Received: 10 August 2022 | Revised: 16 November 2022 | Accepted: 19 November 2022 DOI: 10.1002/cam4.5494 REVIEW Systematic review of population-­based bladder cancer registries: How criteria heterogeneity affects the comparison of incidences José María Caballero1,2 | José María Gili1 | Juan Camilo Pereira1 | Alba Gomáriz1 | Carlos Castillo1 | Montserrat Martín-­Baranera2,3 1 Department of Urology, Hospital Universitari Mútua de Terrassa, Abstract Terrassa Barcelona, Spain Background: The population-­based registry of bladder cancer (BC) raises specific 2 Department of Pediatrics, Obstetrics & problems intrinsic to the tumor, as the inclusion of noninfiltrating, potentially Gynecology and Preventative Medicine at the Autonomous University of malignant and multiple tumors. We performed a systematic review (PRISMA Barcelona, Facultad de Medicina -­ guidelines) of population-­based BC registries to obtain information on their geo- Edificio M, Campus Universitario UAB, graphic areas involved, last dates of real incidence of BC, and rules coding used in Barcelona, Spain 3 BC for uncertain behavior, in situ and multiple tumors. Department of Clinical Epidemiology, Consorci Sanitari Integral, Barcelona, Methods: Using MEDLINE and Google Scholar, we identified scientific publica- Spain tions of in the last 10 years in English or Spanish, whether they were related to a national or international cancer registry, provided information on registry rules, Correspondence José María Caballero, MD, Department and provided data on the incidence of BC. of Urology, Hospital Universitari Mútua Results: After the first screening, a total of 194 references were obtained. After a de Terrassa, Plaça del Dr. Robert, 5, 08021 Terrassa (Barcelona), Spain. second analysis, three registries were selected: International Agency for Research on Email: jcaballero@mutuaterrassa.es Cancer (IARC) is a world registry providing real incidence of BC in the period 2008–­ 2012. Surveillance, Epidemiology, and End Results (SEER) Program registered inci- dence until 2017 in more than 90% of the US population. Spanish Network of Cancer Registries (REDECAN) unifies 14 Spanish registries (27.4% of the population) with real incidence data from 2010 to 2015. The coding and inclusion rules have been modified, but currently, most registries include BC in situ and uncertain behavior tumors. Whenever a new case occurs 36 months after a previous diagnosis, SEER registers those as multiple incident cancers in the same location, while IARC and REDECAN only allow one cancer per location during the lifespan of the patient. Conclusions: Comparison of the incidence of BC among different population-­ based cancer registries is prone to bias due to the methodological differences re- garding the inclusion of carcinomas in situ, indeterminate, and multiple tumors. A good cancer registry could provide better surveillance strategies for BC patients. KEYWORDS bladder cancer, cancer, epidemiology, incidence, population-­based registry This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. © 2022 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. 7540 | wileyonlinelibrary.com/journal/cam4  Cancer Medicine. 2023;12:7540–7551. CABALLERO et al.    | 7541 1 | I N T RO DU CT ION All documents and reports were included, if they met all the inclusion criteria: Population-­based cancer registries are essential to study the incidence of the different types of malignant neoplasms. For 1. The documents were related to a national or inter- these registries to be useful, it is necessary to define the rules national cancer registry. for collecting and storing data, to establish which cases are 2. The documents and reports provided data about BC to be recorded, how they are to be coded, and what type of incidence. registries are generated.1–­5 The rules of each registry to de- 3. The documents and reports provided data of the can- fine primary tumors or multiple tumors6 are an attempt to cer registry program or have a website to consult this provide incidence data that are consistent and reproducible. information. Bladder cancer (BC) is the most common of those that af- fect the urinary tract, the majority of them being urothelial. The exclusion criteria: Depending on their pathology, urothelial tumors can be flat lesions (dysplasia, carcinoma in situ), noninvasive papillary 1. Studies published prior to January 1, 2011. neoplasms limited to the mucosa (papilloma, inverted pap- 2. The documents o reports in which neither a national illoma, papillary neoplasm of low malignant potential, low-­ or international population-­based cancer registry nor a or high-­grade papillary carcinoma), and invasive papillary hospital registry were identified. neoplasms involving the submucosa or beyond (low-­grade 3. Studies in which clear data on the incidence of BC in a or high-­ grade papillary carcinoma). Compared to other defined period were not identified. types of cancer, the BC registry poses specific problems re- 4. Documents in national or international registries in lated above all to the inclusion and coding of noninvasive which it has not been possible to analyze the BC inci- papillary tumors, carcinoma in situ or indeterminate ones. dence registration rules due to incomplete information, In addition, BC frequently presents as multiple tumors, and not having a website or the information being in a lan- with a high probability of recurrence.7,8 guage other than English or Spanish. There is a wide disparity among BC incidences derived from 5. Documents duplicates. the coding rules applied, whether the figures represent real or estimated incidences, whether the crude or adjusted rates are First, the articles were selected based on their titles considered, and the areas included in the different registries. and abstracts, according to the previously established in- For this reason, the aim of this paper is to analyze the different clusion and exclusion criteria. If there were doubts, a sec- methods used to calculate incidence in population-­based BC ond analysis was performed: the full text of the documents registries and thus assess their comparability. was read, subsequently reaching a consensus between the two reviewers on their inclusion or not in the systematic review. The selected articles were grouped according to 2 | M ET H ODS the registry they were reporting data from. Cancer reg- istry websites were reviewed if necessary. After the sec- A systematic review of the literature on population-­based ond screening, an international registry that covered the BC registries and incidence data has been carried out, greater number of countries and a national registry with following the Preferred Reporting Items for Systematic the highest number of publications were chosen for fur- Reviews and Meta-­Analyses (PRISMA)9 guide. Identifying ther analysis. A third cancer registry was chosen that, in scientific publications related to BC registries was the cho- addition to meeting all the inclusion criteria, would pro- sen method to locate these registries. Two electronic da- vide data on our health area. tabases were used, MEDLINE (via Pubmed) and Google Scholar, limited to articles published in the last 10 years in English or Spanish. The search was carried using the fol- 2.2 | Data collection process lowing MeSH terms: “urinary bladder neoplasms” and its synonyms, “registries” and “incidence”. We declare that Data were extracted from the full text of the articles and this revision has not been registered. from the web pages of each cancer registry. Information was obtained on: 2.1 | Registries selection 1. The geographic areas involved in each registry, and the last dates of real and estimated incidence of BC. Two reviewers reviewed all documents separately follow- 2. The BC coding rules, with special interest in regis- ing the eligibility criteria. tration practices related to tumors of uncertain or 7542 |    CABALLERO et al. unknown behavior, carcinoma in situ, multiple tu- (SEER) Program of the National Cancer Institute (NCI) mors, and recurrences. that provides information on cancer statistics in the US population (https://seer.cancer.gov/). 3. 5 articles corresponded to data from the national reg- 3 | R E S U LTS istry of our health area: Spanish Network of Cancer Registries (REDECAN) based on population-­ based 3.1 | Registries selection cancer registries from different provinces of Spain (https://redec​an.org). Title and abstracts of a total of 247 references were 4. The remaining 117 articles corresponded to national screened based on inclusion and exclusion criteria. After registries from China (21 articles), Denmark (10), the first screening, a total of 194 references were obtained France (10), Iran (9), Canada (6), Sweden (8), Japan (Figure 1): (8), Italy (6), the United Kingdom (4), South Korea (4), Norway (3), India (3), Australia (3), Germany 1. 18 articles corresponded to a single international reg- (3), Austria (2), Morocco (2), Egypt (2) and Cyprus, istry: the International Agency for Research on Cancer Lebanon, Ireland, Serbia, the Netherlands, Estonia, (IARC) and its two publications, Cancer Incidence in Brazil, Mexico, Nigeria, Argentina, Mozambique, Five Continents (CI5) and GLOBOCAN. Its official Algeria, Jordan with one article per country. website is https://www.iarc.who.int/ 2. 72 articles obtained data from one U.S. national reg- After the second analysis, according to eligibility cri- istry: Surveillance, Epidemiology, and End Results teria, an international registry that covered the greater FIGURE 1 Bladder cancer registry selection flowchart. CABALLERO et al.    | 7543 number of countries, a national registry with the high- the ICD-­10 version 201016 and the 2011 revision of the est number of publications and a national registry of our International Classification of Diseases for Oncology, health data were chosen for further analysis: IARC, SEER, third edition (ICD-­O-­3) (WHO, 2013).17 Under the term and REDECAN. “neoplasia,” ICD-­10 contains a five-­column table with the following headings for each topography: malignant, sec- ondary or metastatic, in situ, benign, and uncertain and 3.2 | Data on each registry unknown behavior. In contrast, ICD-­O-­3 uses only one set of four digits for topography, which remains the same as in The similarities and differences between the three BC ICD-­10 (e.g., C67 bladder), adding another digit depend- registries included in the analysis, in terms of geo- ing on the exact location e.g., C67 0.2 is a tumor located on graphic areas and population included, and rules for in- the lateral wall of the bladder). In addition, morphological cluding BC cases and multiple tumors, are summarized data is added in the form of four digits that describe the cell in Table 1. type or histology of the tumor, a fifth digit after the slash (/) that describes the behavior (benign /0; uncertain /1; malignant, but not invasive), or in situ/2, malignant 3.2.1 | International Agency for Research on ­invasive/3, metastatic/6); and a sixth digit on the grade, Cancer (IARC) differentiation or phenotype (from grade I if well differ- entiated to grade IV if very undifferentiated or anaplastic) 3.2.1.1 | Geographical areas and dates of cancer (Table 2). registries Currently, most cancer registries collect data on tumors The IARC had two publications: coded based on their behavior as /2 and /3. However, in the case of BC, the situation is different regarding benign 1. The Cancer Incidence in Five Continents (CI5) series tumors, in situ and of uncertain behavior. In volume VI of publishes every 5 years, detailed information on the CI5,18 in order to maintain geographic comparability, only incidence of cancer based on registries from around cases with a /3 code were included, and thus tumors with the world. To date, it comprises 11 volumes, begin- benign behavior, in situ, and unspecified were left out. ning in 1960 with the publication of volume I (32 However, when volume VII19 was elaborated and the dif- records from 29 countries), and ending with volume XI ferent registries were asked about the codes they used for (343 records from 65 countries).10 In total, this world noninvasive and unspecified diagnoses of malignant BC, registry covers 465 million inhabitants. Although in many of them reported that they assigned behavior code some countries the records include practically the / 3 to on-­site diagnoses and unspecified, which made it entire population, in others they only represent a impossible to distinguish these cases. For this reason, the small percentage. Volume XI was published online editors of volume VII decided to accept that noninvasive in 2020, and reported cancers diagnosed between diagnoses of BC were considered malignant by patholo- 2008 and 2012, although it is not necessary to have gists. Thus, since volume VII, the BC registry has included data for the 5 years included in the period (3 years the categories in situ and unspecified. Subsequently, to is sufficient). edit volume XI of IC5, the different registries were asked 2. Since 2001, GLOBOCAN provides estimates of inci- again if they included some nonmalignant diagnoses and dence on the different types of cancer by age and sex, how they specifically coded bladder carcinoma in situ with CI5 being the main source of information. The and unspecified, among others. In this way, in the tables most recent publication, GLOBOCAN 2020,11 offers of volume XI, whenever possible, neoplasms of uncertain incidence estimates for the year 2020 in 185 countries or unknown behavior are included together with invasive or territories for 36 types of cancer that include only cancers and are indicated by a dagger symbol next to the malignant neoplasms, except BC, which may include BC code C67, and an accompanying explanatory note. carcinoma in situ, or tumors of uncertain or unknown Some registries preferred not to include such cases in behavior, in incidence (but not mortality), depend- their dataset, even when they were available in the regis- ing on the definitions of malignancy in each cancer try, in order to maintain continuity over time that ensured registry. comparability. Concerning the presence of multiple tumors, accord- 3.2.1.2 | Urinary bladder cancer coding rules ing to IARC rules, only the first malignant neoplasm in In volumes VIII,12 IX,13 and X14 of CI5, the International an organ or group of organs counts. From the rules of the Classification of Diseases. tenth edition (ICD-­10) (WHO, registry of multiple neoplasms of the IARC,6 the following 1992)15 was used. Instead, in volume XI, they used highlights are worth noting: 7544 |    TABLE 1 The similarities and differences between the data on each registry for bladder cancer IARC SEER REDECAN Type of registry World National (US and Puerto Rico) National (Spain) Geographical area 343 registries of 65 countries 49 states of United States and one territory 14 regional registries (Puerto Rico) Population percentage included 65.59% of world population 99% of national population 27.4% of national population Last data of real incidence 2012 2017 -­2012 for 13 registries -­2015 for one registry Bladder Cancer For BC All malignant BC and since 1997 neoplasms Malignant BC and neoplasms of uncertain or All malignant BCs and since 1997 neoplasms Inclusion Rules incidence of uncertain or unknown behavior BC (not unknown behavior BC (all registries). of uncertain or unknown behavior BC all registries). (not all registries). For multiple Only one cancer per organ counts during Count as multiple tumors: Only one cancer per organ counts during BC tumors the patient's lifetime despite different -­BC occur more than 60 days after an in situ the patient's lifetime despite different histological types. tumor. histological types. -­Micropapillary urothelial carcinoma and urothelial carcinoma of the bladder. -­If non-­urothelial BC, a tumor appears >3 years after the original diagnosis or the last recurrence. Abbreviations: BC, Bladder cancer; IARC, International Agency for Research on Cancer; REDECAN, Spanish Network of Cancer Registries; SEER, Surveillance, Epidemiology, and End Results Program (of the National Cancer Institute); US, United States. CABALLERO et al. CABALLERO et al.    | 7545 T A B L E 2 Bladder cancer coding according to the International 3. Multifocal tumors, that is, masses apparently not in Classification of Diseases for Oncology, third edition (ICD-­O-­3)16 continuity with other primary cancers arising from the TOPOGRAPHY same site or primary tissue, for example, the bladder, C67 BLADDER are counted as a single cancer. C67.0 Trigone of bladder C67.1 Dome of bladder C67.2 Lateral wall of bladder 3.2.1.3 | Incidence of bladder cancer C67.3 Anterior wall of bladder The latest real incidence data from all the global registries C67.4 Posterior wall of bladder that are part of IARC date from the period 2008 to 2012 C67.5 Bladder neck were published in CI5 volume XI.10 Internal urethral orifice C67.6 Ureteric orifice C67.7 Urachus C67.8 Overlapping lesion of bladder 3.2.2 | Surveillance, Epidemiology, and End C67.9 Bladder. NOS Results (SEER) program Bladder wall. NOS Urinary bladder. NOS 3.2.2.1 | Geographic areas and dates of cancer MORPHOLOGY registries 4 digits cellular type (histology) The SEER reports cancer incidence in the US since 1973. 5th digit behavior code for neoplasms Last published in July 2021, incidence data for all can- /0 Benign cers from 2001 through 2017 are included.20 Data from 49 /1 Uncertain whether benign or malignant (Borderline states and one territory (Puerto Rico) met data criteria for malignancy; low malignant potential; uncertain malignant every year during 2013 to 2017, representing 99% of the potential) /2 Carcinoma in situ (intraepithelial; no infiltrating; population of the US and Puerto Rico.20 noninvasive) In the SEER program, timely and accurate calculation /3 Malignant. primary site of cancer incidence rates is slightly hampered by delayed /6* Malignant. metastatic site (malignant. secondary site) reporting: on November 1, cases diagnosed approximately /9* Malignant. uncertain whether primary or metastatic site 2 years earlier are submitted to SEER registries for inci- * Not used by cancer registries dence, exactly 22 months after the end of the specific diag- 6th digit code for histological grading and differentiation nostic year. These data are published in the spring of the 1 Grade I Well differentiated (differentiated. NOS) following year. For example, in November 2020, the cases 2 Grade II Moderately differentiated (moderately well differentiated; intermediate differentiation) diagnosed through 2018 are submitted and incidence data 3 Grade III Poorly differentiated are published in April 2021. 4 Grade IV Undifferentiated (anaplastic) 9 Grade or differentiation not determined. not stated or not 3.2.2.2 | Urinary bladder cancer coding rules applicable The anatomical location and the histology are coded with 812–­813 Transitional cell papillomas and carcinomas. Particular the ICD-­O-­3 (Table 2).17 Only cases defined as malignant cases. are included, except for BC in which, when reporting in- 8120/1 Urothelial papilloma. NOS (transitional cell papilloma. cidence, carcinomas in situ and malignant ones are com- NOS; papilloma of bladder (C67._)) bined.21 Multiple tumors are considered and are recorded 8130/1 Papillary transitional cell neoplasm of low malignant potential (C67._)(papillary urothelial neoplasm of low separately whenever22: malignant potential (C67._)) 8120/2 Transitional cell carcinoma in situ (Urothelial carcinoma 1. an invasive tumor occurs more than 60 days after an in situ) in situ tumor. 8130/2 Papillary transitional cell carcinoma, non-­invasive 2. the patient has micropapillary urothelial carcinoma (C67._)(Papillary urothelial carcinoma. noninvasive (C67._)) and urothelial carcinoma of the bladder. 8120/3 Transitional cell carcinoma. NOS (urothelial carcinoma. 3. a tumor appears in a patient who has being clinically NOS; transitional carcinoma) 8130/3 Papillary transitional cell carcinoma (C67._)(papillary free of disease for more than 3 years after the origi- urothelial carcinoma (C67._)) nal diagnosis or the last recurrence. However, this 8131/3 Transitional cell carcinoma, micropapillary (C67._) rule does not apply when both/all tumors are bladder urothelial carcinoma. 1. The recognition of the existence of two or more pri- mary cancers is not time dependent. 3.2.2.3 | Incidence of urinary bladder cancer 2. A primary cancer is one that originates from a primary SEER contributes to BC incidence data in IARC CI5 site or tissue and is not an extension, recurrence, or publications following IARC criteria. Volume X of CI5 metastasis. (2003–­2007)14 does not include neoplasms of uncertain 7546 |    CABALLERO et al. T A B L E 3 Comparison of the incidences of bladder cancer in Spain and the USA according to IARC (published in Cancer Incidence in Five Continents vol. X13 and XI9) and according to web data or publications from REDECAN23–­29 and SEER19,22 Code Men Women included Registry Publication ICD 10 Period of years CR ASR world CR ASR world Albacete CI5 vol. X C67 # 2003–­2007 54.5 28.9 9.1 3.8 CI5 vol. XI C67 # 2008–­2010 51.9 27.7 8.9 4.3 REDECAN C67. D09 2003–­2007 28.0 3.0 Asturias CI5 vol. X C67 # 2003–­2007 66.1 28.8 13.5 4.9 CI5 vol. XI C67 # 2008–­2010 75.1 33.6 14.4 4.9 REDECAN C67. D09 2003–­2007 28.00 4.00 Canarias CI5 vol. X C67 # 2003–­2006 40.1 27.1 7.3 4.0 CI5 vol. XI C67 # 2008–­2011 45.1 27.4 9.5 4.6 REDECAN 2003–­2007 28.59 9.09 4.66 2.3 2008–­2012 31.14 18.38 6.10 2.62 Castellón CI5 vol. X C67 # 2008–­2012 60.7 34 10.6 4.9 (Valencian CI5 vol. XI Community) REDECAN C67. D09 2013 73.07 36.7 13.76 4.00 2004–­2012 34.00 Ciudad Real CI5 vol. X C67 2004–­2007 64.2 32.1 9.3 3.5 CI5 vol. XI C67 # 2008–­2011 60.1 31.3 12.1 5.5 REDECAN C67. D09 2003–­2007 32.10 3.00 Cuenca CI5 vol. X C67 2003–­2007 56.3 24.4 7.6 2.6 CI5 vol. XI C67 # 2008–­2011 56.2 25.2 10.3 2.9 REDECAN 2003–­2007 24.00 2.00 Euskadi CI5 vol. X C67 # 2003–­2007 66.4 34.1 12.3 4.9 CI5 vol. XI C67 # 2008–­2012 74.2 35.1 17.0 6.8 REDECAN C65-­C68 2003–­2007 65.3 34.00 16.0 8.8 2011–­2015 65.3 16.0 Girona CI5 vol. X C67 # 2003–­2007 66.7 37.5 12.2 5.0 CI5 vol. XI 2008–­2012 65.7 36.6 11.8 5.1 REDECAN 2007–­2009 68.6 35.00 12.7 3.00 2010–­2012 37.4 5.63 Granada CI5 vol. X C67 2003–­2007 54.3 32.2 8.1 4.0 CI5 vol. XI C67 # 2008–­2012 58.0 32.8 10.0 4.5 REDECAN 2003–­2007 32.00 4.00 La Rioja CI5 vol. X C67 # 2003–­2007 64.0 31.6 12.1 4.9 CI5 vol. XI C67 # 2008–­2012 70.5 34.5 15.2 5.8 REDECAN 2003–­2007 31.00 4.00 Mallorca CI5 vol. X C67 # 2003–­2007 70.0 44.5 11.2 5.3 CI5 vol. XI C67 # 2008–­2011 65.5 40.4 10.7 5.4 REDECAN 2006–­2008 28.6 3.00 Murcia CI5 vol. X C67 # 2003–­2007 56.3 37.9 9.3 4.8 CI5 vol. XI C67 # 2008–­2010 62.9 41.1 10.4 5.2 REDECAN 2003–­2007 56.3 37.00 9.3 4.00 Navarra CI5 vol. X C67 # 2003–­2007 72.4 39.8 14.4 6.8 CI5 vol. XI C67 # 2008–­2010 77.8 43.4 18.1 8.5 REDECAN 2003–­2007 39.00 6.00 Tarragona CI5 vol. X C67 2003–­2007 66.5 36.9 11.1 5.0 CI5 vol. XI C67 # 2008–­2012 75.4 40.7 12.5 4.9 REDECAN 2008–­2009 71.3 39.0 10.8 4.0 2011–­2013 76.4 36.1 12.5 4.4 2012–­2014 37.7 5.3 CABALLERO et al.    | 7547 TABLE 3 (Continued) Code Men Women included Registry Publication ICD 10 Period of years CR ASR world CR ASR world SEER CI5 vol. X C67 2003–­2007 (9 registries) 30.8 21.0 10.0 5.4 CI5 vol. XI C67 # 2003–­2007 (18 registries) 29.5 20.8 9.5 5.3 2008–­2012 (9 registries) 15.8 19.6 5.0 5.1 2008–­2012 (18 registries) 15.0 19.0 4.7 4.9 SEER* C67 # 2003–­2007 (9 registries) 37.18 9.26 2003–­2007 (17 registries) 37.22 9.21 2008–­2012 (21 registries) 37.80 9.34 2014–­2018 (21 registries) 34.2 8.5 Note: # (including neoplasms of uncertain or unknown behavior together with invasive cancer). ASR world = world age-­standardized incidence rate per 100,000 inhabitants. Abbreviation: CR, Crude incidence rate per 100,000 inhabitants. a Rate per 100,000 population adjusted for age to the US 2000 US standard population (19 age groups -­census P25-­1130). or unknown behavior together with invasive cancer, but 3.2.3.2 | Urinary bladder tumor coding rules. volume XI (2008–­2012)10 does. In both volumes, the in- For the coding of tumors, the ICD-­O-­3 (ICD-­O-­3.1. since cidences vary depending on the year being considered, 2013) is also used. Initially, for the coding of urinary blad- on the number of registries included, and on the consid- der tumors, the recommendations of the 1995 ENCR were eration of crude or adjusted rate (15.0–­30.8/100,000 in- followed: all bladder tumors should be recorded regard- habitants in males) (Table 3). Alternatively, in the SEER less of histological type and level of infiltration (Table 4).27 publications themselves, which always include neoplasms Tumors /1, /2, /3 were coded according to the pathologi- of uncertain behavior, in situ or unknown, the incidence cal description and the level of infiltration. A particular rates per 100.000 inhabitants are adjusted by age to the case was carcinoma in situ, which was coded as 8010/2. US 2000 US standard population of 9, 17, or 21 registries, The coding of urothelial tumors in the different Spanish which also modifies the figures (34.2–­37.18/100,000 in- REDECAN registries is quite homogeneous, coding infil- habitants in males) (Table 3).23 trates as /3. Problematic cases appear when the degree of infiltration is not specified, the degree is not specified, or neither degree nor infiltration is specified.28 Thus, for ex- 3.2.3 | Spanish Network of Cancer Registries ample, if a urothelial tumor is grade I or grade II, or the (REDECAN) grade is unknown, and information on infiltration is also lacking, in the Navarra registry marked this case with an 3.2.3.1 | Geographic areas and dates of cancer asterisk (*), the Canary Islands code it as /1 and Murcia registries as /3. In contrast, a grade III urothelial tumor for which In Spain, REDECAN was established in 2010 based on the there is no information on infiltration, will be coded as population-­based cancer registries of Albacete, Asturias, /3 in the Navarra and Murcia registries, but as /1 in the the Canary Islands, Castellón, Cuenca, Ciudad Real, Canary Islands. Based on all these classifications, in 2012 Girona, Granada, La Rioja, Mallorca, Murcia, Navarra, REDECAN proposed a consensus regarding the coding of Euskadi, and Tarragona, which represented 27.4% of the noninfiltrating urothelial tumors (Table 5).28 total Spanish population in 2020. REDECAN also provides BC incidence data to IARC, 3.2.3.3 | Incidence of urinary bladder cancer with the latest published data being from 2012.10 Based on The estimates of cancer incidence in Spain for 2018 pub- other publications of REDECAN or of each of the member lished by REDECAN in 201929 are based on their own reg- registries, and through the European Cancer Information istries of 10 types of cancer. They are compared with the System (ECIS) page (publication of the European Network incidences of other countries obtained from ECIS. However, of Cancer Registries, ENCR),24 the real incidence of BC dates for the BC, due to the differences in the definition and in the from 2010 in the records of Albacete, Murcia, and Navarra, inclusion criteria and in order to make the data comparable, up to 2012–­2014 in the case of Tarragona,25 and from 2001 the ECIS estimate for Spain has also been used. Thus, the to 2015 for the Basque Country.26 Estimates of cancer inci- estimated incidence rate of BC by the ECIS for 2018 is 70.2 dence in Spain in recent years are made from the incidence for men and 12.5 for women. In contrast, the value of the data of the provinces with population cancer registries. REDECAN estimate is 91.6 for men and 15.8 for women. 7548 |    CABALLERO et al. T A B L E 4 Recommendations for coding bladder tumors of are not included, but they are in the registries of volume European Network of Cancer Registries (ENCR) (1995)27 XI. In the Canary Islands, the incidences of BC reported All bladder tumors should be registered, whatever the in volumes X and XI of the IC5914—­where neoplasms of histological type and level of invasion. uncertain or unknown behavior are included together Principles: with invasive tumors—­ are higher than those that ap- The coding of tumor behavior (/1, /2, /3) takes into account pear in their respective regional registries and in the 2018 both the anatomopathological definition and the extent of invasion. It is, therefore, essential to have access to reports of estimates30,31(Table 3). any pathological examinations Rules: Tumor behavior code: /1 4 | DISC USSION Normal or slightly abnormal histology: low grade papillary urothelial tumors, not invasive. BC has its own characteristics that differentiate it from In the various anatomopathological classifications, these tumors other types of cancer, especially due to the difficulty in- are called: volved in defining malignancy. Unlike other types of . benign or simple papillomas, cancer, flat carcinomas in situ (/2) and some uncertain . papillary urothelial tumors, tumors (/1), although not coded as invasive (/3), may be- . stage I carcinoma (BRODERS’ classification), . well-­differentiated papillary carcinoma (JEWETT's have clinically as malignant. In addition, not only BC has classification), a high rate of recurrence, but also generally presents as . grade I carcinoma (in the WHO classification), or multicentric, and in some cases with a strong potential for . classes I and IIs (CHOME's classification). infiltration, even if the invasion of the submucosa is not Extent of invasion -­none. observed in the anatomopathological sample. We have re- Tumor behavior code: /2 cently carried out a study on the high incidence of BC in Presence of mitoses and more markedly atypical cells than in an industrialized Mediterranean area, which has led us to the previous categories. It includes both consider the comparability of the incidence of BC between high grade papillary urothelial tumors and flat tumors. Extent of invasion -­none. the different registries.32 Tumor behavior code: /3 The most limiting factor for interpreting BC incidence Invasion present, whatever the anatomopathological definition. rates and estimates is undoubtedly the coding of noninva- Particular cases: sive tumors (considering the level of invasion and grade -­Carcinoma in situ: /2 recorded), which determines their inclusion or not in the The particular entity which consists of carcinoma in situ registries as “bladder cancer”. Superficial neoplasms of displaying clear anaplasia of the superficial epithelium the bladder were initially excluded from cancer registries. without the formation of a papillary structure and without Afterward, and probably linked to a better understanding invasion is coded to 8010/2. of the behavior of noninvasive papillary tumors and car- -­ Anatomopathological examination indicates the existence of a tumor, but it is not possible to determine cinoma in situ, changes were made in the classification of the degree of malignancy on the specimen examined: tumor behavior and, therefore, the registration practices Code: /1 tumor benign or of uncertain malignancy related to the coding of the invasiveness of the BC were -­Anatomopathological proof unavailable, but the clinical modified. Thus, in IARC world registries published in CI5, appearance is confirmed by the clinician: the inclusion or not of superficial tumors was modified. 8000/0: No microscopically confirmation: But since no distinction is made between non-­muscle-­ tumor clinically benign. invasive and muscle-­invasive carcinomas of the bladder, 8000/1: No microscopically confirmation: separate epidemiology of each type cannot be obtained in tumor clinically of uncertain behavior. 8000/3: No microscopically confirmation: a systematic way. Therefore, estimates of BC incidence are tumor clinically malignant. very difficult to interpret without comprehensive informa- tion on how superficial or uncertain bladder tumors have been treated by each of the registries. In general, changes Reviewing the BC incidence data provided by CI5 in in registry procedures are more likely to affect compari- volumes X14 and XI10 for the different registries that are sons between registries than trends in a single registry over part of REDECAN and the data provided by REDECAN time, provided practices have not changed over time.10 in different publications,25,26,29–­31 there may be differences Regarding the coding rules for multiple tumors, those in the incidences provided depending on the tumors in- used by SEER22 in cancer registries in the United States cluded. In the BC incidence registries of Ciudad Real, are different from those of IARC5 that were used in the Cuenca, Granada, and Tarragona presented in volume X rest of the world, which influenced their incidence rates. of IC5,14 neoplasms of uncertain or unknown behavior The SEER rules result in somewhat higher incidence rates CABALLERO et al.    | 7549 TABLE 5 Consensus on the coding of urothelial tumors proposed by REDECAN in 201228 ENCR CIE-­O-­3 WHO Grade CONSENSUS Urothelial papilloma 8120/1 8120/1 8120/0 (−) 8120/0 -­ Papilloma transitional cell, NOS (C67._) 8130/1 Papillary transitional cell neoplasm of low (−) 8130/1 8130/1 (−) 8130/1 -­ malignant potential Papillary transitional cell carcinoma, 8120/1 8130/2 8130/2 1 8130/2 1 noninvasive (Grade I; OMS 1973) (pTa/0a) 8130/1 Non-­grade Papillary transitional cell carcinoma of high 8120/2 8130/2 8130/2 3 8130/2 3 grade*, noninvasive (Grade II/III; OMS 8130/2 Non-­grade 1973) (pTa/0a) Carcinoma in situ 8010/2 8010/2 8010/2 (−) 8010/2 -­ Urothelial carcinoma in situ (pTis/0is) Tumor noninvasive with degree of malignancy -­−−/1 (−) (−) (−) 8010/1 -­ nondeterminate Tumor (urothelial) with level of infiltration 8010/1 1 Low grade non-­determinate 8010/1 3 High grade Tumor with degree of malignancy and level of 8010/1 -­ infiltration non-­determinate Abbreviations: ENCR, European Network of Cancer Registries; ICD-­O-­3, International Classification of Diseases for Oncology, third edition; WHO, World Health Organization. not only because they diagnose multiple tumors if the pa- Tobacco smoking is the most well-­established risk fac- tient has one micropapillary urothelial carcinoma and one tor for BC, causing 50–­65% of male cases and 20–­30% of bladder urothelial carcinoma, but because they allow mul- female cases.34 Occupational exposure is the second most tiple incident cancers to occur in the same body location, important risk factor for BC and it is likely to occur in as long as the new case occurs 2 months to 3 years after occupations in which dyes, rubbers and textiles, paints, a previous diagnosis, whereas IARC rules allow only one leathers, and chemicals are used.34 Any of these regis- cancer per site during a patient's lifetime, unless there are tries consider these confounding factors in relation to several cancers of different histological types. BC incidence. However, these international or national Recently, the ENCR has published new recommenda- associations were created for the development of cancer tions for unifying the great variability among registries in registration and its application to studies of well-­defined the criteria for recording and reporting urinary tract tu- populations. They conduct programs of research concen- mors.33 They insist on the importance of differentiating trating particularly on the epidemiology of cancer and the between recording (registration, coding, and classifica- study of potential carcinogens in the human environment tion) and reporting (counting in the statistics of incidence with many publications about the different risk factors im- and survival) tumors. A cancer registry can record several plicated in the incidence of BC. tumors of the urothelium (of different site, grade, or inva- Finally, in addition to the different BC coding rules, sion) of the same patient but according to international there are other factors that influence the heterogeneity of criteria and for the purposes of comparability, only one or BC incidences. There are also problems in the compara- a part of them is reported. These recommendations must bility of the pathological anatomy of BC. On one hand, be applied to all BC tumors with an incidence date on or there are multiple anatomical pathological classifications after the January 1, 2022.33 to use. On the other hand, there may be different degrees Finally, another limiting factor in registry comparabil- of pathological differentiation within the same tumor and, ity, common to any type of cancer, is that most registries, moreover, bladder tumors are frequently multicentric. except SEER, are affected by reporting delays. The SEER When examining it, there may be difficulties in assessing releases its cancer data with a delay of up to 28 months the degree of infiltration due to the probable deterioration while the latest IARC actual incidence data is from 2010 of the biopsy material and/or its size or depth. Lastly, not to 2012. More recent data correspond to estimates of inci- all pathological reports, coding in pathological anatomy dence based on previous data, which makes interpretation services and extraction of registry data will have the same difficult. quality. 7550 |    CABALLERO et al. In conclusion, the BC registry, unlike other types of ORCID cancer, is complex due to the peculiarities of urothelial tu- José María Caballero https://orcid. mors that make it difficult to define their malignancy. The org/0000-0001-6826-0966 methodological differences used by the different registries Montserrat Martín-­Baranera https://orcid. regarding the inclusion of papillary tumors, carcinomas org/0000-0002-3416-1676 in situ and indeterminate, complicate the comparisons of the incidence of BC between registries. This limitation is REFERENCES worsened by the fact that urothelial tumors are frequently 1. Parkin DM. The role of cancer registries. Int J Clin Oncol. multicentric and have a high rate of recurrence, but the 2008;13:102-­111. rules for defining single or multiple tumors are not homo- 2. Navarro C, Martos C, Ardanaz E, et al. For the Spanish can- cer registries working group. Population-­ based cancer reg- geneous among the different cancer registries. 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