Salivary Gland Carcinomas

Primary salivary gland carcinomas are epithelial malignancies of the major and minor salivary glands in the upper aerodigestive tract. Salivary gland carcinomas are differentiated according to localization (parotid gland, submandibular gland, lingual gland minor salivary glands) and histology. Secondary salivary gland cancers from other primary malignancies must be distinguished from these; this is particularly important if a squamous cell carcinoma is histologically detected in the parotid gland tumor [1].

Salivary gland carcinomas account for less than 6% of malignant neoplasms in the head and neck region, which are further subdivided into more than 24 histological subtypes according to the 2017 WHO classification of head and neck tumors (more details in section 5.5.2 Histology) [2]. Salivary gland carcinomas are therefore a heterogeneous group of head and neck tumors [3]. They are also tumors with an incidence of 0.5-2 patients per 100,000 people per year [4]. About 20% of all salivary gland tumors are malignant. The smaller the affected salivary gland, the higher the risk that it is a malignant tumor: almost 100% of tumors of the lingual gland and about 60% of small salivary gland tumors are malignant. The prevalence is highest in the 4th to 5th decade of life, with no clear gender predominance worldwide; some histologic subtypes show slight gender differences [5- 7]. About 2% of carcinomas occur in children up to 10 years of age and about 16% of patients are younger than 30 years of age [8, 9].

According to most national population-based studies, no relevant change in incidence rates has been observed in recent years, except for the USA, where an increasing incidence is reported without the causes being identified [6]. The interactive internet-based platform Global Cancer Observatory, which includes the GLOBOCAN data, predicts an increase in salivary gland carcinomas in Germany from 1 patient per 100,000 people per year in 2022 to 1.22 patients per 100,000 people per year in 2045 [10]. In the studies and statistics mentioned, a distinction is made at best between carcinomas of the parotid gland (ICD: C07) and all other carcinomas (ICD: C08). A more detailed analysis of the cancer registry data from North Rhine-Westphalia for 2009-2018 did not show any changes in incidence rates over the past years [6]. In this study, all squamous cell carcinomas were excluded due to the problem of differentiating between primary and secondary carcinomas. In Thuringia, an increase in salivary gland carcinomas was observed for many histological types between 1996 and 2011 (squamous cell carcinomas included) [5]. However, it should be noted that the incidence of cutaneous squamous cell carcinoma in Germany has approximately doubled since the 2000s [11]. It can therefore be assumed that secondary squamous cell carcinomas in the parotid gland have also increased during this period, i.e., metastases into the parotid gland from tumors of other locations were not separated from primary tumors of the parotid gland. This inaccuracy must also be taken into consideration when looking at the current data from the Robert Koch Institute (RKI), as all (primary and secondary) salivary gland malignancies are grouped together here (Figure 1). Between 1999 and 2019, there was a significant increase in malignancies in the parotid gland in men and a slight increase in women in Germany. It can be assumed that this increase in men is not due to primary salivary gland carcinomas, but to secondary tumors, mainly due to metastases from squamous cell carcinomas of the skin. For all other localizations, no changes are seen in the RKI data for either sex. In 2019, 365 women and 566 men were diagnosed with tumors in the parotid gland in Germany. In the other localizations, 102 women and 159 men were affected. The corresponding numbers of death for Germany can also be seen in Figure 1. The increasing incidence of salivary gland tumors is reflected in the number of deaths. In 2019, 103 women and 188 men died from parotid carcinoma. 34 women and 35 men died from salivary gland carcinomas of other locations. Since salivary gland carcinomas of the minor salivary glands in particular are not always registered as salivary gland carcinomas, but instead as head and neck tumors of the corresponding location, an underestimation of the number of cases can be assumed here.

*(database query at the Center for Cancer Registry Data; accessed: 15 January 2024). As described in the text, methodological inaccuracies must be taken into account when interpreting the figures.

In its report "Cancer in Germany for 2019/2020", the RKI publishes, as before, only a summary of the survival rates of patients with salivary gland carcinomas (Figure 2). According to this, the 5-year survival rate in 2019/2020 was 76% for women and 58% for men [12]. In North Rhine-Westphalia, the average relative 5-year survival rate for all patients between 2009 and 2018 was 69% [6]. In Thuringia, the 5-year and 10-year survival rates between 1999 and 2011 were 60.1% and 48.2% respectively. [5]. The most important prognostic factors are the TNM formula, the histological type and the tumor grading. Carcinomas of the minor salivary glands are rarely considered separately in population-based studies. Five-year survival rates of 76-86% are reported for carcinomas of the minor salivary glands [13]. The risk factors for poorer survival do not differ in comparison to carcinomas of the major salivary glands.

The pathogenesis of salivary gland carcinomas is unclear. Two concepts are currently being discussed: The histogenetic concept assumes that the histologically very different tumor types (see chapter 5.2.2 Histology) develop from the various cell types of salivary gland tissue. The various tumors are thought to evolve from the basal cells or the acinar cells of the glandular acini or the glandular duct sections through pathological replication [14]. According to the morphogenetic concept, tumors develop from stem cells in the gland, and aberrant pathological gene expression influenced by the microenvironment along with epigenetic changes give rise to the various tumor types [14, 15].

Past exposure to ionizing radiation is the only reliably proven risk factor [16]. This may have been previous radiotherapy in the head and neck area. Exposure to radioactive substances is probably another risk factor. There also appears to be an association with occupation in the rubber manufacturing industry, the hair and cosmetics industry and grain/vegetable cultivation [16- 18]. Lymphoepithelial carcinoma occurs more frequently in patients with AIDS, and the tumors may contain Epstein-Barr virus (EBV) components [19, 20], however, the pathogenic role of HIV or EBV infection is not clear. Overall, the factors mentioned are only responsible for a very small proportion of tumors. In most cases, no cause can be identified. Age is an associated factor, as the incidence increases significantly after the age of 50-60 years.

There are no general recommendations for prevention.

There are currently no specific screening instruments for early detection of salivary gland carcinomas. Patients who have undergone radiotherapy to the head and neck area for another malignancy should have their salivary glands examined if they observe any changes.

In addition to a detailed medical history, a combination of inspection, palpation and mirror examination is part of the diagnostic standard. In addition, as with all head and neck tumors, performance status, nutritional status, psychosocial history, dental status and an assessment of speech and swallowing function should be obtained. A geriatric assessment is also recommended for patients over 65 years of age [23]. The further procedure depends on the location of the salivary gland tumor. An overview is given in Table 1. In patients with facial nerve palsy, a classification of the extent (grading) and an electrophysiological examination are carried out to objectify the severity of the damage [24].

If the histopathological examination of a tumor of the parotid gland reveals a squamous cell carcinoma, a search of a primary tumor must be performed. Primary squamous cell carcinoma of the parotid gland is extremely rare and is a diagnosis by exclusion [25]. As cutaneous squamous cell carcinomas are the most commonly detected primary tumor localization, a careful examination of the body surface and an evaluation of eventual previously removed skin tumors should be performed. If risk factors for head and neck squamous cell carcinoma are present (see Onkopedia guideline on head and neck squamous cell carcinoma), panendoscopy should be considered.

Surgical removal of a salivary gland carcinoma with tumor-free resection margins is the curative treatment of choice. Tumor resection is performed en bloc with a safety margin of 2 cm at best [42]. In the case of tumors of the submandibular gland, resection includes at least the entire gland. For parotid malignancies, the conservative standard is total parotidectomy (parotidectomy level I to IV according to the European Salivary Gland Society (ESGS) classification) [26, 43]. Small monocentric case series indicate that lateral parotidectomy (parotidectomy level I/II according to ESGS classification) may also be sufficient for small, low-grade tumors (T1/T2) if tumor-free safety margins are ascertained [44]. The decision to perform a total parotidectomy for diagnosing intraparotid lymph nodes and to initiate adjuvant radiotherapy should be discussed with the patient. However, grading is often only determined after surgery when the final histology is available. If the tumor exceeds the boundaries of the organ, extended surgery is indicated, eventually including reconstructive plastic surgery.

Some salivary gland tumors, especially those of the parotid gland, only turn out to be salivary gland carcinomas after histopathological examination of the resected tissue. These are typically resected under the suspicion of a benign tumor. If only a single-level parotidectomy was performed in such cases, surgical revision to complete the total parotidectomy (level I to IV according to ESGS) is recommended, unless the tumor is a T1/T2 tumor according to the above criteria. It should be noted that surgical revision should be performed as soon as possible if the facial nerve has already been visualized during the primary operation, as the facial nerve is otherwise much more difficult to identify in scars and the risk of postoperative facial nerve palsy increases significantly.

If facial nerve function is normal preoperatively and the facial nerve does not appear to be involved by the tumor during surgery, the facial nerve is preserved. Surgery with magnifying glasses or a surgical microscope and facial nerve monitoring is therefore recommended. Resection of the nerve, i.e., more radical surgery, provides no oncological advantage in terms of survival, but significantly worsens the patient quality of life [45]. If the facial nerve is involved, a radical parotidectomy is performed with resection of the tumor-infiltrated parts of the nerve. In many cases, this enables a one-stage nerve reconstruction with nerve interposition devices [46]. Nerve reconstruction directly following tumor resection produces better functional results than a two-stage procedure. The need for postoperative radiotherapy is no reason not to perform a one-stage reconstruction. If nerve reconstruction is not feasible, or does not appear beneficial due to a life expectancy of < 1 year, or is not preferred by the patient, other measures (dynamic muscle transfer, static sling procedures) can be performed in one or two steps. As the protection of the eye is functionally very important, the implantation of an upper eyelid weight is recommended for the rehabilitation of eye closure after facial nerve resection without or with nerve reconstruction [47].

Salivary gland carcinomas show cervical lymph node metastases in 10-40% of cases [48]. A curative neck dissection should be performed in all patients with clinical or radiologic evidence of cervical metastases [49]. There is no standard for the extent of curative neck dissection. Depending on the primary tumor location, this should comprise levels II to IV or I to IV or I to V. The inclusion of level V is controversial, as is the question whether this cannot also be adequately treated electively with adjuvant radiotherapy.

An elective neck dissection should be performed prophylactically in patients with stage III/IV salivary gland carcinoma of the major salivary glands and in high-grade cases (e.g., salivary gland carcinoma NOS, squamous cell carcinoma, undifferentiated carcinoma, high-grade mucoepidermoid carcinoma and carcinoma ex pleomorphic adenoma) [50]. This also applies to adenoid cystic carcinoma, although this tumor type tends to metastasize hematogenously. Neck dissection provides further important prognostic information, such as the presence of extracapsular seeding, which is associated with a poorer prognosis. Elective neck dissection should include neck levels II and III for tumors of the parotid gland and neck levels I to III for tumors of the other major and minor salivary glands. In general, however, elective neck dissection for tumors of the minor salivary glands is controversial [51].

Postoperative radiotherapy is indicated in the presence of at least one of the following risk factors [52]: advanced T-stage (T3/T4), high-grade tumor, close or positive resection margins (R+), presence of lymph node metastases (N+), perineural sheath infiltration (Pn1), lymph vessel or blood vessel invasion [L1 or V1]) [53, 54]. Surgery alone is therefore sufficient for early T1/T2 tumors without cervical metastasis or any of the other risk factors mentioned [54]. Adenoid cystic carcinoma has a special position: here, adjuvant radiotherapy is indicated also for T1/T2 tumors, in the case of complete resection (R0) and especially in the case of perineural invasion [55].

Postoperative radiotherapy can be administered for intermediate-grade tumors with a close resection margin (1-3 mm) [56- 58].

When defining the target volume, a distinction is made between high-risk clinical target volume (CTV) and elective CTV. The target volume should be defined on the basis of preoperative imaging, histopathological findings, surgical report, and radiation planning CT using intravenous CM. In the case of postoperative residual tumor, MRI imaging should be chosen for radiation planning. The former primary tumor region, the extent of the affected salivary gland, the resection cavity and affected lymph node levels are included in the high-risk CTV.

The elective CTV contains areas with possible microscopic spread, including lymphatic drainage areas or, in the case of perineural sheath infiltration, and the route of the corresponding nerve tracts to the base of the skull. In the case of parotid carcinomas affecting the deep lobe, the infratemporal fossa and the parapharyngeal space are also included [59- 61].

Elective lymphatic drainage irradiation is performed for T3/4 tumors, high-grade tumors and proven lymph node involvement. In the case of lymph node involvement, at least the subsequent lymph node level should also be irradiated. As a rule, the elective lymph drainage areas are irradiated ipsilaterally. In the case of malignancies of the parotid gland and multiple lymph node metastases with extracapsular extension, bilateral irradiation of the lymph drainage areas can be administered [62]. For malignancies of the submandibular gland and minor salivary glands, bilateral irradiation of the lymphatic drainage areas should be applied in the presence of midline infiltration or at least 2 of the following risk factors: pT3/4, proven lymph node metastases, extracapsular extension, lymphatic vessel or vascular invasion. In the case of a cN0 situation, irradiation of the elective lymphatic drainage areas can be omitted in acinar cell carcinoma and low/intermediate grade adenoid cystic carcinoma [63, 64].

The respective planning target volumes (PTV) result from the CTVs, taking into account the individual positioning uncertainty (usually 3-7 mm expansion of the CTV).

In high-risk CTV, a normofractionated dose of at least 60 Gy should be applied and, in the case of a close/positive resection margin and/or perineural sheath infiltration, at least a dose of 64-66 Gy [65- 68]. In elective CTV, a normofractionated dose of 50 Gy is applied.

Highly conformal radiation techniques (VMAT, IMRT) are standard today. In adenoid cystic carcinoma and existing residual tumor postoperatively, heavy ion irradiation may be useful [65].

Additional chemotherapy such as postoperative radiochemotherapy has so far shown no advantages over postoperative radiotherapy in retrospective analyses [69- 71]. However, there are reports indicating that combined cisplatin-containing radiochemotherapy could improve local tumor control, especially in adenoid cystic carcinomas [72, 73]. The results of the prospective randomized trials (RTOG 1008, NCT01220583 and GORTEC 2016-02, NCT02998385) are pending. These studies investigate radiotherapy alone in the adjuvant situation or, in the GORTEC study, in the definitive treatment setting versus combined cisplatin-containing radiochemotherapy. In the adjuvant setting, simultaneous cisplatin-based radiochemotherapy can therefore be given in individual cases.

There are currently no prospective studies on adjuvant systemic therapy. Retrospective data indicate a survival benefit from adjuvant therapy with trastuzumab after surgery and radiotherapy in the case of Her2/neu expression DAKO3+ [74]. In addition, according to a retrospective analysis, androgen deprivation using bicalutamide or an LH-RH agonist (goserelin, triptorelin), as monotherapy or in combination, in stage IVa androgen receptor-positive salivary duct carcinoma, given adjuvantly after postoperative radiotherapy over 1-5 years, could provide a survival benefit over radiotherapy alone [75]. However, there is currently a lack of evidence for this from prospective clinical trials.

Definitive radiotherapy is indicated for inoperable carcinomas, e.g., tumors involving the base of the skull, or in patients with contraindications to surgery.

When defining the target volume, a distinction is made between high-risk CTV and elective CTV. The target volume should be defined based on pre-therapeutic examination and imaging, histopathological findings, a radiation planning CT with intravenous CM and an MRI. The high-risk CTV should include the macroscopic primary tumor, the entire salivary gland and, if present, lymph node metastases. The elective CTV contains areas with possible microscopic spread, including elective draining lymphatic areas or the route of the corresponding nerve tracts to the base of the skull [59, 60].

Elective lymphatic drainage irradiation is performed for T3/T4 tumors, high-grade tumors, adenocarcinomas, mucoepidermoid carcinomas and proven lymph node involvement. In the case of lymph node metastases, at least the subsequent lymph node level should also be irradiated. As a rule, the elective lymph drainage areas are irradiated ipsilaterally. In the case of submandibular and minor salivary gland malignancies, bilateral irradiation of the lymphatic drainage areas should be performed, if midline invasion is documented or if the risk factors cT3/T4 and lymph node metastases are present [64].

The respective planning target volumes (PTV) result from the CTVs, taking into account the individual positioning uncertainty (usually 3-7 mm expansion of the CTV). In high-risk CTV, a normofractionated dose of at least 72 Gy should be applied [76, 77]. In elective CTV, a normofractionated dose of 50 Gy is given. Highly conformal radiation techniques (VMAT, IMRT) are standard today.

As many salivary gland carcinomas grow slowly, there is a relative resistance to radiotherapy, especially in the case of adenoid cystic carcinoma. Radiation qualities with high linear energy transfer properties are therefore of interest for salivary gland carcinomas, such as carbon ions, recently also in combination with proton therapy [78]. Data on particle therapy for salivary gland carcinomas are only available for selected cases in mostly retrospective cohorts [79]. Particle therapy should therefore be evaluated as a possible alternative to irradiation with photons if better dose application can be achieved in the vicinity of critical organs at risk.

Definitive radiochemotherapy may be considered. There are no clear criteria for the use of definitive radiochemotherapy compared to definitive radiotherapy [73, 80]. There is also no standard for the selection of chemotherapeutic agent(s). In most cases, cisplatin-based therapy is used, referring to data on common head and neck tumors [78, 79, 81].

There is no standard for the treatment of non-curatively treatable salivary gland carcinomas. The rarity and heterogeneity of salivary gland carcinomas make it difficult to conduct large-scale studies on systemic therapy. Accordingly, no large phase III trial data are available in the recurrent or distant metastatic treatment situation. Recommendations for systemic therapy are therefore primarily based on the results of phase II studies or molecularly stratified basket studies. A number of further phase II trials using new substances are currently underway (overview in: [15, 82, 83]). The majority of the therapies listed here have not been approved for use in salivary gland carcinomas. It is therefore recommended to obtain the consent of the patient's health insurance company before administration.

The course of the disease in the metastatic situation is variable, and a relevant proportion of patients remain asymptomatic for a long time. Accordingly, a watch-and-wait strategy is justified in selected cases (low tumor burden, stable disease, no symptoms). In particular, adenoid cystic carcinomas (especially with an isolated pulmonary metastatic pattern), myoepithelial carcinomas and acinar cell carcinomas may show only a slight growth tendency over a long period of time [84- 86]. This also applies to second-line therapy after failure of first-line therapy.

Systemic therapy based on the treatment protocols for head and neck squamous cell carcinomas (HNSCC) is not recommended, as patients with salivary gland carcinoma were excluded from these studies [87]. In addition, the use of immune checkpoint inhibitors - in contrast to the frequent head and neck tumors - has not yet played a decisive role in salivary gland carcinomas. The immuno-oncological approaches with checkpoint inhibitors have so far not been convincing in most cases of salivary gland carcinomas [88, 89].

In patients with high tumor burden and disease dynamics, systemic therapy with one or more chemotherapeutic agents may be indicated. In an indirect comparison, combination chemotherapies show higher response rates than monochemotherapy. Platinum-based chemotherapy regimens (using cisplatin or carboplatin) are mainly used with dosages derived from the therapeutic principles of systemic therapy for the common HNSCC, including the combination with cyclophosphamide and doxorubicin (CAP regimen), platinum doublet with a taxane (not for adenoid cystic carcinoma) or with vinorelbine. The response rates are 20-60% [90, 91]. The combination of carboplatin and paclitaxel is also used in metastatic salivary duct carcinoma [92]. However, the extrapolation of treatment regimens from HNSCC to salivary gland carcinoma should be made with caution, and the individual subtype of salivary gland carcinoma should be taken into account. For example, the activity of paclitaxel in adenoid cystic carcinoma is very limited and its use is therefore not recommended [93]. In the case of a reduced general condition, monochemotherapy with vinorelbine, cisplatin or epirubicin are possible treatment options [90, 94, 95].

In >95% of cases of secretory salivary gland carcinoma, an ETV6-NTRK3 gene fusion is detectable. It results in excessive tyrosine kinase activity. This makes targeted therapy possible. The two tyrosine kinase inhibitors entrectinib and larotrectinib are approved for the treatment of NTRK-positive tumors and show good efficacy in secretory salivary gland carcinoma [96, 97]. Entrectinib achieved a response rate of 57% in a collective of NTRK gene fusion-positive tumor patients. In the subgroup of 7 patients with secretory carcinoma, a response rate of 86% was reported [97]. Immunohistochemical TRK expression correlates with NTRK1 and NTRK2 fusions, although the specificity appears to be lower in the case of salivary gland carcinomas compared to other solid tumors. RNA-based confirmation of gene fusion is necessary before starting treatment with an NTRK inhibitor [98].

Anti-HER2 therapy should be considered for HER2-positive tumors. Up to 30% of mucoepidermoid carcinomas and 40% of salivary duct carcinomas show HER2 overexpression. Phase II studies show very high response rates to HER2 blockade in this setting, e.g., with docetaxel plus trastuzumab (response rate up to 70%) or ado-trastuzumab emtansine after trastuzumab failure [99- 101]. The combination of trastuzumab and pertuzumab is a potential option for patients with a contraindication to taxane therapy. According to a subgroup analysis of a basket study, the response rate with trastuzumab and pertuzumab was 60% [102]. The antibody-chemotherapy conjugate (ADC) trastuzumab-deruxtecan represents a new potential treatment option. A response rate of 37% was achieved in a HER2-positive patient collective without other treatment alternatives [103]. Among the 19 patients with HER2-positive salivary gland carcinoma included in the study, the response rate was 42%. In the meantime, trastuzumab deruxtecan has received tumor diagnostic approval in the USA for HER2-positive (IHC3+; immunohistochemically triple positive) tumor diseases without satisfactory treatment alternatives. The decision regarding the extension of the approval by the European Medicines Agency remains to be awaited.

RET gene fusions are a rare driver in non-small cell lung carcinoma, thyroid carcinoma or tumors of the gastrointestinal tract. In salivary duct carcinomas and secretory carcinomas, the corresponding fusions are described in a small, but relevant proportion. The selective RET kinase inhibitor selpercatinib was investigated in a tumor-agnostic phase I/II study. Among the four patients with salivary gland carcinoma included in the study, the response rate was 50% [104].

In a large-scale molecular profiling study of salivary gland carcinomas, BRAF alterations were detected in 2.7% of all patients [105]. To date, there are case reports in the literature in which clinical activity of corresponding inhibitors (dabrafenib and trametinib) was observed in BRAF-altered salivary gland carcinomas [106].

Antiangiogenic substances represent a therapeutic option for adenoid cystic carcinoma. The multi-tyrosine kinase inhibitor lenvatinib was investigated in a phase II trial involving 33 patients with adenoid cystic carcinoma and progression following prior therapy. The response rate with lenvatinib was 15%, and 75% of the group showed stabilization of the disease [107]. The tyrosine kinase inhibitors sorafenib and axitinib were also tested in phase II trials in adenoid cystic carcinoma. A response rate of 16% was reported with sorafenib and 9% with axitinib [108, 109]. It should be noted that disease progression before the start of treatment was not an inclusion criterion in the studies mentioned. In another recent randomized phase II study, axitinib showed a significantly better progression-free survival rate at 6 months (73.0%) than a wait-and-see approach (23.0%) in patients with recurrent or metastatic adenoid cystic carcinoma [110]. The combination of axitinib with the checkpoint inhibitor avelumab was also investigated in relapsed or metastatic adenoid cystic carcinoma and resulted in an 18% response with a progression-free survival of 7.3 months and an overall survival of 16 months in a non-randomized study [111].

In contrast to other salivary gland carcinomas, salivary duct carcinomas very frequently exhibit androgen receptor expression (80%). Androgen deprivation is a possible treatment option as first-line therapy or as second-line therapy in the event of progression after chemotherapy or low disease burden in the case of high nuclear androgen receptor positivity (>70%) [112] There are reports indicating that patients with androgen receptor-positive salivary duct carcinoma or salivary gland carcinoma NOS benefit from androgen deprivation therapy with leuprorelin or bicalutamide [113, 114]. In a phase II study, the combination of leuprorelin and bicalutamide achieved a response rate of 40% in salivary gland carcinoma [115]. In a castration-resistant situation, the use of bicalutamide plus LHRH agonists was clinically effective according to a phase II study [116]. For second-line therapy, the use of abiraterone should be weighed against enzalutamide or chemotherapy. In a phase II study of 24 patients, abiraterone resulted in disease control in 62% and a median PFS of 3.6 months [116]. Enzalutamide achieved disease control in 67% of study participants, which translated into a median PFS of 5.6 months and overall survival of 17 months [117]. In double HER2-positive/androgen receptor-positive salivary duct carcinoma, HER2 blockade and androgen deprivation therapy can be given sequentially [118]. However, the optimal treatment sequence for these double-positive salivary gland carcinomas has not yet been defined.

Especially before second-line or third-line therapy, it is recommended that patients be presented to a molecular tumor board. The possible targets for a personalized treatment decision are shown in Table 6.

Figure 5 shows how molecular testing supports the treatment decision for systemic therapy.

Relapse of salivary gland carcinoma is often very aggressive, with a high risk of distant metastases [122]. Salvage surgery is only possible in selected cases. After resection of a locoregional relapse, radiotherapy is indicated postoperatively in non-pre-irradiated patients as in the primary treatment setting (see chapter 6.3.). Radiotherapy should be performed for locally inoperable or incompletely resected locoregional relapses that have not been previously irradiated, and heavy ion irradiation should be considered for adenoid cystic carcinomas. Re-irradiation with heavy ions or highly conformal stereotactic techniques should be considered for pre-irradiated, locally inoperable or incompletely resected relapses [123, 124].

With regard to distant metastases, adenoid cystic carcinoma is a special case: hematogenous metastases occur in 25-50% of patients in the long-term course [125]. Due to the slow growth, patients with adenoid cystic carcinoma can still have a long life expectancy. For this tumor type, resection of lung metastases for local pulmonary control of the disease is therefore also an option [126]. Alternatives to resection of metastases include other local ablative procedures such as radiofrequency ablation or stereotactic radiotherapy [127].

For the use of systemic treatment for recurrent tumors, please refer to chapter 6.6.

About 5% of all salivary gland tumors affect children [128]. 40-60% of these tumors in children are malignant, i.e., much more common than in adults. Mucoepidermoid carcinoma (45-50%) and acinar cell carcinoma (25-35%) are the most common malignant histologic types in children [9]. The therapeutic principles in children do not differ from that in adults [129]. Surgery is the curative treatment of choice, possibly followed by postoperative radiotherapy (for indications for postoperative radiotherapy, see chapter 6.3.). In children with a pN0 neck, postoperative radiotherapy is generally decided with more restraint. As a rule, postoperative radiotherapy of the soft tissues of the neck is not performed for pN0.