffin-embedded materials either by FISH, RTePCR or next-generation sequencing (NGS). [bib_ref] The role of molecular testing in the differential diagnosis of salivary gland..., Skalova [/bib_ref] Recently, NGS has provided significant input on the molecular characterisation of SGC subtypes, improving diagnostic differentiation between morphologically similar tumour types and also identifying novel driver pathways that determine tumour biology and which may be amenable to targeted pathological findings, especially FNA. Pathological staging is carried out after surgical resection of the primary tumour. There is currently no clear recommendation on differential staging of intraparotid versus cervical nodal metastases; findings from a recent study suggest that these differences should be addressed in future editions of the TNM classification. [bib_ref] The impact of nodal status in major salivary gland carcinoma: a multicenter..., Lombardi [/bib_ref] Pathological report and staging For correct management of major SGC, the pathological report should follow the International Collaboration on Cancer Reporting guidelines. [bib_ref] Data set for the reporting of carcinomas of the major salivary glands:..., Seethala [/bib_ref] Operative procedure; specimens submitted; tumour site, focality and dimensions; histological tumour type and grade; perineural invasion; lymphovascular invasion; extent of invasion and margin status are required (see Section 3 of the Supplementary Material, available at https://doi.org/10.1016/j.esmoop. 2022.100602). [bib_ref] Data set for the reporting of carcinomas of the major salivary glands:..., Seethala [/bib_ref] The UICC pathological TNM (pTNM) staging system for SGC of the major salivary glands is presented in Supplementary

## Surgery
Surgical management of the primary in parotid gland cancer. The treatment of parotid gland cancer is based on complete surgical excision with free margins. [bib_ref] Surgical treatment of salivary malignant tumors, Lombardi [/bib_ref] The difficulty of this surgery lies in achieving free margins without functional and aesthetic sequelae. Revision surgery following an unexpected post-operative diagnosis of malignancy carries a great risk to an already dissected facial nerve; therefore, every effort should be made to identify malignancy preoperatively, allowing for immediately adequate surgical removal. [bib_ref] Management of salivary gland tumours: United Kingdom National Multidisciplinary Guidelines, Sood [/bib_ref] It is imperative, if preoperative MRI, FNA or core needle biopsy suggests malignancy, to warn the patient of a possibly more extensive procedure. In case of extraparotid or facial nerve extension, an extended surgery sacrificing these elements [e.g. seventh nerve (nVII), infratemporal fossa, mandible, skin] with possible reconstruction must be considered. Functional or aesthetic disorders arising from resection should be considered during treatment planning. [bib_ref] Surgical treatment of salivary malignant tumors, Lombardi [/bib_ref] Resectability should be assessed in a multidisciplinary team meeting, bearing in mind that surgery, if possible, is the optimal treatment. A cancer should be considered unresectable if macroscopic tumour is likely to be left behind.
The reference procedure is a total parotidectomy. For low-grade, early-stage (cT1-T2N0) tumours in the superficial lobe, a superficial parotidectomy can suffice, especially if malignancy is a post-operative discovery on the definitive histology. For advanced-stage (all but cT1-T2N0) and/or preoperatively known intermediate-or high-grade tumours, a total parotidectomy is preferable. No consensus exists in the literature on how many millimetres thick a margin must be to be considered 'free'.
The presence or absence of facial nerve paralysis before surgery influences the choice of procedure: it is logical to try to preserve the facial nerve if there is no preoperative paralysis and to sacrifice it in case of preoperative paralysis. [bib_ref] Surgical treatment of salivary malignant tumors, Lombardi [/bib_ref] In the absence of preoperative paralysis and in case of intra-operative macroscopic invasion of the facial nerve, sacrifice or preservation of the nerve is decided on a caseby-case basis, depending on the histology of the tumour and extent of invasion of the nerve, as well as the age and wishes of the patient. It is important to collect as much information as possible about the tumour before surgery, discuss scenarios with the patient and be able to do a graft during the ablative procedure. A remote dissection of the nerve branches with an extended resection and frozen section analysis of the nerve section limits may be necessary, especially in AdCC, which is characterised by tumour extensions along and in nerves. [bib_ref] Adenoid cystic carcinoma: a review of recent advances, molecular targets, and clinical..., Dillon [/bib_ref] Preoperative facial paralysis is a major negative prognostic factor. [bib_ref] Surgical treatment of salivary malignant tumors, Lombardi [/bib_ref] It imposes a wide surgery with often unsatisfactory excisional limits. Addressing the nerve deficit during resection is the appropriate therapeutic approach. [bib_ref] Surgical treatment of salivary malignant tumors, Lombardi [/bib_ref] [bib_ref] Reconstruction of facial nerve after radical parotidectomy, Renkonen [/bib_ref] Surgical management of the primary in minor SGC and cancer of the sublingual gland. Minor SGC, a rare entity, may arise in all mucous membranes of the head and neck (including the nasal cavity, nasopharynx, oropharynx, hypopharynx, cervical oesophagus, larynx, trachea and oral cavity). Cancer of the sublingual gland is 10 times less frequent than minor SGC. 9

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C. van Herpen et al.
Surgery is the mainstay of treatment for primary resectable disease with the traditional open approach being the most widely used, although endoscopic and robot-assisted approaches have recently been described. [bib_ref] National analysis of oropharyngeal salivary gland malignancies treated with transoral robotic surgery, Bollig [/bib_ref] In a series of 450 patients with minor SGC, multivariate analysis showed advanced clinical stage and unfavourable histological subtype to be associated with poor disease-specific survival. [bib_ref] Minor salivary gland tumors of the head and neck-Memorial Sloan Kettering experience:..., Hay [/bib_ref] This was confirmed in a large Surveillance, Epidemiology and End Results (SEER) database study of 1426 patients with minor SGC of the oropharynx. [bib_ref] Minor salivary gland carcinoma of the oropharynx: a population-based analysis of 1426..., Goel [/bib_ref] It is generally accepted that a 1-cm free margin is adequate in most tumours; however, it is often the case that only millimetric margins are achievable. AdCC is particularly known for perineural spread (as described earlier), requiring detailed surgical planning and wide margins, including resection of bony structures. [bib_ref] Surgical treatment of salivary malignant tumors, Lombardi [/bib_ref] Surgical management of the primary in submandibular gland cancer. The most common submandibular gland malignant tumour type is AdCC. [bib_ref] Patterns of lymph node metastasis and their influence on outcomes in patients..., Han [/bib_ref] [bib_ref] Submandibular gland cancer: specific features and treatment considerations, Aro [/bib_ref] Tumours confined within the submandibular gland require resection of the gland and the surrounding level Ib lymph nodes to ensure negative margins. In case of high-grade malignancy without clinical evidence of cervical lymph node involvement, selective neck dissection involving level I, II and III lymph nodes is standard procedure as the prevalence of cervical lymph node metastasis in submandibular gland malignancies is high, exceeding that of the parotid malignancies. [bib_ref] Surgical treatment of salivary malignant tumors, Lombardi [/bib_ref] [bib_ref] Submandibular gland cancer: specific features and treatment considerations, Aro [/bib_ref] [bib_ref] Prognostic factors for long term results of the treatment of patients with..., Vander Poorten [/bib_ref] Careful surgical planning is needed for AdCC, as clear margin surgery may require resection of important structures such as the lingual, hypoglossal and marginal mandibular nerves, floor of the mouth muscles and the skin. Although the risk of nodal metastasis in AdCC is low, this tumour has a propensity for infiltrating the adjacent lymph nodes and perineural spread. [bib_ref] Surgical treatment of salivary malignant tumors, Lombardi [/bib_ref] [bib_ref] Patterns of lymph node metastasis and their influence on outcomes in patients..., Han [/bib_ref] [bib_ref] Submandibular gland cancer: specific features and treatment considerations, Aro [/bib_ref] While it can be difficult to distinguish between direct invasion and embolic lymph node metastasis, some studies have identified a higher nodal spread than expected. [bib_ref] Patterns and treatment of neck metastases in patients with salivary gland cancers, Yoo [/bib_ref] Elective neck dissection (END) for submandibular gland malignancies should be planned based on cytological and radiological findings. Whenever malignancy is suspected, frozen section analysis can dictate extension of surgery locally and to involve at least level Ib but most frequently level I, II and III lymph nodes. 32 Management of the cND neck in salivary gland malignancies. The reported incidence of positive neck nodes in parotid carcinomas varies between 10% and 40% and they occur more frequently in patients with high-grade malignancy, advanced T status, facial nerve involvement and extraglandular invasion. [bib_ref] High incidence of lymph node metastasis in major salivary gland cancer, Stennert [/bib_ref] [bib_ref] Major and minor salivary gland tumors, Guzzo [/bib_ref] The most frequently involved lymph node levels are II, III and IV 38 ; however, involvement of levels I and V is also non-negligible. [bib_ref] Patterns and treatment of neck metastases in patients with salivary gland cancers, Yoo [/bib_ref] [bib_ref] Treatment of the neck in carcinoma of the parotid gland, Ali [/bib_ref] When carrying out therapeutic neck dissection for clinically or radiologically positive lymph nodes (cN), the recommendation is to carry out a comprehensive neck dissection of levels I-V. [bib_ref] Patterns and treatment of neck metastases in patients with salivary gland cancers, Yoo [/bib_ref] [bib_ref] Treatment of the neck in carcinoma of the parotid gland, Ali [/bib_ref] The incidence of lymph node metastasis for submandibular carcinomas at initial presentation is around 8%-33%. [bib_ref] The indications for elective treatment of the neck in cancer of the..., Armstrong [/bib_ref] Positive lymph nodes are often found in level I followed by levels II and III, although all lymph nodes can be involved with the possibility for skip metastases in levels IV and V. Some series have even shown positive lymph node involvement of 40% and 25% in levels IV and V, respectively, warranting a level I-V neck dissection for submandibular gland carcinomas with cN disease. [bib_ref] Patterns of lymph node metastasis and their influence on outcomes in patients..., Han [/bib_ref] For minor SGC, the same applies, but depending on the origin of the primary, lymph nodes outside the neck may be involved that are relatively inaccessible for surgery, such as retropharyngeal or mediastinal nodes.
END for the cN0 neck in parotid gland carcinoma. In a cN0 neck parotid gland carcinoma with clinical and histopathological factors indicating a 15%-20% chance of occult regional metastasis, END is strongly recommended. Clinical prognostic factors for pathologically positive lymph nodes (pN) are age >54 years, pain, nVII dysfunction and >T2 status. [bib_ref] Predicting occult lymph node metastasis in parotid cancer, Frankenthaler [/bib_ref] [bib_ref] Multivariate analysis of risk factors for neck metastases in surgically treated parotid..., Santos [/bib_ref] A study using END in T1-T2 N0 patients reported a cN0 pN rate of 17%. [bib_ref] Occurrence of lymph node metastasis in early-stage parotid gland cancer, Stenner [/bib_ref] 

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AdCC. [bib_ref] High incidence of lymph node metastasis in major salivary gland cancer, Stennert [/bib_ref] [bib_ref] The indications for elective treatment of the neck in cancer of the..., Armstrong [/bib_ref] AcCC and low-grade MEC were previously considered to have low pN rates but routine ENDs have revealed higher than expected rates, especially for highgrade AcCC. [bib_ref] High incidence of lymph node metastasis in major salivary gland cancer, Stennert [/bib_ref] [bib_ref] Patterns of lymph node spread and its influence on outcome in resectable..., Klussmann [/bib_ref] [bib_ref] Treatment of the neck in carcinoma of the parotid gland, Ali [/bib_ref] [bib_ref] Occurrence of lymph node metastasis in early-stage parotid gland cancer, Stenner [/bib_ref] [bib_ref] Indication for elective neck dissection for N0 carcinoma of the parotid gland:..., Kawata [/bib_ref] [bib_ref] Salivary acinic cell carcinoma: reappraisal and update, Vander Poorten [/bib_ref] Regarding the best treatment strategy, some clinicians use END followed by postoperative RT, while others prefer to use elective neck irradiation (ENI) (see RT section). [bib_ref] Predicting occult lymph node metastasis in parotid cancer, Frankenthaler [/bib_ref] [bib_ref] Patterns of nodal involvement for clinically N0 salivary gland carcinoma: refining the..., Lau [/bib_ref] [bib_ref] The role of radiotherapy in the treatment of malignant salivary gland tumors, Terhaard [/bib_ref] [bib_ref] Patterns of nodal relapse after surgery and postoperative radiation therapy for carcinomas..., Chen [/bib_ref] [bib_ref] Elective neck management for high-grade salivary gland carcinoma, Herman [/bib_ref] Some clinicians propose a routine END for every patient with suspected or known parotid gland cancer; reported rates of cN0 pN range from 22% to 45% in series where all patients underwent END. [bib_ref] High incidence of lymph node metastasis in major salivary gland cancer, Stennert [/bib_ref] [bib_ref] Occurrence of lymph node metastasis in early-stage parotid gland cancer, Stenner [/bib_ref] [bib_ref] Elective neck dissection versus observation in primary parotid carcinoma, Zbaren [/bib_ref] [bib_ref] Head and neck salivary gland carcinomas-elective neck dissection, yes or no?, Nobis [/bib_ref] The lymph node levels to address are II, III and IV. 39,40 A significant proportion (53%-80%) of patients with pN disease on neck dissection will also have metastatic deposits in the 'first echelon' intraparotid lymph nodes (see earlier Surgical management of the primary in parotid gland cancer section). [bib_ref] Surgical treatment of salivary malignant tumors, Lombardi [/bib_ref] [bib_ref] The indications for elective treatment of the neck in cancer of the..., Armstrong [/bib_ref] [bib_ref] Deep lobe parotidectomy: clinical rationale in the management of primary and metastatic..., Olsen [/bib_ref] In one study, 1-11 parotid lymph nodes were retrieved, with 80% of parotid nodes involved in cN0 pN patients. [bib_ref] Patterns of lymph node spread and its influence on outcome in resectable..., Klussmann [/bib_ref] There is still no direct evidence that resection of these nodes increases locoregional control. Taken together, three scenarios exist: 1. Low risk of occult nodal disease (T1-T2 tumours, lowgrade tumours, young patients) After resection of the primary, a watch-and-wait policy to the neck can be defended [bib_ref] Treatment of the neck in carcinoma of the parotid gland, Ali [/bib_ref] Most clinicians will carry out a level II dissection with frozen section, converting into a comprehensive neck dissection in the rare pN cases, [bib_ref] Surgical treatment of salivary malignant tumors, Lombardi [/bib_ref] END for the cN0 neck in minor SGC. For minor SGC, when the neck is surgically entered as an approach to the primary, it is logical to also address the neck surgically. The occult metastatic rate for laryngeal, sinonasal, external acoustic meatus and lacrimal gland origin is too low to justify END. In oral cavity (levels I, II, III and IV) and oropharyngeal (levels II, III and IV) minor SGC, and in high-grade MEC and AdCC, the occult rates largely exceed 20% and END is indicated. [bib_ref] Recent trends in the management of minor salivary gland carcinoma, Vander Poorten [/bib_ref] [bib_ref] Cervical lymph node metastasis in high-grade transformation of head and neck adenoid..., Hellquist [/bib_ref] END is frequently advocated for all high-stage and high-grade tumours. In a recent French study, however, no benefit in terms of event-free survival was demonstrated when comparing patients with cN0 AdCC undergoing END with those who did not, except when the site of origin was the oral cavity. In this series, the majority (58%) of 322 cases were of minor salivary gland origin. [bib_ref] Should a neck dissection be performed on patients with cN0 adenoid cystic..., Atallah [/bib_ref] In a large series of 3005 patients with MEC of the oral cavity and oropharynx, END was associated with a survival benefit for patients with high-grade and clinical stage T3-4 disease. [bib_ref] Prognostic factors and occult nodal disease in mucoepidermoid carcinoma of the oral..., Ellis [/bib_ref] END for the cN0 neck in submandibular gland carcinoma.
For preoperatively known submandibular gland cancers with otherwise cN0 neck, inclusion of the submandibular gland in a selective neck dissection (levels I, II and III) is considered the standard procedure, revealing occult metastasis rates of 21%-23%. [bib_ref] Prognostic factors for long term results of the treatment of patients with..., Vander Poorten [/bib_ref] [bib_ref] Patterns of nodal involvement for clinically N0 salivary gland carcinoma: refining the..., Lau [/bib_ref] [bib_ref] Perez & Brady's Principles and Practice of Radiation Oncology, Halperin [/bib_ref] The use of intensity-modulated RT (IMRT) or volumetric modulated arc therapy (VMAT) is recommended. For parotid gland cancer invading the deep lobe, the infratemporal fossa and the parapharyngeal space should be included in the field. After incomplete resection, a dose of 33 A 2 Gy is described for the primary tumour region plus a 1 cm margin, with 30 A 2 Gy after a clear resection. [bib_ref] Patterns of nodal involvement for clinically N0 salivary gland carcinoma: refining the..., Lau [/bib_ref] [bib_ref] Perez & Brady's Principles and Practice of Radiation Oncology, Halperin [/bib_ref] In case of extensive perineural invasion the nerve pathway to the base of the skull should be delineated. [bib_ref] Guidelines for clinical target volume definition for perineural spread of major salivary..., Armstrong [/bib_ref] Indications for ENI (25 A 2 Gy over 5 weeks) are the same as the indications for END. In general, ENI is indicated in case of T3-T4 cN0 tumours and high-or intermediate-grade subtypes, and also depends on the primary site. [bib_ref] Perez & Brady's Principles and Practice of Radiation Oncology, Halperin [/bib_ref] The ipsilateral neck node levels II and III should be treated in parotid gland tumours and ipsilateral levels I, II and III in submandibular gland tumours. Bilateral ENI is indicated for tumours crossing the midline. For minor SGC, the highest risk for subclinical neck disease is a pharyngeal location, high-grade disease and T3-T4 tumours. Ipsilateral ENI is recommended for levels I, II and III.
Post-operative RT is indicated for all cases of pN neck. A dose of 30 A 2 Gy is recommended for the involved level, and 33 A 2 Gy in case of extranodal disease. For the ipsilateral elective levels I-V, a dose of 25 A 2 Gy is recommended. [bib_ref] Perez & Brady's Principles and Practice of Radiation Oncology, Halperin [/bib_ref] Combining post-operative RT with chemotherapy. There are no large series analysing the role of combined chemotherapy (ChT) and RT in the post-operative setting in SGC. In the phase II Radiation Therapy Oncology Group (RTOG) 1008 study (NCT01220583) both scenarios are being compared, but no results are available yet.
Combining post-operative ChT with RT in major SGC has been evaluated retrospectively using data from the US National Cancer Database. The addition of ChT was restricted to late-stage tumours with adverse features and did not result in a survival benefit. [bib_ref] Adjuvant therapy in major salivary gland cancers: analysis of 8580 patients in..., Cheraghlou [/bib_ref] In a retrospective cohort study, platinum-based post-operative chemoradiotherapy (n 14 37) was compared with post-operative RT only (n 14 103). In the chemoradiotherapy group, more patients had N disease, positive surgical margins and perineural invasion. In multivariate analysis, progressionfree survival (PFS) was not improved by the addition of ChT. [bib_ref] Adjuvant radiotherapy versus concurrent chemoradiotherapy for the management of highrisk salivary gland..., Mifsud [/bib_ref] Comparable results were reported in a subset of patients with high-risk SGC. [bib_ref] Concurrent chemoradiotherapy in the adjuvant treatment of high-risk primary salivary gland malignancies, Gebhardt [/bib_ref] [bib_ref] Association of adjuvant chemoradiotherapy vs radiotherapy alone with survival in patients with..., Amini [/bib_ref] In an ongoing phase III, multicentre, randomised, open-label, French study, postoperative or primary RT alone is being compared with concomitant RT plus cisplatin on days 1, 22 and 43 for SGC and nasal cancer. No results are available yet. [bib_ref] A rationale for chemoradiation (vs radiotherapy) in salivary gland cancers? On behalf..., Cerda [/bib_ref] The level of evidence for combining ChT with RT is low and this treatment is not recommended outside of a clinical study.
Primary RT for unresectable SGC. The primary treatment for SGC without distant metastasis is surgery with postoperative RT when indicated; however, curative primary RT is indicated for patients with functionally unresectable disease or who are unsuitable for surgery due to comorbidities.
Taking locoregional control, survival and complications into account, the treatment options are photon treatment or particle treatment with protons, neutrons or carbon ions (C12). In most institutes, primary photon therapy up to 70 Gy is still applied. Particle treatment, particularly C12 and especially for AdCC and tumours involving the base of the skull, may be an alternative with a potentially higher locoregional cure rate compared with photons; however, these treatment options have limited availability. The literature supporting the use of particle treatment is described in Section 5 of the Supplementary Material, available at https://doi.org/10.1016/j.esmoop.2022.100602.
No randomised studies have been carried out to compare primary treatment with chemoradiotherapy versus RT alone. Most published studies report small series with different histological subtypes, using a variety of ChT regimens. [bib_ref] Concurrent chemoradiotherapy in the adjuvant treatment of high-risk primary salivary gland malignancies, Gebhardt [/bib_ref] There is currently no evidence to support the combination of particle therapy and simultaneous ChT in SGC. 65

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## Management of locally recurrent and metastatic disease

## Rt
RT may be used for the management of locally recurrent disease and/or for palliation.
RT for recurrent disease. Local recurrence within the highdose area following initial RT remains a challenge. When surgery is not an option, systemic treatments (either ChT or targeted agents) offer limited benefit with very moderate overall response rates and are therefore rarely successful in alleviating local symptoms. Before the introduction of particle therapy, re-irradiation with photons was used with utmost caution, especially in anatomically challenging sites. Meanwhile, three groups have shared their experience of reirradiation using scanned C12 in SGC, [bib_ref] Reirradiation of salivary gland tumors with carbon ion radiotherapy at CNAO, Vischioni [/bib_ref] [bib_ref] Feasibility of re-irradiation using carbon ions for recurrent head and neck malignancies..., Hayashi [/bib_ref] [bib_ref] Re-irradiation of adenoid cystic carcinoma: analysis and evaluation of outcome in 52..., Jensen [/bib_ref] reporting 1-year and 2-year overall survival (OS) rates of up to 90% and 64%, respectively, although late toxicities were observed. Based on these studies, re-irradiation with C12 appears feasible with response rates of around 60% and moderate toxicities in heavily pre-treated patients; however, C12 has limited availability in Europe. Protons are becoming more widely available, but evidence is lacking to support the added value. Further dose escalation should be employed cautiously. There is no evidence to support the combination of re-irradiation and ChT for primary treatment of SGC.
RT for palliation. In the RTOG 8502 study, an RT regimen of 4 A 3.7 Gy over 2 days was repeated in cycles of 4 weeks. Seven out of 75 patients had salivary gland histology. Palliative response was observed in 65% of patients, significantly correlating with the number of cycles. [bib_ref] Palliative head and neck radiotherapy with the RTOG 8502 regimen for incurable..., Lok [/bib_ref] For palliative RT of head and neck cancer, the 'Christie scheme' (16 A 3.125 Gy over 4 weeks) resulted in a 45% complete response rate and 28% partial response rate. [bib_ref] Hypofractionated radiotherapy denoted as the "Christie scheme": an effective means of palliating..., Tans [/bib_ref] This schedule may also be considered in patients with metastatic SGC with a relatively long life expectancy. For patients with AdCC or AcCC and a WHO performance status score of 0-1, an even more prolonged RT schedule for palliation of locoregional disease or symptomatic distant metastases might be considered. Nevertheless, in case of short life expectancy or a WHO performance status of 2-3, a short fractionation schedule is usually preferred.
Oligometastatic disease. For oligometastatic disease, locoregional treatments such as surgery, 71-73 radiofrequency ablation 74 or stereotactic RT 75 can be considered in selected cases, especially in AdCC. In one study, a prolonged diseasefree interval (>36 months) and radical resection were the main prognostic factors in 109 patients with AdCC and lung metastases who underwent metastasectomy. [bib_ref] Lung metastasectomy in adenoid cystic cancer: is it worth it?, Girelli [/bib_ref] Systemic treatment for recurrent and/or metastatic disease
In case of R/M disease, systemic treatment is challenging but can be urgent, depending on tumour subtype and behaviour. For all types of SGC with distant metastases (71% of patients will present or develop R/M disease), median OS is 15 months and 1-, 3-and 5-year OS rates are 54.5%, 28.4% and 14.8%, respectively. [bib_ref] Risk factors and survival associated with distant metastasis in patients with carcinoma..., Nam [/bib_ref] This, however, varies widely between subtypes. The rarity of SGC and its extensive heterogeneity hinders large-scale patient accrual in prospective trials. The number of clinical trials evaluating systemic therapy in R/M SGC is low and their interpretation is difficult because most phase II studies include all SGC subtypes, pathological review for correct histopathological subtyping is missing and data on efficacy are not presented by subtype. [bib_ref] Advances and challenges in precision medicine in salivary gland cancer, Lassche [/bib_ref] An overview of targeted therapies evaluated in SGC is presented in Supplementary MEC. The reported risk of distant metastasis in MEC is 16% at 10 years. [bib_ref] Salivary gland carcinoma: independent prognostic factors for locoregional control, distant metastases, and..., Terhaard [/bib_ref] In R/M MEC, responses with cisplatin alone or in combination with other agents [e.g. cisplatineadriamycinecyclophosphamide (CAP) or cisplatinegemcitabine] and paclitaxel as monotherapy have been observed in small patient cohorts (three responses on paclitaxel monotherapy in 14 patients in the largest MEC cohort). [bib_ref] Systemic therapy in metastatic salivary gland carcinomas: a pathology-driven paradigm?, Alfieri [/bib_ref] The CRTC1-MAML2 gene fusion, which is commonly present in MECs, causes up-regulation of the epidermal growth factor receptor (EGFR) ligand amphiregulin, [bib_ref] Aberrantly activated AREG-EGFR signaling is required for the growth and survival of..., Chen [/bib_ref] suggesting a potential role for EGFR inhibitors. Reports of clinical benefit with an EGFR inhibitor in patients with MEC are, however, anecdotal and require further investigation.
AdCC. To date, no systemic treatment has been shown to improve OS in patients with R/M AdCC. Metastatic AdCC is generally characterised by multiple locoregional recurrences accompanied by distant metastases in about half of cases. The lung is the most common site of distant spread followed by the lymph nodes, bone, liver, etc. Despite these characteristics, survival of patients with R/M AdCC is generally prolonged, with an OS rate of 40% at 10 years. [bib_ref] Lung metastasectomy in adenoid cystic cancer: is it worth it?, Girelli [/bib_ref] In this context, active surveillance could be a rational proposal in highly selected patients (asymptomatic, low tumour burden, lung metastases and stable disease). Lung metastasectomy should be considered in patients without other R/M tumour deposits, provided that a complete surgical resection is feasible and disease-free interval from primary diagnosis is >36 months. [bib_ref] Lung metastasectomy in adenoid cystic cancer: is it worth it?, Girelli [/bib_ref] Systemic treatment should be reserved for patients with progressive and/or symptomatic disease that is not otherwise manageable. A cisplatin-based regimen seems to guarantee the highest response rate: 13% with cisplatin alone and 25% (95% CI 11% to 39%) with CAP. [bib_ref] Systemic therapy in the management of metastatic or locally recurrent adenoid cystic..., Laurie [/bib_ref] Duration of response ranges widely from 7 to 77 months. Carboplatin seems to have limited activity, and no response has been reported with paclitaxel or gemcitabine. [bib_ref] Systemic therapy in the management of metastatic or locally recurrent adenoid cystic..., Laurie [/bib_ref] Compounds tailored for actionable targets such as EGFR, KIT and fibroblast growth factor receptor have failed to demonstrate any activity. [bib_ref] Systemic therapy in metastatic salivary gland carcinomas: a pathology-driven paradigm?, Alfieri [/bib_ref] Strategies focused on pathogenetic targets seem more promising. Clinical trials are currently evaluating two agents with different strategies: CB103, which targets NOTCH oncogene transcription factors (NCT03422679), and AL101, which inhibits gamma secretase (ACCURACY; NCT03691207). Partial response was observed in 15% of patients (6/39) treated with AL101 at 4 mg, and further drug titration is being studied. [bib_ref] 919MO ACCURACY a phase II trial of AL101, a selective gamma secretase..., Ferrarotto [/bib_ref] Trials targeting MYB, the hallmark of AdCC, are underway. A study combining MYB DNA vaccination with anti-programmed cell death protein 1 immunotherapy is currently recruiting patients (MYPHISMO; NCT03287427). Antiangiogenic agents (sorafenib, lenvatinib and axitinib) have been investigated in recent years, but response rates did not exceed 15% 79 (see , available at https://doi.org/10. 1016/j.esmoop.2022.100602). In this context, axitinib was the first agent to demonstrate a significant PFS prolongation compared with placebo in a phase II randomised trial (hazard ratio 0.25, 95% CI 0.14-0.48), [bib_ref] Randomized phase II study of axitinib versus observation in patients with recurred..., Kang [/bib_ref] becoming the new backbone for future trials. The activity of immune checkpoint inhibitors alone is null in patients with R/M AdCC. [bib_ref] Systemic therapy in metastatic salivary gland carcinomas: a pathology-driven paradigm?, Alfieri [/bib_ref] Given the disappointing results of systemic treatments, participation in clinical trials is strongly recommended.

## Esmo open
AcCC. Distant metastases occur in 19% of patients with AcCC. No data on ChT are available and the role of the HTN3-MSANTD3 fusion gene (present in 4% of patients) is unknown and not targetable yet. Nevertheless, NTRK gene fusion analysis must be carried out in patients with R/M AcCC because secretory carcinoma is often misclassified as AcCC, and tumours with NTRK fusion genes respond extremely well to targeted therapy (see below).
Polymorphous adenocarcinoma. The prognosis of patients with polymorphous adenocarcinoma is generally good and distant metastases are rare, reported in only 4.3% of patients at presentation. [bib_ref] Polymorphous adenocarcinoma of the salivary glands: reappraisal and update, Vander Poorten [/bib_ref] No data on ChT or targeted therapy are available.
Adenocarcinoma NOS. CAP, paclitaxel monotherapy and gemcitabine or vinorelbine in combination with cisplatin have led to limited response rates in adenocarcinoma NOS. If the tumour is androgen receptor positive and/or has HER2 amplification, it is most likely a salivary duct carcinoma and must be treated in the same way as salivary duct carcinoma (see below). [bib_ref] Treatment relevant target immunophenotyping of 139 salivary gland carcinomas (SGCs), Locati [/bib_ref] Salivary duct carcinoma. Fifty-four percent of patients with salivary duct carcinoma treated with curative intent will develop locoregional recurrences and/or distant metastases. In patients with distant metastases, spread to lungs (54%) and bones (46%) has been reported most frequently, but a high rate of brain metastasis has also been observed (18%). [bib_ref] Systemic therapy in the management of recurrent or metastatic salivary duct carcinoma:..., Uijen [/bib_ref] Given the dismal prognosis and high prevalence of distant metastasis (also in case of local or locoregional recurrence), systemic therapy is often required. The median OS for patients with R/M disease receiving best supportive care is only 5 months. [bib_ref] Androgen deprivation therapy for androgen receptor-positive advanced salivary duct carcinoma: a nationwide..., Boon [/bib_ref] Agents targeting androgen receptors and/or HER2 are promising and are the best studied therapies in patients with salivary duct carcinoma. A prospective phase II trial evaluating the effect of combined androgen blockade with leuprorelin acetate and bicalutamide in 36 patients with SGC (of which 34 were salivary duct carcinoma) demonstrated partial or complete response in 41.7% of patients (95% CI 25.5% to 59.2%) and stable disease in 44.4% (95% CI 27.9% to 61.9%). [bib_ref] A prospective phase II study of combined androgen blockade in patients with..., Fushimi [/bib_ref] Given the low rate of grade 3/4 toxicity, combined androgen blockade plays an important role in the palliative treatment of androgen receptorpositive salivary duct carcinoma. Androgen deprivation therapy (ADT) may also be beneficial in the adjuvant setting. Based on retrospective data, adjuvant ADT results in significantly improved 3-year disease-free survival in patients with stage IVa androgen receptor-positive salivary duct carcinoma [48.2% (95% CI 14.0% to 82.4%) versus 27.7% (95% CI 18.5% to 36.9%) in the control group, which did not receive adjuvant ADT]. [bib_ref] Adjuvant androgen deprivation therapy for poor-risk, androgen receptorpositive salivary duct carcinoma, Van Boxtel [/bib_ref] In HER2-positive salivary duct carcinoma, trastuzumab combined with taxane-based ChT is the best studied regimen, with an overall response rate of 70.2% (95% CI 56.6% to 81.6%) and median OS of 39.7 months (95% CI not reached) reported for trastuzumabedocetaxel in 57 patients with salivary duct carcinoma. [bib_ref] Phase II trial of trastuzumab and docetaxel in patients with human epidermal..., Takahashi [/bib_ref] This combination could potentially be amplified with the addition of another agent targeting HER2 (e.g. pertuzumab, lapatinib) or, after progressive disease, replacement of trastuzumab with the antibodyedrug conjugate trastuzumabeemtansine (T-DM1). An oral presentation at the American Society of Clinical Oncology congress in 2019 emphasised the potential of T-DM1 in HER2-amplified SGC, as 9 out of 10 patients (0-3 lines of prior treatment, median of 2) responded to this treatment. Presumably most of these patients had salivary duct carcinoma. Median PFS was not reached after a median follow-up of 12 months. [bib_ref] Ado-trastuzumab emtansine in patients with HER2 amplified salivary gland cancers (SGCs): results..., Li [/bib_ref] In analogy with the positive results achieved in HER2-positive breast cancer by adding pertuzumab to docetaxeletrastuzumab and the cases reported for this combination in salivary duct carcinoma, this triple combination deserves pursuit in clinical studies in salivary duct carcinoma. In patients co-expressing HER2 and androgen receptors, it is currently unclear whether targeting androgen receptors or HER2 is the best approach. In case of extensive or rapidly progressive disease, HER2targeting therapy in combination with taxane-based ChT is the reasonable choice over antihormonal therapy, as in breast cancer, but there is no evidence for this approach (expert opinion).
Besides androgen receptors and HER2, a number of mutations are observed in lower frequencies in salivary duct carcinoma, which form a genetic landscape highly similar to apocrine breast cancer. [bib_ref] Comprehensive molecular characterization of salivary duct carcinoma reveals actionable targets and similarity..., Dalin [/bib_ref] These include mutations in TP53 (53%-68%), PIK3CA (18%-26%), HRAS (16%-23%), BRAF (4%) and AKT1 (1.5%). Reports of use of these targets in clinical practice are scarce. [bib_ref] First-line treatment of widely metastatic BRAF-mutated salivary duct carcinoma with combined BRAF..., Lin [/bib_ref] When these mutations are identified, patients should be preferably treated in basket studies.
The most frequently used ChT regimen in R/M salivary duct carcinoma is carboplatinepaclitaxel. [bib_ref] Systemic therapy in metastatic salivary gland carcinomas: a pathology-driven paradigm?, Alfieri [/bib_ref] Although 30%-60% of salivary duct carcinomas demonstrate IHC positivity for programmed death-ligand 1, no phase II data with immune checkpoint inhibitors are available. [bib_ref] The immune microenvironment and expression of PD-L1, PD-1, PRAME and MHC I..., Xu [/bib_ref] Secretory carcinoma. The body of evidence for the efficacy of tropomyosin receptor kinase (TRK) inhibitors (e.g. larotrectinib, entrectinib, repotrectinib, in patients with secretory carcinoma and NTRK gene fusions is expanding. [bib_ref] NTRK fusion-positive cancers and TRK inhibitor therapy, Cocco [/bib_ref] A recent phase II trial evaluating the efficacy of larotrectinib in NTRK fusion-positive patients included 12 patients with secretory carcinoma and reported a response rate of 75%. Median PFS was not reached after a median follow-up of 9.9 months. [bib_ref] Efficacy of larotrectinib in TRK fusion-positive cancers in adults and children, Drilon [/bib_ref] Responses in patients with secretory carcinoma have also been observed with entrectinib and repotrectinib. [bib_ref] NTRK fusion detection across multiple assays and 33,997 cases: diagnostic implications and..., Solomon [/bib_ref] For treatment with TRK inhibitors, RNA confirmation is needed.
Other SGC subtypes. For some histological subtypes, little or no clinical evidence is available to make hard recommendations for additional IHC staining or molecular evaluation to identify therapeutic targets. For these subtypes, IHC staining for androgen receptors and evaluation of HER2 expression, preferably by IHC staining and FISH, are advocated. Besides this, use of an NGS panel which includes frequently affected genes in other cancers that are currently targetable with anticancer drugs (e.g. PIK3CA, BRAF, NRAS, MET) is suggested. Regarding gene fusions, which are often not present in commercially available panels, it is important to test specifically for NTRK gene fusions, as these have great implications for individual patients.

## Recommendations

## Rt
Re [bib_ref] Summary of the guidelines for preventing opportunistic infections among hematopoietic stem cell..., Dykewicz [/bib_ref] [bib_ref] Purpose of quality standards for infectious diseases, Gross [/bib_ref] Statements without grading were considered justified standard clinical practice by the authors. Future updates to this CPG will be published on esmo.org as a Living Guideline version or an eUpdate, to be made available at: https://www.esmo.org/ guidelines/head-and-neck-cancers/salivary-gland-cancer. and Merck, personal fees as an invited speaker for Sanofi and fees paid to his institute as local Principal Investigator (PI) for BMS. LDL reports personal fees for advisory board membership of Eli Lilly, Merck Serono and MSD, personal fees as an invited speaker for Biogen, EISAI, IPSEN, Sanofi Regeneron and SunPharma and fees paid to her institute as local PI for EISAI. She also reports non-remunerated leadership roles with the Endocrine Tumour Group and as an Officer for the Scientific Chairs Council of European Organisation for Research and Treatment of Cancer (EORTC), affiliate for the Italian Association of Medical Oncology (AIOM) and the Multidisciplinary Salivary Gland Society (MSGS) and an advisory role for Associazione Italiana Oncologia Cervico Cefalica (AIOCC). JH reports personal fees from stocks/shares from RiverD/ MarginGuide. EK reports personal fees for full-or part-time employment as the Consumer Lead for the National Cancer Research Institute (NCRI) and a non-remunerated role as a member of the Board of Directors of Salivary Gland Cancer UK. CE reports personal fees for advisory board membership of BMS, MSD, Merck Serono and Innate Pharma, fees paid to her institute for advisory board membership for F-star
[fig] Figure 1: Work-up of major salivary gland nodules. Purple: general categories or stratification; white: other aspects of management. AdCC, adenoid cystic carcinoma; CNB, core needle biopsy; CT, computed tomography; FDGePETeCT, [ 18 F]2-fluoro-2-deoxy-D-glucoseepositron emission tomographyecomputed tomography; FNA, fine-needle aspiration; MRI, magnetic resonance imaging. a CNB considered when FNA is non-diagnostic or if more histological information is required. [/fig]
[fig] Figure 3: Treatment algorithm for minor or sublingual SGC. Purple: general categories or stratification; red: surgery; dark green: radiotherapy; white: other aspects of management; blue: systemic anticancer therapy. ChT, chemotherapy; END, elective neck dissection; ND, node dissection; RT, radiotherapy; SGC, salivary gland cancer. a Definition of high-grade tumours is described in Section 1 of the Supplementary Material, available at https://doi.org/10.1016/j.esmoop.2022.100602. [/fig]
[fig] Figure 4: Treatment algorithm for submandibular gland cancer. Purple: general categories or stratification; red: surgery; dark green: radiotherapy; white: other aspects of management; blue: systemic anticancer therapy. ChT, chemotherapy; CNB, core needle biopsy; FNA, fine-needle aspiration; ND, node dissection; RT, radiotherapy. a Definition of high-grade tumours is described in Section 1 of the Supplementary Material, available at https://doi.org/10.1016/j.esmoop.2022.100602. [/fig]
[fig] ACKNOWLEDGEMENTS: Manuscript editing support was provided by Louise Green and Jennifer Lamarre (ESMO Guidelines staff) and Angela Corstorphine and Sian-Marie Lucas of Kstorfin Medical Communications Ltd (KMC); this support was funded by ESMO. Nathan Cherny, Chair of the ESMO-MCBS Working Group, Urani Dafni, ESMO-MCBS Working Group Member/ Frontier Science Foundation Hellas and Giota Zygoura of Frontier Science Foundation Hellas provided review and validation of the ESMO-MCBS scores. Nicola Latino (ESMO Scientific Affairs staff) provided coordination and support of the ESMO-MCBS scores and Angela Corstorphine and Sian-Marie Lucas of KMC provided medical writing and editing support in the preparation of the ESMO-MCBS table; this support was funded by ESMO. Joaquin Mateo (Chair of the ESMO Translational Research and Precision Medicine Working Group) and Dr Svetlana Jezdic (ESMO Medical Affairs Advisor) provided validation support for ESCAT scores. [/fig]
[fig] FUNDING: No external funding has been received for the preparation of this guideline. Production costs have been covered by ESMO from central funds.DISCLOSURE VVP reports fees paid to his institute as an invited speaker from Atos Medical, Bristol Myers Squibb (BMS) and Ethicon e Johnson & Johnson and non-remunerated roles as a member of the Board of Directors and Secretary General of the Multidisciplinary Salivary Gland Society. BB reports personal fees for advisory board participation from Merck Sharp & Dohme [/fig]
[table] Table S5 ,: available at https://doi.org/10. 1016/j.esmoop.2022.100602. Minor SGCs are staged similarly to SCC, according to the site in which they arise (e.g. oral cavity, pharynx, sinuses, etc.). [/table]
[table] Table S6 ,: available at https:// doi.org/10.1016/j.esmoop.2022.100602. [/table]