Essentials Of Oral Cancer

Abstract

Oral cancer is one of the 10 most common cancers in the world, with a delayed clinical detection, poor prognosis, without specific biomarkers for the disease and expensive therapeutic alternatives. This review aims to present the fundamental aspects of this cancer, focused on squamous cell carcinoma of the oral cavity (OSCC), moving from its definition and epidemiological aspects, addressing the oral carcinogenesis, oral potentially malignant disorders, epithelial precursor lesions and experimental methods for its study, therapies and future challenges. Oral cancer is a preventable disease, risk factors and natural history is already being known, where biomedical sciences and dentistry in particular are likely to improve their poor clinical indicators.

Full text

Int J Clin Exp Pathol 2015;8(9):11884-11894
www.ijcep.com /ISSN:1936-2625/IJCEP0012234
Review Article
Essentials of oral cancer
César Rivera
Department of Basic Biomedical Sciences, University of Talca (UTALCA) Talca, Maule Region, Chile; Department of
Oral Diagnosis, School of Dentistry, State University of Campinas (UNICAMP) Piracicaba, São Paulo, Brazil; Mass
Spectrometry Laboratory, Brazilian Biosciences National Laboratory (LNBio), National Center for Research in
Energy and Materials (CNPEM) Campinas, São Paulo, Brazil
Received July 1, 2015; Accepted August 20, 2015; Epub September 1, 2015; Published September 15, 2015
Abstract: Oral cancer is one of the 10 most common cancers in the world, with a delayed clinical detection, poor
prognosis, without specic biomarkers for the disease and expensive therapeutic alternatives. This review aims to
present the fundamental aspects of this cancer, focused on squamous cell carcinoma of the oral cavity (OSCC),
moving from its denition and epidemiological aspects, addressing the oral carcinogenesis, oral potentially malig-
nant disorders, epithelial precursor lesions and experimental methods for its study, therapies and future challeng-
es. Oral cancer is a preventable disease, risk factors and natural history is already being known, where biomedical
sciences and dentistry in particular are likely to improve their poor clinical indicators.
Keywords: Mouth neoplasms, oral cancer, oral squamous cell carcinoma, carcinogenesis, neoplasm staging, tu-
mor microenvironment
Introduction
Oral cancer is a highly relevant problem of glob-
al public health, especially for dental surgeons.
It is located within the top 10 ranking incidence
of cancers and despite the progress in research
and therapy, survival has not improved signi-
cantly in the last years, representing a continu-
ing challenge for biomedical science. This
paper aimed to report key aspects of this can-
cer, integrating clinical, histological and molec-
ular concepts for a better understanding of
their biological pathways, allowing the reader
and researcher construct a map which could
serve to place and integrate this growing
information.
Denition
Oral cancer is a malignant neoplasia which aris-
es on the lip or oral cavity. Is traditionally
dened as a squamous cell carcinoma (OSCC),
because in the dental area, 90% of cancers are
histologically originated in the squamous cells
[1]. It has different levels of differentiation and
a propensity for lymph node metastasis [2].
Epidemiology
Oral cancer is two to three times more preva-
lent in men than women in most ethnic groups
[http://seer.cancer.gov/statfacts/html/oralcav.
html]. In worldwide reports, cancers of all
regions of the oral cavity and pharynx are
grouped and collectively represent the sixth
most common cancer in the world [3]. According
to the latest reports of the International Agency
for Research on Cancer (IARC) for oral cancer
(ICD-10 code C00-08: Lip, Oral Cavity) which
includes lips, tongue, gingiva, mouth oor,
parotid and salival glands, annual incidence is
higher around the world, which is over 300.000
diagnosed cases, and the annual mortality is
about 145,000 death [http://globocan.iarc.fr/
Pages/summary_table_pop_sel.aspx]. Table 1
shows the incidence and mortality for oral can-
cer according to the regions of the World Health
Organization (WHO), and those that present the
most critical numbers are WHO South-East Asia
region (SEARO) and WHO Europe region (EURO).
Specically by area, those that are character-
ized by a high incidence of oral cancer are found
in South and Southeast Asia (Sri Lanka, India,

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11885 Int J Clin Exp Pathol 2015;8(9):11884-11894
Pakistan and Taiwan), areas of the West
(France) and Eastern Europe (Hungary, Slovakia
and Slovenia), Latin America and the Caribbean
(Brazil, Uruguay and Puerto Rico) and Pacic
regions (Papua New Guinea and Melanesia) [3].
The incidence also varies according to the
Human development index of the United
Nations Development Programme (UNDP).
According to this index, incidence is higher in
countries with better development indicators
(Table 1). The GLOBOCAN grouping shows that
the crude rate and age-standardized incidence
rate (worldwide) are higher in more developed
regions, but mortality is higher in less devel-
oped areas, which shows social inequality.
Risk factors
Oral cancer is a preventable disease, where
smoking and alcohol-considered major risk fac-
tors-are present in 90% of cases [4], having
them both a synergic effect [5].
Tobacco
In 2007 the IARC concluded that “there is quite
evidence to establish that snuff smoke is carci-
nogenic, and for example, it causes cancer of
the oral cavity and pancreas” [6]. The risk for
developing oral cancer is 3 times higher in
smokers compared with nonsmokers [7]. Be-
sides, the risk for oral cancer is 35% lower in
people who quit smoking four years ago than
those who continue smoking, and not higher in
persons with no smoking antecedents for over
20 years when compared with people who have
never smoked [8]. An environment with ciga-
rette smoke is also risky; the risk for oral can-
cer is 87% higher in those who never smoked,
but were exposed to an environment with ciga-
rette smoke (involuntary smoking) compared
with those who never smoked and not have
been exposed [9]. Cigarette smoke weakens
immunity in the oral cavity by promoting gingivi-
Table 1. GLOBOCAN cancer incidence and mortality, all ages, both sexes by population
Incidence
Population Numbers Crude rate ASR (W) Accumulative risk
WHO African Region (AFRO) 13,484 1.5 2.7 0.30
WHO Americas Region (PAHO) 49,200 5.2 4.1 0.48
WHO East Mediterranean Region (EMRO) 20,681 3.3 4.6 0.52
WHO Europe Region (EURO) 65,933 7. 3 4.6 0.53
WHO South-East Asia Region (SEARO) 103,464 5.6 6.4 0.73
WHO Western Pacic Region (WPRO) 47,524 2.6 2.0 0.22
UNDP Very High Human Development 92,338 8.0 4.8 0.54
UNDP Low Human Development 40,954 3.1 5.2 0.59
GLOBOCAN More Developed Regions* 100,823 8.1 4.7 0.54
GLOBOCAN Less Developed Regions* 199,550 3.4 3.7 0.42
Mortality
Numbers Crude rate ASR (W) Accumulative risk
WHO African Region (AFRO) 8,530 1.0 1.8 0.20
WHO Americas Region (PAHO) 12,803 1.3 1.0 0.12
WHO East Mediterranean Region (EMRO) 10,997 1.8 2.5 0.30
WHO Europe Region (EURO) 25,202 2.8 1.7 0.19
WHO South-East Asia Region (SEARO) 65,734 3.5 4.1 0.48
WHO Western Pacic Region (WPRO) 22,068 1.2 0.9 0.09
UNDP Very High Human Development 26,970 2.3 1.2 0.14
UNDP Low Human Development 25,238 1.9 3.3 0.39
GLOBOCAN More Developed Regions* 33,313 2.7 1.4 0.16
GLOBOCAN Less Developed Regions* 11,2040 1.9 2.1 0.24
WHO, World Health Organization; UNDP, United Nations Development Programme; GLOBOCAN Global Burden of Cancer Study
2012. *The designation for more developed and less developed regions are intended for statistical convenience and do not
necessarily express a judgment about the stage reached by a particular country or area in the development process. More
developed regions: all regions of Europe plus Northern America, Australia/New Zealand and Japan. Less developed regions:
all regions of Africa, Asia (excluding Japan), Latin America and the Caribbean, Melanesia, Micronesia and Polynesia. ASR (W),
World age-specic rates.

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11886 Int J Clin Exp Pathol 2015;8(9):11884-11894
tis, periodontitis and oral cancer [10]. This
smoke contains several elements that promote
cancer and they basically can be grouped into
three distinct groups: nitrosamines, benzopy-
renes and aromatic amines. These chemicals
are called pre-carcinogens, which must suffer
coordinated alterations by oxidative enzumes,
so that the nal product becomes poor in elec-
trons and into an agent to be covalently bound
to the DNA, generating an adduct mutated
region [11]. In addition to oxidation, enzymatic
or non-enzymatic metabolism can also produce
carcinogens, such as free radicals, which have
unpaired electrons that make them extremely
reactive being capable of promoting mutations
by complex mechanisms [11]. Snuff consump-
tion expose the oral epithelium to free radicals
of oxygen and nitrogen that can affect antioxi-
dant defense mechanisms. Elevated levels of
these free radicals are found in oral precancer
and cancer [12].
Alcohol
Alcohol (ethanol) can act as a both locally and
systemically risk factor: increased permeability
of oral mucosa, dissolving lipids components of
the epithelium, causing epithelial atrophy and
interference in DNA synthesis and repair; it also
has genotoxicity and mutagenic effects, caus-
ing decreased salivary ow, affects the liver's
ability to deal with toxic or potentially carcino-
genic compounds, and their chronic use is
associated with an impairment of innate and
acquired immunity, resulting in increased sus-
ceptibility to infections and neoplasms [13].
Other factors
Among other risk factors, there is the human
papillomavirus (mainly associated with carci-
noma of the oropharynx [14]) and ultraviolet
radiation (UV). The IARC classies human papil-
lomavirus 16 (HPV16) as a cause for cancers of
Figure 1. OSCC multistep progress. The development of squamous cell carcinoma of the oral cavity is considered
a complex multistep process. Normal oral mucosal keratinocytes are chronically exposed to risk factors, which
can break the homeostasis and generate genetic instability. Key genetic alterations occurring in TP53, NOTCH1
(Notch homolog 1, translocation-associated [Drosophila]), EGFR (epidermal growth factor receptor), CDKN2A (cy-
clin-dependent kinase inhibitor 2a) genes STAT3 (signal transducer and activator of transcription 3), Cyclin D1, Rb
(retinoblastoma) plus LOH (loss of heterozygosity). The proliferation and uncontrolled growth, along with a battery
discharge granted adaptive advantages over the surrounding cells, which promote local invasion and orchestrate a
collaboration of the surrounding stromal cells. Among the factors secreted by tumor cells are MMP2 (matrix metal-
loproteinase 2), MMP9 (matrix metalloproteinase 9), MMP13 (matrix metalloproteinase 13), ROS (reactive oxygen
species), VEGF (vascular endothelial growth factor), CXCL1 (chemokine [CXC motif] ligand 1), CXCL8 (chemokine
[CXC motif] ligand 8), PDGF (platelet-derived growth factor), IL-8 (inteleukin 8), FGF-2 (broblast growth factor 2),
TGF-β (transforming growth factor-β), TNF-α (tumor necrosis factor-α), IL-1 (inteleukin 1), GMCSF (granulocye-macro-
phage colony-stimulating factor). This microenvironment promotes cell adhesion loss (ex. E-cadherin) and facilitates
epithelium mes enchymal transition (EMT), Vimentin and N-cadherin can be expressed in these cells. CAFs markers
(tumor-associated broblasts) are α-SMA (α-smooth muscle actin) and integrin α6. Endothelins can contribute to
pro-migratory paracrine signaling between CAFs and oral cancer cells. It also promotes CXCL1 and CXCL8 endothe-
lial cell proliferation and survival. Endothelial cells produce factors like EGF, which increase migration.

Oral cancer
11887 Int J Clin Exp Pathol 2015;8(9):11884-11894
the oral cavity and pharyngeal tonsils, and
HPV18 as possible causes of oral cancer
[http://monographs.iarc.fr/ENG/Classication/
index.php]. The most-common sites of HPV-
related head and neck squamous cell carcino-
ma (HNSCC) are the tonsils and base of tongue
within the oropharynx, with a prevalence rate of
75%; HPV-related HNSCC is rare in nonoropha-
ryngeal sites. The presence of HPV is an estab-
lished prognostic biomarker of favourable out-
come in locally advanced oropharyngeal can-
cers [15]. Evidence shows that HPV contributes
to carcinogenesis by two virus-encoded pro-
teins: E6 protein promotes the degradation of
p53 tumor suppressor gene product; E7 that
promotes the degradation of the tumor sup-
pressor gene product pRb (retinoblastoma pro-
tein) [16], causing a deregulation of the cell
cycle control, which also leads to an overex-
pression of the inhibitor of cyclin dependent
kinase p16Ink4a [14]. Ultraviolet radiation, mainly
the UVB is also involved in lip cancer.
Table 2. TNM Denitions for Oral Cancer*
Primary tumor (T)
TX Cannot be assessed
T0 No evidence of primary tumor
Tis Carcinoma in situ (CIS)
T1 Tumor 2 cm or less in greatest dimension
T2 Tumor more than 2 cm but not more than 4 cm in greatest dimension
T3 Tumor more than 4 cm in greatest dimension
T4a Moderately advanced local disease. Lip: Tumor invades through cortical bone, inferior alveolar nerve, oor of
mouth, or skin (chin or nose).
Oral cavity: Tumor invades through cortical bone, into deep/extrinsic muscle of tongue (genioglossus,
hyoglossus, palatoglossus, and styloglossus), maxillary sinus, or skin of face.
T4b Very advanced local disease. Lip and oral cavity: Tumor invades masticator space, pterygoid plates, or skull
base; or encases internal carotid artery
Regional lymph nodes (N)
NX Cannot be assessed
N0 No regional lymph node metastasis
N1 Metastasis in a single ipsilateral lymph node, 3 cm or less in greatest dimension
N2 Metastasis as specied in N2a, 2b, 2c (see below)
N2a Metastasis in a single ipsilateral lymph node, more than 3 cm but not more than 6 cm in greatest dimension
N2b Metastasis in multiple ipsilateral lymph nodes, none more than 6 cm in greatest dimension
N2c Metastasis in bilateral or contralateral lymph nodes, none more than 6 cm in greatest dimension
N3 Metastasis in a lymph node more than 6 cm in greatest dimension
Distant metastasis (M)
MX Distant metastasis cannot be assessed
M0 No distant metastasis
Clinical stages (T+N+M)
0Tis N0 M0
IT1 N0 M0
II T2 N0 M0
III T3 (enough alone), T2 or T1 N1 M0
IV A T4a
T1, T2 or T3
N0 or N1
N2
M0
M0
IV B any T
T4b
N3
any N
M0
M0
IV C any T any N M1
*Modied of IARC (International agency for research on cancer) screening group (http://screening.iarc.fr/atlasoralclassiftnm.
php)

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11888 Int J Clin Exp Pathol 2015;8(9):11884-11894
Microscopic and macroscopic aspects
Carcinogenesis
Clearly the OSCC develops over many years and
during this period there are several neoplasical
sites transforming and taking place in the oral
cavity [17]. Oral carcinogenesis (Figure 1) is a
highly complex multifactorial process that
occurs when epithelial cells are affected by
various genetic alterations [18], including key
disorders on TP53, NOTCH1 (Notch homolog 1
genes are translocation-associated [Droso-
phila]), EGFR (epidermal growth factor recep-
tor), CDKN2A (cyclin-dependent kinase inhibi-
tor 2a), STAT3 (signal transducer and activator
of transcription 3), Cyclin D1, Rb (retinoblasto-
ma) [19]. Probably oral carcinogenesis starts
with the transformation of a limited number of
normal keratinocytes. This transformation can
be expressed via cy togenetic changes and epi-
genetic processes that modify the progression
of the cell cycle, DNA repair mechanisms, cell
differentiation and apoptosis, which may be
caused by random mutation, by exposure to a
variety of biological factors, carcinogens or
errors in the DNA repair process [20], resulting
in an unstable keratinocyte into a pre-cancer-
ization eld and leading to malignant neoplas-
tic changes [20], which can inherit these altera-
tions to their clones. Subsequently, selection
pressures on the microenvironment of the oral
mucosa may act on the heterogeneous clonal
population, allowing perpetuate those cells
with better tools and advantages of adaptabili-
ty, survival and proliferation above their normal
neighboring cells [20, 21]. Tumorigenesis re-
quires multiple essential elements: a limitless
replicative potential, self-sufciency in growth
signals, lack of sensitivity to anti-growth sig-
nals, the ability to evade apoptosis, increased
angiogenesis, invasion and metastasis [22].
Recent evidence supports that the biophysical
and biochemical signs of tumor-associated into
the extracellular matrix inuence the essential
characteristics of cancer and therefore are
essential for malignancy [23].
Tumor microenvironment (TME)
For an effective approach to cancer, it should
be considered as a disease that involves com-
plex interactions among a community of het-
erotypic cells, characterized by the original can-
cerous tissue, the newly formed tissue and
cells surrounding it [24]. The TME of OSCC
include cancer-associated broblasts (CAFs),
immune cells and other supporting cells (Figure
1). Oncogenic changes in gene expression pro-
les contribute to microenvironmental altera-
tions such as ROS accumulation, overproduc-
tion of cytokines and epithelial mesenchymal
transition (EMT). CAFs are some of the most
critical elements of TME, contributing to prolif-
eration, invasion and metastasis. The adaptive
immune response is suppressed in OSCC
through overexpression of cytokines, induced
Figure 2. Opportunities for biomarkers in oral can-
cer. The “natural history” of oral cancer allows the
study of different phases in the progression of ma-
lignancy. One opportunity is given by the generation
of an etiologic eld -inuenced by risk factors “ex-
posome” and their interactions “interactome” that
promotes a state of susceptibility. The passage of
this state to canzerisable eld gives another oppor-
tunity for research. With the diagnosis may emerge
prognostic and predictive biomarkers. Figure modi-
ed from Rivera C. Opportunities for biomarkers
with potential clinical use in oral cancer. Medwave.
2015 Jul 20;15(6):e6186. doi: 10.5867/med-
wave.2015.06.6186.

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11889 Int J Clin Exp Pathol 2015;8(9):11884-11894
apoptosis by T cells and modications in anti-
gen processing machinery [25]. The overex-
pression of cytokines assessments such as
transforming growth factor-β (TGF-β), contrib-
ute to the EMT, immunosuppression, and the
evolution of the CAFs. Inammation and hypox-
ia are the dynamic forces of angiogenesis and
altered metabolism [26]. OSCC uses the glyco-
lytic and oxidative metabolism to feed tumor
genesis through mechanisms which are cou-
pled between regions of cancer cell (parenchy-
ma) and TME cells (stroma) [19].
Some markers for elements in OSCC tumor
microenvironment are shown in Figure 1,
including E-cadherin, cytokeratin, PD-L1, FasL
Table 3. Some cellular lines for the study of OSCC
Line Clinical features Comments
Site Age Sex TNM stage
SCC4 Tongue 55 M T3N0M0 From a patient who had radiation and methotrexate treatment for the
tumor for 16 months before the biopsy was taken for culture. Epithe-
lial cell morphology: weak colonies.
SCC9 Tongue 25 M T2N1 The patient who developed this line did not had treatment before the
biopsy was taken (NRT). Compared to SCC25, SCC4 y CAL27, this
line show a higher resistance to cisplatine. Epithelial cell morphol-
ogy: weak colonies.
SCC15 Tongue 55 M T4N1M0 NRT. Epithelial cell morphology: tight colonies.
SCC25 Tongue 70 M T1N1M0 NRT. Compared with SCC15, this line has a higher invasive potential.
Epithelial cell morphology: tight colonies.
CAL27 Tongue 56 M - NRT, isolated from patient with PD-OSCC.
BHY Alveolus 52 M - Isolated from a patient with WD-OSCC of the lower alveolus, highly
invasive to the mandibular bone and the muscle layer of the oral
oor; however, it did not metastasize.
HN Soft palate 60 M - Isolated from a patient with MD-OSCC of the soft palate that metas-
tasized to cervical lymph nodes, lungs, and brain, but did not invade
bone.
HSC-3 Lymph node
metastasis
64 M - Obtained from Japan Health Science Research Resources Bank (To-
kyo, Japan). The primary tumor was on the tongue with lymph node
metastasis, and was MD-OSCC.
HaCaT Skin - - - Human adult low calcium high temperature cells (HaCaT), are spon-
teneously transformed aneuploid immortal keratinocyte cell line from
adult human skin that have the caracteristics of basal epidermal ke-
ratinocites. This cell line currently used as a non-tumorigenic control.
OSCC, oral squamous cell carcinoma; T, primary tumor; N, regional lymph nodes metastasis; M, distant metastasis, NRT, patient
did not receive treatment before the biopsy: WD, well differentiated, MD, moderately differentiated; PD, poorly or undifferenti-
ated.
Table 4. Oral cancer key points
Conceptual framework
It is a preventable disease.
The most important risk factors are snuff and alcohol (chronic exposure), they have a synergistic effect.
Has higher occurrence in people over 50 years.
The genetic instability in keratinocytes allows tumor development.
The erythroplasia and leukoplakia disorders are usually related to oral cancer.
It occurs most frequently on the tongue, oor of the mouth and lower lip.
The diagnosis is conrmed by biopsy and histopathological analysis.
Is diagnosed in advanced clinical stages.
Treatment options include surgery, radiotherapy and chemotherapy.
Until today there are no specic biomarkers.
Population screening reduces mortality.

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11890 Int J Clin Exp Pathol 2015;8(9):11884-11894
(OSCC); CD33, CD144, ALDH (cancer stem cells
markers); N-cadherin, vimentin (EMT); α-SMA,
integrin α6 (CAFs); CD4+CD25+FoxP3+ (T regula-
tory cells); CD8+, TCR, Fas, PD-1 (cytotoxic T
cells), CD4+ (cytotoxic Th2 cells) and CD34+
(myeloid precursor cells) [19].
Potentially malignant disorders and dysplastic
changes
The OSCC can be presented as a “natural his-
tory”, which originates from non-aberrant kera-
tinocytes which are chronically exposed to a
stimulus that breaks its homeostasis, following
an epithelial hyperplasia, dysplasia in different
degrees, carcinoma in situ (CIS) and an inva-
sive carcinoma leading to the generation of dis-
tant metastases [17], with the consequent cli-
nical manifestations. This natural history offers
a map for the different research approaches in
both basic science, translational and clinical-
therapeutic environment.
The rst detectable clinical changes that can
advise of an epithelium on its way to establish-
ing an OSCC are potentially the occurrence of
malignant disorders, including leukoplakia and
erythroplasia which are the most common ones
[27]. Leukoplakia is a white plate uncertain
risk, by excluding other diseases or disorders
which are already known to not increase the
risk for cancer [28]. Microscopically expensive
exhibits several reactive epithelial changes
such as hyperplasia, hyperkeratosis and acan-
thosis. Histologically, a distinction is essential
to be made between dysplastic and non-dys-
plastic leukoplakia. The term refers to epithelial
dysplasia precursor lesions showing cytology
combinations and degrees of atypia (in exam-
ple, hyperchromatism, increased nuclear size,
pleomorphism, dyskeratosis, abnormal mitotic
gures or increased mitosis). When alterations
occurs in the basal or parabasal keratinocytes,
which is called mild dysplasia, the atypia found
in the middle level is called moderate dyspla-
sia; when changes are extended to the surface
layer, the terms advanced dysplasia and carci-
noma are applied in situ (atypia is complete,
from the base to the surface) [16]. About 1%
may progress to malignant transformation [27].
Besides white plates, there are red ones.
Erythroplasia (high malignant potential) is
dened as a red plate that cannot be character-
ized clinically or pathologically as other disease
[27]. If a mixture of red and white change
occurs, the lesions are called erythroleukopla-
kia. Erythroplakias commonly shows some
degree of presence of dysplasia and carcino-
ma. In general, it should be treated because
their high-risk malignant transformation [27].
In general, if a lesion in the oral mucosa does
not heal within three weeks, a malignant tumor
or some other serious condition should be
excluded, indicating a biopsy and its histopath-
ological analysis [29].
Classication of tumors: WHO and gene-ex-
pression prole
The OSCC derived from an epithelial dysplasia
and is characterized by a neoplastic prolifera-
tion mechanism which destroys oncogenic sub-
epithelial basement membrane locally [24].
The ability to metastasize is directly associated
with the degree of tumor differentiation of the
cancer cells [24]. The International Classi-
cation of Tumors of the WHO ranks well differ-
entiated tumors, moderately differentiated
and poorly or undifferentiated [30]. Another fre-
quently studied histological feature is the front
pattern of invasion (degree of cohesion
between invading cancer cells), which is mea-
sured as a good prognostic factor in OSCC [4].
WHO classication is essentially histological
and extremely limited. Since cancer is a com-
plex disease characterized by genetic heteroge-
neity, HNSCCs (including OSCC) can also be
classied based on their gene-expression pro-
le as “basal”, “mesenchymal”, “atypical” and
“classical”. The atypical subtype included most
of the HPV-positive HNSCCs [15]. These sub-
types-added to HPV infection status- have been
validated using independent datasets in The
Genome Cancer Atlas (TGCA) reports [31]. The
TCGA study represents the most comprehen-
sive integrative genomic analysis of HNSCCs.
Staging of oral cancer
The most common sites for the presentation of
oral cancer are the tongue (ventral-lateral edge,
40% of cases), oor of the mouth (30% of
cases) and lower lip [16, 32, 33]. Regardless of
the accessibility of the oral cavity during clinical
examination, oral cancer is usually diagnosed
in advanced stages. The most common rea-
sons for this are the initial misdiagnosis and
ignorance of the patient or the treating profes-
sional [34], which evidently decreases the

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11891 Int J Clin Exp Pathol 2015;8(9):11884-11894
chances of survival, despite therapeutic strate-
gies [24].
In the clinical-therapeutic eld, most models
take part in center their base decisions on clini-
cal and pathological information along with the
health of the patient [24]. In OSCC, as in most
other cancers, the prognosis depends largely
on factors which are more related to lifestyle
such as smoking, alcohol consumption, medi-
cal comorbidity and undeniably the step (stag-
ing) of tumor [35].
The TNM staging system (tumor-lymph node-
metastasis) is based on the best estimate of
the extent of disease before treatment (Table
2). Assessment of the primary tumor is based
on inspection and palpation, where the proper
nodal drainage areas are examined by careful
palpation and also imaging studies can help
in metastases [http://www.cancer.gov/cancer-
topics/pdq/treatment/lip-and-oral-cavity/Heal-
thProfessional/page3]. But so far, the data
delivered by the conventional TNM is insuf-
cient to predict the response to nonsurgical
treatment, which keeps the door permanently
open to molecular studies in order to search for
biomarkers. Information obtained from clinical
examination and imaging are used to assign a
clinical stage (cTNM), which is then used to
stratify patients (clinical stage) for selection of
therapeutic and report the results of treatment
alternatives. The differentiation between local-
ized disease (stages I and II) of advanced dis-
ease (III and IV) is essential [24]. If the patient
undergoes through surgical resection, its pa-
thologic stage (pTNM) derived from tumor histo-
pathology and/or regional lymph nodes, is use-
ful in the selection of postoperative adjuvant
therapy and in order to estimate the prognosis
[35].
Biomarkers
Until today, there is no specic biomarkers for
oral cancer. But latest studies show that elevat-
ed levels of interleukin-8 and SAT can catego-
rize between patients with OSCC and healthy
patients, with high sensitivity and specicity
[36]. Predicting the malignant transformation
of dysplasia also shown promising results.
Recent evidence shows that a loss-of-heterozy-
gosity (LOH) status of chromosomes 3p and 9p
is a predictive spin, high-risk lesions (3p &/or
9p LOH) had a 20-fold increase OSCC risk com-
pared to low-risk lesions (3p & 9p retention)
[37]. Although there are no biomarkers, neo-
plastic progression allows windows to nding
them (Figure 2, modied from [38]).
Experimental studies for oral cancer
In addition to traditional clinical studies and
descriptive
studies of samples, assumptions
that are related to oral cancer can be tested
from cell lines which are originally isolated from
patients with carcinoma and also from animal
models of chemical carcinogenesis and trans-
genic animals. Table 3 shows some of the cell
lines most commonly used for the experimental
study of OSCC with an allusion to their origin
and biological behavior (see references for
more information: SCCs 4, 9, 15 and
25
[39-
43];
CAL 27
[44];
BH Y,
HN
and HSC-3 [45],
HaCaT [46]). Genetic manipulation of cells
allows silencing and overexpression of certain
products, which can also be brought in vitro or
in vivo (animal models). Chemical carcinogene-
sis is useful to study the progressive changes
that occurs throughout oral carcinogenesis
from normal tissues, through dysplastic chang-
es until the invasive carcinoma [47]. The most
frequently used chemicals are the 9,10-dimeth-
yl-1,2-benzanthracene (DMBA) and 4-nitroquin-
oline-1 oxide (4NQO). DMBA is highly irritating
and it has some limitations for the study of
OSCC (it produces inammatory response and
necrosis of granulation tissue appearance)
[48]. 4NQO form adducts which are similar to
those induced by carcinogens containing snuff,
and is more effective in inducing carcinogene-
sis and it causes extensive inammation when
compared with DMBA [48, 49]. Genetic app-
roaches are particularly useful for studying the
basics of oral cancer in its different stages and
new therapeutic methods in a large number of
animals by generating transgenic animals [50].
Management
The prognosis for patients with OSCC still
remains poor, despite therapeutic advances in
this and many other malignancies. Early diag-
nosis and treatment remains to be the key to
improving survival of patients [51].
Therapeutic alternatives
Among the approaches to the treatment of
OSCC such as surgery, radiation therapy (exter-

Oral cancer
11892 Int J Clin Exp Pathol 2015;8(9):11884-11894
nal beam radiotherapy and/or brachytherapy),
and coadjutant therapy (chemotherapy with
agents such as cisplatin, carboplatin, 5-uoro-
uracil, paclitaxel and docetaxel) is included [16,
52], it still remains as a high economic cost and
highly damaging treatment/alternatives [53].
The OSCC is typically treated by one or a combi-
nation of these alternatives. The choice of one
or the other depends not only on the location,
size and stage of the primary tumor; it is also
subjected to the comorbidities presented by
the patient, nutritional status, its ability to toler-
ate treatment and the patient's wishes to face
therapy [54]. In resectable tumors, surgery is
superior to all alternative therapies [53, 55].
Approximately one third of patients with OSCC
are diagnosed in stage I/II disease. The local/
regional therapy includes surgery, radiotherapy
or a combination of both. A good prognosis for
these patients, with cure rates of 80% (stage I)
and 65% (stage II) is expected [56]. Unfor-
tunately most of OSCC cases are diagnosed in
advanced stages of disease (III or IV) [57], with
survival at 5 years less than 50% [58] and a
cure of 30% [55, 56]. Patients with metastatic
disease, which are untreated show a survival of
about 4 months [57].
Oral cancer causes substantial damage in
speech, swallowing and chewing function,
where pain is the main symptom. Among the
causes of the onset or exacerbation of pain
there are mediators in the tumor microenviron-
ment, lack of palliative therapy, a dense trigem-
inal innervation and continuous oral function,
and pain due to treatment and opioid tolerance
[58].
Prevention and future challenges
There is now sufcient understanding of the
causes to prevent a third of all cancers in the
world and it has sufcient information to enable
early detection and well-timed treatment of
another third of cases [59], where the OSCC
countenances this opportunity. For oral cancer
there is evidence that the visual examination as
part of a population screening program reduc-
es mortality in patients at high risk [60], it is
also possible to change lifestyles and impose
barriers to the triggering factors. Education to
the general population and for those with par-
ticular risk, a good theoretical basis to meet
key aspects of oral cancer (Table 4) plus the
constant updating in oral pathology healthcare
providers, should be signicant to decrease the
red numbers that have accompanied this dis-
ease in recent decades. The search for specic
biomarkers for the disease should not be aban-
doned, and future research should enable
progress toward dening the susceptibility eld
(etiological factors and their interaction) [53], in
order to put a stop to the story that begins with
genetic instability keratinocytes.
Disclosure of conict of interest
None.
Address correspondence to: César Rivera, Depart-
ment of Basic Biomedical Sciences, Faculty of
Health Sciences, University of Talca, Avenida Lircay
S/N, Maule Region, Talca, ZIP 3460000, Chile.
ORCID: 0000-0002-5491-4233; E-mail: contacto@
cesarrivera.cl
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