Introduction
Premalignant lesions of the oral mucosa encompass a
category of disorders that necessitate early identification.
During the World Health Organization meeting
on the "histological definition of premalignant lesion,"
two distinct definitions were established: "premalignant
lesion" and "premalignant condition." A premalignant lesion is characterized as "morphologically differentiated
tissue exhibiting a heightened propensity to
progress to cancer relative to its normal state," while
a premalignant condition is described as "a generalized
phenomenon associated with a markedly elevated
risk of cancer".[] Based on these definitions, localized
cases such as leukoplakia and erythroplakia, palatal lesions
resulting from reverse smoking, and actinic cheilitis are classified as "premalignant lesions," whereas
generalized cases like sideropenic dysphagia (a potential
premalignant condition) are cited as examples of
"premalignant condition".[]
The origin of premalignant lesions in the oral mucosa
remains poorly understood, and research on this
topic is ongoing.[] Certain studies in the literature
indicate that oral premalignant lesions correlate with
various nutritional factors, including smoking, betel
(areca quid) chewing, excessive alcohol consumption,
diabetes, body mass index, and low vegetable intake;
however, not all risk factors have been elucidated.[-]
Timely identification of oral premalignant lesions is
crucial for survival, as they may evolve into lethal diseases
like carcinoma in situ or severe dysplasia in later
stages.[] The principal strategy against these lesions
should focus on diminishing disease incidence and decreasing
the occurrence of oral premalignant lesions by
preventing risk factors.
Given that premalignant instances are localized lesions
with an elevated risk of malignant transformation
relative to normal tissues, the early identification of these
lesions is crucial for preventing progression to more severe
cancer in the future. Moreover, despite several advancements
in the diagnosis and treatment of cancer
and premalignant lesions, mortality and morbidity are
escalating globally, and there remains a lack of consensus
among experts regarding their causation.[,] This
study was conducted with a cohort of patients diagnosed
with oral premalignant lesions and a control group without
such lesions. It was designed as a cross-sectional
prospective research study aimed at identifying the risk
factors influencing premalignant lesions in human life.
Methods
This study adhered to the principles of the Declaration
of Helsinki, and ethical approval was secured by the
Clinical Research Ethics Committee of the Faculty of
Medicine (no: KAEK: 2955, Date: 20/04/2022). This prospective
cross-sectional study included 180 patients who
presented to the Department of Oral and Maxillofacial
Radiology at the Faculty of Dentistry from January 2023
to November 2023. The case group comprised 90 patients
diagnosed clinically with oral premalignant lesions, while
the control group included 90 healthy individuals devoid
of such lesions. All patients having a history of trauma,
surgery, cysts, tumors, malignant disorders, and prior
malignancy in the orofacial region were excluded from
the study. Patients unable to independently respond to
the questionnaire were excluded from this study.
The research was conducted using a questionnaire
comprised of closed-ended questions directed at the
patients. The questionnaire of 14 items, including 4
aimed at assessing the demographic characteristics of
the participants and 10 focused on evaluating the correlation
between oral premalignant lesions and various
causes. All surveys were administered in person to the
patients, and the initial four questions inquired about
age, gender, educational attainment, and occupation.
The remaining 10 questions inquired about the presence
and quantity of amalgam fillings, systemic diseases,
frequent medications, parafunctional habits, the
duration of these habits (in years), as well as smoking
and alcohol consumption and their respective durations,
with responses duly documented.
Statistical Analysis
Based on the participants" responses, storage analyses
were conducted using IBM SPSS Statistics (Version 22.0.
Armonk, NY: IBM Corporation ) to assess the outcomes.
To ascertain the appropriate statistical analysis
method for evaluating hypotheses regarding the comparison
of continuous variables based on lesion locations,
the Kolmogorov-Smirnov and Shapiro-Wilk
tests were employed to assess data normality, while the
Levene Test was utilized to examine variance homogeneity.
Due to the absence of parametric distribution assumption
qualities in the data set, the Mann-Whitney
U Test, a nonparametric hypothesis test, was employed
for analyses involving two groups. The Pearson chisquare
test was employed to analyze potential differences
between groups, while the Mann-Whitney U test
was utilized to compare lesion locations, with a level of
significance set at p<0.05.
Results
Among the 180 patients involved in the study, 89
(49.4%) were female and 91 (50.6%) were male. The patients"
ages varied from 16 to 72 years, with a mean age
of 43.8 years. An equal number of patients was included
in both the case and control groups of the study. The
predominant location of premalignant lesions in the
case group was the cheek mucosa at 37.8% (n=68), succeeded
by the tongue and lip mucosa at 12.2% (n=22).
Table 1 presents the socio-demographic and cultural
distribution of the patients. Among the patients, 37.2%
(n=67) were secondary school graduates, 30.6% (n=55)
were high school graduates, and 32.2% (n=58) were
university graduates. Regarding occupational distribution,
housewives constituted the predominant occupation at 37.8% (n=68), followed by other occupational
sectors (education, finance, health) at 31.1% (n=56).
Of the participants, 42.8% (n=77) engaged in smoking
and tobacco usage, but only 0.6% (n=1) were habitual
alcohol consumers. Parafunctional habits were identified
in 32.2% (n=58) of patients, with teeth grinding
being the most prevalent habit at 25% (n=45). Systemic
disease was identified in 39.4% (n=71) of patients, with endocrine diseases being the most prevalent, accounting
for 42.3% (n=30). Amalgam fillings were identified
in 51.1% (n=92) of patients.
Table 1 Demographic and cultural characteristics of the patients
Table 2 presents the average age, quantity of amalgam
fillings, length of parafunctional habits (in years),
daily cigarette use, and average smoking duration (in
years) of patients in both groups. The average number
of amalgam fillings was 2.6±1.7, the average duration of parafunctional habits was 6.2±5.9 years, the average
number of daily smokes was 12.9±8.3, and the average
duration of smoking was 9.9±13.1 years.
Table 2 Descriptive statistics of patients characteristics and habits
Our cross-sectional survey investigation revealed
a statistically significant association between the presence
of premalignant lesions and educational status
(p=0.004). The incidence of lesions diminishes with an
increase in educational attainment.
Our investigation identified a statistically significant
correlation between the existence of premalignant
lesions and the presence of amalgam fillings
(p<0.001). It can be concluded that an increase in the
number of amalgam fillings correlates with a rise in
the incidence of lesions.
Aspirin was the pharmaceutical utilized in our
study, and an statistically significant correlation was
identified with the occurrence of premalignant lesions
(p<0.001). Aspirin consumption elevates the occurrence
of oral premalignant lesions.
Our investigation identified a significant connection
between the existence of premalignant lesions and
paraphunctional habits, tobacco smoking, and systemic
disorders (p<0.001 for all).
The existence of parafunctional behaviors, smoking,
tobacco use, and systemic disorders elevates the
frequency of oral premalignant lesions. Table 3 presents
data assessing the correlation between the existence
of premalignant lesions and other parameters.
Table 3 Association of the presence of lesions with other factors
There was no statistically significant difference between
premalignant lesions for gender (p=0.297).
Table 4 presents the statistical analysis of the factors
assessing the existence of lesions. No statistically
significant difference was observed between age and
duration of parafunctional habits and the existence of
lesions (p=0.096, p=0.051, respectively). The quantity
of amalgam fillings and the length of smoking shown a
statistically significant correlation with the existence of
lesions (p=0.006, p<0.001, respectively).
Table 4 Comparison of patients characteristics according to presence of lesion
Discussion
The oral mucosa is a region where a considerable percentage
of premalignant lesions, exceeding 5%, progress
to malignancy.[] Consequently, the diagnosis of premalignant
lesions is crucial for the early identification
of potential cancerous developments. The examination
of risk factors, including tobacco use, betel quid chewing,
alcohol consumption, HPV, mucosal inflammation,
and oral mucosal trauma from teeth and prosthetic
devices, believed to contribute to the development of
premalignant lesions, has garnered heightened interest
in numerous clinical and scientific investigations.[]
Given that the majority of risk factors can be mitigated,
the development of premalignant lesions and oral cancer
can be regarded as predominantly avoidable conditions.
Nonetheless, its manifestation in patients outside
of risk categories remains feasible.[] Our research
will aid in diminishing the progression of premalignant
lesions to potential oral malignancies by investigating
the risk factors associated with the development of
these lesions and implementing preventive measures.
Although our survey investigation revealed no statistically
significant difference in the prevalence of premalignant
lesions by gender, Nair et al.[] identified
a greater prevalence of oral potentially malignant illnesses
and oral cancer in men. A comparable discovery was documented by Chung et al.[] A study conducted
in Taiwan indicated a statistically significant difference
between numerous oral potential malignant illnesses
and gender. This disparity in our study may stem from
the smaller population size and the almost equal distribution
of male and female participants while examining
the risk variables for premalignant lesions. Furthermore,
the disparities shown in our study may also stem
from racial composition, variations in social customs,
and variances in average age.
A study indicated that a high socioeconomic index
and elevated education level serve as preventive factors
against oral premalignant lesions.[] Our questionnaire
investigation revealed a statistically significant correlation
between the existence of premalignant lesions and
educational attainment, leading to the conclusion that
the incidence of lesions diminishes with higher educational
levels. We also determined that occupational status
was statistically significant as a pertinent risk factor
in the development of premalignant lesions. A separate
study proposed the socioeconomic index as a potential
factor in the development of oral malignancies.[] The
prevalence of oral premalignant lesions is likely elevated
among individuals with lower educational attainment
and socioeconomic status, as they have reduced access to
medical care, are less inclined to seek treatment for oral
premalignant lesions, and place diminished emphasis on
oral health information due to their limited knowledge.
Dental amalgams are often utilized posterior restorative
materials in dentistry. The research has demonstrated
a correlation between mercury contact allergy
and the development of oral lichen planus.[]
A case report on oral leukoplakia indicated that the
lesions fully resolved within three weeks following the
replacement of amalgam restorations, with no recurrence
seen during a five-year follow-up period.[] In
our investigation, a statistically significant correlation
was identified between the existence of oral premalignant
lesions and the presence of amalgam fillings. The incidence of lesions may rise with an increase in the
number of amalgam fillings. These instances, aligned
with our findings, indicate that addressing clinically
identifiable premalignant lesions is crucial for preventing
oral cancer, with an emphasis on eliminating risk
factors. Should premalignant lesions in patients with
amalgam restorations exhibit resistance to standard
treatment modalities, it is advisable to conduct a patch
test; if a reactivity to mercury or amalgam constituents
is observed, such restorations should be substituted.
Our investigation identified aspirin as the utilized
medication, revealing a statistically significant correlation
between the occurrence of premalignant lesions and
aspirin usage. Consequently, we conclude that aspirin
consumption elevates the incidence of oral premalignant
lesions. with a separate study, distinct from our findings,
Jayaprakash et al.[] examined 529 head and neck squamous
cell carcinoma cases and 529 healthy individuals
from 1992 to 1998, revealing that aspirin use resulted
with a 25% reduction in the incidence of oral squamous
cell carcinomas among non-smokers and a 33% reduction
among smokers. A previous investigation revealed
that the risk of oral cancer escalated in young individuals
who used low-dose aspirin, corroborating our finding.[] While certain studies have identified beneficial
outcomes associated with prolonged (>5 years) aspirin
consumption, the underlying mechanisms of aspirin's
antineoplastic properties remain contentious.[] The inability
to distinctly identify other risk factors among the
individuals may have impacted our results. A substantial
cohort with a diverse age range is required to assess the
overall impact of aspirin on oral premalignant lesions.
Our investigation identified a statistically significant
correlation between the prevalence of premalignant
lesions and parafunctional habits, with teeth clenching
and grinding being the most prevalent parafunctional
habit. Parafunctional habits may induce chronic
trauma, which we believe could contribute to cancer.
Experimental investigations into chemically induced
carcinogenesis via mechanical irritation of the oral mucosa
have demonstrated that chronic trauma may serve
as a promoter and risk factor for oral neoplasms.[,]
A further study corroborating this notion determined
that parafunctional habits elevate the probability of
premalignant lesion development following persistent
trauma.[] Chronic inflammation can trigger the carcinogenic
process by inducing the release of cytokines,
which may lead to oxidative stress and subsequent DNA
damage.[] Epidemiological studies typically investigate
the correlation between chronic trauma generated
by prostheses and malignancy. Most studies exclude additional traumatic factors, such as faulty dentition or
parafunctional habits, and fail to examine the correlation
between oral premalignant conditions.[,]
Tobacco is recognized to have over 60 carcinogenic
substances. These compounds expedite the inflammatory
process upon contact with the oral mucosa, and
prolonged use may result in pathological alterations in
the oral mucosa.[] A separate investigation indicated
that smokers have a greater risk of developing oral premalignant
lesions compared to nonsmokers, aligning
with our findings.[] In instances of oral premalignant
lesions attributable to smoking, quitting of smoking
may lead to partial or total regression of the lesion.[]
A meta-analysis indicated that smokers have a threefold
increased chance of acquiring oral cancer compared to
non-smokers.[] Furthermore, it has been reported
that smoking prevalence and the occurrence of smoking-
related malignancies have markedly declined due
to anti-smoking initiatives implemented in numerous
affluent nations in recent years.[] This study identified
a statistically significant link between smoking and
tobacco use and the development of oral premalignant
lesions, indicating that these factors contribute to the
production of such lesions and are critical risk factors.
Numerous studies in the literature have identified a
positive relationship between diabetes and the onset of
oral possibly malignant illnesses.[,] The diabetic
individual exhibits inadequate oral hygiene, diminished
salivation, and xerostomia, which may heighten vulnerability
to oral mucosal illnesses and infections.[] This
study indicated that systemic diseases, including respiratory,
cardiovascular, hematological, endocrinological, renal,
autoimmune, allergic, and gastrointestinal disorders,
may elevate the incidence of oral premalignant lesions.
This research possesses certain limitations. This
is a cross-sectional study. The study comprised adult
patients, and risk factors for the establishment of premalignant
lesions in the juvenile population could not
be assessed. Ultimately, it is advisable to assess the risk
variables associated with premalignant lesions and
do research involving a broader population to obtain
more definitive conclusions.
Conclusion
The current study enhances the literature by assessing
the risk variables associated with oral premalignant lesions.
It is crucial to identify risk factors to avoid the
progression of clinically detectable oral premalignant
lesions into oral carcinomas and to mitigate exposure
to these risk factors among affected persons.
Ethics Committee Approval: The study was approved by
the Akdeniz University Faculty of Medicine Clinical Research
Ethics Committee (no: 2955, date: 20/04/2022).
Informed Consent: Informed consent was obtained from
all participants.
Conflict of Interest Statement: The authors have no conflicts
of interest to declare.
Funding: The authors declared that this study received no
financial support.
Use of AI for Writing Assistance: No AI technologies utilized.
Author Contributions: Concept - R.Ş.G., B.S.S., S.G.Y.; Design
- B.S.S.; Supervision - R.Ş.G.; Data collection and/or
processing - S.G.Y., R.Ş.G.; Data analysis and/or interpretation
- R.Ş.G., B.S.S., S.G.Y.; Literature search - R.Ş.G., B.S.S.;
Writing - R.Ş.G., B.S.S., S.G.Y.; Critical review - R.Ş.G, S.G.Y.
Peer-review: Externally peer-reviewed.
References
van der Waal I. Potentially malignant disorders of the
oral and oropharyngeal mucosa; terminology, classification
and present concepts of management. Oral Oncol
2009;45(4?5):317-23.
Vigneswaran N, El-Naggar AK. Early detection and
diagnosis of oral premalignant squamous mucosal lesions.
Biomed Opt Otorhinolaryngol Head Neck Surg
2016:601-17.
Vlková B, Stanko P, Minárik G, Tóthová ?, Szemes T,
Ba?asová L, et al. Salivary markers of oxidative stress
in patients with oral premalignant lesions. Arch Oral
Biol 2012;57(12):1651-6.
Chung CH, Yang YH, Wang TY, Shieh TY, Warnakulasuriya
S. Oral precancerous disorders associated with
areca quid chewing, smoking, and alcohol drinking in
southern Taiwan. J Oral Pathol Med 2005;34(8):460-6.
Saini R, Al-Maweri SA, Saini D, Ismail NM, Ismail
AR. Oral mucosal lesions in non-oral habit diabetic
patients and association of diabetes mellitus with
oral precancerous lesions. Diabetes Res Clin Pract
2010;89(3):320-6.
Hashibe M, Jacob B, Thomas G, Ramadas K, Mathew
B, Sankaranarayanan R, et al. Socioeconomic status,
lifestyle factors and oral premalignant lesions. Oral
Oncol 2003;39(7):664-71.
Thomas G, Hashibe M, Jacob BJ, Ramadas K,
Mathew B, Sankaranarayanan R, et al. Risk factors
for multiple oral premalignant lesions. Int J Cancer
2003;107(2):285-91.
Yardimci G, Kutlubay Z, Engin B, Tuzun Y. Precancerous
lesions of oral mucosa. World J Clin Cases
2014;2(12):866.
Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA,
Jemal A. Global cancer statistics 2018: GLOBOCAN
estimates of incidence and mortality worldwide
for 36 cancers in 185 countries. CA Cancer J Clin
2018;68(6):394-424.
Torre LA, Siegel RL, Ward EM, Jemal A. Global cancer
incidence and mortality rates and trends-an update.
Cancer Epidemiol Biomarkers Prev 2016;25(1):16-27.
Abati S, Bramati C, Bondi S, Lissoni A, Trimarchi M.
Oral cancer and precancer: A narrative review on the
relevance of early diagnosis. Int J Environ Res Public
Health 2020;17(24):9160.
Malki AM, Raad SB, Abu-El-Ruz R. Prevention of oral
cancer. In Development of oral cancer: risk factors and
prevention strategies. New York City: Springer International
Publishing; 2017, p. 193-217.
Nair DR, Pruthy R, Pawar U, Chaturvedi P. Oral cancer:
Premalignant conditions and screening-an update.
J Cancer Ther 2012;8(Suppl 2):S57-66.
Marmot M, Feeney A. General explanations for social
inequalities in health. IARC Sci Publ 1997;(138):207-28.
Laine J, Konttinen YT, Beliaev N, Happonen RP.
Immunocompetent cells in amalgam-associated
oral lichenoid contact lesions. J Oral Pathol Med
1999;28(3):117-21.
Gönen ZB, Asan CY, Etöz O, Alkan A. Oral leukoplakia
associated with amalgam restorations. J Oral Sci
2016;58(3):445-8.
Jayaprakash V, Rigual NR, Moysich KB, Loree
TR, Nasca MA, Menezes RJ, et al. Chemoprevention
of head and neck cancer with aspirin: A casecontrol
study. Arch Otolaryngol Head Neck Surg
2006;132(11):1231-6.
de la Cour CD, Verdoodt F, Aalborg GL, von Buchwald
C, Friis S, Dehlendorff C, et al. Low-dose aspirin
use and risk of head and neck cancer-a Danish nationwide
case?control study. Br J Clin Pharmacol
2021;87(3):1561-7.
Macfarlane T, Macfarlane GJ, Thakker NS, Benhamou
S, Bouchardy C, Ahrens W, et al. Role of medical history
and medication use in the aetiology of upper
aerodigestive tract cancers in Europe: The ARCAGE
study. Ann Oncol 2012;23(4):1053-60.
Pérez MA, Raimondi AR, Itoiz ME. An experimental
model to demonstrate the carcinogenic action
of oral chronic traumatic ulcer. J Oral Pathol Med
2005;34(1):17-22.
Sato T. A study on effect of mechanical irritation in development
and progression of tongue cancer. Kokubyo
Gakkai Zasshi 1995;62(4):532-50.
Piemonte ED, Lazos JP, Brunotto M. Relationship
between chronic trauma of the oral mucosa, oral potentially
malignant disorders and oral cancer. J Oral
Pathol Med 2010;39(7):513-7.
Villa A, Villa C, Abati S. Oral cancer and oral erythroplakia:
An update and implication for clinicians. Aust
Dent J 2011;56(3):253-6.
Reddy R, Bhat A. Malignant potential of oral submucous
fibrosis due to intraoral trauma. Indian J Med Sci
2000;54(5):182-7.
Rosenquist K, Wennerberg J, Schildt EB, Bladström
A, Hansson BG, Andersson G. Oral status, oral infections
and some lifestyle factors as risk factors for oral
and oropharyngeal squamous cell carcinoma: A population-
based case-control study in southern Sweden.
Acta Otolaryngol 2005;125(12):1327-36.
Kumar S, Debnath N, Ismail MB, Kumar A, Kumar A,
Badiyani BK, et al. Prevalence and risk factors for oral
potentially malignant disorders in Indian population.
Adv Prev Med 2015;2015:2081-7.
Abidullah M, Kiran G, Gaddikeri K, Raghoji S. Leukoplakia:
Review of a potentially malignant disorder. J
Clin Diagn Res 2014;8(8):ZE01-4.
Bewley AF, Farwell DG. Oral leukoplakia and oral
cavity squamous cell carcinoma. Dermatol Clin
2017;35(5):461-7.
Gandini S, Botteri E, Iodice S, Boniol M, Lowenfels
AB, Maisonneuve P, et al. Tobacco smoking and cancer:
A meta-analysis. Int J Cancer 2008;122(1):155-64.
MacMonegle AJ, Nonnemaker J, Duke JC, Farrelly
MC, Zhao X, Delahanty JC, et al. Cost-effectiveness
analysis of the real cost campaign"s effect on smoking
prevention. Am J Prev Med 2018;55(3):319-25.
Lozada-Nur F, Miranda C. Oral lichen planus: Epidemiology,
clinical characteristics, and associated diseases.
Semin Cutan Med Surg 1997;16(4):273-7.
Dikshit RP, Ramadas K, Hashibe M, Thomas G, Somanathan
T, Sankaranarayanan R. Association between
diabetes mellitus and pre-malignant oral diseases:
A cross sectional study in Kerala, India. Int J
Cancer 2006;118(2):453-7.
Bánóczy J, Albrecht M, Rigó O, Ember G, Ritlop B. Salivary
secretion rate, pH, lactobacilli and yeast counts in
diabetic women. Acta Diabetol 1987;24:223-8.
