CLINICAL REVIEW David W.

Eisele, MD, Section Editor

DIAGNOSIS AND MANAGEMENT OF PAROTID CARCINOMA

WITH A SPECIAL FOCUS ON RECENT ADVANCES IN
MOLECULAR BIOLOGY
Vincent Vander Poorten, MD, PhD,1 Patrick J. Bradley, MB, BCh, BAO, DCH, MBA, FRCS
(Ed, Eng, Ir), FHKCORL, FRCSLT (Hon), FRACS (Hon),2 Robert P. Takes, MD, PhD,3
Alessandra Rinaldo, MD, FRCSEd ad hominem, FRCS (Eng, Ir) ad eundem, FRCSGlasg,4
Julia A. Woolgar, FRCPath, PhD,5 Alfio Ferlito, MD, DLO, DPath, FRCSEd ad hominem, FRCS
(Eng, Glasg, Ir) ad eundem, FDSRCS ad eundem, FHKCORL, FRCPath, FASCP, IFCAP4
1
Department of Otorhinolaryngology–Head and Neck Surgery and Leuven Cancer Institute, University Hospitals Leuven,
Leuven, Belgium
2
Department of Otolaryngology–Head and Neck Surgery, Nottingham University Hospital, Queens Medical Centre,
Nottingham, United Kingdom
3
Department of Otolaryngology–Head and Neck Surgery, Radboud University Nijmegen Medical Center, Nijmegen,
The Netherlands
4
Department of Surgical Sciences, ENT Clinic, University of Udine, Udine, Italy. E-mail: a.ferlito@uniud.it
5
Oral Pathology, University of Liverpool Dental Hospital, Liverpool, United Kingdom

Accepted 26 October 2010

Published online 25 May 2011 in Wiley Online Library (wileyonlinelibrary.com). DOI: 10.1002/hed.21706

Abstract: Recent progress in diagnosis, treatment, progno-

sis, and outcome of parotid cancer is reviewed. Modern imaging
allows evaluation of the anatomical extent of the cancer and its
relationship to the facial nerve, and the World Health Organization
(WHO) Histological Classification facilitates accurate, consistent
diagnosis. Surgery remains the treatment of choice with preserva-
tion of a functioning facial nerve. Resection of the facial nerve
should only be undertaken when there is clinical evidence of
nerve dysfunction. The NO neck should be treated in advanced-
stage and high-grade cancers, but the choice between elective
surgery and elective irradiation remains controversial. Low-stage,
low-grade tumors can generally be cured by surgery alone. Post-
operative radiotherapy improves locoregional control in all other
tumor stages and grades. Currently, the diagnostic and thera-
peutic approach to parotid cancer offer few options for a class of
neoplasms that has many subtypes each with a unique molecular
background and variable clinical behavior. Nonetheless, this
approach results in a satisfactory locoregional cancer control,
making distant metastasis the most frequent cause for treatment
failure. At present, systemic treatment for distant failure is disap-
pointing, although recent progress in molecular biology has sug-
gested that adding targeted therapy should achieve tumor
response or stabilization. Although disease control remains vari-
able, the prognosis of individual patients can be increasingly
accurately predicted by multivariate analysis. V C 2011 Wiley Peri-
odicals, Inc. Head Neck 34: 429–440, 2012
Keywords: salivary gland neoplasms; parotid gland; carcinoma;
review; management; molecular biology
Correspondence to: A. Ferlito
This article was written by members of the International Head and Neck
Scientific Group.
V
C 2011 Wiley Periodicals, Inc.
Salivary gland carcinomas have an incidence of 4 to
135 patients per million per year, with the highest
reported rates being in Inuit Eskimos.1,2 Approxi-
mately 70% of salivary carcinomas arise in the pa-
rotid gland,3–5 accounting for 1% to 3% of all head
and neck carcinomas.6 Prognostic factors relating to
the patient, cancer type and stage, and management
account for the variability in cure rates.7
WORKUP
Typically, a parotid tumor presents as a pre-auricular
swelling. The proportion of tumors arising in the deep
lobe is similar to that in the superficial or lateral lobe,
but deep lobe tumors are comparatively rare given that
the deep lobe accounts for only 10% to 20% of parotid
tissue. A small number of deep lobe tumors present
with only a submucosal swelling of the lateral orophar-
ynx or soft palate.8,9 One percent of tumors arise in the
accessory gland on the masseter muscle.10 Less than
25% of parotid tumors are malignant.11 Local pain, a
rapid increase in swelling, presence of neck lymph
nodes, fixity or ulceration to skin, or deep structures, or
facial nerve weakness, or paralysis are useful clinical
indicators of malignancy, especially when present to-
gether.12–14 Pain has been reported in up to 44% of
patients with parotid cancer.15 Facial nerve weakness
or paralysis is present in up to 25% of patients inde-
pendent of T classification.13,16–19 There is a 6% risk of
parotid cancer in a patient presenting with facial palsy
where no other abnormal signs are found on initial
workup including magnetic resonance imaging (MRI)
(Bell’s palsy type presentation). The risk of carcinoma

Diagnosis and Management of Parotid Carcinoma HEAD & NECK—DOI 10.1002/hed March 2012 429
remains high when paresis is slow in onset, progres-
sive, without recovery within 8 months, only present in
isolated branches, or if tics are present.20,21
The workup aims to evaluate and assess the ana-
tomic location, extent of local tissue and cervical node
invasion, and the likelihood of malignancy. These fac-
tors will determine the likely risk of damage to or the
need for removal of the facial nerve during surgery.
Ideally, the exact histological type should be known
before surgery, but with current diagnostic technolo-
gies, combined with myriad histopathologies, this in-
formation is frequently not available.
Radiological imaging is generally not indicated for
mobile circumscribed tumors (where location and
extent are clinically obvious) but is strongly advised
when tumor mobility is impaired.13,22–24 MRI outper-
forms computed tomography (CT) in evaluating retro-
mandibular parotid tissue, the area surrounding the
stylomastoid foramen, facial nerve invasion, and peri-
neural extension.21–23,25 Conventional MRI alone is
generally not able to accurately determine the benign
or malignant nature compared to fine-needle aspira-
tion cytology (FNAC).26 The addition of diffusion-
weighted MRI, however, seems to improve the preop-
erative identification of malignancy based on the tis-
sue-specific diffusion pattern.27 Positron emission
tomography (PET) with or without CT may be consid-
ered in strongly suspicious but unproven cancers or
in the patient with an FNAC-proven malignancy
when it is necessary to exclude (gross) metastatic dis-
ease.28–33 PET fails in differentiating benign from ma-
lignant primary salivary disease because Warthin’s
tumors and pleomorphic adenomas also show an
increased uptake.34,35
FNAC performed as part of the patients workup is
an important tool. Accurate tumor typing is not
always possible, but when performed by an experi-
enced cytologist, FNAC is safe and can discriminate
between a malignant and a benign lesion with 79%
accuracy. This information often will aid the surgeon
planning the timing and likely extent of surgery and
help with patient counseling.36–41 Ultrasound-guided
FNAC is recommended.25,42 An immediate onsite
processing and evaluation of the needle aspirate with
repeat puncture if unsatisfactory, results in the high-
est accuracy.22 In a series of 1355 FNACs of salivary
gland neoplasms, 80.5% correct identification of
malignancy (true-positive), 4.6% suspicious lesions,
11.9% false-negatives, and 3% uninterpretable or
unsatisfactory samples were achieved. Even when
FNAC suggests benign disease, removal of the tumor
for histopathology remains mandatory.36,43 Diagnostic
accuracy of FNAC could be improved in the future by
incorporating high throughput techniques such as
cDNA microarrays, which would give a rapid tumor-
specific overview of overexpressed oncogenes and
underexpressed tumor suppressor genes.44 Incisional
biopsy is only advised for large tumors presenting
with ulceration or infiltration of the skin.
430 Diagnosis and Management of Parotid Carcinoma
This workup currently results in a summary of
local, regional, and distant disease extent as reflected
in the TNM classification.45 This information com-
bined with other clinical, histopathological, patient,
and tumor features determines treatment planning.
The diagnostic role of the TNM classification is to
facilitate comparison of treatment results. Over the
years, the definition of T categories has changed, and
this complicates the comparison of older and recent
studies. Older studies used the 1987 Union Interna-
tionale Contre le Cancer (UICC)/1988 American Joint
Committee on Cancer (AJCC) classification that
remained unchanged in the 1992 UICC/AJCC edition,
in which T classification consists of tumor size (T1–
T4) and an a-b suffix indicating local extension.46
This suffix system, difficult to work with, was abol-
ished in the 1997 UICC/AJCC edition47 which used
evidence from multivariate analyses suggesting soft
tissue invasion and facial nerve dysfunction increase
the T level independent of tumor size. In the 2002
UICC/AJCC edition, the T definition changed to
include a resectable category T4a and an unresectable
category T4b. The T category definition has remained
unchanged in the seventh UICC/AJCC edition.45,48
Besides this diagnostic role, there exists an inde-
pendent prognostic role for anatomic extent as sum-
marized in the TNM components.6,17,49–53 For this
prognostic purpose, TNM combinations with the same
outcome are put together in a stage group, defined
using empirical guidelines that result from observa-
tional studies. However, multivariate analyses need
validation like every prognostic system.54 Such a vali-
dation attempt by the Japanese Joint Committee on
Cancer questioned the adequacy of the 1997 UICC/
AJCC stage grouping guidelines. For example, in
1074 patients with parotid carcinoma, only 9 belonged
to the stage III subgroup.55 A system in which 1 sub-
group is virtually unused is obviously poorly
balanced.43
TREATMENT OF THE PAROTID TUMOR AND
THE NECK
The tumor size, relationship to the seventh nerve and
degree of invasion into surrounding tissues determine
the extent of surgery. Most frequently, the surgeon is
dealing with a patient who has a superficial or lateral
lobe tumor, with normal preoperative facial nerve
function and a ‘‘standard’’ superficial or lateral paroti-
dectomy is adequate. Deep lobe tumors or with facial
nerve involvement demand more extensive surgery.
Some authors have advocated a total conservative
parotidectomy in every case of suspected malignancy,
as this reveals occult metastatic disease in the deep
parotid lymph nodes in a significant number of
patients.11,56 Indeed, Armstrong et al57 showed in 1992
that parotid lymph nodes are involved in a 53% of elec-
tive neck dissections. Until a prospective randomized
evaluation proves the oncological benefit of this
HEAD & NECK—DOI 10.1002/hed March 2012
approach, clinical experience to date shows low local
recurrence of primary tumors that are well localized in
the superficial lobe and, hence, superficial to the facial
nerve, and adequately removed. It is likely that postop-
erative radiotherapy will also control possible micro-
scopic deep lobe lymph node deposits.58 Facial nerve
branches are only sacrificed when preoperatively para-
lyzed, or invaded by or completely surrounded by
tumor. Most preoperatively intact nerves can be dis-
sected macroscopically free from the tumor. More sen-
sitive than clinical examination is electromyography,
and in suspected malignant tumors this can be consid-
ered to help in counseling the patient on the possible
likely need for nerve resection and reconstruction.59
There is consensus that residual microscopical disease
left behind on a spared nerve branch can be controlled
by radiotherapy.18,43,51,60–62 Nerve sacrifice in these
instances often induces disproportionate morbidity at
the expense of minor gain in tumor control.19 Charabi
et al62 found that radical parotidectomy fails to
improve survival compared to conservative nerve man-
agement in patients with residual microscopic disease.
When nerve resection is necessary or indicated,
frozen section of resection margins is recommended
because of possible skip tumor deposits and immediate
cable grafting results in the best cosmesis and func-
tion. The greater auricular nerve combines easy avail-
ability and access, a good or matching diameter, and
adequate or appropriate arborization.63,64 Should there
be a need for a longer defect, the greater auricular
nerve can be backtracked to include the cervical sen-
sory plexus branches. An alternative is to use the sural
nerve.59 Electromyography signs of re-innervation
should appear after 4.5 months. The first clinical move-
ments appear from 6 months on, but a 2-year period is
necessary to reach the maximum or final result,59,63,64
usually graded, when complete re-innervation, as a
House–Brackmann grade II or III (light to obvious pa-
resis with synkinesis but possible eye closure).65 Nega-
tive prognostic factors for a good final result are
presence and duration of preoperative facial nerve
weakness or paralysis and patients aged >60 years
old.65 Radiotherapy does not impair the results of cable
grafting and Brown et al64 reported a House–Brack-
mann grade III or IV in 69% of irradiated patients com-
pared to 78% of nonirradiated patients (p ¼ .54), and
replicated previously reported experimental findings of
80% axon recovery in both irradiated and nonirradi-
ated facial nerves.64,66
Regional metastasis at presentation is reported in
15% to 29% of patients,15,67 and most frequently
involves levels II, III, and IV,57 and when treated sur-
gically requires a (modified) radical neck dissection,
or removal of levels I to V, with radicality toward the
accessory nerve, jugular vein, or sternocleidomastoid
muscle dictated by proximity or involvement by carci-
noma.68 In patients with pNþ disease, radiotherapy
to the parotid area and the ipsilateral neck doubles
locoregional control and improves survival.53,68–72
Diagnosis and Management of Parotid Carcinoma
In most patients presenting with a cN0 neck, elec-
tive neck surgery is considered if there are risk factors
for occult nodal disease, but elective radiotherapy
seems a good alternative.71 A routine frozen section of
the subdigastric lymph nodes or a IIA selective neck
dissection at the beginning of the parotidectomy may be
a good strategy, especially when nodes are enlarged or
the tumor is large. If these contain metastases of 3 mm
or more, it is best to consider the neck as cNþ and per-
form a comprehensive neck dissection.49,73,74 The risk
factors for occult neck disease are large primary tumor
size (>4 cm) and histology with clinical high-grade
behavior, implying a 20% and 49% risk for occult nodal
metastasis, respectively.57,71,75 Age >54 years, perilym-
phatic spread and extraparotid extension, when jointly
present, correspond to a 95% risk of positive neck me-
tastasis.75 These high-risk patients benefit from elec-
tive neck treatment. Nodal metastases are reportedly
rare at presentation of adenoid cystic carcinoma (ACC)
so elective neck dissection is not recommended.73
The levels in the neck to address are levels II to
IV,71 and this approach is especially indicated if re-
moval of the primary is combined by surgical access
in the neck. Ferlito et al73 advocate elective dissection
of sublevel IB and levels II, III, and upper V. Some
European authors propose a routine elective neck dis-
section for all patients with parotid carcinoma. Using
this strategy, Zbären et al76,77 reported a 22% occult
rate and a better locoregional control compared to ob-
servation. It must be noted that the patients in their
series did not receive radiotherapy. Stennert et al11
report a 45% occult rate in their patients who all
underwent neck dissection. A Brazilian group78 found
37% occult metastasis as predicted by histology (ade-
nocarcinoma, undifferentiated carcinoma, high-grade
mucoepidermoid carcinoma [MEC], salivary duct car-
cinoma [SDC], and squamous cell carcinoma, together
accounting for a 68% occult rate), T classification, and
severe desmoplasia. The surgical approach to the N0
neck can be optimized using preoperative ultrasound-
guided FNAC of the neck and peroperative frozen sec-
tion.39,43 The MD Anderson group75 promotes elective
radiotherapy to the N0 neck after resection of high-
risk tumors. The advantages are 2-fold: preoperative
and peroperative adequate typing of salivary carcino-
mas is difficult (accuracy 51% to 62%), and the indica-
tions for elective neck treatment largely concur with
the indications for postoperative radiotherapy to the
primary.79 This means that the information needed to
preoperatively classify a tumor as high-risk is often
not available at the moment the decision for neck sur-
gery has to be made.22,68,79–81 Furthermore, radio-
therapy will be needed if a cN0 neck is pNþ, and is
effective in controlling microscopic disease.58,72 Only
a prospective randomized trial will determine
whether an elective neck dissection (followed by
radiotherapy if indicated) provides a better result
than elective radiation alone for cN0 high-risk
patients.78
HEAD & NECK—DOI 10.1002/hed March 2012 431
 A discussion of the complications of surgery and
radiotherapy and their management is beyond the
scope of this review.
RESECTED SPECIMEN: HISTOTYPING, GRADING,
AND MOLECULAR STUDIES
The pathologist is expected to accurately categorize
the tumor using the 2005 World Health Organization
(WHO) classification7 (featuring 24 different pheno-
types: Table 1), grade the tumor (where applicable),
and describe negative prognostic features such as
perineural growth, lymphovascular invasion, and
involved margins. Increasingly, molecular biological
studies are performed.7
Histotyping. A clear relationship between histologic
types and biological aggressiveness is often lacking.82
In population-based studies, the majority of carcino-
mas are acinic cell carcinoma (ACN), ACC, and MEC
(15% to 17%, 16% to 27%, and 14.5% to 19.2%,
respectively).67,83
To facilitate clinical use, the different histotypes are
divided into clinically low-grade (ACN, polymorphous
low-grade carcinoma, and low-grade MEC), intermedi-
ate-grade (ACC and epithelial myoepithelial carci-
noma), and high-grade groups (high-grade MEC, SDC,
carcinoma ex pleomorphic adenoma, adenocarcinoma
not otherwise specified [NOS], and undifferentiated car-
cinoma). When opting to work with 2 groups, intermedi-
ate-grade tumors are attributed to the high-grade
group: ACC is hard to cure with a protracted clinical
course, and epithelial intermediate-grade myoepithelial
carcinoma is linked to a recurrence rate of 40% and a
disease-specific survival (DSS) of only 60%.84–87 The
clinical grade assignment does not always parallel clini-
cal behavior. Allegedly, low-grade histotypes can show
aggressive subgroups, such as a high-grade ACN
subgroup with poorer prognosis.88,89 Conversely, a low-
grade variant of microscopically typical SDC has been
documented.90,91
Grading. Optical grading by the pathologist is an
attempt to explain variable biologic behavior within
tumors of the same histotype. Unfortunately, grading
shows poor inter-examiner and intra-examiner consis-
tency and independent prognostic power is low.19,92,93
Grading is established in the 3 most frequent tumors:
MEC,92–99 ACN89,100 and ACC.101–104 Grading of MEC
into low-grade versus intermediate-grade and high-
grade types guides treatment selection: low-grade,
low-stage, and completely resected MEC requires no
additional radiotherapy.22 On the other hand, the
aggressive ‘‘high-grade’’ subset of patients with ACN
(16.5% of 438 graded tumors) are postoperative radio-
therapy candidates.88,89,105
Generally, ‘‘optical grading’’ parallels other impor-
tant prognostic factors (age, stage,96,104 irradicality,
and perineural growth).49,106 This explains why, in
432 Diagnosis and Management of Parotid Carcinoma
Table 1. The WHO 2005 histologic classification of malignant salivary
gland tumors.7
1. Acinic cell carcinoma
2. Mucoepidermoid carcinoma
3. Adenoid cystic carcinoma
4. Polymorphous low-grade adenocarcinoma
5. Epithelial myoepithelial carcinoma
6. Clear cell carcinoma, NOS
7. Basal cell adenocarcinoma
8. Sebaceous carcinoma
9. Sebaceous lymphadenocarcinoma
10. Cystadenocarcinoma
11. Low-grade cribriform cystadenocarcinoma
12. Mucinous adenocarcinoma
13. Oncocytic carcinoma
14. Salivary duct carcinoma
15. Adenocarcinoma NOS
16. Myoepithelial carcinoma
17. Carcinoma in pleomorphic adenoma
18. Carcinosarcoma
19. Metastasizing pleomorphic adenoma
21. Small cell carcinoma
22. Large cell carcinoma
23. Lymphoepithelial carcinoma
24. Sialoblastoma
Abbreviations: WHO, World Health Organization; NOS, not otherwise specified.
multivariate analysis, grading often fails to remain in
the final model because coinciding factors are more
reliably reproducible.
Molecular Studies. In the last 2 decades, molecular
markers have been intensively studied. These can
serve as prognostic factors and as therapeutic targets.
For prognostic use, molecular biological factors
may prove more reliable than optical grading. To
date, cell cycle-based proliferation markers, Ki-67
(nuclear antigen found in proliferating cells),96,107,108
proliferating cell nuclear antigen (essential co-factor
of DNA polymerase delta),92,109,110 human telomerase
reverse transcriptase,111 terminal deoxynucleotidyl
transferase-mediated deoxyuridine triphosphate nick-
end labeling (TUNEL), identification of DNA breaks
in apoptotic cells,112 and argyrophylic nucleolar orga-
nizer (AgNOR) region-associated proteins113,114 have
been well studied. These molecules mark the endpoint
of the cascade of cumulative genetic and epigenetic
events inducing deranged growth, reflecting the num-
ber of cells going through the cell cycle toward divi-
sion. The prognostic role of these proliferation
markers has been confirmed in ACC, ACN, MEC, and
SDC82,115 with correlation between optical grading
and outcome. Importantly, they remain independent
prognostic variables in multivariate models that
include classical clinicopathological factors, indicating
their extra contribution. 92,96,107–110,116–122 The
advantage of these endpoint-markers or overall prolif-
eration indices is that they are relatively cheap,
widely applicable, and correlate well with prognosis.
In this respect, Ki-67 staining is probably the best-
HEAD & NECK—DOI 10.1002/hed March 2012
examined and most readily available supplementary
examination to predict biologic aggressiveness.
The prognostic value of different elements of cas-
cades that finally result in deranged growth have also
been assessed. However, prognostic value can only be
attributed to those factors standing firm in multivari-
ate analysis that includes classical clinical and patho-
logical factors. Many of these factors have also been
investigated for their therapeutic potential, and this
information can be found in Table 2.123–133
Markers can be grouped into classes. Seven group-
ing are detailed below:
Group 1. Growth factor receptor proteins and their
ligands. This category contains stem cell factor receptor
(c-KIT), angiogenesis-related growth factor receptors
(vascular endothelial growth factor-receptor [VEGF-R],
platelet derived growth factor-receptor [PDGF-R], basic
fibroblast growth factor-receptor [bFGF-R], interleu-
kin-8 [IL-8], placental growth factor [PlGF], transform-
ing growth factor beta [TGFb]), the ErbB/HER family
of human epidermal growth factor receptors (EGFRs;
aka HER-1 or ErbB-1; HER-2 or HER-Neu or ErbB-2;
HER-3 or ErbB-3; HER-4 or ErbB-4) and insulin-like
growth factors (IGF)-I/II and the receptor IGF-1R. The
best-investigated factors are briefly considered. The c-
KIT is a transmembrane tyrosine kinase that is found
in 80% to 94% of ACC134,135 and in 100% of lymphoepi-
thelial-like salivary gland carcinomas and myoepithe-
lial carcinomas, but in none of the other types
studied.134 In ACC, high c-KIT expression (>50%) was
significantly more observed in grade 3 or solid type
ACC by Holst et al,136 but the opposite, high expression
only in grade 1 (cribriform type) and 2 (tubular type)
was found by Freier et al.137 In the category of angio-
genesis-related growth factor receptors, Lim et al138
describe an independent prognostic role for VEGF in
multivariate analysis. VEGF expression is observed in
a large proportion of salivary gland cancers, mainly in
advanced-stage disease and associated with worse
DSS.139 In the family of ErbB/HER of human epider-
mal growth factor receptors, ErbB-1 or EGFR identifi-
cation and overexpression have been described in
MEC,140 SDC127 and ACC, with the rate of expression
correlating with tumor aggressiveness127,140 HER-Neu
or ErbB-2 has been described and found overexpressed
in ACC and implies bad prognosis.116,140 A worse prog-
nosis also holds for HER-2 overexpression in
SDC.122,128,141 Overexpression of ErbB-2 and amplifica-
tion of its gene has also been described in about 30% of
MEC128,140,142 and is also described here as a negative
prognostic marker in multivariate analysis, independ-
ent of histopathological grade, tumor size, and involve-
ment of regional lymph nodes.142 HER-3 or ErbB-3
expression has been noted in aggressively behaving
ACC.140
Group 2. Cell cycle oncogenes are activated by the
above mentioned growth factor-growth factor receptor
interaction. Among them are sex-determining region
Y-box 4 (SOX-4), nuclear factor jB (NFjB), human rat
Diagnosis and Management of Parotid Carcinoma
Table 2. Molecular targets and corresponding therapies studied in
salivary gland carcinoma.
Salivary gland
Molecular target carcinoma type Molecular therapy
c-KIT ACC Imatinib123–126
ErbB-1 All types Cetuximab127
Gefinitib128
ErbB-2 All types Trastuzumab129,130
Lapatinib131
VEGF–family ACN Axinitib132
NFjB–proteasomes ACC Bortezomib133
degrading its
inhibitor (I-jB)-a
Abbreviations: cKIT, stem cell factor receptor; ACC, adenoid cystic carcinoma;
ErbB-1, human epidermal growth factor receptor 1; ErbB-2; human epidermal
growth factor receptor 2; VEGF, vascular endothelial growth factor; ACN; acinic cell
carcinoma; NFjB, nuclear factor-kappa B.
sarcoma viral oncogene homolog (H-RAS), phosphati-
dylinositol 3 phosphate kinase/serine-threonine protein
kinase Akt (PI3K/AKT), sarcoma (Schmidt-Ruppin A-2)
viral oncogene homolog (Src), signal transducer and ac-
tivator of transcription 3 (STAT3), mammalian target of
rapamycin (mTOR, activated by AKT and regulates pro-
tein synthesis depending on nutrient availability), and
cyclin D1. Frierson et al143 found in a large microarray
analysis of ACC that SOX-4 was the most significantly
overexpressed cell cycle oncogene. In ACC cell lines,
increased apoptosis after SOX-4 knockdown suggests
that this oncogene exerts its activity via downregulation
of inhibitors of the NFjB pathway (inhibitor protein [I-
jB]-a) and by upregulation of apoptosis inhibitors such
as survivin.144 Mutations of H-RAS are found in pleo-
morphic adenoma, but more frequently in carcinoma ex
pleomorphic adenoma,145 in adenocarcinoma,146 and
almost half of MEC. In MEC, the frequency of H-RAS
mutations parallels tumor grade.147 In ACC, Greer et
al148 attributed a prognostic role to cyclin D1, and in
MEC, high cyclin D1 expression seems to follow hyper-
methylation/inactivation of secreted frizzled-related
proteins (SFRPs) and parallels tumor stage, grade, and
decreased survival.149
Pleomorphic adenoma gene 1, a specific proto-onco-
gene in salivary gland tumorigenesis, is transcribed and
overexpressed after a t(3;8)(p21;q12) chromosome trans-
location resulting in b catenin promoter swapping, in a
large percentage of pleomorphic adenomas. This causes
deregulated expression of pleomorphic adenoma gene 1
target genes via by the IGF-II IGFIR mitogenic signal-
ing pathway.150 Another fusion oncogene, MEC translo-
cated 1 gene with exons 2 to 5 of the mastermind-like
gene (MECT1-MAML2), t(11;19)(q14-21;p12-13)151
results in a fusion protein typically indicating low-grade
MEC and has been postulated as an alternative for opti-
cal grading.152 Unfortunately, recent evidence shows
outlier cases of fusion-positive MEC associated with
advanced-stage lethal disease.153
Group 3. Proteins involved in DNA damage repair.
Well studied are p53 and ERCC1 (excision repair
HEAD & NECK—DOI 10.1002/hed March 2012 433
cross-complementation group 1). The p53 mutations
in ACC correlated with worse outcome,154 but in a
large Finnish multivariate analysis,117 this did not
offer additional information over a model that
included classical clinical and pathological factors,
although this large study did not focus on the ACC
subgroup but studied all salivary gland types.
Group 4. Proteins involved in apoptosis. The Bcl-2
group contains pro-apoptotic proteins such as Bax,
Bad, and Bak and anti-apoptotic proteins such as Bcl-
2, Bcl-xL, and survivin. High Bcl-2 expression in sali-
vary gland neoplasms relates to poor prognosis and
advanced T and N classification in patients with pa-
rotid cancer.155
Group 5. Proteins involved in cell–cell adhesion
(hemidesmosome proteins B180 and B230, E-cadherin,
a-catenin),156–158 migration (matrix metalloprotease, hep-
aranase),82,159 and epithelial-mesenchymal transition
(NBS-1 and snail).115
Group 6. Estrogen, progesterone, and androgen
receptors.115,127
Group 7. Microarray technology can offer a quick,
tumor-specific overview of genome-wide overexpressed
oncogenes and underexpressed tumor suppressor
genes, and can be used as a prognostic blueprint of a
tumor.160 This is established and helps in guiding
treatment for other tumors such as breast cancer, but
to date still remains to be fully explored for salivary
gland cancers.
POSTOPERATIVE RADIOTHERAPY
Once the tumor is resected and pathologically staged
and graded, postoperative radiotherapy is often indi-
cated. Traditionally, postoperative radiotherapy to the
primary was delivered by conformal wedged-pair
beams to a dose of 60 Gy22,53,72 but has been replaced
by 3-dimensional (3D) conformal radiotherapy and
lately, intensity modulated radiotherapy is becoming
the standard.161,162 Radiotherapy is indicated in
advanced stage disease (stage III and IV) and with
adverse prognostic factors (perineural and vascular
invasion, close or positive margins, histological high-
grade). With the lack of randomized trials on prognos-
tic factors, the evidence for using postoperative radio-
therapy lies in retrospective reports (with a bias of
selecting prognostically negative patients for combined
therapy) demonstrating improved locoregional control
in the combined treatment group.50,72,162–166 The
Dutch Head and Neck Oncology Cooperative Group53
showed relative-risk for local recurrence in surgical
patients was 9.7 times that of patients receiving com-
bined surgery and radiotherapy. This confirms the
older very good matched-pair analysis of parotid and
submandibular carcinomas by Armstrong et al69
describing a significantly improved DSS and local con-
trol in patients with stage III and IV and nodal disease
(Nþ) treated with radiotherapy after resection. The
adagium is that postoperative radiotherapy can only be
434 Diagnosis and Management of Parotid Carcinoma
omitted for stage I to II lesions in ACN and low-grade
MEC if complete resection does not reveal other
adverse pathological factors (close surgical margins,
perineural or lymphovascular invasion, or recurrent
disease).43,49 For high-risk salivary gland carcinomas,
a single report supporting the usefulness of a postoper-
ative platinum-based concomitant chemoradiation
scheme has been recently published.167
RADIOTHERAPY AND CHEMOTHERAPY IN
UNRESECTABLE DISEASE
Unresectable salivary gland cancer or resectable can-
cer in poor surgical candidates is controlled by con-
ventional photon radiotherapy in 17% to 57% at 10-
year follow-up. The percentages at the upper limit of
this range are found in series dealing with mainly
early stage disease.168,169 A reduced oxygen enhance-
ment factor, less variability of sensitivity through the
cell cycle and decreased repair of sublethal cell dam-
age explain why neutron radiotherapy reaches 5-year
local control in up to 75% in unresectable disease,
especially for ACC,168,170–173 This option remains
unattractive because of poor survival benefit (distant
metastasis in 40% of patients after 51 months) and
frequent, severe late side effects, including cervical
myelopathy, sensorineural hearing loss, and necrosis
of soft tissues, mandibular and temporal bones and
temporal lobe of the brain. In this patient group,
chemotherapy remains of palliative use only. A tem-
porary complete remission in about 20% seems the
best achievable result.174–178 In metastatic adenocar-
cinoma NOS, high response rates are observed with
cisplatin, doxorubicin, and cyclophosphamide.
Unfortunately, these responses are generally short-
lived.179 The explored targeted therapies are listed in
Table 2, but none has significantly improved outcome
in this patient group.
OUTCOMES AND PROGNOSIS
Treatment results from major centers have to be
appreciated in their specific context of stage, percent-
age high-grade, treatment period and corresponding
treatment regimens, patient inclusion criterion, and
adequacy of follow-up (Table 3).3,6,15,18,49,51,61,67,180–185
The decision to exclude palliative intent patients in
the 1999 Manchester series,61 results in a patient
cohort with relatively low stage (80% stage I/II) and
DSS in the high range of the results displayed in Ta-
ble 3. In contrast, the 1999 Amsterdam series49 that
includes palliative patients, increased proportion of
advanced stage disease (25% stage IV), has a lower
overall DSS.
Many univariate6,16,164,166,182,183,186,187 and multi-
variate statistical analyses6,17,49–51,61,180–182,188 have
focused on prognostic factors in salivary carcinoma to
determine the individual patient’s prognosis compared
to the overall results in Table 3. Important
prognostic factors include histotype,52,189 grade,190
HEAD & NECK—DOI 10.1002/hed March 2012
 index was validated in a nationwide database and
Table 3. DSS for parotid carcinoma.
subsequently in an international database, indicating
Publication No. of its usefulness.15,67 A recent validation effort in a Bra-
Research group year patients DSS 5 y DSS 10 y zilian population did not show the same performance
Spiro3 1986 623 55% 47% of the index,193 but a critical analysis of the studied
Spiro et al51 1989 62 63% 47% population and the methods used identified several
Kane et al6 1991 194 69% 58% possible explanations.194 The prognostic value of
Poulsen et al180 1992 209 71% 65%
Leverstein et al18 1998 65 75% 67%
molecular markers is uncertain. Batsakis92 rightly
Therkildsen et al181 1998 251 76% 72% stated 15 years ago that critical multivariate assess-
Renehan et al61 1999 103 78% 65% ment of putative molecular biological prognostic fac-
Vander Poorten et al49 1999 168 59% 54% tors together with clinical and pathological factors,
Harbo et al182 2002 152 57% 51%
and proper validation, are needed before acceptance.
Godballe et al183 2003 85 52%
Vander Poorten et al67 2003 231 62% Ideally this exercise should be performed on a large
Lima et al184 2005 126 72% 69% multicenter scale.195
Mendenhall et al185 2005 224 57%
Vander Poorten et al15 2009 237 69% 58%
Abbreviation: DSS, disease-specific survival.

stage,6,17,49,51,52,78 age,6,51,52,75,190 sex,6,50 pain,6,16,49,183
skin invasion,49,50 and facial nerve dysfunction (peri-
neural growth),17,49,50,52,53,183 treatment (resection mar-
gins),49,180,190,191 and comorbidity.192
Prognostic studies use different outcomes: sur-
vival, DSS, recurrence (any recurrence,15,49,67 local
recurrence,53 neck recurrence,53,78 and distant metas-
tasis52,53). It is customary to cite the relevant prog-
nostic factors separately with a ‘‘p value’’ that mirrors
the so-called ‘‘importance’’ of that factor. The clinician
is then expected to make an intuitive amalgam of
different prognostic factors. A better-than-intuitive
amalgam is offered by a prognostic index combining
the multivariate important patient and tumor-specific
prognostic factors, each with their proper mathemati-
cal weight, into a single number that corresponds to
an estimate of tumor recurrence.49,190 Such an index
was constructed for the situation before (PS1) and af-
ter (PS2) primary treatment (Table 4).46,49 After com-
pletion of the formula, the resulting score places the
patient in 1 of 4 prognostic groups. This prognostic
CONCLUSIONS
Preoperative evaluation increasingly informs clinician
and patient about the extent and nature of resectable
disease and helps determine the extent of surgery.
Ideally, this should result in an adequate resection of
all clinically obvious disease using a conservative
approach to the facial nerve. The histopathological
information determines the need for postoperative
radiotherapy to the primary tumor site and Nþ neck,
and the need for elective treatment of the N0 neck.
Recent literature provides a clear image of the likely
treatment and outcome. Treatment fails most fre-
quently with distant spread to the lungs, liver, or
bones. Unraveling the molecular biological mecha-
nism of tumorigenesis may provide more effective
treatments. Several targeted therapies have been
tried, but to date their benefit is unproven. Further
progress in this difficult area will require multi-insti-
tutional and international databases, and collection
and sharing of tumor samples in tissue banks. This
approach may provide the necessary and appropriate
material for the assessment and validation of diag-
nostic and prognostic approaches, and could facilitate

Table 4. Prognostic indices PS1 (pretreatment variables) and PS2 (posttreatment variables).49

PS1 ¼ 0.024 Aþ0.62 Pþ0.44 Tþ0.45 Nþ0.63 Sþ0.91 F PS2 ¼ 0.018 Aþ0.39 Tþ0.34 Nþ0.70 Sþ0.56 Fþ0.78 PGþ0.65 PM
Variable No. to enter in the formula Variable No. to enter in the formula

A ¼ age at diagnosis No. in years A ¼ age at diagnosis No. in years

P ¼ pain on presentation 1 ¼ no pain, 2 ¼ pain
or numbness
T ¼ clinical T classification* <2 cm ¼ 0, 2–4 cm ¼
1, 4–6 cm ¼ 2, >6 cm ¼ 3
N ¼ clinical N classification* N0 ¼ 0, N1 ¼ 1, N2a ¼ 2, N2b
¼ 3, N2c ¼ 4, N3 ¼ 5)
S ¼ skin invasion 1 ¼ no invasion, 2 ¼ invasion
F ¼ facial nerve dysfunction 1 ¼ intact function,
2 ¼ paresis-paralysis
*1992 TNM Classification of the Union Internationale Contre le Cancer.46
T ¼ clinical T classification*
N ¼ clinical N classification*
S ¼ skin invasion
F ¼ facial nerve dysfunction
PG ¼ perineural growth in the
resection specimen
PM ¼ positive surgical margins
<2 cm ¼ 0, 2–4 cm ¼ 1,
4–6 cm ¼ 2, >6 cm ¼ 3
N0 ¼ 0, N1 ¼ 1, N2a ¼ 2,
N2b ¼ 3, N2c ¼ 4, N3 ¼ 5
1 ¼ no invasion, 2 ¼ invasion
1 ¼ intact function,
2 ¼ paresis-paralysis
1 ¼ no, 2 ¼ yes
1 ¼ no, 2 ¼ yes

Diagnosis and Management of Parotid Carcinoma HEAD & NECK—DOI 10.1002/hed March 2012 435
multi-center and international treatment trials when
promising agents are identified.
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