126 The Open Dentistry Journal, 2012, 6, 126-130

Open Access

Current Aspects on Oral Squamous Cell Carcinoma

Anastasios K. Markopoulos*

Oral Medicine/Pathology Aristotle University of Thessaloniki, Greece

Abstract: Oral squamous cell carcinoma is the most common malignant epithelial neoplasm affecting the oral cavity.
This article overviews the essential points of oral squamous cell carcinoma, highlighting its risk and genomic factors, the
potential malignant disorders and the therapeutic approaches. It also emphasizes the importance of the early diagnosis.

Keywords: Oral squamous cell carcinoma, overview.

INTRODUCTION
Worldwide, oral cancer accounts for 2%–4% of all can-
cer cases. In some regions, the prevalence of oral cancer is
higher, reaching the 10% of all cancers in Pakistan, and
around 45% in India [1,2]. In 2004-2009 over 300,000 new
cases of oral and oropharyngeal cancer were diagnosed
worldwide. During the same time period, over 7,000 affected
individuals died of these cancers [3].
Oral cancer includes a group of neoplasms affecting any
region of the oral cavity, pharyngeal regions and salivary
glands. However, this term tends to be used interchangeably
with oral squamous cell carcinoma (OSCC), which repre-
sents the most frequent of all oral neoplasms. It is estimated
that more of 90% of all oral neoplasms are OSCC [4].
Despite the advances of therapeutic approaches, percent- Fig. (1). OSCC of the vestibule with raised exophytic margins.
ages of morbidity and mortality of OSCC have not improved
significantly during the last 30 years. Percentages of morbid-
ity and mortality in males are 6.6/100,000 and 3.1/100,000
respectively, while in females the same percentages are
2.9/100,000 and 1.4/100,000 [5]. Additionally, the incidence
of OSCC is increasing among young white individuals age
18 to 44 years, particularly among white women [6]. The
percentage of 5-year survival for patients with OSCC varies
from 40-50%. Regardless of the easy access of oral cavity
for clinical examination, OSCC is usually diagnosed in ad-
vanced stages. Most common reasons are the initial wrong
diagnosis and the ignorance from the patient or from the at-
tending physician [7].

CLINICAL FEATURES
One of the real dangers of this neoplasm, is that in its Fig. (2). OSCC of the buccal mucosa presenting as an asympto-
early stages, it can go unnoticed. Usually at the initial stages matic ulcer.
it is painless but may develop a burning sensation or pain
when it is advanced. Common sites for OSCC to develop are by clinically obvious premalignant lesions, especially
on the tongue, lips and floor of the mouth. Some OSCCs erythroplakia and leukoplakia. Usually, OSCC presents as an
arise in apparently normal mucosa, but others are preceded ulcer with fissuring or raised exophytic margins (Fig. 1). It
may also present as a lump (Fig. 2), as a red lesion (erythro-
plakia), as a white (Fig. 3) or mixed white and red lesion, as
a non-healing extraction socket or as a cervical lymph node
*Address correspondence to this author at the Aristotle University, Dept. of
Oral Medicine/Pathology, University Campus, 54124 Thessaloniki, Greece; enlargement, characterized by hardness or fixation. OSCC
Tel: +30 2310 999523; Fax: +30 2319 999532; should be considered where any of these features persist for
E-mail: [email protected] more than two weeks.

1874-2106/12 2012 Bentham Open

Current Aspects on Oral Squamous Cell Carcinoma The Open Dentistry Journal, 2012, Volume 6 127

oncogenetic potential. The predominant viral type, in most

studies, was HPV16. HPV was more frequently detected in
OSCCs of the oropharynx and tonsil than at other head and
neck sites. Research on the participation of HPV in oral car-
cinogenesis has conflicting results. The percentage of the
reported infected neoplastic cells varies from 0-90%.Several
research groups proposed that HPV is implicated in the ini-
tial stages of carcinogenesis, while others have suggested a
short-term (“hit and run”) role of HPV. It is believed that
viral protein E6 binds to p53 causing its breakdown, while
E7 reacts with retinoblastoma protein (pRb), a tumor sup-
pressor protein, inhibiting its function. The functional de-
regulation of these oncosuppressive key molecules results in
an incontrollable cellular proliferation and to disturbances of
apoptosis, leading to oral cancer. It is currently believed that
Fig. (3). Leukoplakia of the lateral surface of the tongue undergo- HPV infection of oral mucosal cells per se is not enough for
ing malignant transformation. malignant transformation unless cells are exposed to chemi-
cal carcinogens, such as benzopyrene [19-23].
RISK FACTORS Epstein-Barr Virus
The greatest risk factor for oral cancer in the western Epstein-Barr virus is known to be the infective agent in
world is the use of tobacco and alcohol [8-12]. Although the infectious mononucleosis. While its contribution to malig-
risk factors are independent, their action seems to be com- nant transformation of B cells is well documented the par-
bined. Tobacco smoking is associated with 75% of all cases ticipation in pathogenesis of OSCC remains unclear. Some
of oral cancer. Tobacco smoking carries a six-fold risk of investigators proposed that the dominant oncoprotein of the
developing oral cancer compared to not smoking. Oral can- latent phase (LMP-1) is expressed in oral epithelial malig-
cer is also six times more likely to develop in alcohol drink- nant cells [23, 24].
ers than in non-drinkers. The combination of tobacco and
Hepatitis C Virus (HCV)
alcohol use poses a fifteen-fold risk of oral cancer for users
compared to non-users [13]. The prevalence of oral squamous cell carcinoma is higher
While tobacco and alcohol use are traditionally the great- in HCV infected patients. In a Japanese study, it has been
est risk factors, it is important to consider other known risk shown that HCV infection was strongly associated with the
factors, such as betel quid chewing, in certain ethnic popula- occurrence of multiple primary carcinomas as well as pri-
tions. Betel quid chewing is popular in Indian and Taiwanese mary OSCC [25].
populations and is associated with a significantly increased
POTENTIALLY MALIGNANT DISORDERS
risk of oral cancer [14-16]. Areca nut, narcotics and cannabis
use has also been found to be a risk factor for oral cancer [17]. In a recently held WHO workshop it was recommended that
OSCC is most common in older males, in lower socio- the distinction between potentially malignant lesions and poten-
economic groups and in ethnic minority groups. tially malignant conditions should be abandoned and rather to
use the term potentially malignant disorders instead [26].
Other factors also play a role. These include:
Some precancerous disorders can progress to OSCC.
• An impaired ability to repair DNA damaged by These are the following:
mutagens
• Erythroplakia
• An impaired ability to metabolize carcinogens
• Leukoplakias, particularly:
• Deficiencies of vitamins A, E or C or trace elements
-Erythroleukoplakia (nodular or verrucous)
• Immune defects.
-Proliferative verrucous leukoplakia
The inadequate immune response may predispose to can-
• Actinic cheilitis
cer development. The most common oral malignancy in in-
dividuals with HIV infection is Kaposi’s sarcoma. There is a • Lichen planus (mainly the erosive and atrophic type)
high prevalence in patients with B cell Hodgkin lymphoma. • Sideropenic dysphagia (Plummer-Vinson syndrome)
There is an increased risk of developing OSCC in HIV in-
fected patients and patients submitted to organ transplantations • Submucous fibrosis
and those who are under immunosuppressive therapy [5, 18]. • Dyskeratosis congenita
VIRAL INFECTIONS • Discoid lupus erythematosus
Human Papilloma Virus (HPV) MOLECULAR PATHOGENESIS OF OSCC
More than 100 types of HPV have been identified and are Several studies have been devoted to the significance of
referred as viruses of low or high danger according to their heredity in oral carcinogenesis. The relative danger of the
128 The Open Dentistry Journal, 2012, Volume 6 Anastasios K. Markopoulos

disease development in first degree relatives of patients with STAGING OF OSCC

oral cancer varies from 1.1-3.8 odds ratios [27]. Several
Staging of OSCC is performed using the TNM system.
genes are implicated in genetic predisposition of oral cancer.
cTNM is the stage given after the clinical examination of the
Gene polymorphisms participating in the metabolism of
patient, while pTNM is the stage after the histopathological
xenobiotic factors, such as cytochrome P450 1A1 (CYPIA 1)
and glutathione S-transferase mu 1 (GSTM1) are blamed for examination of the surgical specimen. However, this tradi-
tional way of staging is often inadequate. Evaluation of other
the increase of relative danger in the carriers [28, 29]. Indi-
features of the neoplasms, such as degree of differentiation,
viduals with alcohol dehydrogenase 3 genotype are prone to
type of infiltration and degree of recurrence [44] facilitate
the development of oropharyngeal cancers [30, 31].
the exact diagnosis and permit the selection of the appropri-
However, the relation of oral cancer with an autosomal ate therapeutical approach.
dominant type of heredity has been rarely recorded, mainly
in patients with Fanconi’s anemia. THERAPEUTIC APPROACHES AND PROGNOSIS
OSCC arises as a consequence of multiple molecular Despite advances in surgery and radiotherapy, which re-
events that develop from the combined effects of an individ- main the standard treatment options, the mortality rate has
ual's genetic predisposition and exposure to environmental remained largely unchanged for decades, with a 5-year sur-
carcinogens [32], such as, tobacco, alcohol, chemical car- vival rate of around 50% [45]. In the primary (I and II)
cinogens, ultraviolet or ionizing radiation and micro- stages the treatment of choice is surgery and/or radiotherapy,
organisms [33-35]. Chronic exposure to carcinogens may which usually result in permanent cure. Combination of sur-
damage individual genes as well as larger portions of the gery, radiotherapy or chemotherapy is used for the treatment
genetic material, such as chromosomes. Genetic damages of the 3rd or 4th stage of OSCC. Oral care is especially impor-
may activate mutations or amplification of oncogenes that tant when radiotherapy is to be given, since there is a liabil-
promote cell survival and proliferation. Mutations include ity particularly to mucositis, xerostomia and osteonecrosis.
DNA general hypomethylation, hyper- or hypomethylation
of certain genes such as cyclin D, and alterations of chroma- It is generally accepted that prognosis is best in early
tin [36, 37]. Oncogenes are broadly categorized as follows: OSCC, especially those that are well-differentiated and not
(i) growth factors or growth factor receptors (hst-1, int-2, metastasized: unfortunately, most OSCC are diagnosed at a
EGFR/erbB, c-erbB-2/Her-2, sis), (ii) transcription factors late stage of the disease. The prognosis of OSCC varies on
(myc, fos, jun, c-myc), (iii) intracellular signal transducers a number of factors that are related to the tumor, to the tre -
(ras, raf, stat-3); (iv) inhibitory factors of apoptosis (bcl-2, atment, and to the patient [46]. However, five year survival
bax) and (v) cell-cycle regulators (cyclin D1) [38]. Genetic rates in the advanced stages do not exceed 12% of the cas-
damages may also inactivate tumor suppressor genes in- es. Most patients with advanced OSCC usually die within th-
volved in the inhibition of cell proliferation. All these events e first 30 months of their disease [47, 48].
may lead to cell dysregulation to the extent that growth be-
comes autonomous and invasive mechanisms develop.
Metastases from OSCC, when present, will occur in cer-
As OSCC grows and invades, new blood vessel forma- vical lymph nodes in almost 80% of patients. Cervical lym-
tion occurs. This angiogenesis is an essential part of tumor phadenectomy (radical neck dissection) is traditionally ap-
formation [39]. plied in these cases [49]. More recently, selective neck dis-
Field cancerization is a theory of oral carcinogenesis. section has been developed in order to reduce the morbidity
of radical neck dissection [50].
According to this theory since the oral epithelium is exposed
to carcinogenic factors, the entire area is at increased risk for Efforts to increase the efficacy of radiotherapy, espe-
the development of malignant lesions from the accumulation cially in local advanced disease, include, altered fractionated
of genetic alterations of oncogenes and tumor suppressor radiotherapy or concomitant chemo-radiotherapy (CT-RT)
genes [40]. [51].
In cancerization field, multiple oral cancers may develop As for chemotherapy, cisplatin-based chemoradiation
from independent cell clones. This hypothesis has been sup- remains the standard for locoregionally advanced head and
ported by data from chromosome X inactivation studies, neck SCC [52].
microsatellite analysis, and p53 mutational analysis [41].
Currently, targeted molecular therapy, like therapy with
However, more recent genetic studies suggested that multi-
monoclonal antibodies and gene therapy, has been applied to
ple cancers can be clonally related and derived from expan-
sion of an original clone [42]. These results gave rise to a oral cancer patients. This treatment modality has limited or
modification of cancerization field theory, the patch field nonexistent side effects on normal cells of the body, unlike
carcinoma model [43]. According to this model, a stem cell surgery, chemotherapy, and radiotherapy. Targeted molecu-
located in the oral epithelium acquires a genetic alteration lar therapy can also act as a complement to other existing
and generates daughter cells, all of which share the genetic cancer therapies and has been mainly focused on four mole-
alteration. This patch of cells expands to a size of several cules; epidermal growth factor receptor (EGFR), cyclooxy-
centimeters to the surrounding oral mucosa and macroscopi- genase-2 (COX-2), peroxisome proliferator-activated recep-
cally is often undetectable. In some instances it may appear tor
(PPAR
), and progesterone receptor. These molecules
with distinct morphological characteristics, like leukoplakia are associated with the proliferation and the differentiation of
or erythroplakia. OSCC [53].
Current Aspects on Oral Squamous Cell Carcinoma The Open Dentistry Journal, 2012, Volume 6 129

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Received: May 26, 2012 Revised: July 01, 2011 Accepted: July 08, 2011

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