View of Oral cancer in Slovenia, 1985–2014

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1 National Institute of Public Health, Ljubljana, Slovenia

2 Slovenian Cancer Registry, Institute of Oncology Ljubljana, Ljubljana, Slovenia

3 Chair of Public Health, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia Correspondence/

Korespondenca:

Barbara Artnik, e: barbara.

artnik@mf.uni-lj.si Key words:

oral cancer; cancer burden;

incidence; time trend;

public health Ključne besede:

rak ustnega predela; breme raka; incidenca; časovni trend; javno zdravje Received: 11. 6. 2018 Accepted: 9. 7. 2019

11.6.2018 date-received

9.7.2019 date-accepted

Oncology Onkologija discipline

Original scientific article Izvirni znanstveni članek article-type

Oral cancer in Slovenia, 1985–2014 Rak ustnega predela v Sloveniji v letih 1985–2014 article-title Oral cancer in Slovenia, 1985–2014 Rak ustnega predela v Sloveniji v letih 1985–2014 alt-title oral cancer, cancer burden, incidence, time

trend, public health rak ustnega predela, breme raka, incidenca, časovni trend, javno zdravje

kwd-group The authors declare that there are no conflicts

of interest present. Avtorji so izjavili, da ne obstajajo nobeni

konkurenčni interesi. conflict

year volume first month last month first page last page

2019 88 11 12 493 508

name surname aff email

Barbara Artnik 3 barbara.artnik@mf.uni-lj.si

name surname aff

Jona Blatnik 1

Vesna Zadnik 2

eng slo aff-id

National Institute of Public

Health, Ljubljana, Slovenia Nacionalni inštitut za javno

zdravje, Ljubljana, Slovenija 1 Slovenian Cancer Registry,

Institute of Oncology Ljubljana, Ljubljana, Slovenia

Epidemiologija in register raka Republike Slovenije, Onkološki inštitut Ljubljana, Ljubljana, Slovenija

2

Chair of Public Health, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia

Katedra za javno zdravje, Medicinska fakulteta, Univerza v Ljubljani, Ljubljana, Slovenija

3

Oral cancer in Slovenia, 1985–2014

Rak ustnega predela v Sloveniji v letih 1985–2014

Jona Blatnik,¹ Vesna Zadnik,² Barbara Artnik³

Abstract

Background: Oral cancer is a collective name for lip cancer, oral cavity cancer and oropharyn- geal cancer; it is one of the most prevalent malignancies in Slovenia. The aim of our study was to analyse the burden of oral cancer in a thirty-year period (1985–2014) in Slovenia.

Methods: All new cases of oral and pharyngeal cancer (C00–C14) in Slovenia diagnosed between the years 1985–2014 were retrieved from the population based Slovenian Cancer Registry. The analysis of the burden of oral cancer was performed for three primary locations: lip (C00.0–2), oral cavity (C00.3–9, C02.0–3, C02.8–9, C03, C04, C05.0, C05.8–9, C06) and oropharynx (C01, C02.4, C05.1–2, C09, C10). Time trends in the incidence of oral cancer for three primary locations were presented with average annual percent changes in crude incidence rates.

Results: 9,442 new cases of oral and pharyngeal cancer were observed between 1985 and 2014.

Final analysis was performed for 7,190 new cases of lip, oral cavity and oropharyngeal cancer;

83.4% of patients were men and 16.6% were women. Average age of a patient at diagnosis was 59.8 years ± 11.3. The highest incidence of lip cancer was observed in 80+ age group, and the highest incidence of oral and oropharyngeal cancer was observed in 55–59 age group. The proportion of male patients was higher in all three cancer groups. The majority of new cases of lip cancer were diagnosed at a localised stage, whereas the majority of new cases of oral and oropharyngeal cancer were diagnosed at a regional stage. Survival rates were highest for patients with lip cancer and lowest for patients with oropharyngeal cancer. A thirty-year time trend showed that the incidence of lip cancer was decreasing, whereas the incidence rates of oral cavity cancer and oropharyngeal cancer were increasing.

Conclusion: Oral cancer is one of the biggest public health and socioeconomic problems of modern society. Early detection of oral cancer improves survival rates and the quality of life of patients. It is necessary to pay attention to the burden of this disease and manage its prevention and control.

Izvleček

Izhodišče: Rak ustnega predela zajema področja ustnice, ustne votline in ustnega dela žrela in v Sloveniji predstavlja eno najpogostejših malignih bolezni. Namen raziskave je bil prikazati breme raka ustnega predela v tridesetletnem obdobju (1985–2014) v Sloveniji.

Metode: Iz baze podatkov Registra raka Republike Slovenije smo pridobili podatke (incidenca, preživetje) o vseh primerih raka ustno-žrelnega predela (C00–C14) v letih 1985–2014. Analizo bre- mena raka ustnega predela smo pripravili za tri osnovna primarna mesta: ustnico (C00.0–2), ustno votlino (C00.3–9, C02.0–3 in C02.8–9, C03, C04, C05.0 in C05.8–9, C06) in ustni del žrela (C01, C02.4, C05.1–2, C09, C10). Časovne trende števila novih primerov raka po posameznem mestu smo prikazali v obliki deleža povprečne letne spremembe grobe incidenčne stopnje.

Rezultati: Pridobili smo podatke o 9.442 primerih raka ustno-žrelnega predela za obdobje 1985–

Slovenian Medical

Journal

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1 Introduction

Oral cancer is a collective name for lip cancer, oral cavity cancer and oropharyngeal cancer. It is ranked 6^th among all cancer cases in the world. The annual incidence is around 400,000 cases and varies widely across the globe (1). The highest incidence of oral cancer is in Sri Lanka, India, Pakistan, Bangladesh, Hungary, and France (2).

The major etiologic factors responsi- ble for up to 90% of cases are tobacco and alcohol use. Other cancer-related factors include human papillomavirus (HPV) infection, marijuana smoking, low-fruit and vegetable consumption diets, poor oral hygiene, social inequality, exposure to hazardous chemicals in the workplace, chronic trauma to the oral mucosa, UV radiation, immunosuppression (3-5). In the recent years, researchers have paid increasing attention to the role of HPV infection, having identified a high proportion of HPV-positive cases of oral cancer (16.2% in Europe) (6). The infection is associated with early first sexual intercourse, a greater number of sexual partners, oral

2014. V končno analizo smo vključili vse primere raka ustnega predela (N = 7.190). Med preis- kovanci je bilo 83,4 % moških in 16,6 % žensk. Povprečna starost preiskovancev ob postavitvi diagnoze je bila 59,8 let ± 11,3. Največ primerov raka ustnice je v starostni skupini nad 80 let, največ primerov raka ustne votline in ustnega dela žrela pa v starostni skupini 55–59 let. Pri vseh treh skupinah raka je večji delež moških kot žensk. Največ primerov raka ustnice odkrijemo v omejenem stadiju, največ raka ustne votline in ustnega dela žrela v razširjenem stadiju. Najboljše je preživetje bolnikov z rakom ustnice, najslabše pri bolnikih z rakom ustnega dela žrela. Trides- etletni časovni trend raka prikazuje upadanje števila primerov raka ustnice, nasprotno pa število primerov raka ustne votline in ustnega dela žrela narašča.

Zaključek: Rak ustnega predela je eden pomembnejših javnozdravstvenih, socialnih in ekon- omskih problemov sodobne družbe. Zgodnje odkrivanje raka prispeva k izboljšanju preživetja in h kakovosti življenja bolnikov, zato je potrebno še posebno pozornost posvečati obvladovanju te bolezni.

Cite as/Citirajte kot: Blatnik J, Zadnik V, Artnik B. Oral cancer in Slovenia, 1985–2014. Zdrav Vestn.

2019;88(11–12):493–508.

DOI: https://doi.org/10.6016/ZdravVestn.2845

sexual practices, and same-sex practices (7-9).

Oral cancer is more commonly reported in men over 50, although changes in smoking and drinking habits have led to an increase in cancer among women. In 1950, the ratio of males to females was 6:1, whereas today it is 2:1 (4). Due to HPV infections, the incidence in the developed world is rising among young adults, especially men with higher socioeconomic status, with no other risk factors for cancer or only a minor factor (10-12). A typical cancerous lesion in an ulcer, which most commonly occurs on the tongue, floor of the mouth and cheeks. Up to 70% of cancers arise from a precancerous lesion (4,13).

Histologically, 95% are squamous cell carcinomas (14,15). Although early diagnosis is relatively straightforward, most cases of oral cancer are detected in the advanced stage. The average 5-year survival rate is only about 50%. Survival has remained virtually unchanged in recent decades despite advances in diagnosis and treatment (4). A review article by Lafaurie et

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al. summarizes that HPV-positive cases of oral cancer have better outcomes than HPV-negative cases of oral cancer (16). A systematic examination and meta-analysis of oropharyngeal cancer by O’Rorke et al.

found a 52% lower risk of disease progression, 63% lower risk of disease recurrence, and 53% reduced mortality (17). Their findings are also supported by Strojan et al.’s study conducted between 2007 and 2008 on histopathological specimens of patients with oropharyngeal cancer in Slo- venia; HPV infection is an independent determinant of a reduced risk of oropharyngeal cancer progression and reduced mortality (11).

Oral cancer is one of the most common malignancies also in Slovenia, accounting for 54% of cases of head and neck cancer that is ranked 5^th for men, 14^th for women, and 8^th for overall cancer incidence (18).

The purpose of our study was to present the burden of oral cancer over a thirty-year period (1985–2014) in Slovenia.

Basic epidemiological indicators were studied: incidence and time trend with re- spect to each cancer site, gender and age of patients, stage at diagnosis, and especially the observed survival of patients over a 10-year period (2005–2014).

2 Methods

2.1 Data sources, subjects, and inclusion criteria

We obtained data on all cases of oral and pharyngeal cancer in the period from 1985 to 2014 from the database of the Cancer Registry of the Republic of Slove- nia (CRS) (cases of head and neck cancer without cases of throat, nasal cavity and paranasal sinuses, and middle ear malignancies). The site of malignancy is defined in the CRS by the tenth revision of the International Statistical Classification of Diseases and Related Health Problems (ICD-10). Our analysis incorporated all cases registered with ICD-10 codes between C00 and C14. We obtained ano-

nymized information about:

• patient gender and age;

• date of diagnosis;

• hospital where they were diagnosed;

• site and morphology;

• cancer stage;

• vital status and date of death of the de- ceased;

• healthcare region, statistical region, and the administrative unit of the place of residence.

The analysis excluded all subjects that were reported to the CRS with the following primary sites C07, C08, C11, C12, C13, C14; the exclusion is explained in the discussion section of this article.

Data on the number and age structure of the population in this period were obtained from the data portal of the Statisti- cal Office of the Republic of Slovenia.

2.2 Defining oral cancer

The classification of oral cancer is not clearly defined in the literature. This problem is further addressed in the discussion section of this article. For defining oral cancer in our analysis we used ICD-10 and the eighth edition of the TNM Classi- fication of Malignant Tumors of the Union for International Cancer Control (UICC) (19). The primary sites of the oropharyngeal region (C00 – C14) were classified in- to the following groups:

• lip (C00.0–2);

• oral cavity (C00.3–9, C02.0–3 and C02.8–9,C03, C04, C05.0 and C05.8–9, C06);

• oropharynx (C01, C02.4, C05.1–2, C09, C10);

• salivary glands (C07, C08);

• nasopharynx (C11);

• pyriform sinus (C12);

• hypopharynx (C13);

• other (C14).

The analysis was prepared for three basic primary sites: the lip, oral cavity, and oropharynx. The classification of individ-

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ual anatomical cancer sites by ICD-10 of the three sites is presented in Table 1.

2.3 Data analysis

For the entire thirty-year period (1985–

2014), we reported the incidence and proportions of oral cancer by individual site, gender, patient age, and stage of cancer at diagnosis. We also estimated the thirty-year incidence trend by site. We have prepared a more detailed presentation for the last ten-year period (2005–2014).

We provide the incidence, the proportion of all cancer cases, cumulative risk, gross incidence rate, age-standardized rate, and estimated percentages of annual gross and age-standardized incidence rates for each site. The observed patient survival by site is also added.

Data were analysed using the Micro- soft Excel 2016 and IBM SPSS Statistics for Windows software (version 24.0) (20). We used the direct standardization method and the world standard population for the age standardization of incidence rates. The time trends of the number of new cancer cases by site were analysed using the Join- point Regression Program (version 4.1.1;

Bethesda, MD: Statistical Research and Applications Branch, National Cancer In- stitute, October 2014) (21). The trends are thus presented in the form of an average annual percent change (AAPC) of a gross incidence rate. The 95% confidence inter- val values were also calculated for each AAPC. The limit of statistical significance of the trends was set at p < 0.05.

3 Results

We obtained data for all oral and pharyngeal cancer cases (C00 – C14; N = 9,442; N - number of new cancer cases) for the 1985–2014 period. All cases of oral cancer (C00 – C06, C09 and C10; N

= 7,190) were included in the final analysis. The difference in the number of cancer cases (N = 2.252) represents those cases of oral and pharyngeal cancer that were ex-

cluded from the analysis (C07, C08, C11 – C14).

The incidences and proportions by site are shown in Table 1. There were 5,994 (83.4%) men and 1,197 (16.6%) women among the subjects. The average age of the subjects at diagnosis was 59.8 years ± 11.3;

in males 58.9 years ± 10.5 and in females 64.0 years ± 14.1.

3.1 Incidence and survival of patients with oral cancer

Table 2 presents basic epidemiological data on oral cancer. Similar cancer fact sheets (CFS) are also displayed at SLORA’s online portal (18). In the last decade, the number of new cases of oral cavity cancer in men was almost three times the number of new cases in women, and the number of new cases of oropharyngeal cancer in men was almost six times the number of new cases in women. Oral cavity cancer accounts for less than one percent of all cancers (with and without non-melanoma skin cancer), and oropharyngeal cancer accounts for a good two percent of all cancers (with and without non-melanoma skin cancer). Men born in Slovenia in 2014 are five times more likely to develop lip cancer by the age of 75 than women; the risk of oral cavity cancer is almost three times higher as in women; the risk of developing oropharyngeal cancer is six times higher as in women.

The distribution of patients by age at diagnosis is similar for oral cavity and oropharyngeal cancer, whereas the age structure of patients with lip cancer is different (Figure 1).

Most cases of lip cancer are in the 80 + age group, and most cases of oral cavity and oropharyngeal cancer are in the 55–59 age group. There were 19 cases of oral cavity cancer before the age of 30, and no cases of oral cavity or oropharyngeal cancer before that age were reported. The youngest patient with oral cavity cancer was 19 years old.

In all three cancer groups the propor-

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Table 1: Oral cancer burden, 1985−2014.

Cancer site ICD-10 Incidence (N) Proportion regarding

cancer site (%)

Lip C00.1 – external lower lip 697 90.0

C00.0 – external upper lip 71 9.2

C00.2 – external lip, unspecified 6 0.8

SUM 774 100.0

Oral cavity C04.9 – floor of mouth, unspecified 667 23.2

C02.1 – border of tongue 446 15.5

C06.2 – retromolar area 190 6.6

C04.1 – lateral floor of mouth 174 6.0

C02.9 – tongue, unspecified 169 5.9

C02.3 – anterior two-thirds of tongue, part unspecified 153 5.3

C04.8 – overlapping lesion of floor of mouth 149 5.2

C06.9 – mouth, unspecified 140 4.9

C03.1 – lower gum 132 4.6

C04.0 – anterior floor of mouth 115 4.0

C03.0 – upper gum 86 3.0

C06.0 – cheek mucosa 86 3.0

C02.8 – overlapping lesion of tongue 72 2.5

C05.8 – overlapping lesion of palate 59 2.0

C05.0 – hard palate 54 1.9

C00.9 – lip, unspecified 37 1.3

C06.1 – vestibule of mouth 36 1.3

C02.2 – ventral surface of tongue 23 0.8

C00.4 – lower lip, inner aspect 19 0.7

C05.9 – palate, unspecified 18 0.6

C02.0 – dorsal surface of tongue 15 0.5

C06.8 – overlapping lesion of other and unspecified parts of

mouth 14 0.5

C03.9 – gum, unspecified 8 0.3

C00.5 – lip, unspecified, inner aspect 3 0.1

C00.6 – commissure of lip 3 0.1

C00.3 – upper lip, inner aspect 3 0.1

C00.8 – overlapping lesion of lip 2 0.1

SUM 2873 100.0

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tion of men is higher than the proportion of women. Most cases of lip cancer are detected in the localised stage, and most cases of oral cavity and oropharyngeal cancers in the regional stage. The survival of patients is the highest in those with lip cancer, and the lowest in patients with oropharyngeal cancer. Over the last 10 years, the average 1-/3-/5-year survival of patients with oropharyngeal cancer has not significantly improved compared to the 1985–2014 period and still remains low (Table 3).

3.2 Time trend of lip, oral cavity, and oropharyngeal cancer in the years 1985–2014

The thirty-year time trend of oral cancer shows a decrease in the number of cases of lip cancer, but in contrast, the number of cases of oral cavity and oropharyngeal cancer is increasing (Figure 2). There were

Table 2: Incidence and risk of oral cancer occurrence, 2005−2014.

Incidence (average 2005–2014) Lip Oral cavity Oropharynx

Men Women Both

sexes Men Women Both

sexes Men Women Both sexes

Number of new cases per year 16 7 23 73 28 101 109 19 128

Percentage of all cancers (%) 0.2 0.1 0.2 1.06 0.48 0.79 1.6 0.3 1.0

Percentage of all cancers except non-

melanoma skin (%) 0.3 0.1 0.2 1.25 0.58 0.95 1.9 0.4 2.2

Risk of cancer occurrencebefore age 75

(CR) (%) 0.10 0.02 0.06 0.54 0.17 0.35 0.81 0.13 0.46

Crude incidence rate per 100,000 1.6 0.8 1.1 7.3 2.7 4.9 10.9 1.9 6.3

Age-standardised incidence rate (ARS)

per 100,000 (W) 0.9 0.2 0.5 4.5 1.5 3.0 6.8 1.1 3.8

Estimated annual change of crude

incidence rate latest 10 years (%) -2.5 -12.5 -5.2 -0.9 0.3 -0.6 1.7 0.3 2.0

Estimated annual change of ASR over

the past 10 years (%) -4.6 -16.5 -7.0 -2.0 -1.8 -1.9 -0.9 2.9 0.6

no sudden changes in the incidence increase or decrease during this period.

4 Discussion

4.1 Burden of oral cancer

The results of our research showed that the number of new oral cancer cases in Slovenia by individual site is as expected.

Most lip cancer cases are in the 80 + age group. This is due to the long-term effects of solar radiation and the associated effects of other risk factors (22). Lip cancer most often occurs on the external lower lip, which is exposed to sunlight, the effects of alcohol, and hot smoke when smoking tobacco more than the upper lip. Immu- nosuppressant therapy is also an important risk factor (23). On average, younger people are more affected by oral cavity and oropharyngeal cancer, since tobacco and alcohol use, which are the most common

Cancer site ICD-10 Incidence (N) Proportion regarding

cancer site (%)

Oropharynx C10.9 – oropharynx, unspecified 902 25.5

C01 – base of tongue 505 14.2

C09.9 – tonsil, unspecified 462 13.0

C10.8 – overlapping lesion of oropharynx 424 12.0

C09.0 – tonsillar fossa 284 8.0

C05.1 – soft palate 197 5.6

C10.0 – vallecula 148 4.2

C10.2 – lateral wall of oropharynx 147 4.1

C09.1 – tonsillar pillar (anterior)(posterior) 136 3.8

C05.2 – uvula 119 3.4

C09.8 – overlapping lesion of tonsil 84 2.4

C10.3 – posterior wall of oropharynx 82 2.3

C10.1 – anterior surface of epiglottis 46 1.3

C02.4 – lingual tonsil 6 0.2

C10.4 – branchial cleft 1 0.0

SUM 3543 100.0

SUM 7190

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tion of men is higher than the proportion of women. Most cases of lip cancer are detected in the localised stage, and most cases of oral cavity and oropharyngeal cancers in the regional stage. The survival of patients is the highest in those with lip cancer, and the lowest in patients with oropharyngeal cancer. Over the last 10 years, the average 1-/3-/5-year survival of patients with oropharyngeal cancer has not significantly improved compared to the 1985–2014 period and still remains low (Table 3).

3.2 Time trend of lip, oral cavity, and oropharyngeal cancer in the years 1985–2014

The thirty-year time trend of oral cancer shows a decrease in the number of cases of lip cancer, but in contrast, the number of cases of oral cavity and oropharyngeal cancer is increasing (Figure 2). There were

Table 2: Incidence and risk of oral cancer occurrence, 2005−2014.

Incidence (average 2005–2014) Lip Oral cavity Oropharynx

Men Women Both

sexes Men Women Both

sexes Men Women Both sexes

Number of new cases per year 16 7 23 73 28 101 109 19 128

Percentage of all cancers (%) 0.2 0.1 0.2 1.06 0.48 0.79 1.6 0.3 1.0

Percentage of all cancers except non-

melanoma skin (%) 0.3 0.1 0.2 1.25 0.58 0.95 1.9 0.4 2.2

Risk of cancer occurrencebefore age 75

(CR) (%) 0.10 0.02 0.06 0.54 0.17 0.35 0.81 0.13 0.46

Crude incidence rate per 100,000 1.6 0.8 1.1 7.3 2.7 4.9 10.9 1.9 6.3

Age-standardised incidence rate (ARS)

per 100,000 (W) 0.9 0.2 0.5 4.5 1.5 3.0 6.8 1.1 3.8

Estimated annual change of crude

incidence rate latest 10 years (%) -2.5 -12.5 -5.2 -0.9 0.3 -0.6 1.7 0.3 2.0

Estimated annual change of ASR over

the past 10 years (%) -4.6 -16.5 -7.0 -2.0 -1.8 -1.9 -0.9 2.9 0.6

etiological factors (4), have a synergistic and multiplicative risk effect (3).

In 2007, the International Agency for Research on Cancer (IARC) included HPV as a group of carcinogenic agents (24). The association between HPV infection and oropharyngeal cancer has been demonstrated (25,26), so recently a growing influence on developing oropharyngeal cancer in the younger population has been attributed to an HPV infection (3,27). The population attributable fraction (PAF) is calculated based on the frequency of the infection in the cancer tissue and the rela- tive risk of infection (28). This signifies the number of new cancer cases that could be prevented if the HPV infection was avoid- ed or if the HPV infection was successful- ly treated. Oral cavity and oropharyngeal cancers attributable to HPV infection account for 4.3% and 30.8%, respectively (29,30). In our study we show, like Hae- ggblom et al. in their systematic review of the literature on the prevalence of HPV in oropharyngeal cancer (31) that more new cases of oropharyngeal cancer occur in the lymphoepithelial tissue (base of the tongue, C01; tonsils, C09) than other sites

of the oropharynx. Haeggblom et al. have found HPV more frequently in lymphoepithelial tissue than in non-lymphoepithelial tissue of the oropharynx (31). The influence of risk factors on the development of oral cancer can only be inferred from the data we used in the study, but we can- not determine their correlation. CRS does not record data on smoking status, alcohol consumption, and HPV status of patients (11).

When observing gender based disease prevalence, the results of our study show that men are more likely to develop oral cancer. Lip cancer occurs three times more often, oral cavity cancer four times more often, and oropharyngeal cancer seven times more often than in women. The highest proportion of localised stage of the disease is found in lip cancer, whereas oral cavity and oropharyngeal cancer is dom- inated by a higher proportion of regional stage of the disease, which is associated with poorer survival of patients. There are several reasons for this. The accessibility of individual oral sites for clinical examination and self-examination varies from person to person. Irregular visits to the

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dentist can also contribute to cancer development, as well as inaccurate and irregular examinations of the oral area when visiting a selected dentist or physician.

Over the last decade, the gross incidence rate and age-standardized rate of oral cancer have been declining, except for oral cavity cancer in women and oropharyngeal cancer in both sexes where they are on the rise.

When reporting the incidence of oral cancer, we considered the calculation with and without non-melanoma skin cancer.

It has been suggested that in Slovenia – as well as in other European population cancer registries – the registration of non-melanoma skin cancer and those malignancies treated in outpatient settings is less detailed (32). In Slovenia, non-melanoma skin cancer accounted for 18% of all new cancer cases in 2014 (33). In some countries, cancer registries do not have ac- cess to outpatient (and treated) non-melanoma skin cancer cases, therefore, they

are not registered. This is the reason why non-melanoma skin cancer is excluded from international comparisons (34).

4.2 Time trend of oral cancer Our time trend analysis aimed at presenting the longest possible timeframe.

CRS holds data on incidence and prevalence from 1950 onwards, and mortality and survival rates from 1985 onwards.

Year 1985 thus served as the beginning of our thirty-year analysis (35).

The number of new cases of lip cancer is declining. This is a reflection of the successful awareness of the harmful effects of solar radiation and UV protection (36,37), and also tobacco and alcohol policy mea- sures (38,39). Nevertheless, prevention in this area needs to be strengthened. In contrast, the number of new cases of oral cavity and oropharyngeal cancer is increasing.

Recommendations and awareness-raising on the harmful effects of alcohol and to- Figure 1: New cases of oral cancer by cancer site and patient age at diagnosis, 1985−2014.

100 200 300 400 500 600 700

Figure 2: Time trend of oral cancer by cancer site, 1985−2014.

* AAPC – average annual percent change of crude incidence rate, 1985–2014.

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are not registered. This is the reason why non-melanoma skin cancer is excluded from international comparisons (34).

4.2 Time trend of oral cancer Our time trend analysis aimed at presenting the longest possible timeframe.

CRS holds data on incidence and prevalence from 1950 onwards, and mortality and survival rates from 1985 onwards.

Year 1985 thus served as the beginning of our thirty-year analysis (35).

The number of new cases of lip cancer is declining. This is a reflection of the successful awareness of the harmful effects of solar radiation and UV protection (36,37), and also tobacco and alcohol policy mea- sures (38,39). Nevertheless, prevention in this area needs to be strengthened. In contrast, the number of new cases of oral cavity and oropharyngeal cancer is increasing.

Recommendations and awareness-raising on the harmful effects of alcohol and to- Figure 1: New cases of oral cancer by cancer site and patient age at diagnosis, 1985−2014.

100 200 300 400 500 600 700

Figure 2: Time trend of oral cancer by cancer site, 1985−2014.

* AAPC – average annual percent change of crude incidence rate, 1985–2014.

bacco smoking in reducing incidence are not sufficient on their own. The changing trends in the incidence of oral cavity and oropharyngeal cancer in the Slovenian population are probably due to changes in exposure to risk factors in recent decades (11). The proportion of smokers has declined from 36% (40) since 1978 to 22.6% in 2012 (it has been decreasing in male smokers and has been stagnant in women since 2001) (41). Drinking ex-

cessive amounts of alcohol is declining but remains above the EU average, with increasing high-risk intoxication several times a year and from 1 to 3 times a month (42,43). The increasing incidence of oropharyngeal cancer is largely attributed to an HPV infection (25,26). The proportion of people consuming fruits and vegetables, who have cancer-protective effects, is also declining (44,45).

Table 3: New cases of oral cancer by patient sex and cancer stage, 1985−2014, and observed survival, 2005−2014.

Cancer site Lip Oral cavity Oropharynx

N % N % N %

Sex M 574 74.2 2291 79.7 3129 88.3

W 200 25.8 582 20.3 414 11.7

Stage localised 708 91.5 991 34.5 541 15.3

regional 54 7.0 1783 62.1 2857 80.6

remote 1 0.1 46 1.6 104 2.9

no available

data 11 1.4 53 1.8 41 1.2

Observed survival 1-year / 94 / 78 / 68

3-year / 79 / 55 / 46

5-year / 70 / 45 / 37

10-year / 43 / 33 / 25

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A direct comparison of the trend observed in our study to other studies is not possible, as these studies track multi-year cancer trends for the entire oral and pharyngeal region (C00 – C14). According to EUCAN 2012 data, the incidence in Slovenia was 12.6/100,000 inhabitants. In Northern Europe the incidence is highest in Denmark (13.0/100,000 inhabitants), in Western Europe in France (15.0/100,000 inhabitants), in Southern Europe in Por- tugal (15.4/100,000 inhabitants), in East- ern Europe in Hungary (23.3/100,000 inhabitants). Hungary also has the highest incidence in Europe, almost nine times the incidence in Cyprus, where it is the lowest (2.7/100,000 inhabitants) (27). Great Brit- ain sees an increase in the burden of oral cavity cancer, in south-east England between 1987 and 2006 especially tongue and tongue base, gum and palate cancers (46).

In the Netherlands, the incidence of oral cavity cancer increased from 1991 to 2010, as did mortality, and patient survival improved. The incidence of oral cavity cancer has replaced laryngeal cancer as the most frequently occurring cancer in the head and neck area in the Netherlands (47). In Denmark, the incidence of oral cavity and oropharyngeal cancer increased between 1980 and 2012 (48). The United States saw a decrease in incidence and mortality, but an increase in both within certain demo- graphic groups in the years 1975–2004 (49). An increase in the incidence of oropharyngeal cancer was reported in New Zealand and Queensland, Australia in the 1982–2010 period, while the incidence of oral cavity cancer remained unchanged or decreased in men in Queensland (50).

4.3 Inconsistent reporting of oral cancer in Slovenia

In Slovenia, oropharyngeal cancer is the main contributor to the burden of oral cancer as per our analysis. There are diffi- culties in accessing this area during clinical examination, and patients themselves do not notice or feel a change in the mu-

cosa only when it is accompanied by more serious symptoms (pain, swelling, bleed- ing from the wound, difficulty in chewing and swallowing) (4).

Oral cavity cancer is most commonly found (69%) at the floor of mouth and tongue, as these two sites are most exposed to the main risk factors. Half of the cases of oral cavity cancer (N = 1.335) are defined as an “overlapping lesion” or “unspecified site”. This means that the cancer was discovered late, in its advanced stage, so the exact origin is more difficult to determine. Furthermore, the primary site is inaccurately described and is registered in the CRS with the category “unspecified site”. Unpublished results show that between 1994 and 1995 there was a sharp increase in the definitions of “overlapping lesion” and a decline in the definitions of

“unspecified site”. This is due to a change in the recording of new cancer cases according to the ICD-10 classification, which succeeded the ICD-8, where “overlapping lesions” and “unspecified site” were a joint category. CRS, however, does not correct for previously entered data.

Cancer reporting in Slovenia has been mandatory and statutory since CRS was established at the Institute of Oncology Ljubljana in 1950. All hospitals in the Re- public of Slovenia, public health institutes, and other legal and natural persons per- forming healthcare services must provide the prescribed information on the Cancer Registration Form regularly. In addition to presenting the burden of cancer in the country, this data serve as the starting point for evaluating the success of oncology prevention, diagnosis, treatment, reha- bilitation, palliative care, and the planning of cancer management capabilities and resources.

The physician reporting the disease on the Cancer Registration Form fills in or identifies the primary site of cancer de- scriptively, but not by coding the ICD-10 category and subcategory. This information is transferred to the registry where the site is coded with the ICD-10 category

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and subcategory. Subcategory cancer coding is often difficult, as the site description on the application form is often lacking in information. Which ICD-10 category entered in the registry is the most appro- priate for some vague description of a site, is determined by international and CRS- agreed rules. The registry spends a great deal of time searching for incompletely recorded or even incorrect information on the registration form (33,51).

4.4 Recommendations for defining oral cancer

The definition of oral cancer is not con- sistent in the literature either (52). Text- books, professional articles, and websites of foreign associations (National Cancer Institute (53), American Joint Committee on Cancer (54), American Head & Neck Society (55), American Cancer Society (56), Cancer Research UK (57)) lack clear definitions. We find different classifica- tions. Most inconsistencies are found in the classification of lip, lingual tonsils, and soft palate cancers under oral cavity cancer.There are several reasons for the dif- ficulties in defining oral cancer. From a clinical point of view, this pathology is managed by dentists, family medicine specialists, maxillofacial and oral surgeons, ENT specialists, etc. The anatomical area is very diverse and there are no clear tran- sitions between structures. Embryologi- cally, the lip, oral cavity, and pharynx are formed from the primary oral cavity (ectoderm) and foregut (endoderm), which are separated by the oropharyngeal mem- brane by the 8^th embryonic week. Thus, the development of the lip, cheek, hard palate, and ventral surface of the tongue originates from the ectoderm, and the soft palate, pharynx, and dorsal surface of the tongue develop from the endoderm (58).

In addition, there are numerous risk factors for oral cancer (3).

For the definition of oral cancer (Ta- ble 1) we also used current articles in the

field of defining oral cancer (2,3,52) in addition to the international classifica- tions mentioned under methods section of this article. Tapia and Goldberg (52) highlight the non-uniform classification of the definition of oral cancer and its site.

Their findings were supported in the following years by Radöi and Luce (3) with a systematic review of 102 articles from different countries (all continents), which provided definitions of the oral cavity of individual authors. We upgraded the definitions referred to in their article (3) by a separate definition for the lip (vermilion border and lipstick area). This is signifi- cant because, in lip cancer, the risk factors and age of the patients at diagnosis are different from cases of oral cavity and oropharyngeal cancer (22). The lingual tonsil and soft palate were classified as part of the oropharynx. For the purpose of com- parative studies, these three sites can be classified under the oral cavity. Catego- ries C07 and C08 were excluded from the analysis, since most salivary gland cancers are not squamous cell carcinomas, and the etiological factors are different from the etiologic factors of oral cancer (59,60).

The C11 category was also excluded from the analysis due to differences in etiological factors (61,62). Categories C12 and C13 were excluded from the analysis because of their anatomical location, which does not belong to the oral region. Cate- gory C14 was excluded from the analysis, although it includes malignant neoplasms of other and ill-defined sites in the lip, oral cavity and pharynx (pharynx, Waldeyer’s ring, overlapping lesions of lip, oral cavity and pharynx). Only 23 such cases have been identified in 30 years.

4.5Recommendations for the prevention and early detection of oral cancer

Dentists and physicians need to pay attention to any changes in the oral area, especially in the at-risk population, which is more likely to develop oral cancer. The most at risk are men over the age of 50, with lower socioeconomic status, exces- sive alcohol consumers and smokers. Due

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to changing trends in the incidence of oral cancer and the increasingly important role of HPV infection (25,26), more attention should be paid to the younger population.

Advice on safe sex and possible additional protection against HPV infection is recommended. HPV vaccination was intro- duced in Slovenia in 2009 and is voluntary.

Free vaccination is available for girls aged 11–12 years, as the vaccine’s effectiveness is greatest if administered before first sexual activity. The vaccine is also available for boys and adult women (63). The efficacy of vaccination against HPV infection in both sexes in the prevention of oral cancer, in contrast to the effectiveness of vaccination in cancer prevention in the anogenital area, has not yet been demonstrated (64- 68). Despite the introduction of the vaccination, the most important prevention against HPV infection, which could lead to the development of oral cancer, are safe sex and preventive dental/medical examinations.

The ratio between the number of dentists and the population of Slovenia (1/1,370) allows each person to be exam- ined by a dentist once a year. During the check-up the dentist inspects the entire oral area, whether or not the person re- ports any problems (69). People need to be empowered to take responsibility for taking care of their own oral health. We need to explain to them that we have no influence on some risk factors, such as gender and age, while other risk factors are variable (tobacco and alcohol use, unbalanced diet, poor oral hygiene, sun exposure, HPV infection, lower socioeconomic status). Regular visits to the dentist and self-examination of the oral area, which is recommended once a month, are crucial, regardless of the absence of any problems. The course of treatment for a patient with oral cancer from the onset of the first symptom to the diagnosis proce- dure is not well defined. In case of a visi- ble change (changes in soft tissues, white or red spots or wounds that do not heal within two weeks), the person should visit

the dentist immediately or is referred by the dentist (if necessary) to a specialist examination or is scheduled for follow-up examinations more often.

As many as 80% of patients with oral cancer are referred for treatment by dentists (69). Selected general physicians, family medicine specialists, also play an important role in detecting precancerous and cancerous lesions in the oral area, as they see their patients more often than their dentists. One part of the clinical examination during the visit with a family medicine specialist is a basic oral examination (70). The guidelines for patient management from diagnosis onwards are set out in detail and are freely available on the Institute of Oncology website (71).

Continuing professional training for dentists and physicians is essential to the advancement of oral cancer knowledge.

The acquired knowledge should be used to raise awareness of the importance of prevention and early detection of oral cancer among individuals and the public, as only this will establish the continuity of preventive action in this field. In addition to general advice for reducing the risk of cancer (72), we should also emphasize the promotion of oral health to help raise awareness of the importance of oral health for overall health and the risk factors for oral cancer.

5 Conclusion

Following a thorough review of the literature and other available data, the definition of the oral area has not been gener- ally established in the Slovenian space. The analysis of the data also revealed that the identification of the exact primary cancer site on the Cancer Registration Form is incomplete, which may lead to inaccurate epidemiological cancer data. That is why we have presented the classification of oral cancer, which is suitable for the Slovenian space in terms of etiological factors and the clinical and epidemiological treatment of this cancer. For future epidemiological

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monitoring of the burden of oral cancer we recommend the described classification per site: the lip, oral cavity, and oropharynx.

Oral cancer is one of the major public health, social, and economic problems of modern society. Our contribution wishes to highlight the problem of late detection of this cancer despite the accessibility of the oral area for a clinical examination.

Early cancer detection contributes to im-

proving the survival and quality of life of patients, and particular attention should be paid to the management of this disease.

6 Acknowledgements

The authors wish to acknowledge the help provided by CRS, especially Katarina Lokar and Tina Žagar, for their participa- tion in conducting the research and statistical data processing.

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