TREND OF THE INCIDENCE AND MORTALITY RATE OF LIP CANCER IN CENTRAL SERBIA FROM 1999-2014

Uvod: Karcinom usne je najčešći oralni karcinom. Cilj ovog rada bio je da se prikaže i proceni trend incidencije i mortaliteta od karcinoma usne u centralnoj Srbiju u periodu od 16 godina, od 1999. do 2014. Materijal i metode: Epidemiološka studija zasnovana je na podacima koji su javno dostupni iz registra karcinoma “Incidencija i mortalitet od raka u centralnoj Srbiji” koji objavljuje Institut za javno zdravlje Srbije za period od 1999. do 2014. godine. Trend i godišnja procentualna promena (APC), sa odgovarajućim 95% intervalom poverenja, izračunati su pomoću joinpoint regresione analize. Rezultati: U centralnoj Srbiji, u periodu 1999. 2014. godine, registrovano je ukupno 1922 novoobolelih od karcinoma usne (1402 muškarca i 520 žena). Stopa incidencije i standardizovana stopa incidencije imaju statistički značajan trend pada u muškoj populaciji (p = 0,001, odnosno p < 0,001) tokom ispitivanog perioda, sa APC 4,3%, odnosno 5,2%. Kod žena, incidencija i standardizivana stopa incidencije pokazuju statistički značajan trend pada u periodu 2003.2011. godine, odnosno 2006. 2011. godine, sa APC 12,3, odnosno 24,3%. Standardizovana stopa mortaliteta kod muškaraca pokazuje statistički značajan trend pada kod muškaraca sa APC, 4,5%. Zaključak: U ispitivanom periodu trend incidencije kod muškaraca pada. Kod žena trend je divergentnog karaktera. Stopa mortaliteta karcinoma usne kod oba pola je niska i stabilna.


Introduction
Cancer develops in the interaction of risk factors which include internal factors such as genetic susceptibility and hormonal factors and external factors such as life style and environmental factors.Lip cancer, along with other oral and pharyngeal cancer is the sixth most common cancer type worldwide 1,2 .Lip cancer is far more common in men 3 .Male predominance is a result of occupational and behavioral differences among sexes.Outdoor working and outdoor activities are far more frequent in males.The population over 60 is the most affected with lip cancer.Over 60% of new cases of lip cancer occurred in older patients 4 .
Squamous cell carcinomas (SCCs) is the dominant histological type of lip cancer 5 .SCCs are typical of the lower lip, while basal cell carcinoma (BCC) is more frequent in the upper lip 6,7 .Because of its location, lip cancer shares risk factors with skin cancers and cancers of the oral cavity and nasopharynx.Therefore, the main risk factors for lip cancer are: smoking, alcohol consumption and sun exposure, especially for external lip cancer 8 .Serbia was recognized as a country with a large proportion of potentially avoidable oral cancer 9 .The aim of this study was to present and estimate trends in the incidence and mortality of lip cancer in Central Serbia from 1999 to 2014.

Materials and Methods
This registry-based study was carried out based on the data extracted from publicly available Yearbooks of the Institute of Public Health of Serbia -Incidence and Mortality in Central Serbia, from 1999 to 2014, in which the incidence and mortality rates were aggregated and stratified by sex, 5-year age groups, and diagnosis.The age-standardized incidence and mortality rate in both sexes were calculated based on those data.Lip cancer was coded according to the tenth Revision of International Classification of Disease (codes C00-C96) 10 .Mortality to incidence ratio (MIR) was calculated by dividing the crude rate of mortality by crude rate of incidence for each year.The trend and the annual percentage change (APC) of the incidence and mortality rate with corresponding 95% confidence intervals (95% CI) were calculated by performing join point Trend i godišnja procentualna promena incidencije i mortaliteta sa 95% intervalom poverenja (95%CI) izračunati su joinpoint regresionom analizom.Optimalan broj prelomnih tačaka dobijen je metodom Monte Karlo permutacije.Za analizu trenda korišćen je programski paket Joinpoint Regression Program verzija 4.1.0(dostupan na http: //surveillance.cancer.gov/joinpoint).Promena trenda je smatrana statistički značajnom ukoliko je pvrednost manja od 0,05.

Results
A total number of 1,922 cases (1,402 in men and 520 in women) of lip cancer were registered in Central Serbia from 1999 to 2014.The men to women ratio was 2.8:1.Table 1 presents the distribution of new cases of lip cancer, the crude rate of incidence and mortality, the age-standardized incidence and mortality rate (ASR-W; to the world population) and mortality to incidence rate (MIR) to the specified rates according to the years of observation in males.The highest CR and ASR-W of incidence in males were in 2001 (5.0, 2.9 respectively), and the lowest values of those rates were in 2011 (1.5, 0.8 respectively).In males, the CR and ASR-W of mortality rate were highest in 2006 (0.9, 0.4, respectively), and lowest in 2012 (0.3, 0.2, respectively).
In females, the highest CR and ASR-W of incidence in 2009 (1.9, 1.0, respectively), and the lowest values of those rates were in 2010 and 2011 (0.6, 0.2, respectively).In females, the CR and ASR-W of mortality rate were highest in 1999 and 2012 (0.4, 0.2, respectively).

Discussion
The main finding of the study is a decreasing trend of the incidence of lip cancer in men and low and stable mortality in both sexes.In the study period, the incidence rate in females showed divergent trends, and after a significant decrease in the incidence between 2006 and 2011, there was the trend of a non-significant increase until the end of the study period.The results of significantly decreased rates are also coherent with the data published for lip cancer in Belgrade from 1999-2010 11 .Lip cancer profile in Belgrade almost matches Central Serbia profile.In global terms, a declining incidence trend of lip cancer in Central Serbia parallels observations from Europe (3) and the United States 12 .The male:female ratio (2.8) is similar to the global M/F ratio (2.5) 4 .Generally, a declining trend of M/F ratio was noticed partly due to decreasing of incidence in males, and partly due to rising of incidence in females, especially the incidence of the upper lip cancer 3,13 .
A recently published study 9 established that 60% of cancers of the oral cavity, the oesophagus, the larynx, the corpus uteri and the bladder are considered to be avoidable which indicates great opportunities for prevention.Therefore, the focus of public health activities should be on measures of prevention and reduction of lip cancer risk factors.The main modifiable risk factors for lip cancers are smoking 3,14 and alcohol consumption 15,16 and sun exposure.The first step in risk factors reduction at the national level was done with the creation of a legislation framework for tobacco control 17 .
Yet, Serbia still has a reputation of a country with a very high prevalence of smoking.The smoking cessation is also related to socio-economic factors.It was established that the most addicted people were the poorest women 18 .Smoking and alcohol consumption are well established risk factors 1,19 .Smoking and drinking alcohol have an individual and synergistic effect.The combination of smoking and heavy drinking creates 38 times higher risk for lip cancer compared to the risk of abstainers from both habits 20 .The high lip cancer incidence matched the great alcohol consumption in Central and Eastern Europe 4 .The above-mentioned findings suggest that high prevalence of risk factors for lip cancer was registered in Serbia only in a few studies, which implies that improved and expanded surveillance of risk factors at the national level is needed.
The decreasing trend of lip cancer incidence in males might be the first result of controlling tobacco use.Additionally, the downward trend of lip cancer incidence in males may also be caused by less sunlight exposure due to a reduction in the population living in rural areas 21 .A similar effect could be achieved with a reduction of outdoor occupancy.Sunlight and radiation were established as strongly suggestive risk factors for lip cancer 19 .The effect of sunlight exposure on the carcinoma mechanism depends on the time of exposure and different activities.Long-term and constant exposure to sunlight during work is a predictor of lip cancer, but exposure during holidays and leisure seems to have a protective effect 22 .In the group of possible risk factors of lip cancer, special attention was drawn to the HPV infection 23 .Recent data showed that the prevalence of the overall and 16/18 HPV infections in Serbian women was high in women with a healthy appearance and a cytologically normal cervix 24 .The above-mentioned facts complete the image of Serbia as a region with the high prevalence of lip cancer risk factors.
Almost the whole of the study period is characterized by low mortality/incidence ratio, which implies that lip cancer was timely diagnosed in Central Serbia.The early detection and treatment of lip cancer are related to better prognosis.Therefore, the development of screening program is needed, especially in younger population that is affected 25 .
The global ASR-W of lip cancer in 2012 was estimated at 0.3/100,000 with pronounced regional differences.Regarding the GLOBOCAN estimates in 2012, Serbia was ranked at the 12 th place by the incidence rate of lip cancer in males and at the 21 st place by the incidence of lip cancer in females.Considering the mortality rate, this comparison with GLOBOCAN 2012 estimates showed that Serbia was placed at the 15 th place in males and at the 14 th place in females.Central and Eastern Europe is considered as a region with a relatively high incidence rate of lip cancer 19,26 .Almost one fifth of new cases (19,2%) occurred in Central and Eastern Europe 4 .Serbia is surrounded with countries with the high prevalence of this cancer.The highest rates of lip cancer mortality are typical for Eastern Europe 27 , particularly for males from Bulgaria, the Czech Republic, Hungary, Poland, Romania and Slovakia.An extremely high rate of mortality was observed in Hungary in the mid-1990's.

Limitations of the study
Several possible limitations of this study should be considered.Strategies for cancer control are based on the epidemiology data.Therefore, the quality of cancer registers is crucial.The potential classification problem arises from the position of lip cancer 3 .This cancer is a form of oral cancer located at the junction between the oral cavity and the skin which could be misdiagnosed as skin cancer 28 .The quality of data related to the cause of death in Serbia was assessed as moderate by the World Health Organization 29 .The percentage of unknown and ill-defined cancer deaths for the most recent year indicated that cause-of-death data in Serbia were of moderate quality 30 .Furthermore, GLOBOCAN 2012 categorized data from Serbia as B2 which means high quality regional data (coverage between 10% and 50%) for the incidence rates and medium quality for complete vital registration for the mortality rates.

Conclusion
Pooled evidence implies that the profile of lip cancer in Central Serbia is stable and declines in the study period.After 2011, there are indications of a slight increase in female incidence.The mortality for the same period follows the pattern of incidence.Based on that, it can be concluded that the epidemiological picture of lip cancer is not dramatic.However, predictions for this cancer indicate its increase based on population growth and aging.Additionally, developing countries were affected by transition from infectious diseases to noncommunicable diseases 31 , which implicates further possible increasing trend.Therefore, the high prevalence of risk factors, especially smoking habits, alcohol consumption, indicates that there is a place for public health activities at the national level.Those activities should be focused on cost-effective policies to reduce alcohol and tobacco use and persistent dissemination of information about the risks of sun over-exposure.

Figure 1 .Slika 2 .
Figure 1.The trend of crude rate of incidence of lip cancer in Central Serbia from 1999-2014

Figure 2 .Slika 3 .
Figure 2. The trend of crude rate of mortality of lip cancer in Central Serbia from 1999-2014

Figure 3 .Slika 4 .
Figure 3.The trend of ASR-W of incidence of lip cancer in Central Serbia from 1999-2014

Figure 4 .
Figure 4.The trend of ASR-W of mortality of lip cancer in Central Serbia from 1999-2014

Table 1 .
The number of newly registered cases, the crude rate and the age-standardized incidence and mortality rate of lip cancer in males from Central Serbia from 1999-2014 Broj novoregistovanih pacijenata, stopa incidencije i mortaliteta i standardizovana stopa incidecnije i mortaliteta karcinoma usta kod žena u centralnoj Srbiji od 1999.do 2014.

Table 2 .
The number of new cases, the crude rate and the age-standardized incidence and mortality rate of lip cancer in females from Central Serbia from 1999-2014 Analiza trenda incidencije i mortaliteta karcinoma usta u centralnoj Srbiji u periodu od 1999.do 2014.

Table 3 .
Joinpoint analysis of the trend in the crude rate of incidence and mortality rate of lip cancer in Central Serbia from 1999-2014