BACKGROUND: Previous population-based studies on second primary cancers (SPCs) in urothelial cancers have focused on known risk factors in bladder cancer patients without data on other urothelial sites of the renal pelvis or ureter. AIMS: To estimate sex-specific risks for any SPCs after urothelial cancers, and in reverse order, for urothelial cancers as SPCs after any cancer. Such two-way analysis may help interpret the results. METHODS: We employed standardized incidence ratios (SIRs) to estimate bidirectional relative risks of subsequent cancer associated with urothelial cancers. Patient data were obtained from the Swedish Cancer Registry from years 1990 through 2015. RESULTS: We identified 46 234 urinary bladder cancers (75% male), 940 ureteral cancers (60% male), and 2410 renal pelvic cancers (57% male). After male bladder cancer, SIRs significantly increased for 9 SPCs, most for ureteral (SIR 41.9) and renal pelvic (17.2) cancers. In the reversed order (bladder cancer as SPC), 10 individual FPCs were associated with an increased risk; highest associations were noted after renal pelvic (21.0) and ureteral (20.9) cancers. After female bladder cancer, SIRs of four SPCs were significantly increased, most for ureteral (87.8) and pelvic (35.7) cancers. Female bladder, ureteral, and pelvic cancers associated are with endometrial cancer. CONCLUSIONS: The risks of recurrent urothelial cancers were very high, and, at most sites, female risks were twice over the male risks. Risks persisted often to follow-up periods of >5 years, motivating an extended patient follow-up. Lynch syndrome-related cancers were associated with particularly female urothelial cancers, calling for clinical vigilance.

Biomedical Center Faculty of Medicine and Biomedical Center in Pilsen Charles University Prague Pilsen Czech Republic

Cancer Gene Therapy Group Translational Immunology Research Program University of Helsinki Helsinki Finland

Center for Community Based Healthcare Research and Education Department of Functional Pathology School of Medicine Shimane University Shimane Japan

Center for Primary Health Care Research Lund University Malmö Sweden

Department of Family Medicine and Community Health Department of Population Health Science and Policy Icahn School of Medicine at Mount Sinai New York New York USA

Department of Surgery University Health Network Toronto Ontario Canada

Department of Urology Helsinki University Hospital Helsinki Finland

Division of Cancer Epidemiology German Cancer Research Center Heidelberg Germany

Division of Molecular Genetic Epidemiology German Cancer Research Center Heidelberg Germany

Division of Pediatric Neurooncology German Cancer Research Center Heidelberg Germany

Hopp Children's Cancer Center Heidelberg Germany

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Roupret M, Babjuk M, Comperat E, et al. European Association of Urology Guidelines on upper urinary tract urothelial carcinoma: 2017 update. Eur Urol. 2018;73(1):111‐122. PubMed

Antoni S, Ferlay J, Soerjomataram I, Znaor A, Jemal A, Bray F. Bladder cancer incidence and mortality: a global overview and recent trends. Eur Urol. 2017;71(1):96‐108. PubMed

Cai Q, Chen Y, Xin S, et al. Temporal trends of bladder cancer incidence and mortality from 1990 to 2016 and projections to 2030. Transl Androl Urol. 2020;9(2):153‐165. PubMed PMC

Teoh JY, Huang J, Ko WY, et al. Global trends of bladder cancer incidence and mortality, and their associations with tobacco use and gross domestic product per capita. Eur Urol. 2020;78(6):893‐906. PubMed

Malmstrom PU, Gardmark T, Sherif A, et al. Incidence, survival and mortality trends of bladder cancer in Sweden 1997‐2016. Scand J Urol. 2019;53(4):193‐199. PubMed

Patja K, Hakala SM, Boström G, Nordgren P, Haglund M. Trends of tobacco use in Sweden and Finland: do differences in tobacco policy relate to tobacco use? Scand J Public Health. 2009;37(2):153‐160. PubMed

Kohlmann W, Gruber SB. Lynch syndrome. In: Adam MP, Ardinger HH, Pagon RA, et al., eds. GeneReviews(R). Seattle, WA: University of Washington, Seattle University of Washington; 1993.

Yu H, Hemminki O, Forsti A, Sundquist K, Hemminki K. Familial urinary bladder cancer with other cancers. Eur Urol Oncol. 2018;1(6):461‐466. PubMed

Aragon‐Ching JB, Nizam A, Henson DE. Carcinomas of the renal pelvis, ureters, and urinary bladder share a carcinogenic field as revealed in epidemiological analysis of tumor registry data. Clin Genitourin Cancer. 2019;17(6):436‐442. PubMed

Moller P, Seppala TT, Bernstein I, et al. Cancer risk and survival in path_MMR carriers by gene and gender up to 75years of age: a report from the prospective Lynch syndrome database. Gut. 2018;67(7):1306‐1316. PubMed PMC

Wischhusen JW, Ukaegbu C, Dhingra TG, et al. Clinical factors associated with urinary tract cancer in individuals with Lynch syndrome. Cancer Epidemiol Biomark Prev. 2020;29(1):193‐199. PubMed PMC

Dominguez‐Valentin M, Sampson JR, Seppälä TT, et al. Cancer risks by gene, age, and gender in 6350 carriers of pathogenic mismatch repair variants: findings from the prospective Lynch syndrome database. Genet Med. 2020;22(1):15‐25. PubMed PMC

Gupta S, Provenzale D, Llor X, et al. NCCN guidelines insights: genetic/familial high‐risk assessment: colorectal, version 2.2019. J Natl Compr Cancer Network. 2019;17(9):1032‐1041. PubMed

De Angelis R, Sant M, Coleman MP, et al. Cancer survival in Europe 1999‐2007 by country and age: results of EUROCARE‐5—a population‐based study. Lancet Oncol. 2014;15(1):23‐34. PubMed

Engholm G, Hakulinen T, Gislum M, et al. Trends in the survival of patients diagnosed with kidney or urinary bladder cancer in the Nordic countries 1964‐2003 followed up to the end of 2006. Acta Oncol. 2010;49(5):655‐664. PubMed

Lundberg FE, Andersson TM, Lambe M, et al. Trends in cancer survival in the Nordic countries 1990‐2016: the NORDCAN survival studies. Acta Oncol. 2020;59(11):1266‐1274. PubMed

Nilsson S, Ragnhammar P, Glimelius B, Nygren P. A systematic overview of chemotherapy effects in urothelial bladder cancer. Acta Oncol. 2001;40(2–3):371‐390. PubMed

Witjes JA, Bruins HM, Cathomas R, et al. European Association of Urology guidelines on muscle‐invasive and metastatic bladder cancer: summary of the 2020 guidelines. Eur Urol. 2021;79(1):82‐104. PubMed

Bermejo JL, Sundquist J, Hemminki K. Bladder cancer in cancer patients: population‐based estimates from a large Swedish study. Br J Cancer. 2009;101(7):1091‐1099. PubMed PMC

Muller J, Grosclaude P, Lapotre‐Ledoux B, et al. Trends in the risk of second primary cancer among bladder cancer survivors: a population‐based cohort of 10 047 patients. BJU Int. 2016;118(1):53‐59. PubMed

Kwon WA, Joung JY, Lim J, et al. Risk of second primary cancer among bladder cancer patients: a population‐based cohort study in Korea. BMC Cancer. 2018;18(1):617. PubMed PMC

Adjei Boakye E, Buchanan P, Hinyard L, et al. Trends in the risk and burden of second primary malignancy among survivors of smoking‐related cancers in the United States. Int J Cancer. 2019;145(1):143‐153. PubMed

Naser‐Tavakolian A, Ghodoussipour S, Djaladat H. Upper urinary tract recurrence following bladder cancer therapy: a review of surveillance and management. Curr Opin Urol. 2019;29(3):189‐197. PubMed

van Doeveren T, van de Werken HJG, van Riet J, et al. Synchronous and metachronous urothelial carcinoma of the upper urinary tract and the bladder: are they clonally related? A systematic review. Urol Oncol. 2020;38:590‐598. PubMed

Nuhn P, Novara G, Seitz C, et al. Prognostic value of prior history of urothelial carcinoma of the bladder in patients with upper urinary tract urothelial carcinoma: results from a retrospective multicenter study. World J Urol. 2015;33(7):1005‐1013. PubMed

Chattopadhyay S, Hemminki A, Forsti A, Sundquist K, Sundquist J, Hemminki K. Second primary cancers in patients with invasive and in situ squamous cell skin carcinoma, Kaposi sarcoma and Merkel cell carcinoma: role for immune mechanisms? J Invest Dermatol. 2019;140(1). 10.1016/j.jid.2019.04.031. PubMed DOI

Chattopadhyay S, Sud A, Zheng G, et al. Second primary cancers in non‐Hodgkin lymphoma: bi‐directional analyses suggesting role for immune dysfunction. Int J Cancer. 2018;143:2449‐2457. PubMed

Travis LB, Demark Wahnefried W, Allan JM, Wood ME, Ng AK. Aetiology, genetics and prevention of secondary neoplasms in adult cancer survivors. Nat Rev Clin Oncol. 2013;10(5):289‐301. PubMed

Liu H, Hemminki K, Sundquist J. Renal cell carcinoma as first and second primary cancer: etiological clues from the Swedish family—cancer database. J Urol. 2011;185(6):2045‐2049. PubMed

Hemminki K, Yu H, Hemminki O, Sundquist J. RE: familial cancer clustering of urothelial cancer: a population‐based case‐control study. J Natl Cancer Inst. 2018;110(11):1277‐1278. PubMed

Centre for Epidemiology . Cancer Incidence in Sweden 2012. Stockholm, Sweden: The National Board of Health and Welfare; 2013.

Holmang S, Amsler‐Nordin S, Carlson K, Holmberg E, Johansson SL. Completeness and correctness of registration of renal pelvic and ureteral cancer in the Swedish Cancer Registry. Scand J Urol Nephrol. 2008;42(1):12‐17. PubMed

dos Santos Silva I. Cancer Epidemiology: Principles and Methods. Lyon, France: IARC; 1999. 442 p.

Seisen T, Granger B, Colin P, et al. A systematic review and meta‐analysis of clinicopathologic factors linked to Intravesical recurrence after radical nephroureterectomy to treat upper tract urothelial carcinoma. Eur Urol. 2015;67(6):1122‐1133. PubMed

Lonergan PE, Porten SP. Bladder tumor recurrence after urothelial carcinoma of the upper urinary tract. Transl Androl Urol. 2020;9(4):1891‐1896. PubMed PMC

Cosentino M, Palou J, Gaya JM, Breda A, Rodriguez‐Faba O, Villavicencio‐Mavrich H. Upper urinary tract urothelial cell carcinoma: location as a predictive factor for concomitant bladder carcinoma. World J Urol. 2013;31(1):141‐145. PubMed

Li H, Zhang Q, Shuman L, et al. Evaluation of PD‐L1 and other immune markers in bladder urothelial carcinoma stratified by histologic variants and molecular subtypes. Sci Rep. 2020;10(1):1439. PubMed PMC

Hemminki K, Hemminki O, Försti A, Sundquist K, Sundquist J, Li X. Surveillance bias in cancer risk after unrelated medical conditions: example urolithiasis. Sci Rep. 2017;7:8073. PubMed PMC

Zhang L, Hemminki O, Chen T, et al. Familial clustering, second primary cancers and causes of death in penile. Vulvar Vaginal Cancers Sci Rep. 2019;9(1):11804. PubMed PMC

Lynch HT, Lynch PM, Lanspa SJ, Snyder CL, Lynch JF, Boland CR. Review of the Lynch syndrome: history, molecular genetics, screening, differential diagnosis, and medicolegal ramifications. Clin Genet. 2009;76(1):1‐18. PubMed PMC

Hortlund M, Arroyo Muhr LS, Storm H, Engholm G, Dillner J, Bzhalava D. Cancer risks after solid organ transplantation and after long‐term dialysis. Int J Cancer. 2017;140(5):1091‐1101. PubMed

Rama I, Grinyo JM. Malignancy after renal transplantation: the role of immunosuppression. Nat Rev Nephrol. 2010;6(9):511‐519. PubMed

Hemminki K, Liu H, Sundquist J. Second cancers after testicular cancer diagnosed after 1980 in Sweden. Ann Oncol. 2010;21:1546‐1551. PubMed

Zhang L, Hemminki O, Chen T, et al. Second cancers and causes of death in patients with testicular cancer in Sweden. PLoS One. 2019;14(3):e0214410. PubMed PMC

Schaapveld M, Aleman BM, van Eggermond AM, et al. Second cancer risk up to 40 years after treatment for Hodgkin's lymphoma. N Engl J Med. 2015;373(26):2499‐2511. PubMed

Ji J, Sundquist K, Sundquist J, Hemminki K. Comparability of cancer identification among death registry, cancer registry and hospital discharge registry. Int J Cancer. 2012;131:2085‐2093. PubMed

Hemminki K, Li X. Level of education and the risk of cancer in Sweden. Cancer Epidemiol Biomark Prev. 2003;12:796‐802. PubMed

Hemminki K, Zhang H, Czene K. Socioeconomic factors in cancer in Sweden. Int J Cancer. 2003;105:692‐700. PubMed

Lipfert FW, Wyzga RE. Longitudinal relationships between lung cancer mortality rates, smoking, and ambient air quality: a comprehensive review and analysis. Crit Rev Toxicol. 2019;49(9):790‐818. PubMed