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LITERATURE REVIEW
Embryology, the major salivary glands develop from the 6th - 8th weeks of
The parotid enlage develops first, growing in a posterior direction as the facial
VII. However, the Parotid gland is the last to become encapsulated, after the
are often included within these lymph nodes. The minor salivary glands arise from
oral ectoderm and nasopharyngeal endoderm. They develop after the major
1. Parotid gland
The parotid gland, the largest of the salivary glands, is palpable over the
muscle (which indents the gland) and the mastoid process. The parotid gland
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extends from the level of the external auditory canal and zygomatic arch to the
angle of the mandible and is separated medially from the carotid sheath by the
posterior belly of digastric muscle, the styloid process, and its associated
with the superficial layer of deep cervical fascia. The Parotid fascia consists of
Superficial layer – extends from the masseter and SCM to the Zygoma, and
Deep layer – extends from the fascia of the posterior belly of the Digastric
muscle, and forms the Stylomandibular membrane separating the Parotid and
Submandibular glands. The Parotid fascia sends septa into the glandular
tissue, which prevents the possibility of separating the glandular tissue from
its investing fascia. The attachments of the Parotid fascia include Anterior >
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component accounts for the majority of the gland and lies on the lateral
surface of the masseter muscle, which is it self on the lateral surface of the
through the stylomandibular tunnel between the posterior border of the ramus
of the mandible, the stylomandibular ligament, and the skull base superiorly.
digastric, and the mandibular ramus). One of the simplest methods is the use
of the facial nerve line connecting the lateral surface of the posterior belly of
digastric to the lateral surface of the mandibular ramus5. The contents of the
parotid gland include the following: Lymph nodes, Facial nerve (VII),
parotid fascia, and about 15-20 lymph follicles embedded in the gland,
superficial to the facial nerve. The deep lobe may contain one or at the very
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most two of these follicles. Blood supply, the external carotid artery enters the
deep aspect of the gland just above the point where it is covered by the
gland, giving off the transverse facial, internal maxillary and, finally, the
sympathetic fibers arise from the carotid plexus and the parasympathetic fibers
nerve) arises from the glossopharyngeal cranial nerve that has joined the
gland; by the time the nerve crosses the temporomandibular joint, it contains
only sensory (Vth nerve) fibers from the scalp. Taste and mastication are the
principal stimuli (unconditioned reflex) but others such as sight, thought and
smell of food (conditioned reflex) also play a role. Taste and mechanical
stimuli from the tongue and other areas of the mouth excite parasympathetic
nerve impulses in the afferent limbs of the salivary reflex which travel via the
glossopharyngeal (CN IX), facial (CN VII), vagal (CN X) (taste) and the
carried to the salivary nuclei located approximately at the juncture of the pons
and the medulla. In turn impulses from the salivary centres can be modulated
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i.e. stimulated or inhibited by impulses from the higher centres in the central
nervous system; for example, the taste and smell centres in the cortex and the
as a result of the inhibitory effect of higher centres on the salivary nuclei. The
fibres carrying on to the parotid gland and via the facial nerve synapsing in the
glands. Parasympathetic stim ulation also increases the blood flow to the
2006).
temporal and maxillary veins. This has the same direction as the artery but lies
superficial to it and immediately deep to the facial nerve. It exits at the tail of
the gland, at which point the mandibular branch of the facial nerve crosses
2. Submandibular gland
anatomists to refer to the mandible as the ‘submaxilla’. This gland lies in the
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Digastric muscle and the inferior margin of the mandible. The gland is
positioned medial and inferior to the mandibular ramus partly superior and
partly inferior to the base of the posterior half of the mandible. The gland
forms a ‘C’ around the anterior margin of the Mylohyoid muscle, which
divides the Submandibular gland into a superficial and deep lobe. The deep
lobe comprises the majority of the gland. The Marginal Mandibular branch of
Platysma. As is the case with the Parotid gland, the Submandibular gland is
invested in its own capsule, which is also continuous with the superficial layer
The Submandibular duct (Wharton’s duct) exits the medial surface of the
gland and runs between the Mylohyoid (lateral) and Hyoglossus muscles and
cavity lateral to the lingual frenulum on the anterior floor of mouth. The
length of the duct averages 5 cm. The Lingual nerve wraps around Wharton’s
duct, starting lateral and ending medial to the duct, while CN XII parallels the
the Lingual nerve, and Wharton’s duct is absolutely essential prior to resection
the Submandibular gland comes from the Submental branch of the Facial
artery (off of the External Carotid artery). The Facial artery forms a groove in
the deep part of the gland, then curves up around the inferior margin of the
mandible to supply the face. The Facial artery and vein are the first blood
superficially over the inferior border of the mandible. The Facial vein courses
over the lateral surface of the Submandibular gland. One method of preserving
the Marginal Mandibular nerve is to identify and ligate the Facial vein 2 - 3
cm inferior to the mandible and elevate the vein and all superior tissue
Venous drainage is provided by the Anterior Facial vein, which lies deep
deep cervical and jugular chains of nodes. Perivascular lymph nodes near the
Facial artery are often involved with cancer originating in the Submandibular
(Rosen F. S. 2001).
3. Sublingual Gland
This is the smallest of the major salivary glands. The almond shaped
gland lies just deep to the floor of mouth mucosa between the mandible and
Wharton’s duct and the Lingual nerve pass between the Sublingual gland and
Sublingual gland has no true fascial capsule. Also unlike the Parotid and
which exit the superior aspect of the gland and open along the Sublingual fold
on the floor of mouth. Occasionally, several of the more anterior ducts may
join to form a common duct (Bartholin’s duct), which typically empties into
Wharton’s duct. Of note, the ducts of the sublingual glands are too small for
sources:
a. Sympathetic innervation from the cervical chain ganglia via the Facial
artery
Unlike the major salivary glands, the minor salivary glands lack a
branching network of draining ducts. Instead, each salivary unit has its own
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simple duct. The minor salivary glands are concentrated in the Buccal, Labial,
Palatal, and Lingual regions. In addition, minor salivary glands may be found
at the superior pole of the tonsils (Weber’s glands), the tonsillar pillars, the
base of tongue (von Ebner’s glands), paranasal sinuses, larynx, trachea, and
bronchi. The most common tumor sites derived from the minor salivary
glands are the palate, upper lip, and cheek. Most of the minor glands receive
parasympathetic innervation from the Lingual nerve, except for the minor
glands of the palate, which receive their parasympathetic fibers from the
Palatine nerves, fed by the Sphenopalatine ganglion (Kontis and John, 1998).
cancers of the head and neck. Salivary gland cancer starts in one of the salivary
glands. Salivary glands make saliva, which contains enzymes to begin the process
of digesting food as well as antibodies and other substances that help prevent
infections of the mouth and throat. There are two main types of salivary glands:
the major salivary glands and minor salivary glands. The major salivary glands
are consisted of three sets, the parotid glands in front of the ears, the
submandibular glands below the jaw and the sublingual glands under the floor of
the mouth and on the sides of the tongue. The minor salivary glands are several
hundreds and are located beneath the lining of the lips, tongue, in the roof of the
mouth, and inside the cheeks, nose, sinuses, and larynx (Dimas et al, 2015).
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Neoplasms of salivary gland origin are tumors that involve mainly major
glands. Most salivary gland tumors are benign. There are many types of benign
tumors, and benign mixed tumors (pleomorphic adenomas). Tumors in the minor
salivary glands are less common, but they are more often malignant than benign.
These tumors most often start in the palate (Dimas et al, 2015).
C. CLASSIFICATION
1) Epidemiology
but the age ranges from the first to the tenth decades {703}. There
2) Clinical features
of most tumours varies from about 2-5 cm but some reported cases
have been massive {388}. In the palate, tumours are usually seen at
the junction of the hard and soft palate unilaterally. In the hard
3) Pathology
atypia and 45% had scattered atypical cells with no foci. Overall,
that the luminal cells stained strongly positive for N-CAM in the
malignant transformation.
4) Diagnosis
b. Whartin Tumor
1) Epidemiology
rare before 40. The relative sex incidence has changed during the
last half-century: In 1953 the male to female ratio was 10:1 {786},
al,2009).
a) Clinical features
(Elledge et al,2009).
b) Pathology
c) Diagnosis
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features:
sialogram)
c. Ductal Papilloma
predilection for the minor salivary glands. They tend to occur in the
middle-aged and elderly and rarely in children. The three types of ductal
1) Epidemiology
(Brannon et al,2001).
2) Clinical features
3) Pathology
less than 1–1.5 cm. The lesion often has a reddish color. The
2001).
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d. Oncocytoma
1) Epidemiology
2) Clinical features
3) Pathology
2002).
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based regimens have been the most frequently explored, but the
e. Monomorphic Tumors
have a predilection for development in the upper lip and parotid gland.
Typically, patients are older persons (mean age, 61 years), but a broad age
extent and location of the tumor) for parotid lesions and excision with a
1) Epidemiology
2) Clinical features
3) Pathology
(Tsurumi et al).
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4) Diagnosis
f. Sebaceous Tumors
1) Epidemiology
et al, 2009).
2) Clinical features
3) Pathology
within the islands were united by well formed desmosomes and many had
1) Epidemiology
2) Clinical features
Patient arrived with a mass which was firm, fixed, and non-
3) Pathology
4) Diagnosis
a. Mucoepidermoid carcinoma
salivary gland cancer. Most start in the parotid glands. They develop less
mouth. These cancers are usually low grade, but they can also be
very hard to get rid of completely because it tends to spread along nerves.
These tumors tend to come back after treatment (generally surgery and
radiation), sometimes many years later. The outlook for patients is better
c. Adenocarcinomas
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gland cells (cells that normally secrete a substance). There are many types
1. Acinic cell carcinoma: Most acinic cell carcinomas start in the parotid
age than most other salivary gland cancers. They are usually low
grade, but how far they have grown into nearby tissue is probably a
tend to start in the minor salivary glands. They usually (but not
microscope, these cancers have enough features to tell that they are
are most common in the parotid glands and the minor salivary glands.
rare. Some of these tend to be low grade and usually have a very good
outcome:
• Cystadenocarcinoma
• Sebaceous adenocarcinoma
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• Sebaceous lymphadenocarcinoma
• Mucinous adenocarcinoma
Other rare adenocarcinomas are more likely to be high grade and may
• Oncocytic carcinoma
• Carcinosarcoma
mainly in the major salivary glands. Both the grade of the cancer and how
far it has spread (its stage) are important in predicting outcome. (Spiro R,
1998)
men. It can develop after radiation therapy for other cancers in the
low grade, but it can come back after treatment or spread to other
D. EPIDEMIOLOGY
Salivary gland tumors account for about 3% of all head and neck cancers,
with the majority affecting the parotid gland. The incidence of salivary gland
tumor has been increasing in men, while it has stayed relatively constant in
women. Although there are many factors that negatively affect the prognosis of
patients with salivary gland tumor, the most important factors are histologic type,
grade, and clinical stage at presentation. The 10-year disease-specific survival for
early-stage parotid gland tumor is 97%, compared with 20% for a late-stage
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tumor. Therefore, assessing the tumor early and accurately is important for
al, 2012).
Unlike most other head and neck cancers, the causes of salivary gland
tumors are poorly understood. Unlike head and neck squamous cell carcinoma,
these neoplasms have not been positively linked to tobacco and/or alcohol use,
in salivary tumors has been suggested, with reports indicating mixed and
human papilloma virus types 16 and 18, type B particles, and type C particles are
treat a benign conditions (hypertrophied tonsils, enlarged thyroid, acne, etc.), and
salivary gland tumors. Case studies from the 1970s and 1980s reported increased
salivary gland neoplastic risks for people employed in certain occupations, such
(Sun et al., 1999). Radiation therapy in low doses has aslso been associated with
squamous cell carcinomas found to be increased. As with other forms of head and
control mechanisms of cell division are being studied as possible causes (Olopade
et al., 2000). The discovery of estrogen receptors in both normal salivary glands
and salivary tumors suggests a possible link between endogenous hormones and
salivary gland tumors (Sun et al., 1999). Two theories have also been developed
trying to explain the etiology of the salivary gland tumors: the bicellular stem cell
theory and the multicellular theory. Recent evidence suggests the bicellular stem
cell theory as the more probable etiology of salivary gland neoplasms, that more
logically can explain the development of neoplasms that contain multiple discrete
cell types. According to this theory tumors arise from 1 of 2 undifferentiated stem
cells: the excretory duct or the intercalated duct reserve cell. Excretory stem cells
1999).
F. RISK-GROUP CLASSIFICATIONS
1. Older age
2. Male gender
3. Radiation exposure
Radiation treatment to the head and neck area for other medical
4. Family history
usual risk of developing salivary gland cancers. But most people who
get salivary gland cancer do not have a family history of this disease.
Some studies have suggested that people who work with certain metals
(nickel alloy dust) or minerals (silica dust), and people who work in
cancer, but these links are not certain. The rarity of these cancers
Tobacco and alcohol can increase the risk for several cancers of the
head and neck area, but they have not been strongly linked to salivary
7. Diet
Some studies have found that a diet low in vegetables and high in
animal fat may increase the risk of salivary gland cancer, but more
among heavy cell phone users. In this study, most of the tumors seen
were benign (not cancer). Other studies looking at this issue have not
G. PATOFISIOLOGY
of the salivary ductal system are the main source of neoplastic transformation.
duct cells, myoepithelial cells, and acinar cells, is unclear (Sapp et al. (1997) ; Yu
and Donath (2001)). Recent work has focused on studying protooncogene and
53, epidermal growth factor (EGF), Ki-67, p63, and p73 (Yoo and Robinson
(2000); Vered et al. (2002); Weber et al. (2002); Bilal et al. (2003); Pinto et al.
(2000)). Mutation in p53 have been found in both benign and malignant salivary
gland neoplasms and some evidence suggests that the presence of p53 mutations
wide variety of solid tumors. H-Ras mutations have been shown in a significant
(Friedman and Lim, 2001). In recent studies vascular endothelial growth factor
(VEGF) was found to be expressed in over 50% of the salivary gland carcinomas
tested and could be correlated with clinical stage, recurrence, metastasis, and
with salivary gland tumors, while more recently research is focusing on factors
H. CLINICAL SYMPTOMS
common for these lesions to be present for several years, sometimes decades,
before patients seek treatment. If untreated, parotid tumors can reach remarkable
malignant parotid neoplasms present with pain. Other symptoms include fluid
draining from the ear, pain, numbness, weakness, and trouble swallowing (Regezi
et al., 2003).
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I. CLINICAL EXAMINATION
1. Imaging tests
create pictures of the inside of your body. Imaging tests may be done for a
cancer, to learn how far cancer may have spread, and tohelp find out if
2. X-rays
If you have a lump or swelling near your jaw, your doctor may order
x-rays of the jaws and teeth to look for a tumor. If you have been
diagnosed with cancer, an x-ray of your chest may be done to see if the
cancer has spread to your lungs. This also provides other information
about your heart and lungs that might be useful if surgery is planned.
your body. Unlike a regular x-ray, CT scans can show the detail in soft
tissues (such as internal organs). A CT scan can show the size, shape, and
position of a tumor and can help find enlarged lymph nodes that might
contain cancer. If needed, CT scans can also be used to look for tumors in
other parts of the body. Instead of taking one picture, like a regular x-ray,
then combines these into images of slices of the part of your body that is
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being studied. Before the scan, you may be asked to drink 1 to 2 pints of a
liquid called oral contrast. This helps outline the intestine so that certain
areas are not mistaken for tumors. This is most often needed for CT scans
This helps better outline structures in your body. The injection can cause
some flushing (redness and warm feeling). Some people are allergic and
get hives or, rarely, more serious reactions like trouble breathing and low
blood pressure. Be sure to tell the doctor if you have any allergies or have
ever had a reaction to any contrast material used for x-rays. A CT scanner
has been described as a large donut, with a narrow table that slides in and
out of the middle opening. You need to lie still on the table while the scan
is being done. CT scans take longer than regular x-rays, and you might
feel a bit confined by the ring you have to lie in while the pictures are
being taken.
Like CT scans, MRI scans make detailed images of soft tissues in the
body. But MRI scans use radio waves and strong magnets instead of x-rays.
The energy from the radio waves is absorbed and then released in a pattern
translates the pattern into very detailed images of parts of the body. A
contrast material called gadolinium is often injected into a vein before the
scan to better see details. MRI scans can help determine the exact location
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and extent of a tumor. Sometimes they can help a doctor tell a benign tumor
from a malignant one. They can also help tell if any lymph nodes are
enlarged or if other organs have suspicious spots, which might be due to the
hour – and are a little more uncomfortable. You may have to lie on a table
that slides into a narrow tube, which is confining and can upset people who
have a fear of enclosed spaces. Newer, more open MRI machines can
sometimes be used instead if needed. The MRI machine makes buzzing and
clicking noises that you may find disturbing. Some places will provide
A PET scan looks for areas of high cellular activity (which might be a
sign of cancer), rather than just showing if areas look abnormal based on
their size or shape. This test can help show whether an abnormal lump or
tumor seen on another imaging test may be cancer. If you have been
diagnosed with cancer, your doctor may use this test to see if the cancer
has spread to lymph nodes or other parts of the body. A PET scan can also
be useful if your doctor thinks the cancer might have spread but doesn’t
radioactivity used is very low and will pass out of the body over the next
day or so. Because cancer cells in the body are growing quickly, they
absorb more of the radioactive sugar. After about an hour, you are moved
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onto a table in the PET scanner. You lie on the table for about 30 minutes
body. The picture is not finely detailed like a CT or MRI scan, but it can
able to do both a PET and CT scan at the same time (PET/CT scan). This
lets the doctor compare areas of higher radioactivity on the PET scan with
6. Biopsy
suggest you have salivary gland cancer, but the actual diagnosis is made
from a lump or tumor for testing. This type of biopsy can be done in a
doctor’s office or clinic. It’s done with a thin, hollow needle much like
those used for routine blood tests. Your doctor may first numb the area
over the tumor with local anesthesia. The doctor then puts the needle
directly into the tumor and pulls cells and a few drops of fluid into a
syringe. The sample is then sent to a lab, where it’s checked under a
microscope to look for cancer cells. Doctors may use FNA if they are not
sure whether a lump is a salivary gland cancer. The FNA might show the
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salivary gland cancer. In some cases this type of biopsy can help a person
are taken out to be able to tell for certain what a tumor is made of. But
sometimes not enough cells are removed, or the biopsy is read as negative
(normal) even when the tumor is cancer. If the doctor is not sure about the
8. Incisional biopsy
This type of biopsy may sometimes be done if the FNA biopsy does
not get a large enough sample to examine. In this procedure, the surgeon
numbs the area over the tumor, makes a small incision (cut) with a scalpel
and takes out a tiny part of the tumor. The specimen is sent to the lab to be
looked at by the pathologist. These types of biopsies are not done often for
9. Surgery
may not always provide a clear answer. If this is the case but the physical
exam and imaging tests suggest that cancer may be present, the doctor
may advise surgery to remove the tumor completely. This can both
provide enough of a sample for a diagnosis and treat the tumor at the same
time (see the “Surgery for salivary gland cancer” section for more
information). In some cases if the exams and tests suggest cancer is likely,
the doctor may skip the FNA biopsy altogether and go directly to surgery
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to remove the tumor. The specimen is then sent to the lab to confirm the
diagnosis.
a. Standard Therapies
surgical excision, depending though on the type, size, and stage of salivary
gland cancer and patient’s. In most cases involving the parotid gland,
subclinical disease (Spiro (1998); Le et al. (1999), and Schram and Imola,
b. Experimental Therapies
gene therapy studies have also shown some interesting and promising