Predictive value of mitotic figure counts in tumor progression of non-invasive high-grade papillary urothelial carcinoma of the urinary bladder: A retrospective study from a single cancer center

Background: Urothelial carcinoma (UC) is the most common type of bladder malignancy. Although the majority of UC present as non-invasive tumors, a subset of them progress into invasive cancer and cause significant morbidity and mortality. Objective: In this study, we examined the association between tumor mitotic activity associated and the progression of non-invasive high-grade papillary UC of the bladder. Methods: Forty-four cases of tumors that met the selection criteria were retrieved from the Department of Pathology archives, and, for each case, mitotic figures were counted in 10 high-power fields (HPF) by two independent pathologists. Tumor progression was defined as the invasion of the tumor into the subepithelial connective tissue (lamina propria) or beyond during follow-ups. In addition, tumors that later exhibited distant metastases were included in the tumor progression group. Results: Our study revealed that the average mitotic count per 10 HPF in the tumor progression group was significantly higher (p = 0.001) than in the progression-free group. Furthermore, tumors with more than three mitotic counts per HPF in initial biopsies posed a high risk of tumor progression within the 19.5 ± 6.1 months of follow-ups. Conclusion: The findings of our study provided valuable information for further stratification of risk factors among patients with non-invasive high-grade papillary UC of the bladder. Patients with high mitotic figure count in their initial biopsies should be monitored closely or treated earlier to prevent their tumors from progressing into invasive carcinoma.
- Sung H, Ferlay J, Siegel RJ, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71(3):209-249. doi: 10.3322/caac.21660
- 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. doi: 10.1016/j.eururo.2016.06.010
- Ploeg M, Aben KH, Kiemeney KA. The present and future burden of urinary bladder cancer in the world. World J Urol. 2009;27:289-93. doi: 10.1007/s00345-009-0383-3
- Siegel RL, Giaquinto AN, Jemal A. Cancer statistics. CA Cancer J Clin. 2024;74:12-49. doi: 10.3322/caac.21820
- Colin P, Koenig P, Ouzzane A, et al. Environmental factors involved in carcinogenesis of urothelial cell carcinomas of the upper urinary tract. BJU Int. 2009;104:1436-1440. doi: 10.1111/j.1464-410X.2009.08838.x
- 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. doi: 10.1016/j.eururo.2020.09.006
- Eble JN, Sauter G, Epstein JI, Sesterhenn IA. Tumors of the urinary system and male genital organs. In: WHO Classification of Tumors. 3rd ed. Switzerland: WHO; 2002.
- Humphrey PA, Moch H, Cubilla AL, Ulbright TM, Reuter VE. The 2016 WHO classification of the tumors of the urinary system and male genital organs-part B: Prostate and bladder tumors. Eur Urol. 2016;70(1):106-119. doi: 10.1016/j.eururo.2016.02.028
- Amin MB, Berney DM, Comparat EV, et al. Tumors of the urinary system and male genital organs. In: WHO Classification of Tumors. 5th ed. Switzerland: WHO; 2022.
- Culpan M, Keser F, Iplikci A, Kir G, Atis G, Yildirim A. The clinical impact of tumor grade heterogeneity in non-muscle-invasive urothelial carcinoma of the bladder. Medeni Med J. 2021.36(4):310-317. doi: 10.4274/MMJ.galenos.2021.48447
- Ho P, Moran GW, Wang V, et al. The effect of tumor grade heterogeneity on recurrence in non-muscle invasive bladder cancer. Urol Oncol. 2022;40(2):60.e11-60.e16. doi: 10.1016/j.urolonc.2021.07.003
- Cattoretti G, Becker MH, Key G, et al. Monoclonal antibodies against recombinant parts of the Ki-67 antigen (MIB 1 and MIB 3) detect proliferating cells in microwave-processed formalin-fixed paraffin sections. J Pathol. 1992;168(4):357-363. doi: 10.1002/path.1711680404
- Chowdhury GM, Kojima K, Kanayama H, Tsuji M, Kurokawa Y, Kagawa S. The proliferation index of MIB-1 as a prognostic factor for patients with transitional cell carcinoma of the upper urinary tract. Cancer. 1996;78(4):827-833. doi: 10.1002/(SICI)1097-0142(19960815)78:4<827::AID-CNCR20>3.0.CO;2-W
- Li R, Heydon K, Hammond ME, et al. Ki-67 staining index predicts distant metastasis and survival in locally advanced prostate cancer treated with radiotherapy: An analysis of patients in radiation therapy oncology group protocol 86-10. Clin Cancer Res. 2004;10(12):4118-4124. doi: 10.1158/1078-0432.CCR-1052-03
- Amin MB, Trpkov K, Lopez-Beltran A, Grignon DJ. Best practices recommendations in the application of immunohistochemistry in the bladder lesions: Report from the International Society of Urologic Pathology consensus conference. Am J Surg Pathol. 2014;38(8):e20-e34. doi: 10.1097/PAS.0000000000000240
- Morinaga S, Ishiwa N, Noguchi Y, et al. Growth index, assessed with Ki-67 and ssDNA labeling; a significant prognosticator for patients undergoing curative resection for hepatocellular carcinoma. J Surg Oncol. 2005;92(4):331-336. doi: 10.1002/jso.20309
- Goyal S, Singh UR, Sharma J, Kaur N. Correlation of mitotic indices, AgNor count, Ki-67 and Bcl-2 with grade and stage in papillary urothelial bladder cancer. Urol J. 2014;11(1):1238-1247.
- Quintero A, Alvarez-Kindelan J, Luque RJ, et al. Ki-67 MIB1 labeling index and the prognosis of primary TaT1 urothelial cell carcinoma of the bladder. J Clin Pathol. 2006;59(1):83-88. doi: 10.1136/jcp.2004.022939
- Mai KT, Flood TA, Williams P, Kos Z, Belangeret EC. Mixed low-and high-grade papillary urothelial carcinoma: Histopathogenetic and clinical significance. Virchows Arch. 2013;463(4):575-81. doi: 10.1007/s00428-013-1456-7
- Van Bergeijk SA, Stathonikos N, Ter Hoeve ND, et al. Deep learning supported mitoses counting on whole slide images: A pilot study for validating breast cancer grading in the clinical workflow. J Pathol Inform. 2023;4:100316. doi: 10.1016/j.jpi.2023.100316