UNIVERSITY OF JORDAN

DENTISTRY 2016

Oral Pathology
Slide Sheet 11

Done by:
Saif Abu-Hammour

Corrected by:

Doctor:
Dr. Azmi Darwazeh

CONTACT US: ASNAN LAJNEH

This will be the last lecture in this course

Potentially Malignant Oral Disorders

SOME 'not ALL' squamous cell carcinoma can be preceded by potentially malignant
oral disorders 'oral precursor lesion or oral pre-cancers':
1- Potentially malignant lesions:
a. Leukoplakia
b. Erythroplakia
c. Chronic Hyperplastic Candidosis
White or red lesions, they are potentially malignant, some of them have epithelial
dysplasia, some of them have the tendency to become squamous cell carcinoma,
but again that doesn’t mean that all of them will change to oral cancer.
2- Epithelial atrophy disorders are also a predisposing factor to oral cancer;
some lesions may show epithelial atrophy and increased the risk of
developing oral squamous cell carcinoma because carcinogenic materials can
penetrate it faster and will reach the stem cells located in the basal layer
where mitosis happens and can cause mutation.
Predisposing factors to atrophy:
1- Syphilis (tongue atrophy)
2- Oral submucous fibrosis in India due to their chewing habit
3- Plummer-Vinson Syndrome
4- Solar keratosis (in the lower lip)
5- Lichen planus (mucosal atrophy, very low percentage may develop into
squamous cell carcinoma)
(We will discuss all of them in more details in next semester)
Squamous cell carcinoma as other malignant tumors caused by a defect or mutation
in two main classes of genes:
1- Tumor suppressor gene: the most common gene is
TP53 'they encode proteins that are normally involved
in inhibiting cell proliferation or promoting apoptosis'
2- Oncogenes: C-myc, ras, erb B-1 'they encode cell cycle
proteins that normally increase cell proliferation'

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Clinical presentation of squamous cell carcinoma
The clinical presentation of the oral cancer is very important for diagnosis, because
the early diagnosis of the oral cancer is the key to improving patient prognosis.

Early lesions:
Early lesions may be similar in appearance to benign lesions but they are malignant,
they may be present as a small ulcer, white lesions 'it could be early lesion or
potentially malignant lesion as leukoplakia', red lesion 'it also could be early lesion
or potentially malignant lesion as erythroplakia', clustered lesions, or chronic
fissure.
Note: so if you see red or white lesions, then you have to be suspicious and examine
them carefully or ask a specialist to see them because they can be early lesions of
squamous cell carcinoma and you have to follow-up with them and to take a biopsy
to rule out the malignancy.
They are chronic, persistent and asymptomatic

Red patch White patch Clustered lesions

Signs of malignancy:
(1) Chronicity
(2) Painless
(3) Induration (hard lesion)
(4) Fixation (means that the tumor is infiltrating the
underlying tissues and it is not mobile)
(5) Chronic ulcer
(6) Painless lymph node enlargement (could be metastasis),
so when you see red lesion, white lesion, ulcer, or
clustered lesion you should examine the lymph nodes in
the head and the neck and look for any signs of

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 enlargement because it could be a clinical signs of localized metastatic
carcinoma in the cervical lymph nodes. It is very important to know if there is
lymph node metastases because the prognosis will be bad 'the survival rate is
around 50%'.
Note: But remember not all lymphadenopathy is associated with metastatic
squamous cell carcinoma, some of them could be a just a reaction of the lymph
node to the antigen of the tumor, so you need to take a biopsy 'fine-needle
aspiration biopsy' to rule any metastases. Usually if there is an aggressive local oral
cancer, they remove also the cervical lymph node with the primary tumor as a
preventive procedure 'lymph node dissection'

Late lesions:
In the advanced or late lesions, it easier to recognize them as squamous cell
carcinoma. You could see a big deep ulcer with necrotic base and elevated margins,
you could see large exophytic mass with or without ulceration, fungating mass with
necrosis, tissue disfigurement (necrosis and changing in the shape of the organ, like
in the lower lip for example), or you could see all the features in single lesion (red
and white patches, ulcer and nodule in the same lesion)
Also you could see all the signs of the malignancy that mentioned in the early lesion.
Infiltration of the oral musculature may result in functional disturbances, particularly
if the tumor involves the tongue or floor of mouth. Because of reduced mobility of
the tongue patients may complain of impaired speech or of difficulty in swallowing.
Pain may be a feature of an advanced lesion. Bone invasion may be detected on
conventional radiography and may be suggested clinically by mobility of teeth (if
you find ulcer for example on the gingiva or buccal vestibule, it might cause mobility
of teeth). Occasionally, pathological fracture of the mandible (if you see for example
a chronic ulcer on the alveolar mucosa or the ridge and you take a radiograph, you
may find a bone resorption in that area) and/or neural invasion may cause altered
sensation over the distribution of the trigeminal nerve.

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 Clinical appearance of late-stage squamous cell carcinoma

Histopathology of cancer
A tissue biopsy is required for a definitive diagnosis of oral squamous cell carcinoma.
It looks like a crab, it is simply an infiltration of the surface epithelium to the
underlying tissue and later on to reach the blood vessels or the lymph nodes
(regional or distant metastasis)
First the oral squamous cell carcinomas invade the lamina propria then the
connective tissue of the submucosa (if there is submucosa) or if there is no
submucosa then invasion to the bone (for example hard palate), then vascular
invasion of either lymphatic channels or small blood vessels (metastasis)
There is variable lymphocytic and plasma cell infiltration in the stroma supporting
the invasive malignant epithelium, which probably
represents a reaction by the host's immune system
to tumor antigens as well as a response to tumor
necrosis and ulceration.
As you can see in the figure, the surface epithelium
is no longer limited above the basement membrane,
here we see an infiltration of the underlying tissue.

Pattern of invasion:
It is very important to know the pattern of invasion to be able to predict the
prognosis of the cancer. We classify the tumor according to the pattern of invasion
 The cohesive invasion: composed of large islands and broad stands of
carcinoma that present a 'pushing- invasive front' (one unit pushing front)
 The non-cohesive invasion: is more infiltrative with small islands, thin strands,
and single malignant cells (small island or individual cells)

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If it invading one unit pushing front it has a better prognosis while if it invading
underlining tissue with a small island or individual cells has a poor prognosis because
individual invading cells can go faster throw tissue and blood vessels lymphatic, etc.
So the pattern of invasion is important prognostic factor: one unit invading is better
than individual cells because individual cells have more tendencies to metastases so
the cancer is more dangerous and the surgeon needs to remove the lymph nodes in
addition to the cancerous cells. "the capcaity for tumor cells to distrupt the basement
mebrane and penetrate underying stroma, is the distinguishing feature of malginancy "

Differentiation:
If the tumor is similar to the surface epithelium (in histology) so it’s a good
prognosis while if you can’t differentiate so it’s poor prognosis, here the tumor has a
lot of mutation and there is a major changes in cell’s properties
(more invasion, metastasis, immunity resistance, easy to spread,
etc.)
 Well-differentiated tumors:
The tumor is similar to the surface epithelium (clearly recognizable
as squamous epithelium cells) and it makes keratin and the nuclear
and the cellular pleomorphism is not prominent and there are
relatively few mitotic activity, so the mutations are still low. 'Good
prognosis'
 Moderately differentiated tumors:
It shows less keratinization and more nuclear and
cellular pleomorphism, and increased number of mitotic
figures, but still readily identified as squamous cell
carcinoma. 'Moderate prognosis'
 Poorly differentiated (anaplastic):
It’s not similar to the surface epithelium at all,
keratinization is absent and the cells show prominent
nuclear and cellular pleomorphism and abundant
"hyperchromatism (dense in color), more DNA in nucleus,
and variation in size and shape of the nuclei", often
abnormal mitoses (arrow). In some poorly differentiated
neoplasms the cells may be so abnormal as to hardly be
recognizable as epithelial cells. Poor prognosis
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Spreading:
 Lymphatic: As we said, oral squamous cell carcinoma usually spreads to the
lymphatic (the cervical lymph nodes in the head and neck)
 Vascular: It may invade blood vessels and distal metastases happened (maybe
to lung, brain, bone).
 Perineural invasion: It may also spread around the nerve (for example, the
tumor invade the bone of the mandible and reach the nerves) and it’s very
dangerous because it’s very hard to remove and has a high recurrence rate.
 Invasion of bone: in this case the surgeon needs to remove 1-2 cm from the
normal bone (resection margin or surgical margin), because they fair that the
malignant growth extends past the edges or the margin of the removed tumor
into the cancellous bone. The actual size of the tumor is larger than the size
shown on the radiographs.
 Metastatic spread

Prognosis
The survival rate of patient with oral squamous cell carcinoma depends on number
of factors:
 Delay of treatment: the most important
The earlier the diagnosis, the better the prognosis.
More delay treatment → bigger size of the tumor → more metastasize → hard for
surgery → more complication and maybe death (bad prognosis)
So you as dentist have to perform an examination of your patient's mouth during a
routine dental visit to screen for oral cancer. And if you find anything abnormal then
refer them to a specialist.
 Age: the more the age the poorer the prognosis (for example a 70 years old
patient has less survival rate then 40 years old patient).
But what about very young patient?
In young adults is fortunately uncommon. However, since it is so rare, we expect the
patient had a huge mutation in the genes that develop into aggressive oral cancer so
the prognosis is poor. So as conclusion, old patients and very young patients have
poor prognosis.

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Also a young patients are often misdiagnosed and inappropriately treated leading to
delay in definitive treatment because it uncommon in their age. This may, in turn,
lead to a poorer prognosis for these patients.
It is debatable if oral cancer in younger adults carries an inherently poor prognosis.
 Male: male's poor prognosis than woman because of delay treatment (usually
males are careless so they discover the cancer in late stages)
 Posterior location: the lip or the tip of the tongue have better prognosis and
easier to treat than posterior region of the tongue or soft palate for example
because the patient discovers anterior areas earlier then posteriors. So
anterior regions have better prognosis than posterior regions
 Anaplastic (poorly differentiated) cancer has poor prognosis than well-
differentiated one, and also the pattern of invasion (one unit invasion has
better prognosis then individual cells). There will be more chance of spreading
and metastasis if the tumor appears aggressive histologically. If the surgeon
find in the pathological report that the tumor is aggressive, then he might
remove the cervical lymph node as a preventive procedure 'lymph node
dissection' because there could be a few cancer cells in the lymph nodes that
need to be removed.
 TNM stage
 T describes the size of the original (primary) tumor (the diameter of the
tumor).
 N describes nearby (regional) lymph nodes that are involved.
 M describes distant metastasis (spread of cancer from one part of the
body to another).
Clinical staging of carcinoma of the lip and oral cavity
T - Primary tumor
 T1: tumor 2cm or less in greatest dimension and 5mm or less in depth of
invasion.
 T2: tumor 2cm or less in greatest dimension and more than 5mm but no more
than 10mm in depth of invasion or tumor more than 2cm but not more than
4cm in greatest dimension and depth of invasion no more than 10mm.
 T3: tumor more than 4 cm in greatest dimension or more than 10mm depth of
invasion.
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  T4a: (lip) tumor invades though cortical bone, inferior alveolar nerve, floor of
mouth, or skin (of the chin or the nose)
 T4a: (oral cavity) tumor invades though cortical bone of mandible or maxillary
sinus, or invades the skin of the face.
 T4b: (lip and oral cavity) tumor invades masticator space, pterygoid plates, or
skull base, or encases internal carotid artery.
N - Regional lymph nodes
 N0: No regional lymph nodes metastasis
 N1: Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest
dimension without extra-nodal extension.
 N2a: Metastasis in a single ipsilateral lymph node, more than 3 cm but less
than 6cm greatest dimension without extra-nodal extension.
 N2b: Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm
greatest dimension without extra-nodal extension.
 N2c: Metastasis in bilateral or contralateral lymph nodes, none more than 6
cm greatest dimension without extra-nodal extension.
 N3a: Metastasis in lymph node more than 6 cm greatest dimension without
extra-nodal extension.
 N3a: Metastasis in a single or multiple lymph nodes without clinical extra-
nodal extension.
M - Distant metastasis
 M0: no distant metastasis
 M1: metastasis to distant organs (beyond regional lymph nodes)
Stage grouping
Stage I T1 N0 M0
Stage II T2 N0 M0
Stage III T3 N0 M0
T1, T2, T3 N1 M0
Stage IVA T4a N0, N1 M0
T1, T2, T3, T4a N2 M0
Stage IVB Any T N3 M0
T4b Any N M0

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Stage IVC Any T Any N M1

Doctor said you need to know how to grade it, and keep in mind that the
pathological grading is more accurate than the clinical grading.

Verrucous Carcinoma
There are also a few uncommon histological variants of oral squamous cell
carcinoma, one of them is the verrucous carcinoma.
 It’s a type of squamous cell carcinoma that infiltrate laterally rather than
deeply, so it will spread laterally on the surface. The name relates to the
verruciform (warty) surface.
 Males > 60 y
 Mandibular buccal sulcus and adjacent areas
 It is associated mostly with tobacco chewing & snuff-dipping
 Slowly growing, white, exophytic, papillary, diffusely distributed
 Thickened well-differentiated squamous epithelium with minimal dysplasia.
 Metastasis uncommon

Histopathology:
 Closely-packed papillary masses
 Heavily keratinized stratified squamous epithelium
 Well-defined lower border (well differentiated)
 Spread laterally not deeply

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 Well-differentiated epithelium

Blunt rete processes

Intense CICI

The prognosis here is better than the densely infiltrating squamous cell carcinoma.

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Basal cell carcinoma (rodent ulcer)
 It is the most common skin cancer and frequently
occurs in the mid-face and adjacent sun-exposed skin
in elderly people, it may present on the lips,
particularly the upper lip, but many are probably skin
tumors that have spread to involve the vermilion
border, so you as dentist need to know about it in
order to diagnose it and refer the patient to the
specialist.
 Upper face
 The typical basal cell carcinoma presents as a slow-
growing nodule that eventually ulcerates centrally.
 It manifests clinically as papule so the dentist should
diagnose this papule because people usually neglect it
and it’s the dentist responsibility to discover that it isn’t
normal.
 It enlarges and could transform into Rodent ulcer
(papule → enlarge → Rodent ulcer) (see the figure)
 Central crusted ulcer with elevated rolled border

Histopathology:
Microscopically, basal cell carcinoma are composed of
sheets and islands of squamous cells resembling those in
the basal layer of epidermis, referred as 'basaloid' cells
(Proliferation of basaloid epithelium)
Invasion to the area (local distraction).
Late metastases to distant areas. 'Very rare'

Basal cell carcinoma is

locally invasive and
metastatic spread is very
rare

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Melanocytic naevi:
 Melanocytic naevi (often referred to as moles) are
exceedingly common benign hamartomatous lesions,
formed by increased proliferation of melanocytes.
 Developmental lesions particularly found on the skin of the
head and neck, they appear rarely in oral mucosa and the
most common sites are (hard palate and buccal mucosa).
 Focal collection (nests) of rounded melanocytes.
 They may present as slightly elevated, pigmented lesion on the hard palate or
buccal mucosa.
 Childhood & adolescence: 20-30/person.
 Oral naevi rare: adults, slightly elevated or flat, and most often brown in color
(but it could vary from oink to black).

Histologically, there three many variants:

1- Junctional activity: when melanocytes are at the basal region between
epithelium and the underlying lamina propria.

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 2- Compound naevus: when melanocytes are found in the epithelium and the
underlying lamina propria.

3- Intra-mucosal naevus "the most common type": in the late stage of the
lesion, the melanocytes are found ONLY in the underlying tissue.

They consider them as different stages of the same lesions, the lesion starts as
junctional then compound then intra-mucosal, so the intra-mucosal naevus is the
most common because it is the end stage of all lesions.
Malignant change exceedingly rare.

Blue naevus "rare"

 The fourth type of Melanocytic naevi.
 Dark-blue dome-shaped papule or flat macule.
 Second most common type of naevus in the oral mucosa, and
the most common site is the hard palate.
 Heavily pigmented spindle melanocytes, deep and flat, that's
why appear bluish in color.
 The cause of this naevus is failure of melanocytes to migrate
to the surface epithelium coming from neural crest as origin.

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 +

Malignant melanoma
It is a malignant tumor, it appears at sun exposed skin, and it could appear on the
mucus membrane of the mouth.
Has two types:
1. Superficial (lateral) spreading type:
- Most common, brown, black irregular
macule/plaque
- Radial growth (laterally) in the initial stage and
then vertical growth.
- Better prognosis

2. Nodular type:
- Red/brown/black nodules/ulcerated
- Infiltrate deeply.
- Little or no radial growth.
- bad prognosis
Keep in mind that the most prognostic factor in the melanoma is the depth of the
lesion (more chance to metastasis), and as we mentioned earlier that the superficial
type spreads laterally, while the nodular type spreads deeply, so the prognosis of
the first type is better than the second one.

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Oral melanoma 'rare'
 Variable in color
 It can start as a macule then enlarge into a papule or a nodule then to
ulceration and destruction, so it could start as benign small macule (similar to
naevus) but later on it start to appear darker and get larger.
 Men 40-60 years.
 Maxillary >> Mandibular
 Posterior maxillary alveolar ridge & hard palate.
 Asymptomatic at early stage.
 Later rapid growth with destruction & spread.

Histopathology:
Biopsy: Intensely pigmented round/spindle Cs.
In rare cases, the lesions don’t cause pigmentation (just melanocytes infiltrating the
underlying tissue without pigmentation), so here we need to do
immunohistochemistry test to diagnose these cases.

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