Abigail C.

Schnieders, MD
Robert P. Zitsch III, MD

Lumpy Lucielle

68 year old female

presents with 6 month
history of lump on
the left side of her face

Case Presentation

Mass has been slowly enlarging. No pain, no

fluctuation in size. Asymptomatic otherwise.
Any other key elements of history?
What would you like to do next?

Case Presentation

PE:
Large 4cm mass of the left tail of parotid
Non compressible, firm
Facial nerve intact and symmetric bilaterally
No displacement of oropharyngeal tissue on intraoral
examination
No palpable cervical lymphadenopathy

What else will you consider in your diagnostic workup?

Case Presentation

Next steps?

Case Presentation

CT guided FNA

Results
neoplastic lesion
PA vs adenoid cystic

Salivary Gland Malignancies

3% of all head and neck malignancies

0.9 per 100,000 US

Diverse group of malignancies

Behavior dependent on histologic type

Etiology not well understood

Possible low dose radiation exposure

John B Sunwoo. Malignant Neoplasms of the Salivary Glands. Cummings Ch. 88

Rate of Malignancy &

Location

the smaller the gland, the more likely the tumor

will be malignant

Salivary Gland Carcinoma

Malignant neoplasm is most commonly seen with

which gland?
1.
2.
3.
4.

Parotid
Sublingual gland
Submandibular gland
Minor salivary gland

Salivary Gland Carcinoma

Malignant neoplasm is most commonly seen with

which gland?
1.

Parotid
1.

2.
3.
4.

Although only 20-25% of parotid neoplasms are

malignant, 75-80% of salivary gland neoplasms are
located in the parotid, thus making the total number of
malignancies highest in this location

Sublingual gland
Submandibular gland
Minor salivary gland

Salivary Gland Carcinoma

Which histologic subtype is most commonly found

in the parotid gland?
1.
2.
3.
4.

Acinic Cell carcinoma

Adenoid Cystic carcinoma
Adenocarcinoma
Mucoepidermoid carcinoma

Salivary Gland Carcinoma

Which histologic subtype is most commonly found

in the parotid gland?
1.
2.
3.
4.

Acinic Cell carcinoma

Adenoid Cystic carcinoma
Adenocarcinoma
Mucoepidermoid carcinoma
1.

80-90% of these tumors occur within the parotid gland

Salivary Gland Carcinoma

Which of the following subtypes is most commonly

found in the submandibular and minor salivary
glands?
1.
2.
3.
4.

Acinic Cell carcinoma

Adenoid Cystic carcinoma
Mucoepidermoid carcinoma
Squamous Cell carcinoma

Salivary Gland Carcinoma

Which of the following subtypes is most commonly

found in the submandibular and minor salivary
glands?
1.
2.

Acinic Cell carcinoma

Adenoid Cystic carcinoma
1.

3.
4.

2/3 of these tumors arise from minor salivary glands

Mucoepidermoid carcinoma
Squamous Cell carcinoma

Clinical Presentation

Asymptomatic Mass
Range from indolent to rapidly growing

Pain
Can be associated with infection, cystic degeneration
May indicate invasion of perineural tissue
Spiro et al
2807 patients
10% - pain
10% - CN VII paralysis

Episodic swelling
Gland obstruction
Spiro RH. Salivary neoplasms: overview of a 35-year experience with 2,807 patients. Head Neck Surg. 1986;8(3):177-184.

Parapharyngeal Space
Involvement

Mass on oral
examination
Alterations in speech
and swallow due to
mass effect
70-80% of
parapharyngeal space
tumors are benign

Parapharyngeal Space Tumors Author: Christine G Gourin, MD, FACS; Chief Editor: Arlen D Meyers

Prestyloid vs. Post-styloid

space

Parapharyngeal space divided into

compartments by the fascia of the
tensor veli palatini

The prestyloid compartment

contains:
retromandibular portion of the
deep lobe of the parotid gland,
adipose tissue, and lymph nodes
associated with the parotid gland

The poststyloid compartment

contains:
the internal carotid artery, the
internal jugular vein, CNs IX- XII,
the sympathetic chain, and lymph
nodes.
Management of Tumors of the Parapharyngeal Space. Ricardo L. Carrau, MD, Jonas T. Johnson, MD, Eugene N. Myers, MD |May 1, 1997. Department of Otolaryngology,
University of Pittsburgh Medical Center, Pennsylvania

Pathogenesis
Reserve cell theory

Neoplasms arise from stem cells of the salivary duct

system

Multicellular theory
Neoplasms arise from differentiated cells along the gland

Type of neoplasm dependent on stage of differentiation

of the cell at the time of neoplastic transformation
Intercalated duct
Adenoid cystic & acinic cell carcinoma

Excretory duct
Mucoepidermoid, squamous cell, ductal carcinoma

Pathogenesis

WHO Classification

Classification

Prevalence by Histologic Subtype

Name that tumor

Mucoepidermoid carcinoma

Mucoepidermoid Carcinoma

Most common salivary gland malignancy

80-90% occur in parotid

Second most common malignancy of the SMG

Female predominance
Mean age of 45
Also the most common salivary gland cancer in
pediatric population

Mucoepidermoid Carcinoma

Grossly appear as bluish cyst

May disguise as mucocele

Histologically: hallmark is
mixed population of cells
Mucous
Epithelial (squamoid)
Intermediate

Clinical behavior and

treatment based on grade

Mucoepidermoid Carcinoma

Increase in grade = loss of

cystic formations and more
solid nests of tumors
Several different grading
systems
Designed to identify tumors
that develop progressive
disease
Brandwein et al
Refined grading system
such that low grade
tumors did not show
tendency to metastasize

Mucoepidermoid Carcinoma
Low grade

Cystic areas with mucin

High proportion of mucous cells to
epidermoid cells
Well-circumscribed, pushing
margins
Capable of local invasion and
metastasis
5-yr survival = 70%

High grade

Solid
Low proportion of mucous cells to
epidermoid cells
Differentiation from scca

Characterized by invasion of
adjacent normal structures,
atypical mitoses, perineural
invasion, lymph node metastases
5-yr survival = 47%

Name that tumor

Adenoid cystic carcinoma

Bonus Points: which histologic subtype?
cribriform

Adenoid Cystic Carcinoma

Biologically and clinically distinct subtype of

salivary gland carcinoma
10% of salivary gland neoplasms
Second most common malignancy of parotid
M=F
Peak incidence between 50-60

Adenoid Cystic Carcinoma

Contradictory clinical course

Slow growing
Infiltrative
Multiple recurrences over a protracted course
Frequent distant metastases

Adenoid Cystic Carcinoma

Grossly: solid, light tan, firm, well circumscribed, but

unencapsulated

Adenoid Cystic Carcinoma

Histologically:
Differentiate toward
cells of normal salivary
gland acini
Infiltrates surrounding
tissues
Characterized by
basaloid epithelial nests
in a hyaline stroma
Perineural invasion is a
typical feature

Adenoid Cystic Carcinoma

Grade I
Tubular ACC
Small tubule-like
structures with
epithelial lining sitting
in a pink, hyalinized
and hypocellular
stroma

35%

Adenoid Cystic
Grade II

Cribriform
Swiss cheese pattern of
vacuolated areas
Nests of basaloid cells
arranged around glandlike spaces
Central spaces look like
glandular lumina but are
really extracellular
cavities containing
ground substance and
myxoid material
produced by tumor cells

44%

Adenoid Cystic Carcinoma

Grade III
Solid
Solid sheets/ nests
of basaloid cells
no gland-like
structures
no defined
architecture

21%

Adenoid Cystic Carcinoma

Perineural invasion
Identified in 70-75% of cases
Typically associated with a poorer prognosis

Adenoid Cystic Carcinoma

Persson et al
Recent identification of tumor specific translocation in
six patients
t(6;9) (q22-23;p23-24)
Fuses MYB oncogene to transcription factor gene
NF1B
Leads to activation of MYB targets
Apoptosis, cell cycle control, cell growth

Name that Tumor!

Hints:
2 cell types
Serous acinar
Clear cells

4 histologic patterns

Acinic cell carcinoma

Name that Tumor!

Hints:
Ductal component
Myoepithelial cells

A:
Epithelial-myoepithelial

FNA
Among tumors of the head and neck, FNA of the salivary
gland are considered to have the highest rate of error
College of American Pathologists Inter-laboratory
Comparison Program
5 year review of data (6249 cases)
73% sensitivity

False negatives:
Lymphoma, Acinic cell, low grade mucoepidermoid, Adenoid
cystic

91% specificity

False postive:

Adenoid cystic
Monomorphic adenoma/ Pleomorphic adenoma

Lymphoma

Warthins

Batsakis JG, Sneige N, El-Naggar AK. Fine-needle aspiration of salivary glands: its utility and tissue effects. Ann Otol Rhinol Laryngol 1992;101:185

FNA

Debate over cost effectiveness

Ultimate surgical removal in most cases
May impact necessity for intraoperative frozen section analysis
Extent of tumor spread, margins, confirming diagnosis

Advantages
Potential to obtain definitive diagnosis
Direction of management
Preoperative patient counseling
Disadvantages
Hemorrhage/ infarction may obscure final diagnosis
Delay in definitive treatment
Surgical excision still needed for definitive diagnosis

Batsakis JG, Sneige N, El-Naggar AK. Fine-needle aspiration of salivary glands: its utility and tissue effects. Ann Otol Rhinol Laryngol 1992;101:185

Imaging

Which modalities are best for imaging salivary gland

masses?

US
CT
MRI
PET

Ultrasound

US cannot definitively
determine malignancy
Malignant features:

Irregular shape/ borders

Blurred margins
Hypoechoic structure
Intraglandular nodes

Many benign neoplasms

can also have these
features

CT
The periparotid fat strip
separating the deep lobe of the
parotid gland from the
parapharyngeal space is an
important anatomic landmark
Allows for the differentiation
of deep lobe parotid tumors
involving the parapharyngeal
space from tumors that arise
from ectopic salivary gland
tissue in the parapharyngeal
space.

MRI
Benign and malignant
lesions are
distinguishable on T1
Separation from fatty
parenchyma
Sorn and Biller

35 tumors examined by MRI

Benign tumors = low T1 and
high T2 with well defined
margins
Malignant lesions = low T1
and T2 signal with poorly
defined margins

Freling and colleagues

116 patients with parotid

masses
No correlation between
malignancy and signal
intensity or margin analysis

PET

Potential role for staging and management in salivary

gland carcinomas
Kim et al

Retrospective review of 55 patients

Compared PET/CT and CT/MRI
Sensitivity/ specificity for PET 96%/92%
Sensitivity/ specificity for MRI/CT 54%/83%

Tumor grade was unassociated with sensitivity of the test

Identified the need for additional surgery in 47% of

patients
Roh JL, Ryu CH, Choi SH, et al. Clinical utility of 18F-FDG PET for patients with salivary gland malignancies. J Nucl Med 2007;
Razfar A, Heron DE, Branstettar BF, et al. Positron emission tomographycomputed tomography adds to the management of salivary gland
malignancies.Laryngoscope 2010; 120:734738.

Staging

Surgical Treatment

Mainstay of treatment is surgery

Parotidectomy
Lateral lobe tumors can be treated with superficial
parotidectomy
Partial deep lobe resection can be performed to achieve
negative margins

Total parotidectomy indicated for

High grade malignant tumors with high risk for metastasis
Any parotid lesion with intraglandular or cervical node
metastases
Any lesion within the deep lobe itself

Surgical Treatment

SMG
Gland excision with level Ib dissection recommended

Sublingual
Wide local excision with level I dissection
Reconstruction with STSG or free tissue transfer

MSG
Most frequent location palate
Partial or total maxillectomy

Management of Neck

Spiro RH. Management of malignant tumors of the salivary glands. Oncol 1998;12(5):671. (Review of treatment guidelines for malignant
neoplasms of the salivary glands.)

Management of the Neck

Management of the N0 neck
Neck dissection recommended
with
Tumors >4cm
High grade histology

Management of the N+ neck

Ipsilateral MRND for clinically
or radiographically positive
nodes
Incidence of multilevel node
involvement

Radiation Therapy

Adjuvant radiation therapy improves local control

T3/T4
High grade
Positive nodes
Perineural involvement
Close or positive surgical margin
Bone, cartilage, muscle involvement
Recurrent disease

Radiation Therapy

Neutron beam radiation

Higher rates of locoregional control compared to
conventional radiation
Advanced stage
Recurrent disease
Incomplete resection

Higher degree of tumor destruction with less toxicity

to surrounding tissue
Particularly good for adenoid cystic
Prott FJ, Micke O, Haverkamp U et al. Results of fast neutron therapy of adenoid cystic carcinoma of the salivary glands. Anticancer Res 2000;20(5C):3743. (The University of Munster experience
with neutron-beam radiotherapy and adenoid cystic carcinoma.)
Douglas JG et al. Treatment of salivary gland neoplasms with fast neutron radiotherapy.Arch Otolaryngol Head Neck Surg 2003;129 (9):944. (The University of Washington experience with and
their evaluation of the efficacy of neutron-beam radiotherapy for adenoid cystic carcinoma.

Radiation Therapy

Chen et al
Retrospective analysis of 140 patients with ACC
Omission of postoperative RT independently
predicted local recurrence
hazard ratio of 5.82

Identified certain features of tumors whereby

postoperative radiation therapy is useful controlling
locoregional recurrence
Advanced stage tumors, presence of positive margins,
high grade tumors, neural/ bone involvement
Chen AM. 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

Radiation Therapy

Dutch Head and Neck Oncology Cooperative Group

Terhaard et al
Retrospective multivariate analysis of 565 patients
Surgery alone = relative risk of local recurrence of 9.7
compared with those patients treated by surgery and
postoperative RT
Improved regional control in N+ neck
86%vs 62%

No effect on development of distant metastases or overall

survival
Terhaard CH. The role of radiotherapy in the treatment of malignant salivary gland tumors. Int J Radiol Biol Phys 2005; 61:103-111

Adjuvant Radiotherapy
Terhaard et al
386/498 patients received adjuvant RT
10 year local control rates:
Adjuvant RT

Surgery only

T3/T4 tumors

84%

18%

Close margins

95%

55%

Positive margins

82%

44%

Bone invasion

86%

54%

P<0.001
Same results were not observed for T1/T2 tumors
T1 95% vs 83%
T2 91% vs 88%

Radiation Therapy

Armstrong et al
Retrospective matched pair analysis
Postoperative RT improved local control in stage
III/IV
5 year local control rates
Surgery + RT = 51%
Surgery alone = 17%

5 year determinate survival rates

51.2% and 9.5%

No difference in outcomes between two treatment

groups in patients with stage I and II
Armstrong JG. Malignant tumors of the major salivary glands. A matched pair analysis of the role of combined surgery and
postoperative radiotherapy. Arch Otolarynol Head Neck Surg. 1990;116:290-3

Radiation Therapy

Matsuba et al
Study of high grade malignancies of parotid
5 year local control rates
70% with post op RT
20% without

Adjuvant Radiation Therapy

Chemotherapy

Typically limited to palliative

Partial responses in 50%
Pain control

Paclitaxel
Chemotherapy alone does not improve survival rates
ChemoRT increases local control and

Chemotherapy

Mostly based on small patient series, often with

multiple histologic subtypes within studies
Eastern Cooperative Oncology Group
Phase II trial
Single agent paclitaxel in 45 patients
8/31 with mucoepidermoid or adenocarcinoma had
partial response
0/14 of adenoid cystic carcinoma showed response
Gilbert J. Phase II trial of taxol in salivary gland malignancies: a trial of the Eastern Cooperative Oncology Group. Head
Neck 2006; 28 (3):197-204

Chemo Radiation

Concurrent chemoRT
After primary surgical resection in high risk patients
After surgical resection for recurrence
In inoperable patients

Pederson AW, Haraf DJ, Blair EA, et al. Chemoreirradiation for recurrent salivary gland malignancies. Radiother Oncol 2010; 95:308311.
Tanvetyanon T, Qin D, Padhya T, et al. Outcomes of postoperative concurrent chemoradiotherapy for locally advanced major salivary gland carcinoma. Arch Otolaryngol Head Neck Surg
2009; 135:687692.
Katori H, Tsukuda M. Concurrent chemoradiotherapy with cyclophosphamide, pirarubicin, and cisplatin for patients with locally advanced salivary gland carcinoma. Acta Otolaryngol 2006;
126:13091314.

ChemoRT

Tanvetyanon et al

24 patients with locally advanced major salivary gland

carcinoma

12 treated with postoperative RT

12 treated with postoperative concurrent chemoradiotherapy

All but 1 patient had stage III or IV disease

Close or positive margins noted in 83%
Median radiation dose was 63 Gy
Platinum based regimens were used in chemoRT arm
Overall 3 year survival
Radiation alone = 44%
Chemoradiation = 83%
P= 0.05

Tanvetyanon T. Outcomes of Postoperative Concurrent Chemoradiotherapy for Locally Advanced Major Salivary Gland Carcinoma. Arch Otolaryngology Head
Neck Surg 2009; 135 (7): 687-692

Post-Operative ChemoRT

Tanvetyanon T. Outcomes of Postoperative Concurrent Chemoradiotherapy for Locally Advanced Major Salivary Gland Carcinoma. Arch
Otolaryngology Head Neck Surg 2009; 135 (7): 687-692

Management

Head Neck Pathol 2009 March; 3(1) 69-77

Molecular Targeting

Recent interest in molecular targeting of salivary gland

malignancies
Molecular markers
EGFR

Overexpression in all histologic subtypes

Lapatinib (tyrosine kinase inhibitor of EGRF and HER2)
Phase II study showed disease stability in 36%

HER2

Ductal carcinoma

C-kit

Adenoid cystic
Imatinib (c-kit inhibitor)

Although there is overexpression of these molecular markers,

the rates of true genetic mutation is much lower
Papaspyrou G, Hoch S, Rinaldo A, et al. Chemotherapy and targeted therapy in adenoid cystic carcinoma of the head and neck: a review. Head Neck 2010
Locati LD, Perrone F, Losa M, et al. Treatment relevant target immunophenotyping of 139 salivary gland carcinomas (SGCs). Oral Oncol 2009; 45:986990.

ChemoRT

Radiation Therapy Oncology Group

Recently opened a phase II randomized trial
Comparing radiation and concurrent cisplatin with
radiation alone in high risk patients after surgical
resection

Prognostic Variables

Overall 10-year disease free

survival rate of patients with
salivary gland malignancies
~47-74%

References

Pederson DJ, Blair EA, et al. Chemoreirradiation for recurrent salivary gland malignancies. Radiother Oncol 2010;
95:308311.
Tanvetyanon T, Qin D, Padhya T, et al. Outcomes of postoperative concurrent chemoradiotherapy for locally
advanced major salivary gland carcinoma. Arch Otolaryngol Head Neck Surg 2009; 135:687692.
Katori H, Tsukuda M. Concurrent chemoradiotherapy with cyclophosphamide, pirarubicin, and cisplatin for
patients with locally advanced salivary gland carcinoma. Acta Otolaryngol 2006; 126:13091314.
Papaspyrou G, Hoch S, Rinaldo A, et al. Chemotherapy and targeted therapy in adenoid cystic carcinoma of the
head and neck: a review. Head Neck 2010
Locati LD, Perrone F, Losa M, et al. Treatment relevant target immunophenotyping of 139 salivary gland
carcinomas (SGCs). Oral Oncol 2009; 45:986990
Roh JL, Ryu CH, Choi SH, et al. Clinical utility of 18F-FDG PET for patients with salivary gland malignancies. J Nucl
Med 2007;
Razfar A, Heron DE, Branstettar BF, et al. Positron emission tomographycomputed tomography adds to the
management of salivary gland malignancies.Laryngoscope 2010; 120:734738

Batsakis JG, Sneige N, El-Naggar AK. Fine-needle aspiration of salivary glands:

its utility and tissue effects. Ann Otol Rhinol Laryngol 1992;101:185\
Cummings . Chapter 88
Bailyes. Chapter 109