S a l iva ry G l an d

Malignancies
Cristina P. Rodriguez, MDa, Upendra Parvathaneni, MBBS, FRANZCRb,
Eduardo Méndez, MD, MSc,d, Renato G. Martins, MD, MPHa,*

KEYWORDS
 Salivary cancer  Therapy  Review  Management  Systemic

KEY POINTS
 Salivary gland cancers are morphologically and biologically diverse.
 Surgical resection with postoperative radiation is considered a treatment standard for
localized disease.
 Systemic therapy can be considered for patients with unresectable or metastatic disease
with the goal of palliation of symptoms.

INTRODUCTION

Primary salivary gland malignancies represent less than 5% of all new head and neck
cancers, with approximately 3000 new cases diagnosed in the United States annually.
These diverse cancers arise from the malignant transformation of the various myoepi-
thelial, ductal, and acinic components of 3 paired major (parotid, submandibular, and
sublingual) and minor salivary glands distributed throughout the upper aerodigestive
tract. The World Health Organization classifies 24 subtypes1 characterized by marked
biological heterogeneity. For example, high-grade mucoepidermoid carcinomas, sali-
vary duct carcinomas, malignant mixed tumors, and high-grade adenocarcinomas
have the most aggressive clinical course, with frequent early spread to regional lymph
nodes and distant sites. In contrast, adenoid cystic carcinomas generally display an
indolent natural history with a propensity for local or distant recurrence even 10 to
15 years after initial treatment. Knowledge of these unique factors is essential in plan-
ning the nuances of therapy.

Conflicts of Interest: The authors have no potential conflicts of interest to disclose.

a
Division of Medical Oncology, Department of Medicine, University of Washington, 825 East-
lake Avenue East, MS G4940, Seattle, WA 98109, USA; b Division of Radiation Oncology,
Department of Medicine, University of Washington, 1959 Northeast Pacific Street, Box, Seattle,
WA 98195, USA; c Department of Otolaryngology, Head and Neck Surgery, University of Wash-
ington, 1959 Northeast Pacific Street, Box 356515, Seattle, WA 98195, USA; d Clinical Research
Division, Fred Hutchinson Cancer Research Center, 1959 Northeast Pacific Street, Box 356515,
Seattle, WA 98195, USA
* Corresponding author.
E-mail addresses: rgmart@uw.edu; rgmart@u.washington.edu

Hematol Oncol Clin N Am 29 (2015) 1145–1157

http://dx.doi.org/10.1016/j.hoc.2015.08.002 hemonc.theclinics.com
0889-8588/15/$ – see front matter Ó 2015 Elsevier Inc. All rights reserved.
1146 Rodriguez et al

INITIAL EVALUATION

The clinical presentation of a salivary gland mass can reveal a great deal about its na-
ture, with certain symptoms and physical findings associated with malignancy. Rapid
growth and/or pain (either localized or referred to the temporomandibular joint or the
ear), and paresthesias/hypesthesias caused by perineural spread are concerning
signs for malignancy.2,3 Facial nerve dysfunction, firmness and fixation of a mass,
the presence of trismus for tumors of the parapharyngeal space, and nodal involve-
ment in the neck are findings that increase suspicion for a malignant process.4–6
Computed tomography (CT) and MRI are the two most common imaging modalities
used to evaluate salivary gland lesions, with the latter being the method of choice for
patients with palpable masses and a strong suspicion for malignancy.7,8 Contrast
enhancement per se cannot distinguish benign versus malignant processes but it
can be critical in delineating the extent of the lesion. Irregular margins; bony invasion;
presence of metastatic lymph nodes; and perineural spread along cranial nerve VII
(stylomastoid foramen), cranial nerve V-3 (foramen ovale), or V-2 (foramen rotundum)
can all be concerning signs of malignancy.6,9 Necrosis can also characterize malig-
nancy, particularly in primary squamous cell carcinomas of the salivary glands (likely
caused by squamous metaplasia in patients with chronic inflammation). In addition,
PET is now being studied for its utility in evaluating salivary gland tumors. Keyes
and colleagues10 found high sensitivity (100%) but low specificity (30%) in predicting
malignancy in a cohort of 26 patients with parotid masses.
Histologic confirmation can be acquired before a definitive surgical procedure and
this can be useful in planning the type and extent of definitive therapy. Fine-needle
aspiration biopsy (FNAB) is the most widely used method for obtaining diagnostic tis-
sue because of its convenience as an office procedure and its associated high sensi-
tivity and specificity.11,12 In clinical scenarios in which surgical resection of a growing
lesion is planned regardless of the histology, patients may opt to forgo FNAB. With
respect to obtaining tissue for surgical preplanning, clinicians should consider the
risk of performing unnecessary surgery before knowing the diagnosis based on per-
manent section evaluation. A frozen section intraoperatively can be useful for a diag-
nosis but its value compared with FNAB is controversial because its accuracy
depends on the experience of the on-call pathologist. Some studies have shown
that intraoperative diagnoses can change after permanent section examination.13,14
Others have shown the sensitivity and specificity of frozen sections to be 77% and
100%.15 The risk of either test is in performing unnecessary surgery, like a radical
resection or a cervical lymphadenectomy, if a diagnosis of an aggressive malignancy
is erroneously reported. Thus, the ultimate scope of treatment should be reserved until
permanent section analysis is performed.

SURGICAL MANAGEMENT

Surgical excision of a primary salivary gland malignancy can be curative for most cases
when the tumor is small, low grade, and easily accessible. Parotid malignancies are most
curable with surgery, followed by the submandibular and sublingual glands. Ultimately,
prognosis depends on the gland of origin, histology, grade, and extent of disease (ie,
American Joint Commission for Cancer stage). Bulkier tumors or those of aggressive his-
tology/grade are best treated with surgery first, followed by adjuvant therapy.
Surgery of the Parotid Gland and Management of the Facial Nerve
Among parotid tumors, avoiding injury to the facial nerve is critical when tumors are
not fixed to, or encasing, the nerve. Thus, surgery typically involves removing the
 Salivary Gland Malignancies 1147

superficial lobe of the gland above the plane of the facial nerve or the deep lobe just
underneath it. A superficial parotidectomy can be considered the treatment of choice
for most tumors in the superficial lobe of the gland. Enucleation of a tumor should be
avoided because this has been associated with tumor spillage and higher recurrence
rates. However, patients should be consented for total parotidectomy in cases in
which there is deep lobe involvement, because preservation of the nerve often re-
quires removing the superficial lobe to then dissect any deep lobe component from
the nerve.
The decision on whether or not the facial nerve should be sacrificed is complex
and should be considered on a case-by-case basis. When dealing with a malignant
tumor, some general guidelines can be followed, such as preservation of the nerve
when the tumor is not involving it. In contrast, sacrifice may be necessary if preser-
vation would lead to grossly positive margins or tumor spillage.16–18 This decision
can also be influenced by the options available postoperatively. For example, clini-
cians may err on the side of nerve sacrifice in cases of recurrent disease in which
surgical salvage is considered after failed radiation therapy (RT). In cases in which
the tumor is noted to abut the mastoid bone or the stylomastoid foramen, the patient
should be consented for a mastoidectomy to identify the nerve trunk more proxi-
mally. This procedure would expose a portion of uninvolved nerve for grafting if sac-
rifice is required at the level of the stylomastoid foramen. Besides nerve grafting
when the nerve is not working preoperatively or must be sacrificed, the surgeon
should be prepared for facial reanimation procedures, such as a gold-weight eyelid
implant and/or oral commissure facial sling suspension, to prevent corneal damage
and preserve oral competence. This outcome can be accomplished either at the
time of tumor resection or later, as an elective procedure. Larger tumors involving
the ear canal or middle ear require a temporal bone resection. Patients should be
counseled with respect to hearing loss if the ear canal is involved and requires
obliteration.

Surgery of the Submandibular and Sublingual Glands

Surgery for tumors of the submandibular and sublingual glands also has its own set
of special considerations. When submandibular malignancy is known a priori, clini-
cians must avoid shelling out the gland, and instead dissection should incorporate
the adjacent lymph nodes of a level I cervical lymphadenectomy. Surgical manage-
ment of a sublingual gland malignancy can be approached transorally. Obtaining
negative margins for the sublingual gland can be more challenging because it is
not encapsulated by the cervical fascia as is the submandibular gland, because of
its location abutting the lingual cortex of the mandible, and its close relationship
to the lingual nerve and Wharton duct of the submandibular gland. Often reposition
of this duct is necessary to avoid chronic obstruction and inflammation of the sub-
mandibular gland.
Surgical considerations for minor salivary glands vary depending on their location. In
general, the goal is to perform a wide local excision with clear margins confirmed intra-
operatively with frozen sections. The procedure is determined by the location and
extent of disease. Given the most common locations where tumors present, mainly
the palate and base of tongue, surgical defects can have a significant impact on
speech, swallowing, and velopharyngeal competence. Because of the low risk of
occult metastatic spread, a prophylactic neck dissection is often not warranted.
Smaller tumors of the parapharyngeal space may be approached transorally, whereas
larger ones require a transcervical/transparotid approach with or without a
mandibulotomy.19
1148 Rodriguez et al

Management of the Neck

The overall incidence of cervical lymph metastases is low for patients with malignant
salivary cancer, with about 16% of parotid carcinomas and 8% of submandibular/sub-
lingual malignancies presenting with lymphadenopathy. Surgical management of cer-
vical lymph nodes is usually performed in the presence of adenopathy or high-grade
histology. Because of the low risk of occult disease, a prophylactic neck dissection is
not often performed in other circumstances. Often the final diagnosis of the tumor de-
pends on permanent pathologic analysis after tumor resection. Thus, treatment of the
lymph nodes would be considered after the initial surgery. When the risk of occult dis-
ease is higher because of aggressive histology or high-grade features (such as
advanced T and N descriptors, positive resection margins, perineural invasion) and
the need for adjuvant treatment to the resected bed is indicated, management of
the N0 neck can be accomplished effectively in this setting.20,21

RADIATION THERAPY

Unresectable locally advanced tumors with involvement of the skull base or encasing
of the carotid vessels, and patients who decline surgery because of the requirement of
sacrifice of an intact facial nerve or who are otherwise challenged with medical comor-
bidities, could be treated with primary RT.22,23 Mendenhall and colleagues24 reported
on 160 patients who were treated with surgery and RT and compared outcomes with
64 patients treated with RT alone. The 10-year local control rate was 42% for RT alone
versus 90% for surgery plus RT. There are obvious selection biases favoring com-
bined modality treatment in these patients, because the patients receiving RT alone
tend to have more medical comorbidities that often preclude effective control of the
cancer by diminishing tolerance to treatment.
Small, well-localized, low-grade tumors excised with clear margins are best treated
with surgery alone.25–28 High-grade, advanced stage (T3/4), and inadequately excised
tumors treated with surgery alone have a poor prognosis compared with those treated
with adjuvant RT, with an overall local regional control rate of 82% compared with
59% for the group treated with surgery alone in several nonrandomized
studies.24–27,29–37 High tumor grade, advanced stage (T3/4), close or positive margins,
and nodal involvement24–28,32 are the pathologic factors most commonly associated
with a high risk of locoregional failure (30%–60%) after surgery. These patients are
the ones most likely to benefit from the addition of postoperative radiotherapy.
A recurring theme with most high-grade salivary gland cancers is that, despite
adequate long-term locoregional control rates of 80% to 90%, with surgery and RT,
the overall rate of distant failures is in the order of 30% to 50%. Effective systemic
therapy agents are likely to dramatically affect the survival outcome in these patients,
and several novel agents are being studied.
Evaluation of response following primary RT to indolent varieties of salivary gland
cancers, including adenoid cystic carcinomas, poses a problem. Radiological re-
sponses in these tumors are gradual, and often barely perceptible when annual interval
images are compared. In addition, histologic appearances of posttreatment biopsy-
detected residual tumor can be confusing, and do not necessarily represent active ma-
lignancy. Hence, patient management should take into consideration the presence of
symptoms suggesting disease recurrence/progression in these situations.

Neutron Radiotherapy
Fast neutrons are a form of radiation with high linear energy transfer (LET) that directly
damages DNA, independent of the presence of molecular oxygen. In comparison,
 Salivary Gland Malignancies 1149

low-LET radiation (X rays, electrons, protons) causes mostly indirect DNA damage,
mediated by an oxygen-dependent pathway. In addition, high-LET RT has significantly
higher relative biological effectiveness (RBE) for slowly cycling tumors.38 The RBE for
neutron radiotherapy (NRT) versus fractionated RT was 8.0, compared with 3 to 3.5 for
most late-responding normal tissues, with a therapeutic gain factor of 2 to 2.5. Dam-
age by NRT is not readily repairable and there is less variation of sensitivity through the
cell cycle.38 Therefore, NRT has a clear theoretic advantage compared with low-LET
radiation in tumor models that have 1 or more of the mechanisms discussed earlier
contributing to radioresistance to low-LET radiotherapy.
A prospective Radiation Therapy Oncology Group (RTOG)/Medical Research Coun-
cil (MRC) randomized controlled study39 compared low-LET radiotherapy (X rays and
electrons) with NRT for unresectable primary and recurrent salivary gland tumors. This
study could only enroll 32 patients over a 6-year period, which indicates the rarity of
the disease and the difficulty in conducting a prospective multicenter randomized
study. An interim analysis at 2 years on 25 eligible patients showed that the NRT group
achieved significantly better local control both at the primary site and in the lymph
nodes (67% vs 17%; P<.005) and there was a trend toward improved survival (62%
vs 25%; P 5 .1). Hence, the data monitoring committee deemed it unethical to offer
any treatment other than NRT for salivary gland cancers. With longer follow-up the sur-
vival curves merged and patterns of failure analysis showed that delayed distant me-
tastases accounted for most of the failures in the NRT arm, and local/regional failures
predominated in the low-LET arm. The toxicity was worse with NRT in this study, with
9 patients having at least 1 severe or greater complication compared with 4 patients
on the low-LET arm. There were no fatal events in either arm. In our experience at the
University of Washington, using modern RT techniques, severe toxicity is rare. A retro-
spective study of 148 patients reported by Douglas and colleagues40 showed only 6%
of patients developing grade 3 or 4 complications using the RTOG/European Organi-
sation for Research and Treatment of Cancer grading system. To date, NRT is
currently available only at our center, the University of Washington, creating an issue
with access and logistics.
Using conventional RT, selected institutional outcomes seem favorable. For
example, Pohar and colleagues29 reported a local control rate of 85% with primary
RT, and Wang and Goodman41 reported a 5-year actuarial local control of 100% for
9 unresectable parotid gland tumors treated with RT. However, comparison between
studies is hampered by methodological problems.
In the postoperative setting, multiple investigators24–27,42 showed good local control
rates of approximately 80% to 85% for patients treated with conventional RT. There
are also a few recently reported good outcomes with proton beam therapy43; howev-
er, longer follow-up will be important to interpret the results in the context of the nat-
ural history of salivary gland malignancies.

SYSTEMIC THERAPY

The use of systemic agents in salivary gland cancers is often considered among pa-
tients with recurrent/metastatic disease who are not deemed candidates for curative
intent therapy. The different histologic subtypes and the heterogeneous natural history
within these groups make the determination of the standard of care for systemic ther-
apy challenging. Table 1 outlines the most common of these histologic subtypes.
Several issues complicate the interpretation of the data:
1. Metastatic salivary tumors are rare. Consequently, it is difficult to conduct random-
ized studies.
1150 Rodriguez et al

Table 1
Relative frequencies of most common salivary gland carcinoma histologies

Histology Frequency (%)

Mucoepidermoid carcinoma 34
Adenoid cystic carcinoma 21
Adenocarcinoma 21
Acinic cell carcinoma 7
Other subtypes 13

Data from Spiro RH. Management of malignant tumors of the salivary glands. Oncology (Williston
Park) 1998;12(5):672.

2. Single or multi-institutional phase II trials almost always include all histologies, even
though they may have different biological behaviors and responses to therapy. The
small number of patients included in each histology may lead to misinterpretation of
drug activity.44,45
3. Subsets of salivary gland cancers, such as adenoid cystic and acinic cell carci-
nomas, frequently have an indolent growth pattern. The development of asymp-
tomatic, slowly growing pulmonary metastasis can be observed years after the
initial diagnosis, which makes it difficult to interpret the time to progression and sta-
ble disease rates described in the studies, particularly considering the lack of
randomization.
4. As a consequence of the neurotropism of some of these histologies, particularly
adenoid cystic carcinomas, patients may be very symptomatic (nerve palsies/pa-
ralysis). However, they may have disease that it is not easily measurable, particu-
larly in the setting of prior surgeries and radiotherapy, and consequently may be
excluded from clinical trials.

The Role of Conventional Chemotherapy

Several conventional chemotherapy agents have some activity in advanced salivary
gland tumors. These agents include cisplatin, paclitaxel, vinorelbine, epirubicin, mitox-
antrone, and methotrexate.46
In the mid-1990s investigators from Italy conducted a randomized phase II trial
comparing single-agent vinorelbine with the combination of vinorelbine and
cisplatin.47 Exemplifying the difficulties discussed earlier, this study randomized
only 36 patients between both arms. Multiple histologies were included but most pa-
tients had adenoid cystic carcinoma (n 5 22) or adenocarcinoma (n 5 9). Patients
treated with the combination had a higher response rate (45% vs 19%). More patients
were alive at 12 months with the combination (6 vs 1). The investigators concluded that
the combination of cisplatin and vinorelbine was superior to single-agent vinorelbine.
Investigators of the National Cancer Institute Clinical Trials Group conducted a
phase II study investigating the use of gemcitabine in combination with cisplatin (car-
boplatin was used when cisplatin was contraindicated).48 A total of 32 patients were
treated. Multiple histologies were included, with a predominance of adenoid cystic
carcinoma (n 5 10) and adenocarcinoma (n 5 8). The initial doublet included cisplatin
in 27 cases. Toxicities observed were those expected with these combinations.
Prespecified criteria required 13 responses to declare the combination as active; how-
ever, only 8 (24%) responses were observed.
Gilbert and colleagues44 published results from a phase II trial of single-agent pacli-
taxel in salivary gland cancers conducted through the Eastern Cooperative Oncology
 Salivary Gland Malignancies 1151

Group (ECOG). Fifty patients with salivary gland cancer were enrolled in this study,
with adenocarcinomas, mucoepidermoid carcinomas, and adenoid cystic carcinomas
representing the most common histologies. Note that patients were not required to
have evidence of disease progression to participate. There were 8 partial responses
to paclitaxel. None of the 14 patients with adenoid cystic carcinoma showed an objec-
tive response to systemic therapy, and the median overall survival of the cohort of pa-
tients was12.5 months.

Studies of Target Agents

The use of drugs directed to specific molecular abnormalities (target therapies) has
transformed the therapy for many malignancies. Because these agents are approved
for use in common tumors they have been tested in salivary gland tumors. Most of this
work has not been based in the characterization of activating mutations and many
remain in abstract format.
Overexpression of c-kit was identified in a high proportion of patients with adenoid
cystic carcinoma.49 Small case series suggested possible activity of imatinib,50 a drug
approved for the therapy for gastrointestinal stromal tumors because of its inhibition of
c-kit. Based on this observation, investigators from Canada conducted a phase II trial
of imatinib in patients with unresectable or metastatic adenoid cystic carcinoma
expressing c-kit.51 Sixteen patients were included and no responses were observed.
This lack of activity was confirmed by investigators from Israel.52 These disappointing
results are likely explained by the fact that c-kit activating mutations, not expression,
are the biomarkers that predict response, and are rarely present in adenoid cystic
carcinoma.53
Epidermal growth factor receptor (EGFR) is strongly expressed by immunohisto-
chemistry (IHC) in 24% of adenoid cystic carcinomas and 52% of mucoepidermoid
carcinomas.54 However, activating mutations are rarely present. Based on the IHC
data and the activity in other tumor types, several EGFR targeting agents were tested
in salivary gland malignancies. However, gefitinib55 and cetuximab56 were not associ-
ated with any objective responses. As an example of the challenges in the conduct
and interpretation of trials in this disease, the investigators of the cetuximab article
were encouraged by the proportion of patients achieving stable disease (80%) and
recommended further investigation of EGFR targeting.
HER2 overexpression by IHC and even amplification detected by fluorescence in
situ hybridization (FISH) can be found in a few cases of salivary malignancies. Salivary
duct carcinomas (SDCs) have the highest rates of both 31 IHC and FISH high polys-
omy or amplification.57 Investigators from Boston, Massachusetts, treated 13 patients
with SDC and HER2 expression by IHC58 with a combination of paclitaxel, carboplatin,
and trastuzumab. Eight patients received adjuvant therapy, which makes analysis of
efficacy challenging. Among the 5 patients who received palliative therapy, all had
31 IHC and amplification by FISH. One patient had a complete response, 2 patients
had a partial response, and 2 others had progressive disease. The investigators also
described that 2 of the patients treated for metastatic disease had received prior tras-
tuzumab as a single agent with prolonged disease control. The frequent finding of
HER2 amplification suggests that this may be a viable target in SDC.
Carcinoma ex pleomorphic adenomas, adenocarcinomas, and SDCs have been
observed to overexpress estrogen, progesterone, and androgen receptors, making
hormonal therapy an intriguing avenue for targeted therapeutics. However, data on
the success of this approach are limited to case reports.59–62
Based on 2 observed responses in patients with adenoid cystic carcinoma in a
phase I study of vorinostat, investigators from Detroit, Michigan, led a multicenter
1152 Rodriguez et al

phase II trial.63 Thirty patients with locally advanced or metastatic disease were
enrolled. The treatment was well tolerated. Only 2 patients had confirmed partial re-
sponses, both documented late during treatment, after 8 and 10 cycles. Twenty-six
patients had stable disease and 45% of those lasted 12 months. Overall, the median
progression-free survival was 11.4 months.

ONGOING RESEARCH AND FUTURE DIRECTIONS

Scientific inquiry and prospective clinical investigation among salivary gland malig-
nancies are challenging because of this disease’s infrequency and underlying hetero-
geneity in both histology and biological behavior. Notwithstanding, thoughtful clinical
trial design coupled with improvements in molecular profiling technology holds prom-
ise in being able to answer relevant clinical questions in the management of this dis-
ease, and may ultimately lead to improvements in therapeutic outcomes.

Locally Advanced Disease

Among salivary gland carcinomas treated with curative intent, the observed survival
improvement over the past 3 decades is widely attributed to the adoption of postop-
erative RT.27,42,64 RT is now considered a treatment standard despite the absence of
prospective clinical data supporting its use. In this population, patients with high-risk
features such as advanced T and N stages, and positive margins of resection,
continue to have suboptimal outcomes and represent a population in need of better
treatment options.
In resected squamous cell carcinomas of the head and neck with extracapsular
nodal extension and positive margins, benefit from the addition of systemic
platinum-based chemotherapy to postoperative radiation has been shown by 2 large
clinical trials jointly published in 2004.65,66 This intensified treatment strategy is
intuitively attractive among high-risk resected salivary gland malignancies. Single-
institution data with small numbers have reported encouraging results of platinum-
based chemoradiation in the postoperative setting.
The NRG/RTOG has recently completed a randomized phase II clinical trial (RTOG
1008 NCT01220583) comparing postoperative RT alone with postoperative cisplatin
concurrent with radiation. Note that the design of this study limited enrollment to
the most commonly occurring, highest risk resected salivary gland subtypes in an
effort to limit the biological heterogeneity inherent in this disease.
Also noteworthy is that RTOG 1008 was an unprecedented attempt to study this
rare malignancy in the cooperative group setting. Feasibility was one of its primary
end points, which was met with accrual exceeding projected rates. This adjuvant trial
also mandated tumor tissue submission and successfully established a prospectively
collected salivary gland cancer tissue repository to be used for correlative studies. The
success of its completion supports the cooperative groups as a viable setting for the
conduct of large clinical trials with the potential to answer critical management ques-
tions in rare diseases.

Recurrent/Metastatic Disease
There is currently no standard of care for the management of salivary gland malig-
nancies that are not amenable to curative intent treatment. As previously described,
the low incidence and heterogeneity of histologic and clinical behavior pose significant
challenges for clinical investigation.
In order to arrive at relevant and interpretable results, the design of clinical trials in
the metastatic setting has to accommodate these unique disease features. Modifying
 Salivary Gland Malignancies 1153

the study design to include patients with demonstrated progression of measurable

disease, or more aggressive disease subtypes, may enrich the patient population
for those in which drug activity may be more objectively determined.
Molecular profiling technology is evolving at a rapid pace and represents a tool with
tremendous potential to identify drug targets in this disease. Because of the absence
of US Food and Drug Administration–approved targeted drugs for this indication, the
role of the routine use of this technology in the clinical setting is unclear. Single-
institution reports using genomic profiling are emerging and suggest that these could
lead to appropriate drug selection and resultant clinical benefit to patients.67 Further
study of these techniques and their validation in predicting responses to novel agents
and/or identifying driver mutations are needed in order to facilitate rational drug selec-
tion for clinical investigation.
In addition, therapeutic approaches targeting immune evasion by malignant tu-
mors are gaining relevance in both solid and hematologic malignancies.68 Immuno-
therapy and immune checkpoint inhibitors are currently unexplored in salivary gland
malignancies. There are provocative preclinical and clinical data suggesting that his-
tone deacetylate inhibitors alter the biology of intratumoral regulatory T cells and
may increase tumor PD-L1 expression, and lead to improved responses to PD-1
checkpoint inhibitors in other epithelial malignancies.69–72 Vorinostat is a histone
deacetylase inhibitor that has been studied in adenoid cystic carcinomas.63 Our
group is about to embark on a clinical trial examining the combination of vorinostat
and pembrolizumab (a PD-1 inhibitor) in patients with recurrent metastatic salivary
gland carcinomas, with the aim of defining the activity and toxicity profiles of these
agents in this disease.

REFERENCES

1. Seifert G, Sobin LH. Histological typing of salivary gland tumors. WHO interna-
tional histological classification of tumors. 2nd edition. Berlin (Germany); New
York; Heidelberg (Germany): Springer-Verlag; 1991.
2. Speight PM, Barrett AW. Salivary gland tumors. Oral Dis 2002;8(5):229–40
[Review].
3. Theriault C, Fitzpatrick PJ. Malignant parotid tumors. Prognostic factors and op-
timum treatment. Am J Clin Oncol 1986;9(6):510–6.
4. Witten J, Hybert F, Hansen HS. Treatment of malignant tumors in the parotid
glands. Cancer 1990;65(11):2515–20.
5. Pedersen D, Overgaard J, Søgaard H, et al. Malignant parotid tumors in 110
consecutive patients: treatment results and prognosis. Laryngoscope 1992;
102(9):1064–9.
6. Zbären P, Schüpbach J, Nuyens M, et al. Carcinoma of the parotid gland. Am J
Surg 2003;186(1):57–62.
7. Thoeny HC. Imaging of salivary gland tumours. Cancer Imaging 2007;7:52–62
[Review].
8. Yousem DM, Kraut MA, Chalian AA. Major salivary gland imaging. Radiology
2000;216(1):19–29 [Review].
9. Som PM, Curtin HD. 3rd edition. Head and neck imaging, vol. 2. St Louis (MO):
Mosby; 1996. p. 877–912.
10. Keyes JW Jr, Harkness BA, Greven KM, et al. Salivary gland tumors: pretherapy
evaluation with PET. Radiology 1994;192(1):99–102.
11. Zurrida S, Alasio L, Tradati N, et al. Fine-needle aspiration of parotid masses.
Cancer 1993;72(8):2306–11.
1154 Rodriguez et al

12. Wong DS, Li GK. The role of fine-needle aspiration cytology in the management of
parotid tumors: a critical clinical appraisal. Head Neck 2000;22(5):469–73.
13. Hillel AD, Fee WE Jr. Evaluation of frozen section in parotid gland surgery. Arch
Otolaryngol 1983;109(4):230–2.
14. Wheelis RF, Yarington CT Jr. Tumors of the salivary glands. Comparison of frozen-
section diagnosis with final pathologic diagnosis. Arch Otolaryngol 1984;110(2):
76–7.
15. Seethala RR, LiVolsi VA, Baloch ZW. Relative accuracy of fine-needle aspiration
and frozen section in the diagnosis of lesions of the parotid gland. Head Neck
2005;27(3):217–23.
16. Scianna JM, Petruzzelli GJ. Contemporary management of tumors of the salivary
glands. Curr Oncol Rep 2007;9:134–8.
17. Day TA, Deveikis J, Gillespie MB, et al. Salivary gland neoplasms. Curr Treat Op-
tions Oncol 2004;5:11–26.
18. Bell RB, Dierks EJ, Homer L, et al. Management and outcome of patients with ma-
lignant salivary gland tumors. J Oral Maxillofac Surg 2005;63(7):917–28.
19. Olsen KD. Tumors and surgery of the parapharyngeal space. Laryngoscope
1994;104(5 Pt 2 Suppl 63):1–28 [Review].
20. Bhattacharyya N, Fried MP. Nodal metastasis in major salivary gland cancer: pre-
dictive factors and effects on survival. Arch Otolaryngol Head Neck Surg 2002;
128(8):904–8.
21. Stennert E, Kisner D, Jungehuelsing M, et al. High incidence of lymph node
metastasis in major salivary gland cancer. Arch Otolaryngol Head Neck Surg
2003;129(7):720–3.
22. Conley J, Baker DG. “Cancer of the salivary glands.” Cancer of the head and
neck. New York: Churchill Livingstone; 1981. p. 524–56.
23. Vikram B, Strong EW, Shah JP, et al. Radiation therapy in adenoid cystic carci-
noma. Int J Radiat Oncol Biol Phys 1984;10:221–3.
24. Mendenhall WM, Morris CG, Amdur RJ, et al. Radiotherapy alone or combined
with surgery for salivary gland carcinoma. Cancer 2005;103:2544–50.
25. Terhaard CHJ, Lubsen H, Rasch CRN, et al. The role of radiotherapy in the treat-
ment of malignant salivary gland tumors. Int J Radiat Oncol Biol Phys 2005;61:
103–11.
26. Chen AM, Granchi PJ, Garcia J, et al. Local-regional recurrence after sur-
gery without post-operative irradiation for carcinomas of the major salivary
glands: implications for adjuvant therapy. Int J Radiat Oncol Biol Phys
2007;67:982–7.
27. Armstrong JG, Harrison LB, Spiro RH, et al. Malignant tumors of major salivary
gland origin. A matched-pair analysis of the role of combined surgery and post-
operative radiotherapy. Arch Otolaryngol Head Neck Surg 1990;116(3):290–3.
28. Kokemueller H, Swennen G, Brueggemann N, et al. Epithelial malignancies of the
salivary glands: clinical experience of a single institution—a review. Int J Oral
Maxillofac Surg 2004;33:423–32.
29. Pohar S, Gay H, Rosenbaum P, et al. Malignant parotid tumors: presentation, clin-
ical/pathologic prognostic factors, and treatment outcomes. Int J Radiat Oncol
Biol Phys 2005;61:112–8.
30. Frankenthaler RA, Luna MA, Lee SS, et al. Prognostic variables in parotid gland
cancer. Arch Otolaryngol Head Neck Surg 1991;117:1251–6.
31. Miglianico L, Eschwege F, Marandas P, et al. Cervico-facial adenoid cystic carci-
noma: study of 102 cases. Influence of radiation therapy. Int J Radiat Oncol Biol
Phys 1987;13:673–8.
 Salivary Gland Malignancies 1155

32. Renehan AG, Gleave EN, Slevin NJ, et al. Clinico-pathological and treatment-
related factors influencing survival in parotid cancer. Br J Cancer 1999;80:
1296–300.
33. Chen AM, Bucci MK, Weinberg V, et al. Adenoid cystic carcinoma of the head
and neck treated by surgery with or without postoperative radiation therapy:
prognostic features of recurrence. Int J Radiat Oncol Biol Phys 2006;66:152–9.
34. North CA, Lee DJ, Piantadosi S, et al. Carcinoma of the major salivary glands
treated by surgery or surgery plus postoperative radiotherapy. Int J Radiat Oncol
Biol Phys 1990;18:1319–26.
35. Tran L, Sadeghi A, Hanson D, et al. Major salivary gland tumors: treatment results
and prognostic factors. Laryngoscope 1986;96:1139–44.
36. Reddy SP, Marks JE. Treatment of locally advanced, high-grade, malignant tu-
mors of major salivary glands. Laryngoscope 1988;98:450–4.
37. Bissett R, Fitzpatrick P. Malignant submandibular gland tumors. A review of 91
patients. Am J Clin Oncol 1988;11:46–51.
38. Hall EJ, Giaccia AJ. Radiobiology for the radiologist. 6th edition. Philadelphia:
Lippincott Wilkins & Williams; 2006.
39. Laramore GE, Krall JM, Griffin TW, et al. Neutron versus photon irradiation for un-
resectable salivary gland tumors: final report of an RTOG-MRC randomized trial.
Int J Radiat Oncol Biol Phys 1993;27:235–40.
40. Douglas JD, Silbergeld DL, Laramore GE. Gamma knife stereotactic radiosurgi-
cal boost for patients treated primarily with neutron radiotherapy for salivary
gland neoplasms. Stereotact Funct Neurosurg 2004;82:84–9.
41. Wang CC, Goodman M. Photon irradiation of unresectable carcinomas of salivary
glands. Int J Radiat Oncol Biol Phys 1991;21:569–76.
42. Garden AS, el-Naggar AK, Morrison WH, et al. Postoperative radiotherapy for
malignant tumors of the parotid gland. Int J Radiat Oncol Biol Phys 1997;37(1):
79–85.
43. Frank SJ, Cox JD, Gillin M, et al. Multifield optimization intensity modulated proton
therapy for head and neck tumors: a translation to practice. Int J Radiat Oncol
Biol Phys 2014;89(4):846–53.
44. Gilbert J, Li Y, Pinto HA, et al. Phase II trial of Taxol in salivary gland malignancies
(E1394): a trial of the Eastern Cooperative Oncology Group. Head Neck 2006;28:
197–204.
45. Till BG, Martins RG. Response to paclitaxel in adenoid cystic carcinoma of the
salivary glands. Head Neck 2008;30:810–4.
46. Laurie SA, Licitra L. Systemic therapy in the palliative management of advanced
salivary gland cancers. J Clin Oncol 2008;24:2673–8.
47. Airoldi M, Pedani F, Succo G, et al. Phase II randomized trial comparing vinorel-
bine versus vinorelbine plus cisplatin in patients with recurrent salivary gland ma-
lignancies. Cancer 2001;91:541–7.
48. Laurie SA, Siu LL, Winquist E, et al. A phase II study of platinum and gemcitabine
in patients with advanced salivary gland cancer. Cancer 2010;116:362–8.
49. Jeng YM, Lin CY, Hsu HC. Expression of c-kit is associated with certain subtypes
of salivary gland carcinoma. Cancer Lett 2000;154:107111.
50. Alcebo JC, Fabrega JM, Arosena JR, et al. Imatinib mesylate as treatment for
adenoid cystic carcinoma of the salivary glands; report of two successfully
treated cases. Head Neck 2004;26:829–31.
51. Hotte SJ, Winquist EW, Lamont E, et al. Imatinib mesylate in patients with adenoid
cystic cancers of the salivary gland expressing c-kit: a Princess Margaret Hospi-
tal phase II consortium study. J Clin Oncol 2005;23:585–90.
1156 Rodriguez et al

52. Pfeffer MR, Talmi Y, Catane R, et al. Phase II study of imatinib for advanced
adenoid cystic carcinoma of the head and neck salivary glands. Oral Oncol
2007;43:33–6.
53. Wetterskog D, Wilkerson PM, Rodrigues DN, et al. Mutation profiling of adenoid
cystic carcinomas from multiple anatomical sites identifies mutations in the
RAS pathway, but no KIT mutations. Histopathology 2013;62:543–50.
54. Clauditz TS, Gontarewicz A, Lebok P, et al. Epidermal growth factor receptor
(EGFR) in salivary gland carcinomas: potential as therapeutic target. Oral Oncol
2012;48:991–6.
55. Jakob JA, Kies MS, Glisson BS, et al. Phase II study of gefitinib in patients with
advanced salivary gland cancers. Head Neck 2015;37(5):644–9.
56. Locati LD, Bossi P, Perrone F, et al. Cetuximab in recurrent and/or metastatic sali-
vary gland carcinoma: a phase II study. Oral Oncol 2009;45:574–8.
57. Etti T, Stiegler C, Zeitler K, et al. EGFR, HER2, surviving, and loss of pSTAT3 char-
acterize high-grade malignancy in salivary gland cancer with impact on prog-
nosis. Hum Pathol 2012;43:921–31.
58. Limaye SA, Posner MR, Krane JF. Trastuzumab for the treatment of salivary duct
carcinoma. Oncologist 2013;18:294–300.
59. Nasser SM, Faquin WC, Dayal Y. Expression of androgen, estrogen, and proges-
terone receptors in salivary gland tumors. Frequent expression of androgen re-
ceptor in a subset of malignant salivary gland tumors. Am J Clin Pathol 2003;
119(6):801–6.
60. Jaspers HC, Verbist BM, Schoffelen R, et al. Androgen receptor-positive salivary
duct carcinoma: a disease entity with promising new treatment options. J Clin On-
col 2011;29(16):e473–6.
61. Campos-Gómez S, Flores-Arredondo JH, Dorantes-Heredia R, et al. Case report:
anti-hormonal therapy in the treatment of ductal carcinoma of the parotid gland.
BMC Cancer 2014;14:701.
62. Elkin AD, Jacobs CD. Tamoxifen for salivary gland adenoid cystic carcinoma:
report of two cases. J Cancer Res Clin Oncol 2008;134(10):1151–3.
63. Goncalves PH, Kummar S, Siu LL, et al. A phase II study of suberoylanilide
hydroxamic acid (SAHA) in subjects with locally advanced, recurrent, or met-
astatic adenoid cystic carcinoma. J Clin Oncol 2013;31, 203(suppl):[abstr:
6045].
64. Terhaard CH, Lubsen H, Van der Tweel I, et al. Salivary gland carcinoma: inde-
pendent prognostic factors for locoregional control, distant metastases, and over-
all survival: results of the Dutch Head and Neck Oncology Cooperative Group.
Head Neck 2004;26(8):681–92 [discussion: 692–3].
65. Bernier J, Domenge C, Ozsahin M, et al. Postoperative irradiation with or without
concomitant chemotherapy for locally advanced head and neck cancer. N Engl J
Med 2004;350(19):1945–52.
66. Cooper JS, Pajak TF, Forastiere AA, et al. Postoperative concurrent radiotherapy
and chemotherapy for high-risk squamous-cell carcinoma of the head and neck.
N Engl J Med 2004;350(19):1937–44.
67. Chintakuntlawar AV, Okuno SH, Andress Rowe Price K. Genomic testing may
offer therapeutic opportunity in salivary gland cancers. J Clin Oncol 2015;
33(Suppl) [abstr: e17053].
68. Disis ML. Immune regulation of cancer. J Clin Oncol 2010;28(29):4531–8.
69. Christiansen AJ, West A, Banks KM, et al. Eradication of solid tumors using his-
tone deacetylase inhibitors combined with immune-stimulating antibodies. Proc
Natl Acad Sci U S A 2011;108(10):4141–6.
 Salivary Gland Malignancies 1157

70. Shen L, Ciesielski M, Ramakrishnan S, et al. Class I histone deacetylase inhibitor

entinostat suppresses regulatory T cells and enhances immunotherapies in renal
and prostate cancer models. PLoS One 2012;7(1):e30815.
71. Wrangle J, Wang W, Koch A, et al. Alterations of immune response of non-small
cell lung cancer with azacytidine. Oncotarget 2013;4(11):2067–79.
72. Yang H, Bueso-Ramos C, DiNardo C, et al. Expression of PD-L1, PD-L2, PD-1
and CTLA4 in myelodysplastic syndromes is enhanced by treatment with hypo-
methylating agents. Leukemia 2014;28(6):1280–8.