Primary multiple cancer in practice of urological oncologist

Primary multiple malignancies (PMMs) are defined as two or more malignant tumors of various pathogenic origin detected simultaneously or sequentially in one patient. Despite the successes of modern medicine, the incidence of PMMs is steadily increasing. According to worldwide statistics, the incidence of PMMs in the oncological population has increased from 2.4 to 8.0 % over the course of the 20 year span. The number of patients with PMMs is also increasing in the Russian Federation. Total of 58,217 PMMs were detected for the first time in our country in 2021, which constitutes 10.0 % of all newly diagnosed malignant neoplasms. Two tumors are usually observed among patients with PMMs (in 84–100 % of patients), three tumors occur in 9.9–16.0 % of these patients, four in 1.62 %, and five or more occur in only 0.095 %.

Currently, the pathogenesis of this condition has not yet been fully studied. There are hypotheses that endogenous, exogenous, hereditary, and therapeutic factors are involved in the occurrence of PMMs. Endogenous factors include immunologic status, endocrine factors, and hereditary predisposition. Exogenous factors are represented by lifestyle and environmental factors such as smoking and alcohol, low physical activity, as well as prolonged exposure to ultraviolet radiation and industrial pollution. Iatrogenic factors, including radiation therapy and chemotherapy, can also increase the risk of developing PMMs.

This article represents a clinical case of a patient born in 1942, in whom, during 11 years of follow-up care, primary multiple synchronous metachronous cancers of 5 localizations and 4 histological types were verified and treated. The presented clinical case is interesting for a very rare number of neoplasms and a relatively high duration of follow-up period. The authors describe in detail each stage, the choice of diagnostic methods and the definition of treatment tactics with an assessment of the accuracy of clinical decision-making.

1. Malignant neoplasms in Russia in 2021 (morbidity and mortality). Edited by Kaprin AD, Starinsky VV, Shakhzadova AO. Мoscow: P. Hertsen Moscow Oncology Research Institute – Branch of the National Medical Radiology Research Centre of the Ministry of Health of the Russian Federation, 2022, 252 p. (In Russ.). Available at: https://oncology-association.ru/wp-content/uploads/2022/11/zlokachestvennye-novoobrazovaniya-v-rossii-v-2021-g_zabolevaemost-i-smertnost.pdf

2. Billroth T. Handbuch fur Studierende and Artze, 14. Die allgemeine chirurgische pathologie und therapie. Berlin: Auflage; 1889.

3. Warren S, Gates O. Multiple primary malignant tumors: a survey of the literature and a statistic study. Am J Cancer. 1932;16:1358–1414.

4. Moertel CG. Multiple primary malignant neoplasms: historical perspectives. Cancer. 1977;40:1786–1792. https://doi.org/10.1002/1097-0142(197710)40:4+3.0.co;2-2

5. Selchuk VY. Primary multiple malignant tumors (clinical presentation, treatment, and patterns of development). Diss. Moscow, 1994. (In Russ.).

6. Lv M, Zhang X, Shen Y, Wang F, Yang J, Wang B, et al. Clinical analysis and prognosis of synchronous and metachronous multiple primary malignant tumors. Medicine (Baltimore). 2017 Apr;96(17):e6799. https://doi.org/10.1097/md.0000000000006799

7. Liu Z, Jin C, Zhang Y, Jiang Y, Wang J, Zheng L. Identification of BRAF, CCND1, and MYC mutations in a patient with multiple primary malignant tumors: a case report and review of the literature. World J Surg Oncol. 2023 May 24;21(1):158. https://doi.org/10.1186/s12957-023-03036-3

8. Zheng R, Li H, Ye Y, Guan L, Li H, Ye Z, et al. Clinicopathological features and prognostic analysis of 77 patients with multiple primary cancers. J BUON. 2020 Jul-Aug;25(4):2110–2116.

9. Muller J, Grosclaude P, Lapôtre-Ledoux B, Woronoff AS, Guizard AV, Bara S, 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 Jul;118(1):53–59. https://doi.org/10.1111/bju.13351

10. Gladkov OA, Zukov RA, Matveev VB, Mitin T, Nosov DA, Popov AM. Practical recommendations for the drug therapy of bladder cancer. RUSSCO practical recommendations. Malignant tumours. 2022;12(3S2):589–606. (In Russ.). https://doi.org/10.18027/2224-5057-2022-12-3s2-589-606

11. Sylvester RJ, Oosterlinck W, Holmang S, Sydes MR, Birtle A, Gudjonsson S, et al. Systematic Review and Individual Patient Data Meta-analysis of Randomized Trials Comparing a Single Immediate Instillation of Chemotherapy After Transurethral Resection with Transurethral Resection Alone in Patients with Stage pTa-pT1 Urothelial Carcinoma of the Bladder: Which Patients Benefit from the Instillation? Eur Urol. 2016 Feb;69(2):231–244. https://doi.org/10.1016/j.eururo.2015.05.050

12. Nosov DA, Volkova MI, Gladkov OA, Karabina EV, Krylov VV, Matveev VB, et al. Practical recommendations for the drug therapy of prostate cancer. RUSSCO practical recommendations, part 1. Malignant tumours. 2023;13(3S2-1):640–660. (In Russ.). https://doi.org/10.18027/2224-5057-2023-13-3s2-1-640-660

13. The compilation of the complete Guidelines should be referenced as: EAU Guidelines. Edn. presented at the EAU Annual Congress Milan 2023. ISBN 978-94-92671-19-6.

14. Bratan F, Niaf E, Melodelima C, Chesnais AL, Souchon R, Mège-Lechevallier F, et al. Influence of imaging and histological factors on prostate cancer detection and localisation on multiparametric MRI: a prospective study. Eur Radiol. 2013 Jul;23(7):2019–2029. https://doi.org/10.1007/s00330-013-2795-0

15. Borofsky S, George AK, Gaur S, Bernardo M, Greer MD, Mertan FV, et al. What Are We Missing? False-Negative Cancers at Multiparametric MR Imaging of the Prostate. Radiology. 2018 Jan;286(1):186–195. https://doi.org/10.1148/radiol.2017152877

16. Dickinson L, Ahmed HU, Allen C, Barentsz JO, Carey B, Futterer JJ, et al. Magnetic resonance imaging for the detection, localisation, and characterisation of prostate cancer: recommendations from a European consensus meeting. Eur Urol. 2011 Apr;59(4):477– 494. https://doi.org/10.1016/j.eururo.2010.12.009

17. Turkbey B, Rosenkrantz AB, Haider MA, Padhani AR, Villeirs G, Macura KJ, et al. Prostate Imaging Reporting and Data System Version 2.1: 2019 Update of Prostate Imaging Reporting and Data System Version 2. Eur Urol. 2019 Sep;76(3):340–351. https://doi.org/10.1016/j.eururo.2019.02.033

18. Nishiyama N, Hotta H, Takahashi A, Yanase M, Itoh N, Tachiki H, et al. Upper tract urothelial carcinoma following intravesical bacillus Calmette-Guérin therapy for nonmuscle-invasive bladder cancer: Results from a multi-institutional retrospective study. Urol Oncol. 2018 Jun;36(6):306.e9-306.e15. https://doi.org/10.1016/j.urolonc.2018.02.009

19. Cowan NC, Turney BW, Taylor NJ, McCarthy CL, Crew JP. Multidetector computed tomography urography for diagnosing upper urinary tract urothelial tumour. BJU Int. 2007 Jun;99(6):1363–1370. https://doi.org/10.1111/j.1464-410x.2007.06766.x

20. Janisch F, Shariat SF, Baltzer P, Fajkovic H, Kimura S, Iwata T, et al. Diagnostic performance of multidetector computed tomographic (MDCTU) in upper tract urothelial carcinoma (UTUC): a systematic review and meta-analysis. World J Urol. 2020 May;38(5):1165– 1175. https://doi.org/10.1007/s00345-019-02875-8

21. Sharma V, Miest TS, Juvet TS, Toussi A, Packiam V, Chamie K, et al. The Impact of Upper Tract Urothelial Carcinoma Diagnostic Modality on Intravesical Recurrence after Radical Nephroureterectomy: A Single Institution Series and Updated Meta-Analysis. J Urol. 2021 Sep;206(3):558–567. https://doi.org/10.1097/ju.0000000000001834

22. Ayyathurai R, Soloway MS. Monitoring of the upper urinary tract in patients with bladder cancer. Indian J Urol. 2011 Apr;27(2):238– 244. https://doi.org/10.4103/0970-1591.82844

23. Fritsche HM, Burger M, Svatek RS, Jeldres C, Karakiewicz PI, Novara G, et al. Characteristics and outcomes of patients with clinical T1 grade 3 urothelial carcinoma treated with radical cystectomy: results from an international cohort. Eur Urol. 2010 Feb;57(2):300–309. https://doi.org/10.1016/j.eururo.2009.09.024

24. Turker P, Bostrom PJ, Wroclawski ML, van Rhijn B, Kortekangas H, Kuk C, et al. Upstaging of urothelial cancer at the time of radical cystectomy: factors associated with upstaging and its effect on outcome. BJU Int. 2012 Sep;110(6):804–811. https://doi.org/10.1111/j.1464-410x.2012.10939.x

25. Moschini M, Sharma V, Dell'oglio P, Cucchiara V, Gandaglia G, Cantiello F, et al. Comparing long-term outcomes of primary and progressive carcinoma invading bladder muscle after radical cystectomy. BJU Int. 2016 Apr;117(4):604–610. https://doi.org/10.1111/bju.13146