Salivary gland cancer: ESMO-EURACAN Clinical Practice Guideline for

diagnosis, treatment and follow-up

SUPPLEMENTARY MATERIAL

SUPPLEMENTARY TEXT

SECTION 1. DIAGNOSTIC IMAGING

The algorithm for evaluating a suspected major salivary gland mass varies according
to the specific clinical setting. In all clinical settings, where the mass is superficial,
ultrasound should be used as the first imaging step. Ultrasound is effective in
assessing the actual glandular origin,1 but its use is limited when dealing with a solid
lesion; neither the signal pattern nor the shape is adequate for differentiating benign
from malignant neoplasms. The pooled sensitivity of ultrasound in this setting is
66%, with a specificity of 92%.2

When a mass cannot be completely delineated by ultrasound, and in all clinical

settings suggesting a malignancy, magnetic resonance imaging (MRI) is the
preferred imaging modality. The sensitivity and specificity of computed tomography
(CT) and [18F]2-fluoro-2-deoxy-D-glucose–positron emission tomography–CT (FDG–
PET–CT) for predicting malignant tumours are lower than MRI3,4 and MRI has
greater tissue discrimination. It is important for MRI to combine different pulse
sequences: standard T2 and T1 weighting with diffusion weighting with apparent
diffusion coefficient map and dynamic analysis post paramagnetic contrast agent
administration are recommended. This ‘multiparametric approach’ has a pooled
sensitivity of 80% and specificity of 90%.2 The use of contrast-enhanced CT (CE-CT)
is mostly limited to patients in whom MRI is contraindicated (e.g. those with a cardiac
pacemaker, claustrophobia, ferrometallic prostheses or foreign bodies) or in addition
to MRI when there is a suspicion of bone invasion.

Multiparametric MRI is indicated to demonstrate glandular or extraglandular spread. 5

While the invasion of cortical bony structures can be more easily identified by CE-
CT, the permeative invasion of an adenoid cystic carcinoma (AdCC) into
spongiotic/diploic bones (skull base, mandible) may be missed by CT, particularly
when it presents as replacement of medullary fat bone marrow in the absence of

1
gross cortical erosions. Such findings are better detected with a non-contrast T1
weighted MRI sequence.6 Post-contrast high-resolution MRI is the modality of choice
to detect perineural spread. According to the site of origin of the neoplasm, the facial
nerve (parotid gland) and the maxillary and mandibular branches of the trigeminal
nerve (minor salivary glands of the palate, submandibular and sublingual glands)
should be scrutinised by MRI. The cavernous sinus, Meckel's caves and geniculate
ganglion, which are ‘intra-cranial terminal stations’, should be included in the field of
view of the MRI study. The sensitivity of MRI for perineural spread has been reported
to be greater than CT (92.6% versus 87.9%, respectively)7; however, incomplete
mapping of all involved nerves lowers MRI sensitivity to 20%-37%.

Regardless of the imaging technique used (MRI or CT), the study should be
extended to include the ipsilateral and contralateral neck levels or integrated with
ultrasound examination of neck lymph nodes. Several recent reports underline that
FDG–PET–CT is not inferior to CT and MRI, and in some studies has been shown to
be more sensitive in detecting nodal involvement in salivary gland cancer (SGC).3,8,9

Distant metastases at presentation are infrequent. In staging SGC, chest CT is

recommended in cT3-4 N0 and all stages of AdCC. FDG–PET–CT is recommended
for treatment planning in lymph node-positive or high-grade SGC.3 The following
SGCs may be considered high grade: SGCs graded as high according to criteria
[e.g. high-grade mucoepidermoid carcinoma (MEC), high-grade acinic cell carcinoma
(AcCC)]; all high-grade transformed tumour types [e.g. AdCC, AcCC, secretory
carcinoma, epithelial-myoepithelial carcinoma, myoepithelial carcinoma, MEC,
polymorphous adenocarcinoma (PAC), clear cell carcinoma10]; all AdCC, basal cell
adenocarcinoma, adenocarcinoma not otherwise specified (NOS), salivary duct
carcinoma, myoepithelial carcinoma, epithelial-myoepithelial carcinoma, carcinoma
ex pleomorphic adenoma (CxPA) including subtypes such as salivary duct ex
pleomorphic adenoma and myoepithelial ex pleomorphic adenoma), sebaceous
adenocarcinoma, carcinosarcoma, poorly differentiated carcinoma (including
undifferentiated, small and large cell neuroendocrine carcinoma) and
lymphoepithelial carcinoma.

Bone is the second most common site for distant metastases in SGC, after lung. 11
Although the sensitivity of FDG–PET is comparable to that of morphologic imaging
techniques, its specificity has been reported to be significantly higher.12

2
SECTION 2. HISTOLOGICAL SUBTYPES

MEC

MEC is the most common SGC13 and consists of three cell types: (i) mucinous cells,
which are often large and goblet-like and frequently line cystic spaces; (ii)
epidermoid cells that are nonkeratinising and may even look frankly squamous; (iii)
intermediate cells which are more basal or cuboidal. In addition to clinical stage,
tumour grade is a prognostic factor that may guide treatment decisions. MEC is
classified into three histological grades (low, intermediate and high) based on
evaluation of necrosis, mitoses, atypical nuclei and relative size of the cystic
component.14 Translocations t(11;19) and t(11;15), leading to the CRTC1-MAML2
and CRTC3-MAML2 fusions, respectively, are present in 40%-80% and 5% of
MECs, respectively.15 Some studies indicate that fusion-positive MECs are
diagnosed at an earlier stage with a lower grade and a better prognosis than fusion-
negative tumours,16 while others have not demonstrated a prognostic role for the
translocation.17 MAML2 rearrangements have been detected in up to 75% of low-
grade and intermediate-grade MECs, but fewer than 50% of high-grade MECs seem
to be fusion positive. Among high-grade MECs, fusion-negative tumours behave
much more aggressively than fusion-positive tumours. It has been proposed that
CRTC1-MAML2 fusion-negative high-grade carcinomas with MEC-like morphological
features and scanty mucin content actually represent a heterogenous group of other
high-grade carcinomas, in line with their more aggressive behaviour.16 Compared
with other histological subtypes, MEC presenting as local/locoregional disease has a
good prognosis, with a 5-year survival rate of 75.2% [95% confidence interval (CI)
73.8% to 76.7%]. For high-grade disease (26%), the 5-year survival rate drops to
48.5% (95% CI 45.4% to 51.9%).18

AdCC

AdCC is a relentlessly growing tumour, composed of epithelial and myoepithelial

cells that form various growth patterns (tubular, cribriform and solid), and is
associated with MYB-NFIB and MYBL1-NFIB fusions. Despite bland
histopathological features, AdCC is aggressive and characterised in most cases by

3
perineural and intraneural invasion and distant spread that may develop over years
and decades. Mutations in the NOTCH gene family are present in around 14% of
patients with AdCC at presentation (especially in patients with solid histology), are
increasingly present in recurrent or metastatic disease (40%) and are associated
with poor outcome.19,20 Relapsed and disseminated tumours are generally incurable,
and overall prognosis is poor, with 15- or 20-year survival rates of 23%-40%.21

AcCC

AcCC exhibits serous acinar and lacks mucinous differentiation. It is characterised

by solid, microcystic, follicular, less commonly papillary-cystic architectures, often
with a prominent lymphoid stroma. Neoplastic cells are heterogeneous with the most
common cell type being the serous acinar cell which features periodic acid-Schiff
(PAS)-positive, diastase-resistant basophilic cytoplasmic zymogen granules, with
variable intercalated duct-type, nonspecific glandular, vacuolated and rarely clear
cells. High-grade tumours exhibit, in addition to conventional areas, a component of
high-grade adenocarcinoma (with variable cribriform, solid, trabecular growth
patterns) or poorly-differentiated/undifferentiated carcinoma. The majority of AcCC
cases harbour a t(4;9)(q13;q31) rearrangement that places the active enhancer
regions of the SCPP gene cluster upstream of the NR4A3/NOR-1 gene, resulting in
upregulation of NR4A3 via enhancer hijacking.22 Nuclear staining for NR4A3/NOR-1
or NR4A2/Nurr1 has been identified in 98% and 2% of cases, respectively.22,23 The
prognosis of patients presenting with local/locoregional AcCC is generally good, with
a 20-year disease-specific survival (DSS) rate of 64.3% for patients with stage IV
disease.24 Notably, this value is derived from a large retrospective database study
from 1973-2009; however, in 2010 mammary analogue secretory carcinoma, which
was formerly frequently classified as AcCC, was defined as a separate entity with
excellent prognosis (see below). Therefore, data going back further than 2010 may
be biased.25

PAC and cribriform adenocarcinoma of salivary gland

PAC and cribriform adenocarcinoma of salivary gland (CASG) are related entities
with partly differing clinicopathological and genomic profiles; they are the subject of

4
an ongoing taxonomical debate.26,27 Classical variant PACs, originally called
polymorphous (low-grade) adenocarcinomas, are characterised by hotspot point
E710D mutations in the PRKD1 gene,28 whereas CASGs are characterised by
translocations involving the PRKD1-3 genes.29 In the 2017 WHO Classification of
Head and Neck Tumours, cribriform adenocarcinoma of (minor) salivary gland origin
is a subcategory of PAC,30 but for the purpose of reporting, differentiating between
these entities may be helpful given the noticeably different behavioural profiles,26,27
with CASGs being more frequently extrapalatal, commonly at the base of the tongue,
with a propensity for nodal metastasis. The prognosis of patients with PAC is
generally good, with 5- and 10-year DSS rates of 98.6% and 96.4%, respectively.31

Intraductal carcinoma

Intraductal carcinoma is a rare, low-grade SGC with histomorphological features

reminiscent of atypical ductal hyperplasia or ductal carcinoma in situ of the breast.
The tumour is, in typical cases, characterised by intraductal and intracystic
proliferation of luminal ductal cells exhibiting solid, cribriform and papillary patterns.
Notably, recurrent NCOA4-RET and TRIM27-RET fusion transcripts have been
observed in intraductal carcinomas.32,33 As these genetic aberrations are recurrent,
they serve as powerful diagnostic tools in SGC diagnosis, and therefore also in
refinement of SGC classification.

Salivary duct carcinoma

Salivary duct carcinoma is a high-grade adenocarcinoma with morphological and

molecular features similar to invasive ductal carcinoma of the breast, including
androgen receptor expression in 90% of cases and human epidermal growth factor
receptor 2 (HER2) gene amplification in 30% of cases. Additional common molecular
alterations in salivary duct carcinoma include mutations in TP53, PIK3CA and HRAS,
and loss or mutation of PTEN.34,35 The majority of salivary duct carcinomas (74%)
have alterations in either the mitogen-activated protein kinase (MAPK) pathway
(BRAF, HRAS and NF1) or in HER2/neu, indicating that MAPK pathway activation
and HER2 amplification are the major oncogenic drivers in salivary duct carcinoma.36
Gene fusions involving the PLAG1 and HMGA2 oncogenes are specific for benign

5
pleomorphic adenomas and they have also been described in salivary duct
carcinoma arising in pleomorphic adenoma.36 Reported 3-, 5- and 10-year survival
rates in patients with salivary duct carcinoma are 70.5% (95% CI 61.4% to 77.8%),
43% (95% CI 33% to 52%) and 26% (95% CI 15% to 37%), respectively.37

Adenocarcinoma NOS

The diagnosis of adenocarcinoma NOS is reducing due to advances in molecular

diagnostics. Androgen receptor expression is observed in some cases of
adenocarcinoma NOS, and HER2 gene amplification can also occur. Fifteen-year
survival rates for low-, intermediate- and high-grade adenocarcinoma NOS have
been reported as 54%, 31% and 3%, respectively.38

CxPA

CxPA is subclassified by histological type and extent of invasion. Noninvasive

CxPAs (intracapsular) are completely confined within the capsule of the original
pleomorphic adenoma, lacking penetration of the capsule. Intracapsular CxPA has a
very low reported rate of recurrence and regional metastasis.39 Minimally invasive
CxPAs (<4-6 mm extension beyond the pleomorphic adenoma border) are
prognostically favourable.40 Widely invasive carcinomas extend beyond 6 mm. Prior
to diagnosing a noninvasive CxPA, sectioning of the entire lesion for histological
evaluation is recommended in order to exclude the presence of invasive growth.
Prognosis parallels the degree of invasion, with noninvasive and minimally invasive
cancers having a better prognosis than invasive CxPAs,41 even if
intracapsular/minimally invasive CxPAs can also recur and cause death. There is a
trend toward worse disease-free survival and DSS in patients with myoepithelial
carcinoma.42

Secretory carcinoma

Secretory carcinoma, formerly known as mammary analogue secretory carcinoma,43

shows morphological, genetic and immunohistochemical similarities to breast
secretory carcinoma.44 One of the main differential diagnoses is AcCC, which

6
typically contains a basophilic cytoplasm with PAS-positive zymogen granules and a
more diverse cytological profile compared with secretory carcinoma. The presence of
a chromosomal translocation, t(12;15), between the ETV6 gene on chromosome 12
with NTRK3 on chromosome 15, generates the fusion product ETV6-NTRK3.43 A
small subset of secretory carcinomas show alternative fusions, such as ETV6-RET45,
ETV6-MET46 and VIM-RET.47 Importantly, ETV6-NTRK3 and ETV6-RET fusions may
serve as a target for therapy. Secretory carcinoma behaves relatively indolently and
has an estimated 5- and 10-year survival rate of 95%. Recurrent or metastatic
disease is rare and mainly occurs in high-grade transformation tumours.48

SECTION 3. HISTOLOGICAL DIAGNOSIS

Histological tumour grade

The histological (microscopic) grading of SGCs has been shown to be an

independent prognostic factor and plays a role in optimising therapy, with high-grade
tumours requiring intensified treatment strategies (see Figures 2, 3 and 4). Further,
there is often a positive correlation between histological grade and clinical stage.41
Nevertheless, most SGC types have an intrinsic biological behaviour and attempted
application of a universal grading scheme is not recommended.41 By assigning a
histological type, the tumour grade itself is often implied. As such, a generic grading
scheme is no longer recommended for SGCs.49

Carcinoma types for which grading systems exist and are relevant are incorporated
into histological type. The major diagnostic categories amenable to grading include
AdCC, MEC, PAC and adenocarcinoma NOS.40,41

High-grade transformation has evolved into an important concept of tumour

progression in SGCs. Historically designated as ‘dedifferentiation’, it describes
progression of a typically monomorphic, low-grade carcinoma into a pleomorphic,
high-grade carcinoma.50 The importance of this phenomenon is that tumours
demonstrating high-grade transformation show an aggressive clinical course that
deviates drastically from the usual behaviour for a given tumour type, thus alerting
the treating team to the potential need for more aggressive treatment. Tumours for
which this phenomenon is well characterised include AcCC, AdCC, epithelial-
myoepithelial carcinoma, secretory carcinoma51 and many others.50

7
Perineural invasion

Perineural invasion is diagnostically useful because it establishes a malignant

categorisation. The value of perineural invasion as a prognosticator varies
depending on tumour type.52 Involvement of a specifically named nerve (e.g. facial
nerve) is incorporated into staging and is assigned a more advanced stage.49 It is
well known that AdCC can extend along nerves beyond the tumour margins;
however, studies on perineural invasion in AdCC have provided conflicting results
with regard to whether it is a risk factor for local recurrence.53 A thorough
documentation, to include the extent of perineural invasion, histological pattern of
perineural and intraneural invasion, localisation and size of involved nerves, should
be considered and may be prognostically relevant.54

Lymphovascular invasion

Lymphovascular invasion is nearly always diagnostic for SGC (metastasising

pleomorphic adenoma being the obvious exception). Existing data are limited but
support its prognostic value, although this varies by tumour type and study.55

Extent of invasion

Macroscopic extraparenchymal extension is the parameter required to upstage a

tumour to T3 and is thus more important than microscopic extraparenchymal
extension. Bone, skin and facial nerve involvement are parameters that define stage
T4a.49

Margin status

Complete surgical excision to include cancer-free margins is the primary treatment

for SGCs, because retrospective studies have shown an increased risk for
recurrence and decreased survival with close or positive surgical margins.55,56 Unlike
mucosal sites, there are no data to indicate a specified critical margin distance that
yields a prognostic difference. Occasionally, SGCs may show encapsulation similar

8
to that of pleomorphic adenoma. In superficial parotid gland lesions, a tumour that
rests on the facial nerve with its capsule may thus be resected conservatively (i.e.
dissecting the tumour capsule from the nerve) in order to spare and minimise injury
to the facial nerve. Thus, it is not uncommon for such tumour margins to be judged
‘close’ with the tumour capsule forming the deep margin. It is not clear whether this
scenario indicates an increased risk of local recurrence. There are limited data on
the use of extracapsular dissection (a tissue sparing technique recently developed
for benign tumours) in SGCs that suggest a favourable outcome even with close
margins, but this is likely influenced by selection bias, since most carcinomas treated
by extracapsular dissection are slow growing and low-grade tumours that were not
diagnosed as malignant preoperatively.55,57

Frozen section

Intra-operative frozen sections can be indicated to evaluate margins of resection,

perineural invasion and lymph nodes, but only if the result is expected to alter
management at the time of surgery.58 Frozen section analysis has high specificity
(99%) and sensitivity (98.5%).59

SECTION 4. POST-OPERATIVE RADIOTHERAPY

In a matched pair analysis of patients treated for major SGC, post-operative

radiotherapy (RT) improved local control from 17% to 51%.60 This analysis, however,
was based on data collected several decades ago and the treatment groups covered
different time periods: surgery alone from 1939-1965; combined treatment from
1966-1982.

In another study of 8580 patients with major SGC, four subgroups were analysed:
early stage (T1-2) versus late stage (T3-4) and presence or absence of adverse
features (AdCC, intermediate to high grade, positive margins and pN+).61 After
propensity score matched analysis, post-operative RT improved overall survival (OS)
in case of adverse features, but not in early stage without adverse features.

Survival was analysed in 2017 patients with minor SGC (70% oral cavity, 15% nasal
cavity).62 The patients were divided into three subgroups with decreasing OS rates,

9
based on a propensity score matched analysis. Post-operative RT resulted in a 24%
survival benefit in patients with advanced T/N category, AdCC, high-grade disease
and nasopharynx location. A web-based tool for predicting survival impact of
adjuvant RT was developed; however, important data such as surgical margins and
perineural and vasoinvasion were lacking.62

One of the largest and most detailed retrospective cohort studies is the Dutch Head
and Neck Cooperative study, which included 565 patients with SGC, excluding minor
SGC of the nasal cavity.63,64 The reported relative risk for surgery alone, compared
with combined treatment, was 9.7 for local recurrence and 2.3 for regional
recurrence. The UK National Multidisciplinary Guidelines for the Management of
Salivary Gland Tumours are mainly based on this study.65 Post-operative RT is
particularly effective if there are close (<5 mm) or microscopic positive resection
margins, enhancing local control from around 50% to 80%-95% in T3-T4 tumours,66
from 54% to 86% in pathologically confirmed bone invasion and from 60% to 88% in
perineural invasion.64 Grading was not evaluated in this study. Post-operative RT
was an independent prognostic factor for patients with pN+ neck involvement,
improving regional control from 62% to 86%. For completely resected T1 or T2
tumours with no bone or perineural invasion, surgery alone can result in a >90% 10-
year local control rate and adjuvant RT is not indicated.67

Several cohort studies in patients with AdCC have reported improved outcomes with
the addition of RT to surgery.68,69 In a cohort of 101 patients with M0 AdCC, post-
operative RT improved the 5-year local control rate and disease-free survival
compared with surgery alone (81.0% versus 53.4%, P = 0.0003 and 71.3% versus
50.0%, P = 0.0052, respectively).70 In a series of 140 patients, besides T4 stage and
nerve invasion, omission of RT was an independent negative prognostic factor for
local control; however, this was only observed in patients treated with >60 Gy.68 In
case of specifically named perineural invasion (e.g. facial nerve), a radiation field
including the extension of the nerve to the base may prevent recurrences.71

In a cohort of 87 cases with SGC of the parotid gland (n = 70) or submandibular

gland (n = 17), post-operative RT was an independent prognostic factor for local
control, in addition to facial paresis.70 In another study of patients with parotid gland
cancer, 56 patients treated with surgery alone were compared with 91 patients

10
treated with combined therapy.72 In multivariate analysis, post-operative RT
improved local control, but not OS.

In a study of patients with SGC, 10-year locoregional control was significantly

improved in patients who received surgery plus RT versus RT alone for stage I-III
and stage IV disease (89% versus 71% and 60% versus 20%, respectively).73
Although the RT group included a higher number of patients with minor SGC, T4
tumours and AdCC, the significant difference remained in multivariate analysis.

SECTION 5. PARTICLE THERAPY

Photon treatment

In some small retrospective studies of patients with predominantly T4 disease

treated with primary curative photon treatment, 5-year locoregional control rates of
up to 50% have been reported; however, after 10 years, these rates may drop to
30%.64,73,74 A radiation dose of >66 Gy (2 Gy fractions) is advised (preferably 70
Gy).64,74

Particle treatment

Particle therapy regimens vary widely, ranging from normofractionated protons75,76 to

mixed beam77 and hypofractionated carbon ions (C12).78,79 Fractionation regimens
have never been prospectively compared, hence the choice of fractionation remains
at the discretion of the treating institution. Particle RT with biologically effective
doses >70 Gy yields promising local control rates, especially in advanced tumours,
with mostly mild acute and late toxicity. Depending on the proportion of very
advanced cases (T4), reported local control rates are ~60%-70% at 5 years.78,80

Experience with C12-only regimens indicates a consistently mild toxicity profile. A

pooled analysis of 289 patients with AdCC across four Japanese particle centres
reported a local control rate of 88% at 2 years (median follow-up 30 months).79
Longer-term follow-up of 69 patients with AdCC in China reported a 5-year local
control rate of 73%.78 Subgroup analysis of patients with T4 tumours in the C12
cohorts showed no significant difference in either local control or OS between
subtotal resection and definitive RT without prior surgery, suggesting that subtotal

11
and/or potentially mutilating surgery can be avoided on the condition that high-dose
RT can be applied.

In one study, a combination of photons and passive scattered protons up to 75.9 Gy

following partial or complete resection in 50% of cases was evaluated in 23
patients.75 Late toxicity was very high (grade 3 late neurological toxicity in 10 out of
23 patients), potentially due to passive scanning technique. In another study, 35
patients were treated with scanned protons for AdCC; 26 post-operatively (70 Gy in
35 fractions) and 9 as primary therapy (75.6 Gy in 35 fractions).76 The 2-year local
control and progression-free survival rates were 92% and 74%, respectively.
Nevertheless, the reported median follow-up of 2.5 years was short and should
ideally exceed 5 years, which would also allow for the detection of late toxicity.
Similar to the C12 cohorts, resection did not impact OS in high-dose proton therapy,
albeit at lower overall case numbers.76

Studies comparing photon treatment with particle therapy

One randomised study compared photon treatment with neutron therapy.81 The
study had to be stopped because of a difference in 2-year locoregional control after
inclusion of only 32 patients. The 10-year locoregional control probability was 17%
after photon therapy and 56% after neutron therapy; however, survival was equal
and late morbidity was higher with neutron therapy.

In a retrospective (not case controlled) study of 75 patients with unresectable or

recurrent AdCC, photon treatment was compared with neutrons and demonstrated 5-
year local control rates of 32% and 75%, respectively.82 Survival rates were equal,
and grade 3/4 late toxicity was higher for neutrons (4% versus 19%, respectively).

In one prospective study, intensity-modulated RT (IMRT) photon therapy (n = 37)

was compared with IMRT with a C12 boost (n = 58) for unresectable or partially
resected AdCC. The choice of treatment was based on the availability of C12.
Although the study was not randomised, 5-year locoregional control and OS rates
were higher with a C12 boost than without (60% versus 40% and 77% versus 59%,
respectively).77 Acute and late toxicity were comparable.

There are no prospective studies directly comparing photons with protons.

12
SECTION 6. FOLLOW-UP, LONG-TERM IMPLICATIONS AND SURVIVORSHIP

All decisions around follow-up monitoring and its frequency should be made between
the patient and the treating clinical team. Decisions should take into consideration
tumour histology, tumour aggressiveness and the wishes of the patient.

In patients with AdCC, frequent and prolonged follow-up is recommended since

relapse and distant metastases might occur several years after diagnosis.
Locoregional imaging (preferably head and neck MRI with contrast imaging) is
suggested every 3-4 months for the first 2 years, every 6 months from the third to the
fifth year and then on an annual basis thereafter. A chest CT at least annually should
also be considered.83

For patients with other types of SGC with no evidence of disease activity, regular
scans 1-2 times per year are suggested for the first 1-2 years, before moving to less
frequent scans. Patients with residual/recurrent or metastatic disease should be
scanned more regularly (i.e. 2-4 times per year), but when a low growth rate is
present, the imaging frequency can be decreased. MRI scans are the best imaging
tool for locoregional recurrent disease. There is no consensus on the value of FDG–
PET–CT in follow-up, surveillance and assessing local recurrence compared with
conventional imaging.84 Chest CT can be carried out at each imaging timepoint and
annually, and a CT of the abdomen is advised annually. In some SGCs, metastatic
disease can occur after >5-10 years; therefore, in addition to regular imaging,
patients should be informed about the risk of recurrent or metastatic disease and the
symptoms to look out for.

Reconstruction of the facial nerve is best done at the moment of the ablative
surgery.58 Prosthetic rehabilitation, such as implant-retained epitheses, prostheses
and obturators, with or without soft-tissue and/or bone reconstruction, should be
incorporated into the primary surgical plan.58

Quality of life is underexamined in patients with SGC, who often experience

relationship, social, work and psychological problems. Quality of life is of paramount
importance, and open and honest communication with clinicians from the start of
treatment allows patients to make informed, subjective decisions. Patient-clinician
team trust is key.

13
Late toxicities and long-term effects of treatment include shoulder pain, telegesis,
xerostomia, neck immobility, problems with speech and eating, progressive deafness
and jaw stiffness. A good multidisciplinary recovery programme is needed for every
patient with SGC.

Clinicians should direct patients to relevant patient organisations so they can access
support and information. Studies to better understand SGC are urgently needed.
Collaboration between patients and clinicians assists research by ensuring studies
are appropriate for patients and by increasing awareness of the studies and
therefore patient participation.

14
Supplementary Table S1. WHO classification of malignant tumours of the
salivary glands40 a

ICD-O
codeb

Malignant tumours

Mucoepidermoid carcinoma 8430/3

Adenoid cystic carcinoma 8200/3

Acinic cell carcinoma 8550/3

Polymorphous adenocarcinoma 8525/3

Clear cell carcinoma 8310/3

Basal cell adenocarcinoma 8147/3

Intraductal carcinoma 8500/2

Adenocarcinoma NOS 8140/3

Salivary duct carcinoma 8500/3

Myoepithelial carcinoma 8982/3

Epithelial-myoepithelial carcinoma 8562/3

Carcinoma ex pleomorphic adenoma 8941/3

Secretory carcinoma 8502/3

Sebaceous adenocarcinoma 8410/3

Carcinosarcoma 8980/3

Poorly differentiated carcinoma

Undifferentiated carcinoma 8020/3

Large cell neuroendocrine carcinoma 8013/3

Small cell neuroendocrine carcinoma 8041/3

Lymphoepithelial carcinoma 8082/3

15
 ICD-O
codeb

Squamous cell carcinoma 8070/3

Oncocytic cell carcinoma 8290/3

Uncertain malignant potential

Sialoblastoma 8974/1

ICD-O, International Classification of Diseases for Oncology; NOS, not otherwise

specified.
a Reproduced from El Naggar et al.40 with permission.
b The morphology codes are from the International Classification of Diseases for
Oncology (ICD-O). Behaviour is coded /0 for benign tumours; /1 for unspecified,
borderline or uncertain behaviour; /2 for carcinoma in situ and grade III intraepithelial
neoplasia; and /3 for malignant tumours.

16
Supplementary Table S2. The Milan system for reporting salivary gland
cytopathology: Implied ROM and recommended clinical management85 a

Diagnostic category ROM (%)b Management

I. Non-diagnostic 25 Clinical and radiological

correlation/repeat FNA
cytology

II. Non-neoplastic 10 Clinical follow-up and

radiological correlation

III. Atypia of undetermined 20 Repeat FNA cytology or

significance surgery

IV. Neoplasm

A. Neoplasm: benign <5 Surgery or clinical follow-upc

B. Neoplasm: SUMP 35 Surgeryd

V. Suspicious for malignancy 60 Surgeryd

VI. Malignant 90 Surgeryd,e

FNA, fine-needle aspiration; ROM, risk of malignancy; SUMP, salivary gland

neoplasm of uncertain malignant potential.
a Reproduced from Faquin and Rossi85 with permission.
b The following ranges for risk of malignancy for diagnostic categories have been
cited in the literature: non-diagnostic 0%-67%; non-neoplastic 0%-20%; atypia of
undetermined significance 10%-35%; neoplasm: benign 0%-13%; SUMP 0%-100%;
suspicious for malignancy 0%-100%; and malignant 57%-100%.86-91
cA subset of patients may be followed clinically.
d Intra-operative consultation may be helpful to determine the extent of surgery.
e Extent of surgery depends upon type and grade of malignant tumour.

17
Supplementary Table S3. Biomarkers and molecular targets for precision medicines and corresponding ESCAT scores

Biomarker or genomic Method of detection Drug match ESCAT scorea,b

alteration

Androgen receptor in IHC Androgen receptor blocker + II-B92

salivary duct carcinoma gonadotropin-releasing hormone
or adenocarcinoma agonist92

HER2 in salivary duct IHC for HER2 protein expression (3+) or Anti-HER2 antibodies (e.g. II-B93
carcinoma or FISH for HER2 gene amplification trastuzumab)93
adenocarcinoma

NTRK fusion in secretory NGS or WGS TRK inhibitors (e.g. entrectinib, I-C94-96
carcinoma larotrectinib)94-96

ESCAT, ESMO Scale for Clinical Actionability of Molecular Targets; HER2, human epidermal growth factor receptor 2; IHC,
immunohistochemistry, NGS, next generation sequencing; NTRK, neurotrophic tyrosine receptor kinase; TRK, tropomyosin
receptor kinase; WGS, whole genome sequencing.
a ESCAT scores apply to genomic alterations only. These scores have been defined by the guideline authors and validated by the
ESMO Translational Research and Precision Medicine Working Group.
b II-B, alteration–drug match is associated with antitumour activity with evidence from prospective clinical trials showing that the
alteration–drug match in a specific tumour type results in increased responsiveness when treated with a matched drug, however,
no data are currently available on survival end points; I-C, alteration–drug match is associated with improved outcome with

18
evidence from clinical trials across tumour types or basket clinical trials showing clinical benefit associated with the alteration–drug
match, with similar benefit observed across tumour types.97

19
Supplementary Table S4. Key molecular alterations in selected SGCs

Tumour type Chromosomal Gene fusion/ Prevalence

alteration rearrangement (%)

Secretory t(12;15)(p13;q25) ETV6-NTRK3 95

carcinoma43,45 t(12;10) ETV6-RET 4.5

Mucoepidermoid t(11;19)(q21;p13) CRTC1-MAML2 40-80

carcinoma15 t(11;15)(q21;q26) CRTC3-MAML2 5

Acinic cell t(4;9)(q13;q31) NR4A3/NOR-1 Majority

carcinoma22

Adenoid cystic t(6;9)(q22-23;p23-24) MYB-NFIB 25-80

carcinoma15 t(8;9) MYBL1-NFIB 10-20

Polymorphous 14q12 Hotspot activating 20

adenocarcinoma, PRKD1 somatic
classical variant28 point mutation
(E710D)

Polymorphous t(1;14)(p36.11;q12) ARID1A-PRKD1 24

adenocarcinoma, t(X;14)(p11.4;q12) DDX3X-PRKD1 13
cribriform variant29
PRKD2 and PRKD3 16
rearrangements

Salivary duct 17q21.1 HER2 amplification 30

carcinoma34-36 3q26.32 PIK3CA, NRAS, 20
HRAS, etc mutation

Myoepithelial CHCHD27-PLAG1
carcinoma98 PLAG1-CTNNB1

PLAG1-LIFR

Other PLAG1
rearrangements

20
 Epithelial- HRAS mutation, 82.7
myoepithelial codon 61
carcinoma99,100 PIK3CA 20.7

and/or AKT1 6.5

Intraductal inv(10)(q11.21q11.22) NCOA4-RET

carcinoma32,33 TRIM27-RET

Hyalinising clear cell t(12;22)(q13;q12) EWSR1-ATF1 80-90

carcinoma101,102
EWSR1-CREM 5

Pleomorphic t(3;8)(p21;q12) PLAG1-CTNNB1

adenoma36 t(5; 8)(p11;q12) PLAG1-LIFR

Other PLAG1
rearrangements

HMGA2
rearrangements

SGC, salivary gland cancer.

21
Supplementary Table S5. Pathological TNM staging of major SGC according to the UICC 8th Edition103 a
Primary tumour (T) Regional lymph nodes (N) Distant metastasis (M)
pTX Primary tumour cannot be assessed pNX Regional lymph nodes cannot be pM0 No distant metastasis
assessed
pT0 No evidence of primary tumour pN0 No regional lymph node metastasis pM1 Distant metastasis
pT1 Tumour ≤2 cm in greatest dimension pN1 Metastasis in a single ipsilateral
without extraparenchymal extensionb lymph node, ≤3 cm in greatest
dimension without extranodal
extension
pT2 Tumour >2 cm but ≤4 cm in greatest pN2a Metastasis in a single ipsilateral
dimension without extraparenchymal lymph node, <3 cm in greatest
extensionb dimension with extranodal extension,
or >3 cm but ≤6 cm in greatest
dimension without extranodal
extension
pT3 Tumour >4 cm and/or tumour with pN2b Metastasis in multiple ipsilateral
extraparenchymal extensionb lymph nodes, none >6 cm in
greatest dimension, without
extranodal extension
pT4a Tumour invades skin, mandible, ear pN2c Metastasis in bilateral or contralateral
canal and/or facial nerve lymph nodes, none >6 cm in

22
 greatest dimension, without
extranodal extension
pT4b Tumour invades base of skull, and/or pN3a Metastasis in a lymph node, >6 cm in
pterygoid plates and/or encases greatest dimension without
carotid artery extranodal extension
pN3b Metastasis in a lymph node, >3 cm in
greatest dimension with extranodal
extension, or multiple ipsilateral, or
any contralateral, or bilateral node(s)
with extranodal extension
TNM, tumour–node–metastasis; UICC, Union for International Cancer Control; SGC, salivary gland cancer.
a Reproduced from Brierley et al.103 with permission.
b Extraparenchymal extension is clinical or macroscopic evidence of invasion of soft tissues or nerve, except those listed under T4a
and T4b. Microscopic evidence alone does not constitute extraparenchymal extension for classification purposes.

23
Supplementary Table S6. Studies evaluating targeted therapy in different histological subtypes of SGC (angiogenesis
inhibitors are excluded)104 a

Subtype Study type Target Drug(s) N Response Prior target

identificationb

Mucoepidermoid Case EGFR Cetuximab, gefitinib, 5 x 1 PR 40%, CR 40%, PR/PD 20% Variable
carcinoma reports105-109 erlotinibc

Phase II110 EGFR Cetuximab 2 n.a.d No

Phase II111 EGFR Gefitinib 2 n.a.d No

Phase II112 EGFR/ Lapatinib 2 n.a.d Yes

ERBB2

Adenoid cystic Phase II113 f c-KIT Imatinib 71 RR 2.8%, SD 48% Variable

carcinomae (6 trials)

Phase II114 c-KIT Dasatinib 40 PR 2.5%, SD 50% Yes

Phase II110 g EGFR Cetuximab 23 SD 87% No

Phase II111 g EGFR Gefitinib 18 PR/CR 0% No

Phase II112 EGFR/ Lapatinib 21 SD 79% Yes

ERBB2

24
 Phase I115 g NOTCH1 Brontictuzumab 12 PR 17%, SD 25% Yes

Phase I NOTCH1 Crenigacestat 22 Unconfirmed PR 5%, SD 68% No

expansion116
g

Salivary duct Phase II92 i Androgen Leuprorelin acetate 36 CR 11.1%, PR 30.6%, SD Yes
carcinomah receptor + bicalutamide 44.4%

Phase II93 HER2 Trastuzumab + 57 CR 14%, PR 56%, SD 25%, Yes

docetaxel PD 5%

Phase II117 HER2 Trastuzumab- 10j OR 90% Yes

emtansine

Secretory Phase II94 TRK Larotrectinib 12 n.a.d Yes

carcinoma
Case TRK Entrectinib 2x1 PR Yes
reports95,96 Repotrectinib

All SGC Phase II118 HRAS Tipifarnib 13 PR 8%, SD 58% Yes

ChT, chemotherapy; CR, complete response; EGFR, epidermal growth factor receptor; HER2, human epidermal growth factor
receptor 2; n.a., not available; NOS, not otherwise specified; OR, overall response; PD, progressive disease; PR, partial response;
RR, response rate; RT, radiotherapy; SD, stable disease; SGC, salivary gland cancer; TRK, tropomyosin receptor kinase.
a Reproduced from Lassche et al.104 with permission from Elsevier.

25
b This column lists whether the targeted agent was only administered to patients with the known genetic aberration, upregulation or
protein overexpression at which it was aimed.
c Cetuximab was combined with either ChT or RT.
d Proportion of responding patients with the specific histological subtype not specified.
e Not all studies/case reports are included in this table. See also the review by Alfieri et al. 119
f One trial combined imatinib with cisplatin.
g Evidence of disease progression not required.
h Not all studies/case reports are included in this table. See also the review by Schmitt et al. 120
i Only 34 of 36 included patients had salivary duct carcinoma; two had adenocarcinoma NOS.
j Ten patients with HER2-positive SGC; presumably most patients had salivary duct carcinoma.

26
Supplementary Table S7. Studiesa evaluating angiogenesis inhibitors in SGC, with a focus on adenoid cystic carcinoma

Drug Subtype Study type N Response Median PFS Median OS

rate (%) (months) (months)
Axitinib121 Adenoid cystic Phase II 33 9.1 5.7 n.a.
carcinoma
Axitinib122 Adenoid cystic Phase II 26 8 5.5 26.2
carcinoma
Axitinib123 Adenoid cystic Randomised 60 [30 started axitinib (A); A: 0%; O: 0% A: 10.8; A: not
carcinoma phase II 30 observation arm (O)] O: 2.8 reached;
O: 27.2
Lenvatinib124 Adenoid cystic Phase II 32 15.6 17.5 n.a.
carcinoma
Lenvatinib125 Adenoid cystic Phase II 28 11.5 9.1 27
carcinoma
Sorafenib126 Adenoid cystic Phase II 23 11 11.3 19.6
carcinoma
Sorafenib127 All Phase II 37 (19 adenoid cystic 16 5.9 23.5
carcinoma)
Sunitinib128 Adenoid cystic Phase II 14 0 7.2 18.7
carcinoma

27
n.a., not available; OS, overall survival; PFS, progression-free survival; SGC, salivary gland cancer.
a Only studies that have been published in a peer-reviewed publication are included.

28
 Supplementary Table S8. ESMO-MCBS table for new therapies/indications in SGC

Therapy Disease setting Trial Control Absolute HR (95% CI) QoL/toxicity ESMO-
survival gain MCBS
scorea

Secretory carcinoma

Entrectinib Adult and paediatric STARTRK-1; Single arm ORR: 57% 3

patients 12 years of STARTRK-2; (Form 3)
age and older with ALKA-372-001129
Median DoR:
solid tumours
10.4 months
expressing an NTRK
Phase I/II
gene fusion, who
have disease that is Median PFS:
locally advanced, NCT02097810 11.2 months
metastatic or where
NCT02568267
surgical resection is
likely to result in EudraCT 2012-

severe morbidity, and 000148-88

who have not

received a prior
NTRK inhibitor, and

29
 who have no
satisfactory treatment
options

Larotrectinib Adult and paediatric Studies of Single arm ORR: 79% 3

patients with solid larotrectinib in (Form 3)
tumours that display patients with
Median DoR:
an NTRK gene NTRK fusion-
35.2 months
fusion, who have positive tumours
disease that is locally (including
advanced, metastatic SCOUT and Median PFS:
or where surgical NAVIGATE)94,130 28.3 months
resection is likely to
result in severe
Phase I/II
morbidity, and who
have no satisfactory
treatment options NCT02122913

NCT02637687

NCT02576431

30
CI, confidence interval; DoR, duration of response; ESMO-MCBS, ESMO-Magnitude of Clinical Benefit Scale; HR, hazard ratio;
NTRK, neurotrophic tyrosine receptor kinase; ORR, overall response rate; PFS, progression-free survival; QoL, quality of life; SGC,
salivary gland cancer.
a ESMO-MCBS v1.1131 was used to calculate scores for new therapies/indications approved by the EMA or FDA. The scores have
been calculated by the ESMO-MCBS Working Group and validated by the ESMO Guidelines Committee
(https://www.esmo.org/guidelines/esmo-mcbs/esmo-mcbs-evaluation-forms).

31
Supplementary Table S9. Levels of evidence and grades of recommendation
(adapted from the Infectious Diseases Society of America-United States Public
Health Service Grading Systema)

Levels of evidence

I Evidence from at least one large randomised, controlled trial of good

methodological quality (low potential for bias) or meta-analyses of well-
conducted randomised trials without heterogeneity

II Small randomised trials or large randomised trials with a suspicion of bias

(lower methodological quality) or meta-analyses of such trials or of trials
demonstrated heterogeneity

III Prospective cohort studies

IV Retrospective cohort studies or case-control studies

V Studies without control group, case reports, expert opinions

Grades of recommendation

A Strong evidence for efficacy with a substantial clinical benefit,

strongly recommended

B Strong or moderate evidence for efficacy but with a limited clinical benefit,
generally recommended

C Insufficient evidence for efficacy or benefit does not outweigh the risk or
the disadvantages (adverse events, costs, etc.), optional

D Moderate evidence against efficacy or for adverse outcome, generally not

recommended

E Strong evidence against efficacy or for adverse outcome, never

recommended
a Reprinted by permission of Oxford University Press on behalf of the Infectious
Diseases Society of America.132,133

32
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