Anouk E Hentschel1, Bas W G van Rhijn2, Johannes Bründl3, Eva M Compérat4, Karin Plass5, Oscar Rodríguez6, Jose D Subiela Henríquez6, Virginia Hernández7, Enrique de la Peña7, Isabel Alemany8, Diana Turturica9, Francesca Pisano10, Francesco Soria9, Otakar Čapoun11, Lenka Bauerová12, Michael Pešl11, H Max Bruins13, Willemien Runneboom14, Sonja Herdegen3, Johannes Breyer3, Antonin Brisuda15, Andrea Scavarda-Lamberti16, Ana Calatrava16, José Rubio-Briones17, Maximilian Seles18, Sebastian Mannweiler19, Judith Bosschieter20, Venkata R M Kusuma21, David Ashabere21, Nicolai Huebner22, Juliette Cotte23, Laura S Mertens24, Daniel Cohen25, Luca Lunelli26, Olivier Cussenot26, Soha El Sheikh27, Dimitrios Volanis25, Jean-François Coté28, Morgan Rouprêt23, Andrea Haitel29, Shahrokh F Shariat30, A Hugh Mostafid21, Jakko A Nieuwenhuijzen20, Richard Zigeuner18, Jose L Dominguez-Escrig17, Jaromir Hacek31, Alexandre R Zlotta32, Maximilian Burger3, Matthias Evert33, Christina A Hulsbergen-van de Kaa14, Antoine G van der Heijden13, Lambertus A L M Kiemeney34, Viktor Soukup11, Luca Molinaro35, Paolo Gontero9, Carlos Llorente7, Ferran Algaba36, Joan Palou6, James N'Dow5, Marko Babjuk30, Theo H van der Kwast37, Richard J Sylvester5. 1. Urology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands; Surgical Oncology (Urology), Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands. 2. Surgical Oncology (Urology), Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands; Urology, Caritas St. Josef Medical Center, University of Regensburg, Regensburg, Germany; Surgical Oncology (Urology), University Health Network, Princess Margaret Cancer Center, University of Toronto, Toronto, Canada. Electronic address: basvanrhijn@hotmail.com. 3. Urology, Caritas St. Josef Medical Center, University of Regensburg, Regensburg, Germany. 4. Pathology, Tenon Hospital, AP-HP, UPMC Paris VI, Sorbonne University, Paris, France. 5. EAU Guidelines Office Board, European Association of Urology, Arnhem, the Netherlands. 6. Urology, Fundacio Puigvert, Universitat Autònoma de Barcelona, Barcelona, Spain. 7. Urology, Hospital Universitario Fundación Alcorcón, Madrid, Spain. 8. Pathology, Hospital Universitario Fundación Alcorcón, Madrid, Spain. 9. Urology Clinic, Citta' della Salute e della Scienza, University of Studies of Torino, Torino, Italy. 10. Urology, Fundacio Puigvert, Universitat Autònoma de Barcelona, Barcelona, Spain; Urology Clinic, Citta' della Salute e della Scienza, University of Studies of Torino, Torino, Italy. 11. Urology, General Teaching Hospital and 1st Faculty of Medicine, Charles University Praha, Prague, Czech Republic. 12. Pathology, General Teaching Hospital and 1st Faculty of Medicine, Charles University Praha, Prague, Czech Republic. 13. Urology, Radboud University Medical Center, Nijmegen, the Netherlands. 14. Pathology, Radboud University Medical Center, Nijmegen, the Netherlands. 15. Urology,Teaching Hospital Motol, Prague, Czech Republic. 16. Pathology, Fundación Instituto Valenciano de Oncología (I.V.O.), Valencia, Spain. 17. Urology, Fundación Instituto Valenciano de Oncología (I.V.O.), Valencia, Spain. 18. Urology, Medical University of Graz, Graz, Austria. 19. Pathology, Medical University of Graz, Graz, Austria. 20. Urology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, the Netherlands. 21. Urology, Royal Surrey County Hospital-NHS Foundation Trust, Guildford, Surrey, United Kingdom. 22. Urology, Comprehensive Cancer Center, Medical University Vienna, Vienna General Hospital, Vienna, Austria. 23. Urology, Pitié Salpétrière Hospital, AP-HP, GRC n 5, ONCOTYPE-URO, Sorbonne University, Paris, France. 24. Surgical Oncology (Urology), Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, the Netherlands. 25. Urology, Royal Free London-NHS Foundation Trust, Royal Free Hospital, London, United Kingdom. 26. Urology, Tenon Hospital, AP-HP, UPMC Paris VI, Sorbonne University, Paris, France. 27. Pathology, Royal Free London-NHS Foundation Trust, Royal Free Hospital, London, United Kingdom. 28. Pathology, Pitié Salpétrière Hospital, AP-HP, Pierre et Marie Curie Medical School, Sorbonne University, Paris, France. 29. Pathology, Comprehensive Cancer Center, Medical University Vienna, Vienna General Hospital, Vienna, Austria. 30. Urology,Teaching Hospital Motol, Prague, Czech Republic; Urology, Comprehensive Cancer Center, Medical University Vienna, Vienna General Hospital, Vienna, Austria. 31. Pathology, Teaching Hospital Motol, Prague, Czech Republic. 32. Surgical Oncology (Urology), University Health Network, Princess Margaret Cancer Center, University of Toronto, Toronto, Canada. 33. Pathology, Caritas St. Josef Medical Center, University of Regensburg, Regensburg, Germany. 34. Health Evidence, Radboud University Medical Center, Nijmegen, the Netherlands. 35. Pathology, Citta' della Salute e della Scienza, University of Studies of Torino, Torino, Italy. 36. Pathology, Fundacio Puigvert, Universitat Autònoma de Barcelona, Barcelona, Spain. 37. Pathology, University Health Network, Princess Margaret Cancer Center, University of Toronto, Toronto, Canada.
Abstract
BACKGROUND: Papillary urothelial neoplasm of low malignant potential (PUN-LMP) was introduced as a noninvasive, noncancerous lesion and a separate grade category in 1998. Subsequently, PUN-LMP was reconfirmed by World Health Organization (WHO) 2004 and WHO 2016 classifications for urothelial bladder tumors. OBJECTIVES: To analyze the proportion of PUN-LMP diagnosis over time and to determine its prognostic value compared to Ta-LG (low-grade) and Ta-HG (high-grade) carcinomas. To assess the intraobserver variability of an experienced uropathologist assigning (WHO) 2004/2016 grades at 2 time points. MATERIALS AND METHODS: Individual patient data of 3,311 primary Ta bladder tumors from 17 hospitals in Europe and Canada were available. Transurethral resection of the tumor was performed between 1990 and 2018. Time to recurrence and progression were analyzed with cumulative incidence functions, log-rank tests and multivariable Cox-regression stratified by institution. Intraobserver variability was assessed by examining the same 314 transurethral resection of the tumorslides twice, in 2004 and again in 2018. RESULTS: PUN-LMP represented 3.8% (127/3,311) of Ta tumors. The same pathologist found 71/314 (22.6%) PUN-LMPs in 2004 and only 20/314 (6.4%) in 2018. Overall, the proportion of PUN-LMP diagnosis substantially decreased over time from 31.3% (1990-2000) to 3.2% (2000-2010) and to 1.1% (2010-2018). We found no difference in time to recurrence between the three WHO 2004/2016 Ta-grade categories (log-rank, P = 0.381), nor for LG vs. PUN-LMP (log-rank, P = 0.238). Time to progression was different for all grade categories (log-rank, P < 0.001), but not between LG and PUN-LMP (log-rank, P = 0.096). Multivariable analyses on recurrence and progression showed similar results for all 3 grade categories and for LG vs. PUN-LMP. CONCLUSIONS: The proportion of PUN-LMP has decreased to very low levels in the last decade. Contrary to its reconfirmation in the WHO 2016 classification, our results do not support the continued use of PUN-LMP as a separate grade category in Ta tumors because of the similar prognosis for PUN-LMP and Ta-LG carcinomas.
BACKGROUND:Papillary urothelial neoplasm of low malignant potential (PUN-LMP) was introduced as a noninvasive, noncancerous lesion and a separate grade category in 1998. Subsequently, PUN-LMP was reconfirmed by World Health Organization (WHO) 2004 and WHO 2016 classifications for urothelial bladder tumors. OBJECTIVES: To analyze the proportion of PUN-LMP diagnosis over time and to determine its prognostic value compared to Ta-LG (low-grade) and Ta-HG (high-grade) carcinomas. To assess the intraobserver variability of an experienced uropathologist assigning (WHO) 2004/2016 grades at 2 time points. MATERIALS AND METHODS: Individual patient data of 3,311 primary Ta bladder tumors from 17 hospitals in Europe and Canada were available. Transurethral resection of the tumor was performed between 1990 and 2018. Time to recurrence and progression were analyzed with cumulative incidence functions, log-rank tests and multivariable Cox-regression stratified by institution. Intraobserver variability was assessed by examining the same 314 transurethral resection of the tumorslides twice, in 2004 and again in 2018. RESULTS: PUN-LMP represented 3.8% (127/3,311) of Ta tumors. The same pathologist found 71/314 (22.6%) PUN-LMPs in 2004 and only 20/314 (6.4%) in 2018. Overall, the proportion of PUN-LMP diagnosis substantially decreased over time from 31.3% (1990-2000) to 3.2% (2000-2010) and to 1.1% (2010-2018). We found no difference in time to recurrence between the three WHO 2004/2016 Ta-grade categories (log-rank, P = 0.381), nor for LG vs. PUN-LMP (log-rank, P = 0.238). Time to progression was different for all grade categories (log-rank, P < 0.001), but not between LG and PUN-LMP (log-rank, P = 0.096). Multivariable analyses on recurrence and progression showed similar results for all 3 grade categories and for LG vs. PUN-LMP. CONCLUSIONS: The proportion of PUN-LMP has decreased to very low levels in the last decade. Contrary to its reconfirmation in the WHO 2016 classification, our results do not support the continued use of PUN-LMP as a separate grade category in Ta tumors because of the similar prognosis for PUN-LMP and Ta-LG carcinomas.