To review the studied risk factors that linked to aetiology of oral cancer in the Sudan. There have been numerous reports in the increase in the incidence of oral cancer from various parts of the world. A recent trend for a rising incidence of oral cancer, with the absence of the well established risk factors, has raised concern. Although, there are inconsistent data on incidence and demographical factors, studies suggest that the physiologic response to risk factors by men and women vary in different populations.
This review principally examines 33 publications devoted to aetiology of oral cancer in the Sudan, in addition to some risk factors that are commonly practiced in the Sudan.
Several studies examining risk factors for oral cancer include tobacco use (Smoked and Smokeless), alcohol consumption, occupational risk, familial risk, immune deficits, virus infection and genetic factors.
Toombak use and infection with high risk Human Papilloma Virus (HPV) were extensively investigated and linked to the aetiology of oral cancer in Sudan.
The incidence rates of oral cancer are 3.7% for men
and 2.6% for women in the Sudan [
There are mainly 4 smokeless tobacco products: loose
leaf or chewing tobacco, snuff, plug tobacco and twist or roll tobacco. Chewing
tobacco and snuff are by far the most widely distributed types of smokeless tobacco.
Initially, snuff was used for nasal application (sniffing). However, snuff is now
habitually used orally by insertion it between lower gum and cheek or lip (dipping)
[
The oral use of snuff in North America and Western
Europe is causally associated with an increased risk for cancer of the oral cavity
and pharynx. Snuff dipping has also been incriminated as being associated with cancer
of the nasal cavity, oesophagus, pancreas, kidney and urinary bladder [
However, all these risk factors are beyond the scope of the present review. The main goal of this paper was to review the studied risk factors that linked to aetiology of oral cancer in Sudan.
In this review 33 studies published up to August 2012 in the aetiology of oral cancer from Sudan were included. They were identified through searches of the MEDLINE database, using the keywords: "Sudan", "Toombak", "infection", "HPV", "Oral hygiene", "Alcohol", "Hot meals", "Cancer", "Oral squamous cell carcinoma" and "risk factors". Papers were also searched among those quoted as references in the retrieved studies, as well as, in a few previous reviews. Only papers in English were considered.
In the Sudan, oral snuff, known locally as toombak,
is home-made from finely ground leaves of
Natron: Natron or atron (sodium bicarbonate (Na2H(CO3)2.2H2O).
Atron, opposed to lime in other parts of the world, is probably added to toombak
for its alkaline effects. It has been shown that at high pH (11.0 - 11.8) nicotine
is completely protonated and its rate of absorption is increased [
Epidemiological evidence suggests that toombak is
a risk factor for cancer of the oral cavity and possibly of the oesophagus in the
Sudan [
In Sweden, snus (locally known as snus), was introduced
since the year 1637. The study by Idris et al. compared between snus (Sweden) and
Toombak. Snus and toombak dippers develop a clinically and histologically characteristic
lesion at the site of dipping. Snus was associated with a lower risk of cancer of
the oral cavity (relative risk: RR 5-6-fold) compared to high risk of toombak (RR
7.3-73.0-fold) [
Clinical (n = 281) and histopathological (n = 141)
characteristics of toombak-associated oral mucosal lesions detected in an epidemiological
study in northern Sudan in 1992/93 found Parakeratosis, pale surface staining of
the epithelium and basal cell hyperplasia were commonly observed, but epithelial
dysplasia was infrequent (10/141) [
In a study investigated the effects of toombak on
primary normal human oral keratinocytes, fibroblasts, and a dysplastic oral keratinocytic
cell line, compare to Swedish snuff, a potential for toombak, higher than for Swedish
snuff, to damage human oral epithelium [
The study by Ibrahim et al. [
Several studies from Sudan have proved that toombak
use is a major risk factor that responsible of high frequencies of potential malignant
oral lesions and oral cancers and in particular OSCCs in the Sudan. Most of tumours
were observed at the site of dip application (lower lip). Oral cancer seems to be
gender-specific, as the majority of cases were males [
However, all of the preceded discussed literatures support the criminal role of toombak in the aetiology of oral cancer in the Sudan. Probably toombak has a major role but it is not alone responsible of oral cancer in the Sudan, particularly in the recent years with dramatic increase in overall cancer risk.
Most oral cancer cases and deaths are due to both
individual predisposition, linked to specific genetic characteristics, and exposure
to carcinogens, caused by lifestyle behaviours, particularly tobacco [
Nicotine is only a minor component of tobacco leaves
and constitutes about 5% of the total weight of dry plant leaves. This substance
is the main psychoactive alkaloid of tobacco. When tobacco smoke is inhaled, 25%
of the nicotine reaches the brain in about seven seconds. Nicotine functions by
binding to nicotinic acetylcholine receptors, causing increased heart rate, vasoconstriction,
and alertness [
Tobacco carcinogenicity is more than evident and
about one fourth of oral cancer cases are attributable to cigarette smoking [
More than 60 carcinogens are present in cigarette
smoke and at least 16 in unburned tobacco have been identified. The most important
are tobacco-specific nitrosamines, such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone
(NNK) and N-nitrosonornicotine (NNN), polycyclic aromatic hydrocarbons (PAH), such
as benzopyrene, and aromatic amines. In particular, NNK, NNN and PAH have been causally
linked to oral cancer. The activity of carcinogens is generally exerted through
DNA adducts [
Few women admit to tobacco use due to cultural norms
in the society, and among males the estimated prevalence is around 20% [
A house to house cross-sectional survey of a random
population sample of 4,535 households was performed, as the first survey on tobacco
in the Sudan. Of the 23,367 household members identified, 21,648 (92.6%) eligible
individuals were questioned about tobacco use. Results showed that, among children
and adolescents (4 - 17 years) prevalence of tobacco use was quite low (2%, range
1 - 2%), but there was an abrupt increase up to 25% in late adolescence. Among the
adult population aged 18 years and older the prevalences of toombak use (34%) and
cigarette smoking (12%) among males were significantly higher than among females
(2.5 and 0.9%, respectively) [
As part of the development of a screening procedure
for oral cancer and precancer, exfoliative cytology (EFC) was applied to a retrospective
cohort to assess the presence and severity of oral epithelial atypia (ET) in 300
subjects (100 toombak dippers; 100 cigarette smokers; 100 non-tobacco users) without
prior knowledge of the subjects’ tobacco exposure. ET was ascertained in 29 subjects
and could not be ascertained in the remaining 271. Among the 29 subjects with ET,
there were 11 (38%) toombak dippers, 14 (48%) cigarette smokers and 4 (14%) non-tobacco
users. Among the 271 subjects without ET, there were 89 (33%) toombak dippers, 86
(32%) cigarette smokers and 96 (35%) non-tobacco users. For the ET among toombak
dippers and cigarette smokers, adjusted OR and the 95% CI were found to be 3 (0.91
- 9.7) and 4 (1.2 - 12.3), respectively [
Both in tobacco smoke and smokeless tobacco, carcinogenic
N-nitroso compounds (NOC) are implicated as DNA-damaging agents in cancers of the
aerodigestive tract and the pancreas. Poor oral hygiene was found to contribute
to the formation of nitrosamines in the oral cavity. The evidence so far accumulated
demonstrates that tobacco habits increase endogenous NOC formation, thus adding
to the burden of exposure by preformed carcinogenic NOC in tobacco products [
However, in view of these studies, smoked tobacco has a role in aetiology of oral cancer, but how far this is contributing in oral cancer in Sudan and how far it is significant is unknown, since there is lack of data in this context.
Alcoholic beverages are a heterogeneous group of
beverages, with variable number, type and concentration of components. The common
components are ethanol and water. Carbon dioxide, minerals (mostly potassium, phosphates
and sodium), amino-acids, organic and inorganic acids, polyphenols and carbohydrates
are prevailing in beers. Alcohols, carbohydrates (mainly sugar and pectin), organic
acids, minerals (mostly potassium, iron, phosphates and calcium), polyphenols, vitamins
and carbon dioxide are the major wine components, while spirit and liqueur composition
is very assorted, with common components being alcohols, acids (mainly fatty and
acetic acid), esters, aldehydes, terpenes, ethereal oils and volatile bases [
Regular alcohol consumption is associated with an
increased risk for oral cancer. Such association is dose-dependent. Indeed, among
individuals consuming 4 - 5 drinks daily, the risk for cancer of the oral cavity
is 2 - 3 folds higher than among non-drinkers [
Overall, 7 - 19% oral cancer cases are attributable
to heavy alcohol drinking [
Since alcohol consumption is considered illegal in
Sudan, no available data about the relationship between alcoholic beverage consumption
and oral cancerous development. However, there is only one Sudanese study published
in this context. The study evaluated cytological atypical changes in apparently
healthy oral mucosa exposed to smoking, alcohol, hot meals, and peppers. The features
of cytological atypia were verified among 10 individuals, including 5 smokers, 2
alcohol users, 2 hot meals and peppers consumers, and one non-exposed. For atypia
among tobacco smokers, the adjusted Odds Ratio (OR) and the 95% CI were found to
be 2 (0.246 - 16.24). Increased keratinisation was detected among 27 (45%) of the
smokers (P < 0.0001), 17 (32.7%) of the pepper and hot meals consumers (P < 0.005),
4 (11.8%) of the alcohol consumers, and among 2 (3.7%) of the non-exposed group.
Statistical analyses revealed a greater mean number of AgNORs per nucleus in smokers
(3.68) followed by (2.82) alcohol consumers, compared to the habitual peppers and
hot meal consumers (2.28) and the non-exposed group (2.00) [
However, no available data about alcoholic consumers in the Sudan, approximately 95% of the habitual use to drink in hide, since it is considered as illegal and social stigma. Consequently, nobody can estimated or even imagine its burden as a risk contributes to the aetiology of oral cancer in the Sudan.
The HPV are a large family of non-enveloped DNA viruses,
mainly associated with cervical cancers. Recent epidemiologic evidence has suggested
that HPV may be an independent risk factor for oropharyngeal cancers [
HPVs are small DNA viruses with about 7900 nucleotide
bases long [
The HPV genome encodes DNA sequences for six early
(E1, E2, E4, E5, E6, and E7) proteins associated with viral gene regulation and
cell transformation, two late (L1 and L2) proteins which form the shell of the virus,
and one region of regulatory DNA sequences. The different HPV types are characterized
by genotypic variations in the DNA base-sequences of E6 and E7. It is these genotypic
differences that permit stratification of the virus oncogenic phenotype into high,
intermediate-, and low-risk types [
In the case of high-risk HPV infection and under
favourable conditions, the viral genome is integrated into the host genome, which
is the necessary event for the keratinocytes immortality. During this process of
integration, the circular form of viral genome breaks at the level of the E1 and
E2 regions, never at the level of the E6 or E7 region. Different studies have shown
that the integrated part of the genome corresponds to E1, E6, and E7, while the
regions from E2 to E5 are lost and are not transcribed in the tumours. The loss
of E2 during this process of integration produces the loss of E6 and E7 control.
Therefore, the sequences E6 and E7 are directly involved in the cellular cycle by
inhibiting the normal functions of p53 and pRb, respectively. The protein p53 is
known as the "genome’s guard" and in the case of DNA damage, the p53 can provoke
the arrest of cellular division and assure the time necessary for DNA repair. If
damage cannot be repaired, p53 is able to induce the programmed cellular death and
prevent the propagation of DNA damage in subsequent generations of cells. In the
case of other types of tumours, p53 is usually mutated and acts as a real
Nevertheless, few studies have investigated the role
of viruses in general and HPV in particularly in the aetiology of oral cancer in
the Sudan. The first study investigated potentially malignant oral mucosal lesions
from Sudanese patients (9 hyperplasias/40 dysplasias). HPV was found in only 2 Sudanese
cases, both of which harboured both type 6 and type 11: both these cases demonstrated
mild epithelial dysplasia [
Furthermore, very limited studies have investigated
the role of other viruses such as, Epstein-Barr virus (EBV) and Herpes Simplex Virus
(HSV) in the aetiology of oral cancer in Sudan beside HPV. Using PCR/DNA sequencing,
a study has investigated the prevalence of HPV, HSV and EBV DNA in brush biopsies
obtained from 150 Sudanese toombak dippers and 25 non-toombak dippers in formalin-fixed
paraffin-embedded tissue samples obtained from 31 patients with oral dysplasias
(25 toombak users and 6 non-users), and from 217 patients with oral cancers (145
toombak users and 72 non-users). In the brush tissue samples from toombak users,
HPV was detected in 60 (40%), HSV in 44 (29%) and EBV in 97 (65%) of the samples.
The corresponding figures for the 25 samples from non-users were 17 (68%) positive
for HPV, 6 (24%) positive for HSV and 21 (84%) for EBV. The formalin-fixed samples
with oral dysplasias were all negative for HPV. In the 145 oral cancer samples from
toombak users, HPV was detected in 39 (27%), HSV in 15 (10%) and EBV in 53 (37%)
of the samples. The corresponding figures for the samples from non-users were 15
(21%) positive for HPV, 5 (7%) for HSV and 16 (22%) for EBV. These findings illustrate
that prevalence of HSV, HPV and EBV infections are common and may influence oral
health and cancer development. These observations warrant further studies involving
toombak-associated oral lesions, to uncover the possible mechanisms of these viral
infections in the development of oral cancer, and the influence of toombak on these
viruses [
Genetic factors have enhancing roles in many cancers
including oral cancer. Limited studies have dealt with the investigation of association
between genetic factors and level of risk for development of oral cancer in Sudan.
In a study aiming to explore possible range of gene expression profiles in head
and neck squamous cell carcinomas (HNSCC) and pair wised normal controls from Sudanese
(n = 72) and Norwegian (n = 45) patients using a 15K cDNA microarray and to correlate
the findings with clinicopathologic variables. Differences in gene expression between
tumour and nontumour tissues were identified in HNSCCs. Analysis of the two population
groups revealed a common set of 73 genes within three main biological pathways.
This indicates that the development of HNSCCs is mediated by similar biological
pathways regardless of differences related to race, ethnicity, lifestyle, and/or
exposure to environmental carcinogens. Of particular interest, however, was the
valuable association of gene expression signature found with toombak use and anatomic
site of the tumours [
The prevalence of mutations in exons 2 and 3 of the
S100A4 gene was analyzed in the 14 OSCCs from toombak-dippers and in 25 cases of
OSCCs from the control non-snuff-dippers. Of the 14 OSCCs investigated from toombak-dippers,
mutations in the p21waf1 exon 2 were found in 43% (6 out of 14), compared to 14%
(2 out of 14), 22% (6 out of 27) and 14% (5 out of 35) found in those from non-snuff-dippers
from the Sudan, Scandinavia and the USA/UK, respectively [
A recent study investigated the prevalence of p53
codon 72 polymorphism in brush biopsies obtained from a Sudanese population. A total
of 174 individuals were included in the study; chronic toombak users (n = 152) and
non-users (n = 22). DNA was extracted from all the samples and genotyped for the
codon 72 polymorphism by polymerase chain reaction/restriction fragment length polymorphism.
The Arg/Pro genotype was found in 53% of the 174 study participants, compared to
21% found with Arg/Arg and 26% found with Pro/Pro. Stratifying by toombak use, 28
(18%), 45 (29%) and 79 (52%) of the 152 samples from toombak users had Arg/Arg,
Pro/Pro and Arg/Pro respectively, compared to 9 (41%), 0 (0%) and 13 (59%) found
in the 22 samples from non users. The differences between the samples from toombak
users and non users in Arg/Arg and Pro/Pro codon 72 polymorphism and HPV infection
were statistically significant (P < 0.05). The study indicated that a high prevalence
of the genotype Arg/Pro at the p53 codon 72 may contribute to susceptibility to
OSCC, especially in combination with the use of carcinogenic tobacco-specific nitrosamine
(TSNA)-rich toombak [
Besides tobacco and alcohol, other risk factors have
been studied in relation to oral cancer in Sudan. Among these factors, diet and
nutrition have been suggested to play an important role [
Epidemiological studies conducted in various populations
reported an inverse association between intake of fruit and vegetables and the risk
of cancer of the oral cavity [
The evidence on the role of milk and dairy products,
as well as coffee and tea, on the risk of cancer of the oral cavity and pharynx
is scanty, and does not indicate any consistent association [
Toombak plays a major role in the aetiology of oral cancer in Sudan, since it is a potent carcinogenic, as well as it acts as a synergistic factor enhances the carcinogenesis of other etiological factors, such as genetic factors and viruses. The role of Human Papilloma Virus in aetiology of oral cancer is reasonable, but the question how far is it without toombak? The real contribution of other risk factors such as viruses other than Human Papilloma Virus, smoked tobacco and alcohol still need more investigation other factors that have increased risk or reverse risk need more investigation.
The author report no conflict of interest related to the present study.