2023 Update Clinical

Received: 1 May 2023
DOI: 10.3322/caac.21807
REVIEW ARTICLE
- -
Revised: 14 June 2023 Accepted: 14 June 2023
The evolving landscape of salivary gland tumors
Conor E. Steuer MD1 | Glenn J. Hanna MD2 | Kartik Viswanathan MD, PhD3 |
James E. Bates MD4 | Azeem S. Kaka MD5 | Nicole C. Schmitt MD5 |
Alan L. Ho MD6 | Nabil F. Saba MD7
1
Department of Hematology‐Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia, USA
2
Dana Farber Cancer Institute, Harvard University, Cambridge, Massachusetts, USA
3
Department of Pathology and Laboratory Medicine, Winship Cancer Institute of Emory University, Atlanta, Georgia, USA
4
Department of Radiation Oncology, Winship Cancer Institute of Emory University, Atlanta, Georgia, USA
5
Department of Otolaryngology, Winship Cancer Institute of Emory University, Atlanta, Georgia, USA
6
Memorial Sloan Kettering Cancer Center, New York, New York, USA
7
Winship Cancer Institute of Emory University, Atlanta, Georgia, USA
Correspondence
Conor E. Steuer, Winship Cancer Institute of Abstract
Emory University, 1365 Clifton Road NE, Salivary gland cancers are a rare, histologically diverse group of tumors. They range
Room C‐2110, Atlanta, GA 30322, USA.
Email: csteuer@emory.edu from indolent to aggressive and can cause significant morbidity and mortality.
Surgical resection remains the mainstay of treatment, but radiation and systemic
therapy are also critical parts of the care paradigm. Given the rarity and hetero-
geneity of these cancers, they are best managed in a multidisciplinary program. In
this review, the authors highlight standards of care as well as exciting new research
for salivary gland cancers that will strive for better patient outcomes.
KEYWORDS
cancer, head and neck, multimodality, salivary gland carcinoma, targeted therapy
EPIDEMIOLOGY OF SALIVARY GLAND (SDC) and metastatic squamous cell carcinoma.2 Among the various
MALIGNANCIES histologic types, mucoepidermoid carcinoma (MEC) is the most
common primary salivary gland malignancy, followed by adenoid
Salivary gland malignancies are uncommon, comprising approxi- cystic carcinoma (ADCC), and acinic cell carcinoma (AciCC) (Table 1).
mately 6%–8% of all head and neck cancers.1 Although wide varia- The development of salivary gland neoplasms is multifactorial,
tions in incidence have been reported around the world, depending involving complex environmental and genetic interactions.3 Ionizing
on the population studied, salivary gland malignancies occur at an radiation, chemical exposure, obesity, autoimmune disorders, and
incidence of approximately 1.1 cases per 100,000 individuals in the viral infections (such as Epstein–Barr virus in lymphoepithelial car-
United States.2 At younger ages, women seem to have a higher cinoma) have been implicated, although direct links have yet to be
prevalence; however, generally speaking, this sex distribution dif- established. Mutations in tumor suppressors/oncogenes and chro-
ference plateaus because of an increase in the prevalence of certain mosomal translocations can also promote the development of sali-
malignancies among older men, particularly salivary duct carcinoma vary gland neoplasms (both benign and malignant).
-
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© 2023 The Authors. CA: A Cancer Journal for Clinicians published by Wiley Periodicals LLC on behalf of American Cancer Society.
CA Cancer J Clin. 2023;73:597–619. wileyonlinelibrary.com/journal/caac 597

598
TABLE 1 Clinicopathologic features of commonly encountered primary salivary gland neoplasms.a
-
Sex
Histologic entity Grade Common locations Age range distribution Outcomes Histomorphologic features Ancillary studies Molecular findings
Common malignant neoplasms
Mucoepidermoid More often low‐grade but can Parotid > palate > Wide range, peaks F:M, ~3:2 Patients with low‐grade MEC Admixture of squamoid cells p63‐positive, mucicarmine‐ CRCT1::MAML2 >> CRTC3::
carcinoma be intermediate‐grade or submandibular in second have excellent outcomes (intermediate and positive in goblet type MAML2; rare EWSR1::
(MEC) high‐grade gland > minor decade of life (92%–100% 5‐year epidermoid type) and cells POU5F1
salivary gland survival) vs. those with mucinous cells; can be
high‐grade MEC (0%– cystic or oncocytic;
52% 5‐year survival); grading by Brandwein,
treatment of Katabi, AFIP, modified
intermediate‐grade Healey systems; no
tumors may depend on universally accepted
stage (intermediate‐ grading system yet
grade 5‐year survival,
62%–100%)
Acinic cell More often low‐grade but can Parotid is most common Approximately fifth F:M, ~1.5:1.0 Usually good outcomes with Variable architecture: solid, NR4A3‐positive; DOG1 t(4;9) most common;
carcinoma be high‐grade decade of life low‐grade tumors (~90% papillocystic, microcystic, membranous staining, enhancers placed
20‐year survival); local follicular patterns; SOX10‐positive, upstream of NR4A3‐
and distant metastases variable cytology: mammaglobin‐negative promoting proliferation
can occur; outcomes vacuolated, clear,
appear worse in cases oncocytic, or large and
with high‐grade polygonal with basophilic
transformation granules
Carcinoma ex‐ Usually high‐grade (if ductal Parotid is most common Sixth or seventh Slightly more F than M Outcome depends on extent Carcinoma component is Stains depend on carcinoma Often with PLAG1 and
pleomorphic carcinoma ex‐PA) but decades of life of invasion; 5‐year most often high‐grade component; p53, Ki67, HMGA2 fusion genes,
adenoma (ex‐ can also be low‐grade overall survival rate ductal adenocarcinoma androgen receptor can similar to PA; additional
PA) (often with myoepithelial ~25%–65% with local or (usually salivary duct be considered for genetic instability, copy‐
carcinoma ex‐PA) distant metastasis; those carcinoma); subset has salivary duct arising in number alterations;
with intracapsular myoepithelial carcinoma PA; myoepithelial TP53 mutation; HER2
carcinoma ex‐PA ex‐PA (usually low‐ markers for amplification
(without invasion) or grade) myoepithelial carcinoma;
minimally invasive PLAG1 and HMGA2 IHC
disease (<4–6 mm can be considered for PA
invasion beyond PA component
border) fare better
Adenoid cystic Usually low‐grade but can Major salivary glands > Approximately fifth F:M, ~1.5:1.0 Long clinical course with Infiltrative, biphasic salivary p40, smooth muscle actin‐ MYB::NFIB, MYBL1::NFIB
carcinoma show high‐grade minor salivary decade of life frequent recurrences gland malignancy; positive in myoepithelial translocations; NOTCH
transformation glands and distant metastases, variable architecture: cells, KIT‐positive and alterations seen with
with approximately 50% solid, tubular, cribriform; cytokeratin 7 (CK7)‐ solid type adenoid cystic
10‐year overall survival; characteristic sharp, positive in ductal cells; carcinoma; wide
high‐grade, NOTCH1 punched‐out spaces with MYB IHC usually diffuse mutational array
mutational status, age, basophilic matrix; tumor affecting several
advanced stage, margin cells have scant pathways
SALIVARY GLAND CARCINOMA

status can affect cytoplasm, angulated
outcomes hyperchromatic nuclei
Secretory carcinoma Usually low‐grade but can Parotid > oral cavity Adults, wide age F≈M Usually indolent; lymph node Circumscribed/infiltrative CK7‐positive, S100‐positive, ETV6::NTRK3 fusions are
show high‐grade and submandibular range, around metastasis in ~25%; with variable solid/cystic, mammaglobin‐positive, most common
transformation gland fourth to fifth worse outcomes with follicular, papillocystic p63/p40‐negative
decade of life high clinical stage and architectures; occasional
high‐grade perineural invasion
transformation
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T A B L E 1 (Continued)
STEUER
Sex
ET AL.
Salivary duct High‐grade Parotid is most common Older males in M>F Poor prognosis with high risk Resembles breast high‐grade Androgen receptor‐positive, HER2 gene amplification,
carcinoma sixth to of recurrence, regional ductal carcinoma; HER2‐positive; estrogen PI3K alterations,
seventh and distant metastasis; oncocytic cells with receptor‐negative and complex genetic profile
decade of life 5‐year survival <45% nuclear pleomorphism progesterone receptor‐
and prominent nucleoli, negative
comedo‐type necrosis,
abundant mitoses;
sarcomatoid
transformation, rhabdoid
features, micropapillary
features may be seen;
extensive perineural and
angiolymphatic invasion
can be seen
Polymorphous Usually low‐grade but can Palate is most common Wide range, most F:M, ~2.0:1.0 Overall prognosis is excellent; Infiltrative, monophasic, CK7‐positive, S100‐positive, PRKD1 alterations (hot‐spot
adenocarcinoma show high‐grade followed by other common in low risk of local uniform malignancy with mammaglobin‐negative, E170D mutation in
transformation oral cavity sites fifth to recurrence and distant open chromatin, oval p63‐positive, p40‐ conventional type;
seventh metastasis but can occur; nuclei, and occasional negative PRKD1 rearrangements
decades of life cribriform/papillary small nucleoli; arranged in cribriform/papillary
architecture, high‐grade in trabecular, type)
transformation, large‐ microcystic, cribriform,
nerve perineural and or papillary patterns;
angiolymphatic invasion, perineural invasion is
and PRKD fusions common
associated with
aggressive behavior
Intraductal Usually low‐grade but Parotid is most common Wide age range of F~M Generally excellent outcomes Four types: intercalated, small Myoepithelial cells Oncocytic type, TRIM33::RET
carcinoma (or apocrine type can be presentation after complete resection amphophilic cells with highlighted by p63, or B‐Raf V600E;
intercalated low‐grade or high‐grade if all in situ; frankly oval nuclei; oncocytic, calponin, smooth muscle intercalated type,
duct carcinoma) invasive carcinomas and abundant eosinophilic actin; depending on NCOA4::RET; apocrine
ex‐intraductal carcinoma cytoplasm with enlarged subtype, can be type, PI3K alterations;
can show worse nuclei and prominent androgen receptor‐ mixed types, mixed/hybrid
outcomes nucleoli; apocrine, bubby positive and HER2‐ type, TRIM27::RET
eosinophilic cytoplasm positive (apocrine) or
and apical snouting; and S100‐positive and
mixed, hybrid of other mammaglobin‐positive
types (oncocytic, intercalated,
and hybrid types)
Epithelial‐ Usually low‐grade; high‐grade Parotid and Sixth or seventh Slight F > M Indolent course but can Biphasic malignancy with Ductal cells are positive for HRAS alterations
myoepithelial transformation can occur submandibular decades of life locally recur; local and multinodular growth CK7; myoepithelial cells
carcinoma glands > other sites distant metastases are pattern; inner ductal are positive for smooth
rare; high‐grade cells; myoepithelial cells muscle actin, calponin,
transformation is more are abundant; clear and p40/p63
aggressive cytoplasm
Basal cell Grading is not typically Very rare, parotid Sixth or seventh F≈M Local recurrence can occur in Infiltrative, biphasic, basaloid Positive for p40, calponin, A subset may arise from
adenocarcinoma reported decades of life approximately one third malignancy in solid, and smooth muscle actin membranous type (CYLD
of cases but outcomes tubular, trabecular, or in myoepithelial cells; alterations); molecular
usually excellent after membranous CK7‐positive in ductal data are limited; complex
surgery with clear architectural patterns; cells alterations, including
margins; local and distant peripheral palisading of PI3K
metastases are rare nuclei; perineural and
vascular invasion can
occur
-
(Continues)
599
600
Sex
-
Hyalinizing clear cell Usually low‐grade; high‐grade Minor salivary gland in Fifth to eighth F>M Usually good outcomes with Clear/eosinophilic cells CK7‐positive, p63‐positive, EWSR1::ATF1 fusion
carcinoma transformation can occur palate, base of decades of life low‐grade cases; local arranged in nests, negative for
tongue most recurrence and lymph trabeculae, or cords in a myoepithelial markers
common sites node metastases can dense hyalinized or
occur; distant metastases desmoplastic stroma;
and death rare; high‐ high‐grade
grade transformation can transformation with
be more aggressive necrosis, marked nuclear
atypia, and significant
mitotic activity can occur
Microsecretory Low‐grade but <30 cases Minor salivary gland Wide age range of Slight F > M Excellent outcomes with no Microcystic‐predominant, CK7‐positive, S100‐positive, MEF2C::SS18 fusion
carcinoma reported to date tissue in palate and presentation, reported recurrences or monotonous, mammaglobin‐negative,
buccal mucosa average age in metastases intercalated, duct‐like p63‐positive, p40‐
most common sites the fourth tumor cells with negative
decade of life attenuated, eosinophilic‐
to‐clear cytoplasm,
basophilic secretions,
subtle infiltrative growth
in a fibromyxoid
background
Mucinous Usually low‐grade Intraoral minor salivary Peaks in eighth F~M Nodal metastases can occur Variable architecture: Positive for CK7 and NKX3.1; Recurrent AKT1 p.E17K
adenocarcinoma gland sites decade of life at presentation; papillary papillary, colloid, or negative for CK20, alteration and can have
form typically indolent; signet ring forms, but can CDX2, p63, p40, TTF1, concurrent
colloid or signet‐ring be mixed; abundant, S100, calponin, smooth TP53mutation
patterns are associated mucinous‐type muscle actin, and
with risk of recurrence epithelium androgen receptor
and metastases
Sclerosing Low‐grade Intraoral minor salivary Fifth to eighth F>M Excellent, without evidence Infiltrative, biphasic ducts/ CK7, p40, and p63 highlight a NA
microcystic gland sites: tongue, decades of life of locoregional tubules with an biphasic population
adenocarcinoma lip mucosa, floor of recurrence or distant attenuated,
mouth, and buccal metastases; surgical myoepithelial cell layer
mucosa excision is treatment of within dense, sclerotic
choice, and adjuvant stroma; perineural
radiation can be invasion is common
considered in the
appropriate context (e.g.,
positive margins)
Common benign neoplasms
PA Low‐grade (benign) Parotid > Wide range, F:M, ~1.4:1.0 Excellent if completely Well demarcated, biphasic CK7, p40, and p63 highlight a PLAG1 and HMGA2
submandibular > average age in excised; risk of salivary gland neoplasm biphasic population; rearrangements are most
palate >> fourth decade recurrence associated with variable epithelial positive for PLAG1 or common
SALIVARY GLAND CARCINOMA

sublingual gland >> of life with incomplete excision, and myoepithelial HMGA2 immunostain
other oral cavity young age (30 years or morphology and
sites younger) and increased architecture in a
mitotic activity chondromyxoid matrix;
filopodial extension can
occur
Warthin tumor Low‐grade (benign) Parotid is most common Seventh decade of M>F Complete excision is usually Papillary‐cystic structures Not routinely done Not routinely done; may have
(associated with life curative lined by oncocytic, clonal alterations
cigarette smoking) bilayered epithelium
with lymphoid stroma
and germinal centers
STEUER
ET AL.
Sex
Basal cell adenoma Low‐grade (benign) Parotid is most common Older adults, fifth Slight F > M Excellent prognosis with very Variable morphology: solid, CK7, p40, and p63 highlight a Beta‐catenin alterations;
followed by decade of life low recurrence rate; trabecular, tubular, and biphasic population; membranous type may
submandibular or older exception is membranous patterns; patchy nuclear beta‐ be associated with
gland membranous type, with basaloid cells with scant catenin and nuclear LEF1 Brooke–Spiegler
~25% risk of recurrence cytoplasm with staining syndrome (CYLD
peripheral palisading; alterations)
membranous pattern
with hyaline material
surrounding nests
Oncocytoma Low‐grade (benign) Parotid is most common Sixth to eighth F~M Excellent outcomes Well circumscribed lesion of p63 highlights basal cell NA
decades of life oncocytes with abundant population
eosinophilic cytoplasm,
central nucleus, and
prominent nucleolus
Myoepithelioma Low‐grade (benign) Parotid is most common Wide age range, F~M Usually excellent; may rarely Variable morphology: Positive for CK7 and NA
followed by hard/ third decade recur if incompletely plasmacytoid, spindle, myoepithelial markers:
soft palate of life excised; if long‐standing epithelioid, hyaline. or calponin, S100, smooth
or multiply recurrent, clear cell features muscle actin
then may (exceptionally
rarely) undergo
malignant
transformation
Sclerosing Low‐grade (generally benign) Parotid is most common Wide age range, F:M, 3.0:2.0 Usually good; recurrences can Circumscribed lobular Periodic acid–Schiff Genetic alterations in PI3K
polycystic fourth decade occur, and exceptionally architecture, irregular (diastase‐resistant) and pathway most common:
adenoma (SPA) of life rare cases of in situ and distribution of ducts with GCDFP‐15–positive PTEN, PIK3CA, PIK3R1
invasive carcinomas ex‐ eosinophilic secretions/ staining in acini; positive
SPA have been foamy macrophages and for progesterone
documented acini with receptor and CK AE1/
intracytoplasmic AE3 in ductal cells;
granules; stroma may myoepithelial cells: p40,
show fibrosis, p63, calponin, smooth
fibroadipose tissue and muscle actin
lymphoid aggregates
Abbreviations: AFIP, Armed Forces Institute of Pathology; F, female; F:M, female to male ratio; IHC, immunohistochemistry; M, male; NA, not available; PI3K, phosphoinositide 3‐kinase.
a
This is not a comprehensive list because the number of entities continues to increase with molecular testing; commonly encountered neoplasms and a few newer entities are mentioned here.
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602
- SALIVARY GLAND CARCINOMA
ANATOMY OF THE SALIVARY GLAND DIAGNOSIS OF SALIVARY GLAND CARCINOMAS
The salivary gland unit is composed of luminal ductal cells and is Fine‐needle aspiration (FNA) is commonly used in the initial eval-
surrounded by abluminal myoepithelial cells or noncontractile basal uation of a salivary gland lesion for several reasons. First, it is a
cells, depending on the duct caliber.4 The composition of the acinar rapid and minimally invasive technique with high diagnostic sensi-
component depends on the anatomic site.5 The parotid gland is tivity and specificity.7,8 On‐site evaluation capabilities can provide
composed primarily of serous acinar cells, the submandibular gland is useful information, including whether the lesion represents a pri-
composed of an admixture of serous and mucinous cells, and the mary salivary gland tumor or metastasis (in the appropriate clinical
sublingual gland/minor salivary glands are composed entirely of context) and whether the lesion is high‐grade or low‐grade, which
mucinous cells. Malignancies can arise from these various cell types, can help with surgical planning. Second, FNAs enable the collection
and a few commonly encountered entities are discussed below and in of sufficient material to triage for appropriate ancillary studies,
Table 1.3,6 A general rule of thumb is that, the smaller the gland, the including for immunohistochemistry and flow cytometry.9,10 Finally,
more mucinous cells and the higher likelihood of malignancy associ- in patients who have unresectable disease or are recommended to
ated with the site. proceed with primary systemic therapy, cytologic material can be
used for molecular studies to identify potential targetable
alterations.
CLINICAL PRESENTATION The Milan System for Reporting Salivary Gland Cytopathology
was established in 2018 for the standardized reporting of salivary
The most common presenting symptom of salivary malignancy is gland cytology findings.10 The six‐tiered system consists of non-
a painless parotid or neck mass. Sublingual gland malignancies diagnostic, nonneoplastic, atypia of undetermined significance, benign
may present at late disease stage as a mass in the floor of neoplasm, salivary gland neoplasm of uncertain malignant potential,
mouth. The presence of pain, a rapidly growing mass, facial suspicious for malignancy, and malignant. Each category has an asso-
weakness, or lingual weakness/paresthesias (in the case of sub- ciated risk of malignancy based on aggregated data from multiple
lingual tumors) are ominous signs that usually indicate high‐grade institutions, which can help guide clinicians in making management
malignancy. decisions (Table 2). The criteria have been reviewed elsewhere in
It is important to note that the differential diagnoses of a greater detail.11–13
swelling/mass lesion is broad. For this review, we focused on fea- Although FNA cytology can be helpful to guide management,
tures of key primary salivary gland neoplasms; however, salivary particularly in cases that are classified as nonneoplastic, benign
gland involvement by nonneoplastic tumor‐like conditions (i.e., neoplasm, and malignant, indeterminate lesions (classified as atypia
nodular oncocytic hyperplasia, necrotizing sialometaplasia, salivary of undetermined significance, salivary gland neoplasm of uncertain
duct cyst, among others), mesenchymal neoplasms, hematolymphoid malignant potential, or suspicious for malignancy) that cannot be
processes, direct extension of cutaneous malignancies, and metas- further resolved on ancillary testing may require surgical evaluation
tases can also be observed and should be considered in the dif- with intraoperative frozen consultation.10 The most important
ferential, depending on the clinical history and presentation, challenge is to determine whether the lesion is low‐grade or high‐
radiologic findings, and laboratory data.6 grade or if it is a certain histologic type (i.e., ADCC), because this
T A B L E 2 The Milan System for Reporting Salivary Gland Cytopathology: Diagnostic categories, associated risk of malignancy, and
suggested management.
Risk of
Diagnostic category malignancy Suggested management
Nondiagnostic (category I) 15% Clinical, radiologic correlation or repeat fine‐needle aspiration
Nonneoplastic (category II) 11% Clinical and radiologic follow‐up
Atypia of undetermined significance (category III) 30% Repeat fine‐needle aspiration or surgery
Neoplasm: Benign (category IVa) <3% Conservative surgery or clinical follow‐up
Salivary gland neoplasm of undetermined 35% Surgery with intraoperative frozen consultation to determine
malignant potential (category IVb) extent of surgery
Suspicious for malignancy (category V) 83% Surgery with intraoperative frozen consultation to determine
extent of surgery
Malignant (category VI) 98% Surgery or systemic therapy depending on the lesion
STEUER ET AL.
- 603
can drive the extent of surgery, most notably the decision to Mucoepidermoid carcinoma
include or omit a neck dissection. Sampling representative areas
that appear distinct within the tumor may provide insight into MEC represents the most common primary salivary gland malignancy
whether there are high‐grade features, including tumor necrosis, in both the pediatric and adult populations, occurring most commonly
marked nuclear atypia, and increased mitotic activity.14 Ultimately, in the parotid, followed by the submandibular and sublingual glands.
if a lesion is encapsulated/well demarcated, then the evaluation of MECs can occur over a wide age range, with a mean age of 45 years
invasion will require submission of the entire periphery for histo- and a female predilection of 1.1–1.5:1.0.
logic examination.
Histopathologic features
PATHOLOGIC ANALYSIS OF THE SURGICALLY
EXCISED TUMOR The cell types comprising an MEC include mucous‐producing cells
(mucocytes), intermediate cells, and squamoid cells. These tumors
A morphologic pattern‐based approach, such as establishing a can vary in terms of the amount of cystic or solid components, and
biphasic or monophasic population, and broadly categorizing the they generally lack keratinization. Several histologic variants have
lesion as basaloid, oncocytoid, cystic/secretory/mucinous, or solid‐ been described, including clear cell, oncocytic, sclerosing, Warthin‐
nested/spindled can help focus the differential diagnosis and enable like, ciliated, spindle cell, and mucoacinar types.
the selection of immunohistochemistry for classification15 MEC is graded as low‐grade, intermediate‐grade, or high‐grade
(Figure 1). Challenging cases with significant morphologic or based on histologic parameters and depending on the grading sys-
immunohistochemical overlap may require molecular studies for tem used (Armed Forces Institute of Pathology, Memorial Sloan
definitive classification. Benign salivary gland neoplasms (such as Kettering Cancer Center, Brandwein, or modified Healey) used. The
pleomorphic adenoma [PA], Warthin tumor, basal cell adenoma, and Armed Forces Institute of Pathology system uses fewer histologic
oncocytoma) are far more common, and some details are provided parameters but tends to assign a lower grade to more aggressive
at the end of Table 1, but these are not the primary focus of this tumors, whereas the Brandwein system tends to upgrade tumors
review. more often. The modified Healey and Memorial Sloan Kettering
Cancer Center grading systems use several qualitative parameters
and fall in the middle, but these criteria are not well defined. To date,
there is no universal grading system for MEC. Histologically, low‐
grade MECs tend to be well circumscribed/mostly cystic with abun-
dant mucocytes, intermediate‐grade MECs have more solid areas,
and high‐grade MECs tend to be infiltrative with significant mitotic
activity, necrosis, nuclear pleomorphism, angiolymphatic, bone, and
perineural invasion.
The squamoid populations in MECs are positive for squamous
markers p40/p63 and the mucocytes are positive with the mucin
stain. MECs are negative for SOX10/S100 (myoepithelial markers).
MAML2 rearrangement is specific for MEC, which can be detected
with fluorescence in situ hybridization; however, molecular confir-
mation is necessary.
Outcomes
F I G U R E 1 Representative histologic images of commonly
encountered salivary gland malignancies. (A) Acinic cell carcinoma The 5‐year overall survival rates are 90%, 86%, and 55% for low‐
(black arrow indicates the tumor; blue arrow, normal parotid
grade, intermediate‐grade, and high‐grade MEC, respectively.3,6
tissue), (B) adenoid cystic carcinoma, (C) polymorphous
adenocarcinoma, (D) salivary duct carcinoma, (E) secretory Advanced stage, age, male sex, high‐grade tumor, and a positive
carcinoma, (F) carcinoma ex‐pleomorphic adenocarcinoma (inset margin are associated with lower overall and disease‐free survival.
shows low‐grade myoepithelial carcinoma component),
(G) mucoepidermoid carcinoma, low‐grade, (H) intraductal
carcinoma, and (I) basal cell adenocarcinoma (black arrow and inset
Adenoid cystic carcinoma
show focus of border invasion with associated desmoplastic stromal
response). All glass slides are stained with hematoxylin and eosin,
and images were captured from digital scanned slides or directly ADCC comprises approximately 25% of all primary salivary gland
from the slide. carcinomas and occurs in both major and minor salivary glands.
604
ADCC is slightly more frequent in women, with a median age of oncocytic, or clear cell appearances, with ill‐defined cell borders and
presentation at around the sixth decade of life. small nuclei. High‐grade transformation, depicted by solid growth,
necrosis, nuclear pleomorphism, and increased proliferative activity,
can be noted in conjunction to low‐grade areas. AciCCs with high‐
Histopathologic features grade transformation can exhibit perineural and lymphovascular
invasion.
On histology, ADCC is an infiltrative, basaloid, biphasic neoplasm Confirmatory immunostains typically include NR4A3, SOX10,
composed of ductal cells and myoepithelial cells. The myoepithelial and DOG1 in low‐grade cases. Nuclear NR4A3 expression is gener-
cells have clear cytoplasm with small, hyperchromatic, angulated ally maintained in AciCCs with high‐grade transformation, whereas
nuclei, whereas the ductal cells have more eosinophilic cytoplasm. SOX10, DOG1 and S100 are less consistent. Molecular testing can be
ADCCs can show tubular, cribriform, or solid architectural patterns. helpful in identifying the NR4A3 rearrangement in challenging cases.
The cribriform pattern has microcystic spaces that can contain a
hyaline or mucoid basement membrane‐type material. ADCCs are
commonly associated with perineural invasion. Outcomes
Immunohistochemistry will highlight the biphasic epithelial and
myoepithelial components with cytokeratin 7/KIT and p40/p63/cal- The 5‐year and 10‐year overall survival is >90% for low‐grade
ponin, respectively. MYB overexpression occurs in most ADCCs and AciCC, whereas it decreases to approximately 27% for patients
can lend support to the diagnosis. However, the most specific test for with AciCC demonstrating high‐grade transformation. A reduced
ADCC is the identification of either MYB::NFIB or MYBL1::NFIB overall survival of approximately 22% is also seen in patients who
translocations with fluorescence in situ hybridization or molecular have AciCC with distant metastases.3,6
testing. NOTCH1 alterations are enriched in the more aggressive solid
variant of ADCC.
Secretory carcinoma
Outcomes SC occurs over a wide age range, often in the fourth to fifth decade of
life, and with equal distribution among men and women. The most
ADCC has a long, progressive clinical course with multiple re- common anatomic site of presentation for SC is the parotid, and sites
currences and, ultimately, a fatal outcome. The solid variant and high‐ in the oral cavity and submandibular gland are less frequent.
grade transformation are associated with worse outcomes. The re-
ported 10‐year overall survival and recurrence‐free survival rates are
50% and 60%, respectively.3,6 Histopathologic features
SC is most often low‐grade and can either be well circumscribed or

Acinic cell carcinoma infiltrative. Architecturally, this tumor can demonstrate variable
cystic/solid, tubular, follicular, or papillocystic patterns with eosino-
AciCC is composed of malignant acinar cells with variable degrees of philic to granular/vacuolated cytoplasm, small uniform nuclei, and
differentiation. Because of the classification of several secretory dense luminal secretions.
carcinomas (SCs) as AciCCs before molecular clarification, the precise SC shows a distinct immunoprofile with S100, SOX10, and
incidence is unclear, but it is considered to be the second most mammaglobin positive staining, whereas DOG1 and NR4A3 (shown
common salivary gland malignancy (approximately 12% of all in AciCC) are negative. Moreover, SC does not show p40/p63
epithelial salivary gland malignancies). The parotid is the most com- myoepithelial staining. If needed, ETV6 or RET rearrangements can
mon site, followed by submandibular and minor salivary gland sites. be demonstrated through molecular testing.
AciCC occurs over a wide age range, often in the fourth to fifth de-
cades of life, and shows a 1.5:1.0 female:male distribution ratio.
Outcome
Histopathologic features Most SCs are low‐grade, with indolent behavior and good outcomes
(approximately 95% and 90% 5‐year and 10‐year overall survival,
AciCCs can have variable architecture, including solid, microcystic, respectively), but can demonstrate lymph node/distant metastases in
follicular, and papillary‐cystic growth patterns. Tumor‐associated approximately 25% of patients. Advanced clinical stage is a reported
lymphoid proliferation can be prominent in the periphery. AciCCs adverse prognostic factor. In the limited data available, high‐grade
can have serous acinar cell (with basophilic zymogen granules), transformation was associated with worse outcomes (with an
intercalated ductal phenotype, vacuolated, nonspecific glandular, approximately 5.5‐fold hazard ratio).3,6,16,17
STEUER ET AL.
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Carcinoma ex‐pleomorphic adenoma nucleoli. Perineural and angiolymphatic invasion are frequent. A
subset may arise from a preexisting PA. Histologic variants, including
Carcinoma ex‐PA (CXPA) accounts for roughly 12% of all salivary sarcomatoid transformation with spindle cells and heterologous dif-
gland malignancies, with most occurring in the parotid gland and ferentiation, mucin‐rich, basal‐like, micropapillary, oncocytic, and
arising from a preexisting/recurrent PA. Patients are usually in the rhabdoid subtypes, have been reported but are typically seen with a
sixth or seventh decade of life, and there is a slight predilection for conventional SDC component.3,6
women. SDCs are most often positive for AR, Her2/Neu, and cytokeratin
7 and negative for SOX10 and S100. Common molecular alterations
include TP53 (55%), HRAS (23%), PIK3CA (23%), and amplification of
Histopathologic features ERBB2 (35%). A small subset of SDCs may harbor PTEN or BRAF al-
terations. If arising in the context of a PA (i.e., SDC ex‐PA), then
Carcinomas arising from the ductal component tend to be high‐grade, HMGA2 or PLAG1 alterations can be identified.
most often being SDC ex‐PA, whereas those arising from the
myoepithelial component tend to be low‐grade. Rare cases of carci-
nosarcoma with both malignant epithelial and sarcomatous compo- Outcomes
nents have been reported. Depending on the extent of invasion
beyond the PA border, CXPAs can be classified as intracapsular SDC is an aggressive malignancy with locoregional and distant me-
(carcinoma is confined within the PA border), minimally invasive tastases. Overall, outcomes are poor, with reported 5‐year and 10‐
(carcinoma invades <4–6 mm beyond the PA border), or invasive (≥6 year disease‐specific survival rates of approximately 64% and 56%,
mm beyond the PA border). respectively.3,6,18
Immunohistochemistry for PLAG1 or HMGA2 followed by All of the aforementioned entities, including other less common
confirmation with fluorescence in situ hybridization testing can help entities not discussed here, are detailed in Table 1. It must be noted
identify a PA component. The presence of androgen receptor (AR) that the portfolio of salivary gland neoplasms continues to expand
staining in a ductal carcinoma arising from a PA would be in keeping with increased use of molecular testing, and the current list is not
for an SDC ex‐PA. Additional complex molecular alterations in TP53, comprehensive.
HRAS, PIK3CA, and/or amplification of EGFR or MYC may occur in the
course of tumor progression.
STAGING OF SALIVARY GLAND NEOPLASMS
Outcomes For major salivary glands (i.e., parotid, submandibular, and sublingual
glands), the eighth edition the American Joint Cancer Committee
Patients with CXPA have an overall 5‐year survival ranging from 25% tumor, node, metastasis (TNM) staging is prognostic.19 The general
to 75%, which varies in part because of the better outcomes seen principles for the T category staging involve size of the tumor, the
with minimally invasive and intracapsular CXPAs compared with the presence or absence of extraparenchymal extension, and the extent
invasive type. Reported adverse prognostic factors include large tu- of involvement of adjacent structures. In the absence of extrapar-
mor size (>4 cm), lymph node metastases, and distant metastasis. In enchymal extension, defined as clinical and/or macroscopic evidence
general, CXPAs behave aggressively, with up to 70% showing local of extension beyond salivary gland parenchyma, tumor size cutoffs of
and/or distant recurrences.3,6 2 and ≤4 cm define T1 and T2, respectively. Of note, microscopic
extraparenchymal extension alone does not warrant the upstaging of
tumor size. At >4 cm or in the presence of grossly identifiable
Salivary duct carcinoma extraparenchymal extension, the tumor is classified as T3. Should the
tumor involve proximal structures, including skin, mandible, ear canal,
SDC is a high‐grade malignancy resembling its mammary apocrine and/or facial nerve, it is staged as T4a; whereas, with more extensive
carcinoma counterpart. SDCs account for up to 10% of all salivary spread to involve the pterygoid plates or skull base or to encase the
gland malignancies, commonly affecting men in the sixth or seventh carotid artery, it is staged as T4b. The nodal N category depends on a
decade of life. combination of laterality of the involved nodes, metastatic deposit
size cutoffs of 3 or 6 cm, and the presence of extranodal extension.
The presence of distant metastases would lead to an M1
Histopathologic features classification.
In the context of minor salivary glands in other sites, including
SDCs are highly infiltrative, with complex architecture and comedo‐ oral cavity, sinonasal tract, and trachea, the current recommendation
type necrosis. Tumor cells have abundant eosinophilic/apocrine is to apply site‐specific TNM staging protocols using a combination of
cytoplasm with marked nuclear pleomorphism and prominent tumor size and anatomic structures involved.3
606
Surgical considerations certainly useful for patient counseling and surgical planning, many
tumors do not fit neatly into high‐grade/low‐grade categories.
Adequate surgical resection is the most effective form of treatment Furthermore, the histologic grade and subtype may be unclear based
for salivary gland cancers (SGCs). However, the extent of surgery for on FNA biopsy or even frozen section.37 Lymphovascular invasion is
salivary gland carcinoma is one of the most widely debated topics in also associated with occult metastases,38 but this also may not be
head and neck surgical oncology, particularly as it relates to the appreciated at the time of surgery. Thus the surgeon must often
extent of node dissection. Reconstructive techniques for contour or make a judgment call based on the available imaging and intra-
skin defects and facial nerve deficits have progressed in recent years operative findings.
and have been extensively reviewed elsewhere.20–27 We review If the decision has been made to perform elective neck dissec-
general surgical principles of salivary gland malignancies here. tion, the extent of dissection must be determined. It is well estab-
lished that the most likely area of spread for parotid cancers is to
levels II and III; submandibular, sublingual, and minor salivary cancers
Extent of resection for the primary tumor often spread to levels I–III.33,34,37–41 External jugular nodes, another
frequent area of nodal spread, are also typically resected. The deci-
For submandibular gland, sublingual gland, or minor salivary gland sion to dissect levels I, IV, and V for parotid cancers is a topic of
carcinomas, complete resection is recommended, with a generous ongoing debate. Some authors have argued that dissection of level I
margin whenever possible. Most parotid tumors arise within the has already been partially completed after parotidectomy and adds
superficial lobe, and these tumors are often in direct contact with the little additional morbidity; similarly, dissection of level IV is not much
facial nerve. The general consensus among head and neck surgeons, more extensive once levels II and III have been dissected.37 Occult
which is supported in the National Comprehensive Cancer Network metastases in level V are very unlikely in the absence of clinically
guidelines, is to preserve the facial nerve whenever a dissection plane evident nodes elsewhere,42 and a level V dissection may result in
28,29
can be established between the nerve and the tumor. It is also significant morbidity, which often results from stretch injury to the
established that the facial nerve or some of its branches should be spinal accessory nerve. As such, some surgeons prefer to avoid this
sacrificed in the event of preoperative facial weakness or gross in- by limiting their level V dissection to removal of level Vb just behind
vasion/engulfment by the tumor.28,29 For primary salivary malig- the sternocleidomastoid muscle. Of note, there is no strong evidence
nancies, there are no strong data to suggest that oncologic outcomes that elective neck dissection improves survival outcomes for salivary
are improved by performing a total parotidectomy or a radical cancers.34,37
parotidectomy (including facial nerve resection) for tumors in the
superficial lobe without gross nerve involvement.30,31 Depending on
the extent of the tumor, resection of the lateral temporal bone, EXTENT OF NECK DISSECTION FOR PATIENTS
masseter muscle, and/or mandible may be required to achieve an WITH CLINICALLY NODE‐POSITIVE DISEASE
adequate resection.28
Although neck dissection is recommended when clinically involved
nodes are seen on physical examination or imaging, the extent of
ROLE OF ELECTIVE NECK DISSECTION FOR dissection in this situation is controversial. Most experts on this have
CLINICALLY NODE‐NEGATIVE NECK advocated for selective neck dissection including levels II–IV or I–IV,
depending on the primary site.33,34 However, others have advocated
When the neck is clinically staged as N0 based on examination and for a comprehensive (levels I–V) neck dissection.41,43 One study
imaging, the decision to perform elective neck dissection is largely demonstrated that 60% of patients undergoing neck dissection with
based on the specific tumor grade and histology, in addition to the clinically evident anterolateral neck disease also had occult nodal
primary site. In minor salivary malignancies, elective neck dissection metastases in level V.42 However, this was a single‐institution,
32,33
may improve regional disease control. For carcinoma of the retrospective study, and it is unclear whether these patients could
major salivary glands, elective neck dissection should be considered have been adequately treated with adjuvant radiotherapy. It is
for T3/T4 tumors or high‐grade histology.29,34,35 A review of >20,000 notable that no regional recurrences were seen in patients who did
cases of parotid cancer in the National Cancer Database showed a not undergo level V dissection.42
high incidence of occult nodal metastasis in high‐grade malignancies,
including MEC, AciCC, ADCC, and adenocarcinoma, with the highest
incidence of occult metastasis seen in SDC.35 The authors recom- Reconstructive considerations
mended elective neck dissection for high‐grade tumors of those
histologic subtypes versus observation for low‐grade tumors.35 A There are three components in the consideration of reconstruction
systematic review and meta‐analysis of elective neck dissection for after parotid malignancy extirpation: (1) restoration of volume, (2)
salivary malignancies reported similar results based on high‐grade cutaneous reconstruction to create a low‐tension closure, and (3)
36
histology and T3/T4 tumors. Although this information is facial reanimation procedures for any neural sacrifice.
STEUER ET AL.
- 607
First, restoration of volume is indicated in both benign and ma- varieties of reconstructive options for providing cutaneous coverage
lignant cases and can be tackled in a variety of ways. For the patient are wide and include cervicofacial advancement and submental island
with a relatively small intraparenchymal defect, with preservation of myocutaneous, supraclavicular fasciocutaneous, and free fasciocuta-
the superficial musculoaponeurotic system and subcutaneous tissue, neous flaps. Cervicofacial advancement is limited by its random blood
either no reconstruction is needed or a small fat graft can be used, supply and often is plagued by distal necrosis, especially in patients
depending on the skin thickness and aesthetic goals of the patient. with any vascular disease or history of smoking. Furthermore, inci-
Typically, younger patients with slimmer facial skin will benefit the sion design must be determined before ablative surgery; and, if
most from fat grafting in this scenario. Fat grafting is an excellent margins need to be revised, this can create a logistical issue for
reconstruction option for volume defects because it resists infection, this flap.
remains supple, has no foreign body reaction, and will grow with the The submental island myocutaneous flap is becoming the gold
44
patient in the pediatric population. Dermal fat grafting has the standard for cutaneous reconstruction of parotid defects in many
additional advantage of resisting unpredictable reabsorption, which institutions.26,48 It has the advantages of simple harvest (with new
45–47
is common with standard fat grafting. If the superficial muscu- modifications),49 excellent skin color match, relatively quick harvest,
loaponeurotic system and subcutaneous tissue are excised to achieve minimal donor site morbidity (some limitation of neck extension), and
an oncologic margin, the necessity for volume reconstruction in- shorter hospital stay versus free‐flap reconstruction. The submental
creases. Adjuvant radiation will certainly cause more resorption of island flap can be used for defects up to 14 � 6 cm, but this depends
grafts, but this is variable and depends on how quickly the graft on the submental laxity of the patient. Technical modifications
vascularizes, which is a function of technique of harvest and vascu- include taking the mylohyoid muscle with the flap to avoid any
larity in the wound bed. Ultimately, the decision to perform volume difficult small‐vessel dissection and preoperative understanding of
reconstruction can be readily assessed intraoperatively by the sur- venous drainage patterns (external jugular vs. internal jugular vein) to
geon by comparing facial symmetry after tumor extirpation. Any type ensure the flap will not become congested. Furthermore, the anterior
of fat grafting involves a donor site (typically thigh or abdomen), with jugular vein can be coupled to an additional vein (typically external
associated donor site complications, and also requires a longer time jugular) using loupe magnification to give additional venous drainage,
for drain placement to prevent seroma. Fat grafting has also been when indicated. Although there are reports of surgeons experiencing
shown to decrease Frey syndrome and sialocele, so it is useful to repetitive failure of this flap,50 in experienced hands, the rate of
counsel patients on these points when discussing risks and benefits. success of this flap is >95%.26 If a two‐team approach is being used, it
Other options for volume reconstruction include vascularized is important the ablative team is aware that a submental flap is being
options, such as the superiorly based sternocleidomastoid flap (based raised and the neck dissection should be done after the flap is
off the occipital artery), the temporoparietal fascia flap (based off the mobilized completely.
superficial temporal artery), the temporalis flap (based off the in- The supraclavicular flap is another reasonable regional option for
ternal maxillary artery), and the submental island musculodermal parotid defects; however, depending on the length of the patient's
flap. The sternocleidomastoid flap suffers from issues with muscle neck, the distal aspect of this flap may experience venous congestion
atrophy, variable devascularization based on the extent of neck or ischemia because the flap becomes less reliable the more distally is
dissection, and creating limited neck mobility. The temporoparietal it raised. It is also essential that the skin overlying the triangle of the
fascia flap is limited by minimal volume reconstruction with an anterior border of the trapezius, the posterior border of the ster-
extended temporal incision and potential injury to the frontal branch nocleidomastoid, and the clavicle is not raised during neck dissection.
of the facial nerve. The temporalis flap causes an extended incision Furthermore, there should be no injury to the transverse cervical
with temporal wasting and muscle atrophy and has fallen out of use arterial system. Given these multiple constraints, this flap is used
given this defect. Although the submental flap is an excellent option, much less frequently for cutaneous parotid coverage.
it involves an extended incision, limits neck mobility to some degree, Finally, free‐flap reconstruction offers the most versatility and
and adds operative time. Vascularized flaps have the great advantage reach and is ideal for larger defects, which potentially involve the
of resisting resorption in the postoperative period, especially with ramus of the mandible or the skull base. The anterolateral thigh flap,
the addition of adjuvant radiation. A preoperative discussion with the the radial forearm free flap, the rectus abdominis myocutaneous flap,
patient on their aesthetic goals in the context of expected adjuvant and the latissimus flap are the most common free flaps for recon-
therapy is the most prudent approach in deciding what, if anything, to struction of these defects. Although free flaps offer great versatility,
do for restoration of volume. they require a much greater burden of hospital resources and lead to
Cutaneous reconstruction is indicated when extirpation of tumor more patient morbidity. Specifically, they require more operating
leaves a skin defect that will be under excessive tension if closed room staff, longer operative time, and longer hospital stay and result
primarily. If a tumor reaches the subcutaneous tissue, skin will typi- in more patient donor site morbidity.26,51 For this reason, free flaps
cally need to be removed to ensure a good margin and healthy skin in are reserved for defects that cannot readily be reconstructed with a
the extirpated bed. Furthermore, when diagnostic core biopsy or submental island myocutaneous flap.
incisional biopsy is done (despite the lack of indication to do this), Briefly, facial reanimation is indicated any time the facial nerve is
skin should be excised along the tract to ensure clear margins. The sacrificed or the buccal or zygomatic branches are sacrificed.
608
Typically, the marginal mandibular nerve and temporal branch of the their neck. The authors recommend a dose ≥60 grays (Gy) for
facial nerve do not benefit from reinnervation and can be conser- adjuvant RT with a dose‐response relationship seen.54,55 This dose
vatively managed by contralateral application of Botulinum toxin. remains the standard to the present time. Other analyses of larger
Intraoperatively, the ideal reinnervation is to connect the masseteric databases, such as the Surveillance, Epidemiology, and End Results
nerve to the buccal branch of the facial nerve.52 This is a relatively database, show an overall survival benefit to the addition of adjuvant
easy and quick procedure, which produces excellent results given the RT in patients with high‐grade or locally advanced (T3/T4 or lymph
supercharged nature of the nerve to the masseter. Patients typically node‐positive) disease.56 Similar results are seen in analyses of the
can produce an appreciable smile after 3–6 months of this nerve National Cancer Database.57
transfer. Cable grafts from the facial nerve main trunk to peripheral One specific histology that often portends an increased risk for
branches produce tone, but rarely produce significant movement. local recurrence is ADCC. Single‐institution, retrospective analysis
Static or dynamic slings can also be used, but these must be discussed has suggested that patients with ADCC have improved locoregional
with the patient preoperatively and can always be done in a delayed control with the addition of adjuvant RT. This is predominantly
fashion. Finally, it is important to consider eyelid procedures at the because of its propensity for neurotropic spread along the cranial
time of facial nerve sacrifice in select patients. Typically, a brow lift nerves.58 For patients with adenoid cystic tumors, magnetic reso-
(direct or indirect), a gold weight, and a lateral tarsal strip are done to nance imaging and careful clinical examination of cranial nerve
reduce morbidity in the eye after nerve sacrifice. Although this can function are recommended to best define any potential perineural
certainly be done in a delayed fashion, it is important to consider this invasion.59 In many patients, elective cranial nerve irradiation is
at the time of parotidectomy for patients who cannot easily undergo performed in this setting to minimize the risk of recurrence along the
anesthesia or who have social situations which limit multiple ap- cranial nerves, which can be devastating. This can be clinically quite
pointments or procedures. challenging because the cranial nerves themselves are often chal-
lenging to see on a computed tomography simulation done for radi-
ation treatment planning. Contouring guidelines to help guide
RADIOTHERAPY radiation treatment volumes in this setting can be extremely
helpful.60
Radiation therapy (RT) is a critical component in the treatment of
salivary gland malignancies. Most typically, this occurs in the adju-
vant setting after surgical resection with standard postoperative in- Definitive radiotherapy
dications, including positive margins, nodal spread, perineural
invasion, and specific histologic subtypes. However, in patients with Although surgical resection remains the optimal treatment for pa-
unresectable tumors or patients who are not candidates for the tients with salivary gland malignancies, there are some patients who
operating room, definitive RT can be used. The propensity of certain have very locally advanced tumors that are not amenable to com-
types of salivary gland tumors to spread along cranial nerves brings plete surgical resection because of invasion into critical nearby
an added layer of complexity to target volume contouring for these structures. In addition, some patients may have other medical
patients because elective cranial nerve RT is often considered. For comorbidities that preclude them from undergoing surgical resection
these situations, in which target volumes approach critical normal safely. In these cases, definitive RT should be offered for patients
structures, novel RT modalities, such as proton therapy, may be with nonmetastatic disease. No prospective evidence exists to guide
useful. treatment in these situations, and the available retrospective data
are often heterogeneous with respect to histology and other risk
factors, which makes interpretation challenging. Single‐institution,
Adjuvant radiation retrospective reports suggest that 5‐year locoregional control after
definitive RT is lower than in patients who undergo upfront surgical
Whereas little prospective evidence exists to guide treatment de- resection. However, a bevy of clinical and pathologic factors (T
cisions in the adjuvant setting, indications for adjuvant RT are rela- classification, N classification, histologic grade, perineural invasion,
tively standard, although they depend significantly on the histology of among others) influence outcomes.61,62 A prior Dutch analysis sug-
the resected tumor. Benign tumors, such as Pas, do not need adjuvant gested a higher total dose ≥66 Gy with standard fractionation for
RT unless positive margins are seen or in situations of multiple lines patients with unresectable tumors. However, other guidelines sug-
of recurrence or multifocal recurrence.53 For patients with malignant gest 70 Gy.54,63
tumors, indications for adjuvant RT are based primarily on retro- Alternative radiation modalities have long been considered for
spective historical data. In a review from the Dutch Head and Neck salivary gland malignancies to improve local control, especially in the
Oncology Cooperative Group, postoperative RT improved local definitive setting. In the 1980s, a Radiation Therapy Oncology
control in patients with pathologic T3–T4 disease, close or positive Group‐Medical Research Council cooperative study randomized 32
margins, bone invasion, and perineural invasion. Postoperative RT patients with inoperable, recurrent, or unresectable malignant sali-
improved regional control for patients who had any nodal disease in vary gland tumors to receive either conventional photon RT or
STEUER ET AL.
- 609
neutron RT. The 2‐year locoregional control rate was significantly randomized patients with salivary gland tumors who had traditional
higher with neutron therapy (67% vs. 17%; p < .005).64 This benefit in risk factors (pathologic T3 [pT3]/pT4 disease, pathologic lymph node‐
locoregional control persisted with 10‐year follow‐up; however, no positive disease, close [<1 mm] or positive margins, or aggressive
significant difference in overall survival was seen. In addition, there histologic subtype) to receive either adjuvant RT alone or adjuvant
was an increased incidence of severe long‐term toxicity in the neutron RT with concurrent weekly cisplatin, with a primary end point of
arm.65 This increased toxicity, along with improved outcomes with overall survival.73 The results of this study are eagerly awaited.
photon RT seen in more contemporary series and the scarcity of
neutron facilities in the United States, has led to neutron RT pre-
dominantly falling out of favor in this setting, at least in the United Chemotherapy in the recurrent/metastatic setting
States.62 More recently, proton therapy has been used in the treat-
ment of SGCs, although with a predominate focus of reducing toxicity For salivary gland tumors that metastasize or are no longer amenable
of treatment. Single‐institution reports describe minimal toxicity to curative therapy, the first decision is whether to pursue systemic
associated with proton therapy in both the definitive and adjuvant therapy or expectant management. This is often a decision based on
settings and very promising locoregional control.66,67 Proton therapy patient preferences, histology, and aggressiveness of the tumor.
may be specifically beneficial in patients who have either extensively Expectant management may be appropriate for low‐grade tumors with
locally invasive tumors or perineural invasion involving the skull base, low disease burden. In expectant management, metastasectomy for
which may be in close proximity to critical normal structures, such as slow‐growing tumors is a reasonable option and has demonstrated the
the brainstem, optic nerves, or temporal lobe. However, no pro- ability to lead to prolonged disease intervals for selected patients.74
spective evidence exists to support the use of proton therapy in this For patients who opt for or are counseled to initiate systemic
setting. In addition, hypofractionated (high dose‐per‐fraction) tech- therapy, chemotherapy remains the mainstay of treatment. However,
niques, such as stereotactic body RT, may be considered in the there are no large, randomized trials that can inform treatment de-
definitive setting either alone or as a boost after a lower dose of cisions. Based on limited data, a mainstay of treatment is combination
conventionally fractionated RT. Although small retrospective series therapy, which typically includes cisplatin or carboplatin. In general,
suggest oncologic outcomes at least comparable to those of response rates range between 20% and 45%, although such therapy
conventionally fractionated RT, there are no prospective data to appears to have little activity in specific subsets.75 For example, in a
support the use of stereotactic body RT in salivary gland retrospective analysis, the overall response rate to carboplatin and
malignancies.68,69 paclitaxel was 29%, although the response rate specific to ADCC was
<10%.76,77
In addition to cytotoxic chemotherapy, multitargeted tyrosine
SYSTEMIC THERAPY kinase inhibitors have been studied in select patients. Lenvantinib,
axitinib, and sorafenib all have been used and have demonstrated
Chemotherapy in the curative setting only modest benefit, with response rates ranging from 5% to 25%,
depending on drug and SGC cytopathologic subtype, but with sig-
Unlike in squamous cell carcinoma of the head and neck, there are no nificant toxicity.78–80 Overall, whereas both chemotherapy and
large prospective data to inform clinicians on the use of adding tyrosine kinase inhibitors form the backbone for our treatment of
chemotherapy to radiation for high‐risk SGCs after surgical resec- SGCs, clearly other treatment modalities and clinical research are
tion. Salivary gland carcinomas are a heterogeneous grouping of needed.
histologies, and large clinical studies in this setting are difficult to
perform. Retrospective institutional and national database studies
have reported mixed results with the addition of postoperative IMMUNOTHERAPY FOR SALIVARY GLAND
chemotherapy to radiation.70,71 Because of this, the use of chemo- CANCERS
therapy is often debated and, in practice, a decision is often made
based on clinical judgement and discussion with the patient. Patho- Given the limited, standard, systemic therapy options for patients
logic features, such as close/positive margins, high‐grade histologies with SGCs, we recommend participation in a clinical trial.81 There-
like SDCs, and multiple involved lymph nodes, are often used as poor fore, there is a need for collaborative efforts in the investigation of
prognostic indicators and scenarios that prompt discussion about the novel therapeutic options, including immunotherapy, in the man-
role of systemic treatment.72 agement of metastatic SGCs. The programmed death 1 (PD‐1) re-
Cisplatin is typically the chemotherapy chosen to be given with ceptor inhibits T‐cell function when binding to its ligands, PD‐L1 and
radiation, extrapolated from its use in squamous cell carcinoma of the PD‐L2.82 PD‐L1 expression has been observed in 22.8% of SGCs and
63
head and neck and its general efficacy in salivary gland carcinomas. was associated with worse disease‐free and overall survival in a
Fortunately, a clinical trial has completed enrollment and should retrospective series.83
provide guidance in this area. Radiation Therapy Oncology Group One of the main studies testing the clinical activity of PD‐1 in-
trial RTOG 1008 (ClinicalTrials.gov identifier NT01220583) hibitors in SGC is Keynote‐028 (ClinicalTrials.gov identifier
610
NCT02054806), which is a phase 1b trial enrolling patients with encodes a tyrosine kinase receptor member of the epidermal growth
different tumor types.84 The study enrolled patients who had PD‐L1– factor receptor family. These four receptors are capable of hetero-
positive SGC for which standard therapy was ineffective or was dimerization, leading to cell‐signal transduction that can facilitate
deemed inappropriate. In total, 26 patients with SGC were enrolled tumor growth.92 Amplification of the HER2 gene or protein over-
based on PD‐L1 expression >1% and received pembrolizumab 10 expression is suggested in several solid tumor malignancies.93
mg/kg every 2 weeks for up to 2 years. The objective overall In the early 2000s, it became evident that more clinically
response rate was 12% (three patients achieved a partial response), aggressive SGCs often overexpressed or demonstrated amplification
with a median duration of response of 4 months (range, 4–21 in the proto‐oncogene HER‐2/neu.94 Because SDC shares histologic
85
months). Despite the limited responses observed, a disease con- resemblance to invasive ductal carcinoma of the breast, HER2
trol rate of 58% as well as durable responses were observed in this expression was also potentially important in salivary tumors
heavily pretreated population. It is worth indicating that the reported (whether primary or metastatic). Larger efforts to score multiple
responses are equivalent to those observed with tyrosine kinase in- salivary cancer histologies for HER2 overexpression demonstrated
hibitor use in subtypes of SGC, such as ADCC.86 These data suggest that the overall frequency was low, around 17%,95,96 but that high‐
that there may be value in using PD‐1 inhibitors in biomarker‐ grade histologic features correlated with HER2 expression among
selected patients with advanced SGC. subtypes such as SDC, MEC, and CXPA, in which HER2 positivity
Keynote‐158 (ClinicalTrials.gov identifier NCT02628067) is a ranged from 21% to 83%. A systematic review of 80 studies sum-
subsequent study enrolling patients with metastatic SGC. PD‐L1– marized HER2 overexpression among SDCs at 45% and, among
positive disease was noted in 25.7% of patients. Despite a response MECs, at 84%.97 Furthermore, it is unclear whether HER2 expression
rate of only 4.6%, enrichment of responses was noted in PD‐L1– is prognostic; in one study specifically in SDC, HER2 expression was
positive patients, and the duration of response exceeded 2 years in associated with a propensity for distant metastatic spread and
few patients, reinforcing the value of PD‐1 inhibitors in a selected decreased 5‐year survival.98
87
group of SGCs. Despite the small number of patients with SGC on There are various ways to measure HER2 oncogene activity, and
Keynote‐158, a subsequent analysis indicated a high tumor mutation most scoring in SGCs has recapitulated testing practices adopted
burden (TMB‐high status) correlated with improved responses to from breast cancer.99 Although these cutoffs have been used in
88
anti–PD‐1 therapy. scoring SGCs, there is no clear standardization or scoring rubric
Combination immunotherapeutic approaches have not been available that is specific to these tumors, and HER2 positivity can
commonly investigated in SGCs. A phase 2 trial combining the PD‐1 vary considerably across different studies. Notably, several series
inhibitor nivolumab and the CTLA4 inhibitor ipilimumab is currently have demonstrated lower 3+ IHC expression and HER2 gene
enrolling patients with recurrent, metastatic SGC (excluding ADCC) amplification concordance compared with breast cancer.100,101
and assessing the response rate as its primary end point. Among the Although speculative, it is plausible that HER2 protein over-
32 enrolled patients, five confirmed partial responses were noted, expression is regulated independently from gene amplification in
89
with regressions ranging between 66% and 100% in target lesions. salivary cancers or that the rates of gene transcription and protein
A phase 2 basket trial of the same combination revealed a response degradation are important.101 Other work has suggested that HER2
rate of 4% in patients with ADCC.90 signaling in SDC may potentiate the phosphoinositide 3‐kinase
Although PD‐L1 appears to be a predictive biomarker for clinical pathway.102
benefit to immune checkpoint inhibitors in other malignancies, better Despite the variation in scoring and expression patterns across
markers are needed in SGC, which can be achieved only in larger salivary histologies, it is important to routinely assess HER2 IHC
prospective studies. Although the results with immunotherapy are (with reflex ISH testing, when appropriate) in clinical practice among
currently rather limited, future research focusing on introducing all high‐grade salivary cancers (specifically SDC and MEC), particu-
novel combinatorial approaches that could enhance the benefit to larly in the setting of recurrent or metastatic disease given the
immunotherapy in these diseases will need to be pursued. None- therapeutic implications.
theless, the American Society of Clinical Oncology issued its guide-
lines for immunotherapy and biomarker testing in head and neck
cancers indicating that pembrolizumab may be offered to patients HER2‐directed therapies in the recurrent, metastatic
who have PD‐L1–positive, recurrent or metastatic SGCs and immu- setting
notherapy, albeit with a moderate quality of evidence and a strength
of recommendation noted to be weak (recommendation 6.2).91 The first prospective trial to evaluate the HER2‐directed antibody
trastuzumab in patients who had SGC with HER2 IHC overexpression
(2+ to 3+) was published in 2003. Fourteen patients with locore-
Targeting HER2 gionally advanced or metastatic tumors received trastuzumab 2 mg/
kg weekly after a loading dose until progression with minimal evi-
The HER‐2/neu proto‐oncogene is positioned on chromosome 17q dence of activity (objective response rate, 8%).103 The dual erbB2
and regulates cell growth and development, whereby the gene (gene encoding HER2) and the epidermal growth factor receptor
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inhibitor lapatinib (1500 mg daily) also were evaluated in patients Trastuzumab deruxtecan (T‐DXd; DS‐8201a) is a novel antibody‐
who had advanced SGC with 2+ HER2 tumor expression, and no drug conjugate with a humanized anti‐HER2 antibody that has a
responses were observed among 17 patients, although eight patients cleavable peptide‐based linker and a potent topoisomerase I inhibitor
(47%) had stable disease (which lasted ≥6 months in four pa- payload. The drug‐to‐antibody ratio is two‐fold higher than that of T‐
tients).104 Extrapolating from advanced breast cancer, adding taxane DM1, enabling efficient drug delivery, and the payload is membrane‐
therapy to HER2‐targeted treatment was later explored. A single‐ permeable, allowing a neighboring tumor cell cytotoxic effect.111
arm, Japanese, phase 2 trial of trastuzumab (6 mg/kg every 3 These properties have made T‐DXd appealing to investigate among
weeks after a loading dose) in combination with docetaxel (70 mg/m2 solid tumors with low or heterogeneous HER2 expression. Tsurutani
every 3 weeks) among 57 participants with HER2‐overexpressing (3+ and colleagues evaluated T‐DXd (5.4–6.4 mg/kg, every‐3‐week
IHC expression or gene amplified), advanced SGC reported a dosing at optimization) among 60 patients with previously treated,
response rate of 70% and a median progression‐free survival (PFS) of HER2‐expressing solid tumors (≥1+ HER2 IHC expression) in a phase
8.9 months.105 The combination was well tolerated, with expected 1 dose‐finding trial.112 Therapy was well tolerated with some nausea,
cytopenias observed. A small series reported the use of trastuzumab decreased appetite, and vomiting. Eight patients with SGC were
with paclitaxel and carboplatin (TCH) (every 3 weeks for six cycles) included with some tumor regression observed.
among patients with HER2 2+ to 3+, advanced salivary cancer with Given the benefits of sequential HER2 targeting in salivary
favorable activity, including one complete response lasting for >4 cancer, as newer HER2‐directed therapies surface and the lower
years (the median duration of response was 18 months).106 Fifteen limits of HER2 expression are redefined, incorporating these thera-
patients in the phase 2a multibasket MyPathway study (ClinicalTrials. pies into practice is important, particularly given the limited benefit
gov identifier NCT02091141) had HER2‐amplified and/or over- of cytotoxic chemotherapy and the lack of approved therapies in this
expressing (with or without mutations) salivary cancers and were disease. The latter rely on willing and determined clinicians securing
treated with dual anti‐HER treatment using trastuzumab and per- off‐label approval for these drugs or ensuring access to clinical trials
tuzumab (420 mg intravenously every 3 weeks after a loading dose). for these patients.
The response rate was 60%, with a median duration of 9.2 months
and a median PFS of 8.6 months.107 Based on these combined data,
trastuzumab is often combined with platinum and/or taxane therapy HER2‐directed therapies in the adjuvant setting
(the latter is sometimes combined with pertuzumab) in the first‐line
setting for advanced HER2‐overexpressing salivary cancers. Moving beyond the advanced disease setting, the use of adjuvant
When HER2‐targeting antibody‐drug conjugates emerged, in- HER2‐based therapy to mitigate the risk of disease relapse, partic-
terest turned to exploring agents like trastuzumab emtansine (T‐ ularly distant metastatic spread, is of great interest. A case series of
DM1), even among patients with prior trastuzumab exposure. The nine patients who received adjuvant chemoradiation using weekly
National Cancer Institute‐Molecular Analysis for Therapy Choice carboplatin and paclitaxel with RT followed by trastuzumab mainte-
(NCI‐MATCH) precision medicine study treated 38 patients who nance continued up to 1 year.113 Median disease‐free survival and
had HER2‐amplified tumors (greater than 7 copy numbers) with overall survival were longer among TCH‐treated patients compared
various solid tumors using T‐DM1 (3.6 mg/kg every 3 weeks), and with comparable patients who received chemoradiation alone. No
two partial responses were observed, both in patients who had difference in outcomes according to HER2 expression intensity or
108
SGC. Li and colleagues treated 10 patients who had HER2‐ amplification status was noted (recognizing the small sample size).
amplified (identified by next‐generation sequencing), advanced However, six patients who received adjuvant TCH with HER2‐
SGCs as part of a larger basket study and demonstrated a response expressing (2+ to 3+) salivary cancers recurred at a median follow‐
rate of 90%, with five complete responses among patients who had up of 5.2 years.
been treated with prior trastuzumab and pertuzumab; the median Some experts routinely use this or a similar trastuzumab‐based
PFS was not reached (95% confidence interval, from 4 to ≥22 regimen in the adjuvant setting for HER2‐overexpressing salivary
months).109 Notably, patients had received a median of two prior cancer tumors if they secure off‐label approval. The first prospective,
lines (range, zero to three prior lines) of systemic therapy before multicenter trial of adjuvant HER2 therapy using 1 year of T‐DM1 is
enrollment. The latter data suggest that sequential HER2 targeting enrolling in the United States for patients with locoregionally
can be beneficial for patients with HER2‐overexpressing, advanced advanced, HER2‐expressing (2+ to 3+) SGCs who have undergone
SGCs in the second line and beyond. Illustrating this point, a small surgery followed by adjuvant weekly cisplatin with radiotherapy
series from the Netherlands treated 13 patients who had HER2‐ (ClinicalTrials.gov identifier NCT04620187). Cisplatin was chosen in
positive SDC with combined docetaxel, trastuzumab, and pertuzu- that study because platinum‐taxane radiosensitization may increase
mab in the first line, with 58% responding (median PFS, 6.9 mucositis risk, and cisplatin is the preferred radiosensitizer in
months); then, seven patients from the same cohort went on to mucosal head and neck squamous cell cancers. Future studies may
receive second‐line T‐DM1, with a 57% response rate and a median investigate adjuvant T‐DXd therapy for HER2 low‐expressing sali-
PFS of 4.4 months.110 vary tumors in the adjuvant or even neoadjuvant setting.
612
Targeting androgen receptor 5α‐dihydrotestosterone, are known to negatively affect combined

androgen‐blockade response.121 Upstream of testosterone, steroid
AR is a nuclear steroid hormone receptor that is expressed in several synthesis can also be enhanced by upregulation of the cytochrome
human tissues, with testosterone and 5α‐dihydrotestosterone as its P450 family 17 subfamily A polypeptide 1, but this enzyme has not
main ligands. AR regulates the transcription of several effector genes been observed in SDC despite being identified in prostate tumors.122
through direct DNA interactions, with aberrations in signaling leading A phase 2, second‐line study evaluating the cytochrome P450 family
114
to oncogenic potential in prostate cancer and other cancers. 17 inhibitor abiraterone with ADT enrolled 24 patients with AR‐
Similar to HER2, AR expression measured by IHC varies among positive disease who had previously been treated with ADT alone.
different types of SGCs and most frequently has been identified The response rate was 21%, with a median duration of response of
among SDCs (range, 64%–98%).115 The frequency of AR expression 5.8 months and a median PFS of 3.6 months.123 These data support
in other salivary cancer subtypes is 0%–30%. The variability in re- the use of sequential ADT for so‐called castrate‐resistant, AR‐
ported expression among SDCs may reflect improvements in histo- positive salivary cancers. Another phase 2 study using the next‐
logic classification and technical issues around staining. generation oral antiandrogen enzalutamide (160 mg daily) among
Studies have demonstrated that AR IHC‐negative SDC can 46 patients with advanced, AR‐positive salivary cancer (28% had
demonstrate detectable messenger RNA signaling in AR, which may received prior ADT) yielded a 15% response rate (4% confirmed),
suggest a mechanism of acquired activation in some tumors.116 In with a median PFS of 5.6 months.124 Notably, the latter study did not
prostate cancer, resistance to androgen‐targeted therapies can occur continue ADT with enzalutamide. Furthermore, studies have not
when the full‐length AR gene is spliced to yield variants that lose the aligned in their definition of AR overexpression because some pro-
117
ligand‐binding domain. AR‐V7 is a variant that includes only exons tocols require ≥1% nuclear AR staining, whereas others have used a
1–3 and has been identified in SDCs.118 Other genetic alterations in combination of an intensity score (0–3) and high nuclear expression
AR signaling that have been identified in SDCs include X chromosome (≥70%) to enrich patient selection. How AR splice variants or ac-
(housing the AR gene) polysomy; FOXA1 mutations, which regulate quired resistance evolve with sequential AR‐directed therapy in
AR transcription; and FASN mutations, which disrupt the enzymatic salivary cancer is not well understood.
116
regulation of fatty acid synthesis. These collective molecular ob- We believe that the sequential use of AR‐directed therapy in AR‐
servations suggest that targeting AR in overexpressing salivary can- overexpressing salivary cancers, particularly SDC, is important in the
cers is important to consider and that mechanisms of acquired recurrent, metastatic setting, and clinical trial participation should
resistance could be relevant with exposure to androgen‐blocking always be encouraged. When both AR and HER2 overexpression are
therapies. observed in a particular tumor, preference is often given to targeting
HER2 certainly if 3+ IHC status or gene amplification is identified.
Combining AR and HER2 therapies in practice is not typically
Androgen‐deprivation therapy in the recurrent, favored.
metastatic setting
Borrowing from the therapeutic armamentarium of prostate cancer, ADT in the adjuvant setting
androgen‐deprivation therapy (ADT) has been explored to treat pa-
tients who have salivary cancer with tumor AR expression. In a Whether adjuvant ADT should be incorporated as part of post-
retrospective series of patients with AR‐positive salivary cancer who operative therapy for patients with locoregionally advanced, AR‐
received the oral antiandrogen bicalutamide with a gonadotropin positive salivary cancers is not yet known. A group of European in-
hormone‐releasing hormone agonist, 65% of patients demonstrated a vestigators published a retrospective study of 22 patients with stage
119
response. In 2018, the first prospective phase 2 trial reported a IVA, AR‐positive SDC treated with adjuvant ADT for a median
42% response rate when using the gonadotropin hormone‐releasing duration of 1 year compared with a control group of 111 patients
hormone agonist leuprolide with bicalutamide among 36 patients who were not treated after surgery. At a median follow‐up of nearly
who had advanced, AR‐positive salivary gland carcinoma, with a 2 years, the 3‐year disease‐free survival rate was 48% in the ADT‐
median PFS of 8.8 months.120 Although this established combined treated group versus 28% among similar controls.125 Future trials
androgen blockade with a gonadotropin hormone‐releasing hormone should aim to prospectively address this question, but execution has
agonist and an oral antiandrogen as a first‐line option in these tu- been difficult given the relative rarity of the condition and the need
mors, it is unclear whether using cytotoxic chemotherapy first is to agree on the preferred form of ADT and duration of therapy.
preferable. The European Organization for Research and Treatment
of Cancer Head and Neck Cancer Group/UK Clinical Research
Network 1206 trial is a randomized phase 2 study that aims to Targeted therapy
address this question (ClinicalTrials.gov identifier NCT01969578).
Downregulation of AR pathway signaling or upregulation of As mentioned above, one of the primary challenges of managing
SRD5A1, the enzyme that promotes conversion of testosterone to malignant salivary tumors is that they are rare entities that
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encompass a broad diversity of diseases, including more than 20 genetic diversity can affect clinical outcomes because some alter-
histologic subtypes.126 This complexity predictably extends to the ations are enriched in metastatic versus primary tumors and are
127–129
underlying biology of these diseases. The growing importance associated with a worse prognosis.141 The most common genetic al-
of molecular profiles for SGC diagnosis, prognosis, and therapeutic terations (apart from MYB/MYBL‐1) among recurrent and/or meta-
interventions is reflected in part by the inclusion of molecular al- static tumors are activating alterations in the NOTCH1 gene, which
terations in the World Health Organization definitions for some SGC have been associated with a significantly worse prognosis.141,151–153
histologies. Among the most critical for identifying actionable ther- Bulk RNA sequencing experiments have also demonstrated that tu-
apeutic interventions are NTRK3 and RET rearrangements for SCs mors with MYC/NOTCH activation (ADCC‐I) have a worse prognosis
and intraductal carcinomas, respectively, as well as AKT1 mutations than ADCC‐II tumors characterized by TP63 and receptor tyrosine
for mucinous adenocarcinomas.126 Although the trials were not kinases.154 This is one of a growing number of observations that gene
specific to SGCs, there are now US Food and Drug Administration‐ expression signatures can effectively identify ADCC cohorts with a
approved therapies for RET (selpercatinib, pralsetinib) and NTRK worse prognosis.149,154–157 Even more striking are emerging data
(entrectinib, larotrectinib) rearrangements available based on high regarding the high degree of intratumoral heterogeneity that exists
response rates and clinical efficacy for patients who have tumors within ADCC primary and metastatic tumors. Whole‐exome
130–133
harboring the relevant genomic alterations. sequencing demonstrated that greater than one third of ADCCs
Advanced genomic, transcriptomic, and proteomic profiling of possess intratumoral heterogeneity, resulting in distinct mutation
SGCs has produced sophisticated insights into the underlying biology profiles not only in individual metastatic sites within a patient, but
of some SGC tumors. Several reviews have comprehensively anno- even within different regions of one tumor.141 MYB itself can
tated the specific molecular features of each SGC tumor type.128,129 contribute to intratumoral heterogeneity by driving distinct expres-
Here, we discuss two of the most well characterized SGC subtypes to sion programs in myoepithelial cells versus luminal cell lineages.146
date—ADCC and SDC—to illustrate that the heterogeneity and An alternative MYB promoter was also recently discovered that
complexity of these diseases require that therapies be personalized produces an N‐terminally truncated MYB protein that drives a
to individual tumor biology. Although both diseases have a high distinct transcriptional signature from full‐length protein.158 Single‐
134–138
propensity for recurrence and metastasis, SDCs are more cell RNA sequencing has confirmed significant heterogeneity in
aggressive tumors associated with poorer survival.137,139,140 These both the malignant and stromal compartments of ADCC tumors,
differences in clinical behavior are associated with biologic distinc- including the discovery that the ADCC‐I and ADCC‐II signatures
tions and opportunities for rational therapeutic intervention. delineated in bulk sequencing can be observed within individual cell
ADCCs are characterized by a relatively quiet genome, with a low populations in all ADCCs and that NOTCH activation in luminal cells
rate of mutation (~0.3 mutations per megabase) and hence a limited is likely activated through paracrine interactions with myoepithelial
number of actionable targets for treatment (<10%).141 The discovery cells.159 These advanced insights illustrate that, despite the low TMB,
that a significant proportion of ADCC tumors are characterized by ADCCs possess a high degree of complexity that must be accounted
142–145
rearrangements of the MYB gene (6q23.3) first highlighted this for when designing rationally targeted therapies.
oncogenic transcription factor as a critical driver of the disease. Later Profiling studies of SDCs highlight several important biologic
work demonstrated that the rearrangement facilitates interaction of differences with ADCC tumors. Genomic analyses reveal that SDCs
the MYB promoter with super‐enhancers to drive MYB over- have a higher TMB, with >60% of patients estimated to have
146
expression. A large, multi‐institutional study recently reported actionable alterations in their tumors.129,160–162 Although SDCs are
alterations in the MYB locus in 62.1% of ADCC tumors, with 39.1% of not characterized by recurrent rearrangements,127 SDCs still can
0
all tumors harboring MYB rearrangements, 16.1% with 3 loss of the infrequently possess targetable fusion genes (e.g., ALK, NTRK3, RET)
gene, and 3.1% with a gain of an intact MYB allele.147 High MYB that may be matched to highly effective therapeutics.160–162
protein expression can also be found among rearrangement‐negative Apart from AR and HER2, which are discussed above, the most
ADCCs,142,145,148 suggesting that alternative mechanisms of MYB common recurring mutations detected in SDCs include TP53 in over
overexpression likely exist. A small percentage of ADCCs lacking one half of all tumors and PIK3CA and/or HRAS mutations in >20% of
MYB activation can alternatively harbor rearrangement and over- tumors.127,129,160,161,163 Both TP53 mutation and MYC amplification
expression of the MYBL1 gene.149,150 MYB and MYBL1 are closely have been associated with a worse prognosis.163 The genomic profile
related transcription factors that produce similar gene expression of SDCs appears to be different within molecular cohorts defined by
profiles in ADCCs,149 supporting the hypothesis that the expression AR and HER2 status,163 illustrating that these two genes may define
programs driven by this transcription factor family are critical for critical biologic subsets. Gene expression profiling has also high-
ADCC oncogenesis. lighted the potential importance of the NOTCH and TGF‐β pathway
Whereas MYB/MYBL‐1, in the context of low mutational burden, signaling,164 as well as enrichment for immune‐mediated
confers a degree of biologic consistency among ADCCs, a compre- processes.164,165
hensive interrogation of the genomic landscape reveals a high degree Hence, the biologic insights developed to date for ADCC and
of tumor heterogeneity, including the recent report of >9000 SDC reveal not only significant differences among different SGC
genomic alterations detected in >1000 ADCC tumors.141 This tumor types, but also heterogeneity within each histology. Studies
614
focused on the immune profile of different SGC histologies have also ORCID
uncovered significant heterogeneity in the expression of T‐cell im- Conor E. Steuer https://orcid.org/0000-0001-6528-6319
mune checkpoint proteins, TMB, tumor‐infiltrating lymphocytes, and
immune tumor microenvironment composition,164–169 which may R E F E R EN CE S
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identifies a paracrine interaction that may drive oncogenic notch

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The evolving landscape of salivary gland tumors

CA Cancer J Clin. 2023;73:597–619. wileyonlinelibrary.com/journal/caac 597

Common malignant neoplasms

SALIVARY GLAND CARCINOMA

Common benign neoplasms

SALIVARY GLAND CARCINOMA

ANATOMY OF THE SALIVARY GLAND DIAGNOSIS OF SALIVARY GLAND CARCINOMAS

Nondiagnostic (category I) 15% Clinical, radiologic correlation or repeat fine‐needle aspiration

Nonneoplastic (category II) 11% Clinical and radiologic follow‐up

Neoplasm: Benign (category IVa) <3% Conservative surgery or clinical follow‐up

SC is most often low‐grade and can either be well circumscribed or

Targeting androgen receptor 5α‐dihydrotestosterone, are known to negatively affect combined

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