Stability Over Time Of High Incidence Bladder Cancer In An Industrialized Area In North-Eastern Spain. A Longitudinal Study In A Region Of 400,000 Inhabitants.

Purpose: To study whether the incidence of bladder cancer in an industrialized area in North-Eastern Spain remains as high as in the nineties. Methods: Patients diagnosed with histologically conrmed primary bladder cancer, during 2018-2019, in an area in North-Eastern Spain (430,883 inhabitants) were included. Crude incidence rates were estimated per 100,000 person-year based on the number of individuals getting their rst diagnosis. Direct age-standardized incidence rates were calculated applying both the European and the World Standard Populations. Results: 295 patients were included (mean age 72.5±10.3 years; 89.8% men). The crude rate was 62.6 (95%CI:55.0-70.1) for men and 6.8 (95%CI:4.4-9.3) for women. The annual rate adjusted to the European Standard Population was 85.3 (95%CI:75.0-95.5) for men and 7.0 (95%CI:4.5-9.5) for women, and adjusted to the World Standard Population, 31.7 (95%CI:27.9-35.5) and 2.9 (95%CI:1.8-3.9) respectively. Conclusion: The incidence of bladder cancer in this area in North-Eastern Spain is one of the highest in men and one of the lowest in women, both in Europe and Worldwide. The decrease in the industrial activity has not led to a decrease in bladder cancer incidence. The heterogeneity of bladder cancer registries in terms of denition and inclusion criteria makes it dicult to compare results.


Introduction
Bladder cancer (BC) is the most common of those affecting the urinary tract, and the tenth most common cancer in the World, accounting for 3% of all new annual cancer diagnoses. It is four times more frequent in men than in women. According to 2018 estimates, 549,393 new cases were diagnosed worldwide (424,082 men and 125,311 women) with a total mortality of 199,922 (148,270 men and 51,652 women) [1][2][3][4].
BC is typical of industrialized areas, being three times more frequent in wealthy areas than in emerging ones, although the highest mortality rates occur in developing countries [5,6]. The highest incidences of BC are observed in Southern Europe, Western Europe and North America [1][2][3][4]. In Spain, the 2018 incidence of BC per 100,000 person-year adjusted to the World Standard Population was 27.5 in men and 5.6 in women [5,7]. The estimated incidence may vary depending on the year, and whether the rate considered is raw or adjusted to either the World or the European Standard Populations. In Spain, the crude annual rate of new BC diagnoses is 41.8-65.0 per 100,000 men and 7.5-14.7 per 100,000 women; when adjusting by age, according to the European Standard Population, gures are 32.7-70.2 in men and 6. 2-12.5 in women [7,8]. Certain areas of Spain, such as Murcia, the Balearic Islands or Tarragona [6], show even higher incidences, among the highest in Europe; in fact, in some industrialized areas, BC is the second most frequent cancer after lung cancer [8]. Previous studies in our area of the North-East of Spain demonstrated a high incidence of BC in men: data from 1992-1994 showed an annual crude rate for men and women of 44.1 and 6.2 cases per 100,000 person-year, respectively, and an annual incidence adjusted for age to the European Standard Population of 52.2 and 5.4 cases, respectively, per 100,000 person-year [9,10]. Therefore, in men, the adjusted rate was very high, while it was intermediate in women when compared to other Spanish areas, and very low when compared to other European ones [10]. There is no recent study on the incidence of BC in this area, although indirect data suggest that it might be much higher [9,10]. The aim of this study is to estimate the current incidence of BC cases in an industrialized area of the North-East of Spain, and to describe the histological characteristics of the tumours.

Methods
West Vallès Occidental is a highly industrialized and urbanized healthcare area of the Catalonia (North-Eastern Spain) with 430,883 inhabitants (211,784 men and 219,099 women) [11], public healthcare services relying on two centres, the Hospital Universitari Mútua de Terrassa and the Consorci Sanitari de Terrassa.
From January 1st, 2018 to December 31th, 2019, all patients attended in these two hospitals, diagnosed with a primary urothelial BC, with histological con rmation, were included in the study. Exclusion criteria were applied for those cases with non-urothelial BC, with a recurrence of a previously diagnosed BC, and for those who were not residents of the study area. Demographic data Age and gender) and histological data (TNM, 1973 WHO, and 2004-2016 WHO tumour classi cations) were recorded. This study was approved by the Ethics and Research Committee of the Hospital Universitari Mútua de Terrassa and conformed to the principles of the declaration of Helsinki.
Statistical analysis was carried out using the SPSS package for Mac, version 21. Analysis of demographic data and histological variables according to gender and age was carried out with the Chisquare test for qualitative factors; Student's t tests, or Mann-Whitney test whenever required, were applied to compare quantitative variables between groups. The annual crude incidence was estimated based on the number of cases registered during the years 2018-2019 at both participating hospitals. For age and gender groups, speci c incidence rates were calculated using the 2019 municipal data from IDESCAT as denominators [11]. The direct method was applied to adjust rates for age and gender, using as references the European Standard Population of 2013 [12] and the World Standard Population [13]. The number of BC cases in 2018 and their crude and adjusted rates in our area under study compared to several European countries are presented in table 1 [5,7]. The crude annual incidence in our area was very high in men (62.6), this indicator being similar to the one in Spain (65.0), but becoming higher when adjusted to the European Standard Population (85.3 vs 70.2) or to the World Standard Population (31.7 vs 27.5) [5,7].
The incidence rate in men adjusted to the World Standard Population in our area under study was much higher than in other areas of the World (Fig. 1), and ranked third, after Greece and Lebanon when compared to the countries with the highest BC incidence rates in men ( Fig. 2) [4]. On the other hand, in women, in 2018, the incidence rate adjusted to the World Standard Population was the lowest when compared to the countries with the highest incidences in men ( Fig. 2) [4]. In our area of the North-East of Spain, the incidence of BC in men, adjusted to the European Standard Population, ranks second after Greece among the European countries, with a much lower incidence in women (table 1) [5,7].

Discussion
The incidence of BC in our area of the North-East of Spain was very high in men, as reported in previous studies [9,10]. When considering the crude annual rate, such gure was similar to the one in Spain for the same period, but became higher when adjusting to the European or the World Standard Populations) [4,5,7]. When comparing with all European countries, in 2018 the incidence of BC in men, adjusted to the European Standard Population, ranked second after Greece [5,7], and third after Greece and Lebanon when adjusted to the World population [4]. Alternatively, the incidence in women was much lower, ranking the lowest of all European countries whether considering the crude or the adjusted rate (European Standard Population), and one of the lowest when considering the incidence adjusted to the World Standard Population [4,5,7].
According to the previously published incidence of BC in our area under study during the period 1992-1994 both the crude and the age-adjusted annual incidence have risen in both sexes, although the increase in men is notably higher [9,10]. In our area of North-Eastern Spain, the high incidence of BC in men could be related to a high prevalence in this area of well-known risk factors for BC, such as smoking, residence in industrialized areas and occupational exposures to certain carcinogenic products [10,14]. In 2015, 27.7% of the population of our area under study declared to be a smoker, a percentage above the average for Catalonia, which was 25.7% [15]. Although in our area data on the proportion of smokers by gender were not available in 2018, in Catalonia such prevalence was higher in men (30.9%) than in women (20.5%), a percentage that increased up to 40.3% in the group of men from 35 to 44 years [16].
In relation to the occupational exposure, historically the high incidence of BC in this area was related to the existence of an important textile industry since the mid-19th century. The decline of textile industry began in the 1970s, becoming marginal at the end of the eighties. The 1992-1994 studies, where a high incidence was observed, only found some moderate occupational risk in relation to previous and prolonged exposures in the textile industry [10,14], as a signi cant percentage of the population had previously worked in this sector without the current security conditions. Our study shows that, more than three decades after the receding of the textile industry, the incidence of BC in men has not decreased, in fact it is higher than before. Currently most workers in the studied area belong to the service sector (58.6%), followed by the industrial sector (32.4%), construction (8.7%) and agriculture (0.2%) [17]. It is probable that factors, such as the textile industry, which favoured the high incidence of BC in the past, have been replaced by others related to pollution or dietary habits.
The mean age of BC diagnosis was similar to the one reported in other series [8, 9,18], without differences between both genders. As in the previous study [9], the incidence of this cancer in our healthcare area is ten times higher in men than in women, while in the World Population it is only four times higher. The discrepancy in incidence between genders in different countries has been attributed to differences in the prevalence of tobacco use. Thus, countries like Lebanon, where smoking is culturally prevalent among women, have the highest incidence of BC [1][2][3]. Other factors that may reduce women's predisposition to BC would be those related to hormonal and genetic factors and lower occupational exposure to carcinogenic products in agriculture, textile, chemical or construction industries [19][20][21]. Finally, certain dietary habits such as the consumption of coffee and alcohol, low consumption of fruits and vegetables, and diets rich in red meat and animal proteins, are factors possibly implicated in the higher incidence in men than in women [21][22][23][24].
The histological characteristics of the tumours are similar to other series [8,18], with predominance of grade 1 and 2 low-grade tumours (51.2%), and those limited to the Ta (60.7%) and T1 mucosa (22.4%), muscle invasive tumours being rare (12.2%) and metastatic spread exceptional (2.3%). Unlike the previous study in our area, we have not found that grade 3 tumours were more frequent in those over 65 years, nor that Ta tumours were signi cantly more frequent in patients under 65 years of age [9,10]. Neither did we observe a relationship between the degree of in ltration and gender, so that the percentage of invasive tumours was not signi cantly higher in women in the present study [9,18].
The possibility that residents in our healthcare area were diagnosed and treated for BC in centres other than the referral hospitals might have led to a certain underestimation of the incidence of BC. However, according to the 2017 health survey of the National Institute of Statistics (INE), in Spain, 83.4% of the population uses the public health system exclusively, 15.4% attends both public and private centres, and only 0.9% is an exclusive user of the private health system [25]. Another limitation, shared with other epidemiological studies on BC, is related to the di culty of comparing different series. First, the national and international BC registries are not homogeneous because there are differences in de nition and inclusion criteria [26][27]. Despite the use of systematic classi cations of tumours such as the TNM classi cation, some speci c characteristics of bladder cancer lead to great heterogeneity when labelling the tumour. Some registries include non-invasive tumours (Tis and Ta) while others only include invasive ones (T1 or higher). Furthermore, the nomenclature is prone to confusion, since the term "invasive" does not have a clear de nition; it may be applied either to describe tumours that invade the lamina propia (T1) or to refer, depending on clinicians, to those that invade the bladder muscle layer (T2 or higher). In parallel, given that Ta tumours may account for up to 50% of BC, their inclusion or exclusion has an important effect when assessing incidence, survival or mortality [27]. In addition, bladder carcinoma in situ has clinical, diagnostic, and therapeutic implications that do not correspond to the ones of carcinoma in situ of other organs; in many cancer registries, often with no participation of urologists, those cancers are not included. Secondly, it is di cult to make comparisons between adjusted rates, and it has already been suggested that incidences adjusted to the European Standard Population of 2013 are not comparable with those adjusted to the previous European population of 1976 that many registries have used. Finally, another epidemiologically relevant factor is the high rate of relapses of super cial BC delayed in time, which can be mistakenly considered as new onset cases.

Conclusions
The incidence of BC in an industrialized area of North-Eastern Spain is one of the highest in men and one of the lowest in women, both in Europe and in the World. The decline in the industrial activity has not led to a decrease in BC annual rates; therefore, a case-control study would be valuable to identify the risk factors speci cally related to the high incidence in this area. The histological characteristics of BC are like those of other regions, except for a greater prevalence of low-grade Ta carcinoma, regardless of gender and age. Lastly, the epidemiological analysis of BC would bene t from more standardized and homogeneous registries to strengthen comparisons and draw clinical conclusions.

Declarations
Funding Incidence of bladder cancer adjusted to the World Standard Population in 2018, worldwide and in the study area. Source: GLOBOCAN 2018 [4].

Figure 2
Incidence of bladder cancer in 2018, adjusted to the World Standard Population, in the countries with the highest incidence rate in men, compared to that of the study area. Source: GLOBOCAN 2018 [4].