REVIEW

Australian Dental Journal 1999;44:(3):147-156

Current concepts in oral cancer

Philip B. Sugerman, BDS, PhD, FRACDS, FDSRCS, FFOP RCPA*
Neil W. Savage, MDSc, PhD, FFOP RCPA, FICD

Abstract
Over 750 new intra-oral squamous cell carcinomas
are registered in Australia each year. In this article,
the authors review the epidemiology, aetiology,
genetics and spread of intra-oral squamous cell
carcinoma. The mechanisms of field cancerization
are discussed. The prevention of intra-oral
squamous cell carcinoma is highlighted and future
treatments are presented.
Key words: Oral cancer, epidemiology, aetiology, genetics,
spread, prevention, therapy.
(Received for publication February 1999. Revised June
1999. Accepted June 1999.)

Introduction
Intra-oral squamous cell carcinoma accounts for
approximately one per cent of all cancers and one
per cent of all cancer-related deaths in men and
women in Australia. It is estimated that 75 per cent
of all intra-oral squamous cell carcinomas in
Australia are attributable to smoking and alcohol.
Therefore, patient awareness of the risks of smoking
and alcohol may help prevent many intra-oral
squamous cell carcinomas.
Cancer in Australia
The anatomical location of malignancies is coded
by the World Health Organization (WHO).1 There
were 75 498 new cancers (excluding non-melanocytic
skin cancer) registered in Australia in 1994. Prostate
cancer was the most common followed by colorectal
cancer, breast cancer, lung cancer and melanoma
(Table 1). Of the 42 619 cancers registered in males
in Australia in 1994, the most common was prostate
cancer. Of the 32 879 cancers registered in females
in Australia in 1994, the most common was breast
cancer (Table 2). Lung cancer in males and breast
cancer in females were the most common cancers
causing death in Australia in 1994 (Table 3).2
*CJ Martin Postdoctoral Fellow and Registrar in Oral Medicine and
Pathology, Department of Dentistr y, The University of Queensland.
Reader in Oral Medicine and Pathology, Department of Dentistr y,
The University of Queensland.
Australian Dental Journal 1999;44:3.

Oral cancer in Australia

The 1994 Australian oral cancer incidence and
mortality data are presented in Table 4.There were
1906 new oral cancers (all sites) registered in
Australia in 1994; 1299 in males and 607 in females.
As a comparison, there were 1121 new cancers of
the cervix uteri (ICD9-180) registered in Australia
in 1994.The lip is by far the most common site for
cancer in the oral region (Table 4).The incidence of
oral cancer in Australia is relatively stable over time.
The authors define intra-oral cancer as cancer
affecting the oral tissues excluding lip cancer (ICD9140) and major salivary gland cancer (ICD9-142).
Intra-oral cancer includes tongue (ICD9-141), gum
(ICD9-143), floor of mouth (ICD9-144) and other
mouth (ICD9-145). Using this definition, there
were 804 new intra-oral cancers registered in
Australia in 1994; 515 in males and 289 in females.
The tongue is the most common site for intra-oral
cancer in Australia and the majority of intra-oral
cancers (all sites) are in men (Table 4). Conservative
estimates suggest that 95 per cent of intra-oral cancers
are squamous cell carcinomas (SCCs). Hence,
there were approximately 764 new intra-oral SCCs
registered in Australia in 1994; 489 in males and 275
in females. Intra-oral SCC therefore accounts for
approximately one per cent of all cancers in men and
women in Australia. Deaths resulting from intra-oral
SCC (288 in 1994) account for approximately one
per cent of all cancer-related deaths in Australia.2 The
mortality to incidence (M:I) ratio for oral cancers at
various sites is shown in Table 4. The data give no

Table 1. The most common cancers registered

in Australia in 19942*
Rank

Cancer

1
2
3
4
5

prostate (ICD9-185)
colorectal (ICD9-153/154)
breast (ICD9-174/175)
lung (ICD9-162)
melanoma (ICD9-172)

Number of cases
12 787
10 016
9 764
7 306
6 776

*The anatomical location of malignancies is coded by the World

Health Organization.1
147

Table 2. The most common male and female cancers registered in Australia in 1994 (number of
cases)2*
Rank

Males

1
2
3
4

prostate (ICD9-185)
colorectal (ICD9-153/154)
lung (ICD9-162)
melanoma (ICD9-172)

Females
12 787
5 433
5 196
3 695

breast (ICD9-174)
colorectal (ICD9-153/154)
melanoma (ICD9-172)
lung (ICD9-162)

9 694
4 583
3 801
2 110

*The anatomical location of malignancies is coded by the World Health Organization. 1

Table 3. The most common male and female cancers causing death in Australia in 1994 (number of
deaths)2*
Rank

Males

1
2
3

lung (ICD9-162)
prostate (ICD9-185)
colorectal (ICD9-153/154)

Females
4 833
2 613
2 501

breast (ICD9-174)
colorectal (ICD9-153/154)
lung (ICD9-162)

2 669
2 126
1 901

*The anatomical location of malignancies is coded by the World Health Organization. 1

indication of the behaviour of individual tumours,

although they suggest that tongue, major salivary
gland and floor of mouth cancers have the greatest
lethality, whereas lip cancer has relatively low lethality.
In the USA,an estimated 29 800 new cases of oral
cancer are expected to be diagnosed in 1999 and
approximately 8100 people will die of the disease.
Oral cancer accounts for about three per cent of
cancers in men and two per cent of cancers in women.
More than 90 per cent of oral cancers occur in
patients over the age of 45.The incidence increases
steadily with age until 65, when the rate levels off.
Over the last 22 years in the USA, there have been
slight decreases in oral cancer incidence and mortality
rates.Worldwide, oral SCC is the sixth most common
malignancy. Although oral SCC accounts for less
than five per cent of malignant tumours in developed
countries, in parts of India and South East Asia oral
SCC is the most common malignancy, accounting
for up to 50 per cent of malignant tumours in these
regions.
The significance of oral cancer involves its mortality
and the disfigurement and dysfunction associated
with treatment. The rate of curability of cancers of
the lip and oral cavity varies depending on the stage
and the site. Most lip cancers and small cancers of
the retromolar trigone, hard palate and upper gingiva
are highly curable by surgery or radiation therapy.
Small cancers of the anterior tongue, the floor of
the mouth and the buccal mucosa are treated with
radiation therapy or surgery with local control rates of
up to 90 per cent. Moderately advanced and advanced
cancers of the lip can be controlled effectively by
surgery or radiation therapy or a combination of
these. Moderately advanced lesions of the retromolar

National Cancer Institute. CancerNet. Lip and oral cavity cancer. URL:http://
cancernet.nci.nih.gov/clinpdq/soa/Lip_and_oral_cavity_cancer_Physician.html.
Accessed June 1999.
148

trigone without evidence of spread to cervical lymph

nodes are usually curable, with local control rates of
up to 90 per cent. Moderately advanced lesions of
the hard palate, upper gingiva and buccal mucosa
have a local control rate of up to 80 per cent. In the
absence of clinical evidence of spread to cervical
lymph nodes, moderately advanced lesions of the
floor of the mouth and anterior tongue are generally
curable, with survival rates of up to 70 per cent and
65 per cent, respectively. However, for many intraoral cancers, especially those with cervical lymph
node metastases, the five year survival rate is less
than 50 per cent.
The causes of intra-oral SCC (oral cancer)
The current hypothesis in oral carcinogenesis is
that there is an accumulation of genetic mutations in
oral epithelial cells, with tobacco and betel quid
mutagens (possibly facilitated by alcohol) identified
as aetiological agents. It is estimated that 75 per cent
of all intra-oral cancers in Western countries can be
attributed to smoking and alcohol. 3 However, only a
small proportion of individuals who use tobacco,
alcohol or betel quid develop oral cancer and there
is an emerging population of oral cancer patients

Table 4. Oral cancer incidence (and mortality)

in Australia in 1994 2*
Cancer
location
ICD9-140 (lip)
ICD9-141 (tongue)
ICD9-142
(major salivary glands)
ICD9-143 (gum)
ICD9-144 (floor of mouth)
ICD9-145 (other mouth)

Males

Females

Total

M:I
ratio

668 (8) 255 (6) 923 (14) 0.015

235(120) 135(53) 370(173) 0.468
116 (41)
63(21) 179 (62) 0.364
26 (7)
123 (45)
131 (31)

19 (7)
45 (14) 0.311
43(14) 166 (59) 0.355
92(26) 223 (57) 0.256

*The anatomical location of malignancies is coded by the World

Health Organization.1
The mortality to incidence (M:I) ratio is calculated by dividing the
total number of deaths by the total incidence.
Australian Dental Journal 1999;44:3.

Fig.1. Keratotic plaque on the mid-buccal mucosa in a long-term cigarette user.The surface irregularity and fissuring make this type of opaque
keratosis difficult to clinically assess with confidence and biopsy is indicated.This lesion showed an epithelial hyperplasia with keratosis.
Fig. 2. Typical velvet appearance of a speckled leukoplakia/erythroplakia.These lesions are frequently dysplastic and always require histology.
This lesion showed a moderate epithelial dysplasia.
Fig. 3. Discrete erythroplakia on the soft palate in a male cigarette user. The lesion was asymptomatic and without textural change within the
tissues. Biopsy showed a carcinoma in situ. The patient declined any treatment and died from disseminated malignancy several years after initial
presentation.
Fig.4. Non-homogeneous commissural keratotic plaque showing surface irregularity, erythema and surface desquamation.Such lesions require
histology but their clinical presentation may be improved by preliminary use of an antifungal as they frequently have a secondary candidal
component. Biopsy showed an epithelial hyperplasia with moderate dysplasia.

who lack exposure to these agents. Infection of oral

keratinocytes with human papillomavirus (HPV) may
be involved in the development of oral cancer in some
patients. A role for HPV in oral cancer is supported
by findings of HPV in tumour tissue and by studies
showing that HPV immortalizes oral keratinocytes in
vitro.4,5 HPV-immortalized oral keratinocytes become
tumorigenic in mice following exposure to tobaccorelated chemicals in vitro.6 The E6 and E7 genes of
HPV16 and HPV18 encode proteins that are involved
in the direct destruction of the p53 and retinoblastoma
(pRb) growth-regulatory proteins, respectively.4 In
contrast, mutagens in tobacco, alcohol and betel quid
are thought to damage important growth-regulatory
genes in oral kerat i n o cy t e s , resulting in cancer
formation. Chronic infection of oral keratinocytes
with Candida albicans may have a role in oral carcinogenesis. Candida albicans stimulates epithelial cell
proliferation in vitro and oral lesions of chronic
hyperplastic candidosis (candidal leukoplakia) show
epithelial dysplasia and may undergo malignant
Australian Dental Journal 1999;44:3.

transformation.7 F u rt h e rm o r e , C. albicans was

shown in rats to be an effective promoter of 4-nitroquinoline-1-oxide (4NQO)-initiated oral mucosal
squamous cell carcinoma. 8
Oral cancer and epithelial dysplasia
It is unknown if all oral cancers are preceded by
histological epithelial dysplasia.This is mainly because
most oral cancers (at least in Western societies) are
not preceded by a visual lesion and therefore very
few patients have a precancer biopsy at the cancer
site. Epidemiological data suggests that a proportion
of many oral mucosal lesions including idiopathic
white patch (leukoplakia) (Fig. 1), speckled leukoplakia (Fig. 2), erythroplakia (Fig. 3), chronic
hyperplastic candidosis (Fig. 4), oral submucous
fibrosis, discoid lupus erythematosus and dyskeratosis
congenita undergo malignant transformation.
However, biopsy sections of these lesions show marked
variability in the presence of epithelial dysplasia.7
Only a few studies have followed dysplastic oral
149

lesions histologically over a period of time.In a study

of 45 patients with dysplastic oral lesions followed
for up to eight years, 11 per cent of lesions became
malignant while 30 per cent regressed spontaneously.9
It seems that oral cancers are preceded by histological
epithelial dysplasia (which may or may not be
apparent clinically), although not all dysplastic oral
lesions progress to malignancy. At present, it is not
possible to predict which dysplastic oral lesions will
proceed to malignancy and which will regress.10 A
recent molecular study found identical genetic
changes in dysplastic oral lesions and oral cancers in
the same patients, suggesting that the progeny of cells
in a dysplastic oral lesion may, with further modification, ultimately form a malignant lesion.11 This is
the first evidence that a clone of oral keratinocytes
proceeds through stages of transformation from
normal, to dysplastic, to malignant. The finding
suggests that oral keratinocytes suffer genetic damage
at each stage boundary until the accumulated genetic
damage is sufficient for autonomous proliferation
and tumour formation.

cascade-like manner (Fig. 5). MAPK is mitogen

activated protein (MAP) kinase, MEK is MAP
kinase kinaseand Raf is MAP kinase kinase kinase.
The kinase cascade transmits the growth signal from
the cell membrane to the nucleus where the level
of c-myc protein rises sharply (Fig. 5). The c-myc
protein binds DNA and stimulates the transcription
of cyclin D which binds and activates cyclin-dependent kinase (CDK). Active CDK catalyses the
phosphorylation of the retinoblastoma tumour
suppressor protein (pRb). Phosphorylated pRb
releases the E2F transcription factors which are
required for the transcription of DNA replication
proteins (Table 5). DNA replication proceeds,
followed closely by cell division (Fig. 5). Cyclin D and
most of the DNA replication proteins are degraded
and must be newly transcribed with each round of
cell division. Many of the proteins which transmit
the growth signal from the cell membrane to the
nucleus are encoded by oncogenes. As discussed
below, oncogene mutation may stimulate excessive
keratinocyte proliferation in oral cancer.

Oral cancer and cell division

An obvious feature of all oral cancers is excessive
proliferation of oral keratinocytes. Initially, keratinocyte proliferation may be confined to the
epithelial compartment resulting in a thickened and
disorganized epithelium. Individual keratinocytes
show nuclear hyperchromatism (dark staining),
nuclear pleomorphism (abnormal shape), enlarged
nucleoli, increased nuclear:cytoplasmic ratio,
increased mitoses, suprabasal mitoses, abnormal
mitoses and multinucleation. There may be loss of
polarity of the basal cells, drop-shaped rete processes,
irregular epithelial stratification and reduced cellular
cohesion. The intra-epithelial lesion is termed
epithelial dysplasia (graded as mild, moderate or
severe) or carcinoma in situ, depending on extent.
Eventually, the proliferating keratinocytes break
through the epithelial basement membrane (see
The spread of oral cancer below). Malignant
epithelial masses then expand through the underlying
connective tissue and invade lymph and blood vessels
resulting in distant spread.
In this context, oral cancer is a lesion characterized
by dysregulated division of oral keratinocytes.
Knowledge of normal DNA replication and keratinocyte division is the key to understanding
abnormal cell division in oral cancer. Normally, oral
keratinocyte division is stimulated by epidermal growth
factor (EGF) binding the epidermal growth factor
receptor (EGFr) on the surface of basal keratinocytes
(Fig. 5).12 EGF receptor-ligand interaction activates
the ras protein on the cytoplasmic side of the EGFr.
Active ras activates the Raf protein and subsequently
the other cytoplasmic kinases (MEK, MAPK) in a

The genetic basis of oral cancer

Evidence suggests that oral cancer results from
genetic damage.There is increased risk of oral cancer
associated with exposure to genetic mutagens in
tobacco, alcohol and betel quid. Gene mutations
have been detected in oral SCC in chromosomes 3p,
4q, 6p, 8p, 9p, 11q, 13q [retinoblastoma (Rb)
tumour suppressor gene], 14q, 17p (p53 tumour
suppressor gene), 18q [deleted in colon cancer (DCC)
tumour suppressor gene] and 21q.11,13 The genetic
hypothesis predicts a role for hyperactive oncogenes
(growth promoting genes) in oral carcinogenesis.
Oncogenes encode many of the signal-transmitting
proteins (for example, EGFr, ras, cytoplasmic
kinases, c-myc) via which cells respond to external
growth signals (Fig. 5). Normal cells, with normal
oncogenes, will not commit themselves to another

150

Table 5. Proteins required for DNA replication*

. Enzymes required in nucleotide synthesis

. Initiator
proteins bind at replication origin
. DNA helicase
binds initiator proteins and opens the double helix
. Single strand DNA
binding proteins (helix destabilizing proteins)
stabilizes unwound single strand DNA
. DNA polymerase polymerizes deoxyribonucleoside triphosphates
on a single strand DNA template
. (5-to-3)
PCNA (proliferating cell nuclear antigen) tethers DNA
to the DNA template
. polymerase
DNA primase makes RNA primers for lagging strand replication
. DNA ligase joins Okazaki fragments during lagging strand
replication
. Proofreading
exonuclease provides base-paired terminus that
primes DNA synthesis
. DNA topoisomerase transient nick in DNA to allow free rotation
during replication
*Most of these proteins are enzymes which are newly transcribed
with each round of cell division. Many of these proteins are transcribed
by the E2F family of transcription factors (Fig.5).
Australian Dental Journal 1999;44:3.

round of DNA replication and cell division without

stimulation from such external signals. However,
with oncogene mutation, the mutant oncoprotein
may send a growth-stimulatory signal to the
nucleus, regardless of events taking place in the cells
surroundings. The subsequent autonomous proliferation of mutant oncogene-bearing cells results in
tumour formation.
As discussed, the ras oncoprotein lies on the
internal aspect of the membrane-bound EGFr and is
involved in the transmission of the EGF growthstimulatory signal to the nucleus (Fig. 5). In the
inactive state, ras binds guanosine diphosphate
(GDP).When cells are stimulated by EGF, inactive ras
become activated by exchanging GDP for guanosine
triphosphate (GTP). Active ras activates the Raf
protein and subsequently the other cytoplasmic
kinases (MEK, MAPK) in a cascade-like manner
(Fig. 5). After activating Raf, active ras returns to
the inactive state due to its intrinsic guanosine
triphosphatase (GTPase) activity. GTPase hydrolyses
GTP to GDP, thereby releasing a phosphate group
and returning the ras protein to its inactive GDPbound state. The intrinsic GTPase activity of
activated ras is amplified by binding of GTPaseactivating proteins (GAPs). Under normal
circumstances, this mechanism ensures that ras is
active for only a brief period of time following EGF
stimulation and that cell proliferation is tightly
regulated by EGF. However, the control of ras
activity changes dramatically with mutation of the
ras oncogene. Mutant ras protein can bind GAPs,
however GTPase activity is not amplified. Hence,
mutant ras is trapped in its active GTP-bound form
which continues to activate Raf, thus sending a
proliferation signal to the nucleus even in the
absence of binding between EGF and its receptor on
the cell surface.14 In addition, hyperactive ras may
stimulate the transcription of bcl-2 which blocks
caspase 3 activation and hence blocks apoptotic
cell death (discussed below). Many studies have
shown ras oncogene mutation and ras oncoprotein
over-expression in oral SCC.12,15 Furthermore, oral
premalignant lesions and oral cancer may be associated with upregulated EGF receptor expression.16
Oral cancer may, therefore, result from mutation of
an oncogene in the EGF pathway. The mutant
oncoprotein sends a continuous growth signal to the
nucleus resulting in continuous oral keratinocyte
proliferation and tumour development.
Under normal circumstances, the p53 tumour
suppressor protein detects DNA damage (such as ras
oncogene mutation) and halts progression through
the cell cycle. Following DNA damage, there is an
increase in the level of p53 which, in turn, stimulates
the transcription of p21 (Fig. 5). The p21 tumour
suppressor protein is a CDK inhibitor and blocks
Australian Dental Journal 1999;44:3.

F i g .5 . Normal oral keratinocyte division is stimulated by epidermal

growth factor (EGF) binding the EGF receptor (EGFr) which
activates ras. Active ras triggers the kinase cascade (Raf, MEK,
MAPK) resulting in increased levels of c-myc in the nucleus. c-myc
stimulates the transcription of cyclin D which activates cyclin-dependent kinase (CDK). Active CDK catalyzes the phosphorylation of
the retinoblastoma tumour suppressor protein (pRb).
Phosphorylated pRb releases the E2F transcription factors which are
required for the transcription of DNA replication proteins including
proliferating cell nuclear antigen (PCNA). DNA replication proceeds,
followed closely by cell division. Cyclin D and most of the DNA
replication proteins are degraded and must be newly transcribed with
each round of cell division. DNA damage in oral keratinocytes is
detected by p53.As a result, there is an increase in the level of p53
which stimulates the transcription of p21, a CDK inhibitor which
blocks the phosphorylation of pRb. p21 also binds and deactivates
PCNA. p53 stimulates the transcription of Bax which blocks the
activity of bcl-2. Caspase 3 activity is therefore unchecked and
apoptotic cell death proceeds. The dotted lines represent the
apoptotic cell death pathway following DNA damage.

the phosphorylation of pRb, thereby blocking the

release of E2F transcription factors and blocking
DNA replication.The p21 tumour suppressor protein
also binds and deactivates proliferating cell nuclear
antigen (PCNA) (Fig. 5). PCNA is a toroidalshaped protein that encircles and slides along DNA.
PCNA tethers the DNA polymerase catalytic unit to
the DNA template and is therefore essential for
DNA replication. Binding of p21 to PCNA inhibits
the interaction between PCNA and DNA polymerase,
thereby blocking DNA replication. Hence p53,
acting via p21, puts the brakes on DNA replication
and cell division in cells with damaged DNA. In some
instances, p53 will trigger apoptosis (programmed cell
151

death) in cells with damaged DNA. p53 stimulates

the transcription of Bax which blocks the activity of
bcl-2 (Fig.5). bcl-2 normally blocks the activation of
caspase 3, a central mediator of the apoptosis cell
death pathway. When bcl-2 activity is blocked by
Bax, caspase 3 activity is unchecked and apoptotic
cell death proceeds (Fig. 5). p53 also represses the
transcription of bcl-2 which further contributes to
caspase 3 activity and apoptosis in cells with damaged
DNA.
However, if the p53 gene is mutated, the protection
offered by the p53 tumour suppressor protein against
DNA damage (for example, ras oncogene mutation)
is lost. Both alleles of the tumour suppressor gene
must be mutated for the tumour suppressor protein to
become non-functional. A cell which is heterozygous
for a tumour suppressor gene has one normal
allele and one mutant allele and the cell is clinically
normal. If a cell becomes homozygous for the
mutant allele, that is loses heterozygosity, cancer
may develop. In familial cases of retinoblastoma,
children inherit one mutant allele of the Rb tumour
suppressor gene and the other allele is normal. Only
one somatic mutation is required to inactivate the
single normal allele of the Rb gene and for
retinoblastoma to develop. In sporadic cases, both
normal alleles of the Rb tumour suppressor gene in
a single retinoblast are lost by somatic mutation
resulting in retinoblastoma. In the Li-Fraumeni
cancer susceptibility syndrome, children inherit one
mutant allele of the p53 tumour suppressor gene
and the other allele is normal. Again, only one
somatic mutation is required to inactivate the single
normal allele of the p53 gene and patients with this
syndrome are at high risk of developing carcinomas,
sarcomas, lymphomas and brain tumours. Most oral
cancers are sporadic and therefore both normal
alleles of the p53 tumour suppressor gene in a single
oral keratinocyte are lost by somatic mutation. In
this context, the tumour suppressor genes are
recessive, as both alleles must be damaged for
transformation to occur. In contrast, the oncogenes
(for example, ras) are dominant, as mutation of
only one allele results in transformation.
Mutation of the p53 tumour suppressor gene is
the most common genetic lesion in human neoplasia
and p53 is mutated in up to 80 per cent of oral
cancers.17 In oral SCC, p53 mutation correlates with
a history of heavy smoking and is associated with
increased epithelial cell proliferation. Mutation of
p53 may precede18 or accompany19 the transition from
oral pre-cancer to cancer. A common p53 mutation
in many tumours is deletion of one allele accompanied
by a mutation in the central DNA-binding domain
of the remaining allele. Consequently, the mutant
p53 protein is unable to stimulate p21 or Bax
transcription and cells with damaged DNA (for
152

example, mutated ras oncogene) continue to divide,

passing on their gene mutations to subsequent
generations.
By way of a simple example, oral cancer may result
from an activating mutation of the ras oncogene and
a simultaneous deactivating mutation of the p53
tumour suppressor gene in an oral keratinocyte. In
this scenario, oral cancer would evolve from an oral
keratinocyte that has received three genetic hits
from mutagens in tobacco, alcohol, betel quid or
some other source. The first hit would inactivate
one allele of the p53 tumour suppressor gene. The
second hit would inactivate the other allele of the
p53 tumour suppressor gene. The third hit would
activate the ras oncogene.The order of these hits is
probably important, as ras oncogene mutation in the
presence of at least one functional allele of p53
would be expected to result in cell cycle arrest and
apoptosis. As discussed, oral cancer may result from
mutation in other oncogenes in the EGFr/ras/kinase
cascade/c-myc signalling pathway and Califano et al.
identified cumulative tumour suppressor gene
mutations which correlated with the stages of carcinogenesis from normal mucosa, to squamous hyperplasia
(9p), to dysplasia (3p, 17p) to carcinoma in situ (11q,
13q, 14q) to invasive carcinoma (6p, 8 and 4q). 13
Field cancerization
Some oral cancer patients develop SCC over a
broad area of the oral mucosa, with multiple lesions
arising simultaneously or over a period of time.The
high incidence of second primary cancers in patients
with oral SCC was first reported by Slaughter et al.
in 1953.20 The authors proposed the term field
cancerization to describe this phenomenon and
subsequent reports have confirmed their observations.21 Approximately 2-3 per cent of oral cancer
patients develop a second primary cancer each year
after removal of the primary tumour and 90 per cent
of recurrences manifest within two years of initial
treatment.With advances in therapy, more patients
survive initial tumours. Hence, the incidence of
second primary oral cancers is expected to rise.22
U n f o rt u n at e l y, tumour recurrence or a second
primary tumour has a significant adverse effect on
survival of oral cancer. Hence, the identification of a
predictive marker for second primary oral cancers
would have significant prognostic and patient
management implications. Until that time, the rising
incidence of second primary tumours indicates that
prevention should be the primary objective.
The mechanisms of field cancerization are
unknown, although three basic hypotheses were
proposed recently by Ogden.22 Firstly, field changes
(molecular changes throughout the oral mucosa of
oral cancer patients) may predispose to the development of multiple primary cancers. In this scenario, a
Australian Dental Journal 1999;44:3.

large region of the oral mucosa may be exposed to

the aetiological agent(s) which causes independent
transformation of multiple epithelial cells at separate
sites. A single aetiological agent acting at different
sites would cause multiple separate cancers with
identical genetic defects, each arising as a separate
clone within the oral mucosa. Subsequent genetic
modification (due to spontaneous mutation or
continued exposure to exogenous mutagens) may
render the separate clones genetically distinct.
Different aetiological agents acting at different sites
would cause multiple separate cancers with different
genetic defects, each arising as a separate clone within
the oral mucosa. 22
Secondly, the aetiological agent(s) may transform
a single oral epithelial cell. The expanding clone of
cancer cells may spread through the oral mucosa via
local tissue spread, regional blood vessels, seeding
via the saliva into a mucosal erosion or seeding due
to the trauma of surgery. This would give rise to
geographically distinct but genetically identical
cancers. Again, subsequent genetic modification
(due to spontaneous mutation or continued exposure
to exogenous mutagens) may mask the clonal origin
of tumours at different sites.22 Studies have identified
changes in the histologically normal epithelium
adjacent to oral cancers including reduced cytoplasmic area, alterations in keratin expression,
upregulated EGF receptor expression and p53
mutation. These changes suggest that genetically
altered epithelial cells migrate from the pre-neoplastic
(dysplastic) lesion into the surrounding normal oral
epithelium.The clinical significance of p53 mutation
within the normal oral epithelium of oral cancer
patients is unclear. Some reports suggest an
association with the development of second primar y
cancers23 while others find no such association.24
Recent molecular studies have shown that oral cancer
is a clonal proliferation of neoplastic keratinocytes
(that is, oral cancers arise from a single genetically
altered cell) and that multiple primary tumours
result from the migration of clonally-related preneoplastic cells through the oral epithelium.13,25
Thirdly, a tumour may have a paracrine effect on
the adjacent oral mucosa. Of great recent interest is
that tumours have been found to secrete tumour
inhibitory factors including inhibitors of neovascularization. The angiogenesis inhibitor Endostatin
was originally isolated from a murine haemangioendothelioma. Endostatin is a potent inhibitor of
endothelial cell growth and its effect on human solid
tumours (lung cancer, lymphoma, breast cancer,
colon cancer, prostate cancer) is being examined in
clinical trials currently at the University of

EntreMed,Rockville,MD, USA.
Australian Dental Journal 1999;44:3.

Wisconsin, Madison, USA and the University of

Texas, M. D. Anderson Cancer Center, Houston,
USA. Removal of the primary tumour would remove
these inhibitors of cancer development and hence
promote second primary tumour formation.
Alternatively, tumours may secrete promoters of
apoptosis. Removal of the primary tumour would
reduce the level of apoptosis in adjacent tissue and
hence promote second primary tumour formation.22
The spread of oral cancer
As discussed, oral keratinocyte proliferation is
confined initially to the epithelial compartment.
Eventually, the proliferating keratinocytes break
through the epithelial basement membrane and cell
masses expand through the underlying connective
tissue and invade lymph and blood vessels, resulting
in distant spread. Conventional transmission electron
microscopy shows that the epithelial basement
membrane consists of a lamina lucida which underlies
the basal keratinocyte plasma membrane and a
lamina densa located between the lamina lucida and
the underlying connective tissue. The basement
membrane is composed of laminins 1 and 5, type IV
collagen and heparan sulphate proteoglycan (HSPG).
Hemidesmosomes anchor the basal keratinocytes to
the basement membrane and underlying connective
tissue. Hemidesmosomes consist of keratinocyte
cytoplasmic filaments which are linked via a6b4
integrin to external anchoring filaments. Laminin 5,
a component of the anchoring filaments, may serve
as the ligand for a6b4 integrin. Anchoring filaments
penetrate the basement membrane and join anchoring
fibrils in the connective tissue. Anchoring fibrils are
composed of type VII collagen. Thus, the epithelial
basement membrane is a formidable proteinaceous
barrier to tumour cell migration.
Tumour cells penetrate the basement membrane
barrier and spread through the underlying connective
tissue with the help of matrix protein degrading
enzymes called matrix metalloproteinases (MMPs).
MMPs are produced by the tumour cells themselves
or the tumour may stimulate cells in the surrounding
tissue (stroma) to produce MMPs.26 The MMPs are
a family of zinc-containing endo-proteinases and the
MMP gene family encodes more than 20 different
MMPs. MMPs are grouped by their substrate
specificity:
1. The collagenases (MMP-1 and MMP-8)
cleave collagen I, II and III preferentially.
2. The stromelysins (MMP-3, MMP-10 and
MMP-11) cleave laminin.
3. The gelatinases (MMP-2 and MMP-9) cleave
type IV collagen.
Many other matrix proteins are potential substrates
of MMPs including fibronectin, elastin, decorin,
153

vitronectin and proteoglycans. MMPs are secreted

in an inactive form and activated subsequently by
other active MMPs, membrane type MMPs (MTMMPs) or mast cell chymase. The activation of
MMPs is regulated partially by tissue inhibitors of
metalloproteinases (TIMPs).The principal function
of MMPs is the proteolytic degradation of connective
tissue matrix proteins. MMPs are involved in normal
growth and development, tissue remodelling and
angiogenesis. MMPs are also involved in tumour
invasion and metastasis.26 MMP-1, MMP-2,MMP-3
and MMP-9 are highly expressed in oral cancers and
the surrounding stroma (especially at the invading
front of the tumour) and high levels of MMP
expression may indicate a poor prognosis.27 Triggering
of the avb6 integrin, an adhesion molecule expressed
by oral cancer cells, upregulates production of
MMP-2 and MMP-9 which cleave basement
membrane proteins and thus facilitate oral cancer
penetration of the epithelial basement membrane.28
MMPs also have a role in tumour angiogenesis
which is essential for tumour growth and spread.26 In
this context, recent studies have identified vascular
endothelial growth factor (VEGF) in tumour cells
and VEGF receptor expression by endothelial cells
in oral cancer, both of which were associated with
lymph node metastasis.29
Oral cancer prevention
Despite advances in oral cancer therapy, the
survival rate for oral cancer is showing no signs of
improvement. 30 Therefore, emphasis should be
placed on oral cancer prevention. Epidemiological
data indicate that exposure to tobacco, alcohol and
betel quid is associated with an increased risk of
oral SCC. Primary prevention involves reducing
exposure to these carcinogens and has been shown
to be effective in reducing the incidence of oral
cancer. Secondary prevention involves screening for
the early detection of oral cancer. Although easily
detected and often cured in its early stages,most oral
cancers are moderately advanced and have spread to
regional lymph nodes at the time of diagnosis. It
seems, therefore, that screening for oral premalignant
lesions and early oral cancers would decrease oral
cancer morbidity and mortality. However, the
National Cancer Institute (NCI) in the USA does
not recommend screening for oral cancer and points
out that there is insufficient evidence to establish
that screening would decrease oral cancer mortality.i
The authors are currently seeking funds to undertake
a pilot oral cancer screening program in Australia.
Data from this investigation will address directly the

iNational Cancer Institute. CancerNet. Screening for oral cancer. URL:http://

cancernet.nci.nih.gov/clinpdq/screening/Screening_for_oral_cancer_Physician.
html.Accessed June 1999.
154

NCI concerns regarding the efficacy of oral screening.

Due to the cost of population screening, it is
planned to initially target high-risk groups including
smokers and heavy drinkers. However, experience
has shown that the identification and screening of
high-risk individuals is difficult and smokers are often
reluctant to accept an invitation for examination.31
Oral cancer screening can take many forms.
Clinical and histological examination allows the
early detection of oral premalignant and malignant
lesions. Oral cancer occurs in a region of the body
that is generally accessible to physical examination
by the patient, the dentist and the physician.
Screening can be made more efficient by inspecting
the high-risk sites where 90 per cent of all oral
squamous cell cancers arise; the floor of the mouth,
the ventrolateral aspect of the tongue and the soft
palate. The authors recommend that dentists perform
an annual visual oral cancer examination on all of
their patients and obtain a specialist opinion for
suspicious oral lesions, including idiopathic white
patch (leukoplakia) (Fig. 1), speckled leukoplakia
(Fig. 2) and erythroplakia (Fig. 3). Unfortunately, in
Western societies, most oral cancers are not preceded
by a visual lesion, thus limiting the usefulness of
visual oral examination.7 More frequent oral cancer
examinations are recommended for treated oral
cancer patients to monitor the development of second
primary tumours.20,21 Family members of patients
with oral cancer are also at higher risk and therefore
should be examined more frequently.32
Clearly, clinical examination by a dentist is
inefficient for population-based oral screening.
Exfoliative cytology can detect early oral cancer and
can be performed by dentally-untrained personnel.
Exfoliative cytology is rapid and relatively non-invasive
and therefore may be useful in population-based oral
cancer screening programs. However, as with cervical
cytology, oral cytology can give false negative findings
due to inadequate sampling of lesions and the
subjective assessment of smears. Recent studies have
shown that automated, quantitative smear assessment
enhances the diagnostic reliability of oral exfoliative
cytology.33 Whatever screening method is used, a
positive screening result must be confirmed by
definitive investigation including biopsy. The future
promise for oral exfoliative cytology is to identify early
markers of oral cancer and markers of oral cancer
susceptibility, including cytokeratin and heat shock
protein expression, oncogenic viruses and mutations
in oncogenes and tumour suppressor genes.34,35
Individuals with a genetic susceptibility to oral cancer
thus may be identified and preventive measures
instigated, including the elimination of exogenous
carcinogens and regular monitoring. In addition, the
risk of oral cancer may be reduced with dietary
modification, including increased consumption of
Australian Dental Journal 1999;44:3.

fresh fruit, fresh vegetables (particularly carrots,

tomatoes, capsicum and green leaf) and possibly the
micro-nutrients vitamin C, vitamin A and the vitamin
A precursor beta-carotene, although convincing
evidence that individual micro-nutrients are
protective is lacking. Reducing total calories, fat,
butter, eggs and starchy foods may further reduce
the risk of oral cancer.3
As discussed, a proportion of some benign oral
mucosal lesions undergo malignant transformation.
As a form of oral cancer prevention, these lesions
should be treated with the aim of preventing malignant
change.10 The clinical appearance of an oral lesion,
especially a homogeneous white patch, is unreliable
as a predictor of malignant transformation. Oral
white lesions in women are more likely to undergo
malignant transformation than those in men. Other
risk factors for malignant transformation of oral
white lesions include a long duration,involvement of
the floor of mouth or tongue, a non-homogeneous
appearance, the presence of C. albicans, a previous
cancer history, a family history of cancer and ongoing
exposure to aetiological agents (tobacco, alcohol,
betel quid). 36 The presence of epithelial dysplasia in
a biopsy section is suggestive of malignant potential,
although a percentage of dysplastic lesions regress
spontaneously.7 F u rt h e rm o r e , a normal biopsy
result must be viewed with caution as the degree of
dysplasia often varies throughout such lesions. In
future, the identification of oncogene and tumour
suppressor gene mutations in biopsy specimens may
give a clearer indication of the likely behaviour of
suspicious oral lesions.
The choice of treatment for a suspected premalignant oral lesion depends on the history of the lesion,
the clinical appearance, the extent of the lesion, the
degree of epithelial dysplasia, the risks and benefits
of various therapies and the expected level of patient
compliance.10,36 The current recommendation is:
1. Biopsy with or without vital tissue staining
(toluidine blue or Lugols iodine)
2. Elimination of risk factors (tobacco, alcohol,
betel quid, C. albicans).
3. Anti-inflammatory and antimycotic drugs.
4. Surgical resection (scalpel or laser) of persistent
lesions with histology.10
The treatment of suspected premalignant oral
lesions with retinoids (13-cis-retinoic acid, isotretinoin,
fenretinide), beta-carotene, vitamin E, bleomycin
and alpha-tocopherol is under evaluation.36 The
main problems with these agents is their toxicity and
the recurrence of lesions following withdrawal of
treatment.10 No treatment guarantees elimination of
malignant potential and therefore careful follow-up
is required.36
Australian Dental Journal 1999;44:3.

Future therapies for oral cancer

Based on our understanding of oral cancer genetics,
growth and spread, many new oral cancer therapies
are possible. These include monoclonal antibodies
against the EGF receptor, gene therapy to deactivate
oncogenes and reactivate tumour suppressor genes
and inhibition of MMPs to block tumour spread and
metastasis. A prominent area in cancer research is
the study of a group of compounds called angiogenesis inhibitors which block the development of
new blood vessels. Solid tumours cannot grow
beyond 1-2 mm in diameter without inducing the
formation of new blood vessels to supply nutrients
and oxygen to the tumour. Blocking the development
of new blood vessels starves the tumour of nutrients
and oxygen, thereby inhibiting tumour growth and
spread to other parts of the body. Drug resistance is
a major problem with traditional chemotherapeutic
agents. Most cancer cells are genetically unstable
and often produce drug resistant cells. In contrast,
the angiogenesis inhibitors target normal endothelial
cells which are genetically stable. Hence, resistance
to angiogenesis inhibitors is less likely to develop and
data from long-term animal studies and preliminary
clinical trials has shown this to be the case.
Currently, four anti-angiogenesis strategies are
being investigated in clinical trials involving more
than 30 different angiogenesis inhibitors:
1. Block the ability of the endothelial cells to
break down the surrounding matrix using, for
example, Marimastat which is a synthetic MMP
inhibitor.
2. Inhibit endothelial cells directly using, for
example, Endostatin which inhibits endothelial cell
growth.
3. Block factors that stimulate angiogenesis, for
example, SU5416** which blocks VEGF receptor
signalling.
4. Block the action of avb3 integrin,a molecule on
the endothelial cell surface which enhances endothelial
cell survival and promotes angiogenesis using, for
example,Vitaxin which is an anti-integrin antibody.
Further information about clinical trials of angiogenesis inhibitors is available from the National
Cancer Institute, USA.
Conclusion
As discussed, the survival rate for oral cancer is
showing no signs of improvement. Therefore, until
more effective oral cancer therapies are available, the

British Biotech,Annapolis,MD, USA.

**Sugen,South San Francisco, CA,USA.
Ixys,La Jolla,CA,USA.
National Cancer Institute. CancerNet.Anti-angiogenesis information.URL:
h t t p : / / c a n c e rt ri a l s. n c i . n i h . g ov / N C I _ C A N C E R _ T R I A L S / z o n e s / P r e s s I n f o /
Angio.Accesssed June 1999.
155

emphasis should be placed on primary prevention

(reducing exposure to causative agents) and secondary
prevention (early detection and treatment).
Acknowledgements
The authors original work has been funded in
part by the National Health and Medical Research
Council (Australia) and the Australian Dental
Research Foundation Inc.
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Address for correspondence/reprints:

Dr Philip Sugerman,
Oral Biology and Pathology,
Department of Dentistr y,
Floor 5, Physiology Building,
The University of Queensland,
St Lucia, Queensland 4072.
Australian Dental Journal 1999;44:3.