Current Treatment Options in Oncology (2012) 13:58–70

DOI 10.1007/s11864-011-0174-0

Head and Neck Cancer (T Day, Section Editor)

Recurrent Salivary Gland

Cancer
M. Boyd Gillespie, MD, MSc1,3,*
W. Greer Albergotti, BS1
David W. Eisele, MD2

Address
1
Medical University of South Carolina, Charleston, USA
2
University of California, San Francisco, USA
3,*
Department of Otolaryngology, Head and Neck Surgery, 135 Rutledge
Avenue MSC 550, Charleston, SC 29425-5500, USA
Email: gillesmb@musc.edu

Pulished online: 4 January 2012

* Springer Science+Business Media, LLC 2011

Keywords Salivary gland neoplasm I Salivary gland cancer I Salivary gland tumor I Salivary gland surgery I
Recurrent salivary gland cancer I Recurrent salivary gland neoplasm

Opinion statement
Salivary gland cancer is the most diverse cancer in the body consisting of up to 24 dif-
ferent pathologic subtypes. Although these cancers arise within a common group of
glands in the head and neck region, these diverse cancers differ substantially in clinical
behavior. As a result, salivary cancers are often categorized as low, intermediate, or
high-risk for recurrence and metastasis based on histopathologic subtype and tumor
stage. Appropriate risk classification of a given salivary tumor provides a useful guide
to the physicians who determine the appropriate treatment regimen. Low-risk tumors
can be treated successfully with surgery alone, whereas intermediate and high-risk
tumors often require multimodality therapy. Recurrent salivary cancer should be con-
sidered high-risk by definition, especially if previously treated with appropriate therapy,
and therefore requires aggressive multimodality therapy in order to achieve adequate local
control and disease-free survival.

Introduction
Salivary gland cancers are relatively rare accounting for
only 20% of salivary tumors and 5% of head and neck
malignancies [1••]. The incidence rate is estimated to
be 3 new cases per 100,000 people per year world-
wide, with an average of 2,500 new cases per year in
the United States [2••]. The parotid gland is the most
common site for salivary cancer; however, only 20% to
25% of parotid tumors are malignant compared to
40% of submandibular tumors, 50% of minor salivary
gland tumors, and 90% of sublingual tumors [2••].
Salivary gland cancer comprises the most heterogeneous
group of cancers in the body with up to 24 different
cancer subtypes. The relative rarity and significant
diversity of these cancers prevents broad application of
standardized therapy, and therefore requires astute
multi-disciplinary cooperation and decision making
 Recurrent Salivary Gland Cancer Gillespie et al. 59

in order to individualize the best course of care for
a given patient. The risk of locoregional and distal
recurrences of salivary cancer range from 15% to
80% at 5 years but is strongly influenced by the
underlying tumor type and stage. Patients with re-
current salivary cancer can be successfully salvaged
for cure with aggressive multimodality therapy in
many cases, or effectively palliated to improve
locoregional control and provide symptom relief
in the event of distant disease. The role of chemo-
therapy and biologic agents for salivary gland can-
cers has yet to be defined.

Prevention of recurrent salivary cancer by identifying

the high-risk tumor
Recurrent salivary cancer is preventable in many cases if the primary cancer
is treated with the appropriate level of care. Choosing the appropriate ther-
apy requires a determination of whether a given tumor is likely to be a high,
intermediate, or low risk for recurrence and/or metastasis. Risk determina-
tion depends on a variety of factors including patient symptoms, physical
signs, imaging results, histopathological type and features, and molecular
biomarkers.
& Patient evaluation. Most patients with salivary cancer present with
an asymptomatic, slowly enlarging mass in the region of a salivary
gland. The fact that up to 75% of salivary masses are benign, and
most are asymptomatic, may lead to misassumptions on the part of
both the patient and clinician which result in delay of diagnosis and
inappropriate care. Surgical removal of a salivary mass prior to
comprehensive evaluation may greatly increase the risk for persistent
and recurrent salivary cancer.
Although not specific for salivary cancer, pain in a salivary mass is
atypical and should raise the possibility of salivary malignancy [3].
Additional features worrisome for salivary malignancy include rapid
growth, fixation or tethering of the overlying skin, skin or mucosal
ulceration, palpable adenopathy, facial nerve paresis or paralysis,
hypoesthesia of a trigeminal branch, and trismus. Since most salivary
cancers present with none of these features, the best approach is to
assume that a salivary mass is malignant until proven otherwise. This
is especially true in the pediatric population where up to 50% of
primary salivary neoplasms are malignant. Salivary cancers which
invade local structures and nerves should be considered high-risk for
recurrence and metastasis and therefore treated accordingly
regardless of underlying histopathology.
& Imaging. There are several advantages to imaging salivary masses
prior to treatment. Imaging helps confirm that the mass originates
from the salivary gland and is not due to adjacent pathology (eg.
lipoma, adnexal mass, lymph node). Pre-treatment scans assist
operative planning by defining the relationship between the mass
and vital structures nearby such as cranial nerves and vessels. In
addition, imaging can detect possible signs of malignancy not readily
60 Head and Neck Cancer (T Day, Section Editor)

detectable by physical examination such as an ill-defined tumor

border; invasion of surrounding structures (eg. ear canal, muscle,
bone); enhancement or thickening of the facial and trigeminal
nerves; the presence of multifocal disease; and cervical adenopathy.
Cervical ultrasound is sufficient to characterize most superficial
tumors of the parotid and submandibular gland. Advantages of
ultrasound include its ability to describe tumor size and border
regularity; assess the pattern of tumor vascularity; and detect multi-
focal tumor and adjacent lymphadenopathy without exposing the
patient to ionizing radiation. In addition, ultrasound is relatively
inexpensive, available in many surgical offices, and can help guide
accurate fine needle localization for tissue biopsy. Ultrasound,
however, is unable to adequately visualize deep lobe parotid and
minor salivary tumors due to the echo artifact of the mandible, and
does not allow visualization of the facial nerve and canal. If a
malignant process is suspected, magnetic resonance imaging (MRI)
with gadolinium is preferred due to its superior salivary tissue
resolution, assessment of marrow spaces, and its ability to detect
cranial nerve enhancement or thickening [4]. Computed tomography
may be of value if MRI is unavailable, or in addition to MRI if the
tumor is fixed to the temporal bone or mandible due to its superior
detection of bony erosion. Fluorodeoxyglucose-positron emission
tomography (FDG-PET) is rarely indicated in the primary evaluation of
salivary tumors due to expense, lack of supporting evidence, and a high
rate of false positives with benign salivary tumors such as pleomorphic
adenoma and Warthin’s tumor [5]. No imaging technique can reliably
differentiate between benign and malignant salivary tumors, and
therefore radiographic findings alone should not be used as a reason
not to treat a salivary mass. If malignancy is suspected based on history,
examination, and/or fine needle aspiration biopsy, additional imaging
of the chest with either plain film or CT is recommended to assess for
distant disease [6].
& Tissue Biopsy. Fine needle aspiration (FNA) biopsy of salivary
masses provides advantages that guide tumor evaluation, staging,
and pre-treatment planning. Although the diversity of tumor types
creates inaccuracies in precise histopathologic designation, an expe-
rienced head and neck cytopathologist is often able to determine
whether the mass is likely to be benign or malignant based on cel-
lular density, morphology, uniformity, and the presence of mitotic
figures for an overall accuracy of 80% in determining benign versus
malignant disease [7•]. Although an FNA negative for malignancy
does not eliminate the possibility of cancer, and should not be used
as the sole reason not to treat, a biopsy positive for malignancy
greatly increases the true likelihood of cancer. Armed with this in-
formation, the surgeon can plan an appropriate surgery of adequate
length, and counsel the patient concerning the need for neck dis-
section, facial nerve sacrifice, and reconstructive options. The likely
 Recurrent Salivary Gland Cancer Gillespie et al. 61

aggressiveness of the tumor can be assessed if FNA allows for iden-

tification of a probable histopathology. Low-grade cancers generally
have less than a 15% incidence of spread to regional lymph nodes
and include acinic cell carcinoma, low grade mucoepidermoid car-
cinoma, epithelial-myoepithelial carcinoma, basal cell adenocarci-
noma, oncocytic carcinoma, and low-grade polymorphous
adenocarcinoma. Intermediate-grade cancers such as mucoepidermoid
carcinoma, adenoid cystic carcinoma, and carcinoma ex pleomor-
phic have a moderate 15–30% incidence of cervical lymph node
involvement. High-grade cancers including salivary duct carcino-
ma and adenocarcinomas have a metastasis rate 930% and often
have obvious cervical adenopathy at the time of presentation.
& Multidisciplinary Tumor Board. The likelihood that a salivary mass
is malignant can be predicted with 80% probability following a
comprehensive history and examination, appropriate imaging, and
FNA biopsy [8]. Case presentation at a multidisciplinary head and
neck tumor board is recommended prior to treatment for all salivary
tumors that have a high probability for malignancy. The tumor
board team should assign an accurate clinical stage prior to treat-
ment. The T staging of salivary malignancy is unique with T1 (G2 cm)
and T2 (2–4 cm) tumors based on size alone, and more advanced T3
(94 cm. and/or having extraparenchymal extension), T4a (invades
skin, mandible, ear canal, and/or facial nerve), and T4b (invades
skull base and/or pterygoid plates and/or encases carotid artery)
stages dependent on tumor extent. The nodal, metastasis, and group
staging are the same as squamous cell carcinoma of the head and
neck [9]. In addition to staging, the tumor board ensures that current
National Comprehensive Cancer Network (NCCN) guidelines are met
with regard to tumor treatment; assists with surgical planning; and
helps to identify high risk patients. High risk patients (eg. T3/4 tumors;
intermediate to high grade histopathology) will benefit from preoper-
ative evaluation from a radiation oncologist and a dental provider if
postoperative radiotherapy is likely; a reconstructive surgeon if facial
nerve sacrifice or large soft tissue or composite defect is planned; or a
neuro-otologic surgeon if temporal bone resection is required.

Prevention of recurrent salivary cancer by appropriate initial

therapy

& Surgery. Complete surgical excision with negative margins and

without tumor spillage continues to be the primary therapy of choice
for all salivary tumors. The likely extent of surgery can often be
determined preoperatively if the tumor is classified as malignant by
FNA and staged with physical examination and appropriate imaging
(Tables 1 and 2). If preoperative FNA is indeterminate or benign, the
62 Head and Neck Cancer (T Day, Section Editor)
Table 1. Management of primary salivary gland malignancy
Risk Category
Low
• Stage T1, N0 (any pathology)
• Acinic cell, Myoepithelial,
Epithelial-Myoepithelial, Low
grade MEC, Polymorphous low
grade AC, Basal cell AC.
• Marker negative
Moderate
• T2 and/or N1 (any pathology)
• Intermediate or high grade MEC,
Adenoid cystic carcinoma,
Carcinoma ex pleomorphic
• Marker positive
High
• T3/4, N2/3 (any pathology)
• Salivary duct carcinoma, AC NOS,
Undifferentiated carcinoma
• Marker positive
AC adenocarcinoma; MEC mucoepidermoid carcinoma
surgeon should plan to fully excise the mass with a negative margin
but be prepared to extend the surgery based on intraoperative
findings. Findings such nerve encasement, extensive soft tissue
invasion, or adenopathy should alert the surgery to the possibility of
malignancy. Frozen section analysis of the mass can be done if there
is no risk of spillage in order to help determine if nerve sacrifice and/
or neck dissection is indicated.
& Surgical Pathology. The need for adjuvant therapy is largely dependent
on the final pathology of the surgical specimen. Pathological findings
that suggest the need for adjuvant therapy include:
& Tumor grade- intermediate (intermediate grade mucoepidermoid car-
cinoma, adenoid cystic carcinoma, carcinoma ex pleomorphic) or high-
grade (salivary duct carcinoma, adenocarcinoma) that are T1 or greater.
& Tumor size- T3 or greater for any grade tumor
Surgery Radiation
Parotid Partial parotidectomy with VII Not indicated unless
preservation; level 2 dissection • G1 mm margin
SMG Gland excision with level Ib dissection • Positive margin without ability to
re-resect.
Minor Wide local excision only ± local flap; • Tumor spillage
skin graft • Perineural spread
Parotid Subtotal versus total parotidectomy ≥60 Gy to primary and involved
sparing VII if possible; Selective neck ≥44 Gy to uninvolved neck
dissection of levels 1b, 2 a/b, 3; basins; Consider concurrent
consider level 5 if ear canal or chemotherapy if close or positive
postauricular involvement margin or tumor spillage
SMG Wide gland excision with level 1b
(including facial nodes), 2a/b, and
3 dissection
Minor Wide local excision/ composite
resection ± local flap, skin graft,
free tissue transfer, or obturator
Parotid Total versus radical parotidectomy Consider concurrent chemoradiation
with selective neck dissection therapy using platin-based regimen.
(1b, 2a/b, 3, 5); temporal bone
dissection; ± facial nerve grafting
v. static suspension; ± free tissue
transfer
SMG Wide gland excision with level 1b
(including facial nodes), 2a/b, and 3
dissection; ± regional versus free
tissue flap
Minor Same as above
 Recurrent Salivary Gland Cancer Gillespie et al. 63

Table 2. Management of recurrent salivary gland malignancy

Classification Site Surgery Radiation Chemotherapy
Resectable Parotid Radical parotidectomy with VII Radiation or Reirradiation; Cisplatin, CAP,
(PET CT; MRI) sacrifice; ± temporal bone/ Consider neutron beam if Cetuximab
mandible resection; Radical or available; Consider prophy
MRND; facial nerve grafting lactic stenting of carotid
versus static sling; ± regional
or free tissue transfer
Submandibular or Composite mandibulectomy/ As above As Above
Minor Salivary maxillectomy; Radical or
MRND; ± regional or free
tissue transfer
Unresectable Locoregional NA As above As Above
(PET CT; MRI) (Stage T4b)
Distant Metastasis NA Consider palliative radiation if Consider palliative
severe local pain/ tumor load chemo or clinical
trial
MRND modified radical neck dissection

& Extraparenchymal extension

& Neural/ perineural invasion
& Multicentric tumor
& Lymph node metastasis
& Lymphatic/ vascular invasion
& Close (≤1 mm) or positive margins.
& High-Risk Molecular Markers. Given the limited correlation
between tumor grade and biologic behavior, a growing body
of research has focused on whether molecular tumor markers have
prognostic significance. While no salivary tumor marker is frequently
used in clinical practice, the following are among the most-studied
and/or most promising:
& Ki-67. Ki-67 is a cellular protein which is involved in cellular tran-
scription and has been used as a marker of cell proliferation. It has
been shown repeatedly that mucoepidermoid carcinomas and ade-
noid cystic carcinomas which express a higher level of Ki-67 have a
worse 5-year survival which has been validated in multivariate analysis
[10–12]. However, one recent study failed to show that Ki-67 was an
independent prognostic indicator in mucoepidermoid carcinoma when
newer tumor markers such as MECT1-MAML2 (see below) were in-
cluded in the analysis [13]. Various cutoffs for expression have been
employed with 5% expression being the most frequently employed.
At this point, Ki-67 staining may be considered a useful tool in the
evaluation of the aggressiveness of some salivary gland neoplasms.
& p53. p53 is a tumor suppressor protein which helps to control the
cell cycle whose mutation is widely implicated in a variety of human
neoplasms. While it is the most-studied of the salivary gland tumor
markers, it has not been consistently found to be altered in salivary
64 Head and Neck Cancer (T Day, Section Editor)

malignancies with staining ratios varying greatly among studies.

Although p53 accumulation has been shown in some studies to be
an independent prognostic indicator of 5-year survival in mucoepi-
dermoid carcinoma [13], several other studies have been unable to
corroborate this finding [14–16]. There have been similar incon-
gruent findings in adenoid cystic carcinoma and carcinoma ex
pleomorphic adenoma. At this point, there is no role for the use of
p53 in the prognosis of salivary gland neoplasms.
& EGFR. Epidermal growth factor (EGF) is expressed in the salivary
gland where it plays a vital role in the normal development and
differentiation of the acina and ducts. This is of interest due to the
availability of an anti-EGF receptor antibody therapy (cetuximab)
that could be employed against these tumors. The expression of EGF
receptor (EGFR) in salivary cancer varies by histopathology with
salivary duct carcinoma demonstrating the highest rate of expression
(92%), followed by ACC (25–85%), and then mucoepidermoid
carcinoma (25%). However the prognostic significance of EGFR
expression in salivary cancer has not been elucidated [2••].
& HER2. HER2, also known as erbB2, is a member of the same
transmembrane tyrosine kinase receptor family as EGFR. HER2
expression has been examined in salivary duct carcinoma which
histologically resembles breast carcinoma which frequently expresses
HER2. However, only 17 of 66 (26%) tumors tested displayed
significant HER2 expression [17•]. The clinical implications of this
expression have yet to be established.
& MECT1-MAML2. Mucoepeidermoid carcinoma translocated 1–
mastermind like (MECT1-MAML2 also called CRTC1-MAML2) is a
fusion gene from the t(11:19) which is specific to mucoepidermoid
carcinomas and which is thought to provide an improved prognosis. It
has been found to be expressed on 38–60% of MECs [13, 18] and its
expression in MEC tumors been shown to be an independent positive
prognostic indicator, showing generally less aggressive behavior and
better overall survival [13, 19, 20]. Additional studies have found that
this tumor fusion gene is generally expressed in low- and intermediate-
grade MEC but can be found in high grade tumors as well. Even within
the histologically high-grade group, the expression of this gene fusion
creates a less aggressive tumor [18]. However, improved long-term
survival in prospective studies has thus far not been corroborated and
while this is a promising tumor marker its use cannot yet be
advocated in clinical practice.
& p27. p27 is a protein involved in the regulation of the cell cycle
whose decreased expression has been shown to be an independent
negative prognostic factor in overall and disease-free survival in
mucoepidermoid carcinoma which has thus far been corroborated in
a few small studies [13, 21].
& Radiation Therapy. Adjuvant radiation therapy is indicated for
intermediate to high risk disease (Table 2) [1••, 22••]. In a
 Recurrent Salivary Gland Cancer Gillespie et al. 65

meta-analysis of 19 studies of post-operative radiotherapy for

salivary cancer, patients with advanced T 3/4 disease, node pos-
itive disease, or high-grade histopathology demonstrated 3 times
reduced odds of death compared to patients who did not receive
radiation [1••]. The standard and most widely available form is
photon or photon/electron based radiotherapy delivered to a
total dose ≥60 Gy (1.8–2.0 Gy/fraction) with an additional 44–
64 Gy (1.6–2.0 Gy/fraction) to uninvolved nodal groups. Inten-
sity-modulated radiotherapy (IMRT) has allowed sparing of crit-
ical structures within the field such as the spinal cord, inner ear,
and adjacent salivary tissue [22••]. Radiotherapy or concurrent
chemoradiotherapy may be used as
primary therapy in select cases that are deemed to be surgically
unresectable due to advanced stage (T4b), significant medical
comorbidities, or patient refusal to undergo surgical resection.
Adjuvant radiotherapy can successfully control disease in cases where the
postoperative pathology reveals close or microscopically positive
margins preventing the need for immediate re-resection [8]. Re-resection
should be considered if gross tumor remains in the field. Grade 3
radiotherapy-related acute toxicity of the skin and mucosa occur in 25%
of patients, but late toxicity of the skin and soft tissues are rarely observed
[23]. Neutron beam radiotherapy has demonstrated improved
locoregional control over photon therapy for high-grade tumors in both
randomized and non-randomized series, however no long-term survival
advantage was observed in the neutron cohorts due to the high rate of
distant metastasis in these patients [1••]. In addition, neutron therapy is
expensive, not widely available, and significantly more toxic to
surrounding tissues which results in greater risk of complications when
compared to photon and photon/electron based radiotherapy [22••].
& Chemotherapy. Chemotherapy as a single modality is generally
ineffective in the treatment of salivary cancer [24••]. As a result,
chemotherapy is not indicated as a routine adjuvant therapy for
salivary cancer except in select circumstances. However, in a retro-
spective series of 255 patients with major salivary malignancy, 57
patients (22%) developed distant metastasis underscoring the need
for better systemic therapy to address this problem [25]. The lungs
were the most common metastatic site (65%) and adenoid cystic
carcinoma the most frequent histological type involved [25].
Determination of chemotherapy efficacy with clinical trials has been
challenging due to the small number of salivary cancers, the diverse
histopathology, and the lack of routine analysis of molecular
markers. Chemotherapy is sometimes given in concurrent fashion
with adjuvant radiotherapy in select high grade tumors such as
salivary duct carcinoma, adenocarcinoma NOS, and solid-type
adenoid cystic carcinoma due to the higher than average risk
of distant metastatic spread. Other indications for concurrent
chemoradiotherapy include close or positive margins and/or tumor
66 Head and Neck Cancer (T Day, Section Editor)

spillage of an intermediate or high risk tumor (Table 2), unresectable

stage T4b disease, patient comorbidity preventing surgical resection,
or patient refusal to undergo surgery. Cisplatin is first-line therapy
when considering adjuvant chemoradiation therapy since it is the
most extensively studied chemotherapy demonstrating effect across a
broad range of salivary tumor types, and is a known to augment the
local effect of radiation therapy [2••].

Management of recurrent salivary gland cancer

& History and Examination. A certain percentage of salivary gland

cancers will recur despite appropriate initial management. Advanced
high-grade salivary cancers are especially prone to recurrence with an
overall 5 year survival rate of only 35% [1••]. Ongoing follow-up is
essential if recurrent disease is to be detected at a stage where it can still
be successfully treated. Patients routinely receive a comprehensive head
and neck examination at 4 month intervals for the first 2 years, and
every 6 months until year 5. Given the prolonged latency of many types
of salivary malignancy (ex. adenoid cystic carcinoma), prolonged
follow-up beyond five years is indicated in many cases. Patients should
be educated about potential symptoms and signs of recurrence such as
neck or facial swelling, pain, nerve weakness or numbness, change of
voice, swallowing difficulty, or trismus. Physical examination of
patients with recurrent tumors will often reveal signs of advanced
disease including large mass, skin fixation, and cranial neuropathy. If
the patient was originally treated elsewhere, efforts should be made to
obtain the patient’s medical record, previous scans, and pathology
slides for review. A previous study found that the diagnosis was changed
in 7% of outside pathology when reviewed at a high volume head and
neck cancer center [26•]
& Imaging. Recurrent salivary cancer may be difficult to diagnosis on
physical examination alone due to distortion of the anatomy from
previous treatment or flaps, and may be asymptomatic at its earliest
stages. Although there is no standard for the use of imaging in
follow-up, a good rule of thumb would be a follow-up scan,
preferably MRI, at 12 months and 24 months post-treatment since
most head and neck cancers recur within the first 2 years. Follow-up
scans allow a new baseline anatomy to be established by which to
compare any future changes. If a suspected recurrence is visualized,
the scan should be followed by an image-guide biopsy of the
suspicious area. It is advisable to follow patients with high risk
tumors (eg. adenoid cystic carcinoma, high grade mucoepidermoid
carcinoma, salivary duct carcinoma, adenocarcinoma) with yearly
plain films of the chest since the lungs are the most likely site for
distant metastasis. Fluorodeoxyglucose positron emission tomography
 Recurrent Salivary Gland Cancer Gillespie et al. 67

with computed tomography (PET-CT) is generally not used in the

primary evaluation of salivary masses, or prior to biopsy suspected
recurrence, due to poor specificity (increased likelihood of false
positives) with many benign salivary masses (eg. pleomorphic adenoma;
Warthin tumor; oncocytoma) and areas of inflammation demonstrating
increased uptake [5]. PET-CT is often of value to accurately stage the
disease in the event of a biopsy-proven recurrence. PET-CT can assist
locoregional surgical planning by identifying the local extent of disease
and nodal basins that need to be addressed while ruling out the presence
of distant metastasis.
& Tumor Board Evaluation. Unlike primary salivary cancer, all recurrent
salivary cancers are high risk tumors that require extensive multi-
modality therapy. As a result, the need to present these cases to a
multidisciplinary head and neck tumor board cannot be over
emphasized. The main focus of discussion is whether the patient is a
candidate for surgery with curative intent. Poor surgical candidates
include patients that are likely to have gross tumor still present after
resection, or who have carotid artery encasement, intracranial disease,
poor performance status, multiple medical comorbidities, and/or
distant metastasis. Palliative radiation or reirradiation with or without
chemotherapy can be considered if the patient has significant
locoregional pain or morbidity from tumor growth. Physicians
should provide the patient and family with information
concerning potential clinical trials for which the patient may be
eligible by searching the National Institute of Health website
www.clinicaltrials.gov. The option of ongoing pain management
and hospice care should also be discussed with all patients who
are not eligible for curative therapy.
& Surgery. Surgery for recurrent salivary cancer requires an aggressive
approach that seeks tumor extirpation at the expense of functional
preservation. Depending on the location of the recurrent tumor,
attempts to preserve functionally important structures such as skin,
bone, cranial nerves, and the ear canal may increase the risk of a
second unresectable recurrence. Radical surgical extirpation followed
by appropriate adjuvant therapy can achieve 5-year disease free
survival of greater than 60% in many cases [27]. The surgical team
should counsel patients and families about the necessity of the
aggressive surgical approach and the likely postoperative deficits, but
should reassure them that structures will be preserved if doing so
does not compromise oncologic results. The surgery should consist
of removal of the previous scar line and underlying scar tissue or flap
due to the possibility of tumor spread along multiple pathways
through scar. Nerves encased by tumor should be sacrificed with the
proximal margin sent for frozen section analysis to determine
whether there is neural or perineural spread requiring additional
resection. Underlying bone should be resected on either side of the
tumor to avoid leaving tumor within periosteal or cortical tissue.
68 Head and Neck Cancer (T Day, Section Editor)

Neuro-otologic surgeons can assist with lateral temporal bone

resection and closing off of the eustachian tube. Neck dissection
should address all at-risk basins and previously dissected sites. Most
patients will require functional restoration with either static sling or
nerve grafting, with or without regional flap or free tissue transfer.
& Radiation. Radiation therapy for recurrent salivary cancer is chal-
lenging due to the fact that most salivary cancers that recur have
already received previous radiation therapy. Nevertheless, since the
latency between primary therapy and recurrence may be 3 years or
more, many patients may be candidates for reirradiation protocols.
In a retrospective review 14 patients with recurrent salivary cancer,
maximal surgical resection followed by concurrent chemotherapy
and reirradiation (median dose 66 Gy; range, 30–72 Gy) achieved
locoregional control of 72% and 52% at 1 and 3 years, respectively
[28•]. Overall survival was 36% at 3 years and 27% at 5 years [28•].
Newer techniques such as intraoperative radiotherapy and gamma
knife stereotactic radiosurgery will likely play and expanding role in
the future, especially for difficult recurrences at the skull base. Pro-
phylactic stenting of the carotid artery should be considered in
patients at-risk for carotid blow out.
& Chemotherapy. Chemotherapy has been poorly studied in the setting
of recurrent and/or metastatic salivary carcinoma but is frequently
utilized due to the lack of available alternatives. The optimal regimen to
use in the setting of recurrent and/or metastatic disease is difficult to
discern given the small number of cases and diverse histopathology of
salivary cancer. To date there has been no randomized phase 3 trials of
chemotherapy for salivary gland cancer. Several salivary cancers have
histopathological and molecular features similar to cancers elsewhere
(ex. salivary duct carcinoma and breast cancer), and therefore could
potentially benefit from chemotherapeutic agents that have worked
well for these other sites. A number of agents have been used including
single and combination therapy with traditional chemotherapeutic
agents such as cisplatin, miltoxantrone, epirubicin, gemcitabine, pacli-
taxel, vinorelbine, CAP (cyclophosphamide, doxorubicin, cisplatin),
gemcitabine and cisplatin, 5-fluorouracil and hydroxyurea [29••].
Response rates in phase 2 studies of 40 or fewer patients have ranged
from 0 to 100%, with a typical duration in responders of 6 to 9 months
[2••].The only single-agent therapy to show meaningful rates of
response for recurrent or metastatic adenoid cystic carcinoma (ACC) is
cisplatin which demonstrated complete or partial response rates of 15–
70% in phase 1 trials [30]. Likewise, cisplatin is the favored agent in
phase 2 trials of combination regimens for metastatic ACC, most of
which achieve short-term clinical response rates of 25% regardless of the
other agents used [29••, 31]. Adenocarcinoma NOS demonstrates
improved response to CAP compared to ACC [32].The role of novel
small molecule therapy in salivary gland cancers continues to be a topic
of interest. In a short-term phase 2 trial of 30 patients (23 adenoid cystic
 Recurrent Salivary Gland Cancer Gillespie et al. 69

carcinoma) with recurrent and/or metastatic salivary carcinoma,

cetuximab, an anti-EGFR antibody, achieved either partial response or
stable disease in 50% of patients regardless of EGFR expression with
minimal toxicity [24••]. Therefore, expression of EGFR may not be
required to achieve a response to EGFR-targeted therapy due to poten-
tial alternative pathways of action. Trastuzumab, an anti-HER2
antibody, has proven effective in the treatment of HER2 expressing
breast carcinoma. In a phase 2 trial of trastuzumab for recurrent and/or
metastatic salivary cancer, only 14 of 126 patients (15%) screened
positive for HER2, and only 1 patient out of 14 (7%) had a documented
partial response to treatment [33]. Ongoing research to determine the
sensitivity of certain histopathologies with particular molecular markers
to various chemotherapeutic and small molecule agents holds promise
for expansion of these modalities in the future.

Disclosure
No potential conflicts of interest relevant to this article were reported.

References and Recommended Reading

Papers of particular interest, published recently, have been
highlighted as:
• Of importance
•• Of major importance

1.•• Jeannon JP, Calman F, Gleeson M, et al. Management
of advanced parotid cancer: a systematic review. Eur J
Surg Oncol. 2009; 35: 908–915.
Well-written meta-analysis of the available information on
salivary gland cancer that covers the critical issues.
2.•• Surakanti SG, Agulnik M. Salivary gland malignancies:
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Excellent broad review of major chemotherapy classes that
have been used to treat salivary cancer to date.
3. Lee YYP, Wong KT, King AD, Ahuja AT. Imaging
of salivary gland tumors. Eur J Radiol.
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4. Shah GV. MR imaging of the salivary glands. Magn
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patient population. Arch Otolaryngol Head Neck
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Important paper from Memorial Sloan Kettering on the role
of FNA in the diagnosis of salivary tumors.
8. Kaszuba SM, Zafereo ME, Rosenthal DI, et al. Effect
of initial treatment on disease outcome for patients
with submandibular gland carcinoma. Arch
Otolaryngol Head Neck Surg. 2007;133:546–50.
9. www.cancer.gov
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cell carcinomas of salivary gland origin. Immuno-
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70 Head and Neck Cancer (T Day, Section Editor)
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mucoepidermoid carcinomas of the salivary glands.
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17.• Williams MD, Roberts DB, Lies MS, et al. Genetic
and expression analysis of HER-2 and EGFR genes
in salivary duct carcinoma: empirical and thera-
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The paper summarizes the main issues of why tumor
markers may play an important role in the treatment of
salivary malignancy in the future.
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the MECT1/MAML2 translocation in salivary
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of mucoepidermoid carcinoma. Clin Can Res.
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CRTC1/3-MAML2 fusions on histological classification
and prognosis of mucoepidermoid carcinoma.
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22.•• Terhaard CHJ. Postoperative and primary radiother-
apy for salivary gland carcinomas: indications, tech-
niques, and results. Int J Radiat Oncol Biol Phys.
2007; 69 Suppl: S52–S55.
Excellent review of the role of radiotherapy for salivary can-
cer summarizing evidence concerning major issues.
23. Alterio D, Jereczek-Fossa BA, Griseri M, et al. Three-
dimensional conformal postoperative radiotherapy
in patients with parotid tumors: 10 years experience
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recurrent and/or metastatic salivary gland carcinomas:
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First large clinical trial investigating the role of novel small
moleculae therapy for salivary cancer.
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pathological factors are predictors of distant metas-
tasis from major salivary gland carcinomas. Int J Oral
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second opinion surgical pathology on the practice
of head and neck surgery: a decade experience at a
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Large series stressing the importance of having an experi-
enced head and neck pathologist when treating head and
neck tumors.
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cancer of the parotid gland: how well does surgery
work for locoregional failure? ORL J Otorhinolaryngol
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28.• Pederson AW, Haraf DJ, Blair EA, et al. Chemoreir-
radiation for recurrent salivary malignancies. Radio-
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evidence of the relative safety of reirradiation proto-
cols in recurrent salivary cancer.
Paper provides evidence of the relative safety of reirradiation
protocols in recurrent salivary cancer
29.•• Laurie SA, Ho AL, Fury MG, et al. Systemic ther-
apy in the management of metastatic or locally
recurrent adenoid cystic carcinoma of the salivary
glands: a systematic review. Lancet Oncol. 2011;
12: 815–824.
Excellent review of the role of chemotherapy in the man-
agement of advanced salivary cancer.
30. Papaspyrou G, Hoch S, Rinaldo A, et al. Chemo-
therapy and targeted therapy in adenoid cystic
carcinoma of the head and neck: a review. Head Neck
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31. Laurie SA, Siu LL, Winquist E, et al. A phase 2 study
of platinum and gemcitabine in patients with
advanced salivary gland cancer. Cancer.
2010;116:362–8.
32. Debaere D, Vander Poorten V, Nuyts S, et al.
Cyclophosphamide, doxorubicin, and cisplatin in
advanced salivary gland cancer. B-ENT. 2011;7:1–
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33. Haddad R, Colevas AD, Krane JF, et al. Herceptin in
patients with advanced or metastatic salivary gland
carcinomas: a phase 2 study. Oral Oncol.
2003;39:724–7.