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Oral Squamous Cell Carcinoma: Epidemiology, Clinical Presentation and

Treatment

Article in Journal of Cancer Therapy · January 2012

DOI: 10.4236/jct.2012.34037

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Journal of Cancer Therapy, 2012, 3, 263-268 263
doi:10.4236/jct.2012.34037 Published Online August 2012 (http://www.SciRP.org/journal/jct)

Oral Squamous Cell Carcinoma: Epidemiology, Clinical

Presentation and Treatment
Liviu Feller, Johan Lemmer
Department of Periodontology and Oral Medicine, University of Limpopo, Medunsa Campus, Pretoria, South Africa.
Email: [email protected]

Received June 15th, 2012; revised July 20th, 2012; accepted July 31st, 2012

ABSTRACT
Squamous cell carcinoma accounts for 90% of all oral cancers. It may affect any anatomical site in the mouth, but most
commonly the tongue and the floor of the mouth. It usually arises from a pre-existing potentially malignant lesion, and
occasionally de novo; but in either case from within a field of precancerized epithelium. The use of tobacco and betel
quid, heavy drinking of alcoholic beverages and a diet low in fresh fruits and vegetables are well known risk factors for
oral squamous cell carcinoma. Important risk factors related to the carcinoma itself that are associated with a poor
prognosis include large size of the tumour at the time of diagnosis, the presence of metastases in regional lymphnodes,
and a deep invasive front of the tumour. Squamous cell carcinoma is managed by surgery, radiation, and chemotherapy
singularly or in combination; but regardless of the treatment modality, the five-year survival rate is poor at about 50%.
This can be attributed to the fact that about two-thirds of persons with oral squamous cell carcinoma already have a
large lesion at the time of diagnosis.

Keywords: Oral Squamous Cell Carcinoma; Epidemiology; Clinical Course; Field of Precancerization

1. Introduction with oral SCC has not improved despite advances in di-
agnostic techniques and improvements in treatment mo-
Oral cancer is the sixth most common cancer worldwide
dalities. Indeed, the incidence and prevalence of oral SCC
[1]. More than 90% of all oral cancers are squamous cell
are increasing, particularly in younger persons [5,6].
carcinoma (SCC) [2,3]. The most important risk factors
The aim of this article is to review the epidemiology,
for oral SCC are use of tobacco or betel quid and the re-
clinical features, and prognosis of oral SCC.
gular drinking of alcoholic beverages. However, infec-
tion with high-risk human papillomavirus (HPV) geno-
2. Epidemiology of Oral SCC
types, and a diet low in fresh fruits and vegetables have
also recently been implicated in the aetiopathogenesis of Oral SCC more frequently affects men than women (M:F
oral SCC [1,4]. The highest incidence and prevalence of = 1.5:1) most probably because more men than women
oral SCC is found in the Indian subcontinent where the indulge in high-risk habits. The probability of developing
risk of developing oral SCC is increased by the very oral SCC increases with the period of exposure to risk
prevalent habits of chewing tobacco, betel quid and ar- factors, and increasing age adds the further dimension of
eca-nut [2]. The mutagenic effects of tobacco, alcohol, age-related mutagenic and epigenetic changes. In the
betel quid or areca-nut are dependent upon dose, upon USA the median age of diagnosis of oral SCC is 62 years.
frequency and upon duration of use, and are accelerated However, the incidence of oral SCC in persons under the
and exaggerated by the concurrent use of two or more of age of 45 is increasing [7]. The reason for this is obscure.
these agents [4]. A number of conditions have been associated with an
However, as not all persons who practice these high- elevated risk of developing oral SCC including Li Frau-
risk habits will develop oral SCC, and as oral SCC may meni syndrome, Plummer-Vinson syndrome, Fanconi
be idiopathic, there must be person-specific genetic cha- anemia, chemotherapy induced immunosuppression of
racteristics and environmental factors which may either organ transplantation, dyskeratosis congenita, xeroderma
afford protection against the development of oral SCC, or pigmentosum and discoid lupus erythematosus [8].
may predispose to or even promote the development of In Western countries oral SCC affects the tongue in
oral SCC. 20% - 40% of cases and the floor of the mouth in 15% -
In the last 30 years, the 5-year survival rate of patients 20% of the cases, and together these sites account for

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264 Oral Squamous Cell Carcinoma: Epidemiology, Clinical Presentation and Treatment

about 50% of all cases of oral SCC [3,9]. The gingivae, pation, and if extracapsular spread into the surrounding
palate, retromolar area and the buccal and labial mucosa connective tissue has occurred, they will be fixed and
are oral sites less frequently affected [7]. matted [5]. Importantly, in about 20% - 40% of cases
The ventral surface of the tongue and the floor of the with no clinical or imaging evidence of metastatic spread
mouth are the sites most commonly affected by SCC be- to lymphnodes at the time of diagnosis of oral SCC,
cause they are lined by thin non-keratinised epithelium. histopathological examination of the regional lymphnodes
Not only do carcinogens readily penetrate this thin epi- will show metastatic growth [14]. Furthermore, in one
thelium to reach the progenitor cell compartment, but- study, 21% of cases of SCC of the head and neck in
carcinogens, particularly tobacco products and alcohol in which the regional lymphnodes appeared to be free of
solution, constantly accumulate in the floor of the mouth metastatic growth when examined microscopically, in
and bathe the tissues of the floor of the mouth and the fact, molecular analysis proved them to harbour can-
ventrum of tongue [5]. cerous cells [15].
The mean 5-year survival rate of persons with oral The presence of extracapsular lymphnode spread is
SCC is about 50% with no gender difference; but black associated with a high-rate of local and regional recur-
persons have a lower five year survival rate than persons rence, distant metastasis and mortality [14]. About 8% of
of other races [5,7,10,11]. Other socio-demographic fac- patients with oral SCC will have distant metastases at the
tors such as age, potentially carcinogenic habits (using time of diagnosis [14], most frequently to the lungs [5].
alcohol, tobacco, betel quid) or socio-economic status are Important factors at the time of diagnosis of oral SCC-
not consistently related to survival rates [9]. determining survival are the presence of regional lym-
The stage of advancement of oral SCC at the time of phnode metastases, the size (surface dimension) and
diagnosis is the most important prognostic factor [8]. Oral depth (extent of local infiltration) of the carcinoma, the
SCC is most frequently diagnosed late in the course of oral anatomical site affected and the histopathological
the disease because affected persons fail to seek profes- grade of the carcinoma. After treatment, factors correlat-
sional advice timeously, either because they do not un- ing with survival will be whether or not the margins of
derstand the significance of early signs and symptoms, or the resected carcinoma were free of invading carcinoma-
because they are ignorant of the health implications [7]. tous cells, because this will determine whether or not
there will be local recurrence; and whether or not a se-
3. Clinical Features and Course of Oral SCC cond tumour will develop in the same or in a contiguous
epithelialized precancerized field [8,9,16-18].
Oral SCC may take various clinical forms. It may resem- Squamous cell carcinoma of the lip, hard palate and
ble a leukoplakia, a verrucous leukoplakia, an erythro- maxillary gingiva infrequently metastasize to regional lym-
leukoplakia, or an erythroplakia, any of which may even- phnodes, usually run a relative indolent course and have
tually develop into a necrotic looking ulcer with irregular, a relatively favourable prognosis, while SCC of the tongue,
raised indurated borders, or into a broad based exophytic of the floor of the mouth and of the mandibular gingiva-
mass with a surface texture which may be verrucous, peb- often metastasize to regional lymphnodes and are more
bled or relatively smooth. When traumatized, oral SCC aggressive with a less favourable prognosis. In general,
bleeds readily and often becomes superficially secondar- SCCs of the posterior part of the oral cavity are much
ily infected. Oral SCC is usually painless unless it is- more likely to metastasize to regional lymphnodes than
secondarily infected. Large lesions may interfere with nor- are comparable SCCs of the anterior part of the oral cav-
mal speech, mastication or swallowing [3,5,8]. ity [1].
The course of oral SCC is unpredictable, but the TNM Small well-differentiated, low-grade oral SCCs usually
stage (T-tumour size, N-nodal metastasis, M-distant me- metastasize to regional lymphnodes only after invading
tastasis) of the primary tumour correlates well with the connective tissue, muscle or bone. On the other hand,
survival rate [8]. The prognosis is best when the primary poorly-differentiated, high-grade oral SCCs are biologi-
tumour is small and there is no evidence of regional lym- cally more aggressive and tend to metastasize to regional
phnode involvement or distant metastasis. In fact, the 5- lymphnodes early in the course of the disease [1].
year survival rate of persons with early-stage oral SCC ac- Although the grade of histological differentiation of
cording to the TNM staging system may reach 80% - oral SCC reflects the aggressive capacity of the tumour,
90% [3], whereas the five-year survival rate for ad- it appears that as an independent factor, it does not sig-
vanced-stage oral SCC is about 40% [12]. nificantly influence the prognosis [1,19,20]. On the other
About two-thirds of oral SCC are already of substan- hand, the depth of the infiltration of the tumour as deter-
tial size, and will have clinically detectable metastases to mined histopathologically correlates significantly with
cervical lymphnodes at the time of diagnosis [5,12-14]. the prognosis. Oral SCCs that have infiltrated more than
The affected lymphnodes are firm and non-tender to pal- 5 mm into the underlying tissues, are more likely to me-

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 Oral Squamous Cell Carcinoma: Epidemiology, Clinical Presentation and Treatment 265

tastasize to lymphnodes with a poorer prognosis [1,14]. 3.1. Ethnicity and Socio-Economic Status as
The risk of local recurrence is greatest when there are They Relate to Oral SCC
cancerous cells present in the surgical margins, but there
There is a marked variation with regard to the incidence
is an increased risk of recurrence when the carcinoma-
of and mortality from oral SCC between different coun-
free margins are narrower than 5 mm or when there is
tries, between different geographic locations and between
still dysplastic though not frankly malignant epithelium
ethnic/racial groups. This may be attributed to exposure
at the margins. Regardless of the width of the carcinoma-
to different environmental factors and to ethnic-specific
free margins, the risk of local recurrence is related to the
high-risk habits [10].
size and to the depth of infiltration of the primary carci-
Oral SCC is more prevalent in developing than deve-
noma [16,21].
loped countries [7,10]. In Israel, oral SCC is more preva-
Resection margins apparently free of malignant cells
lent among Ashkenazi Jews than among Sephardic-Jews
as determined by histopathological examination have been
probably because of their different geographic origins;
shown by molecular analysis to harbour transformed ke-
[30] and in England it is more prevalent among Indian
ratinocytes with a malignant profile [15]. Therefore, de-
people born in the Indian subcontinent and migrated to
spite apparently successful treatment, persons who have
England than among Indians born in England or among
had oral SCC are at heightened risk of developing recur-
white English people [31].
rence at the same site, from cancerous keratinocytes left
In the United States, the average 5-year survival rate
behind at surgery. A carcinoma that subsequently de-
for black people is lower than for white people with oral
velops within the field of precancerized epithelium
SCC; [10,11] and in general, oral SCC is at a signifi-
from which the primary carcinoma had arisen is techni-
cantly more advanced stage in black people than in white
cally a new carcinoma although it may be immediately
people at the time of diagnosis [11].
contiguous to the site of the primary carcinoma [17,18,
The racial disparity with regard to the stage of oral
22].
SCC, and with regard to the outcome of treatment is
The risk of developing multiple oral SCCs within a cy-
brought about by a complex interaction of factors. It is
togenetically altered precancerized field is higher in young
possible that pathobiologically oral SCC is more aggres-
persons [19,23], and in persons who continue to use to-
sive in blacks than in whites, or that for cultural, educa-
bacco, alcohol and betel quid after successful treatment
tional and socioeconomic reasons blacks delay longer
of the primary carcinoma. It has been reported that about
before seeking medical advice than do whites. Thus while
30% of males and 20% of females who had a primary
socioeconomic status, educational level, cultural influ-
head and neck SCC will develop a second field carci-
ences and limited access to health care services do not
noma within 20 years of the diagnosis of the primary
play any direct role in the development of oral SCC, they
carcinoma [7]. In case of oral SCC, it is estimated that
do indirectly influence the higher morbidity and mortal-
50% of second field carcinomata will affect the mouth
ity from oral SCC in persons from disadvantaged back-
and the oropharynx and 50% the larynx, oesophagus or
grounds [10,11].
lungs [24]. It appears that there are no significant differ-
ences between SCCs of particular oral mucosal sites and
3.2. Prevention and Control of Oral SCC
the risk of developing a second field carcinoma [25,26].
The survival rate after the appearance of a second field The overall aim of cancer prevention is to reduce the
carcinoma is low [23,27]. incidence of the disease; and of cancer control is to de-
Oral SCC can arise from pre-existing potentially ma- tect the disease in its initial stages and to promptly insti-
lignant disorders including oral leukoplakia, erythroplakia, tute effective and efficient treatment [32].
submucous fibrosis and lichenoid dysplastic lesions, or Measures directed at the public to reduce the incidence
can arise de novo [8,28]. There is a debate in the litera- of oral SCC and to alert those at risk to the benefits of
ture with regard to the malignant potential of oral lichen early detection should include education about the risk-
planus, in particular the erosive form. While some re- factors associated with the disease, about the early signs
searchers found an association between oral lichen planus and symptoms of the disease, and about the hazards of
and development of oral SCC, others did not [5,28]. The delaying seeking professional advice. Professional mea-
view of authors of this article is that oral lichen planus sures should include the making available of immediate
does not pose an increased risk of oral SCC. effective and efficient medical treatment, and of screen-
It has been suggested that oral SCC evolving from leu- ing programmes for high-risk populations with a view of
koplakic lesions have a better prognosis than those identifying potentially malignant oral disorders, or early
emerging de novo, but a recent study has shown that the SCC [7].
prognosis is not significantly different in these two This is of paramount importance because in general,
groups of oral SCC [29]. abstinence from the use of tobacco and betel quid, and

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266 Oral Squamous Cell Carcinoma: Epidemiology, Clinical Presentation and Treatment

moderation in the consumption of alcoholic beverages, tic epithelium in post-resection carcinoma-free margins
together with an increase in fresh fruits and vegetables in is of debatable importance, but it is not usually consid-
the diet, may reduce the incidence of oral SCC by almost ered to be a strong indication for further treatment [34].
80% [7]. Twenty to thirty percent of cases of resection of oral
Many healthcare practitioners do not routinely perform SCC with adequate,wider than 5 mm, tumour-free mar-
oral soft tissue examinations for those patients who are gins as evidenced on histopathological examination will
known to practice habits associated with increased risk of develop local or contiguous regional “recurrence” [24,25,
oral cancer. However, in order to increase the rate of 34,35]. There are two possible explanations for this high-
early diagnosis of oral SCC, healthcare practitioners rate of recurrence. Firstly, some carcinomatous kerati-
should make a point, whenever possible, of examining nocytes may have remained in the margins of the surgical
the mouth as part of a general examination. If any suspi- wound, but because there were so few, they were not
cious lesions of the oral soft tissues are detected the pa- detected by histopathological examination; secondly, the
tient should be referred to an appropriately qualified large field of precancerized epithelium comprising pre-
practitioner for further investigation [5,11]. cancerous keratinocytes at different stages of transforma-
There can be little doubt that careful annual examina- tion from which the primary carcinoma developed, was
tion of the mouth in all persons above the age of 40 years not removed at the surgical procedure. Epithelium from a
will result in a significant improvement in the rate of field of precancerization may appear normal microsco-
early detection of oral cancer with all the therapeutic pically, or it may be dysplastic. It may also appear nor-
advantages [5]. A very obvious shortcoming of such an mal microscopically, but nevertheless may harbour kera-
idealised plan is that a great proportion, if not the majo- tinocytes with cytogenetic alterations including loss of
rity of those at risk of oral SCC do not attend annually heterozygosity and p53 mutations [24,36], or epigenetic
for any healthcare. changes in methylations of certain promoters of tumour-
suppressor genes and DNA repair genes [37]. Following
3.3. Treatment acquisition of additional genetic alterations, either kerati-
nocytes in the dysplastic epithelium or the genetically
The treatment of oral SCC generally requires the services
transformed keratinocytes may become cancerous giving
of a multidisciplinary team [1,33], the primary aim of
rise to a new field carcinoma close to where the primary
treatment always being to eradicate the cancer, to prevent
carcinoma had been excised [24,34], creating an impress-
recurrence, and insofar as is possible to restore the form
sion of recurrence.
and function of the affected parts. The selection of a spe-
Thus, the reappearance of SCC in the immediate or
cific treatment modality is dictated by the nature of the
general vicinity of the primary oral SCC, may be a re-
carcinoma and by the general condition of the patient.
currence if the two carcinomata exhibit identical genetic
Salient factors related to the carcinoma include the spe-
profiles; may be a new field carcinoma from a subclone
cific site affected, the clinical size, the extent of local
of cells within the field if the genetic profiles of the two
invasion, histopathological features, regional lymphnode
cancers are similar, but not identical; or may be another
involvement and distant metastasis. Patient factors in-
primary carcinoma from a different clone within the same
clude age, general health status, a history of previously
field of precancerization if the genetic profile of the two
treated oral SCC and high-risk habits [1].
tumours are dissimilar [24].
A variety of modalities are available for the treatment of
It would be greatly advantageous if it were possible to
oral SCC. These include excision/resection, radio-therapy,
treat a field of precancerized oral epithelium. However,
systemic cytotoxic chemotherapy and blocking of epi-
as markers which predict with any degree of certainty
thelial growth factor receptor (EGF-R), or a combina-
progression of precancerized epithelium to SCC have not
tion of these, either concurrently or in an orderly se-
yet been identified, and as only 30% of patients with
quence [6,13].
primary oral SCC will develop a second field tumour,
Surgery is the preferred first line treatment of small,
any type of treatment of a precancerized field is likely to
accessible oral SCCs. However, advanced-stage oral SCC
be harmful to those 70% of patients, who were not going
is usually treated by a combined treatment program of
to develop “local recurrence”.
surgery, chemotherapy, and radiotherapy [1,34]. In cases
Although a precancerized field could be identified by
of recurrent oral SCC, EGF-R inhibitor coupled with
molecular techniques or occasionally histologically, the
chemoradiotherapy, is the first line of treatment [33].
problem is where to take tissue samples since molecu-
Surgical resection of oral carcinoma with tumour free
larly precancerized fields are not clinically identifiable.
margins of less than 5 mm may be followed by local re-
currence and possibly by distant metastasis, and usually
4. Summary
necessitates the administration of post-surgery chemo-
radiotherapy. The importance of the presence of dysplas- Oral SCC arises from within a field of precancerized

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 Oral Squamous Cell Carcinoma: Epidemiology, Clinical Presentation and Treatment 267

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