European Urology - Volume 82, Issue 5

EDITOR EMERITUS (1975–2005) EDITOR EMERITUS (2006–2013)
Claude Schulman, Belgium Francesco Montorsi, Italy
EDITOR-IN-CHIEF
James Catto, UK
ASSOCIATE EDITORS
Maarten Albersen, Belgium Jean-Nicolas Cornu, France Todd Morgan, USA
Giacomo Novara, Italy Sarah Psutka, USA
STATISTICAL EDITOR STATISTICAL ASSOCIATE EDITOR STATISTICAL ASSOCIATE EDITOR

Andrew Vickers, USA Melissa Assel, USA Rodney Dunn, USA
DIGITAL MEDIA EDITOR DIGITAL MEDIA ASSOCIATE EDITOR DIGITAL MEDIA ASSOCIATE EDITOR
Zachary Klaassen, USA Alessandro Larcher, Italy Christopher Wallis, Canada
SURGERY IN MOTION EDITOR IMAGING EDITOR WORDS OF WISDOM EDITOR

Alexander Mottrie, Belgium Jelle Barentsz, The Netherlands George Thalmann, Switzerland
MEDICAL ONCOLOGY EDITOR RADIATION ONCOLOGY EDITOR

Elizabeth Plimack, USA Piet Ost, Belgium
MANAGING EDITOR EDITORIAL OFFICE ASSISTANT COPY EDITOR

Cathy Pierce, USA Kirsten Marshall, UK Compuscript Ltd
EDITORIAL INTERNS
Carissa Chu, USA
Satoshi Funada, Japan
Lisa Moris, Belgium
CONSULTING EDITORS
Ardalan Ahmad, Canada Lars Dyskjot, Denmark Giorgio Ivan Russo, Italy
Neeraj Agarwal, USA Giorgio Gandaglia, Italy Gottfrid Sjodahl, Sweden
Riccardo Campi, Italy Stephanie Gazdovich, Canada Jeremy Y. Teoh, Hong Kong
Samantha Conroy, UK Veeru Kasivisvanathan, UK Roderick Van den Bergh,
Sigrid Carlsson, USA Fumitake Koga, Japan Netherlands
Jozefina Casuscelli, Germany Caroline Moore, UK Christopher Wallis, USA
Douglas Cheung, USA Alessandra Mosca, Italy Mary Elizabeth Westerman, USA
Edmund Chiong, Singapore Declan Murphy, Australia
Timothy Clinton, USA Andrea Necchi, Italy
EUROPEAN UROLOGY
James Catto, Editor-in-Chief
Academic Urology Unit, University of Sheffield
The Medical School
Beech Hill Road, Sheffield S10 2RX, UK
Official Journal of E-mail: [email protected]
Tel: +31 26 389 0680; Fax: +44 114 271 2268
EDITORIAL BOARD
Hashim Ahmed, UK Jack Elder, USA Valeria Panebianco, Italy

Peter Albers, Germany Matthew Galsky, USA Benoit Peyronnet, France
Peter Albertsen, USA John Gearhart, USA Tom Powles, UK
Andrea Apolo, USA Matthew Gettman, USA Benjamin Pradere, Austria
Apostolos Apostolidos, Greece Inderbir Gill, USA Ranjith Ramasamy, USA
Riccardo Autorino, Italy Francesco Greco, Germany Jens Rassweiler, Germany
Marko Babjuk, Czech Republic Jüergen Gschwend, Germany Maria J. Ribal, Spain
Christopher Barbieri, USA Ari Hakimi, USA Jennifer R. Rider, USA
Ricarda Bauer, Germany Noburu Hara, Japan Monique J. Roobol,
Joaquim Bellmunt, Spain Michael S. Hofman, Australia The Netherlands
Karim Bensalah, France Brent Hollenbeck, USA Morgan Roupret, France
Bimal Bhindi, USA Syed Hussain, UK Kazutaka Saito, Japan
Trinity J. Bivalacqua, USA Maha Hussain, USA Andrea Salonia, Italy
Anders Bjartell, Sweden Brant Inman, USA Guiseppe Simone, Italy
Peter Black, USA Kazuto Ito, Japan Guru Sonpavde, USA
Marco Borghesi, Italy R. Jeffrey Karnes, USA Gary Steinberg, USA
Alberto Bossi, France Max Kates, USA Arnulf Stenzl, Germany
Paul Boutros, USA M. Pilar Laguna, Christian Stief, Germany
Alberto Breda, Spain The Netherlands Nazareno Suardi, Italy
Laura Bukavina, USA Alastair Lamb, UK George Thalmann, Switzerland
Steve Campbell, USA Richard S. Lee, USA Houston Thompson, USA
Abdullah Canda, Turkey Seth Lerner, USA Bertrand Tombal, Belgium
Umberto Capitanio, Italy Evangelos Liatsikos, Greece Scott Tomlins, USA
Christopher Chapple, UK Stacy Loeb, USA Quoc-Dien Trinh, Canada
Joseph Chin, Canada Yair Lotan, USA Roderick van den Bergh,
Renzo Colombo, Italy Stephan Madersbacher, Austria The Netherlands
Elisabetta Costantini, Italy Luis Martı́nez-Piñeiro, Spain Theo van der Kwast, Canada
Francisco Cruz, Portugal Surena Matin, USA Bas van Rhijn, The Netherlands
Cosimo De Nunzio, Italy Joshua Meeks, USA Jochen Walz, France
Giuseppe Di Lorenzo, Italy Rodolfo Montironi, Italy Stephen Williams, USA
Jason Efstathiou, USA Alicia Morgans, USA Johannes Witjes, The Netherlands
Shin Egawa, Japan Alicia K. Morgans, USA Christopher Wood, USA
Scott Eggener, USA Nicolas Mottet, France Alex Zlotta, Canada
Behfar Ehdaie, USA James N’dow, UK
The Platinum Hall of Fame is online only at http://www.sciencedirect.com/science/journal/03022838/82/5
EUROPEAN UROLOGY
James Catto, Editor-in-Chief
Academic Urology Unit, University of Sheffield
The Medical School
Beech Hill Road, Sheffield S10 2RX, UK
Official Journal of E-mail: [email protected]
Società Italiana di Urologia (SIU) Tel: +31 26 389 0680; Fax: +44 114 271 2268
The Platinum
Hall of Fame
European Urology would like to recognize the award-winning authors and exceptional reviewers who ensure
that ‘your’ platinum journal remains a cut above the rest.
Best Scientific Paper Prizes 2000 to the Present 2006

Prevalence of Asymptomatic Coronary Artery Disease
2000 in Men with Vasculogenic Erectile Dysfunction:
Laparoscopic Radical Prostatectomy: Technical and
A Prospective Angiographic Study
Early Oncological Assessment of 40 Operations C. Vlachopoulos, K. Rokkas, N. Ioakeimidis, C. Aggeli, A. Michaelides,
B. Guillonneau, X. Cathelineau, E. Barret, F. Rozet, G. Vallancien G. Roussakis, C. Fassoulakis, A. Askitis, C. Stefanadis
European Urology 1999;36:14–20 European Urology 2005;48:996–1002
2001 2007
RPLND or Primary Chemotherapy in Clinical Stage Excellent Long-Term Cancer Control with Elective
IIA/B Nonseminomatous Germ Cell Tumors? Results Nephron-Sparing Surgery for Selected Renal Cell
of a Prospective Multicenter Trial Including Quality of Carcinomas Measuring More Than 4 cm
Life Assessment F. Becker, S. Siemer, M. Hack, U. Humke, M. Ziegler, M. Stöckle
L. Weissbach, R. Bussar-Maatz, H. Flechtner, U. Pichlmeier, European Urology 2006;49:1058–1064
M. Hartmann, L. Keller &
European Urology 2000;37:582–594 Elective Nephron-Sparing Surgery Should Become
Standard Treatment for Small Unilateral Renal Cell
2002 Carcinoma: Long-term Survival Data of 216 Patients
Nonrandomized Comparison of Open Flank versus F. Becker, S. Siemer, U. Humke, M. Hack, M. Ziegler, M. Stöckle
Laparoscopic Nephrectomy in 249 Patients with Benign European Urology 2006;49:308–313
Renal Disease
2008
P. Fornara, C. Doehn, H.-J. Friedrich, D. Jocham
European Urology 2001;40:24–31
Morbidity and Clinical Outcome of Nephron-Sparing
Surgery in Relation to Tumour Size and Indication
J.-J. Patard, A.J. Pantuck, M. Crepel, J.S. Lam, L. Bellec, B. Albouy,
2003
D. Lopes, J.-C. Bernhard, F. Guillé, B. Lacroix, A. De La Taille, L. Salomon,
Laparoscopic Dismembered Pyeloplasty – The Method C. Pfister, M. Soulié, J. Tostain, J.-M. Ferriere, C.C. Abbou, M. Colombel,
of Choice in the Presence of an Enlarged Renal Pelvis A.S. Belldegrun
and Crossing Vessels European Urology 2007;52:148–154
I.A. Türk, J.W. Davis, B. Winkelmann, S. Deger, F. Richter,
M.D. Fabrizio, B. Schönberger, G.H. Jordan, S.A. Loening 2009
European Urology 2002;42:268–275 The Template of the Primary Lymphatic Landing
Sites of the Prostate Should Be Revisited: Results of a
2004 Multimodality Mapping Study
A. Mattei , F.G. Fuechsel, N. Bhatta Dhar, S.H. Warncke,G.N. Thalmann,
The Side Effects of Bacillus Calmette-Guérin in the
T. Krause, U.E. Studer
Treatment of Ta T1 Bladder Cancer do not Predict its
Efficacy: Results from a European Organisation for
Research and Treatment of Cancer Genito-Urinary 2010
Group Phase III Trial Preoperative Aspects and Dimensions Used for an
R.J. Sylvester, A.P.M. Van Der Meijden, W. Oosterlinck, W. Hoeltl, Anatomical (PADUA) Classification of Renal Tumours in
A.V. Bono Patients who are Candidates for Nephron-Sparing
European Urology 2003;44:423–428 Surgery
& V. Ficarra, G. Novara, S. Secco, V. Macchi, A. Porzionato, R. De Caro,
Maintenance Bacillus Calmette-Guérin for Ta T1 Bladder W. Artibani
Tumors is not Associated with Increased Toxicity: Results European Urology 2009;56:786–793
from a European Organisation for Research and Treatment Sponsored By Elsevier
of Cancer Genito-Urinary Group Phase III Trial
2011
A.P.M. Van Der Meijden, R.J. Sylvester, W. Oosterlinck, W. Hoeltl,
A.V. Bono
Positive Surgical Margin Appears to Have Negligible
European Urology 2003;44:429–434 Impact on Survival of Renal Cell Carcinomas Treated
by Nephron-Sparing Surgery
K. Bensalah, A.J. Pantuck, N. Rioux-Leclercq, R. Thuret, F. Montorsi,
2005 P. Karakiewicz, N. Mottet, L. Zini, R. Bertini, L. Salomon, A. Villers,
DD3A3 RNA Analysis in Urine – A New Perspective for M. Soulie, L. Bellec, P. Rischmann, A. De La Taille, R. Avakian, M. Crepel,
Detecting Prostate Cancer J. Ferriere, J. Bernhard, T. Dujardin, et al.
M. Tinzl, M. Marberger, S. Horvath, C. Chypre European Urology 2010;57:466–473
European Urology 2004;46:182–186 Sponsored By Elsevier
http://dx.doi.org/10.1016/j.eururo.2022.09.013
The Platinum
Hall of Fame
2012 F. Porpigalia, M. Manfredi, F. Mele, M. Cossu, E. Bollito, A. Veltri,

Pentafecta: A New Concept for Reporting Outcomes of S. Cirillo, D. Regge, R. Faletti, R. Passera, C. Fiori, S. De Luca
Robot-Assisted Laparoscopic Radical Prostatectomy
V. Patel, A. Sivaraman, R. Coelho, S. Chauhan, K. Palmer, M. Orvieto,
I. Camacho, G. Coughlin, B. Rocco
2019
Value of an Immediate Intravesical Instillation of
2013 Mitomycin C in Patients with Non–muscle-invasive
Pathologic Downstaging Is a Surrogate Marker for Bladder Cancer: A Prospective Multicentre Randomised
Efficacy and Increased Survival Following Neoadjuvant Study in 2243 patients
Chemotherapy and Radical Cystectomy for Muscle- J. Bosschieter, J.A. Nieuwenhuijzen, T. van Ginkel, A.N. Vis, B. Witte,
Invasive Urothelial Bladder Cancer D. Newling, G.M.A. Beckers, R.J.A. van Moorselaar
R. Rosenblatt, A. Sherif, E. Rintala, R. Wahlqvist, A. Ullén, European Urology, Vol. 73, Issue 2, p226–232
M. Nilsson, P.-U. Malmström, the Nordic Urothelial Cancer Group
European Urology 2012;61:1229–1238 2020
2014 Genomic Drivers of Poor Prognosis and Enzalutamide
Final Results of an EORTC-GU Cancers Group Resistance in Metastatic Castration-resistant Prostate
Randomized Study of Maintenance Bacillus Calmette- Cancer
William S. Chen, Rahul Aggarwal, Li Zhang, Shuang G. Zhao,
Guérin in Intermediate- and High-risk Ta, T1 Papillary
George V. Thomas, Tomasz M. Beer, David A. Quigley, Adam Foyea,
Carcinoma of the Urinary Bladder: One-third Dose Denise Playdlea,, Jiaoti Huang, Paul Lloyd, Eric Lu, Duanchen Sun,
Versus Full Dose and 1 Year Versus 3 Years of Xiangnan Guan, Matthew Rettig, Martin Gleave, Christopher P.
Maintenance Evans, Jack Youngren, Lawrence True, Primo Lara, Vishal Kothari,
J. Oddens, M. Brausi, R. Sylvester, A. Bono, C. van de Beek, Zheng Xia, Kim N. Chj, Robert E. Reiter, Christopher A. Maher, Felix
G. van Andel, P. Gontero, W. Hoeltl, L. Turkeri, S. Marreaud, Y. Feng, Eric J. Small, Joshi J. Alumkal on behalf of the West Coast
S. Collette, W. Oosterlinck Prostate Cancer Dream Team
European Urology 2013;63:462–472 European Urology, Vol 76, Issue 5, p562–571
2015 2021
Bacillus Calmette-Guérin Strain Differences Have an Impact
The DaBlaCa-13 Study: Short-term, Intensive
on Clinical Outcome in Bladder Cancer Immunotherapy
Chemoresection Versus Standard Adjuvant Intravesical
C.A. Rentsch, F.D. Birkhðuser, C. Biot, J.R. Gsponer, A. Bisiaux,
C. Wetterauer, M. Lagranderie, G. Marchal, M. Orgeur, C. Bouchier,
Instillations in Non–muscle-invasive Bladder Cancer
A. Bachmann, M.A. Ingersoll, R. Brosch, M.L. Albert, G.N. Thalmann A Randomised Controlled Trial
European Urology 2014;66:677–688 Maria S. Lindgren, Peter Bue, Nessn Azawi, Linea Blichert-Refsgaard,
Maria O. Sundelin, Lars Dyrskjø, Jørgen B. Jensen
2016 European Urology, Vol 78, Issue 6, p856–862
Survival with Newly Diagnosed Metastatic Prostate Cancer
in the ‘‘Docetaxel Era’’: Data from 917 Patients in the Control 2022
Arm of the STAMPEDE Trial (MRC PR08, CRUK/06/019) The Additive Diagnostic Value of Prostate-specific
N.D. James, M.R. Spears, N.W. Clarke, D.P. Dearnaley, J.S. De Bono, Membrane Antigen Positron Emission Tomography
J. Gale, J. Hetherington, P.J. Hoskin, R.J. Jones, R. Laing, J.F. Lester, Computed Tomography to Multiparametric Magnetic
D. McLaren, C.C. Parker, M.K.B. Parmar, A.W.S. Ritchie, J.M. Russell, Resonance Imaging Triage in the Diagnosis of Prostate
R.T. Strebel, G.N. Thalmann, M.D. Mason, M.R. Sydes
Cancer (PRIMARY): A Prospective Multicentre Study
Louise Emmett, James Buteau, Nathan Papa, Daniel Moon, James
2017 Thompson, Matthew J.Roberts, Kris Rasiah, David A. Pattison,
John Yaxley, Paul Thomas, Anthony C. Hutton, Shikha Agrawal,
A Randomized Controlled Trial To Assess and Compare
Amer Amin, Alexandar Blazevski, Venu Chalasani, Bao Ho,
the Outcomes of Two-core Prostate Biopsy Guided by Andrew Nguyen, Victor Liu, Phillip Stricker
Fused Magnetic Resonance and Transrectal Ultrasound European Urology, Vol 80, Issue 6, p690–692
Images and Traditional 12-core Systematic Biopsy
E. Baco, E. Rud, L.M. Eri, G. Moen, L. Vlatkovic, A. Svindland, Best Scientific Paper on Fundamental Research
H.B. Eggesbø, O. Ukimura
Frozen Section for the Management of Intraoperatively
2018 Detected Palpable Tumor Lesions During Nerve-Sparing
Diagnostic Pathway with Multiparametric Magnetic Scheduled Radical Prostatectomy
Resonance Imaging Versus Standard Pathway: Results C. Eichelberg, A. Erbersdobler, A. Haese, T. Schlomm, F.K.H. Chun,
from a Randomized Prospective Study in Biopsy-naı̈ve E. Currlin, J. Walz, T. Steuber, M. Graefen, H. Huland
Patients with Suspected Prostate Cancer
The Platinum
Hall of Fame
2008 2015
Use of Haemostatic Agents and Glues during Targeted Prostate Cancer Screening in BRCA1 and
Laparoscopic Partial Nephrectomy: A Multi-Institutional BRCA2 Mutation Carriers: Results from the Initial
Survey from the United States and Europe of 1347 Cases Screening Round of the IMPACT Study
A. Breda, S.V. Stepanian, J.S. Lam, J.C. Liao, I.S. Gill, J.R. Colombo, E.K. Bancroft, E.C. Page, E. Castro, H. Lilja, A. Vickers, D. Sjoberg,
G. Guazzoni, M.D. Stifelman, K.T. Perry, A. Celia, G. Breda, P. Fornara, M. Assel, C.S. Foster, G. Mitche, K. Drew, L. MÌhle, K. Axcrona,
S.V. Jackman, A. Rosales, J. Palou, M. Grasso, V. Pansadoro, V. Disanto, D.G. Evans, B. Bulman, D. Eles, D. McBride, C. van Asperen,
F. Porpiglia, C. Milani, C.C. Abbou, R. Gaston, G. Janetschek, N.A. H. Vasen, L.A. Kiemeney, J. Ringelberg, C. Cybulski, D. Wokolorczyk,
Soomro, J.J. De la Rosette, P.M. Laguna, P.G. Schulam C. Selkirk, P.J. Hulick, A. Bojesen, A.-B. Skytte, Jiy Lam, L. Taylor,
European Urology 2007;52:798–803 R. Oldenburg, R. Cremers, G. Verhaegh, W.A. van Zelst-Stams,
J.C. Oosterwijk, I. Blanco, M. Salinas, Jackie Ck, D.J. Rosario, S. Buys,
2009 T. Conner, M.G. Ausems, K.-r. Ong, J. Homan, S. Domchek,
Predictive Factors for Progression in Patients with J. Powers, M.R. Teixeira, S. Maia, W.D. Foulkes, N. Taherian, M. Ruijs,
Clinical Stage T1a Prostate Cancer in the PSA Era A.T. Helderman-van den Enden, L. Izatt, R. Davidson, M.A. Adank,
A. Descazeaud, M. Peyromaure, A. Salin, D. Amsellem-Ouazana, L. Walker, R. Schmutzler, K. Tucker, J. Kirk, S. Hodgson, M. Harris,
T. Flam, A. Viellefond, B. Debré, M. Zerbib F. Douglas, G.J. Lindeman, J. Zgajnar, M. Tischkowitz, V.E. Clowes,
European Urology 2008;53:355–362 R. Susman, T. Ramœn y Cajal, N. Patcher, N. Gadea, A. Spigelman,
T. van Os, A. Liljegren, L. Side, C. Brewer, A.F. Brady, A. Donaldson,
2010
V. Stefansdottir, E. Friedman, R. Chen-Shtoyerman, D.J. Amor,
Should All Patients with Non–Muscle-Invasive Bladder L. Copakova, J. Barwell, V.N. Giri, V. Murthy, N. Nicolai, S.-H. Teo,
Cancer Receive Early Intravesical Chemotherapy after L. Grnhalgh, S. Strom, A. Henderson, J. McGrath, D. Gallagher,
Transurethral Resection? The Results of a Prospective N. Aaronson, A. Ardern-Jones, C. Bangma, D. Dearnaley, P. Costello,
Randomised Multicentre Study J. Eyfjord, J. Rothwell, A. Falconer, H. Gronberg, F.C. Hamdy,
S. Gudjœnsson, L. Adell, F. Merdasa, R. Olsson, B. Larsson, T. Davidsson, O. Johannsson, V. Kh, Z. Kote-Jarai, J. Lubinski, U. Axcrona, J. Melia,
J. Richthoff, G. Hagberg, M. Grabe, P.O. Bendahl, W. MÍnsson, F. Liedberg J. McKinley, A.V. Mitra, C. Moynihan, G. Rennert, M. Suri, P. Wilson,
European Urology 2009;55:773–780 E. Killick, The IMPACT Collaborators, S. Moss, R.A. Eeles
Sponsored By Eli Lilly European Urology 2014;66:489–499
2011 2016
Complications in 2200 Consecutive Laparoscopic Molecular Characterization of Enzalutamide-treated
Radical Prostatectomies: Standardized Evaluation and Bone Metastatic Castration-resistant Prostate Cancer
Analysis of Learning Curves E. Efstathiou, M. Titus, S. Wen, A. Hoang, M. Karlou, R. Ashe,
M. Hruza, H. Weiß, G. Pini, A. Goezen, M. Schulze, D. Teber, J. Rassweiler S.M. Tu, A. Aparicio, P. Troncoso, J. Mohler, C.J. Logothetis
Sponsored by Elsevier
2012 2017
Salvage Radical Prostatectomy for Radiation-recurrent Tissue-based Genomics Augments Post-prostatectomy
Prostate Cancer: A Multi-institutional Collaboration Risk Stratification in a Natural History Cohort of
D. Chade, S. Shariat, A. Cronin, C. Savage, J. Karnes, M. Blute, Intermediate- and High-Risk Men
A. Briganti, F. Montorsi, H. van der Poel, H. Van Poppel, S. Joniau, A.E. Ross, M.H. Johnson, K. Yousefi, E. Davicioni, G.J. Netto,
G. Godoy, A. Hurtado-Coll, M. Gleave, M. Dall’Oglio, M. Srougi, L. Marchionni, H.L. Fedor, S. Glavaris, V. Choeurng, C. Buerki,
P. Scardino, J. Eastham N. Erho, L.L. Lam, E.B. Humphreys, S. Faraj, S.M. Bezerra, M. Han,
European Urology 2011;60:205–210 A.W. Partin, B.J. Trock, E.M. Schaeffer
2013
Stage-Specific Impact of Tumor Location on Oncologic 2018
Outcomes in Patients With Upper and Lower Tract SRRM4 Drives Neuroendocrine Transdifferentiation of
Urothelial Carcinoma Following Radical Surgery Prostate Adenocarcinoma Under Androgen Receptor
M. Rink, B. Ehdaie, E.K. Cha, D.A. Green, P.I. Karakiewicz, Pathway Inhibition
M. Babjuk, V. Margulis, J.D. Raman, R.S. Svatek, H. Fajkovic, R.K. Lee, Y. Li, N. Donme, C. Sahinalp, N. Xie, Y. Wang, H. Xue, F. Mo,
G. Novara, J. Hansen, S. Daneshmand, Y. Lotan, W. Kassouf, H. Beltran, M. Gleave, Y. Wang, C. Collins, X. Dong
H.-M. Fritsche, A. Pycham, M. Fisch, D.S. Scherr, S.F. Shariat, for the European Urology 2017;71:68–78
Bladder Cancer Research Consortium (BCRC) and for the Upper Tract
Urothelial Carcinoma Collaboration (UTUCC) 2019
Intravesical Activation of the Cation Channel TRPV4
2014 Improves Bladder Function in a Rat Model for Detrusor
Natural History of Early, Localized Prostate Cancer: Underactivity
A Final Report from Three Decades of Follow-up Y. Deruyver, E. Weyne, K. Dewulf, R. Rietjens, S. Pinto, N. Van Ranst,
M. Popiolek, J.R. Rider, O. Andrén, S.-O. Andersson, L. Holmberg, J. Franken, M. Vanneste, M. Albersen, T. Gevaert, R. Vennekens,
H.-O. Adami, J.-E. Johansson D. De Ridder, T. Voets, W. Everaerts
European Urology 2013;63:428–435 European Urology, Vol. 74, Issue 3, p336–345
The Platinum
Hall of Fame
2020 2010
Antifibrotic Synergy Between Phosphodiesterase Type 5 Characteristics of Spontaneous Activity in the Bladder
Inhibitors and Selective Oestrogen Receptor Modulatorso Trigone
in Peyronie’s Disease Models A. Roosen, C. Wu, G. Sui, R.A. Chowdhury, P.M. Patel, C.H. Fry
Marcus M. Ilg , Marta Mateus , William J. Stebbeds , Uros Milenkovic, European Urology 2009;56:346–354
Nim Christopher, Asif Muneer, Maarten Albersen, David J. Ralph, Sponsored By Elsevier
Selim Cellek
European Urology, Vol. 75, Issue 2, Pages p329–340 2011
Stem Cell Characteristics in Prostate Cancer Cell Lines
M.J. Pfeiffer, J.A. Schalken
2021 European Urology 2010;57:246–255
Gut Bacteria Composition Drives Primary Resistance to Sponsored By Elsevier
Cancer Immunotherapy in Renal Cell Carcinoma Patients
Lisa Derosa, Bertrand Routy, Marine Fidelle, Valerio Iebba, Laurie
2012
Alla, Edoardo Pasolli, Nicola Segata, Aude Desnoyer, Filippo Transplantation of Autologous Differentiated Urothelium
Pietrantonio, Gladys Ferrere, Jean-Eudes Fahrner, Emmanuelle Le in an Experimental Model of Composite Cystoplasty
Chatellier, Nicolas Pons, Nathalie Galleron, Hugo Roume, Connie A. Turner, R. Subramanian, D. Thomas, J. Hinley, S. Abbas,
P.M. Duong, Laura Mondragœn, Kristina Iribarren, Mélodie Bonvalet, J. Stahlschmidt, J. Southgate
Safae Terrisse, Conrad Rauber, Anne-Gaëlle Goubet, Romain Daillère, European Urology 2011;59:447–454
Fabien Lemaitre, Anna Reni, Beatrice Casu, Maryam Tidjani Alou,
Carolina Alves Costa Silva, Didier Raoult, Karim Fizazi, Bernard 2013
Escudier, Guido Kroemer, Laurence Albiges, Laurence Zitvogel Genome-wide Analysis of CpG Island Methylation in
European Urology, Vol 78, Issue 2, p195-206 Bladder Cancer Identified TBX2, TBX3, GATA2, and ZIC4
as pTa-Specific Prognostic Markers
2022 R. Kandimalla, A.A.G. van Tilborg, L.C. Kompier, D.J.P.M. Stumpel, R.W.
Integrated Expression of Circulating miR375 and Stam, C.H. Bangma, E.C. Zwarthoff
miR371 to Identify Teratoma and Active Germ Cell European Urology 2012;61:1245–1256
Malignancy Components in Malignant Germ Cell
Tumors 2014
Lucia Nappi, Marisa Thi, Nabil Adra, Robert J. Hamilton, Indium-111- labeled Girentuximab ImmunoSPECT as
Ricardo Leao, Jean-Michel Lavoie, Maryam Soleimani, a Diagnostic Tool in Clear Cell Renal Cell Carcinoma
Bernhard J. Eigl, Kim Chi, Martin Gleave, Alan So, Peter C. Black, C.H.J. Muselaers, O.C. Boerman, E. Oosterwijk, J.F. Langenhuijsen,
Robert Bell, Siamak Daneshmand, Clint Cary, Timothy Masterson, W.J.G. Oyen, P.F.A. Mulders
Lawrence Einhorn, Craig Nichols, Christian Kollmannsberger European Urology 2013;63:1101–1106
European Urology, Vol 79, Issue 1, p16–19
2015
Best Scientific Paper on Clinical Research Renal Function After Nephron-sparing Surgery
2007 Versus Radical Nephrectomy: Results from EORTC
Randomized Trial 30904
Depressed Contractile Responses to Neurokinin A
E. Scosyrev, E.M. Messing, R. Sylvester, S. Campbell, H. Van Poppel
in Idiopathic but not Neurogenic Overactive Human European Urology 2014;65:372–377
Detrusor Muscle
D.J. Sellers, C.R. Chapple, D.P.W. Hay, R. Chess-Williams
2016
Combination Treatment with Mirabegron and Solifenacin in
Patients with Overactive Bladder: Efficacy and Safety Results
2008 from a Randomised, Double-blind, Dose-ranging, Phase 2
Effects of the M3 Receptor Selective Muscarinic Study (Symphony)
Antagonist Darifenacin on Bladder Afferent Activity of P. Abrams, C. Kelleher, D. Staskin, T. Rechberger, R. Kay,
R. Martina, D. Newgreen, A. Paireddy, R. van Maanen, A. Ridder
the Rat Pelvic Nerve
European Urology 2015:67:577–588
K. Iijima, S. De Wachter, J.-J. Wyndaele
2017
2009 PI-RADS Prostate Imaging – Reporting and Data System:
Marked Gene Transcript Level Alterations Occur Early 2015, Version 2
During Radical Prostatectomy J.C. Weinreb*, J.O. Barentsz*, P.L. Choyk, F. Cornu, M.A. Haider,
T. Schlomm, E. Nðkel, A. Lübke, A. Buness, F.K.-H. Chun, T. Steuber, K.J. Macur, D. Margolis, M.D. Schnall, F. Shtern, C.M. Tempany, H.C.
M. Graefen, R. Simon, G. Sauter, A. Poustka, H. Huland, Thoeny, S. Verma
A. Erbersdobler, H. Sültmann, O.J.C. Hellwinkel European Urology 2016;69:16–40
European Urology 2008;53:333–346 * These authors share first authorship.
The Platinum
Hall of Fame
2018 F.K.-H. Chun, M. Graefen, A. Briganti, A. Gallina, J. Hopp,

CheckMate 025 Randomized Phase 3 Study: Outcomes by M.W. Kattan, H. Huland, P.I. Karakiewicz
Key Baseline Factors and Prior Therapy for Nivolumab
&
Versus Everolimus in Advanced Renal Cell Carcinoma
B. Escudier, P. Sharma, D.F. McDermott, S. George, H.J. Hammers,
hK2 and Free PSA, a Prognostic Combination in Predicting
S. Srinivas, S.S. Tykodi, J.A. Sosman, G. Procopio, E.R. Plimack, Minimal Prostate Cancer in Screen-Detected Men within
D. Castellano, H. Gurney, F. Donskov, K. Peltola, J. Wagstaff, the PSA Range 4–10 ng/ml
T.C. Gauler, T. Ueda, H. Zhao, I.M. Waxman, R.J. Motzer, on behalf of R. Raaijmakers, S.H. de Vries, B.G. Blijenberg, M.F. Wildhagen,
the CheckMate 025 investigators R. Postma, C.H. Bangma, C. Darte, F.H. Schröder
2019 2009
Metabolic Biosynthesis Pathways Identified from Fecal Evaluation of Prostate Cancer Detection with Ultrasound
Microbiome Associated with Prostate Cancer Real-Time Elastography: A Comparison with Step Section
M.A. Liss, J.R. White, M. Goros, J. Gelfond, R. Leach, T. Johnson-Pais, Pathological Analysis after Radical Prostatectomy
Z. Lai, E. Rourke, J. Basler, D. Ankerst, D.P. Shah G. Salomon, J. Köllerman, I. Thederan, F.K.H. Chun, L. Budðus,
European Urology, Vol. 74, Issue 5, p575–582 T. Schlomm, H. Isbarn, H. Heinzer, H. Huland, M. Graefen
2020 &
Extended Versus Limited Lymph Node Dissection in Bladder Radical Prostatectomy for Incidental (Stage T1a–T1b)
Cancer Patients Undergoing Radical Cystectomy: Survival Prostate Cancer: Analysis of Predictors for Residual
Results from a Prospective, Randomized Trial Disease and Biochemical Recurrence
Jürgen E. Gschwend, Matthias M. Heck, Jan Lehmann, Herbert Rübben, U. Capitanio, V. Scattoni, M. Freschi, A. Briganti, A. Salonia, A. Gallina,
Peter Albers, Johannes M. Wolff, Detlef Frohneberg, Patrick de Geeter, R. Colombo, P.I. Karakiewicz, P. Rigatti, F. Montorsi
Axel Heidenreich, Tilman Kðlble, Michael Stöckle, Thomas Schnöller, European Urology 2008;54:118–125
Arnulf Stenzl,, Markus Müller, Michael Truss, Stephan Roth, Uwe-
Bernd Liehr, Joachim LeiÔner, Thomas Bregenzer, Margitta Retz
European Urology, Vol 75, Issue 4, p604–611
2010
Influence of Nerve Transsections and Combined
2021 Bladder Filling on Intravesical Electrostimulation-
Treatment of High-grade Non–muscle-invasive Induced Bladder Contraction in the Rat
L. De Bock, S. De Wachter, J.J. Wyndaele
Bladder Carcinoma by Standard Number and Dose
of BCG Instillations Versus Reduced Number and Sponsored By Eli Lilly
Standard Dose of BCG Instillations: Results of the &
European Association of Urology Research Foundation The Role of Biopsy Core Number in Selecting Prostate
Randomised Phase III Clinical Trial NIMBUS Cancer Patients for Active Surveillance
Marc-Oliver Grimm, Antoine G. van der Heijden, Marc Colombel, M. Ploussard, E. Xylinas, L. Salomon, Y. Allory, D. Vordos, A. Hoznek,
Tim Muilwijk, Luis MartÚnez-Piþeiro, Marko M. Babjuk, Levent C.-C. Abbou, A. de la Taille
N. Türkeri, Joan Palou, Anup Patel, Anders S. Bjartell, Christien European Urology 2009;56:891–898
Caris, Raymond G. Schipper, Wim P.J. Witjes for the EAU Research Sponsored By Eli Lilly
Foundation NIMBUS Study Group
European Urology, Vol 78, Issue 5, p690-698 2011
Midterm Prospective Evaluation of TVT-Secur Reveals
2022 High Failure Rate
Shockwave Lithotripsy Versus Ureteroscopic Treatment J.N. Cornu, P. Sèbe, L. Peyrat, C. Ciofu, O. Cussenot, F. Haab
as Therapeutic Interventions for Stones of the Ureter European Urology 2010;58:157–161
(TISU): A Multicentre Randomised Controlled Non- &
inferiority Trial HYAL-1 Hyaluronidase: A Potential Prognostic Indicator
Ranan Dasgupta, Sarah Cameron, Lorna Aucott, Graeme MacLen- for Progression to Muscle Invasion and Recurrence in
nan, Ruth E. Thomas, Mary M. Kilonzo, Thomas B.L. Lam, James Bladder Cancer
N Dow, John Norrie, Ken Anson, Neil Burgess, Charles T. Clark, M.W. Kramer, R. Golshani, A.S. Merseburger, J. Knapp, A. Garcia,
Francis X. Keeley, Sara J. MacLennan, Kath Starr, Sam McClinton J. Hennenlotter, R.C. Duncan, M.S. Soloway, M. Jorda, M.A. Kuczyk,
European Urology, Vol 80, Issue 1, p46–54 A. Stenzl, V.B. Lokeshwar
Residents’ Corner
2008 2012
Initial Biopsy Outcome Prediction—Head-to-Head Exosomes as Biomarker Treasure Chests for Prostate
Comparison of a Logistic Regression-Based Nomogram Cancer
versus Artificial Neural Network D. Duijvesz, T. Luider, C. Bangma, G. Jenster
The Platinum
Hall of Fame

& Efficacy of enzalutamide following abiraterone acetate
Cancer-Specific and Other-Cause Mortality After Radical in chemotherapy-naive metastatic castration-resistant
Prostatectomy Versus Observation in Patients with prostate cancer patients
Prostate Cancer: Competing-Risks Analysis of a Large A.A. Azad, B.J. Eigl, R.N. Murray, C. Kollmannsberger, K.N. Chi
North American Population-Based Cohort European Urology 2015;67:23–29
F. Abdollah, M. Sun, J. Schmitges, Z. Tian, C. Jeldres, A. Briganti, &
L. Shariat, P. Perrotte, F. Montorsi, P. Karakiewicz Preoperative Prostate-specific Antigen Isoform p2PSA
European Urology 2011;60:920–930 and Its Derivatives, %p2PSA and Prostate Health Index,
Predict Pathologic Outcomes in Patients Undergoing
2013 Radical Prostatectomy for Prostate Cancer: Results
Prospective Assessment of Prostate Cancer Aggressiveness from a Multicentric European Prospective Study
Using 3-T Diffusion-Weighted Magnetic Resonance N. Fossati, N.M. Buffi, A. Haese, C. Stephan, A. Larcher,
Imaging–Guided Biopsies Versus a Systematic 10-Core T. McNicholas, A. de la Taille, M. Freschi, G. Lughezzani,
Transrectal Ultrasound Prostate Biopsy Cohort A. Abrate, V. Bini, J. Palou Redorta, M. Graefen, G. Guazzoni,
T. Hambrock, C. Hoeks, C. Hulsbergen-van de Kaa, T. Scheenen, M. Lazzeri
J. Fütterer, S. Bouwense, I. van Oort, F. Schröder, H. Huisman, J. Barentsz European Urology 2015;68:132–138
& 2017
Immunocytology Is a Strong Predictor of Bladder Renal Cell Carcinoma Programmed Death-ligand 1,
Cancer Presence in Patients With Painless Hematuria: a New Direct Target of Hypoxia-inducible Factor-2
A Multicentre Study Alpha, is Regulated by von Hippel–Lindau Gene
E.K. Cha, L.-A. Tirsar, C. Schwentner, P.J. Christos, C. Mian, Mutation Status
J. Hennenlotter, T. Martini, A. Stenzl, A. Pycha, S.F. Shariat, Y. Messai, S. Gad, M.Z. Noman, G. Le Teuff, S. Couve, B. Janji,
B.J. Schmitz-Drðger S.F. Kammerer, N. Rioux-Leclerc, M. Hasmim, S. Ferlicot, V. Baud,
European Urology 2012;61:185–192 A. Mejean, D.R. Mole, S. Richard, A.M.M. Eggermont, L. Albiges,
F. Mami-Chouaib, B. Escudier, S. Chouaib
2014 &
Prostate-specific Antigen (PSA) Testing Is Prevalent and Results of a Randomised Controlled Trial Comparing
Increasing in Stockholm County, Sweden, Despite No Intravesical Chemohyperthermia with Mitomycin C
Recommendations for PSA Screening: Results from a Versus Bacillus Calmette-Guérin for Adjuvant Treatment
Population-based Study, 2003 –2011 of Patients with Intermediate- and High-risk Non–
T. Nordström, M. Aly, M.S. Clements, C.E. Weibull, J. Adolfsson, Muscleinvasive Bladder Cancer
H. Grönberg
T.J.H. Arends, O. Nativ, M. Maffezzini, O. de Cobelli, G. Canepa,
F. Verweij, B. Moskovitz, A.G. van der Heijden, J.A. Witjes
& European Urology 2016;69:1046–1052
Metformin and Prostate Cancer: Reduced Development of
Castration-resistant Disease and Prostate Cancer Mortality 2018
D.E. Spratt, C. Zhang, Z.S. Zumsteg, X. Pei, Z. Zhang, M.J. Zelefsky Ex Vivo Model of Human Penile Transplantation and
Rejection: Implications for Erectile Tissue Physiology
N.A. Sopko, H. Matsui, D.M. Lough, D. Miller, K. Harris, M. Kates,
2015 X. Liu, K. Billups, R. Redett, A.L. Burnett, G. Brandacher,
Propensity-Matched Comparison of Morbidity and T.J. Bivalacqua
Costs of Open and Robot-Assisted Radical Cystectomies: European Urology 2017;71:584–93
A Contemporary Population-Based Analysis in the &
United States Racial Variation in Patient-Reported Outcomes Following
J.J. Leow, S.W. Reese, W. Jiang, S.R. Lipsitz, J. Bellmunt, Q.-D. Trinh, Treatment for Localized Prostate Cancer: Results from
B.I. Chung, A.S. Kibel, Steven L. Chang the CEASAR Study
European Urology 2014;66:569–576 M.D. Tyson, J. Alvarez, T. Koyama, K.E. Hoffman, M.J. Resnick,
& X.-C. Wu, M.R. Cooperberg, M. Goodman, S. Greenfield,
Survival Outcome and Treatment Response of Patients A.S. Hamilton, M. Hashibe, L.E. Paddock, A. Stroup, V.W. Chen,
with Late Relapse from Renal Cell Carcinoma in the D.F. Penson, D.A. Barocas
Era of Targeted Therapy European Urology 2017;72:307–14
N. Kroeger, T.K. Choueiri, J.-L. Lee, G.A. Bjarnason, J.J. Knox,
M.J. MacKenzie, L. Wood, S. Srinivas, U.N. Vaishamayan, 2019
S.-Y. Rha, S.K. Pal, T. Yuasa, F. Donskov, N. Agarwal, M.-H. Tan, Prospective Implementation of Enhanced Recovery After
A. Bamias, C.K. Kollmannsberger, S.A. North, B.I. Rini, D.Y.C. Heng Surgery Protocols to Radical Cystectomy
European Urology 2014;65:1086–1092 K.H. Pang, R. Groves, S. Venugopal, A.P. Noon, J.W.F. Catto
The Platinum
Hall of Fame
European Urology, Vol. 73, Issue 3, p363–371 Zhu W., Zeng G., Sfakianos J.P., Gupta M., Tewari A., Gozen A.S.,
& Rassweiler J., Skolarikos A., Kunit T., Knoll T., Moltzahn F.,
Substitution Urethroplasty with Closure Versus Thalmann G.N., Lantz Powers A.G., Chew B.H., Sarica K., Shamim
Nonclosure of the Buccal Mucosa Graft Harvest Site: A Khan M., Dasgupta P.
Randomized Controlled Trial with a Detailed Analysis of European Urology, Vol 80, Issue 4, p385–393
Oral Pain and Morbidity
A. Soave, R. Dahlem, H.O. Pinnschmidt, M. Rink, J. Langetepe, Best Paper in Robotic Surgery
O. Engel, L.A. Kluth, B. Loechelt, P. Reiss, S.A. Ahyai, M. Fisch
European Urology, Vol. 73, Issue 6, p910–922 2016
Pilot Validation Study of the European Association of
2020 Urology Robotic Training Curriculum
Prediction of High-grade Prostate Cancer Following A. Volpe, K. Ahmed, P. Dasgupta, V. Ficarra, G. Novara, H. van der Poel,
Multiparametric Magnetic Resonance Imaging: Improving A. Mottrie
the Rotterdam European Randomized Study of Screening European Urology 2015;68:292–299
for Prostate Cancer Risk Calculators
Arnout R. Alberts, Monique J. Roobol, Jan F.M. Verbeek, Ivo G. 2017
Schoots, Peter K. Chiu, Daniël F. Osses, Jasper D. Tijsterman, Harrie
Measuring to Improve: Peer and Crowd-sourced
P. Beerlage, Christophe K. Mannaerts, Lars Schimmöller, Peter
Assessments of Technical Skill with Robot-assisted
Albers, Christian Arsov
European Urology, Vol 75, Issue 2, p310–318 Radical Prostatectomy
K.R. Ghani, D.C. Miller, S. Linsell, A. Brachulis, B. Lane, R. Sarle,
&
D. Dalela, M. Menon, B. Comstock, T.S. Lendvay, J. Montie, J.O. Peabody,
Metastasis-directed Therapy in Treating Nodal
for the Michigan Urological Surgery Improvement Collaborative
Oligorecurrent Prostate Cancer: A Multi-institutional European Urology 2016;69:547–550
Analysis Comparing the Outcome and Toxicity of
Stereotactic Body Radiotherapy and Elective Nodal
Radiotherapy 2018
Elise De Bleser, Barbara Alicja Jereczek-Fossab, David Pasquierd, Multispectral Fluorescence Imaging During
Thomas Zillif,, Nicholas Van Ash, Shankar Siva, Andrei Fodor, Robotassisted Laparoscopic Sentinel Node Biopsy: A
Piet Dirixl, Alfonso Gomez-Iturriaga, Fabio Trippa, Beatrice Dettip First Step Towards a Fluorescence-based Anatomic
Gianluca Ingrosso, Luca Triggiani, Alessio Bruni, Filippo Along, Roadmap
Dries Reynders, Gert De Meerleer, Alessia Surgo, Kaoutar Loukili, N.S. van den Berg, T. Buckle, G.H. KleinJan, H.G. van der Poel,
Raymond Miralbellf, Pedro Silvah, Sarat Chander, Nadia Gisella Di F.W.B. van Leeuwen
Muzio, Ernesto Maranzano, Giulio Francolini, Andrea Lancia, Alison European Urology 2017;72:110–17
Treeh,i, Chiara Lucrezia Deantoni, Elisabetta Ponti, Giulia Marvaso,
Els Goetghebeur, Piet Ost
European Urology, Vol 76, Issue 6, p732–739 2019
Randomized Trial Comparing Open Radical Cystectomy
2021 and Robot-assisted Laparoscopic Radical Cystectomy:
The Clinicopathologic and Molecular Landscape of Clear Oncologic Outcomes
Cell Papillary Renal Cell Carcinoma: Implications in B.H. Bochner, G. Dalbagni, K.H. Marzouk, D.D. Sjoberg, J. Lee,
S.M. Donat, J.A. Coleman, A. Vickers, H.W. Herr, V.P. Laudone
Diagnosis and Management
European Urology, Vol. 74, Issue 4, p465–471
Stanley Weng, Renzo G. DiNatale, Andrew Silagy, Roy Mano,
Kyrollis Attalla, Mahyar Kashani, Kate Weiss, Nicole E. Benfante, 2020
Andrew G. Winer, Jonathan A. Coleman, Victor E. Reuter, Paul Russo,
Robot-assisted AMS-800 Artificial Urinary Sphincter
Ed Reznik, Satish K. Tickoo, A. Ari Hakimi,
European Urology, Vol 79, Issue 4, p468-477 Bladder Neck Implantation in Female Patients with
Stress Urinary Incontinence
2022 Benoit Peyronnet, Gregoire Capon, Olivier Belas, Andrea Manunta,
Is There a Detrimental Effect of Antibiotic Therapy in Clement Allenet, Juliette Hascoet, Jehanne Calves, Michel Belas,
Patients with Muscle-invasive Bladder Cancer Treated Pierre Callerot, Gregoire Robert, Aurelien Descazeaud, Georges
with Neoadjuvant Pembrolizumab? Fournier
Pederzoli F., Bandini M., Raggi D., Marandino L., Basile G., Alfano M., European Urology, Vol 75, Issue 1, p169–175
Colombo R., Salonia A., Briganti A., Gallina A., Montorsi F., Necchi A.
European Urology, Vol 80, Issue 3, p319–322 2021
& Outcomes of Gender Affirming Peritoneal Flap
Effect of Simulation-based Training on Surgical Vaginoplasty Using the Da Vinci Single Port Versus Xi
Proficiency and Patient Outcomes: A Randomised Robotic Systems
Controlled Clinical and Educational Trial Geolani W. Dy, Min Suk Jun, Gaines Blasdel, Rachel Bluebond-
Aydin A., Ahmed K., Abe T., Raison N., Van Hemelrijck M., Garmo H., Langner, Lee C. Zhao
Ahmed H.U., Mukhtar F., Al-Jabir A., Brunckhorst O., Shinohara N., European Urology, Vol 79, Issue 5, p676-683
The Platinum
Hall of Fame
2022 Platinum Award Winners 2018

A DROP-IN Gamma Probe for Robot-assisted 1. Peter Black
2. Christopher Evans
Radioguided Surgery of Lymph Nodes During Radical
3. Joan Palou-Redorta
Prostatectomy
4. Monique Roobol
Paolo Dell’Oglio, Philippa Meershoek, Tobias Maurer,
5. Shahrokh Shariat
Esther M.K. Wit, Pim J. van Leeuwen, Henk G. van der Poel,
Fijs W.B. van Leeuwen, Matthias N. van Oosterom Platinum Award Winners 2019
European Urology, Vol 79, Issue 1, p124–132 1. Stephen Boorjian
2. Fiona Burkhard
Platinum Award Winners 2009 3. Pierre Karakiewicz
1. Fritz Schröder 4. Luis Martinez-Piþeiro
2. Urs Studer 5. Peter Mulders
6. Maria Ribal
Platinum Award Winners 2010
1. Christopher Chapple
1. Prokar Dasgupta
2. Oliver Hakenberg
2. Karim Fizazi
3. Rodolfo Montironi
3. Silke Gillessen
4. Caroline Moore
Platinum Award Winners 2011 5. Declan Murphy
1. Guido Dalbagni 6. Karin Plass
2. Monique J. Roobol
Platinum Award Winners 2012 1. Matthew Cooperberg
1. Anders Bjartell 2. Anthony D’Amico
2. Markus Graefen 3. Emily Zabor
3. Mani Menon
4. Christian Stief Platinum Award Winners 2022
5. Tullio Sulser 1. Morgan Roupre ^t
6. Alexandre Zlotta 2. Stacy Loeb
3. Maria de Santis
Platinum Award Winners 2013 4. Fred Witjes
1. Per-Anders Abrahamsson 5. Borje Ljungberg
2. Walter Artibani
3. Jacqueline Roelofswaard 2007 Reviewers of the Month
4. Maurice Schlief January: Massimo Maezzini (Italy)
5. Claude Schulman February: Hiten R. H. Patel (UK)
6. Pierre Teillac March: Pierre Karakiewicz (Canada)
7. Manfred Wirth April: Christian Gratzke (Germany)
8. Hendrik van Poppel May: Fred Witjes (The Netherlands)
June: Ziya Kirkali (Turkey)
Platinum Award Winners 2014 July: Bertrand Guillonneau (USA)
1. Inderbir Gill August: Chris Chapple (UK)
2. Richard Sylvester September: Axel Heidenreich (Germany)
3. Henk van der Poel October: Jean-Jacques Patard (France)
November: Oliver Reich (Germany)
1. Stephen Freedland Reviewer of the Year 2007
2. Axel Heidenreich Vincenzo Ficarra (Italy)
3. Francesco Montorsi
4. Keith Parsons 2008 Reviewers of the Month
January: Shahrokh Shariat (USA)
February: Alberto Briganti (Italy)
March: Alexander Bachmann (Switzerland)
1. Matthew Gettman
April: Scott Eggener (USA)
2. George Thalmann
May: Roger Dmochowski (USA)
June: Felix K.-H. Chun (Germany)
Platinum Award Winners 2017 July: Giacomo Novara (Italy)
1. Peter Albertsen August: Michael Blute (USA)
2. Axel Bex September: Patrick Bastian (Germany)
3. James N’Dow October: Rafael Badalyan (Armenia)
4. Daniel Sjoberg November: Henk van der Poel (The Netherlands)
The Platinum
Hall of Fame
Reviewer of the Year 2008 September: Sabine Brookman-May (Germany)

Pierre Karakiewicz (Canada) October: Nicolas Mottet (France)
November: Hendrik Isbarn (Germany)
2009 Reviewers of the Month
January: Matthew Gettman (USA) Reviewers of the Year 2012
February: Oliver Hakenberg (Germany) Peter Albertsen (USA)
March: Riccardo Autorino (Italy) Jean-Nicolas Cornu (France)
April: Urs Studer (Switzerland) Gianluca Giannarini (Switzerland)
May: Fritz Schröder (The Netherlands)
June: Petrisor Geavlete (Romania) 2013 Reviewers of the Month
July: Clare Fowler (UK) January: Massimo Lazzeri (Italy)
August: Francisco Cruz (Portugal) February: Guillaume Ploussard (France)
September: John Denstedt (Canada) March: Derya Tilki (Germany)
October: Jacques Irani (France) April: Giuseppe Simone (Italy)
November: Apostolos Apostolidis (Greece) May: Evanguelos Xylinas (USA)
June: Joseph Chin (Canada)
Reviewer of the Year 2009 July: Rodolfo Montironi (Italy)
Henk van der Poel (The Netherlands) August: Matthew Galsky (USA)
September: Hashim Ahmed (UK)
October: Peter Black (Canada)
November: Tobias Klatte (Germany)
January: Ricarda Bauer (Germany)
February: Declan Murphy (Australia) Reviewers of the Year 2013
March: Harry Herr (USA) Francesco Greco (Germany)
April: Marko Babjuk (Czech Republic) Stephen Boorjian (USA)
May: Umberto Capitanio (Italy) Matthew Galsky (USA)
June: Stephen Freedland (USA)
July: Richard Sylvester (Belgium) 2014 Reviewers of the Month
August: Rufus Cartwright (UK) January: Morgan Rouprõt (France)
September: Jens Rassweiler (Germany) February: Malte Rieken (Switzerland)
October: Mike Kattan (USA) March: Jochen Walz (France)
November: George Thalmann (Switzerland) April: Noburo Hara (Japan)
May: Aidan Noon (UK)
Reviewers of the Year 2010 June: Stacy Loeb (USA)
Michael Kattan (USA) July: Dan Sjoberg (USA)
Matthew Gettman (USA) August: Cosimo De Nunzio (Italy)
Giacomo Novara (Italy) September: Michael Abern (USA)
October: Fumitaka Koga (Japan)
2011 Reviewers of the Month November: Christopher Barbieri (USA)
January: Ofer Yossepowitch (Israel)
February: Theo de Reijke (The Netherlands) Reviewers of the Year 2014
March: Evangelos Liatsikos (Greece) Noboru Hara (Japan)
April: Christopher Eden (UK) Aidan Noon (UK)
May: Ofer Gofrit (Israel) Christopher Barbieri (USA)
June: James Catto (UK)
July: R. Houston Thompson (USA) 2015 Reviewers of the Month
August: Karim Bensalah (France) January: Bertram Yuh (USA)
September: Gianluca Giannarini (Italy) February: Francesco Porpiglia (Italy)
October: Mesut Remzi (Austria) March: Henry Woo (Australia)
November: Peter Albertsen (USA) April: Umberto Anceschi (Italy)
Reviewer of the Year 2011 May: Kazutaka Saito (Japan)
Alexander Bachmann (Switzerland) June: Alessandra Mosca (Italy)
July: Giorgio Gandaglia (Italy)
2012 Reviewers of the Month August: Sarah Psutka (USA)
January: Francesco Greco (Germany) September: Daniel Moreira (USA)
February: Stephen Boorjian (USA) October: Boris Gershman (USA)
March: Jean-Nicolas Cornu (France) November: Roderick van den Bergh (The Netherlands)
April: Mark Emberton (UK)
May: Firas Abdollah (Italy) Reviewers of the Year 2015
June: Stephan Madersbacher (Austria) Giorgio Gandaglia (Italy)
July: Michael Rink (Germany) Joseph Chin (Canada)
August: Rik Bryan (UK) Boris Gershman (USA)
The Platinum
Hall of Fame
2016 Reviewers of the Month July: Adam Weiner (USA)

January: Paolo Verze (Italy) August: Stephen Williams (USA)
February: Liam Bourke (UK) September: Daniel Spratt (USA)
March: Brant Inman (USA) October: Jacob Patterson (UK)
April: Maurizio Serati (Italy) November: Ryan Hutchinson (USA)
May: William Parker (USA)
June: Homayoun Zargar (Australia) Reviewers of the Year 2019
July: Ola Bratt (UK) Jacob Patterson (UK)
August: Riccardo Bartoletti (Italy) Daniel Spratt (USA)
September: Zachary Klaassen (Canada) Stephen Williams (USA)
October: Francesco Sanguedolce (Italy)
November: Antonio Galfano (Italy) 2020 Reviewers of the Month
January: Mikkel Fode (DK)
Reviewers of the Year 2016
February: Marco Borghesi (Italy)
Ola Bratt (Sweden)
March: Fumitaka Koga (JP)
Riccardo Bartoletti (Italy)
April: Camilio Porta (Italy)
Zachary Klassen (Canada)
May: Jeery Tosoian (USA)
June: Douglas Cheung (CAN)
2017 Reviewers of the Month July: Xavier Deeux (France)
January: Steeve Doizi (France) August: Yair Lotan (USA)
February: Kazuto Ito (Japan) September: Daniel Geynisman (USA)
March: Harras Zaid (USA) October: Andrea Cocci (Italy)
April: Alberto Bossi (France) November: Riccardo Campi (Italy)
May: Joshua Meeks (USA)
June: Zoran Culig (Austria)
Reviewers of the Year 2020
July: Nicola Fossati (Italy)
Riccardo Campi (Italy)
August: Alexander Kutikov (USA)
Jozefina Casuscelli (Germany)
September: Melissa Assel (USA)
Douglas Cheung (Canada)
October: Maximilien Gilles-André Baron (France)
Fumitaka Koga (Japan)
November: Bimal Bhindi (Canada)
Reviewers of the Year 2017 January: Max Kates (USA)
Alexander Kutikov (USA) February: Mario Álvarez-Maestro (ES)
Melissa Assel (USA) March: David D’Andrea (Austria)
Nicola Fossati (Italy) April: Christian Meyer (Germany)
Kazuto Ito (Japan) May: Abdullah Erdem Canda (Turkey)
June: Hendrik Borgmann (Germany)
2018 Reviewers of the Month July: Imad Bentellis (FR)
January: Andrea Necchi (USA) August: Laura Marandino (CH)
February: Christopher Wallis (Canada) September: Hanan Goldberg (CAN)
March: Ross Mason (Canada) October: Neeraj Agarwal (USA)
April: Joseph Clark (USA) November: Mary Elizabeth Westerman (USA)
May: Giorgio Russo (Italy)
June: Benoit Peyronnet (France) Reviewers of the Year 2021
July: Timothy Lyon (USA) Mario Álvarez-Maestro (Spain)
August: Ardalan Ahmad (Canada) Hendrik Borgmann (Germany)
September: Alastair Lamb (UK) Laura Marandino (Switzerland)
October: Paul Boutros (Canada) Mary Elizabeth Westerman (USA)
November: Paras Shah (USA)
Reviewers of the Year 2018 January: Stephanie Gazdovich (CAN)
Andrea Necchi (USA) February: Sarah Markt (USA)
Christopher Wallis (Canada) March: Zine-Eddine Khene (FR)
Alastair Lamb (UK) April: Sumanta Pal (USA)
May: Laura Bukavina (USA)
2019 Reviewers of the Month June: Michiel van der Heijden (NL)
January: Keith Lawson (Canada) July: Riccardo Bertolo (IT)
February: Alessandro Antonelli (Italy) August: Roger Li (USA)
March: Christopher Filson (USA) September: Carissa Chu (USA)
April: Scott Eggener (USA) October: Timothy Clinton (USA)
May: Sumanta Pal (USA) November: Samantha Conroy (UK)
June: Panagiotis Kallidonis (Greece)
european urology, vol. 82, no v, November 2022
CONTENTS
The Platinum Hall of Fame e125
10.1016/j.eururo.2022.09.013
Platinum Opinion A Plea for Economically Sustainable Evidence-based Guidelines 449

A. Martini, N. Mottet, F. Montorsi, A. Necchi, M.J. Ribal, B. Malavaud
The rising costs of cancer care with the introduction of new agents are a challenge. The
impact of these costs differs among countries. We compare costs for metastatic prostate
cancer, with prices normalized to international dollars, as an example that highlights the
need for cost-effectiveness analyses in trials and treatment guidelines.
Brief Prostate Cancer Detection Percentages of Repeat Biopsy in Patients with Positive 452
Correspondence Multiparametric Magnetic Resonance Imaging (Prostate Imaging Reporting and Data
System/Likert 3–5) and Negative Initial Biopsy. A Mini Systematic Review
N. Grivas, M. Lardas, E.L. Espinós, T.B. Lam, O. Rouviere, N. Mottet, R.C.N. van den Bergh, Members of the
EAU-EANM-ESTRO-ESUR-ISUP-SIOG Prostate Cancer Guidelines Panel
A negative biopsy in patients with Prostate Imaging Reporting and Data System/Likert 3
lesions causes a frequent clinical conundrum that can be due to a false positive magnetic
resonance imaging (MRI) finding or a false negative prostate biopsy. In these patients, we
suggest MRI re-reading and follow-up with repeat multiparametric MRI or standard repeat
biopsy in highest-risk cases.
Platinum Priority The 2022 World Health Organization Classification of Tumours of the Urinary 458
Papers System and Male Genital Organs—Part A: Renal, Penile, and Testicular Tumours
H. Moch, M.B. Amin, D.M. Berney, E.M. Compérat, A.J. Gill, A. Hartmann, S. Menon, M.R. Raspollini,
Original Articles, together with M.A. Rubin, J.R. Srigley, P. Hoon Tan, S.K. Tickoo, T. Tsuzuki, S. Turajlic, I. Cree, G.J. Netto
the Full Length Editorials
The 2022 World Health Organization classification contains new renal tumour entities. Some
Reviews of them are based on a molecular driver event. The classification of penile squamous cell
carcinomas is simplified and based on the presence of human papillomavirus. A new
chapter with tumours of the scrotum has been introduced. Nomenclature changes of
testicular tumours include replacement of the term ‘‘primitive neuroectodermal tumour’’ by
‘‘embryonic neuroectodermal tumour’’. The term ‘‘carcinoid’’ has been changed to
‘‘neuroendocrine tumour’’.
The 2022 World Health Organization Classification of Tumors of the Urinary 469
System and Male Genital Organs—Part B: Prostate and Urinary Tract Tumors
G.J. Netto, M.B. Amin, D.M. Berney, E.M. Compérat, A.J. Gill, A. Hartmann, S. Menon, M.R. Raspollini,
M.A. Rubin, J.R. Srigley, P. Hoon Tan, S.K. Tickoo, T. Tsuzuki, S. Turajlic, I. Cree, H. Moch
The fifth edition of the World Health Organization (WHO) ‘‘Blue Book’’ brings a
comprehensive update on the terminology, epidemiology, pathogenesis, histopathology,
diagnostic molecular pathology, and prognostic and predictive progress in genitourinary
tumors. In this review, we presented a summary of the salient changes introduced in the
WHO 2022 classification of tumors of the prostate and the urinary tract.
Tumors of the Urinary System and Male Genital Organs: 2022 World Health 483
Organization Classification and Multidisciplinarity
R. Montironi, A. Cimadamore
Local Failure Events in Prostate Cancer Treated with Radiotherapy: A Pooled 487
Analysis of 18 Randomized Trials from the Meta-analysis of Randomized
Trials in Cancer of the Prostate Consortium (LEVIATHAN)
T.M. Ma, F.-I. Chu, H. Sandler, F.Y. Feng, J.A. Efstathiou, C.U. Jones, M. Roach 3rd, S.A. Rosenthal,
T. Pisansky, J.M. Michalski, M. Bolla, T.M. de Reijke, P. Maingon, A. Neven, J. Denham, A. Steigler,
D. Joseph, A. Nabid, L. Souhami, N. Carrier, L. Incrocci, W. Heemsbergen, F.J. Pos, M.R. Sydes,
D.P. Dearnaley, A.C. Tree, I. Syndikus, E. Hall, C. Cruickshank, S. Malone, S. Roy, Y. Sun, N.G. Zaorsky,
N.G. Nickols, R.E. Reiter, M.B. Rettig, M.L. Steinberg, V.K. Reddy, M. Xiang, T. Romero, D.E. Spratt,
A.U. Kishan, Meta-analysis of Randomized trials in Cancer of the Prostate MARCAP Consortium
investigators
We provide the strongest evidence to date that local failure is an independent
prognosticator of outcomes in high- and intermediate-risk prostate cancer patients treated
with definitive radiation therapy. Distant metastasis predominantly develops from a clinical
relapse-free state; however, a second wave of distant metastasis occurs subsequent to local
failure, albeit less commonly.
The Deep Blue of Prostate Cancer Metastasis Evolution: The LEVIATHAN Pooled 499
Analysis
D. Chang, P. Blanchard, S. Siva
Prostate Cancer 18
F-PSMA-11 Versus 68Ga-PSMA-11 Positron Emission Tomography/Computed 501
Tomography for Staging and Biochemical Recurrence of Prostate Cancer: A
Prospective Double-blind Randomised Cross-over Trial
K. De Man, N. Van Laeken, V. Schelfhout, W.P. Fendler, B. Lambert, K. Kersemans, S. Piron, N. Lumen,
K. Decaestecker, V. Fonteyne, L. Delrue, F. De Vos, P. Ost
The radiotracer 18F-PSMA-11 has been proved to be noninferior to 68Ga-PSMA-11 for the
detection and staging of prostate cancer in primary and recurrent settings. This tracer can
therefore be used as a cost-efficient alternative.
18 68
F-PSMA-11 as an Attractive Ga-PSMA-11 Alternative for Prostate Cancer Imaging 510
P.J. van Leeuwen, L. Emmett
Overall Survival Update for Patients with Metastatic Castration-resistant 512
Prostate Cancer Treated with Capivasertib and Docetaxel in the Phase 2
ProCAID Clinical Trial
S.J. Crabb, G. Griffiths, D. Dunkley, N. Downs, M. Ellis, M. Radford, M. Light, J. Northey, A. Whitehead,
S. Wilding, A.J. Birtle, V. Khoo, R.J. Jones
ProCAID tested the benefit of using the AKT inhibitor capivasertib with chemotherapy to
treat advanced castration-resistant prostate cancer. This updated analysis provides
evidence that capivasertib addition extends overall survival in patients who have previously
received abiraterone and/or enzalutamide.
A Path to Precision Medicine in Prostate Cancer: Learning from ‘‘Negative’’ Trials of 516
Targeted Therapies
T.B. Dorff, A.K. Morgans
Bladder Cancer Phase 1 Study of Chemoradiotherapy Combined with Nivolumab ± 518
Ipilimumab for the Curative Treatment of Muscle-invasive Bladder Cancer
B.-M. de Ruiter, J.W. van Hattum, D. Lipman, T.M. de Reijke, R. J.A. van Moorselaar, E.J. van Gennep,
A.H. Maartje Piet, M. Donker, T. van der Hulle, J. Voortman, J.R. Oddens, M.C.C.M. Hulshof, A.D. Bins
Concurrent checkpoint inhibition with nivolumab, and combination
nivolumab + ipilimumab added to a hypofractionated mitomycin C/capecitabine
chemoradiotherapy regimen is feasible with acceptable toxicity and shows promising
efficacy in patients with nonmetastatic muscle-invasive bladder carcinoma.
Adding a Fourth Modality to Trimodal Therapy for Muscle-invasive Bladder Cancer 527
P. Ghatalia, E.R. Plimack
Reviews Epidemiology of Renal Cell Carcinoma: 2022 Update 529

L. Bukavina, K. Bensalah, F. Bray, M. Carlo, B. Challacombe, J. Karam, W. Kassouf, T. Mitchell,
R. Montironi, T. O’Brien, V. Panebianco, G. Scelo, B. Shuch, H. van Poppel, C.D. Blosser, S.P. Psutka
We explored the global incidence and mortality of kidney cancer as well as its risk factors.
We also highlight germline and somatic mutations that predispose to kidney cancer
development. The data provide an insight into the complexity of kidney cancer
epidemiology and germline and somatic mutations in patients at risk of developing kidney
cancer.
Surgery in Motion Long-term Follow-up of Detaenial Sigmoid Neobladder Reconstruction for Paediatric 543
Patients with Bladder and Prostate Rhabdomyosarcoma: Technique and Results from a
Single High-volume Centre
P. Xu, C. Chen, B. Chen, E. Bi, W. Du, N. Jiang, Z. Liu, H. Lan, M. Cao, Y. Liu, J. Huang, H. Shen, C. Liu, C. Liu,
A. Xu
The optimal treatment strategy for bladder and prostate rhabdomyosarcoma (B/P RMS)
remains unclear. Primary orthotopic sigmoid neobladder reconstruction after radical
cystectomy for paediatrics with B/P RMS is safe and feasible. The high histocompatibility
and tissue adaptability of children are inspiring.
Single-port Robotic Transvesical Partial Prostatectomy for Localized Prostate Cancer: 551
Initial Series and Description of Technique
J.H. Kaouk, E.L. Ferguson, A.T. Beksac, M.A. Zeinab, A. Kaviani, C. Weight, S. Haywood, M. Eltemamy,
A. Purysko, J.K. McKenney, E. Klein
Partial prostatectomy using a novel single-port robotic transvesical approach is safe and
feasible with minimal postoperative pain, shortened Foley catheter duration, and full
recovery of urine control and potency within few weeks postoperatively in carefully
selected patients with localized low- and intermediate-risk prostate cancer.
Full Length Article Predicting the Need for Biopsy to Detect Clinically Significant Prostate Cancer in 559
Patients with a Magnetic Resonance Imaging–detected Prostate Imaging Reporting
and Data System/Likert 3 Lesion: Development and Multinational External Validation
of the Imperial Rapid Access to Prostate Imaging and Diagnosis Risk Score
M. Peters, D. Eldred-Evans, P. Kurver, U.G. Falagario, M.J. Connor, T.T. Shah, J.J.C. Verhoeff, P. Taimen,
H.J. Aronen, J. Knaapila, I. Montoya Perez, O. Ettala, A. Stabile, G. Gandaglia, N. Fossati, A. Martini,
V. Cucchiara, A. Briganti, A. Lantz, W. Picker, E.S. Haug, T. Nordström, M.B. Tanaka, D. Reddy, E. Bass,
P.S.N. van Rossum, K. Wong, H. Tam, M. Winkler, S. Gordon, H. Qazi, P.J. Boström, I. Jambor, H.U. Ahmed
The five-item Imperial Rapid Access to Prostate Imaging and Diagnosis risk score using age,
prostate-specific antigen density, prior negative biopsy, prostate volume, and highest
magnetic resonance imaging (MRI) score provides a standardised tool for the prediction of
clinically significant prostate cancer in patients with an MRI-detected Prostate Imaging
Reporting and Data System/Likert 3 lesion and can support the decision for prostate
biopsy.
Words of Wisdom Re: Fragmentation of Stones by Burst Wave Lithotripsy in the First 19 Humans 569
H. Yang, M. Stoller
Re: Development and Validation of the Metric-based Assessment of a Robotic 570

Dissection Task on an Avian Model
C. Jamaer, A.-F. Spinoit
Re: Artificial Intelligence for Diagnosis and Gleason Grading of Prostate Cancer: The 571
PANDA Challenge
P. Dasgupta
Re: Active Surveillance Plus Enzalutamide Monotherapy vs Active Surveillance Alone in 572
Patients with Low-risk or Intermediate-risk Localized Prostate Cancer: The ENACT
Randomized Clinical Trial
C. Kesch, B.A. Hadaschik
Re: Darolutamide and Survival in Metastatic, Hormone-sensitive Prostate Cancer 573

A. Vilaseca, M.J. Ribal
Re: Novel Classification for Upper Tract Urothelial Carcinoma to Better Risk-stratify 574
Patients Eligible for Kidney-sparing Strategies: An International Collaborative Study
C. Lonati, N. Suardi
Letters to the Re: Heng Li, Yucong Zhang, Dong Li, et al. Androgen Receptor Splice Variant 7 Predicts e135
Editor Shorter Response in Patients with Metastatic Hormone-sensitive Prostate Cancer
Receiving Androgen Deprivation Therapy. Eur Urol 2021;79:879–86 AR-V7 is Rare in
Hormone-sensitive Prostate Cancer. AR-V7 is Rare in Hormone-sensitive Prostate
Cancer
A.G. Sowalsky, S.R. Plymate, M.C. Haffner, J.S. de Bono, A. Sharp
Reply to Adam G. Sowalsky, Stephen R. Plymate, Michael C. Haffner, Johann S. de e137

Bono, and Adam SharpÕs Letter to the Editor re: Heng Li, Yucong Zhang, Dong Li, et al.
Androgen Receptor Splice Variant 7 Predicts Shorter Response in Patients with
Metastatic Hormone-sensitive Prostate Cancer Receiving Androgen Deprivation
Therapy. Eur Urol 2021;79:879–86: AR-V7 is Rare in Hormone-sensitive Prostate Cancer
H. Li, Y. Zhang, H. Xu
Reply to Andreas SkolarikosÕs Words of Wisdom re: Effect of Robot-assisted Radical e139
Cystectomy with Intracorporeal Urinary Diversion vs Open Radical Cystectomy on 90-
Day Morbidity and Mortality Among Patients with Bladder Cancer: A Randomized
Clinical Trial. Eur Urol. In press
J.W.F. Catto, P. Khetrapal, G. Ambler, N.R. Williams, C. Brew-Graves, J.D. Kelly
Reply to Yuxuan Song, Yiqing Du, and Tao XuÕs Letter to the Editor re: Matthew e141
Mossanen, Filipe L.F. Carvalho, Vinayak Muralidhar, et al. Genomic Features of Muscle-
invasive Bladder Cancer Arising After Prostate Radiotherapy. Eur Urol 2022;81:466–73
F.L.F. Carvalho, M. Mossanen, E.M. Van Allen, K.W. Mouw
Re: Kathia De Man, Nick Van Laeken, Vanessa Schelfhout, et al. 18F-PSMA-11 Versus e143
68
Ga-PSMA-11 Positron Emission Tomography/Computed Tomography for Staging and
Biochemical Recurrence of Prostate Cancer: A Prospective Double-blind Randomised
Cross-over Trial. Eur Urol. 2022;82:501–509
F. Montorsi, G. Gandaglia, D. Robesti, F. Dehò, A. Briganti
Re: Sabrina H. Rossi, Grant D. Stewart. Re: Clinical Validation of a Targeted e144
Methylation-based Multi-cancer Early Detection Test Using an Independent Validation
Set. Eur Urol. 2022;82:442–443
E.A. Klein
Re: Logan G. Briggs, Chanan Reitblat, Paul A. Bain, et al. Prehabilitation Exercise Before e145
Urologic Cancer Surgery: A Systematic and Interdisciplinary Review. Eur Urol
2022;81:157–67. Recommendations for Experiments on Prehabilitation Exercise
Programs for Health Optimization Before Cancer Surgeries
A. Pontes-Silva
Re: Sarah P. Psutka, Roman Gulati, Michael A.S. Jewett, et al. A Clinical Decision Aid to e146
Support Personalized Treatment Selection for Patients with Clinical T1 Renal Masses:
Results from a Multi-institutional Competing-risks Analysis. Eur Urol 2022;81:576–85
M. Wenzel, F.K.-H. Chun, A. Becker
Re: Sophie Knipper, Mehrdad Mehdi Irai, Ricarda Simon, et al. Cohort Study of e148
Oligorecurrent Prostate Cancer Patients: Oncological Outcomes of Patients Treated
with Salvage Lymph Node Dissection via Prostate-specific Membrane Antigen-
radioguided Surgery. Eur Urol. In press. https://doi.org/10.1016/j.eururo.2022.05.031
F. Montorsi, C.A. Bravi, G. Gandaglia, A. Mottrie, A. Briganti
Re: Christian Fuglesang S. Jensen, Dana A. Ohl, Mikkel Fode, et al. Microdissection e149
Testicular Sperm Extraction Versus Multiple Needle-pass Percutaneous Testicular
Sperm Aspiration in Men with Nonobstructive Azoospermia: A Randomized Clinical
Trial. Eur Urol. 2022;82:377–384
B. Li, C. Duan, X. Yao, X. Wu, H. Xu
Reply to Bo Li, Chen Duan, Xiangyang Yao, Xiaoliang Wu, and Hua XuÕs Letter to the e151
Editor re: Christian Fuglesang S. Jensen, Dana A. Ohl, Mikkel Fode, et al.
Microdissection Testicular Sperm Extraction Versus Multiple Needle-pass Percutaneous
Testicular Sperm Aspiration in Men with Nonobstructive Azoospermia: A Randomized
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C.F.S. Jensen, M. Fode, J. Sønksen
Corrigendum Corrigendum to ‘‘The Role of Stereotactic Ablative Body Radiotherapy in Renal Cell e152
Carcinoma’’ [Eur Urol 2022]
M. Ali, J. Mooi, N. Lawrentschuk, R.R. McKay, R. Hannan, S.S. Lo, W.A. Hall, S. Siva
Congress Calendar Congress Calendar e153

The illustration on the cover of this issue is taken from the article by
Rodolfo Montironi and Alessia Cimadamore – Tumors of the Urinary System
and Male Genital Organs: 2022 World Health Organization Classification
and Multidisciplinarity, which is published on pp. 483–486 of this issue.
EUROPEAN UROLOGY 82 (2022) 449–451
available at www.sciencedirect.com
journal homepage: www.europeanurology.com
Platinum Opinion
A Plea for Economically Sustainable Evidence-based Guidelines
Alberto Martini a, Nicolas Mottet b, Francesco Montorsi c, Andrea Necchi d, Maria J. Ribal e,
Bernard Malavaud a,*
a
Department of Urology, Institut Universitaire du Cancer Toulouse-Oncopôle, Toulouse, France; b Department of Urology, University Jean Monnet, St. Etienne,
France; c Division of Exper2;imental Oncology/Unit of Urology, Urological Research Institute, IRCCS San Raffaele Scientific Institute, Milan, Italy; d Department
of Medical Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy; e Department of Urology, Uro-Oncology Unit, Hospital Clinic of Barcelona, University
of Barcelona, Barcelona, Spain
The costs of managing cancer are rising as new agents (EBM) joint guidelines on mPC from five leading Euro-
become available. These agents offer greater efficacy and pean medical societies (European Association of Urol-
more options to affected individuals, but the rising costs ogy, European Association of Nuclear Medicine,
are challenging to many individuals and health care pur- European Society of Urogenital Radiology, European
chasers. The impact of these costs differs between countries, Society for Radiotherapy and Oncology, and Interna-
as prices are not uniform, incomes vary, and affordability tional Society of Geriatric Oncology).
reflects many factors. One approach to understanding com- (2) Medication prices: Current (2020) medication costs
parative costs is to normalize prices into international dol- were obtained from the four most populated coun-
lars, which reflect gross domestic product (GDP), spending tries of the EU and from the UK, each of which were
power, and affluence. To illustrate this, we studied costs under the remit of the EMA in 2020. We selected
for metastatic prostate cancer (mPC). The treatments for the cheapest option for each country when multiple
this disease are usually delivered in the community and formulations were available (eg, LHRH analogs).
so the costs mostly reflect the purchase price [1]. The treat- (3) Conversion into international dollars: We used the
ment of affected men allows us to model the impact of ris- Organization for Economic Cooperation and Develop-
ing costs, and ultimately evaluate the economic ment annual tables (https://data.oecd.org/conversion/
sustainability of treatment guidelines across Europe. purchasing-power-parities-ppp.htm) to convert local
Treatment of mPC has undergone tremendous change prices into international dollars. This currency
since the Huggins Nobel prize lecture [2]. Over time, target- acknowledges differences in purchasing power
ing of the androgen receptor (AR) has been achieved via sur- among European countries. The costs for a year of
gical castration, estrogen administration, and analogs or therapy with each medication by country are dis-
antagonists of luteinizing hormone–releasing hormone played in Table 1.
(LHRH), combined with steroidal and nonsteroidal antian- (4) Trends over time: In the absence of publicly accessi-
drogens. Recently, the European Medicines Agency (EMA) ble data on market penetration by medications, we
approved oral AR-targeting agents (ARTAs) that target non- estimated the share of the guideline-recommended
canonical androgen anabolism or the AR intracellular treatments via author consensus. We assumed that
dynamics. Each of these advances has been accompanied degarelix accounted for 20% of the market following
by increases in costs. The sustainability of scientifically its approval in 2013. For castrate-resistant mPC, abi-
sound but costly mPC guidelines is being questioned [3–5]. raterone acetate (ABI) was recommended in 2013
To understand the comparative affordability of mPC and enzalutamide (ENZA) in 2014, so we assumed
treatment, we undertook a five-stage evaluation. an equal split between the two since then. In the con-
text of hormone sensitive mPC, ABI was the sole med-
(1) Treatment recommendations: We reviewed the ication recommended until 2020, when ENZA and
2010–2020 archives of evidence-based medicine apalutamide (APA) were also introduced. Considering
* Corresponding author. Department of Urology, Institut Universitaire du Cancer de Toulouse, 1, avenue Irène Joliot Curie, 31059 Toulouse, Cedex 9,
France. Tel. +33 686 135851; Fax: +33 531 156076.
E-mail address: [email protected] (B. Malavaud).
https://doi.org/10.1016/j.eururo.2022.08.001
0302-2838/Ó 2022 European Association of Urology. Published by Elsevier B.V. All rights reserved.
450 EUROPEAN UROLOGY 82 (2022) 449–451
Table 1 – Annual cost of medication by country according to 2020 retail prices, normalized by purchasing power paritya
Country Abiraterone 500 Enzalutamide 40 Apalutamide 60 Degarelix 80 LHRH analog (cheapest) Yearly CET
Italy $97 018.91 $101 870.03 $97 012.02 $3859.21 $2224.29 $117 014.57
France $46 926.61 $48 976.86 $46 263.14 $1799.83 $1610.19 $103 405.91
Germany $61 295.74 $56 274.95 $46 101.33 $3435.22 $2180.90 $154 122.08
Spain $68 897.44 $64 378.47 $64 378.47 $3335.46 $1091.82 $108 659.82
UK $47 703.49 $47 697.73 $47 703.49 $2256.45 $1312.33 $128 027.35
CET = cost-effective threshold according to the World Health Organization (WHO) Choosing Interventions that are Cost-Effective (CHOICE) for treatments that
provide a year of good health and cost less than three times the ratio between a country’s gross domestic product and population; LHRH = luteinizing hormone–
releasing hormone.
a
Data are presented in international dollars to account for variation in purchasing power among countries. The far-right column reports the CET by country
according to the WHO-CHOICE initiative. If the cost of a year of treatment providing ‘‘good health’’ falls below the threshold, cost-effectiveness is met.
roughly similar retail prices in Europe (Table 1), an (https://data.worldbank.org) are presented in inter-
equal split among ABI, ENZA, and APA was assumed. national dollars in Table 1 along with the yearly costs
The evolution of the cost of care over time is pre- of mPC drugs for comparison.
sented in Figure 1.
(5) WHO-CHOICE perspective: In 2003, the World Health Our work has highlighted the escalating costs of manag-
Organization (WHO) set up the Choosing Interven- ing mPC in accordance with European guidelines and ques-
tions that are Cost-Effective (WHO-CHOICE) project tions the financial sustainability for national health
to define ‘‘cost effectiveness’’ and suggested paying systems. This is compounded by the high incidence of and
for treatments that cost less than three times the the long time spent on treatment for mPC. The introduction
national GDP divided by the country population for of ARTAs in the European guidelines entailed a 10- to 20-
each year of good health they provide [6]. The fold increase in the corresponding yearly cost of care for
corresponding yearly thresholds derived from the castration-resistant and castration-sensitive mPC. Intrigu-
annual World Bank GDP and population data ingly, important differences across European countries
Fig. 1 – Evolution of the yearly costs of the treatments recommended by guidelines on metastatic prostate cancer. (A) Metastatic castration-sensitive prostate
cancer. (B) Metastatic castration-resistant prostate cancer. The prices presented are in international dollars and normalized by purchasing power parity.
EUROPEAN UROLOGY 82 (2022) 449–451 451
emerged: the yearly cost of therapy was approximately position to promote, if not insist on, cost-effectiveness anal-
twice as expensive in Italy and 40% more expensive in Spain yses in future studies. In the meantime, to increase aware-
than in France or the UK. According to WHO-CHOICE, the ness of this issue, look-up tables that report the WHO-
cost incurred on addition of ARTAs to standard LHRH inter- CHOICE cost-effectiveness threshold for ‘‘one additional
ference would be warranted only if they added one full year year of life in good health’’ for each European country could
of good health for mPC patients, which is quite an exacting be included as an annex to guidelines. Table 1 was con-
metric in view of the evidence published [1]. After EMA structed with that objective in mind. Indeed, without
approval, the policy on medication reimbursement is sub- greater awareness, there is a concrete risk that guidelines
ject to variations across Europe, where primary responsibil- panels will produce compelling compendia of positive evi-
ity in health care systems lies with the member states dence of little resonance in the real world where $1 yields
(article 168.7, Treaty of the Functioning of the European its true value.
Union). On this matter, neither the latency between
approval and reimbursement by national health systems
Conflicts of interest: Andrea Necchi has served as a consultant for Merck,
nor eventual price negotiations were accounted for. How-
AstraZeneca, Janssen, Incyte, Roche, Rainier Therapeutics, Clovis Oncol-
ever, purchasing power parity–adjusted costs, from the per-
ogy, Bayer, Astellas/Seattle Genetics, Ferring, and Immunomedics; has
spective of the WHO suggested thresholds, readily illustrate
received research funding from Merck, Ipsen, and AstraZeneca; and has
the economic burden for a patient or health system for com-
received travel expenses/honoraria from Roche, Merck, AstraZeneca, and
pliance with guidelines.
Janssen. The remaining authors have nothing to disclose.
There are various limitations to our work. We estimated
the market share for many agents, we were unable to
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its potential economic consequences. While this was rarely [8] Sackett DL, Rosenberg WM, Gray JA, Haynes RB, Richardson WS.
if ever addressed in previous clinical trials, we believe that Evidence based medicine: what it is and what it isn’t. BMJ
scientific associations and guideline offices are in a unique 1996;312:71–2.
Brief Correspondence
Prostate Cancer Detection Percentages of Repeat Biopsy in Patients

with Positive Multiparametric Magnetic Resonance Imaging
(Prostate Imaging Reporting and Data System/Likert 3–5) and
Negative Initial Biopsy. A Mini Systematic Review
Nikolaos Grivas a,b,*,y, Michael Lardas c,y, Estefania Linares Espinós d, Thomas B. Lam e,
Olivier Rouviere f, Nicolas Mottet g, Roderick C.N. van den Bergh h,
Members of the EAU-EANM-ESTRO-ESUR-ISUP-SIOG Prostate Cancer Guidelines Panel à
a
Department of Urology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands; b Department of Urology, Lefkos
Stavros Hospital, Athens, Greece; c Department of Urology, Metropolitan General Hospital, Athens, Greece; d Department of Urology, Hospital Universitario La
Paz, Madrid, Spain; e Department of Urology, Aberdeen Royal Infirmary, Aberdeen, UK; f Hospices Civils de Lyon, Department of Urinary and Vascular Imaging,
Hôpital Edouard Herriot, Lyon, France; g Department of Urology, University Hospital, St. Etienne, France; h Department of Urology, Antonius Hospital, Utrecht,
The Netherlands
Article info Abstract
Article history: Multiparametric magnetic resonance imaging (mpMRI) has high sensitivity but low
Accepted July 26, 2022 specificity for prostate cancer (PCa) diagnosis. The aim of our systematic review was
to investigate the proportion of PCa found at a repeat biopsy in patients with a negative
Associate Editor: initial prostate biopsy, despite initial positive mpMRI. Included patients had a Prostate
Giacomo Novara Imaging Reporting and Data System (PI-RADS)/Likert 3–5 lesion on mpMRI prior to
the initial mpMRI-targeted prostate biopsy, which was negative for PCa on histology.
The main outcomes were the overall and clinically significant PCa (csPCa;
Keywords:
International Society of Urological Pathology >1 or any provided definition) percentages
Negative prostate biopsy at a repeat biopsy. Out of 1179 articles identified, nine studies were included (a total of
Multiparametric magnetic 485 patients). For patients with PI-RADS 3 lesions, overall and csPCa detection percent-
resonance imaging ages ranged from 0% to 80% and from 0% to 20%, respectively, while for patients with PI-
Prostate cancer RADS 4 lesions, the corresponding percentages were 15.4–86% and 7.7–57%. An overall
cancer detection percentage of 87.5% was reported in patients with Likert 5 lesions.
Limitation of our review is the small number of studies and the protocol revision that
allowed studies with <50 patients. In patients with a positive MRI result and a negative
initial MRI-targeted biopsy, we suggest MRI re-reading and follow-up with repeat
mpMRI or the standard repeat biopsy in cases at the highest risk.
Patient summary: Literature has shown that in men with an abnormal prostate
magnetic resonance imaging (MRI) scan but a normal biopsy, a significant prostate
à
Members of the EAU-EANM-ESTRO-ESUR-ISUP-SIOG Prostate Cancer Guidelines Panel involved in
group authorship are listed in the Supplementary material.
y
These authors share first authorship.
* Corresponding author. Department of Urology, The Netherlands Cancer Institute-Antoni van
Leeuwenhoek Hospital, Plesmanlaan 121, 1066 CX, Amsterdam, The Netherlands. Tel.
+31205121543; Fax: +31205122459.
E-mail address: [email protected] (N. Grivas).
cancer can be present. MRI scans should be double checked, followed by standard check-
ups or repeat prostate biopsy, especially in highly suspicious cases.
Ó 2022 European Association of Urology. Published by Elsevier B.V. All rights reserved.
Standard systematic prostate biopsy methods have a false was 10.1% (26/256 cases). The corresponding percentages
negative percentage for prostate cancer (PCa) diagnosis of for patients with PI-RADS 3 lesions were 7.5% (6/80) and
20–40% [1]. Multiparametric magnetic resonance imaging 2.5% (2/80), while for patients with PI-RADS 4 lesions, the
(mpMRI) is an important tool for assessing risk status for corresponding percentages were 17% (30/176) and 13.6%
clinically significant PCa (csPCa) in men presenting with (24/176). Barletta et al [7] reported the csPCa (ISUP grade
elevated prostate-specific antigen (PSA) or other clinical >1) percentages from 68 patients with a clinical suspicion
suspicion such as an abnormal digital rectal examination of PCa and negative systematic and targeted biopsies,
[2]. In a Cochrane systematic review (SR), the sensitivity despite PI-RADS 3 lesions on baseline mpMRI. The median
of magnetic resonance imaging (MRI) for detecting csPCa follow-up was 31 mo. The percentage of csPCa was 22%
(defined as International Society of Urological Pathology (15/68). The percentages for patients who had positive
[ISUP] grade 2) was 0.91 [3]. However, specificity was lim- (PI-RADS 3) follow-up mpMRI, had negative follow-up
ited, reaching 0.37 only. A recent SR has shown that per- mpMRI, and were not offered follow-up mpMRI were 32%
centages of csPCa (ISUP grade 2) are 6%, 12%, 48%, and (10/31), 7% (2/29), and 38% (3/8), respectively.
72% for Prostate Imaging Reporting and Data System (PI- Wallström et al [13] reported the outcomes of 19
RADS) scores 2, 3, 4, and 5, respectively [4]. A Likert scor- patients who had PI-RADS 3 lesions and a negative initial
ing system, which is based on subjective radiologists’ targeted biopsy. After repeat mpMRI, they were offered a
assessment without predefined criteria, has shown speci- second round of targeted biopsy at 2 yr after the initial
ficity of 0.77 and sensitivity of 0.94 for PCa diagnosis [5]. biopsy. The percentages of overall and csPCa (ISUP grade
An MRI-targeted biopsy improves (detection ratio: 1.16) >1) detection were 42.1% (8/19) and 10.5% (2/19), respec-
the diagnosis of csPCa (any study definition or ISUP grade tively. An interesting observation was that the median
2) and reduces the diagnosis of insignificant disease (de- PSA values were low in both the initial and the second
tection ratio: 0.66) compared with the standard biopsy [6]. biopsy round (3.2 and 3.7 ng/ml, respectively). Luzzago
A negative initial biopsy despite a prebiopsy positive MRI et al [11] at a median follow-up of 33 mo reported an over-
scan (PI-RADS/Likert 3) can occur due to either a false pos- all cancer detection percentage of 11.4% (4/35) in patients
itive MRI result or a false negative biopsy. The aim of this with PI-RADS 3 lesions on mpMRI and a negative initial
study was to perform an SR of the literature investigating targeted biopsy, while the percentage of csPCa (ISUP grade
the proportion of detected PCa at a repeat biopsy (either >1) was 5.7% (2/35). The corresponding percentages for
clinically significant or any cancer) and the characteristics patients with PI-RADS 4 lesions were 15.4% (2/13) and
of these cases in patients with a negative initial prostate 7.7% (1/13), while 50% (1/2) of the patients with PI-RADS
biopsy, despite initial positive mpMRI. 5 lesions had csPCa. None of the 20 patients with PI-RADS
The review was commissioned and undertaken by the 3 lesion had PCa at a follow-up biopsy. At a median
European Association of Urology (EAU) PCa Guideline Panel, follow-up of 19 mo, Meng et al [12] reported an overall can-
as part of its guideline update for 2023. The protocol for this cer detection percentage of 62.5% (5/8) in patients with per-
review has been published (http://www.crd.york.ac.uk/ sistent PI-RADS 4/5 lesions (on repeat mpMRI) who were
PROSPERO; CRD42022299085). The Supplementary mate- subsequently submitted to a repeat targeted biopsy. The
rial includes full details of the search strategy and the evi- csPCa (ISUP grade >1) percentage was 37.5% (3/8). Costa
dence acquisition process. The study selection process is et al [9] reported, in 16 patients with Likert 5 lesions and
outlined in the Preferred Reporting Items for Systematic an initial negative targeted biopsy, an overall cancer detec-
Reviews and Meta-analyses flow diagram (Supplementary tion percentage of 87.5% (14/16). According to the National
Fig. 1). A total of 2344 records were identified, and 1179 Comprehensive Cancer Network criteria, 6% (1/16), 69%
were screened after removal of duplicates. Of these, 33 arti- (11/16), and 25% (4/16) had low-, intermediate-, and high-
cles were eligible for full-text screening. Finally, nine stud- risk tumors, respectively. Hauth et al [10], after a mean
ies were included; two of these studies had 50 patients follow-up of 17.6 mo, reported an overall cancer detection
[7,8], and after protocol revision, we included seven addi- percentage of 75% (18/24) at the repeat targeted biopsy of
tional studies with <50 patients [9–15]. patients with PI-RADS 4 lesions and a negative initial
Baseline characteristics and PCa detection percentages biopsy. All patients had follow-up mpMRI before the second
are presented in Table 1. Pepe et al [8] reported results from biopsy. Two of 26 patients with baseline PI-RADS 4 lesions
patients with PI-RADS 3 (80 cases) or 4 (176 cases) lesions had MRI downgrading in PI-RADS 2, and MRI monitoring
on mpMRI, who were submitted to an early (6–9 mo) sec- only was offered. Two of 46 patients with baseline PI-
ond round targeted biopsy following a first negative combi- RADS 3 lesions progressed to PI-RADS 4 on repeat imaging.
nation of saturation and a targeted biopsy. No PI-RADS 5 PCa was found in both patients in a subsequent biopsy,
cases were reported. MRI was not repeated. The authors while the rest 44/46 were offered clinical and MRI monitor-
reported an overall PCa detection percentage of 14% ing. In 31 patients who were offered a second targeted
(36/256), while the percentage of csPCa (ISUP grade >1) biopsy after an initial negative targeted biopsy, Venderink
454
Table 1 – Baseline characteristics and PCa detection rates of included studies
PI-RADS/ N Age, n (%), Type of initial iPSA, n (%), mean FU (mo), Follow-up mpMRI csPCa definition Overall csPCa
Likert mean (SD), biopsy (SD), median mean PCa rate
score median [range] (range) rate (%) (%)
[range]
Pepe (2019) [8], Italy, 2016–2018 PI-RADS 3 80 64 [45–75] Systematic and 11.6 (6.7–29) 6–9 No ISUP >1 and/or 7.5 2.5
targeted positive single

core >50%
PI-RADS 4 176 17 13.6
Barletta (2022) [7], Italy, 2013–2020 PI-RADS 3 37 63 [58–69] Systematic and 5.8 [4.1–8.2] 31 [23–43] All except 8 pts ISUP >1 NA 22
targeted had FU mpMRI
PI-RADS 4 26
PI-RADS 5 5
Wallström (2022) [13], Sweden, 2015–2020 PI-RADS 3 19 NA Targeted NA 24 Yes ISUP >1 42.1 10.5
Luzzago (2021) [11], Italy, 2015–2018 PI-RADS 3 20 NA Targeted NA 33 FU mpMRI was ISUP >1 0 0
undertaken
according to clinician’s
preference
PI-RADS 4 13 15.4 7.7
PI-RADS 5 2 NA 50
Meng (2021) [12], USA, 2012–2016 PI-RADS 4 8 NA Systematic and NA 19 Yes ISUP >1 62.5 37.5
targeted
Costa (2017) [9], USA, 2013–2015 Likert 5 16 NA Targeted NA NA No NA 87.5 NA
Venderink (2018) [14], the Netherlands, PI-RADS 3 5 NA Targeted NA NA Yes ISUP >1 80 20
2006–2016
PI-RADS 4 19 53 11
PI-RADS 5 7 86 57
Kinnaird (2020) [15], USA, 2009–2019 PI-RADS 4 21 NA Systematic and NA NA Yes ISUP >1 NA 23.8
targeted
PI-RADS 5 7 42.8
Hauth (2017) [10], Germany, 2013–2015 PI-RADS 4 24 NA Targeted NA 17.6 Yes NA 75 NA
csPCa = clinically significant prostate cancer; FU = follow-up; iPSA = initial prostate-specific antigen; ISUP = International Society of Urological Pathology; mpMRI = multiparametric magnetic resonance imaging; N = number
of patients; NA = not available; PCa = prostate cancer; PI-RADS = Prostate Imaging Reporting and Data System; pts = patients; SD = standard deviation.
Fig. 1 – Detailed flowchart for the management of patients with negative initial prostate biopsy and positive magnetic resonance imaging. mpMRI = mul-
tiparametric magnetic resonance imaging; PI-RADS = Prostate Imaging Reporting and Data System; PSA = prostate-specific antigen.
et al [14] reported that detection percentages for csPCa these findings, we suggest early MRI re-reading preferably
(ISUP grade >1) were 20% (1/5), 11% (2/19), and 57% (4/7) from a high-volume expert radiologist in a tertiary referral
for PI-RADS 3, 4, and 5 lesions, respectively. Regarding over- center. In case of PI-RADS/Likert 3 lesions, we suggest
all cancer detection, the corresponding percentages were clinical follow-up with PSA (density) and repeat mpMRI
80% (4/5), 53% (10/19), and 86% (6/7). In a study with sim- at 6–12 mo. For PI-RADS/Likert 4 lesions, we suggest clin-
ilar design, Kinnaird et al [15] reported detection percent- ical follow-up and repeat MRI to guide decisions on a
ages for csPCa (ISUP grade >1) of 23.8% (5/21) and 42.8% repeat biopsy, while for PI-RADS/Likert 5 lesions, the stan-
(3/7) for PI-RADS 4 and 5 lesions, respectively. The risk of dard repeat biopsy may be considered (Fig. 1). In situations
bias (RoB) of all studies is shown in Supplementary Figure 2. whereby the imaging (PI-RADS 4 or PI-RADS progression)
The RoB was high in most domains in all studies except for or clinical suspicion of csPCa remains high (eg, high or ris-
that of Barletta et al [7]. ing PSA or PSA density), a repeat biopsy should be consid-
A negative biopsy in patients with PI-RADS/Likert 3 ered. In case of MRI-suspicious lesions (PI-RADS 4),
lesions causes a frequent clinical conundrum that can be Wallström et al [13] suggested that the interval for
due to a false positive MRI finding or a false negative pros- rebiopsy should be 3–6 mo. A limitation of our review is
tate biopsy. The reasons for the discrepancy between the protocol revision that allowed studies with <50
mpMRI and biopsy results can be inaccurate targeting patients. The findings of this SR should be interpreted with
and/or technical errors during mpMRI acquisition/needle caution as the available data are based on very few studies
placement accuracy [16]. Our SR confirmed that patients with a limited number of patients and a high RoB. More-
with a higher initial PI-RADS score had higher detection over, the longer interval of a repeat biopsy in some series
percentages for PCa, with PI-RADS 3 detection percentage might have resulted in a slightly higher number of de novo
ranging from 0% to 80%, while the corresponding percent- PCa cases. The detection percentage of repeat targeted
age for PI-RADS 4 lesions ranged from 15.4% to 86%. biopsies could be also affected by newly detected lesions
Moreover, Meng et al [12] reported that 73% of patients due to disease progression. High heterogeneity was also
with benign targeted biopsies had PI-RADS score down- found regarding the interval of repeat mpMRI and the
grading at repeat mpMRI in a median interval of 13 mo, strategy of a repeat biopsy. Finally, the limited number
suggesting repeat imaging only as a follow-up strategy in of included studies could have also attributed to our
these patients. Similarly, Barletta et al [7] and Wallström search strategy that was designed with the goal to opti-
et al [13] reported, respectively, that 56% and 73.1% of mize sensitivity versus specificity. Our panel suggests
PI-RADS 3 lesions were reclassified as negative at repeat MRI re-reading and follow-up with repeat mpMRI to guide
MRI scans. On the contrary, Hauth et al [10] reported that decisions on clinical follow-up or the standard repeat
4.3% of patients with PI-RADS 3 lesions progressed to PI- biopsy in highest-risk cases.
RADS 4. Kohestani et al [17] reported fair to moderate
interobserver agreement for PI-RADS 3 or 4 lesions, Author contributions: Nikolaos Grivas had full access to all the data in
suggesting that MRI interpretation can have a significant the study and takes responsibility for the integrity of the data and the
variability, especially in low-volume centers. Based on accuracy of the data analysis.
Study concept and design: Grivas, Lardas, Espinós, Lam, Rouviere, Mottet, ceuticals, Janssen Cilag, MaxIVAX SA, Orion, Roche, Sanofi Aventis Group,
van den Bergh. Nectar, and ProteoMediX; has received speaker honoraria from Janssen
Acquisition of data: Grivas, Lardas, Espinós, Lam, Rouviere, Mottet, van and Novartis; and participates in multiple trials sponsored by different
den Bergh. companies. Professor Dr. Shane O’Hanlon received travel grants from
Analysis and interpretation of data: Grivas, Lardas, Espinós, Lam, Rouviere, SIOG and ESMO, and research support from Slaintecare. Professor Dr. Jer-
Mottet, van den Bergh. emy Grummet has received a speaker honorarium from Mundipharma, a
Drafting of the manuscript: Grivas, Lardas, Espinós, Lam, Rouviere, Mottet, travel grant from Astellas, and a research grant from Cancer Australia;
van den Bergh. and is the owner of MRI PRO Pty Ltd., an online training platform. Profes-
Critical revision of the manuscript for important intellectual content: Mot- sor Dr. Ann M. Henry is a company consultant for Nucletron-Elektra; par-
tet, Cornford, van der Poel, van den Bergh, Briers, De Santis, Gillessen, ticipates in trials by Cancer Research UK and the National Institute of
Grummet, Henry, Lam, Mason, O’Hanlon, Ploussard, Tilki, Wiegel, Van Health Research (UK); has received travel grants from the Medical
den Broeck, Schoots, Lardas, Liew, Gandaglia, Farolfi, Fossati, Cumber- Research Council, the National Institute of Health Research (UK), and Can-
batch, Espinós, Moris, Willemse, Grivas. cer Research UK; and has received research grants from Cancer Research
Statistical analysis: Grivas, Lardas, Espinós. UK and the Sir John Fisher Foundation. Dr. Thomas B. Lam is a company
Obtaining funding: None. consultant for and has received company speaker honoraria and travel
Administrative, technical, or material support: None. grants from Pfizer, GSK, Astellas, IPSEN, and Consilient Health. Professor
Supervision: Mottet, van den Bergh. Dr. Guillaume Ploussard is a company consultant for Janssen, Takeda, Fer-
Other: None. ring, Ipsen, Astellas, and Koelis; received company speaker honorarium
from Janssen, Takeda, Ferring, Ipsen, Astellas, and Bayer; and received
research support from Ferring. Professor Dr. Henk G. van der Poel is a
Financial disclosures: Nikolaos Grivas certifies that all conflicts of inter- company consultant for Intuitive Surgical; has participated in trials for
est, including specific financial interests and relationships and affiliations Astellas and Steba Biotech; and has received grant and research support
relevant to the subject matter or materials discussed in the manuscript from Astellas. Professor Dr. Derya Tilki has received speaker honoraria
(eg, employment/affiliation, grants or funding, consultancies, honoraria, from Astellas and a travel grant from Janssen. Professor Dr. Thomas Wie-
stock ownership or options, expert testimony, royalties, or patents filed, gel is an advisory board member of Ipsen; receives company speaker
received, or pending), are the following: Professor Dr. Malcolm D. Mason honoraria from Ipsen and Hexal; is a member of the Janssen Steering
is a company consultant for Ellipses Pharma and Oncotherics. Professor Committee; and has participated in the ATLAS/AUO trial. Dr. Thomas
Dr. Theodorus van der Kwast received research support from Google Van den Broeck, Dr. Ivo G. Schoots, Dr. Michael Lardas, Mr. Matthew Liew,
Inc. Professor Dr. Nicolas Mottet is a company consultant for Janssen, Dr. Giorgio Gandaglia, Dr. Nicola Fossati, Mr. Marcus Cumberbatch, Dr.
GE, BMS, Sanofi, and Astellas; has received speaker honoraria from Astel- Roderick C.N. van den Bergh, Dr. Daniela Oprea-Lager, Dr. Lisa Moris,
las, Pierre Fabre, Steba, Janssen, and Ferring; and has received fellowships Dr. Andrea Farolfi, Dr. Peter-Paul M. Willemse, and Dr. Nikolaos Grivas
and travel grants from Astellas, Ipsen, Sanofi, Janssen, and Roche. Profes- have nothing to disclose.
sor Dr. Olivier Rouviere received speaker honorarium from EDAP-TMS,
travels grants and research support from Philips, and participated in clin-
Funding/Support and role of the sponsor: None.
ical trials by EDAP-TMS and Vermon. Dr. Erik Briers has received grants
and research support from Ipsen, the European Association of Urology,
and Bayer; is an ex officio board member for Europa UOMO; is an ethics Peer Review Summary
committee and advisory group member for REQUITE; is a patient advisory
board member for PAGMI; and is a member of SCA and EMA PCWP. Pro-
Peer Review Summary and Supplementary data to this arti-
fessor Dr. Philip Cornford is a company consultant for Astellas, Ipsen, and
cle can be found online at https://doi.org/10.1016/j.eururo.
Ferring; has received company speaker honoraria from Astellas, Janssen,
Ipsen, and Pfizer; has participated in trials run by Ferring; and has
2022.07.025.
received fellowships and travel grants from Astellas and Janssen. Profes-
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Review – Education – Platinum Priority Paper – Editor’s Choice

Editorial by Rodolfo Montironi, Alessia Cimadamore on page 483–486 of this issue
The 2022 World Health Organization Classification of Tumours of the

Urinary System and Male Genital Organs—Part A: Renal, Penile, and
Testicular Tumours
Holger Moch a,*,1, Mahul B. Amin b,c, Daniel M. Berney d,e, Eva M. Compérat f, Anthony J. Gill g,h,1,
Arndt Hartmann i, Santosh Menon j, Maria R. Raspollini k, Mark A. Rubin l, John R. Srigley m,1,
Puay Hoon Tan n,1, Satish K. Tickoo o, Toyonori Tsuzuki p,1, Samra Turajlic q, Ian Cree r,2,
George J. Netto s
a
Department of Pathology and Molecular Pathology, University Hospital Zuerich and University of Zuerich, Zuerich, Switzerland; b Department of Pathology
and Laboratory Medicine, University of Tennessee Health Science Center, Memphis, TN, USA; c Department of Urology, USC Keck School of Medicine, Los
Angeles, CA, USA; d Barts Cancer Institute, Queen Mary University of London, London, UK; e Department of Cellular Pathology, Barts Health NHS Trust, London,
UK; f Department of Pathology, Medical University of Vienna, General Hospital of Vienna, Vienna, Austria; g Sydney Medical School, University of Sydney,
Sydney, Australia; h NSW Health Pathology, Department of Anatomical Pathology and Pathology Group Kolling Institute of Medical Research Royal North Shore
Hospital St Leonards, Sydney, Australia; i Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-University Erlangen-Nürnberg, Erlangen,
Germany; j Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India; k Histopathology and Molecular Diagnostics, University Hospital Careggi,
Florence, Italy; l Department for BioMedical Research (DBMR), Bern Center for Precision Medicine (BCPM), University of Bern and Inselspital, Bern, Switzerland;
m
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; n Division of Pathology, Singapore General Hospital,
Singapore; o Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; p Department of Surgical Pathology, Aichi Medical
University Hospital, Nagakut, Japan; q The Francis Crick Institute and The Royal Marsden NHS Foundation Trust, London, UK; r International Agency for Research
on Cancer (IARC), World Health Organization, Lyon, France; s Heersink School of Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA
Article history: The fifth edition of the World Health Organization (WHO) classification of urogenital
Accepted June 21, 2022 tumours (WHO ‘‘Blue Book’’), published in 2022, contains significant revisions. This
review summarises the most relevant changes for renal, penile, and testicular tumours.
Associate Editor: In keeping with other volumes in the fifth edition series, the WHO classification of uro-
James Catto genital tumours follows a hierarchical classification and lists tumours by site, category,
family, and type. The section ‘‘essential and desirable diagnostic criteria’’ included in
Keywords: the WHO fifth edition represents morphologic diagnostic criteria, combined with
World Health Organization immunohistochemistry and relevant molecular tests. The global introduction of massive
Classification parallel sequencing will result in a diagnostic shift from morphology to molecular anal-
Kidney yses. Therefore, a molecular-driven renal tumour classification has been introduced, tak-
Testis ing recent discoveries in renal tumour genomics into account. Such novel molecularly
Penis defined epithelial renal tumours include SMARCB1-deficient medullary renal cell carci-
Carcinoma noma (RCC), TFEB-altered RCC, Alk-rearranged RCC, and ELOC-mutated RCC.
1
Standing WHO fifth edition members who also served as expert members for the urinary and male
Please visit www.eu-acme.org/europeanurology genital tumour volume.
* Corresponding author. Department of Pathology and Molecular Pathology, University Hospital
to answer questions on-line. The EU-ACME cred-
Zurich, Schmelzbergstrasse 12, CH-8091 Zurich, Switzerland. Tel. +41 44 255 25 00.
its will then be attributed automatically.
E-mail address: [email protected] (H. Moch).
0302-2838/Ó 2022 The Author(s). Published by Elsevier B.V. on behalf of European Association of Urology. This is an open access article
under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Eosinophilic solid and cystic RCC is a novel morphologically defined RCC entity. The
diverse morphologic patterns of penile squamous cell carcinomas are grouped as human
papillomavirus (HPV) associated and HPV independent, and there is an attempt to sim-
plify the morphologic classification. A new chapter with tumours of the scrotum has been
introduced. The main nomenclature of testicular tumours is retained, including the use of
the term ‘‘germ cell neoplasia in situ’’ (GCNIS) for the preneoplastic lesion of most germ
cell tumours and division from those not derived from GCNIS. Nomenclature changes
include replacement of the term ‘‘primitive neuroectodermal tumour’’ by ‘‘embryonic
neuroectodermal tumour’’ to separate these tumours clearly from Ewing sarcoma. The
term ‘‘carcinoid’’ has been changed to ‘‘neuroendocrine tumour’’, with most examples
in the testis now classified as ‘‘prepubertal type testicular neuroendocrine tumour’’.
Ó 2022 The Author(s). Published by Elsevier B.V. on behalf of European Association of
Urology. This is an open access article under the CC BY license (http://creativecommons.
org/licenses/by/4.0/).
1. Concept of molecularly defined renal tumour entities renal tumours include SMARCB1-deficient medullary RCC
[15], TFEB-altered RCC [16,17], Alk-rearranged RCC [18],
Traditionally, renal tumour subtypes have been named on and elongin C (ELOC)-mutated RCC (see below) [19]. It can
the basis of predominant cytoplasmic features (eg, clear cell be argued that ccRCC and metanephric adenomas are also
and chromophobe renal cell carcinoma [RCC]), architectural molecular-defined entities, because VHL inactivation is pre-
features (eg, papillary RCC), anatomical location of tumours sent in most ccRCC cases [13] and BRAF p.V600E mutations
(eg, collecting duct and renal medullary carcinomas), and in almost all metanephric tumours [20]. Importantly, VHL
correlation with a specific renal disease background (eg, wild-type ccRCC probably presents a different clinical phe-
acquired cystic disease-associated RCC), but also by charac- notype [21,22]. Admittedly, the current WHO classification
teristic molecular alterations (eg, MIT family translocation represents a transition from a traditional morphology-
carcinomas and succinate dehydrogenase-deficient renal based classification system to an integrated approach, com-
carcinomas) or familial predisposition syndromes (eg, prising many newly recognised ‘‘molecular entities’’, but it
hereditary leiomyomatosis and RCC [HLRCC] syndrome–as- should be taken into account that renal tumour diagnosis
sociated RCC) [1]. For decades, a relatively strong genotype- according to the WHO classification should be standardised
phenotype correlation was suggested by conventional cyto- as well as usable for local, national, and international com-
genetic and comparative genomic hybridisation analyses for munication. Therefore, a morphologic descriptive diagnosis
renal tumour subtypes, with 3p loss and consecutive von based on LM and immunohistochemistry (IHC), and a com-
Hippel-Lindau (VHL) inactivation in clear cell RCC (ccRCC) ment of the possible underlying molecular alterations is
[2,3], gains of chromosome 7 and 17 in papillary RCC needed for a precise diagnosis. In line with this, the subsec-
[4,5], and losses of multiple chromosomes in chromophobe tion ‘‘essential and desirable diagnostic criteria’’ is included
RCC [6,7]. Although the third edition of the World Health in the WHO fifth edition for each tumour type. This includes
Organization (WHO) classification of urogenital tumours clinical, radiologic, molecular, and histologic criteria, and
named some renal tumour entities on the basis of molecular IHC, as well as molecular biomarkers. In the future, this
alterations (eg, MIT family translocation carcinomas) may be complemented with novel technologies, for exam-
already in 2004 [8], a comprehensive molecular classifica- ple, proteomics or parameters of the tumour microenviron-
tion of renal tumours is premature at the moment [9]. This ment [9]. The integration of classic histologic diagnoses
is in contrast to haematopathology [10], or central nervous with advanced molecular techniques such as methylation
system (CNS) tumour classification [11]. Looking back, the profiling, RNA sequencing, whole-genome sequencing, or
current WHO classification of haematolymphoid neoplasms whole-exome sequencing, is a prerequisite for more person-
evolved from a pure morphologic classification to a classifi- alised therapeutic strategies. Therefore, it is important to
cation that integrates clinical, morphologic, immunopheno- include a pathologist/molecular expert on each trial design
typical, and molecular features in the definition of almost team of future clinical trials [15]. Many laboratories do not
all entities. Parallel to this, the current WHO classification have the capability or access to advanced molecular tools.
for CNS tumours also combined histologic patterns with
molecular diagnostics to form an integrated diagnosis [12].
2. New names and renal tumour entities
In the next years, massive parallel sequencing will be
used more and more to identify molecular alterations in
2.1. Eosinophilic solid and cystic RCC
renal tumours with unusual morphology [13]. Therefore,
the new 2022 WHO classification introduced a molecular- Eosinophilic solid and cystic (ESC) RCC (Fig. 1A) has been
driven renal tumour classification in addition to accepted as a separate entity, with a set of ‘‘classical’’ histo-
morphology-based renal tumours (Table 1) [14]. logic features, a characteristic cytokeration (CK) 20 IHC pro-
Molecular-defined renal tumours may show very heteroge- file, and alterations in the TSC genes [23]. Clinically, ESC RCC
neous morphologic aspects and cannot be diagnosed by was first reported to show an indolent behaviour [24–26].
morphology alone. Such molecularly defined epithelial ESC RCC adds to the spectrum of renal neoplasms associated
Table 1 – ICD-O coding of tumours of the kidney
ICD-O-3.2 ICD-O label (subtypes are indicated in grey text, with the label indented)
Renal cell tumours
Clear cell renal tumours
8310/3 Clear cell renal cell carcinoma
8316/1 Multilocular cystic renal neoplasm of low malignant potential
Papillary renal tumours
8260/0 Papillary adenoma
a
8260/3 Papillary renal cell carcinoma
Oncocytic and chromophobe renal tumours
8290/0 Oncocytoma
8317/3 Chromophobe cell renal carcinoma
Other oncocytic tumours of the kidney
Collecting duct tumours
8319/3 Collecting duct carcinoma
Other renal tumours
8323/1 Clear cell papillary renal cell tumoura
8480/3 Mucinous tubular and spindle cell carcinoma
8316/3 Tubulocystic renal cell carcinoma
8316/3 Acquired cystic disease–associated renal cell carcinoma
8311/3 Eosinophilic solid and cystic renal cell carcinoma
8312/3 Renal cell carcinoma, NOS
Molecularly defined renal carcinomas
8311/3 TFE3-rearranged renal cell carcinomas
8311/3 TFEB-altered renal cell carcinomas
8311/3 ELOC (formerly TCEB1)-mutated renal cell carcinoma
8311/3 Fumarate hydratase–deficient renal cell carcinoma
8311/3 Hereditary leiomyomatosis and renal cell carcinoma
syndrome–associated renal cell carcinoma
8311/3 Succinate dehydrogenase–deficient renal cell carcinoma
8311/3 ALK-rearranged renal cell carcinomas
8510/3 Medullary carcinoma, NOS
8510/3 SMARCB1-deficient medullary-like renal cell carcinoma
8510/3 SMARCB1-deficient undifferentiated renal cell carcinoma, NOS
8510/3 SMARCB1-deficient dedifferentiated renal cell carcinomas
of other specific subtypes
Metanephric tumours
8325/0 Metanephric adenoma
9013/0 Metanephric adenofibroma
8935/1 Metanephric stromal tumour
Mixed epithelial and stromal renal tumours
8959/0 Mixed epithelial and stromal tumour
8959/0 Adult cystic nephroma
8959/0 Paediatric cystic nephroma
Renal mesenchymal tumours
Adult renal mesenchymal tumours
8860/0 Angiomyolipoma
8860/0 Oncocytic angiomyolipoma
8860/0 Angiomyolipoma with epithelial cysts
8860/1 Angiomyolipoma, epithelioid
9161/1 Haemangioblastoma
8361/0 Juxtaglomerular tumour
8361/0 Functioning juxtaglomerular cell tumour
8361/0 Nonfunctioning juxtaglomerular cell tumour
8966/0 Renomedullary interstitial cell tumour
Paediatric renal mesenchymal tumours
8967/0 Ossifying renal tumour of infancy
8960/1 Mesoblastic nephroma
8960/1 Classic congenital mesoblastic nephroma
8960/1 Cellular congenital mesoblastic nephroma
8960/1 Mixed congenital mesoblastic nephroma
8963/3 Malignant rhabdoid tumour of the kidney
8964/3 Clear cell sarcoma of kidney
Embryonal neoplasms of the kidney
Nephroblastic tumours
Nephrogenic rests
Perilobar nephrogenic rests
Intralobar nephrogenic rests
Nephroblastomatosis
8959/1 Cystic partially differentiated nephroblastoma
8960/3 Nephroblastoma
Table 1 (continued)
Miscellaneous renal tumours
Germ cell tumours of the kidney
9084/0 Prepubertal-type teratoma
9084/3 Teratoma with carcinoid (neuroendocrine tumour)
9071/3 Yolk sac tumour, NOS
9085/3 Mixed teratoma–yolk sac tumour
NOS = not otherwise specified; IARC = International Agency for Research on Cancer; WHO = World Health Organization.
Please note that the WHO classification of tumour types is more readily reflected in the table of contents.
These morphology codes are from the International Classification of Diseases for Oncology, third edition, second revision (ICD-O-3.2): International Association
of Cancer Registries (IACR) [Internet]. Lyon (France): International Agency for Research on Cancer; 2021. International Classification of Diseases for Oncology
(ICD-O)—ICD-O-3.2; updated January 25, 2021. Available from: http://www.iacr.com.fr/index.php?option=com_content&view=category&layout=blog&id=100&
Itemid=577. Behaviour is coded /0 for benign tumours; /1 for unspecified, borderline, or uncertain behaviour; /2 for carcinoma in situ and grade III intraep-
ithelial neoplasia; /3 for malignant tumours, primary site; and /6 for malignant tumours, metastatic site. Behaviour code /6 is not generally used by cancer
registries.
This classification is modified from the previous WHO classification, taking into account changes in our understanding of these lesions.
*Codes marked with an asterisk were approved by the IARC/WHO Committee for ICD-O at its meeting in February 2022.
a
These labels have undergone a change in terminology of a previous code.
Fig. 1 – Novel renal tumour entities (H&E staining): (A) eosinophilic solid and cystic renal cell carcinoma. This tumour is diagnosed based on H&E morphology
and immunohistochemistry. Tumour cells are frequently cytokeratin 20 positive. (B) ELOC (formerly TCEB1)-mutated renal cell carcinoma as an example of a
molecularly defined renal tumour type because identification of ELOC mutation is essential. Tumours frequently have a prominent leiomyomatous stroma
within tumour cells with clear cytoplasm. H&E = haematoxylin and eosin.
with alterations in the TSC genes and activation of the mTOR uolisation, but a very heterogeneous and broad morphologic
pathway, which may have consequences for the patient in spectrum, sometimes with mucinous deposits. It is a
terms of selection of specific targeted treatments (such as diagnosis of exclusion, and ALK IHC and/or fluorescence
mTOR inhibitors) [23]. in situ hybridisation should be performed before rendering
a case with an unusual mix of morphologies as ‘‘unclassi-
2.2. ELOC (formerly TCEB1)-mutated RCC fied’’. Its clinical behaviour is very heterogeneous, but some
patients had dramatic responses to targeted ALK inhibitors
ELOC-mutated RCC (Fig. 1B) has a broad morphologic spec- [30].
trum, but the main differential diagnosis is ccRCC or clear
cell papillary RCC. Some of these cases have been reported 2.4. SMARCB1-deficient medullary RCC
in the past as tumours with angioleiomyomatous stroma
[19,27]. ELOC-mutated RCC is a prototype of a molecularly This RCC type occurs within the renal medullary region
based RCC subtype because the diagnosis cannot be made including collecting duct carcinoma and medullary RCC.
without molecular testing. Without molecular corrobora- Whereas collecting duct carcinomas have retained
tion, one would rather diagnose such neoplasms as ccRCC SMARCB1 (also known as INI1), medullary RCC demon-
with prominent fibromuscular septation and CK7 positivity, strates loss of SMARCB1 [31–33]. Therefore, these neo-
and give the differential diagnosis of an ELOC-mutated RCC. plasms are named as SMARCB1-deficient medullary RCC.
According to limited experience, the majority of these neo- SMARCB1-deficient medullary RCC is highly aggressive and
plasms have indolent behaviour after tumour resection [27]. frequently occurs in young patients with sickle cell trait.
Some unclassified RCC cases with medullary phenotype
can show complete loss of SMARCB1, but no association with
2.3. ALK-rearranged RCC
haemoglobinopathies, suggesting that sickle cell is not a pre-
ALK-rearranged RCC is a very rare RCC subtype [18,28,29]. requisite for this genetic lesion [34]. These tumours can be
This RCC has abundant eosinophilic cytoplasm, striking vac- regarded as subtypes of SMARCB1-deficient medullary
RCC. Establishing the molecular profile is likely to have ther- entities’’ with papillary features, actually considered as vari-
apeutic implications as proteasome targeting therapies ants of papillary RCC or emerging/provisional entities. These
emerge [35]. It is important to realise that other renal cancer include papillary renal neoplasm with reversed polarity
subtypes may have secondary SMARCB1 loss, for example, (PRNRP) [47], biphasic hyalinising psammomatous RCC
ccRCC with sarcomatoid transformation, translocation RCC, (BHP RCC) [48], biphasic squamoid/alveolar RCC [49], or
or fumarate hydratase (FH)-deficient RCC [36]. thyroid-like follicular RCC (TLF RCC) [50–52]. Importantly,
some of them have a specific molecular driver alteration,
2.5. TFEB-altered RCC for example, KRAS mutations in PRNRP [53], NF2 mutations
in BHP RCC [54], and EWSR1-PATZ1 fusions in TLF RCC [55].
In the fourth edition of the WHO classification of urogenital
It can be foreseen that these tumours may become indepen-
tumours, TFEB translocated RCC has been included in the
dent molecularly defined RCC entities in a future WHO
family of MiTF translocation carcinomas [37]. In addition
classification.
to TFEB translocations, TFEB amplification has also been
reported in the last years, resulting in the designation of a
novel TFEB-altered RCC category [17]. TFEB-altered RCC 4. Emerging oncocytoma- or chromophobe-like renal
cases are less common than TFE3-rearranged RCC cases. neoplasms
Whereas TFEB-translocated RCC is more indolent than
TFE3-translocated RCC, TFEB-amplified RCC represents The WHO editorial board discussed several entities that
highly aggressive tumours [17]. have remarkably expanded the spectrum of oncocytoma-
or chromophobe-like renal neoplasms. While some of these
2.6. FH-deficient RCC (formerly HLRCC syndrome-associated entities with eosinophilic or oncocytic cytoplasm are now
RCC)
well defined, such as SDH-deficient RCC [56], ESC RCC
HLRCC syndrome-associated RCC with the diagnostic FH [23], and FH-deficient RCC [40,57], others are considered
deficiency was a separate tumour entity in the 2016 WHO emerging entities for which detailed data are being gath-
classification [38]. Post-2016 WHO classification studies ered, such as eosinophilic vacuolated tumour (EVT) [58]
have identified FH deficiency in many cases described as and low-grade oncocytic tumour (LOT) [59–63]. TSC muta-
‘‘unclassified high-grade renal carcinomas’’, ‘‘tubulocystic tions are frequent in ESC RCC [23,64]. Interestingly,
carcinomas with dedifferentiated foci’’, ‘‘type 2 papillary TSC1/2 mutations or activating mTOR mutations have also
carcinomas’’, and ‘‘collecting duct carcinomas’’ [39–41]. been identified in EVT and LOT. Importantly, unclassified
Therefore, FH-deficient RCC is the preferred terminology RCC with oncocytic- or chromophobe-like features can also
for RCC with compatible morphology, negative FH IHC show somatic inactivating mutations of TSC2 or activating
(which is highly specific but incompletely sensitive), posi- mutations of MTOR as the primary molecular alterations
tive 2SC IHC (which is highly sensitive but incompletely [65]. Therefore, it was decided to create a category of ‘‘other
specific), and/or pathogenic FH mutation in the tumour, oncocytic/chromophobe RCC’’ for these tumours with a low
when the clinical and family history of skin and uterine metastatic potential, because the commonly found TSC
leiomyomas is uncertain and the genetic status is unknown mutations can be found in many other tumour types. The
[42]. In familial cases, the term HLRCC syndrome-associated main advantage for creating this category is the potential
RCC is still acceptable. FH-deficient RCC has been targeted of further clinical and molecular studies in these rare
successfully in early-phase studies using erlotinib and beva- tumours. Oncocytic tumours with low malignant potential
cizumab [43]. and EVTs should not be placed into the ‘‘RCC, not otherwise
specified (NOS)’’ group, because the latter are mainly highly
aggressive carcinomas. In contrast, a tumour category of
3. Impact of the novel 2022 WHO classification on
TSC1/2 mutated RCC seems not to be appropriate because
papillary RCC classification
such a molecular-based subtype encompasses a category
of tumours with an extremely broad histologic spectrum.
Delahunt and Eble [44] proposed to distinguish papillary
type 1 and type 2 RCC two decades ago. Morphology of these
variants has been described in the 2004 WHO classification, 5. New classification of penile and scrotal tumours
and molecular differences were reported [45]. Recent molec-
ular studies suggest that type 2 papillary RCC may not consti- The vast majority of malignant tumours of the penis are
tute a single well-defined entity, but rather individual squamous cell carcinomas (SCCs) originating in the inner
subgroups with a different molecular background [46]. The mucosal lining of the glans, coronal sulcus, or foreskin. In
spectrum of papillary RCC is evolving, and some entities are the 2022 WHO Blue Book, scrotal tumour classification finds
now regarded as independent tumours with specific clinical a separate mention for the first time (Table 2). Whereas pre-
and molecular background, for example, sporadic FH- vious classification schemes of penile tumours were exclu-
deficient RCC, tubulocystic RCC, ESC RCC, clear cell papillary sively morphology based, the 2016 WHO classification
RCC, SMARCB1-deficient RCC, and MiTF family RCC. This will introduced a classification based on the relation to human
lead to a new view on the ‘‘remaining’’ papillary RCC and may papillomavirus (HPV) infection [38]. The 2022 WHO classi-
facilitate future research on this ‘‘cleaned up’’ tumour sub- fication followed this paradigm to subclassify tumours into
type. Although papillary RCC type 1 can be regarded as the HPV-associated and HPV-independent types (Table 2) [14].
classical papillary RCC morphology, there are ‘‘emerging This is consistent with the approach used for tumours of
Table 2 – ICD-O coding of tumours of the penis and scrotum the female genital system [66]. Block-type p16 IHC is the
ICD-O- ICD-O label (subtypes are indicated in grey text, with the most practical and reliable method to separate HPV-
3.2 label indented) associated from HPV-independent penile SCC. It is recom-
Benign and precursor squamous lesions mended to report SCC as HPV associated or HPV indepen-
Condyloma acuminatum dent in addition to the histologic diagnosis. If this is not
Squamous cell carcinoma precursors, HPV associated
8077/2 High-grade squamous intraepithelial lesion
possible, the designation SCC, NOS is acceptable.
Squamous cell carcinoma precursors, HPV independent The editorial board tried to simplify the histologic classi-
8071/2 Differentiated penile intraepithelial neoplasia fication within HPV-associated and HPV-independent SCC
Invasive epithelial tumours of the penis and scrotum
Invasive squamous epithelial tumours
categories. Previous HPV-independent SCC subtypes were
8085/3 Squamous cell carcinoma, HPV associated grouped into an overarching SCC histology, for example,
8083/3 Basaloid squamous cell carcinoma SCC of the usual type now includes pseudohyperplastic car-
8054/3 Warty carcinoma
8084/3 Clear cell squamous cell carcinoma
cinomas and acantholytic/pseudoglandular carcinomas. Ver-
8082/3 Lymphoepithelial carcinoma rucous carcinoma is a separate nonmetastasising low-grade
8086/3 Squamous cell carcinoma, HPV independent subtype including carcinoma cuniculatum as a pattern [67].
8086/3 Squamous cell carcinoma, usual type
8051/3 Verrucous carcinoma (including carcinoma cuniculatum)
Other HPV-independent subtypes of SCC are papillary [68]
8052/3 Papillary squamous cell carcinoma and sarcomatoid SCC, the latter with the worst prognosis
8074/3 Sarcomatoid squamous cell carcinoma among all penile carcinomas. Combinations of subtypes
8070/3 Squamous cell carcinoma, NOS
Other epithelial tumours
and patterns should be designated as mixed SCC with speci-
8560/3 Adenosquamous carcinoma fication of the subtypes. HPV-associated SCCs are basaloid
8430/3 Mucoepidermoid carcinoma [69], warty [70], clear cell [71], and lymphoepithelioma-
8542/3 Paget disease, extramammary
Other scrotal tumours
like SCCs [72].
8090/3 Basal cell carcinoma HPV-associated penile intraepithelial neoplasia (PeIN) is
HPV = human papillomavirus; IARC = International Agency for Research an HPV-associated precursor lesion of invasive SCC,
on Cancer; NOS = not otherwise specified; WHO = World Health whereas differentiated PeIN is an HPV-independent precur-
Organization.
Please note that the WHO classification of tumour types is more readily
sor lesion of SCC. The most common HPV-associated PeIN
reflected in the table of contents subtypes are the basaloid (undifferentiated, a term that
These morphology codes are from the International Classification of Dis- should be avoided; Fig. 2A) and warty (Fig. 2B) subtypes.
eases for Oncology, third edition, second revision (ICD-O-3.2): Interna-
tional Association of Cancer Registries (IACR) [Internet]. Lyon (France):
Differentiated PeIN (HPV independent) is characterised by
International Agency for Research on Cancer; 2021. International Classi- a hyperplastic squamous epithelium with hyper- and parak-
fication of Diseases for Oncology (ICD-O)—ICD-O-3.2; updated January 25, eratosis, keratin pearl formation, prominent intercellular
2021. Available from: http://www.iacr.com.fr/index.php?op-
tion=com_content&view=category&layout=blog&id=100&Itemid=577.
bridges, and atypical basal layer cells. Differentiated PeIN
Behaviour is coded /0 for benign tumours; /1 for unspecified, borderline, may be difficult to distinguish from reactive conditions such
or uncertain behaviour; /2 for carcinoma in situ and grade III intraep- as squamous hyperplasia, pseudoepitheliomatous hyper-
ithelial neoplasia; /3 for malignant tumours, primary site; and /6 for
malignant tumours, metastatic site. Behaviour code /6 is not generally
plasia, lichen simplex chronicus, and lichen sclerosis with
used by cancer registries. hyperplastic epithelium. Although some papers have advo-
This classification is modified from the previous WHO classification, cated grading PeIN into grades 1–3, as per WHO 2022, fifth
taking into account changes in our understanding of these lesions.
*Codes marked with an asterisk were approved by the IARC/WHO Com-
edition, all PeIN lesions are considered high grade irrespec-
mittee for ICD-O at its meeting in February 2022. tive of the degree of cytoarchitectural features within a
y
Labels marked with a dagger have undergone a change in terminology of lesion. The WHO 2022 editorial board discourages terms
a previous code.
such as low-grade squamous intraepithelial lesion, low-
and high-grade dysplasia, squamous carcinoma in situ,
Fig. 2 – HPV-associated penile intraepithelial neoplasia (H&E staining): (A) basaloid subtype and (B) warty subtype. H&E = haematoxylin and eosin.
and simplex type of PeIN for differentiated PeIN. Condyloma Although the term ‘‘seminoma’’ remains unchanged, the
accuminatum is regarded as a benign lesion caused by HPV. issue of nomenclature, in the testis and in any other organ,
was discussed by the editorial board [74]. The terms dysger-
minoma, seminoma, and germinoma are used for the same
6. New classification of testicular tumours tumour with a similar appearance throughout the body. To
this end, seminoma was placed in the ‘‘germinoma’’ family
This 2022 WHO classification has been adapted to the new of tumours in the classification, but greater unification of
format of the fifth edition of the classification (Table 3) [14]. terminology would add to better consistency, especially
The testis tumour classification follows the definitions of for cancer researchers and for nonpathologists who have
‘‘category’’, ‘‘family’’, then ‘‘type’’, and then ‘‘subtype’’ with to treat this disease.
a possibility of different patterns that do not fit neatly, espe- Nomenclature changes include replacement of the term
cially in the diversity of germ cell tumours. The term ‘‘vari- ‘‘Primitive neuroectodermal tumour’’ by ‘‘embryonic neu-
ants’’ is reserved for genomic variants and is no longer used roectodermal tumour’’ based on the redundancy of the for-
as a histologic descriptor. mer term and to separate these tumours clearly from
There was a radical revision in the 2016 WHO classifica- Ewing sarcoma [75]. A teratoma with somatic-type malig-
tion, especially to germ cell tumours [38]. The subdivision nancy is a teratoma that develops a distinct secondary com-
of germ cell tumours into the vast majority derived from ponent that resembles a somatic-type malignant neoplasm
germ cell neoplasia in situ (GCNIS) and those unrelated (Fig. 3A). Criteria for the diagnosis of ‘‘teratoma with somatic
has been retained. Added to the noninvasive lesions derived transformation’’ have been modified to move away from
from GCNIS is gonadoblastoma [73]. Although often defined variable field size assessments. It is now recommended to
as a mixed sex-cord stromal tumour, it is composed of neo- make all measurements in millimetres [76]. While previ-
plastic germ cells set in a matrix of immature sex cord cells. ously the diagnosis was established by using the definition
Table 3 – ICD-O coding of tumours of the testis
Germ cell tumours derived from germ cell neoplasia in situ
Noninvasive germ cell neoplasia
9064/2 Germ cell neoplasia in situ
Specific forms of intratubular germ cell neoplasia
9061/2 Intratubular seminoma
9070/2 Intratubular embryonal carcinoma
9061/2 Intratubular trophoblast
9071/2 Intratubular yolk sac tumour
9080/2 Intratubular teratoma
9073/1 Gonadoblastoma
Germinoma family of tumours
9061/3 Seminoma
9061/3 Seminoma with syncytiotrophoblastic cells
Nonseminomatous germ cell tumours
9070/3 Embryonal carcinoma
9071/3 Yolk sac tumour, postpubertal type
9100/3 Choriocarcinoma
9104/3a Placental site trophoblastic tumour of the testis
9105/3 Epithelioid trophoblastic tumour
Cystic trophoblastic tumour
9080/3 Teratoma, postpubertal type
9084/3 Teratoma with somatic-type malignancy
Mixed germ cell tumours of the testis
9085/3 Mixed germ cell tumours
9085/3 Polyembryoma
9085/3 Diffuse embryoma
Germ cell tumours of unknown type
9080/1 Regressed germ cell tumours
Germ cell tumours unrelated to germ cell neoplasia in situ
9063/3 Spermatocytic tumour
9063/3 Spermatocytic tumour with sarcomatous differentiation
9084/0 Teratoma, prepubertal type
9084/0 Dermoid cyst
9084/0 Epidermoid cyst
9071/3 Yolk sac tumour, prepubertal type
8240/3 Well-differentiated neuroendocrine tumour (monodermal teratoma)
9085/3 Mixed teratoma and yolk sac tumour, prepubertal type
b
rs of the testis
Leydig cell tumour
8650/1 Leydig cell tumour
8650/3 Malignant Leydig cell tumour
Sertoli cell tumours
8640/1 Sertoli cell tumour
Table 3 (continued)
8640/3 Malignant Sertoli cell tumour
8642/1 Large cell calcifying Sertoli cell tumour
Granulosa cell tumours
8620/1 Adult granulosa cell tumour
8622/0 Juvenile granulosa cell tumour
Fibroma thecoma family of tumours
8600/0 Thecoma
8810/0 Fibroma
Mixed and other sex cord stromal tumours
8592/1 Mixed sex cord-stromal tumour
8590/0 Signet ring stromal tumour
8590/0 Myoid gonadal stromal tumourb
8590/1 Sex cord stromal tumour, NOS
IARC = International Agency for Research on Cancer; NOS = not otherwise specified; WHO = World Health Organization.
Please note that the WHO classification of tumour types is more readily reflected in the table of contents.
These morphology codes are from the International Classification of Diseases for Oncology, third edition, second revision (ICD-O-3.2): International Association
of Cancer Registries (IACR) [Internet]. Lyon (France): International Agency for Research on Cancer; 2021. International Classification of Diseases for Oncology
(ICD-O)—ICD-O-3.2; updated January 25, 2021. Available from: http://www.iacr.com.fr/index.php?option=com_content&view=category&layout=blog&id=100&
Itemid=577. Behaviour is coded /0 for benign tumours; /1 for unspecified, borderline, or uncertain behaviour; /2 for carcinoma in situ and grade III intraep-
ithelial neoplasia; /3 for malignant tumours, primary site; and /6 for malignant tumours, metastatic site. Behaviour code /6 is not generally used by cancer
registries.
a
Codes were approved by the IARC/WHO Committee for ICD-O at its meeting in February 2022.
b
Labels have undergone a change in terminology of a previous code.
Fig. 3 – Germ cell tumours of the testis (H&E staining): (A) postpubertal teratoma with nephroblastoma-like somatic transformation (note adjacent residual
teratoma) and (B) prepubertal-type teratoma with a low-grade neuroendocrine tumour (note absence of germ cell neoplasia in situ). H&E = haematoxylin and
eosin.
‘‘a nodule of malignant cells equivalent to area seen under new entities ‘‘signet ring stromal tumour’’ [78] and ‘‘myoid
4 objective or expansile nodule overgrowing other GCT gonadal stromal tumour’’ are defined [79].
elements’’, the size criterion has been changed to a 5-mm Two changes are worth highlighting for adnexal tumours
diameter in the fifth edition. The term teratoma with a sec- (Table 4). A well-differentiated papillary mesothelial
ondary malignant component or teratoma with malignant tumour has now been defined as a tumour type with a
transformation should be avoided because it may lead to a favourable prognosis to emphasise its distinction from true
misconception that teratomas lacking somatic-type malig- diffuse mesothelioma [80]. Sertoliform cystadenoma has
nancy are benign. been removed as an entity from testicular adnexal tumours
The word ‘‘carcinoid’’ has been changed to ‘‘neuroen- and placed with Sertoli cell tumours, because these may
docrine tumour’’, with most examples in the testis now originate from cells at the junction of seminiferous tubules
classified as ‘‘prepubertal type testicular neuroendocrine and rete testis that can differentiate towards sex cord stro-
tumour’’ (Fig. 3B) [77]. For sex cord stromal tumours, the mal cells [81].
use of mitotic counts per high-power field has been chan- In conclusion, in the fifth edition of the WHO Blue Book,
ged to per mm2 for malignancy assessments [76], and the the spectrum of RCC is evolving with recognition of emerg-
Table 4 – ICD-O coding of tumours of the testicular adnexa Critical revision of the manuscript for important intellectual content: Moch,
Amin, Berney, Compérat, Gill, Hartmann, Menon, Raspollini, Rubin, Srig-
ICD-O- ICD-O label (subtypes are indicated in grey text, with the
3.2 label indented) ley, Tan, Tickoo, Tsuzuki, Turajlic, Cree, Netto.
Statistical analysis: None.
Ovarian-type tumours of the collecting ducts and rete testis
8441/0 Serous cystadenoma, NOS Obtaining funding: None.
8442/1 Serous borderline tumour, NOS Administrative, technical, or material support: None.
8441/3 Serous cystadenocarcinoma
Supervision: None.
8470/0 Mucinous cystadenoma
8472/1 Mucinous borderline tumour Other: None.
8470/3 Mucinous cystadenocarcinoma
8380/1 Endometrioid tumour, borderline
Financial disclosures: Holger Moch certifies that all conflicts of interest,
8380/3 Endometrioid adenocarcinoma
8310/3 Clear cell adenocarcinoma including specific financial interests and relationships and affiliations rel-
9000/0 Brenner tumour evant to the subject matter or materials discussed in the manuscript (eg,
Tumours of the collecting ducts and rete testis employment/affiliation, grants or funding, consultancies, honoraria, stock
8140/0 Adenoma
8140/3 Adenocarcinoma
ownership or options, expert testimony, royalties, or patents filed,
Paratesticular mesothelial tumours received, or pending), are the following: None.
9054/0 Adenomatoid tumour
9052/0 Well-differentiated papillary mesothelial tumour
9050/3 Mesothelioma Funding/Support and role of the sponsor: None.
9052/3 Epithelioid mesothelioma
9051/3 Sarcomatoid mesothelioma
9053/3 Biphasic mesothelioma Acknowledgments: The The content of this article represents the personal
Tumours of the epididymis views of the authors and does not represent the views of the authors’
8440/0 Cystadenoma of the epididymis
employers and associated institutions. Where authors are identified as
8450/0 Papillary cystadenoma
8140/3 Adenocarcinoma of the epididymis personnel of the International Agency for Research on Cancer/WHO, the
8070/3 Squamous cell carcinoma authors alone are responsible for the views expressed in this article and
9363/0 Melanotic neuroectodermal tumour
they do not necessarily represent the decisions, policy or views of the
IARC = International Agency for Research on Cancer; NOS = not otherwise International Agency for Research on Cancer/WHO.
specified; WHO = World Health Organization.
Please note that the WHO classification of tumour types is more readily
reflected in the table of contents. References
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Review – Prostate Cancer – Platinum Priority Paper – Editor’s Choice

Editorial by Rodolfo Montironi, Alessia Cimadamore on page 483–486 of this issue
The 2022 World Health Organization Classification of Tumors of the

Urinary System and Male Genital Organs—Part B: Prostate and
Urinary Tract Tumors
George J. Netto a,*, Mahul B. Amin b,c, Daniel M. Berney d,e, Eva M. Compérat f, Anthony J. Gill g,h,i,1,
Arndt Hartmann j, Santosh Menon k, Maria R. Raspollini l, Mark A. Rubin m, John R. Srigley n,1,
Puay Hoon Tan o,1, Satish K. Tickoo p, Toyonori Tsuzuki q,1, Samra Turajlic r, Ian Cree s,2,
Holger Moch t,1
a
Heersink School of Medicine, The University of Alabama at Birmingham, Birmingham, AL, USA; b Department of Pathology and Laboratory Medicine,
University of Tennessee Health Science Center, Memphis, TN, USA; c Department of Urology, USC Keck School of Medicine, Los Angeles, CA, USA; d Barts Cancer
Institute, Queen Mary University of London, London, UK; e Department of Cellular Pathology, Barts Health NHS Trust, London, UK; f Department of Pathology,
Medical University of Vienna, General Hospital of Vienna, Vienna, Austria; g Sydney Medical School, University of Sydney, Sydney, Australia; h NSW Health
Pathology, Department of Anatomical Pathology, Royal North Shore Hospital St Leonards, Sydney, Australia; i Pathology Group, Kolling Institute of Medical
Research, Royal North Shore Hospital St Leonards, Sydney, Australia; j Institute of Pathology, University Hospital Erlangen, Friedrich-Alexander-University
Erlangen-Nürnberg, Erlangen, Germany; k Tata Memorial Centre, Homi Bhabha National Institute, Mumbai, India; l Histopathology and Molecular Diagnostics,
University Hospital Careggi, Florence, Italy; m Department for BioMedical Research (DBMR), Bern Center for Precision Medicine (BCPM), University of Bern and
Inselspital, Bern, Switzerland; n Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada; o Division of Pathology,
Singapore General Hospital, Singapore; p Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; q Department of Surgical
Pathology, AichiMedicalUniversity Hospital, Nagakut, Japan; r The Francis Crick Institute and The Royal Marsden NHS Foundation Trust, London, UK;
s
International Agency for Research on Cancer (IARC), World Health Organization, Lyon, France; t Department of Pathology and Molecular Pathology, University
Hospital Zurich, Zurich, Switzerland
Article history: The 2022 World Health Organization (WHO) classification of the urinary and male gen-
Accepted July 3, 2022 ital tumors was recently published by the International Agency for Research on Cancer.
This fifth edition of the WHO ‘‘Blue Book’’ offers a comprehensive update on the termi-
Associate Editor: nology, epidemiology, pathogenesis, histopathology, diagnostic molecular pathology,
James Catto and prognostic and predictive progress in genitourinary tumors. In this review, the edi-
tors of the fifth series volume on urologic and male genital neoplasms present a sum-
Keywords: mary of the salient changes introduced to the classification of tumors of the prostate
World Health Organization and the urinary tract.
Classification Ó 2022 Published by Elsevier B.V. on behalf of European Association of Urology.
Prostate
Urinary tract
Carcinoma
1
WHO fifth edition standing members who also served as expert members for the urinary and male
genital tumors volume.
Please visit www.eu-acme.org/europeanurology * Corresponding author at: Chair of Pathology, Heersink School of Medicine, The University of
to answer questions on-line. The EU-ACME cred- Alabama at Birmingham, Birmingham, AL, USA.
its will then be attributed automatically. E-mail address: [email protected] (G.J. Netto).
0302-2838/Ó 2022 Published by Elsevier B.V. on behalf of European Association of Urology.
1. Introduction Table 1 – The 2022 WHO classification of the prostate and seminal
vesicle
Epithelial tumors of the prostate
The International Agency for Research on Cancer has Glandular neoplasms of the prostate
recently published the 2022 World Health Organization 8440/0 Cystadenoma
(WHO) classification of the urinary and male genital tumors 8148/2 Prostatic intraepithelial neoplasia, high grade
8500/2 Intraductal carcinoma
[1]. The fifth edition of the WHO ‘‘Blue Book’’ offers a com- 8140/3 Acinar adenocarcinoma
prehensive update on the terminology, epidemiology, 8490/3 Signet ring cell–like acinar adenocarcinoma
pathogenesis, histopathology, diagnostic molecular pathol- 8140/3 Pleomorphic giant cell acinar adenocarcinoma
8572/3 Sarcomatoid acinar adenocarcinoma
ogy, and prognostic and predictive progress in genitouri- 8140/3 Prostatic intraepithelial neoplasia–like carcinoma
nary tumors. In this review, the editors of the fifth series 8500/3 Ductal adenocarcinoma
volume present a summary of the salient changes in the 8574/3 Treatment-related neuroendocrine prostatic carcinomas
Squamous neoplasms of the prostate
classification of tumors of the prostate and the urinary tract. 8560/3 Adenosquamous carcinoma
In keeping with the modified terminology scheme that is 8070/3 Squamous cell carcinoma
now in use across the WHO fifth series volumes, the desig- 8147/3 Adenoid cystic (basal cell) carcinomaa
Mesenchymal tumors unique to the prostate
nation of ‘‘subtypes’’ is adopted to replace ‘‘variants’’ for dis- Stromal tumors of the prostate
tinct clinical or morphologic categories within a tumor type 8935/1 Stromal tumor of uncertain malignant potential
(ie, subtypes of invasive urothelial carcinoma that are mor- 8935/3 Stromal sarcoma
phologically distinct and have prognostic significance). The Subtypes are indicated in italicized text. IARC = International Agency for
Research on Cancer; WHO = World Health Organization.
term variant is reserved for designation of genomic rather These morphology codes are from the International Classification of Dis-
than morphologic alterations. eases for Oncology, third edition, second revision (ICD-O-3.2). Behavior is
In another alignment with the fifth series structure, coded /0 for benign tumors; /1 for unspecified, borderline, or uncertain
behavior; /2 for carcinoma in situ and grade III intraepithelial neoplasia; /
metastatic, hematolymphoid, mesenchymal, neuroen- 3 for malignant tumors, primary site; and /6 for malignant tumors,
docrine, and genetic syndrome–related tumors are each dis- metastatic site. Behavior code /6 is not generally used by cancer registries.
cussed in a separate chapter, consolidating these topics This classification is modified from the previous WHO classification,
across various genitourinary organs. Exceptions were made In the 2022 WHO classification structure, metastatic, hematolymphoid,
for ‘‘treatment-related neuroendocrine prostatic carci- mesenchymal, neuroendocrine, and genetic syndrome–related tumors are
noma’’ (t-NEPC) and ‘‘mesenchymal tumors unique to the each discussed in a separate chapter, consolidating these topics across
various genitourinary organs. Exceptions were made for treatment-rela-
prostate’’ as these are thought to have specific biologic ted neuroendocrine prostatic carcinoma and mesenchymal tumors unique
and clinical features that merit keeping them in the prostate to the prostate as they are thought to have specific biologic and clinical
chapter. features that merit keeping them in the prostate chapter.
a
These labels have undergone a change in terminology of a previous
code.
2. Tumors of the prostate
The current edition of the WHO presents a detailed discus-

sion of the recent advances in our understanding of the eti-
ology, pathogenesis, and molecular underpinnings of increasing evidence that lesions previously designated as
prostate cancer. Refinements in the classification, grading, cribriform HGPIN belong to a group of intraductal prolifer-
and prognostication are also discussed. Critical advances ations that border on the diagnosis of intraductal carcinoma
in radiologic imaging solutions, novel therapeutic targets of the prostate (IDC-P) or may be classified as IDC-P [2].
and their predictors of response, and exciting novel applica- Referred to as ‘‘Atypical intraductal proliferation (AIP)’’, it
tions of computational digital pathology are highlighted. encompasses a spectrum of intraductal proliferations that
The following is a brief description of the important clas- are architecturally and/or cytologically more complex than
sification changes and the evolving nomenclature of con- HGPIN, but fall short of meeting the criteria of IDC-P.
ceptually controversial topics that emerged in the fifth Although a consensus on the best terminology for this
edition of the Blue Book (see Table 1). group of lesions is yet to be reached [2–4], so far, the few
studies on the topic have suggested that their clinical course
2.1. Precursor lesions and molecular features are in line with being a short step
away from IDC-P [5,6].
2.1.1. Prostatic intraepithelial neoplasia
Low-grade prostatic intraepithelial neoplasia (LGPIN) is no
longer a recognized entity. This is primarily driven by our 2.1.2. Intraductal carcinoma of the prostate
inability to histologically identify LGPIN, with any degree First recognized as an entity in the WHO 2016 edition, IDC-P
of reproducibility, as a lesion distinct from benign glandular has been investigated extensively. The fifth edition endorses
hyperplasia of the prostate. The term prostatic intraepithe- the fact that current biologic and clinical evidence is heavily
lial neoplasia (PIN) is now restricted to high-grade PIN, and in support of IDC-P representing two distinct entities. Only
the entity is thus renamed as high-grade prostatic intraep- a small minority of IDC-P lesions are thought to be truly
ithelial neoplasia (HGPIN). ‘‘in situ’’ in nature (ie, originating through a progression
Furthermore, the cribriform subtype is no longer consid- from an HGPIN precursor). The great majority of IDC-P
ered a subtype of HGPIN, leaving only three histologic sub- lesions develop as late events in tumor progression, where
types (micropapillary, flat, and tufted). This is based on the high-grade invasive prostate cancer spreads into (colonizes)
pre-existing benign prostatic ducts or acini. Accumulating Molecularly, ERG rearrangement and loss of PTEN
genomic data strongly support this ‘‘intraductal spread’’ ori- expression are enriched in IDC-P [9,21]. IDC-P contains
gin of most IDC-P lesions [7–9]. additional alterations, distinct from HGPIN, which may par-
IDC-P is found in approximately 15–30% of radical tially overlap with high-grade invasive carcinoma (Gleason
prostatectomies and in 14% of biopsies that are also harbor- pattern 4/5) with and without a cribriform pattern. These
ing carcinoma [10,11]. IDC-P without concomitant invasive include higher rates of genomic alteration and genomic
cancer (isolated IDC-P) is an exceedingly rare finding in instability [7,8,22,23]. Several studies have reported a
biopsies and prostatectomies (0.06–0.26%) [12–14]. higher rate of homologous recombinant DNA repair (HRR)
The most widely utilized diagnostic criteria for IDC-P gene defect in invasive prostate cancers that is associated
accept solid/dense cribriform architecture alone as diagnos- with the presence IDC-P component. This has led to national
tic of IDC-P and require marked cytologic atypia (±comedo cancer organizations, such as the National Comprehensive
necrosis) for the diagnosis of IDC-P with less complexity Cancer Network, to recommend germline testing in such
(see Fig. 1) [12]. In general, there is agreement on the neg- patients [24]. Whether such a recommendation will stand
ative prognostic impact of identifying IDC-P and the need to is currently under investigation [25].
report its presence in needle biopsies and radical prostatec-
tomy. Presence of IDC-P correlates with a higher tumor 2.2. Acinar adenocarcinoma
grade, larger volume, and greater likelihood of extrapro-
The fifth edition recognizes several unique ‘‘patterns’’
static extension, seminal vesicle invasion, and pelvic lymph
within acinar type adenocarcinoma. These histologic pat-
node metastasis. It is also strongly associated with bio-
terns are important to denote as these may pose diagnostic
chemical recurrence, progression-free survival, and
(eg, differentiating from benign or atrophic glands) or grad-
cancer-specific mortality after radical prostatectomy [15–
ing challenges. As shown in Table 2, these patterns include
18].
atrophic adenocarcinoma (including aberrant p63+), pseu-
Definitive therapy is an option for patients presenting
dohyperplastic adenocarcinoma, foamy gland adenocarci-
with isolated IDC-P on biopsy, although additional imaging
noma, microcystic adenocarcinoma, and mucinous
and biopsies are often carried on beforehand [2,19]. There-
(colloid) adenocarcinoma. On the contrary, previously des-
fore, it is most crucial, particularly in biopsies, to distinguish
ignated variants that represent distinct clinical or morpho-
IDC-P from HGPIN and AIP, as their clinical implications are
logic categories within acinar adenocarcinoma are now
drastically different.
classified as subtypes. These include signet ring cell–like
While there is wide agreement that isolated IDC-P
adenocarcinoma, pleomorphic giant cell adenocarcinoma,
should not be graded, controversy remains on whether to
and sarcomatoid carcinoma subtypes. PIN-like carcinoma
incorporate IDC-P areas in the calculation of assigned Glea-
subtype is now added to this group as it is no longer
son score when invasive carcinoma is also present. As a
regarded as a subtype of ductal carcinoma of the prostate.
result, there is no consensus on whether to perform
immunohistochemical stains in biopsies containing inva- 2.2.1. PIN-like carcinoma
sive prostate cancer and cribriform/solid lesions that could This subtype of acinar carcinoma is composed of medium to
represent IDC-P, when such determination could impact large glands with flat or tufted lining. The lining epithelium
the assigned Gleason grade [2]. This has resulted in the is pseudostratified and usually contains elongated hyper-
unfortunate divergence in practice guidelines among lead- chromatic nuclei. These morphologic features account for
ing professional societies [2,19,20]. Evidently, judicial use its resemblance to HGPIN (hence the terminology) and to
of immunohistochemical stains should be restricted to ductal adenocarcinoma [26,27]. Some examples can be
where confirmation of IDC-P would potentially change the lined by cuboidal epithelial cells with round nuclei [26]
assigned grade group (GG). (see Fig. 2). PIN-like carcinomas are differentiated from
Fig. 1 – (A) Intraductal carcinoma of the prostate (IDC-P); H&E stains, 2003 amplification. (B) Immunohistochemistry of p63 highlighting the presence of basal
cell layer surrounding IDC-P. H&E = hematoxylin and eosin; IDC-P = intraductal carcinoma of the prostate.
Table 2 – Comparison of the WHO 2016 and WHO 2022 classifications of can be lost and prostate-specific antigen (PSA) is usually
acinar adenocarcinoma of prostate negative [36,37].
WHO 4th edition WHO 5th edition
Acinar adenocarcinoma Prostatic acinar adenocarcinoma 2.2.4. Pleomorphic giant cell adenocarcinoma
Histologic variants Unusual histologic patterns
Pleomorphic giant cell adenocarcinoma is another rare and
Atrophic variant Atrophic adenocarcinoma (including
aberrant p63+) aggressive subtype. It most frequently arises following prior
Pseudohyperplastic Pseudohyperplastic adenocarcinoma treatment with androgen deprivation or radiation. Positiv-
variant
ity for at least one prostate-restricted marker such as PSA,
Microcystic variant Foamy gland adenocarcinoma
Foamy gland variant Microcystic adenocarcinoma P501S, NKX3.1, HOXB13, or AR is usually present. ERG rear-
Mucinous (colloid) Mucinous (colloid) adenocarcinoma rangements are infrequent in this subtype. On the contrary,
variant
a high prevalence of PTEN loss, TP53 mutations, and biallelic
Signet ring-like cell Subtypes
variant pathogenic mutations in homologous DNA repair genes or
Pleomorphic giant cell Signet ring cell–like adenocarcinoma mismatch repair genes is likely [37–40].
variant
Sarcomatoid variant Pleomorphic giant cell adenocarcinoma
Sarcomatoid carcinoma 2.3. Ductal adenocarcinoma
PIN-like carcinoma
PIN = prostatic intraepithelial neoplasia; WHO = World Health
The editors of the current edition of the Blue Book exten-
Organization. sively debated the possibility of reclassifying ductal adeno-
Previously designated ‘‘variants’’ that represent distinct clinical or mor- carcinoma as a subtype of acinar adenocarcinoma, rather
phologic categories (eg, signet ring cell–like adenocarcinoma) are now
classified as subtypes. PIN-like carcinoma subtype is now added to this
than maintaining it as a distinct type of prostate cancer.
group as it is no longer regarded as a subtype of ductal carcinoma of The discussion was primarily driven by the fact that the
prostate. The WHO 2022 edition continues to recognize unique histologic majority of cases of ductal adenocarcinoma are admixed
‘‘patterns’’ within acinar type adenocarcinoma as these may pose diag-
nostic or grading challenges. with acinar adenocarcinoma. Furthermore, the preponder-
ance of evidence shows ductal adenocarcinoma to be clon-
ally related to a coexisting acinar cancer based on shared
ERG rearrangements and other genomic alterations [41–
HGPIN by their glandular crowding and consistent lack of 44]. For this edition of the Blue Book, we elected to maintain
basal cells. Unlike ductal adenocarcinoma, true papillae ductal adenocarcinoma as a distinct type of prostate carci-
with fibrovascular cores, cribriform architecture, and necro- noma; the diagnosis is made only on radical prostatectomy
sis are not present in PIN-like carcinoma. This subtype of specimens wherein there is a minimum 50% component of
acinar carcinoma has a generally favorable prognosis in line ductal carcinoma. In needle biopsies, the term adenocarci-
with its Gleason 3 + 3 = 6 score morphology [27,28]. Intrigu- noma with ductal features is used. The decision to keep duc-
ingly, activating mutations in the RAF/RAS pathway have tal adenocarcinoma as a separate type of adenocarcinoma
recently been illustrated in this subtype, further pointing was based on its distinctive clinical presentation, metastatic
to a distinct biology [29]. behavior, and metastatic pattern. The issue will be revisited
in the next edition with the anticipation that additional
studies may support the integration of ductal carcinoma
2.2.2. Signet ring cell–like adenocarcinoma
as a subtype of acinar type prostate cancer.
In its pure form, signet ring cell–like adenocarcinoma is a
very rare subtype. The term should be reserved for tumors
2.4. Grading
with at least 25% of signet ring cell–like component. The
signet ring cells are generally devoid of mucin; hence, the The WHO 2022 volume continues to endorse the concept of
term signet ring cell like (rather than signet ring cell) should GGs, also referred to as International Society of Urologic
be used. Although intracytoplasmic vacuoles can occur in Pathology (ISUP) grades or simply WHO grades, initially
any Gleason pattern, it is more likely associated with higher proposed at the 2014 ISUP conference and adopted in the
Gleason patterns and therefore associated with poor prog- fourth edition [45,46]. In 2019, additional recommenda-
nosis [30–32]. tions on grading were independently forwarded by ISUP
and the Genitourinary Pathology Society (GUPS). These rec-
2.2.3. Sarcomatoid carcinoma ommendations are not yet fully validated and include some
The rare sarcomatoid subtype is associated with dismal specific differences between ISUP and GUPS [2,19,47].
prognosis [33,34]. It most frequently occurs after irradiation Therefore, the WHO 2022 edition elected to await more
for a high-grade acinar carcinoma [34,35]. The sarcomatous definitive evidence to resolve these differences. Several
morphology may encompass homogeneous spindle cell ele- studies have supported a prognostic significance for the
ments or heterologous leiomyosarcomatous, angiosarcoma- presence of cribriform pattern 4 and the proportion (per-
tous, chondroid, or osseous differentiation. Demonstration cent volume) of any pattern 4 [48–51]. As a result, both
of TMPRSS2-ERG translocation by fluorescence in situ societies recommend reporting an estimate of the percent-
hybridization may be of value in establishing the diagnosis. age of pattern 4 in GG2 and GG3 biopsies. They also recom-
This is especially true in cases where the differential diag- mend noting the presence of invasive cribriform carcinoma
nosis may include ‘‘true’’ mesenchymal tumors or sarcoma- in all Gleason score 7 and 8 cases (GG2–4). Issues remain in
toid subtype of urothelial carcinoma. On relation to interobserver reproducibility in the assessment
immunohistochemistry, androgen receptor (AR) expression of poorly formed and fused gland pattern 4, as well as some
Fig. 2 – (A) PIN-like adenocarcinoma, a subtype of acinar carcinoma of the prostate; H&E stains, 2003 amplification. (B) Immunohistochemistry of p63. Note
absence of basal cell layer. H&E = hematoxylin and eosin; PIN = prostatic intraepithelial neoplasia.
concerning cribriform pattern 4 [52,53]. The latter includes specific genomic alterations that involve TP53, RB1, and
the precise definition of a cribriform pattern, the signifi- PTEN loss [65].
cance of a cribriform gland size (small vs large cribriform), Treatment-related NEPC is considered a distinct clinical
its reproducibility, and consistency in distinguishing it from entity with a spectrum of histologic features ranging from
IDC-P on hematoxylin and eosin staining alone. Differentiat- pure neuroendocrine morphology (most frequently that of
ing invasive cribriform 4 pattern from IDC-P may impact the small cell carcinoma but occasionally large cell neuroen-
final grade assignment of invasive cancer in a given biopsy. docrine carcinoma) to mixed neuroendocrine tumors with
As indicated above in the section on IDC-P, whether such poorly differentiated adenocarcinoma component . The
distinction is needed is a matter of divergence among ISUP histologic and immunohistochemical staining features of
and GUPS [50,53–56]. In order to allow meaningful future t-NEPC overlap with those of primary prostatic small cell
analyses and comparisons of cohorts, the current edition carcinoma. Patients undergoing androgen deprivation ther-
of the WHO classifications recommends the need for apy who develop t-NEPC, on average, do so in <24 mo.
pathologists and authors to specify which of the two Glea- Unfortunately, they will then be destined to dismal median
son grading systems (ISUP vs GUPS) is being used during survival of up to 12 mo [66–68].
routine reporting and publications.
Capitalizing on recent advances in computational digital
pathology, studies have shown that artificial intelligence– 2.6. Diagnostic molecular pathology in prostate cancer
based algorithms can perform prostate cancer grading at a Recent molecular advances that are impacting prostate can-
level of accuracy matching that of experienced, subspecial- cer patient management are detailed in the current edition
ized uropathologists [57–60]. Awaiting prospective valida- of the Blue Book. Among these, identification of HRR defects
tion, such algorithms not only promise significant and Lynch syndrome is of particular importance. This is pri-
improvement in interobserver grading consistency, but marily due to recent revelations that germline (or somatic)
equally a more precise quantification of various Gleason alterations in DNA repair genes such as BRCA1, BRCA2, ATM,
patterns [61,62]. CHEK2, FANCI, PALB2, and MSH2 are present in up to 20% of
aggressive primary and metastatic prostatic carcinoma [69–
72]. Advanced prostate cancer harboring HRR defects are
2.5. Treatment-related neuroendocrine prostatic carcinoma
likely to respond to PARP inhibitors, while those with defec-
In the current edition, castrate-resistant prostate cancer tive DNA mismatch repair (dMMR) are poised to be offered
demonstrating complete (or partial) neuroendocrine differ- immune checkpoint inhibitors (ICIs) [73,74]. Interestingly,
entiation is designated as t-NEPC 26124369 [63]. morphologic correlates (eg, IDC-P and cribriform pattern)
Emerging evidence points to lineage plasticity as an are increasingly elucidated in high-risk patients with
important factor in the progression of advanced prostate tumors that are more likely to harbor DNA repair genetic
cancer following treatment with androgen receptor signal- defect.
ing inhibitors [64]. There is also mounting evidence in sup- For decades, androgen withdrawal and/or AR blockade
port of the mechanistic role of epigenetic alterations in the strategies have been utilized in prostate cancer treatment.
transdifferentiation of prostate cancer into an AR- While an initial tumor response is expected, this ultimately
indifferent state. This seems to occur in a background of fades as patients develop castrate-resistant prostate cancer.
The development of constitutively active AR splice variants 3.1.2. Urothelial papillary proliferation of undetermined
is a salient mechanism underlying hormone therapy resis- malignant potential
tance [75]. Detection of one such variant (ie, AR splice vari- In the 2016 classification, undulating urothelial prolifera-
ant ARv7) in circulating tumor cells and/or circulating cell- tions that were considered precursors of noninvasive low-
free DNA through ‘‘liquid biopsy’’ platforms is increasingly grade papillary carcinoma were given an entity status and
utilized. The assays help predict a poor response to termed ‘‘urothelial proliferation with undetermined malig-
second-generation AR antagonists (eg, abiraterone and nant potential’’. Such lesions have a tented architectural
enzalutamide) [76–78]. appearance with short nonbranching papillae covered by
Finally, several commercial RNA-based genomic prostate mildly atypical urothelium with cytologic features similar
cancer classifier assays have been developed. Their main to those of noninvasive low-grade papillary carcinoma.
application is in guiding management in patients with Such lesions have also been referred to as ‘‘papillary urothe-
very–low-risk and low-risk disease. The added value of such lial hyperplasia’’ [81,82]. In the current WHO edition, these
high cost assays, compared with established clinicopatho- lesions are no longer recognized as a unique entity and are
logic prognostic parameters, in the setting of active surveil- considered either early noninvasive low-grade papillary
lance remains to be determined [24,79]. carcinomas or shoulder extensions of such tumors.
3.2. Noninvasive urothelial papillary neoplasms

3. Tumors of the urinary tract
The four-tiered classification system for papillary urothelial
neoplasms, initially proposed by ISUP in 1998 and subse-
Histologic characteristics remain the gold standard for the quently adopted in the WHO 2004 and WHO 2016 editions,
classification and diagnosis of urothelial tract tumors in is maintained in the 2022 classification. This system is
the current WHO volume. Significant strides have been based on the level of architectural and cytologic disorder,
made toward obtaining an intrinsic comprehensive molecu- has proved to be highly reproducible, and provides clinically
lar classification of urothelial tumors with translational rel- relevant prognostic and management guidance [83–85].
evance to diagnosis, prognosis, and therapeutics. The Every classification system is in need of continuous
critical impact of this progress is fully acknowledged in refinement in order to enhance its reproducibility and clin-
the WHO 2022 volume. This is tempered with a realistic ical impact. Recognizing such need, in the fifth edition, an
understanding that additional prospective data and refined attempt is made to address grading challenges stemming
consensus are needed for such a molecular classification to from the inherent heterogeneity of grade that can be
transition into routine pathology practice. encountered in up to one-third of papillary urothelial
In line with the overall thematic changes in the fifth ser- tumors [86–89]. Neoplasms that are largely low grade but
ies, chapters are split by tumor lineages of differentiation contain a minor (one-tenth or less of tumor volume) com-
that may occur in different urinary tract locations, rather ponent displaying frank high-grade morphology have tradi-
than being based on organ topography. Exceptions are made tionally been assigned a high grade. This practice may have
for entities where histologic findings are particularly useful contributed to a grade migration (the so-called Will Rogers
for the diagnosis and staging of rare tumors (eg, tumors effect) that may represent a divergence from the actual bio-
arising from urachal remnants, diverticula, and urethral logic behavior of such neoplasms. The fifth series proposes
accessory glands; see Table 3). the reporting of papillary tumors as high grade when such
components represent 5% of the tumor [87]. Tumors with
<5% high-grade fraction are to be reported as ‘‘low-grade
3.1. Precursor lesions
tumors with <5% high-grade component’’ [89]. This pro-
3.1.1. Urothelial dysplasia posed pragmatic approach of reporting should result in
For decades, the term urothelial dysplasia has been greatly increased consistency of grading tumors with heteroge-
debated. This is primarily due to the lack of precise defini- neous grade. The hope is that such consistency will better
tional criteria, poor interobserver reproducibility, inability empower prospectively designed studies of larger datasets
to distinguish from atypia of uncertain significance, and that will help address the true biologic behavior of these
lack of robust clinical outcome data. Studies to assess the tumors. Rapid advances in computational and digital
impact on outcome are hamstrung by the frequent multifo- pathology are providing novel artificial intelligence–based
cality of precursor urothelial lesions that may include coex- tools. These tools have the potential to help address issues
isting bona fide urothelial carcinoma in situ (CIS) that is of grade heterogeneity and reproducibility [90].
actually driving outcome [80]. The current edition of the WHO weighs in on the nomen-
From a definitional point of view, dysplasia in the uri- clature of noninvasive urothelial neoplasms with inverted
nary tract is not a synonym of intraepithelial neoplasia. As histology [91,92]. In addition to the dedicated section on
in prior editions, the somewhat nebulous definition as a inverted papilloma, a reference to inverted histology as a
preneoplastic lesion with cytologic changes that fall short recognized pattern is made in the sections on papillary
of those of CIS is maintained in the fifth series. However, urothelial neoplasms of low malignant potential (PUNLMP),
unlike prior editions, the 2022 WHO classification elected and low- and high-grade noninvasive carcinomas. Unlike
not to dedicate a separate section for urothelial dysplasia inverted papilloma, the last three types of neoplasms only
(only a reference is made to it in the section of urothelial rarely present in a pure inverted fashion. The WHO 2022
CIS). classification recommends including the descriptor of ‘‘in-
Table 3 – The 2022 WHO classification of urinary tract tumors

Urothelial tumors
Noninvasive urothelial neoplasms
8120/0 Urothelial papilloma
8121/0 Urothelial papilloma, inverted
8130/1 Papillary urothelial neoplasm of low malignant potential
8130/1 Inverted papillary urothelial neoplasm of low malignant potential
8130/2 Noninvasive papillary urothelial carcinoma, low grade
8130/2 Low-grade papillary urothelial carcinoma with an inverted growth pattern
8130/2 Noninvasive papillary urothelial carcinoma, high grade
8130/2 Noninvasive high-grade papillary urothelial carcinoma with an inverted growth pattern
8120/2 Urothelial carcinoma in situ
Invasive urothelial neoplasms
8120/3 Invasive urothelial carcinoma
8120/3 Conventional urothelial carcinoma
8120/3 Urothelial carcinoma with squamous differentiation
8120/3 Urothelial carcinoma with glandular differentiation
8120/3 Urothelial carcinoma with trophoblastic differentiation
8120/3 Nested urothelial carcinoma
8120/3 Large nested urothelial carcinoma
8120/3 Tubular and microcystic urothelial carcinomas
8131/3 Micropapillary urothelial carcinoma
8082/3 Lymphoepithelioma-like urothelial carcinoma
8122/3 Plasmacytoid urothelial carcinomaa
8031/3 Giant cell urothelial carcinoma
8120/3 Lipid-rich urothelial carcinoma
8120/3 Clear cell (glycogen-rich) urothelial carcinoma
8120/3 Sarcomatoid urothelial carcinoma
8020/3 Poorly differentiated urothelial carcinoma
Squamous cell neoplasms of the urinary tract
8052/0 Squamous papilloma
Squamous cell carcinomas of the urinary tract
8051/3 Verrucous carcinoma
8070/3 Pure squamous carcinoma of the urothelial tracta
Glandular neoplasms
Adenomas
8261/0 Villous adenoma
8211/0 Tubular adenoma
8263/0 Tubulovillous adenoma
Adenocarcinomas
8140/3 Adenocarcinoma, NOS
8144/3 Enteric adenocarcinoma
8480/3 Mucinous adenocarcinoma
8323/3 Mixed adenocarcinoma
8490/3 Signet ring cell adenocarcinoma
8140/2 Adenocarcinoma in situ
Urachal and diverticular neoplasms
8010/3 Urachal carcinoma
8120/3 Invasive urothelial carcinoma
Urethral neoplasms
Urethral accessory gland carcinomas
8140/3 Carcinoma of Littré glands
8140/3 Carcinoma of Skene glands
8140/3 Carcinoma of Cowper glands
Tumors of Mullerian type
8310/3 Clear cell carcinoma
8380/3 Endometrioid carcinoma
Subtypes are indicated in italicized text. IARC = International Agency for Research on Cancer; NOS = not otherwise specified; WHO = World Health Organization.
These morphology codes are from the International Classification of Diseases for Oncology, third edition, second revision (ICD-O-3.2). Behavior is coded /0 for
benign tumors; /1 for unspecified, borderline, or uncertain behavior; /2 for carcinoma in situ and grade III intraepithelial neoplasia; /3 for malignant tumors,
primary site; and /6 for malignant tumors, metastatic site. Behavior code /6 is not generally used by cancer registries.
In the 2022 WHO classification, urinary tract tumors are classified based on tumor lineages of differentiation rather than organ topography. Exceptions are made
for entities where histological findings are particularly useful for the diagnosis and staging of rare tumors (eg, tumors arising from urachal remnants, diverticula,
and urethral accessory glands).
a
These labels have undergone a change in terminology of a previous code.
verted’’ when such a pattern is prominent to acknowledge 3.3. Invasive urothelial carcinoma
its presence and distinction from lamina propria invasion.
Invasive urothelial carcinoma occurs throughout the uri-
This could also offer a pathologic correlate to the unusual
nary tract. The vast majority of cases originate in the uri-
cystoscopic appearance that the urologist may encounter
nary bladder, with 5–10% occurring in the upper urinary
in predominantly inverted tumors.
Table 4 – Comparison of the WHO 2016 and WHO 2022 classifications of urothelial tumors of the urinary tract
WHO 4th edition WHO 5th edition
Urothelial tumors Urothelial tumors
Infiltrating urothelial carcinoma Invasive urothelial carcinoma
Histologic variants of urothelial carcinoma Histologic subtypes of urothelial carcinoma
Nested, including large nested Nested
Microcystic Large nested
Micropapillary Tubular
Lymphoepithelioma like Microcystic
Plasmacytoid/signet ring cell/diffuse Micropapillary
Sarcomatoid Lymphoepithelioma like
Giant cell Plasmacytoid
Poorly differentiated Sarcomatoid
Lipid rich Giant cell
Clear cell Poorly differentiated
Urothelial carcinoma with divergent differentiation Lipid rich
UC with squamous differentiation Clear cell (glycogen Rich)
UC with glandular differentiation Urothelial carcinoma with divergent differentiation
UC with trophoblastic differentiation UC with squamous differentiation
UC with Mullerian differentiation (clear cell adenocarcinoma) UC with glandular differentiation
UC with trophoblastic differentiation
UC with Mullerian differentiation (clear cell adenocarcinoma)
UC = urothelial carcinoma; WHO = World Health Organization.
Previously designated ‘‘variants’’ are now classified as subtypes. New subtypes include large nested and tubular (previously included under nested). The WHO
2022 edition continues to recognize several lineages of divergent differentiation in invasive urothelial carcinoma that have unique diagnostic and/or treatment
implications. These can occur in pure or mixed fashion.
tract. Synchronous or metachronous multifocal tumors are carcinoma includes two newcomers (large nested and tubu-
relatively common [93–95]. Invasive urothelial carcinoma lar) as well as minor nomenclature modification of the
is known to present in a diversity of morphologic appear- existing ones. In that regard, the term ‘‘signet ring’’ is
ances [96]. These include an expanding list of well-defined dropped from plasmacytoid subtype and a qualifier ‘‘glyco-
subtypes that can occur in pure fashion (see Table 4) or gen rich’’ is added to clear cell urothelial carcinoma subtype
more commonly admixed with conventional urothelial car- to further assure its distinction from clear cell adenocarci-
cinoma. The diversity in appearance is further enriched by noma tumors of Mullerian divergent differentiation.
the plasticity in differentiation that neoplastic urothelium Specific subtypes are important to recognize, given their
is capable of. This ‘‘divergent’’ differentiation frequently resemblance to other nonurothelial tumors, their occasional
pursues squamous and/or glandular lineage, but occasion- deceptively benign appearance, and their generally aggres-
ally neuroendocrine, trophoblastic, and Mullerian lineage. sive biologic behavior and occasionally unique therapy
The 2022 classification emphasizes the importance of options. The discussion below is limited to the new sub-
reporting the different components of conventional urothe- types of urothelial carcinoma.
lial carcinoma, histologic subtypes, and/or divergent differ-
entiation in every tumor. It also calls for a consistent 3.3.1.1. Large nested urothelial carcinoma. Previously
attempt to quantify such elements, given potential manage- included under the rubric of nested variant, the large nested
ment implications. subtype is now recognized as a specific subtype given its
Based on their nuclear features, most invasive urothelial unique morphologic and molecular features [97]. As their
carcinomas are graded as high grade. However, rare low- name indicates, these tumors are composed of medium to
grade invasive urothelial carcinomas (lacking marked large nests. The nests vary from having rounded circum-
nuclear atypia) are recognized in the 2022 WHO classifica- scribed borders to occasional stromal-tumor interfaces with
tion. A requirement to grade every invasive urothelial carci- more irregular ragged appearances. The differential diagno-
noma is endorsed, given that occasional studies have sis typically includes the inverted growth pattern of nonin-
pointed to a more favorable outcome in low-grade invasive vasive low-grade urothelial carcinoma and exuberant
tumors than in their high-grade counterparts [91]. The fact proliferation of von Brunn nests. Features such as the pres-
remains that standardized criteria are yet to be established ence of muscular propria invasion, irregular shape of infil-
to be able to reproducibly designate an invasive carcinoma trating nests, and the presence of stromal reaction are all
as low grade. helpful when found. Similar to the nested subtype, the
Finally, the fifth edition maintains the recommendation bland cytologic appearance belies the biologic behavior of
that all invasive histologic subtypes of urothelial carcinoma large nested urothelial carcinoma (see Fig. 3). Approxi-
as well as those with divergent differentiation should be mately 70% of cases present as pT2 tumors, while 58% have
graded as high-grade tumors. extravesical disease (pT3 and/or pN1) at presentation.
One-fifth of patients endure recurrences or metastases,
3.3.1. Histologic subtypes of urothelial carcinoma and 24% died of disease in one series [98,99].
As indicated above and listed in Table 4, the terminology of
histologic subtypes has replaced variants throughout the 3.3.1.2. Tubular and microcystic urothelial carcinomas. Both
fifth series. The ever-expanding list of subtypes of urothelial tubular and microcystic subtypes are closely related to
attempt to quantitate the amount of different components

of divergent differentiation in the pathology report of every
tumor [103–107].
3.4. Urine cytology
The fifth edition fully endorses the adoption of the Paris

System for Reporting Cytology (TPS). Several studies have
shown a significant improvement in diagnostic accuracy
and reproducibility using the TPS system. The system prior-
itizes the identification of high-grade urothelial carcinoma
(HGUC) based on objective and well-delineated nuclear cri-
teria, as summarized in Table 5 and described in detail in
the monogram by Rosenthal et al. [108].
The WHO 2022 accepts the fact that the TPS system is
not without limitations. Among these are the fact that the
cytologic findings of HGUC are indistinguishable from those
of urothelial CIS (ie, staging cannot be achieved on cytol-
ogy). In addition, some subtypes of invasive HGUC, such
as plasmacytoid or micropapillary, may contain cells with
relatively ‘‘bland’’ nuclear features on urine cytology.
Fig. 3 – Large nested subtype of invasive urothelial carcinoma; H&E stains, Finally, TPS acknowledges the inability of cytologic exami-
2003 amplification. H&E = hematoxylin and eosin.
nations to reliably detect and differentiate the different
lesions encompassed under low-grade urothelial neo-
nested urothelial carcinoma, and are hence composed of plasms. These include urothelial papilloma, PUNLMP, and
bland cells arranged in tubular or microcystic structures noninvasive low-grade papillary urothelial carcinoma.
[100,101]. Here again, the depth of the irregular infiltration
and the involvement of muscularis propria are clues that 3.5. Genomic advances and diagnostic molecular pathology in
should help differentiate this subtype from cystitis cystica. urothelial carcinoma
Positivity for urothelial markers such as GATA3 or p63 is
the rule [102]. Tremendous advances have been achieved in the delin-
eation of the various intrinsic genomic subtypes of urothe-
lial carcinoma. The WHO 2022 highlights the potential
3.3.2. Urothelial carcinoma with divergent differentiation impact of the novel molecular taxonomy on the diagnosis
The current WHO classification emphasizes the need to rec- and future management of urinary tract cancers. Since the
ognize the diversity in the histologic appearance, imparted fourth edition, The Cancer Genome Atlas (TCGA) project
by plasticity of histogenesis, of invasive urothelial carci- has produced a second landmark report that builds upon
noma. The various lines of divergent differentiation are its first seminal work [109,110]. The first TCGA publication
shown in Table 4. Most common among them is squamous, characterized four major expression clusters in bladder can-
followed by glandular and neuroendocrine lineage. The rare cer. These were subsequently refined and expanded in the
trophoblastic and Mullerian lineages of divergence have second TCGA study. The molecular subtypes of bladder can-
unique diagnostic and/or treatment implications. As in sub- cer now encompass three subgroups within the luminal
types, it is important to indicate the presence of and subtype, a basal-squamous subtype, and a distinct neuronal
Table 5 – The Paris System for Reporting Cytology

Diagnostic category Diagnostic criteria ROHM (%)
Negative for high-grade urothelial Ca (NHGUC) Benign urothelial, glandular, squamous cells, changes due to 8–24
instrumentation, lithiasis, polyoma, therapy
Atypical urothelial cells (AUC) Required N/C ratio 0.5 and one of: 24–53
Hyperchromasia
Irregular clumpy chromatin
Irregular nuclear contours
Suspicious for high-grade urothelial Ca (SHGUC) Required N/C ratio >0.7 and hyperchromasia, and one of: 59–94
Positive for high-grade urothelial Ca (HGUC) Required cellularity >5 cells and: 76–100
N/C ratio >0.7
Hyperchromasia
Low-grade urothelial neoplasm (LGUN) Required fibrovascular cores and absence of nuclear atypia 0–44
Ca = cancer; ROHM = risk of high-grade malignancy; WHO = World Health Organization.
The WHO 2022 edition fully endorses the adoption of the Paris System for Reporting Cytology.
Fig. 4 – Consensus molecular classification of muscle-invasive bladder cancer: The six consensus classes and their relationships to input molecular subtypes
are shown. In the lower right box, the samples are grouped by their predicted consensus class labels: LumP, LumNS, LumU, stroma-rich, Ba/Sq, and
neuroendocrine (NE)-like. In the left rectangular box, for each consensus class, a bar plot shows the proportion of samples assigned in each input subtype of
each input classification system. Ba/Sq = basal/squamous; LumNS = luminal nonspecified; LumP = luminal papillary; LumU = luminal unstable; MCL = Markov
cluster algorithm; MDA = MD Anderson Cancer Center; TCGA = the Cancer Genome Atlas; UNC = University of North Carolina. Modified with permission from
Kamoun A, de Reyniès A, Allory Y, Sjödahl G, et al. Bladder Cancer Molecular Taxonomy Group. A consensus molecular classification of muscle-invasive
bladder cancer. Eur Urol 2020;77:420–33 [115].
cluster, for a total of five TCGA subtypes. The luminal- Molecular Classification of Muscle-invasive Bladder Cancer’’
papillary subtype (35%) is characterized by the presence of proposal (see Fig. 4) [115].
FGFR alterations and papillary histology, has a lower risk Advanced bladder cancer has emerged as a strong candi-
for progression, and is a candidate for FGFR3 inhibitor ther- date for treatment with numerous ICI agents including
apy in light of a low response to cisplatin-based neoadju- anti–PD-1 and anti–PD-L1 antibodies (eg, nivolumab, pem-
vant chemotherapy (NAC) [111].The luminal-infiltrated brolizumab, and atezolizumab) [116–121]. Although
subtype (19%) is characterized by high expression of epithe- invaluable durable responses have been achieved in some
lial mesenchymal transition and myofibroblast markers, patients, the majority of patients fail to respond. Predictive
and moderate levels of CD274 (PD-L1) and CTLA4 immune biomarkers are needed [122]. As companion diagnostic
marker expression. The latter may account for their biomarkers, PD-L1 immunohistochemical evaluation has
response to immune checkpoint therapy [112]. The luminal been challenging [123]. As indicated above, molecular sub-
subtype (6%) shows high expression of luminal markers (eg, types have shown differential responses to ICIs with the
uroplakin, GATA3, and FOXA1) and KRT20. The basal- luminal-infiltrated and basal-squamous subtypes having a
squamous subtype (35%) is characterized by a higher inci- favorable response. In addition to PD-L1 expression in
dence in women, frequent presence of squamous histology, tumor cells and/or host immune cells, tumor mutational
high expression of basal and stem-like markers (CD44, burden, computational predictions of tumor neoantigens/
KRT5, KRT6A, and KRT14), high expression of CD274 (PD- MHC class I interaction, TGFB expression, and presence of
L1) and CTLA4, immune infiltration, and a higher likelihood microsatellite instability/mismatch repair deficiency
of a response to cisplatin-based NAC and immune check- (dMMR) are all being evaluated as predictors of a response
point therapy [111,113]. The neuronal subtype (5%) is asso- to immunotherapy in bladder and upper tract urothelial
ciated with the worst clinical outcome [114]. carcinoma [122,124–127].
To date, a total of six muscle-invasive bladder carcinoma In conclusion, the fifth edition of the WHO Blue Book
molecular classifications have been proposed. Derived from brings a comprehensive update on the terminology, epi-
largely nonoverlapping datasets, the six classifications demiology, pathogenesis, histopathology, diagnostic molec-
share some subtype-specific molecular features and some ular pathology, and prognostic and predictive progress in
overlaps. To achieve a direly needed consensus, in 2020, a genitourinary tumors. In this review, we presented a sum-
team of international multidisciplinary experts reconciled mary of the salient changes introduced in the WHO 2022
the published classification schemes in a ‘‘Consensus classification of tumors of the prostate and the urinary tract.
Author contributions: George J. Netto had full access to all the data in the [7] Böttcher R, Kweldam CF, Livingstone J, et al. Cribriform and
study and takes responsibility for the integrity of the data and the accu- intraductal prostate cancer are associated with increased genomic
instability and distinct genomic alterations. BMC Cancer
racy of the data analysis.
2018;18:8.
[8] Chua MLK, Lo W, Pintilie M, et al. A prostate cancer ‘‘nimbosus’’:
genomic instability and SChLAP1 dysregulation underpin
Study concept and design: Netto, Amin, Berney, Compérat, Gill, Hartmann, aggression of intraductal and cribriform subpathologies. Eur Urol
Menon, Raspollini, Rubin, Srigley, Tan, Tickoo, Tsuzuki, Turajlic, Cree, 2017;72:665–74.
[9] Lotan TL, Gumuskaya B, Rahimi H, et al. Cytoplasmic PTEN protein
Moch.
loss distinguishes intraductal carcinoma of the prostate from high-
Acquisition of data: Netto, Amin, Berney, Compérat, Gill, Hartmann, grade prostatic intraepithelial neoplasia. Mod Pathol
Menon, Raspollini, Rubin, Srigley, Tan, Tickoo, Tsuzuki, Turajlic, Cree, 2013;26:587–603.
Moch. [10] Kato M, Hirakawa A, Kobayashi YM, et al. The influence of the
presence of intraductal carcinoma of the prostate on the grade
Analysis and interpretation of data: Netto.
group system’s prognostic performance. Prostate
Drafting of the manuscript: Netto. 2019;79:1065–70.
Critical revision of the manuscript for important intellectual content: Netto, [11] Porter LH, Lawrence MG, Ilic D, et al. Systematic review links the
Amin, Berney, Compérat, Gill, Hartmann, Menon, Raspollini, Rubin, Srig- prevalence of intraductal carcinoma of the prostate to prostate
ley, Tan, Tickoo, Tsuzuki, Turajlic, Cree, Moch. cancer risk categories. Eur Urol 2017;72:492–5.
[12] Guo CC, Epstein JI. Intraductal carcinoma of the prostate on needle
Statistical analysis: None.
biopsy: histologic features and clinical significance. Mod Pathol
Obtaining funding: None. 2006;19:1528–35.
Administrative, technical, or material support: Netto. [13] Robinson BD, Epstein JI. Intraductal carcinoma of the prostate
Supervision: Netto. without invasive carcinoma on needle biopsy: emphasis on radical
prostatectomy findings. J Urol 2010;184:1328–33.
Other: None.
[14] Watts K, Li J, Magi-Galluzzi C, Zhou M. Incidence and
clinicopathological characteristics of intraductal carcinoma
detected in prostate biopsies: a prospective cohort study.
Financial disclosures: George J. Netto certifies that all conflicts of interest,
Histopathology 2013;63:574–9.
including specific financial interests and relationships and affiliations rel- [15] Dinerman BF, Khani F, Golan R, et al. Population-based study of the
evant to the subject matter or materials discussed in the manuscript (eg, incidence and survival for intraductal carcinoma of the prostate.
employment/affiliation, grants or funding, consultancies, honoraria, stock Urol Oncol 2017;35:673.e9–673.e14.
[16] Miyai K, Divatia MK, Shen SS, Miles BJ, Ayala AG, Ro JY.
Clinicopathological analysis of intraductal proliferative lesions of
received, or pending), are the following: Mahul B. Amin has scientific prostate: intraductal carcinoma of prostate, high-grade prostatic
advisory, consultancy, and/or stock ownership for his roles in the follow- intraepithelial neoplasia, and atypical cribriform lesion. Hum
ing companies—LabCorp, Precipio, Ibex Analytics, Cell Max, and Verily. Pathol 2014;45:1572–81.
[17] Van der Kwast T, Al Daoud N, Collette L, et al. Biopsy diagnosis of
intraductal carcinoma is prognostic in intermediate and high risk
Funding/Support and role of the sponsor: None. prostate cancer patients treated by radiotherapy. Eur J Cancer
2012;48:1318–25.
[18] Saeter T, Vlatkovic L, Waaler G, et al. Intraductal carcinoma of the
prostate on diagnostic needle biopsy predicts prostate cancer
Acknowledgments: The content of this article represents the personal
mortality: a population-based study. Prostate 2017;77:
views of the authors and does not represent the views of the authors’ 859–65.
employers and associated institutions. Where authors are identified as [19] van Leenders G, van der Kwast TH, Grignon DJ, et al. The 2019
personnel of the International Agency for Research on Cancer/WHO, the International Society of Urological Pathology (ISUP) consensus
authors alone are responsible for the views expressed in this article, conference on grading of prostatic carcinoma. Am J Surg Pathol
2020;44:e87–99.
and they do not necessarily represent the decisions, policy, or views of
[20] Varma M, Epstein JI. Head to head: should the intraductal
the International Agency for Research on Cancer/WHO. component of invasive prostate cancer be graded?
Histopathology 2021;78:231–9.
[21] Han B, Suleman K, Wang L, et al. ETS gene aberrations in atypical
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Platinum Priority
Referring to the article published on pp. 458–468; 459–482 of this issue
Tumors of the Urinary System and Male Genital Organs: 2022 World
Health Organization Classification and Multidisciplinarity
Rodolfo Montironi a,*, Alessia Cimadamore b

a
Molecular Medicine and Cell Therapy Foundation, Polytechnic University of the Marche Region, Ancona, Italy; b Section of Pathological Anatomy,
Polytechnic University of the Marche Region, School of Medicine, United Hospitals, Ancona, Italy
1. Introduction resolved, so the 5th edition will be useful to and appreciated

by uropthalogists and clinicians from the professional point
This issue of European Urology contains two extensive of view. Some topics that we consider important in this role
reviews based on the 5th edition of the World Health Orga- of the 5th edition of the Blue Book and emphasized in the
nization (WHO) Classification of Tumours of the Urinary Sys- two papers are briefly dealt with in subsequent sections
tem and Male Genital Organs, hereafter called the ‘‘Blue here (Appendix A).
Book’’ [1]:
2. Concept of molecularly defined renal tumor entities
Part A: renal, penile, and testicular tumors, by Dr. Holger
Moch et al [2], and
The review by Moch et al [2] contains an interesting section
Part B: prostate and urinary tract tumors, by Dr. George J.
on the current approach to classification of renal cell
Netto et al [3].
tumors, in comparison with hematopathology or central
nervous system tumor (CNS) classifications, where ‘‘the cur-
The two reviews summarize the most relevant changes
rent WHO classification also combined histologic patterns
for renal, penile, testicular, prostate, and urinary tract
with molecular diagnostics to form an integrated diagnosis’’
tumors. The clinical, radiological, molecular, histologic,
[2]. For decades, a genotype-phenotype correlation was put
and immunohistochemical criteria, as well as molecular
forward by conventional cytogenetic and comparative
biomarkers, are described [2]. The aim is to keep different
genomic hybridization analyses for renal cell tumor sub-
specialties—uropathologists, urologists, oncologists, radio-
types. The 3rd edition of the Blue Book named very few
therapists, and basic and translational researchers—in-
renal cell tumor entities on the basis of molecular alter-
formed on contemporary and relevant developments in
ations, such as MIT family translocation carcinomas, already
the ‘‘terminology, epidemiology, pathogenesis, histopathol-
in 2004 [5]. To date, several renal cell tumor subtypes have
ogy, diagnostic molecular pathology, and prognostic and
been identified on the basis of characteristic molecular
predictive progress in genitourinary tumors’’ [3].
alterations (MIT family translocation carcinomas and succi-
An editorial on the 4th edition of the Blue Book and two
nate dehydrogenase–deficient renal carcinomas) or familial
related papers in European Urology were published in 2016
predisposition syndromes (hereditary leiomyomatosis and
by my co-workers, including the senior author (R.M.) of this
renal cell carcinoma [RCC] syndrome–associated RCC) [2].
contribution [4]. Shortcomings of the 4th edition were dis-
However, a comprehensive molecular classification of renal
cussed in that editorial, with a comparison to the 3rd edi-
tumors is premature at present [6].
tion published in 2004 and based on data available up to
It is worth mentioning the pivotal role of the late Dr.
2002. According to the papers by Moch et al [2] and Netto
Ondrej Hes (1968–2022; Charles University Hospital, Plzen,
et al [3] and the 2022 book [1], these weaknesses have been
Czechia) in the recognition of many of these new renal enti-
DOI of original articles: https://doi.org/10.1016/j.eururo.2022.07.002; https://doi.org/10.1016/j.eururo.2022.06.016;

* Corresponding author. Molecular Medicine and Cell Therapy Foundation, Polytechnic University of the Marche Region, Via Tronto 10, 60126 Ancona,
Italy.
E-mail address: [email protected] (R. Montironi).
is a great departure from the previous two editions and

underscores the future role of digital pathology (DP), a key
issue further explored at the time of the COVID-19 pan-
demic that has opened new ways of working for pathology,
including smart working from home [10]. DP allows a
change from classical histopathological diagnosis with a
microscope and glass slides to virtual microscopy with a
computer [10].
Adoption of DP will allow implementation of artificial
intelligence (AI)-based algorithms in practice to capture
‘‘subtle patterns which are currently beyond human recog-
nition’’ [10]. AI-based algorithms play an important role in
more accurate quantification of patterns in genitourinary
tumors, in particular in PCa, thanks to their ability ‘‘to count
every gland and cell belonging to a specific pattern’’ [1,3].
‘‘AI-based algorithms can perform PCa grading at the level
of experienced, subspecialized uropathologists’’ [1–3,10].
5. PCa grading, patient information, and patient

advocacy
Fig. 1 – Dr. Ondrej Hes (1968–2022). Downloaded on July 21, 2022 from
https://iaphd-conference.com/speakers/ondrej-hes/.
The Gleason system has been modified over the years,
most recently after the International Society of Urological
Pathology (ISUP) 2019 consensus conference and the 2019
ties and variants (Fig. 1). He authored several chapters in white paper by the Genitourinary Pathology Society
the 5th edition of the Blue Book [1]. (GUPS) [11,12]. There are some differences between the
recommendations from the two societies that cannot be
resolved on the basis of the currently available evidence
3. Diagnostic, prognostic, and predictive molecular
[1,3,11,12]. ‘‘In the interim, while awaiting more definitive
markers
evidence to resolve the differences between the 2019
The 5th edition of the Blue Book [1], as also indicated by ISUP and GUPS proposals, pathologists should specify
Moch et al [2] and Netto et al [3], provides comprehensive which version of the Gleason grading system recommen-
reports on the latest findings for molecular markers for each dations is being used in routine reporting and publica-
tumor from diagnostic, prognosis, and prediction perspec- tions to allow meaningful analyses and comparisons of
tives. In particular, the new section on Essential and desirable cohorts’’ [1,3,11–13].
diagnostic criteria briefly summarizes ‘‘morphologic diag- It is worth mentioning a recent report on questions
nostic criteria, combined with immunohistochemistry and posed by a patient with intraductal carcinoma of the pros-
relevant molecular tests’’ [1]. Molecular markers were tate, and the differences in grading results according to
already included in the previous editions to some extent. the ISUP and GUPS views. According to the Patient’s feeling
However, advances in knowledge of the molecular charac- section of the report, ‘‘He has expressed his hope that in
teristics of urogenital tumors included in the 5th edition the near future morphology, molecular assays and artificial
allow novel treatment scenarios. For instance, the therapeu- intelligence will form an integrated approach to grade
tic scenario for metastatic castration-resistant prostate can- assessment beyond current practice’’ [13].
cer (PCa) has been enriched by the use of androgen receptor The concept of patient feeling leads to a new field that
signaling inhibitors and, more recently, by immunotherapy needs to be further expanded by scientific societies and in
and PARP inhibitors [7]. future books or editions: patient information and patient
Several examples of other markers for PCa and urinary advocacy. The European Association of Urology (EAU) has
tract tumors and, more generally, neoplasms of the urinary already established two initiatives in which patients are
system and male genital orgasms can be found in the papers involved: EAU Patient Information (https://patients.uro-
by Moch et al and Netto et al and in the book [1–3]. For web.org/) and EAU Patient Advocacy Group (EPAG) [14].
instance, immune checkpoint inhibitors now have a role EPAG members have ‘‘an important role in the production
in the treatment of metastatic RCC [8]. Bladder cancer and assessment of guidelines and protocols and the dissem-
tumors, including their variants, can be divided into two ination of information and knowledge generated by the EAU
molecular subtypes, referred to as luminal and basal. Each as well as to ensure that patients remain at the center of any
subtype may react differently to current chemotherapy or decision-making and activities’’ [14].
immunotherapy [9].
6. Conclusions
4. Digital pathology and artificial intelligence
The knowledge of readers of European Urology has been
The 5th edition of the Blue Book includes a collection of dig- enriched by Moch et al [2] and Netto et al [3] with their vital
ital slides of tumors of the urinary system and male genital updates on neoplasms of the urinary system and male gen-
organs, including the prostate and urinary tract [1–3]. This ital organs and their clinical significance. All this will lead to
Fig. 2 – Cover of the ‘‘Blue Book’’ from the complimentary copy of the senior author.
further improvements in the prevention, diagnosis, and WHO Classification of Tumours of the Urinary System and Male
management of genitourinary cancers in individual cases Genital System and had full access to the 5th edition pub-
via adoption of a multidisciplinary approach in which urol- lished online by the International Agency for Research on
ogists, oncologists, radiotherapists, radiologists, patholo- Cancer and the print version.
gists, and basic and translational researchers work The four examples briefly discussed above reflect the
together for and with the patient. Only this approach will professional and personal experiences of the senior author:
allow full and successful integration of data from all sources Concept of molecularly defined renal tumor entities, and
and is key to success [15]. Diagnostic, prognostic and predictive molecular markers:
Training as uro-oncologist; Digital pathology and artificial
intelligence: Pathologist; and Prostate cancer grading: Rep-
Conflicts of interest: The authors have nothing to disclose.
resentative in patient advocacy groups.
It was beyond the scope of this editorial to cover all the
Appendix A
features of the tumors of the urinary system and male gen-
ital system. Interested readers should refer to the two
The senior author (R.M.) of this contribution was author and
papers and to the ‘‘Blue Book’’ (Fig. 2).
co-author of chapters in the 3rd, 4th, and 5th editions of the
References [8] Lopez-Beltran A, Cimadamore A, Blanca A, et al. Immune checkpoint

inhibitors for the treatment of bladder cancer. Cancers
[1] International Agency for Research on Cancer. WHO classification of 2021;13:131.
tumours: urinary and male genital tumours. ed. 5. Vol. 8. Lyon, [9] Rebola J, Aguiar P, Blanca A, et al. Predicting outcomes in non-
France: IARC; 2022. muscle invasive (Ta/T1) bladder cancer: the role of molecular grade
[2] Moch H, Amin MA, Berney DM, et al. The 2022 World Health based on luminal/basal phenotype. Virchows Arch
Organization classification of tumours of the urinary system and 2019;475:445–55.
male genital organs—part A: renal, penile, and testicular tumours. [10] Cimadamore A, Lopez-Beltran A, Scarpelli M, et al. Artificial
Eur Urol 2022;82:458–68. intelligence and prostate cancer: advances and challenges.
[3] Netto GJ, Amin MB, Berney DM, et al. The 2022 World Health Urologia 2022. https://doi.org/10.1177/03915603211062409, In
Organization classification of tumors of the urinary system and press.
male genital organs—part B: prostate and urinary tract tumors. Eur [11] van Leenders GJLH, van der Kwast TH, Grignon DJ, et al. The 2019
Urol 2022;82:469–82. International Society of Urological Pathology (ISUP) consensus
[4] Montironi R, Cheng L, Scarpelli M, Lopez-Beltran A. Pathology and conference on grading of prostatic carcinoma. Am J Surg Pathol
genetics: tumours of the urinary system and male genital system: 2020;44:e87–99.
clinical implications of the 4th edition of the WHO classification [12] Epstein JI, Amin MB, Fine SW, et al. The 2019 Genitourinary
and beyond. Eur Urol 2016;70:120–3. Pathology Society (GUPS) white paper on contemporary grading of
[5] Eble J, Sauter G, Epstein J, Sesterhenn I. Tumours of the kidney. prostate cancer. Arch Pathol Lab Med 2021;145:461–93.
International Agency for Research on Cancer. Tumours of the [13] Montironi R, Cimadamore A, Scarpelli M, et al. Queries from a
urinary system and male genital organs. Lyon, France: IARC Press; patient with intraductal prostate carcinoma. And how two separate
2004. uropathology societies deal with IDC-P. Eur Urol Today 2021;33
[6] Clark DJ, Dhanasekaran SM, Petralia F, et al. Integrated (1):14.
proteogenomic characterization of clear cell renal cell carcinoma. [14] European Association of Urology. Patient advocacy. https://patients.
Cell 2019;179:964–983.e31. uroweb.org/patient-advocacy/.
[7] Rosellini M, Santoni M, Mollica V, et al. Treating prostate cancer by [15] Montagut C, Albanell J, Bellmunt J. Prostate cancer.
antibody-drug conjugates. Int J Mol Sci 2021;22:1551. Multidisciplinary approach: a key to success. Crit Rev Oncol
Hematol 2008;68(Suppl 1):S32–6.
Platinum Priority – Review – Prostate Cancer

Editorial by David Chang, Pierre Blanchard, Shankar Siva on pp. 499–500 of this issue
Local Failure Events in Prostate Cancer Treated with Radiotherapy: A

Pooled Analysis of 18 Randomized Trials from the Meta-analysis of
Randomized Trials in Cancer of the Prostate Consortium
(LEVIATHAN)
Ting Martin Ma a, Fang-I Chu a, Howard Sandler b, Felix Y. Feng c, Jason A. Efstathiou d,
Christopher U. Jones e, Mack Roach 3rd f, Seth A. Rosenthal e, Thomas Pisansky g, Jeff M. Michalski h,
Michel Bolla i, Theo M. de Reijke j, Philippe Maingon k, Anouk Neven l, James Denham m,
Allison Steigler m, David Joseph n, Abdenour Nabid o, Luis Souhami p, Nathalie Carrier q,
Luca Incrocci r, Wilma Heemsbergen s, Floris J. Pos s, Matthew R. Sydes t, David P. Dearnaley u,v,
Alison C. Tree v,w, Isabel Syndikus x, Emma Hall v, Clare Cruickshank v, Shawn Malone y,
Soumyajit Roy z, Yilun Sun aa,bb, Nicholas G. Zaorsky bb, Nicholas G. Nickols a, Robert E. Reiter cc,
Matthew B. Rettig cc,dd, Michael L. Steinberg a, Vishruth K. Reddy a, Michael Xiang a,
Tahmineh Romero ee, Daniel E. Spratt bb, Amar U. Kishan a,*, on behalf of the Meta-analysis of
Randomized trials in Cancer of the Prostate MARCAP Consortium investigators1
a
Depart of Radiation Oncology, University of California Los Angeles, Los Angeles, CA, USA; b Department of Radiation Oncology, Cedars Sinai, Los Angeles, CA,
USA; c Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA; d Department of Radiation Oncology, Massachusetts
General Hospital, Harvard Medical School, Boston, MA, USA; e Department of Radiation Oncology, Sutter Medical Group, Roseville, CA, USA; f Department of
Radiation Oncology, University of California San Francisco, San Francisco, CA, USA; g Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA;
h
Department of Radiation Oncology, Washington University School of Medicine in St. Louis, St. Louis, MO, USA; i Department of Radiation Therapy, CHU
Grenoble, Grenoble, France; j Department of Urology, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, The Netherlands;
k
Department of Radiation Oncology, Centre Georges François Leclerc, University of Burgundy, Dijon, Burgundy, France; l Luxembourg Institute of Health,
Competence Center for Methodology and Statistics, Strassen, Luxembourg; m School of Medicine and Public Health, Faculty of Health and Medicine University of
Newcastle, Newcastle, NSW, Australia; n Department of Surgery, University of Western Australia; o Department of Radiation Oncology, Centre Hospitaler
Universitaire de Sherbrooke, Sherbrooke, QC, Canada; p Department of Radiation Oncology, McGill University Health Centre, Montreal, QC, Canada; q Centre de
recherche clinique, Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada; r Department of Radiation Oncology, Erasmus Medical Center,
Rotterdam, The Netherlands; s Department of Radiation Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands; t MRC Clinical Trials Unit at
UCL, University College London, London, UK; u Academic Urology Unit, Royal Marsden Hospital, London, UK; v The Institute of Cancer Research, London, UK;
w
The Royal Marsden NHS Foundation Trust, London, UK; x Clatterbridge Cancer Centre, Wirral, UK; y The Ottawa Hospital Cancer Centre, Ottawa Hospital
Research Institute, Ottawa, Ontario, Canada; z Department of Radiation Oncology, Rush University Medical Center, Chicago, IL, USA; aa Department of
Population and Quantitative Health Sciences, Case Western Reserve University School of Medicine, Cleveland, OH, USA; bb Department of Radiation Oncology,
University Hospitals Seidman Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH, USA; cc Department of Urology, University of
California Los Angeles, Los Angeles, CA, USA; dd Division of Hematology/Oncology, Department of Medicine, University of California Los Angeles, Los Angeles, CA,
USA; ee Department of Medicine Statistics Core, University of California Los Angeles, Los Angeles, CA, USA
1
Investigators are listed in the Supplementary material.
* Corresponding author. Department of Radiation Oncology, University of California Los Angeles, 200
Medical Plaza Driveway, Suite #B265, Medical Plaza Driveway, Los Angeles, CA 90095, USA.
Tel. +1 310 825 9775; Fax: +1 310 794 9795.
E-mail address: [email protected] (A.U. Kishan).
under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
Article history: Context: The prognostic importance of local failure after definitive radiotherapy (RT) in
Accepted July 14, 2022 National Comprehensive Cancer Network intermediate- and high-risk prostate cancer
(PCa) patients remains unclear.
Objective: To evaluate the prognostic impact of local failure and the kinetics of distant
metastasis following RT.
Evidence acquisition: A pooled analysis was performed on individual patient data of 12
533 PCa (6288 high-risk and 6245 intermediate-risk) patients enrolled in 18 randomized
trials (conducted between 1985 and 2015) within the Meta-analysis of Randomized
Trials in Cancer of the Prostate Consortium. Multivariable Cox proportional hazard
(PH) models were developed to evaluate the relationship between overall survival
(OS), PCa-specific survival (PCSS), distant metastasis-free survival (DMFS), and local fail-
Keywords: ure as a time-dependent covariate. Markov PH models were developed to evaluate the
Distant metastasis impact of specific transition states.
Local control Evidence synthesis: The median follow-up was 11 yr. There were 795 (13%) local failure
Local failure events and 1288 (21%) distant metastases for high-risk patients and 449 (7.2%) and 451
Pooled analysis (7.2%) for intermediate-risk patients, respectively. For both groups, 81% of distant metas-
Prostate cancer tases developed from a clinically relapse-free state (cRF state). Local failure was signifi-
Radiation therapy cantly associated with OS (hazard ratio [HR] 1.17, 95% confidence interval [CI] 1.06–
1.30), PCSS (HR 2.02, 95% CI 1.75–2.33), and DMFS (HR 1.94, 95% CI 1.75–2.15,
p < 0.01 for all) in high-risk patients. Local failure was also significantly associated with
DMFS (HR 1.57, 95% CI 1.36–1.81) but not with OS in intermediate-risk patients. Patients
without local failure had a significantly lower HR of transitioning to a PCa-specific death
Please visit www.eu-acme.org/europeanurology state than those who had local failure (HR 0.32, 95% CI 0.21–0.50, p < 0.001). At later time
to answer questions on-line. The EU-ACME cred- points, more distant metastases emerged after a local failure event for both groups.
its will then be attributed automatically. Conclusions: Local failure is an independent prognosticator of OS, PCSS, and DMFS in
high-risk and of DMFS in intermediate-risk PCa. Distant metastasis predominantly
developed from the cRF state, underscoring the importance of addressing occult micro-
scopic disease. However a ‘‘second wave’’ of distant metastases occurs subsequent to
local failure events, and optimization of local control may reduce the risk of distant
metastasis.
Patient summary: Among men receiving definitive radiation therapy for high- and
intermediate-risk prostate cancer, about 10% experience local recurrence, and they are
at significantly increased risks of further disease progression. About 80% of patients
who develop distant metastasis do not have a detectable local recurrence preceding it.
Urology. This is an open access article under the CC BY-NC-ND license (http://creative-
commons.org/licenses/by-nc-nd/4.0/).
1. Introduction randomized trials have shown that increased local control

is associated with increased DMFS as well as PCa-specific
Distant metastasis-free survival (DMFS) has been demon- survival (PCSS) [5,7–11]. However, only two randomized
strated to be a strong surrogate endpoint for overall survival controlled trials (RCTs) among many have suggested a dis-
(OS) for localized prostate cancer (PCa) [1,2]. Recent evi- tant metastasis benefit from dose escalation and none iden-
dence derived from prostate-specific membrane antigen tified a PCSS or OS benefit [12,13]. In contrast, while
(PSMA) positron emission tomography/computed tomogra- androgen deprivation therapy (ADT) may have radiosensi-
phy (PET/CT) suggests that occult distant metastases at pre- tizing effects that improve local control, it also has cyto-
sentation may be the true driver of PCa natural history, static and cytotoxic effects on occult microscopic disease
especially for patients with National Comprehensive Cancer and has been shown in multiple randomized trials to
Network (NCCN) high-risk disease [3,4]. This is especially improve not only DMFS, but PCSS and OS as well [14–19].
relevant for assessing the prognostic impact of local failure As each form of treatment intensification has quality of life
and the clinical importance of local treatment intensifica- implications, it is critical to develop a unified framework
tion strategies such as radiotherapy (RT) dose escalation. that takes into account the temporal relationship of local
At the core of dose escalation is the hypothesis that local failure and distant metastasis (ie, first and second ‘‘waves’’
failure eventually ‘‘seeds’’ distant metastases, leading to a of distant metastasis), and how different treatment strate-
‘‘second wave’’ of distant metastases (the first wave being gies (ie, dose escalation and ADT) impact the development
undiagnosed occult metastatic disease at presentation) of distant metastasis and other clinical outcomes. It is
[5,6]. However, data in this domain are not entirely consis- hypothesized that a first wave of distant metastasis stems
tent. Retrospective studies as well as post hoc analyses of from the emergence of occult micrometastatic disease that
was present at the time of initial treatment, which may be Consortium. Although a minority of the trials permitted
followed by a subsequent second wave of distant metastasis node-positive patients, all patients included in this analysis
representing ‘‘seeding’’ from a preceding local failure event. had clinically node-negative disease. For trials that included
The magnitude of the first wave distant metastasis may be ADT, only those with short-term ADT (STADT) and long-
smaller in intermediate-risk patients than in high-risk term ADT (LTADT) were included. STADT was defined as
patients given a lower burden of occult metastasis at initial 3–9 mo of ADT and LTADT was defined as 18–36 mo. Trials
treatment. In this study, we leveraged the Meta-analysis of with nonstandard ADT duration (eg, life-long ADT) and non-
Randomized Trials in Cancer of the Prostate (MARCAP) Con- standard ADT agents (eg, bicalutamide monotherapy) were
sortium to analyze individual patient data from 18 RCTs of excluded (Fig. 1). Intention-to-treat data were used. Trials
definitive RT of varying RT dose levels and ADT durations included in the analysis are listed in Table 1, and trial-
that included local failure as a prespecified endpoint to specific definitions of local failure and distant metastasis
explore the prognostic impact of local failure events and are listed in Supplementary Table 1. All time-to-event out-
the kinetics of distant metastasis after RT in intermediate- come variables were measured from the date of randomiza-
and high-risk PCa. tion to the reported occurrence of the event of interest. If a
specific event was not reported during the follow-up period,
2. Evidence acquisition the patient was considered censored for that particular
event. The reverse Kaplan-Meier (KM) method was used
The current study followed the Preferred Reporting Items to assess the length and completeness of the follow-up.
for Systematic Reviews and Meta-analyses (PRISMA) state- Multivariable Cox proportional hazard (PH) models were
ment regarding the process of identifying eligible trials to developed to evaluate the relationship between OS, PCSS,
be included in the pooled analysis (Fig. 1) [20]. Individual DMFS, and local failure (as a time-dependent covariate),
patient data for 18 RCTs were obtained from the MARCAP while adjusting for the following variables: initial
Fig. 1 – Preferred Reporting Items for Systematic Reviews and Meta-analyses flowchart. ADT = androgen deprivation therapy.
Table 1 – Summary of trials included in study (by treatment categories)
Trial name Trial recruitment year Radiation ADT Median No. of No. of Median
dose (Gy) duration age (yr) intermediate-risk high-risk follow-up
(mo) patients patients (yr)
Low-dose RT alone
RTOG 8610 1987–1991 65–70 NA 72 2 50 6.7
EORTC 22863 1987–1995 70 NA 69 1 87 5.0
RTOG 9408 1994–2001 66.6 NA 72 435 91 9.4
TROG 96.01 1996–2000 66 NA 68 68 148 10
CKTO 9610 1997–2003 68 NA 69 84 111 8.5
EORTC 22991 2001–2008 70 NA 68 46 33 12
RTOG 0126 2002–2008 70.2 NA 71 751 0 8.4
Subtotal 1387 520
High-dose RT alone
CKTO 9610 1997–2003 78 NA 69 84 105 8.4
PCS III 2000–2010 76 NA 72 192 0 11
EORTC 22991 2001–2008 74 or 78 NA 71 166 62 11
RTOG 0126 2002–2008 79.2 NA 71 748 0 8.2
Subtotal 1190 167
Low-dose RT + short-term ADT
RTOG 8610 1987–1991 65–70 4 70 3 48 8.8
RTOG 9202 1992–1995 65–70 4 70 42 456 8.9
RTOG 9408 1994–2001 66.6 4 71 420 94 10
RTOG 9413 1995–1999 70.2 4 70 208 993 8.9
TROG 96.01 1996–2000 66 6 69 148 284 11
ICORG 97-01 1997–2001 70 4 or 8 67 42 135 10
EORTC 22961 1997–2001 70 6 70 30 307 5.9
CKTO 9610 1997–2003 68 6 69 1 30 6.8
MRC RT01 1998–2001 64 3–6 68 141 147 9.2
RTOG 9910 2000–2004 70.2 4 or 9 71 1057 353 8.7
PCS III 2000–2010 70 6 71 193 0 11
EORTC 22991 2001–2008 70 6 70 44 35 11
TROG RADAR 2003–2007 66 or 70 6 70 124 154 11
Subtotal 2453 3036
Low-dose RT + long-term ADT
EORTC 22863 1987–1995 70 36 71 2 86 7.5
RTOG 9202 1992–1995 65–70 24 70 50 487 9.6
EORTC 22961 1997–2001 70 36 69 33 297 6.1
CKTO 9610 1997–2003 68 36 66 5 28 8.0
RTOG 9902 2000–2004 70.2 24 65 0 239 10
PCS IV 2000–2008 70 18 or 36 71 0 617 11
TROG RADAR 2003–2007 66 or 70 18 69 111 158 11
Subtotal 201 1912
High-dose RT + short-term ADT
CKTO 9610 1997–2003 78 6 68 5 20 5.1
MRC RT01 1998–2001 74 3–6 67 129 157 9.2
PCS III 2000–2010 76 6 71 195 0 11
Ottawa 0101 2002–2012 76 6 70 394 0 10
TROG RADAR 2003–2007 74 or 46 Gy/ 23 fx plus HDR-BT boost 6 68 60 186 10
EORTC 22991 2001–2008 74 or 78 6 72 175 56 11
Subtotal 958 419
High-dose RT + long-term ADT
CKTO 9610 1997–2003 78 36 67 3 36 8.3
TROG RADAR 2003–2007 74 or 46 Gy/ 23 fx plus HDR-BT boost 18 68 53 198 10
Subtotal 56 234
Total 6245 6288
ADT = androgen deprivation therapy; fx = fraction; HDR-BT = high-dose-rate brachytherapy; RT = radiation therapy.
prostate-specific antigen (iPSA; continuous variable; per Fine and Gray competing risk regression was performed
10 ng/mL), Gleason score (GS; 6, 7, and 8–10; GS 6 as refer- for PCa-specific mortality (PCSM) and distant metastasis
ence), treatment category (low-dose RT only, low-dose with all-cause mortality death as the competing event; in
RT + STADT, low-dose RT + LTADT, high-dose RT only, these analyses, local failure was a time-independent covari-
high-dose RT + STADT, and high-dose RT + LTADT; low- ate. The hazard function for the development of distant
dose RT as reference [Cox PH model], or RT, STADT, and metastasis over time was estimated via kernel-based meth-
LTADT; RT as reference [Markov model]), T stage (T1–2 ods in subgroups of patients based on local failure status
and T3–4; T1–2 as reference), age (continuous variable; and ADT duration, to provide an overview as an exploratory
per 10 yr), and time from midpoint year of the trial (contin- analysis. Furthermore, within each treatment category, haz-
uous variable). These variables were chosen because of ard rates for distant metastasis over 2-yr intervals were cal-
availability and prior data suggesting that these were of culated using the life-table method for patients with and
prognostic importance. RT doses of 74 Gy were considered without local failure as a time-independent covariate. The
‘‘high dose’’ (presuming an a/b of 3.0). Patients without clin- hypothesis of first and second waves of distant metastasis
ically diagnosed extracapsular extension or seminal vesicle was evaluated based on the hazard rate of distant metasta-
invasion were classified as having T1-T2 disease. sis as well as the event rate of different transition states to
Fig. 2 – Crude rates of events and transition time between disease states in the four-state model. The four states are clinical relapse-free state, local failure
state, distant metastasis state, and death state (all-cause mortality and prostate cancer–specific mortality). (A and B) NCCN high-risk patients, and (C and D)
NCCN intermediate-risk patients. Figures 2A and 2C) show the number of patients in each transition state, with percentage in parenthesis. Percentage was
calculated with the number of patients in the beginning state as the denominator (eg, for distant metastasis to PCSM transition, the denominator was the
number of patients with distant metastasis [ie, 1288 for NCCN high risk]). Arrows with the same fill patterns (solid, dotted, or hashed) share the same
denominator. Figures 2B and 2D show the median transition time between disease states in months with interquartile range in parenthesis; overall cohort of
patients are same as in Figures 2A and 2C). Each transition time in Figures 2B and 2D was calculated based on different subcohorts of patients. ACM = all-cause
mortality; NCCN = National Comprehensive Cancer Network; PCSM = prostate cancer–specific mortality.
distant metastasis over time in local failure and local con- certain treatment subgroups. The Mann-Whitney U test
trol patients. was used to compare the median time to a specific transi-
We developed a four-state model to simultaneously ana- tion state between patients of different risk levels or treat-
lyze multiple events occurring during the natural history of ment categories. The level of significance was set to be 0.05.
PCa (Fig. 2). The model consists of a clinical relapse-free sur- All analyses were carried out via R version 3.6.0/4.1.2 (R
vival state (cRF state, which may or may not include bio- Foundation for Statical Computing, Vienna, Austria) [21]
chemical recurrence), a local failure state, a distant with packages survival [22,23], muhaz [24], KMsurv [25],
metastasis state, and a death state. Patients who did not crrSC [26], cmprsk [27], coxme [28], mstate [29,30], dplyr
have a PCSM event were censored for PCSS. Markov PH [31] and ggplot2 [32], devtools [33], ggforestplot [34], and
models for the four-state model were developed to assess gridExtra [35].
the effects of the aforementioned covariates on PCSS and
OS along with the effect of a transition from the cRF state 3. Evidence synthesis
versus local failure state to the death state. This model
was not stratified by NCCN risk groups. The potential
3.1. Results
heterogeneity between trials was accounted for by includ-
ing random effects in Cox PH and Markov PH models. The A total of 12 533 patients (6288 high risk and 6245 interme-
PH assumption was examined via the diagnostic plot diate risk) were included in the analysis from 18 random-
method. The chi-square test of independence (or Fisher’s ized trials, recruited from 1987 to 2012 (Supplementary
exact test when applicable) was used to assess the associa- Table 1). The median follow-up was 11 yr overall, 12 yr
tion of the rate of transition between disease states with for high-risk patients, and 11 yr for intermediate-risk
patients, using the reverse KM method. The numbers of interval of 37 (IQR 7–61) mo after local failure. Regarding
events of local failure, distant metastasis, PCSM, and all- local failure, 95% (n = 428) of events occurred from a cRF
cause mortality were 795, 1288, 1034, and 3210, respec- state with a corresponding median interval of 50 (IQR 18–
tively, for patients with high-risk PCa; these numbers were 87) mo after initial treatment. For patients who developed
449, 451, 353, and 2374, respectively, for patients with distant metastasis, 52% (n = 235) died of PCa. The median
intermediate-risk PCa. interval from distant metastasis to death was 18 (IQR 8–
We first evaluated the crude rates of events and transit 39) mo. Rates and transit times between four states within
time between states in the four-state model (Fig. 2). For each treatment group are shown in Supplementary Figs. 1
high-risk patients, 39% of distant metastasis events and 2.
occurred within 2 yr after RT; 81% (n = 1042) of distant Next, we assessed the impact of local failure on the
metastases developed from a cRF state, with a median inter- development of distant metastasis and other clinical end-
val of 46 (interquartile range [IQR] 24–76) mo. In contrast, points. In high-risk patients, local failure, as a time-
19% (n = 246) of distant metastases developed after local dependent variable, was significantly associated with a
failure, with a median interval of 24 (IQR 7–55) mo after greater hazard of distant metastasis or death (as a compos-
local failure. With respect to local failure, 92% (n = 729) of ite endpoint, hazard ratio [HR] of 1.94 [95% confidence
events occurred from a cRF state with a corresponding med- interval {CI} 1.75–2.15], p < 0.001; Fig. 3A) in the Cox PH
ian interval of 39 (IQR 22–71) mo after initial treatment. model adjusted for iPSA, GS, treatment categories, T stage,
Among patients who developed distant metastasis, 63% age, and time from midpoint year of the trial. Local failure
(n = 807) died of PCa. The median interval from distant was also significantly associated with PCSS and OS (HRs
metastasis to death was 21 (IQR 10–38) mo. For 2.02 [95% CI 1.75–2.33], p < 0.001 and 1.17 [95% CI 1.06–
intermediate-risk patients, 13% of distant metastasis events 1.30], p < 0.01; Fig. 3B and 3C). In intermediate-risk
occurred within 2 yr after RT; 81% (n = 364) of distant patients, local failure was significantly associated with a
metastases developed from a cRF state, with a median inter- greater hazard of distant metastasis or death (HR 1.57
val of 60 (IQR 36–96) mo. In contrast, 19% (n = 87) of distant [95% CI 1.36–1.81], p < 0.001), but not OS (HR 0.93 [95% CI
metastases developed after local failure, with a median 0.81–1.08], p = 0.35; Fig. 3D and 3E). The model fit was
Fig. 3 – Forest plots of Cox proportional hazard model with local failure as a time-dependent variable. (A) DMFS, (B) PCSS, and (C) OS for NCCN high-risk
patients, and (D) DMFS and (E) OS for NCCN intermediate-risk patients. T1/2, Gleason score 6, and low-dose RT only were used as the reference for their
respective categories. The interactions between the Gleason score and treatment strategies were found to be insignificant and not reported in the forest plots.
See the text for definition of low/high-dose RT and STADT/LTADT. CI = confidence interval; DMFS = distant metastasis-free survival; HR = hazard ratio;
iPSA = initial prostate-specific antigen; LTADT long-term androgen deprivation therapy; NCCN = National Comprehensive Cancer Network; OS = overall
survival; PCSS = prostate cancer–specific survival; RT = radiation therapy; STADT = short-term androgen deprivation therapy.
not attainable for the PCSS endpoint. In the Fine and Gray while those without local failure had an initial peak around
competing risk regression with all-cause mortality death year 3, with a gradual decline for the rest of the study period
as the competing event and local failure as a time- (Fig. 5A). Patients with intermediate-risk disease followed a
independent covariate, local failure was significantly associ- similar trend, although the hazard rate was generally lower,
ated with PCSS (subdistribution HR [sHR] 2.15 [95% CI 1.84– and patients without local failure maintained a steady haz-
2.5], p < 0.001) and distant metastasis (sHR 1.77 [95% CI ard rate without a discernable initial peak (Fig. 5B). Similar
1.46–2.14], p < 0.001) in high-risk patients (Supplementary temporal changes were observed in the hazard rate of dis-
Fig. 3A and 3B). In intermediate-risk patients, local failure tant metastasis over 2-yr intervals using the life-table
was also significantly associated with a greater hazard of method (Supplementary Figs. 6 and 7). In addition, the per-
PCSS (sHR 3.34 [95% CI 2.52–4.44], p < 0.001) and distant centage of distant metastasis events occurring from a cRF
metastasis (sHR 3.63 [95% CI 2.93–4.49], p < 0.001; Supple- state declined over time, while the proportion occurring
mentary Fig. 3C and 3D). In the Markov model derived from after a local failure event increased steadily among both
the four-state model adjusting for the GS, iPSA, T stage, high- and intermediate-risk patients (Fig. 5C and 5D). In
treatment category, age, and time from midpoint year of high-risk patients, 91% and 9% of distant metastasis origi-
the trial, patients who did not have local failure had a signif- nated from a cRF state and a local failure state, respectively,
icantly lower hazard of PCSM than those who had local fail- during 0–2 yr after RT; these changed to 66% and 34%,
ure (HR 0.32 [95% CI 0.21–0.5], p < 0.001; Fig. 4A), but not of respectively, when assessing distant metastasis events
all-cause mortality (HR 1.07 [95% CI 0.88–1.31], p = 0.5; developing between 8 and 10 yr after RT. In intermediate-
Fig. 4B). Patients who developed distant metastasis had a risk patients, 92% and 8% of distant metastasis originated
significantly greater hazard of PCSM (HR 12.85 [95% CI from a cRF state and a local failure state, respectively, dur-
8.67–19.03], p < 0.001) and all-cause mortality (HR 4.81 ing 0–2 yr after RT, and 73% and 27%, respectively, between
[95% CI 3.85–6.01], p < 0.001) than those who developed 8 and 10 years after RT. Similar trends were seen when
only local failure (Fig. 4A and 4B). Crude event rates by 2- stratified by treatment categories (Supplementary Figs. 8
yr intervals are shown for each transition for patients with and 9).
high- and intermediate-risk disease (Supplementary Figs. 4 Finally, we examined the effect of ADT and RT dose on
and 5). various transition states. ADT significantly reduced the inci-
When stratified by local failure status, estimated by dence (24% vs 16%, p < 0.0001) and delayed the onset of dis-
kernel-based methods, high-risk patients with local failure tant metastasis from a cRF state (27.1 vs 48.5 mo,
seem to have a higher risk of distant metastasis numeri- p < 0.0001) in high-risk patients. However, ADT did not sig-
cally, with a steep increase within the first 10 yr after RT, nificantly reduce the rates of distant metastasis from the
Fig. 4 – Forest plots of the Markov model for prostate cancer–specific survival and overall survival in the four-state model. T1/2 and Gleason score 6 were used
as the reference for their respective categories. ADT: transition state indicates that the effect is specific on the respective transition. For example, ‘‘STADT: cRFS
? LF’’ denotes the effect of STADT specifically on the transition between the cRF state and LF state. For those without appended transition states, a
homogeneous effect of the covariate across transitions was assumed. CI = confidence interval; cRFS/cRF state = clinical relapse-free state; DM = distant
metastasis; HR = hazard ratio; iPSA = initial prostate-specific antigen; LF = local failure; LTADT = long-term androgen deprivation therapy; OS = overall
survival; PCSS = prostate cancer–specific survival; STADT = short-term androgen deprivation therapy.
Fig. 5 – Hazard rate of distant metastasis over time and percentage of distant metastasis from a clinically relapse-free state versus a local failure state during
different time periods in NCCN high- and intermediate-risk patients stratified by local failure status. Hazard rates of distant metastasis over time using
kernel-based methods are shown in NCCN (A) high-risk and (B) intermediate-risk patients. Tables below the graphs indicate the number of patients who were
still at a risk of distant metastasis event at different time points. Percentages of distant metastasis from a clinically relapse-free state versus a local failure
state during different time periods are shown in NCCN (C) high-risk and (D) intermediate-risk patients. The percentage of distant metastasis events denotes
the proportion of distant metastasis during the specified 2-yr interval after RT that was preceded by a cRF state versus an LF state. For example, for high-risk
patients at 4–6 yr after RT, 80% of metastatic events arose from a cRF state and 20% from an LF state. The number of distant metastasis events below the
graphs indicate the number of distant metastasis events developed in specific intervals. For example, 337 distant metastasis events developed between 2 and
4 yr after RT. Note that in Figures 5C and 5D), the percentages of all distant metastasis events below the graphs do not add up to 100% as a small percentage of
patients developed distant metastases beyond 14 yr after RT. cRF state = clinically relapse-free state; DM = distant metastasis; LF = local failure;
NCCN = National Comprehensive Cancer Network; RT = radiation therapy.
cRF state (6.4% vs 5.4%, p = 0.13) or delay the time from the by STADT; only delayed first wave was seen in patients trea-
cRF state to distant metastasis for intermediate-risk ted with LTADT with no discernable second wave.
patients (60.3 vs 61.8 mo, p = 0.24). ADT significantly
decreased the local failure rate from a cRF state in both
high-risk (11% vs 20%, p < 0.0001) and intermediate-risk 3.2. Discussion
(6.2% vs 7.8%, p = 0.017) patients. Compared with low- In this individual patient-level pooled analysis of 18 ran-
dose RT, high-dose RT significantly decreased the local fail- domized trials, we demonstrate that the vast majority of
ure rate from a cRF state in high-risk (12% vs 8.0% for low- distant metastasis events (>80%) occur in patients who are
vs high-dose group, p = 0.0007) and intermediate-risk (8.6% clinically relapse free. Local failure events, however, por-
vs 3.7%, p < 0.0001) patients. The proportions of distant tend a poor prognosis in both patients with high-risk dis-
metastasis developed after local failure in regard to the total ease (for whom it is associated with OS, PCSS, and DMFS)
number of distant metastasis events were significantly and those with intermediate-risk disease (for whom it is
reduced with high-dose RT for both high-risk (12% vs 20%, associated with DMFS). We also identified a biphasic pat-
p = 0.0035) and intermediate-risk (13% vs 22%, p = 0.019) tern of distant metastasis development wherein an initial
PCa patients. The hazard rate of distant metastasis over large first wave of distant metastases was followed years
time in patients treated with RT only, RT + STADT, and later by a smaller second wave occurring subsequent to
RT + LTADT in high- and intermediate-risk patients is shown the time when the majority of local failure events occurred.
in Supplementary Fig. 10. Two waves of distant metastases The proportion of distant metastasis events arising from a
were seen in high-risk patients treated without ADT; the cRF state decreased steadily, while the proportion occurring
first wave was reduced, while the second wave was delayed after a local failure event increased over time. Finally, we
demonstrated that the upfront use of ADT in patients with [40], explaining the absence of first wave seen in the com-
high-risk disease decreased distant metastasis development bined cohort in the current study. While a second wave
irrespective of whether the distant metastases originated was not noticeably present in intermediate-risk patients, a
from the cRF state or the local failure state, while dose esca- late-onset increase in local failure to distant metastasis
lation reduced only the development of local failure from transition events and an increase in the proportion of dis-
the cRF state. tant metastasis events arising from the local failure state
These data provide a framework for understanding the over time were still observed, consistent with the concept
patterns of clinical relapse in high- and intermediate-risk of distant seeding from local failure events. As would be
PCa, and how different treatment intensification strategies expected with this framework, dose escalation alone with-
might alter these relapse patterns. The major mode of dis- out ADT is unlikely to robustly augment DMFS as the pre-
tant metastasis development is from a cRF state, likely rep- dominant mode of distant metastasis is from the cRF
resenting the emergence of occult micrometastatic disease state, and not from local failure. On the contrary, ADT pre-
that was present at the time of initial treatment. This can vents the development of distant metastasis by inhibiting
be suppressed with the use of upfront ADT and/or androgen both the cRF state to distant metastasis transition and the
receptor signaling inhibitors such as abiraterone [36,37]. A cRF state to local failure transition. This is consistent with
smaller proportion of distant metastasis events—albeit one the observation that ADT has both a cytostatic and a cyto-
that grows with time—emerges after a local failure event toxic effect [41,42], and synergizes with RT for optimal
has occurred. This proportion can be minimized with the PCa cell killing [43,44]. The effect of ADT on the cRF state
use of both upfront ADT and higher-dose RT; together these to distant metastasis transition in patients with
would be expected to improve local control. Local failure intermediate-risk disease was not significant, although the
events, when these occur, are associated with a worse prog- low event rate likely impacted the power to detect a signif-
nosis. Mechanistically, this might be either because they icant difference, and multiple other lines of evidence sug-
directly seed subsequent distant metastasis events or gest that upfront ADT certainly limits the development of
because cancers that relapse locally may simply be more distant metastasis events in patients with intermediate-
aggressive and thus also more likely to metastasize. In sup- risk disease [19,40]. Emerging strategies, such as focal
port of the former possibility is the distinct temporal pat- microboosts, may be associated with lower rates of regional
tern of distant metastasis development among patients failure, although a significant change in distant metastatic
with and without local failure, as well as the increasing rate failure has not been reported [45].
of distant metastasis over time in patients with local failure. The present study has several limitations. First, despite
Interestingly, we also observed that a minority of local fail- pooling across multiple trials, some treatment subgroups
ure events developed after distant metastases (8.3% and remained small in size, potentially limiting the statistical
4.7% of local failure events in high- and intermediate-risk power of subgroup analysis and generalizability. For exam-
patients, respectively; Fig. 2A and 2C), raising the possibility ple, only 10% of high-risk patients received high-dose RT
that distant metastasis may seed a second wave of local fail- plus ADT. Second, heterogeneity between trials is also a lim-
ure, as observed in a whole-genome sequencing study [38]. itation for a pooled analysis in general, including the cur-
A schematic depiction of transitions over time for patients rent study. We have attempted to mitigate this by using
with high-risk disease, as well as potential effects of ADT random effects in our modeling [46]. Third, there was
use and RT dose escalation, is shown in Supplementary heterogeneity in the definition of local failure and distant
Fig. 11. The peak distant metastasis rate was within 2–4 metastasis across trials (Supplemental Table 1). Some trials
yr of RT completion, with most events arising from a cRF did not specify the definition, while some were reliant on
state. The smaller-amplitude second wave was seen digital rectal examination to determine the local failure sta-
approximately 6–10 yr after RT completion, and coincided tus. Certain trials (eg, RTOG 9902) included regional lymph
with the rise in distant metastases in patients with local node involvement in the definition of local failure. Nonuni-
failure and increase in local failure to distant metastasis form definition of local failure and PSA-driven imaging also
transitions. The true amplitude of the second wave may likely impacted the reliability of cRF-state determination in
be underestimated here given relatively short follow-up certain cases. However, trials with nonconventional defini-
time of certain trials. The first wave was reduced in ampli- tions remained a minority. Fourth, incorporating post-
tude and delayed by the addition of ADT, with LTADT having treatment prostate biopsy [47,48] and/or advanced imaging
more dramatic effect than STADT. The second wave was also such as multiparametric magnetic resonance imaging and
delayed by STADT, while no discernable second wave was PSMA PET/CT at different stages would likely alter the pro-
observed with LTADT (Supplementary Fig. 10). For patients portion of patients labeled as having local failure or distant
with intermediate-risk disease, no first wave of distant metastasis events. Not all patients underwent ascertain-
metastasis was seen, likely due to a lower prevalence of ment of local failure at the time of recurrence. Therefore,
occult metastatic disease at presentation substantiated by the local failure rate in our study is most likely underesti-
studies using PSMA PET/CT [39]. Occult metastatic disease mated. RTOG 9408 showed a 2-yr post-RT repeat prostate
exists in a measurable proportion of unfavorable biopsy positive rate of 20–39% in a patient population of
intermediate-risk patients, given early rise in distant metas- mixed-risk groups treated with or without ADT [49]; this
tasis rates within the first 12 mo after STADT seen in RTOG is considerably higher than the 13% local failure rate in
9408 [40], which is diluted out by minimal occult meta- high-risk patients in the current study, although the RT dose
static disease in the favorable intermediate-risk patients used in RTOG 9408 was low (66.6 Gy in 37 fractions) and
positive biopsies may represent inactive tumor cells with events in both patients with high- and intermediate-risk
severe treatment effect. For example, for PSMA PET/CT, disease. This suggests that in order for a regional/systemic
when used at initial staging, the first wave of distant metas- therapy to improve long-term outcome, local control needs
tases may diminish in amplitude as more patients with to be also optimized to minimize the second wave and vice
occult metastatic disease would have been detected and versa. Finally, ADT reduces the development of distant
excluded from the study; when used at local failure, more metastases from a cRF state and indirectly from a local
distant metastases would be detected concurrently, reduc- failure state by reducing local failure, while higher-dose
ing the rate of local failure to distant metastasis transition RT impacted only the local failure rate, consistent with
while increasing the rate of the cRF state to distant metas- the observation that ADT has a more significant impact
tasis transition. Potentially, this may augment the outcomes on DMFS irrespective of the RT dose than RT dose
of our models and their implications on the impact of treat- escalation.
ment modification (dose escalation, focal boost, and ADT)
on distant metastasis and PCSS outcomes. Fifth, we could
Author contributions: Amar U. Kishan had full access to all the data in the
not distinguish local disease that had a complete response
study and takes responsibility for the integrity of the data and the accu-
initially after RT but subsequently recurred (true local
recurrence) from local disease that never achieved a com-
plete response (locally persistent disease), and the latter
may be more biologically aggressive and may exhibit a dif- Study concept and design: Ma, Kishan, Chu, Spratt.
ferent clinical phenotype including the propensity for dis- Acquisition of data: All authors.
tant metastasis. We were also unable to definitely Analysis and interpretation of data: Ma, Kishan, Chu.
distinguish a local recurrence stemming from the original Drafting of the manuscript: Ma, Kishan, Chu.
prostate tumor or a new primary, especially for a delayed Critical revision of the manuscript for important intellectual content: All
presumed local recurrence; however, the incidence of a authors.
new primary in the prostate is likely low. Additionally, there Statistical analysis: Ma, Kishan, Chu.
was no uniform salvage therapy standard when local failure Obtaining funding: Kishan, Spratt.
or distant metastasis events were discovered, and therefore Administrative, technical, or material support: Kishan, Spratt.
heterogeneous management practices could not be Supervision: Kishan, Spratt.
accounted for. Systemic salvage therapy evolved rapidly Other: None.
during the follow-up periods of most trials included; thus,
the transition of distant metastasis to PCSM is skewed
Financial disclosures: Alison Tree acknowledges support from Cancer
toward earlier trials when systemic therapy was less effec-
Research UK (C33589/A28284 and C7224/A28724) and the National Insti-
tive. Finally, more effective systemic salvage therapies have
tute for Health Research (NIHR) Cancer Research Network. This project
been developed over the years, leading to a prolongation
represents independent research supported by the National Institute for
between distant metastasis and PCSM, as well as an
Health research (NIHR) Biomedical Research Centre at The Royal Marsden
improvement in PCSM and OS. The population studied NHS Foundation Trust and the Institute of Cancer Research, London. The
may not be fully representative of contemporary out- views expressed are those of the authors and not necessarily those of
comes/survival. It is uncertain whether the impact of local the NIHR or the Department of Health and Social Care. Amar U. Kishan
failure on PCSM and OS may be reduced with these more certifies that all conflicts of interest, including specific financial interests
effective therapies. and relationships and affiliations relevant to the subject matter or mate-
rials discussed in the manuscript (eg, employment/affiliation, grants or
4. Conclusions funding, consultancies, honoraria, stock ownership or options, expert tes-
timony, royalties, or patents filed, received, or pending), are the follow-
ing: Amar U. Kishan reports funding support from grant P50CA09213
This patient-level pooled analysis from 18 RCTs provides
from the Prostate Cancer National Institutes of Health Specialized Pro-
high-level evidence that local failure is an independent
grams of Research Excellence, grant W81XWH-22-1-0044 from the
prognosticator of OS, PCSS, and DMFS in high-risk PCa
Department of Defense, grant RSD1836 from the Radiological Society of
and of DMFS in intermediate-risk PCa. With the caveat that
North America, the STOP Cancer Organization, the Jonsson Comprehen-
local failure and distant metastasis may be underestimated
sive Cancer Center, and the Prostate Cancer Foundation; personal fees
in these trials, the predominant mode of distant metastasis
from Varian Medical Systems, Inc., ViewRay Inc., and Intelligent Automa-
development is from a cRF state for both high- and
tion, Inc.; and research support from ViewRay, Inc., the American Society
intermediate-risk PCa, likely from occult metastatic disease for Radiation Oncology (ASTRO), the Prostate Cancer Foundation, and the
at presentation, underscoring the importance of accurate Jonsson Comprehensive Cancer Center, all outside the submitted work.
upfront staging and systemic therapy. This source of dis- Nicholas G. Zaorsky is supported by the National Institutes of Health
tant metastasis constitutes the first wave of distant metas- Grant LRP 1 L30 CA231572-01 and the American Cancer Society – Tri
tases in high-risk patients, which occurred within the first State CEOs Against Cancer Clinician Scientist Development Grant CSDG-
4 yr after the completion of RT. This is inconspicuous in 20-013-01-CCE, and received remuneration from the American College
intermediate-risk patients, likely due to a much smaller of Radiation Oncology for prostate cancer chart review and accreditation
burden of occult metastatic disease. However, particularly of radiation oncology facilities nationally, all outside the submitted work.
at late time points, an increasing proportion of distant Daniel E. Spratt declares personal fees from Janssen, AstraZeneca, and
metastasis events originated after the diagnosis of local BlueEarth, outside the submitted work. All other authors have no conflict
failure, constituting a second wave of distant metastasis of interest to declare.
Funding/Support and role of the sponsor: Funding support for this study adjuvant to definitive radiotherapy in locally advanced carcinoma
comes from the Prostate Cancer Foundation and ASTRO to Amar U. Kis- of the prostate. Int J Radiat Oncol Biol Phys 2001;50:1243–52.
[16] Denham JW, Steigler A, Lamb DS, et al. Short-term neoadjuvant
han. Amar U. Kishan also thanks generous donations from the DeSilva,
androgen deprivation and radiotherapy for locally advanced
McCarrick, and Bershad families. prostate cancer: 10-year data from the TROG 96.01 randomised
trial. Lancet Oncol 2011;12:451–9.
[17] Bolla M, Maingon P, Carrie C, et al. Short androgen suppression and
Data sharing: Data for these analyses were made available to the authors radiation dose escalation for intermediate- and high-risk localized
through agreement with individual contributing institutions. As such, the prostate cancer: results of EORTC trial 22991. J Clin Oncol
authors cannot make these data publicly available due to data use 2016;34:1748–56.
[18] Bolla M, Neven A, Maingon P, et al. Short androgen suppression and
agreement.
radiation dose escalation in prostate cancer: 12-year results of
EORTC trial 22991 in patients with localized intermediate-risk
Peer Review Summary and Supplementary data disease. J Clin Oncol 2021;39:3022–33.
[19] Kishan AU, Sun Y, Pisansky TM, et al. Individual patient data Meta-
Analysis of Randomized Trials in Cancer of the Prostate (MARCAP)
Supplementary data to this article can be found online at Consortium: impact of androgen deprivation therapy use and
https://doi.org/10.1016/j.eururo.2022.07.011. duration with definitive radiotherapy for localized prostate
cancer. Int J Radiat Oncol Biol Phys 2021;111:S5–6.
[20] Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items
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Platinum Priority – Editorial

Referring to the article published on pp. 487–498 of this issue
The Deep Blue of Prostate Cancer Metastasis Evolution: The

LEVIATHAN Pooled Analysis
David Chang a,b, Pierre Blanchard c, Shankar Siva a,b,*

a
Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia; b Department of Radiation Oncology, Peter MacCallum Cancer
Centre, Melbourne, Australia; c Department of Radiation Oncology, Gustave Roussy, Université Paris Saclay, Inserm U1018 Oncostat, Villejuif, France
In this issue of European Urology, Ma et al [1] report on a The intervening time between events was short: 3.7 mo for
pooled analysis of 18 randomised trials from the MARCAP intermediate-risk and 9.6 mo for high-risk disease, com-
consortium that evaluated the prognostic importance of pared to the time to development of distant metastatic
local failure after definitive radiotherapy for intermediate- events after local failure (37.4 mo for intermediate-risk
and high-risk prostate cancer. The authors should be com- and 23.6 mo for high-risk disease). The authors hint that
mended for undertaking this vast, international collabora- metastasis may sometimes give rise to primary prostate
tive effort and performing a detailed analysis of data recurrences. This finding is consistent with the heteroge-
spanning more than three decades. neous and complex nature of prostate cancer spread
Ma et al [1] showed that greater than 80% of distant increasingly being recognised. Gundem et al [4] conducted
metastasis occurs in patients who are clinically free of local whole-genome sequencing of 51 tumours from ten patients
recurrence, indicating that most metastases originate from with metastatic prostate cancer, which allowed the evalua-
occult metastases already present at the time of definitive tion of the phylogenetic relationships between several
radiotherapy. Nevertheless, local failure was associated metastatic tumours. The authors described a complex
with inferior distant metastasis–free survival (DMFS). ecosystem of monophyletic and polyphyletic clonal seeding
Specifically for high-risk prostate cancer, local failure trans- between primary, nodal, and distant sites shared in a multi-
lated to inferior overall survival (OS). For high-risk prostate directional pattern.
cancer, but not intermediate-risk prostate cancer, the The implication of ‘‘second wave’’ metastatic seeding
authors identified a biphasic pattern of distant metastasis from local recurrences or, conversely, secondary seeding
development, with an initial wave speculated to be from of primary tumour after distant failures, is that, once recog-
occult metastases present at the time of radiotherapy and nised, established sites of recurrence may influence patient
a ‘‘second wave’’ of metastases originating from local recur- outcomes. A recently reported series of 401 patients with
rences. This concurs with outcomes from the STAMPEDE oligometastatic disease demonstrated that total metastatic
trial, which demonstrated a survival benefit from irradia- ablation was associated with better OS in comparison to
tion of the prostate in the setting of low-volume metastatic subtotal ablation (adjusted hazard ratio 0.8; p = 0.032) [5].
disease [2]. The survival benefit may have originated from a These findings indicate that ablative treatment of local fail-
reduction in further seeding of metastases from the prostate ures and distant metastases may be important in prevent-
and suppression of a metastasis-supportive systemic envi- ing further locoregional and distant disease. Indeed, total
ronment propagated by the active primary tumour [2,3]. metastatic ablation alongside definitive treatment of the
Dose escalation (74 Gy) reduced local failure rates for primary tumour in combination with systemic treatment,
both intermediate- and high-risk prostate cancer, poten- whether by surgery or ablative radiotherapy, is currently
tially leading to a reduction in distant metastases. A minor- the subject of several randomised controlled trials, includ-
ity of local failures—4.7% for intermediate-risk and 8.3% for ing PRESTO (NCT04115007), PLATON (NCT03784755), and
high-risk cases—developed after distant metastastic events. VA STARPORT (NCT04787744).
DOI of original articles: https://doi.org/10.1016/j.eururo.2022.07.011

* Corresponding author. Peter MacCallum Cancer Centre, 305 Grattan Street, Melbourne, Victoria, Australia. Tel. +61 3 8559 5000.
E-mail address: [email protected] (S. Siva).
The authors discuss several limitations, the significance In conclusion, the LEVIATHAN [1] analysis has dived into
of which should not be underestimated. Of the 48 eligible a deep pool of data in order to provide valuable insights into
trials identified, only 18 were included in the analysis, as the development of prostate metastasis and the temporal
individual patient data were unavailable for 15 trials, five relationship between local failure and late metastasis.
lacked reporting outcomes, and ten were associated with Ongoing research into the significance of local failure and
a nonstandard androgen deprivation therapy (ADT) agent its optimal management in the era of improved diagnostic
or duration or nonuniform ADT usage. In a meta-analysis imaging and advanced therapy is required.
in which less than half of the eligible trials are included, it
is important to list those trials and highlight the potential
differences. Indeed, although unlikely, there could be a
selection bias in the trials included that could affect the pat-
tern of reported results. Acknowledgments: Shankar Siva is supported by a Cancer Council Victo-
The meta-analysis is likely to have significantly under- ria Colebatch Fellowship.
reported local and distant failures. Local failures were iden-
tified clinically, with many studies reliant on digital rectal References
examination, which is associated with low sensitivity and
specificity [6]. Over the past decade, significant advances [1] Ma TM, Chu FI, Sandler H, et al. Local failure events in prostate cancer
treated with radiotherapy: a pooled analysis of 18 randomized trials
in imaging, especially prostate-specific membrane antigen from the meta-analysis of randomized trials in Cancer of the Prostate
(PSMA) positron emission tomography (PET), has improved Consortium (LEVIATHAN). Eur Urol 2022;82:487–98.
the early detection of metastatic prostate cancer. For high- [2] Parker CC, James ND, Brawley CD, et al. Radiotherapy to the primary
risk prostate cancer, the proPSMA multicentre, randomised tumour for newly diagnosed, metastatic prostate cancer
(STAMPEDE): a randomised controlled phase 3 trial. Lancet
trial established superior sensitivity of 85% compared to
2018;392:2353–66.
38% for conventional imaging in detecting metastasis [7]. [3] McAllister SS, Gifford AM, Greiner AL, et al. Systemic endocrine
Furthermore, a retrospective review of 50 patients follow- instigation of indolent tumor growth requires osteopontin. Cell
ing PSMA PET and salvage radical prostatectomy after 2008;133:994–1005.
definitive radiotherapy indicated that PSMA PET is highly [4] Gundem G, Van Loo P, Kremeyer B, et al. The evolutionary history of
lethal metastatic prostate cancer. Nature 2015;520:353–7.
sensitive in detecting local recurrences [8]. Increasing utili- [5] Siva S, Jones G, Bressel M, et al. Impact of operability and total
sation of PSMA PET is likely to significantly impact prostate metastatic ablation on outcomes after stereotactic ablative
cancer outcomes via early and accurate detection of local radiotherapy (SABR) for oligometastases. Int J Radiat Oncol Biol
failure and distant metastases. Therefore, the findings by Phys 2022. https://doi.org/10.1016/j.ijrobp.2022.05.034, In press.
[6] Crook J, Robertson S, Collin G, Zaleski V, Esche B. Clinical relevance of
Ma et al [1] may not be entirely applicable in the modern
trans-rectal ultrasound, biopsy, and serum prostate-specific antigen
era of PSMA PET imaging. following external beam radiotherapy for carcinoma of the prostate.
Most of the trials included in the meta-analysis were Int J Radiat Oncol Biol Phys 1993;27:31–7.
conducted in the 1990s and 2000s. It is important to recog- [7] Hofman MS, Lawrentschuk N, Francis RJ, et al. Prostate-specific
nise the improvements in prostate cancer management that membrane antigen PET-CT in patients with high-risk prostate cancer
before curative-intent surgery or radiotherapy (proPSMA): a
have occurred since then. In the pooled analysis by Ma et al prospective, randomised, multicentre study. Lancet
[1], the median survival for patients with distant metastasis 2020;395:1208–16.
was 18 mo for intermediate-risk and 21 mo for high-risk [8] Pfister D, Haidl F, Nestler T, et al. 68Ga-PSMA-PET/CT helps to select
disease. More contemporary Surveillance, Epidemiology patients for salvage radical prostatectomy with local recurrence after
primary radiotherapy for prostate cancer. BJU Int 2020;126:679–83.
and End Results data from 2000 to 2016 for metastatic pros-
[9] Elmehrath AO, Afifi AM, Al-Husseini MJ, et al. Causes of death among
tate cancer revealed longer median survival of 29 mo [9]. patients with metastatic prostate cancer in the US From 2000 to
Considering the recent advances in systemic therapy, med- 2016. JAMA Netw Open 2021;4:e2119568.
ian survival periods are expected to be much greater in the
modern era and this may potentially amplify the impor-
tance of local disease control for patient outcomes.
Platinum Priority – Prostate Cancer

Editorial by Pim J. van Leeuwen, Louise Emmett on pp. 510–511 of this issue
18
F-PSMA-11 Versus 68Ga-PSMA-11 Positron Emission Tomography/
Computed Tomography for Staging and Biochemical Recurrence of
Prostate Cancer: A Prospective Double-blind Randomised Cross-over
Trial
Kathia De Man a,*, Nick Van Laeken a, Vanessa Schelfhout a, Wolfgang P. Fendler b,
Bieke Lambert c,d,e, Ken Kersemans a, Sarah Piron f, Nicolaas Lumen g, Karel Decaestecker g,
Valérie Fonteyne h, Louke Delrue i, Filip De Vos f, Piet Ost e,j
a
Department of Medical Imaging, Nuclear Medicine, Ghent University Hospital, Ghent, Belgium; b Department of Nuclear Medicine, University of Duisburg-
Essen and German Cancer Consortium (DKTK)-University Hospital Essen, Essen, Germany; c Department of Nuclear Medicine, AZ Maria Middelares, Ghent,
Belgium; d Department of Nuclear Medicine, AZ Jan Palfijn, Ghent, Belgium; e Department of Diagnostic Sciences, Ghent University, Ghent, Belgium; f Laboratory
of Radiopharmacy, Ghent University, Ghent, Belgium; g Department of Urology, Ghent University Hospital, Ghent, Belgium; h Department of Radiation-
Oncology, Ghent University Hospital, Ghent, Belgium; i Department of Medical Imaging, Radiology, Ghent University Hospital, Ghent, Belgium; j Department of
Radiation-Oncology, Iridium Network, Wilrijk, Belgium
Article history: Background: Fluorine-18 (18F)-labelled prostate-specific membrane antigen (PSMA)

Accepted May 13, 2022 offers several advantages over gallium-68 (68Ga) in terms of costs, yield, transport/
distribution, and image resolution.
Objective: This trial investigates the new radiotracer 18F-PSMA-11 via a prospective,
intraindividual crossover design. The trial was powered for noninferiority of
18
F-PSMA-11 over 68Ga-PSMA-11 positron emission tomography (PET)/computed
tomography (CT) in terms of the number of positive PET scans. Secondary endpoints
were as follows: (1) superiority of 18F-PSMA-11 over 68Ga-PSMA-11 with respect to
the number of positive PET scans, the total number of suspicious prostate cancer lesions,
Keywords: and the miPSMA expression score of corresponding lesions; (2) correlation of the PET/CT
Biochemical recurrence images with available follow-up data for 18F-PSMA-11 and 68Ga-PSMA-11; and (3)
Positron emission assessment of the interobserver variability.
tomography/computed Design, setting, and participants: Prostate cancer patients (primary or biochemical
tomography recurrence) were randomised in a double-blind crossover design whereby each patient
Prostate cancer received both 18F-PSMA-11 and 68Ga-PSMA-11 PET/CT.
Staging Outcome measurements and statistical analysis: All scans were reviewed and scored by
18
F-PSMA-11 three independent experienced nuclear physicians following the proposed guideline for
68
Ga-PSMA-11 the interpretation of PSMA-ligand PET/CT, as described by Eiber et al.
* Corresponding author. Department of Medical Imaging, Nuclear Medicine, Ghent University

Hospital, Corneel Heymanslaan 10, Ghent, Belgium. Tel. +32(00)93325461; Fax: +32(009)93323807.
E-mail address: [email protected] (K. De Man).
Results and limitations: In total, 82 patients were included for scan analyses. The pri-
mary endpoint was met: per patient, the proportions of positive scans rated by the
three readers were 67%/67%, 65%/65%, and 73%/70% for 18F-PSMA-11/68Ga-PSMA-11
PET/CT. The miPSMA expression score was higher for 18F-PSMA-11 than for
68
Ga-PSMA-11 for the reference reader. Follow-up data showed identical estimated
sensitivity for both the 18F-PSMA-11 and the 68Ga-PSMA-11 scan (0.92, 0.83, and
0.92 for the three readers). A fair to good agreement among readers (at patient level)
was obtained, which was demonstrated by a Light’s kappa value of 0.59 for both
tracers.
Conclusions: The tracer 18F-PSMA-11 is noninferior to 68Ga-PSMA-11. Superiority of
18
F-PSMA-11 was limited to the miPSMA expression score, given by the reference
reader. Inter-rater agreement was fair to good, and equal for both radiotracers.
Patient summary: In this study, we compared two radiotracers: 18F-PSMA-11 and
68
Ga-PSMA-11. We proved that 18F-PSMA-11 is not inferior to 68Ga-PSMA-11 for
detecting prostate cancer and thus can be used as an alternative. Possible superi-
ority of this tracer should be further investigated in specific subpopulations.
1. Introduction 2.1. Patients
The inclusion criteria comprised recurrent (defined as raising/persisting

The use of prostate-specific membrane antigen (PSMA) PSA after curative treatment) or histopathologically confirmed primary
positron emission tomography (PET)/computed tomogra- prostate cancer. Patients were screened for inclusion by their treating
phy (CT) for biochemical recurrence and even for staging physician, irrespective of prior conventional imaging findings. Intake
prostate cancer is increasing worldwide due to the higher of hormonal medication was allowed. Patients who were underage,
accuracy of PSMA PET/CT than conventional imaging and who were unfit to perform the procedures, or who refused to be
choline PET/CT [1–6]. According to initial protocols, PSMA- informed about accidental findings on scans were excluded. Addition-
11 is labelled with gallium-68. However, the cost and lim- ally, a known history of anaphylactic shock after CT contrast adminis-
ited yield of a 68Ge/68Ga generator in combination with tration, and a serum creatinine concentration above 2 mg/dl and/or an
transport limitations due to the relatively short half-life of estimated glomerular filtration rate below 30 ml/min were considered
this radioisotope (68 min) fuel the search for alternative contraindications. Written, dated, and signed informed consent was
radioisotopes. Fluorine-18 radiotracers offer several advan- obtained from all patients before conducting any trial-related
tages including a longer half-life, a higher positron yield, procedures.
and the possibility to use higher starting activities, making This phase 3 clinical trial encompassed a prospective, double-
large batch production, delayed imaging, distribution to blind, randomised crossover design whereby each patient received
18 68
F-PSMA-11 and Ga-PSMA-11 PET/CT (interscan period ranging
other centres, and cost savings possible. Additionally, F-18
between 4 d and 3 wk). Randomisation of the patients over two study
has lower positron energy than Ga-68, leading to images
arms determined the scan sequence (Fig. 1) and was performed using
with a higher spatial resolution. This could be beneficial
a block randomisation design with block sizes of six. The randomisa-
for detecting small lesions expected in case of low
tion list, created by the clinical trial coordinator, was saved on a
prostate-specific antigen (PSA) values [7].
password-protected folder that only the secretary staff had access
Our research centre contributed to this evolution by
to. Patients were added chronologically to the randomisation list
developing 18F-PSMA-11. A phase 1 trial demonstrated the
based on the date and time that the secretary staff was informed
safety of this tracer and calculated a radiation dose similar about a patient’s participation, and the PET scans were scheduled.
to other radiotracers aimed at PSMA. A phase 2 trial opti- None of the screening or recruiting physician, the patient himself, or
mised the PET protocol [8,9]. the physicians who analysed the scans were aware of the patient’s
In this phase 3 trial, we present a prospective intraindi- allocation at any time.
vidual comparison between 18F-PSMA-11 and 68Ga-PSMA-
11 PET/CT in prostate cancer patients at primary diagnosis 2.2. Acquisition protocol
or biochemical recurrence, aiming to prove noninferiority
18
of 18F-PSMA-11 at patient level. After administration of 2.0 ± 0.2 MBq/kg bodyweight F-PSMA-11 or
68
Ga-PSMA-11, patients underwent a PET scan at 60 ± 5 min p.i. with
2. Patients and methods an acquisition time of 3 min/bed position. The first PET scan was accom-
panied by a low-dose CT scan for attenuation correction, and the second
All procedures were in accordance with the ethical standards of the PET scan was accompanied by a diagnostic CT scan and contrast (Visi-
Ethics Committee of the Ghent University Hospital (2019/0159), and paque) administration. To promote diuresis, patients were administered
with the 1964 Helsinki declaration and its amendments or comparable 20–40 mg furosemide intravenously immediately after tracer injection,
ethical standards (EudraCT nr: 2018-003168-29). The study was sup- unless contraindicated. Patients fasted for at least 4 h before the diag-
ported by the Flemish foundation FWO/TBM (T001517). nostic CT.
68 18
Fig. 1 – Flowchart randomised crossover design Ga-PSMA and F-PSMA PET/CT. CT = computed tomography; PET = positron emission tomography;
PSMA = prostate-specific membrane antigen.
Table 1 – Intensity of PSMA uptake expressed in miPSMA expression scores [11]
Score Uptake Reported PSMA expression

0 Below blood pool No
1 Equal to or above blood pool and lower than liver Low
2 Equal to or above liver and lower than parotid gland Intermediate
3 Equal to or above parotid gland High
2.3. Patient follow-up tion was collected. Equivocal or negative lesions were not included in
the analysis. Readers had no access to medical history details, informa-
Patient data (encompassing histopathology, imaging, and biochemical tion about the used radiotracer, or evaluation forms of the other review-
findings) were collected up to 180 days after the last PET/CT ers. The first reader was considered a reference reader based on her
examination. experience with the 18
F-PSMA-11 radiotracer (phase 1 and 2 trial). To
investigate diagnostic sensitivity, we applied both hard and soft criteria
2.4. Tracer preparation as reported previously (see Fig. 2) [12].
18
The tracer F-PSMA-11 was synthesised as described earlier [10]. The 2.6. Statistics
68
Ga-PSMA-11 tracer was prepared via reconstitution of a PSMA-11 cold
68
kit (ANMI, Liege, Belgium) with eluate from a Ge/68Ga generator (IDB- Sample size calculation was based on a power analysis of noninferiority
Holland, Baarle-Nassau, the Netherlands). Radiochemical purity was tests of correlated proportions, for a noninferiority (one-sided) test of
98.0 ± 0.9% (thin-layer chromatography [TLC]) and >99% (high- difference. Assuming a positivity rate of 85% for both tracers, a maxi-
18
performance liquid chromatography) for F-PSMA-11, and 99.1 ± 0.4% mum difference between the proportions of positive scans for both trac-
68
(TLC) for Ga-PSMA-11. ers of 10% as a one-sided noninferiority limit, a nuisance parameter of
0.05 (which is the sum of the proportions of disconcordant test results),
2.5. Scan and scan analysis an alpha value of 0.025, and a power of 80%, a minimum of 84 patients
should be included in the trial. Estimating a 10% dropout rate, the total
18
All scans were reviewed and scored by three independent experienced number of patients was determined to be 96. Noninferiority of F-
nuclear physicians. Our primary endpoint was evaluation of the noninfe- PSMA-11 was investigated based on a Tango’s score two-sided 95% con-
riority of 18F-PSMA-11 compared with 68Ga-PSMA-11 with respect to the fidence interval (CI) for a difference of proportions of positive scans of
18
number of positive PET scans. The following secondary endpoints were F-PSMA-11 compared with 68Ga-PSMA-11 with matched pairs. Nonin-
18 68
evaluated: (1) superiority of F-PSMA-11 over Ga-PSMA-11, with feriority was concluded if the lower limit of this CI is larger than –0.10.
18 68
respect to the number of positive PET scans, the total number of suspi- Superiority of F-PSMA-11 over Ga-PSMA-11 with respect to the
cious prostate cancer lesions, and the relative intensity of the PSMA number of positive PET scans was statistically assessed by applying a
uptake expressed in miPSMA score [11] of the corresponding lesions McNemar’s test on the proportions of positive PET scans in each group.
(see Table 1); (2) correlation of the PET/CT images with available clinical Hereby, superiority is defined as a difference of minimum 10% in the pro-
follow-up data; and (3) assessment of the interobserver variability with portions of positive PET scans (18F-PSMA-11 > 68
Ga-PSMA-11). The Wil-
regard to scan analysis. coxon signed rank test was applied to investigate differences (number of
Readers used the proposed guide for interpretation of PSMA-ligand suspected prostate cancer lesions and scoring of corresponding sus-
PET/CT as described by Eiber et al. [11]. Lesions with nonphysiological pected lesions) between 18F-PSMA-11 and 68Ga-PSMA-11 scans. Hereby,
tracer uptake above adjacent background tissues were recorded positive superiority was defined as a difference of minimum 10% (18F-PSMA-
68
for prostate cancer. CT findings were used to support the interpretation. 11 > Ga-PSMA-11). Interobserver variability was assessed via a Light’s
If more than ten lesions were present, no detailed anatomical localisa- kappa value.
Fig. 2 – Hard and soft criteria for considering cases positive for prostate cancer as described by Hofman et al. [12]. CT = computed tomography; PET = positron
emission tomography; PSA = prostate-specific antigen; PSMA = prostate-specific membrane antigen.
Table 2 – Patient characteristics and prior treatments of patients with biochemical recurrence or PSA persistence
Primary prostate cancer staging BCR/PSA persistence

Number of patients 19 66 (BCR, n = 63; PSA, persistence n = 3)
Age (yr), median (IQR) 73 (67–76) 69 (65–75)
Gleason score
<8 5 39
8 14 27
PSA value, median (IQR) 14.3 (7.2–27) 0.65 (0.43–1.8)
PSA doubling time (mo), median (IQR) NA 6.4 (2.6–16)
>10 metastasesa 2 6
D’Amico risk stratification [25] High risk: 18 NA
Undetermined: 1 (clinical T stage not
determined)
Prior prostatectomy (+salvage/adjuvant therapy) NA 29 (+20)
Prior radiation therapy (+salvage/adjuvant therapy) NA 6 (+2)
Prior prostatectomy, definitive radiotherapy (+adjuvant/salvage therapy) NA 2 (+6)
Number of patients under ADT at the time of scanning NA 22
CRPC or biochemical recurrence 10
CSBR NA 53 (PSA persistence, n = 3)
ADT = androgen deprivation therapy; BCR = biochemical recurrence; CRPC = castration-resistant prostate cancer; CSBR = castration-sensitive prostate cancer;
CT = computed tomography; IQR = interquartile range; NA = not applicable; PET = positron emission tomography; PSA = prostate-specific antigen;
a
Assessed using 68Ga- or 18F-PSMA PET/CT.
3. Results The examinations were well tolerated, and no drug-related

adverse events were reported. Three patients were excluded
Between April 2019 and March 2020, 96 patients were from the analysis due to technical complications during
enrolled. Eighty-five patients completed the entire protocol. scanning, resulting in 82 included patients (Fig. 3).
Fig. 3 – STARD flow diagram. PSMA = prostate-specific membrane antigen.
The clinical characteristics and prior treatments of these the ordinal structure of this secondary endpoint. No statis-
85 patients can be found in Table 2. tically significant difference was found in the total number
The median administered activity (Q1-Q3) of 18F-PSMA- of suspected prostate cancer lesions in corresponding 18F-
11 and 68Ga-PSMA-11 was 165 (146–181) MBq and 168 PSMA-11 versus 68Ga-PSMA-11 scans for all readers
(150–185) MBq, respectively. Of the patients, 78% (64/82) (p = 0.4/0.9/0.7, depending on the reader). However, a gen-
received furosemide. eral remark was made by the readers that more equivocal
lesions were mentioned in the skeleton with 18F-PSMA-11.
3.1. Primary endpoint: noninferiority They indicated that, after correlation with the CT images,
most of these equivocal lesions were presumably benign
PET images for both 18F-PSMA-11 and 68Ga-PSMA-11 were or nonspecific and, therefore, could not be classified within
positive in 55 out of 82 patients (67%) for the reference prostate cancer (Supplementary Fig. 1).
reader. Every scan deemed positive for 18F-PSMA-11 was Only for the reference reader, a small statistically signif-
also positive for 68Ga-PSMA-11. Noninferiority of 18F- icant difference (p = 0.024; other readers: p = 0.17 and
PSMA-11 compared with 68Ga-PSMA-11 was revealed as p = 0.5) was demonstrated in favour of 18F-PSMA-11 when
the lower limit of the Tango’s score two-sided 95% CI comparing miPSMA scoring of corresponding suspicious
(–0.045, 0.045) exceeded –0.10. Noninferiority was also lesions in both tracers (Supplementary Fig. 2).
reached for the other readers: 95% CI (–0.081, 0.081) and
(–0.024, 0.11) for the second and third readers, respectively. 18
3.3. Evaluation of the diagnostic sensitivity of F-PSMA-11
The proportions of positive scans rated by the three readers compared with that of 68Ga-PSMA-11
were 67%/67%, 65%/65%, and 73%/70% based on 18F-PSMA-
11/68Ga-PSMA-11. Follow-up data were available for 26 patients. Histopathol-
ogy confirmed the presence of prostate cancer in 15 cases
and absence of tumour cells in one case. Soft criteria were
3.2. Secondary endpoints
applicable in ten cases. The estimated sensitivity of the
Based on the McNemar’s test, no superiority of 18F-PSMA-11 18
F-PSMA-11 scan is 0.92 (95% CI [0.76–0.98]), 0.83 (95%
over 68Ga-PSMA-11 could be concluded with respect to the CI [0.64–0.93]), and 0.92 (95% CI [0.76–0.98]) for the three
number of positive PET scans (p = 1 or 0.4, depending on the readers. The estimated sensitivity of the 68Ga-PSMA-11 scan
reader). Superiority of 18F-PSMA-11 PET/CT with respect to is 0.92 (95% CI [0.76–0.98]), 0.83 (95% CI [0.65–0.94]), and
the total number of suspected prostate cancer lesions was, 0.92 (95% CI [0.76–0.98]).
due to a large number of zero cells, analysed via a rank- All prostate cancer lesions confirmed with follow-up
based Wilcoxon signed rank test for matched pairs instead data seen on 68Ga-PSMA PET/CT were also described on
18
of the McNemar-Bowker test of symmetry, maintaining F-PSMA-PET/CT, for the reference reader. One local recur-
Fig. 4 – (A) CT images (A1), 18F-PSMA-11 fused PET/CT (A2), and PET images (A3), and (B) 68Ga-PSMA-11 fused PET/CT (B1) and PET (B2) images showing a lytic
lesion with well-defined sclerotic border in right rib 6 and elevated 18F-PSMA-11 uptake but almost no 68Ga-PSMA-11 uptake. (C) Follow-up images with 68Ga-
PSMA-11 PET/CT half a year later (C1–C3) showed a marked increase of 68Ga uptake in this particular lesion. Stereotactic radiotherapy of this lesion in
combination with androgen deprivation therapy during 6 mo resulted in a drop of PSA levels to undetectable. CT = computed tomography; PET = positron
emission tomography; PSA = prostate-specific antigen; PSMA = prostate-specific membrane antigen.
18 68
Table 3 – Disease extent and anatomic location of positive lesions for F- and Ga-PSMA PET/CT
Number of patients/scans for F-18 Number of patients/scans for Ga-68

No suspicious lesions 27 27
Oligometastatic (3 lesions) 39 41
Polymetastatic (>3 lesions) 16 14
Number of positive lesions for F-18 Number of positive lesions for Ga-68
Local disease/recurrence 32 34
Local lymph nodes 48 51
Distant lymph nodes 7 6
skeletal 23 15
Other (eg, visceral) 2 2
CT = computed tomography; PET = positron emission tomography; PSMA = prostate-specific membrane antigen.
rence was missed on both scans and one lymph node in the in miTNM score was observed in six patients (7%; due to
left obturator loge was described only on 18F-PSMA-11. additional bone lesions and lymph nodes in four and two
patients, respectively). On 68Ga-PSMA-11 PET/CT, additional
3.4. Descriptive evaluation of 18F-PSMA-11 compared with lesions were seen in eight patients in comparison with 18F-
68
Ga-PSMA-11 for the reference reader PSMA PET/CT (10%), mostly located in lymph nodes (n = 7),
On 18F-PSMA-11 PET/CT, additional lesions, in comparison but also in the prostate (n = 2) and skeletal (n = 1). This led
with 68Ga-PSMA-11 PET/CT, were observed for ten patients to a different miTNM score in four patients (5%; all due to
(12%). These were located in the bones (n = 9; see example additional positive lymph nodes). All other lesions were
in Fig. 4) and in lymph nodes (n = 4). Consequent upstaging consistent on both scans.
The extent of the disease and anatomic location of posi- Only for the reference reader, a significantly higher
tive lesions for all patients are listed in Table 3. miPSMA expression score was observed with 18F-PSMA-
A pelvic lymph node dissection, performed in seven out 11. Pattison et al. [15] described, in a prospective intraindi-
of 19 patients with primary prostate cancer, indicated the vidual blinded comparison, a significantly higher uptake at
presence of lymph node metastases in two patients. For most sites of disease and physiological organs for 18F-
the remaining five patients, no tumoural cells were PSMA-1007 than for 68Ga-PSMA-11. The absence of observ-
detected. Based on PSMA PET/CT, the reference reader made ing a higher 18F-PSMA-11 uptake in our study might inher-
an identical conclusion, except for one histology-proven ently be related to the method of analysis. A miPSMA
lymph node metastasised patient with no suspicious PSMA expression score defines the tracer uptake in suspicious
uptake in the lymph nodes on both the 68Ga-PSMA-11 and lesions relative to the uptake in specific organs (liver/aortic
the 18F-PSMA-11 PET/CT scan. arch/parotid gland). Consequently, if a higher 18F-PSMA-11
uptake is observed in both suspicious lesions and physio-
3.5. Evaluation of interobserver variability logical organs, this effect is moderated when calculating
the miPSMA expression score.
The agreement between the raters (at patient level) for diag- A fair to good agreement was seen between all readers,
nosing prostate cancer was fair to good, and identical for which was identical for the 18F-PSMA-11 and 68Ga-PSMA-
both 18F-PSMA-11 and 68Ga-PSMA-11 (Light’s kappa = 0.59; 11 PET/CT scans. The lack of perfect alignment for both
p = 0.003, 95% CI [0.20–0.98] and p = 0.002, 95% CI [0.22– radiotracers may reflect the different degrees of experience
0.97] for 18F-PSMA-11 and 68Ga-PSMA-11, respectively). with PSMA PET/CT between all readers, as previously
described for 68Ga-PSMA-PET/CT [20]. Additionally, the
4. Discussion absence of prior training and the fact that no clinical history
was provided to the readers might have diminished the
While multiple F-18 radiotracers aimed at PSMA have been level of agreement. Furthermore, moderate interobserver
developed, this is the largest prospective phase 3 clinical agreement is also seen for miT staging in literature, which
trial that intraindividually compares an F-18–based radio- might contribute to our result as local recurrence occurred
tracer with 68Ga-PSMA-11 [13–16]. in a substantial number of our patient population (32–
With regard to 18F-PSMA-11, a smaller prospective head- 34/82 for 18F-PSMA-11 and 68Ga-PSMA PET/CT) [21].
to-head study in 37 prostate cancer patients with biochem- Although comparable detection rates were observed
ical relapse after initial treatment has been performed with between both tracers in our trial, more equivocal lesions
similar diagnostic values for 68Ga-PSMA-11 and 18F-PSMA- were visualised on 18F-PSMA PET/CT, especially in the skele-
11 [17]. In the current phase 3 clinical trial, noninferiority ton (Supplementary Fig. 1), which is a known pitfall of 18F-
of 18F-PSMA-11 compared with 68Ga-PSMA-11, with respect labelled PSMA tracers. Multiple studies comparing 68Ga-
to the number of positive PET scans, was proved. and 18F-labelled PSMA ligands mention more benign lesions
Despite the theoretical F-18 isotope advantages, no supe- with the 18F-labelled ligand [7,22,23]. Discrepancies
riority of 18F-PSMA-11 with respect to the number of positive between the three readers, particularly regarding the 18F-
PET scans and the total number of suspected lesions could be PSMA-11 scans, can hypothetically be attributed to PSMA
demonstrated by the reference reader. This might be related uptake in lesions considered to be benign by some readers
to the broad inclusion criteria. Based on the F-18 isotope’s and malignant by other readers [24]. As Rauscher et al.
characteristics, theoretically superiority of 18F-PSMA-11 [23] emphasised, CT plays an important role in the evalua-
should most likely be sought in detecting very small lesions, tion of benign PSMA-ligand–positive bone lesions. In clini-
as can be found in the early course of recurrent disease and in cal practice, we believe that sufficient training in
patients with low PSA values. Figure 4, for example, shows a interpretation and close collaboration with the radiologist
small bone lesion with clearly increased 18F-PSMA-11 uptake will be of great importance to reach a correct conclusion.
and only faint 68Ga-PSMA-11 uptake. The enhanced 68Ga- For this trial, the major limitation is that not all 18F-
PSMA uptake on subsequent follow-up PET/CT favours the PSMA-11– or 68Ga-PSMA-11–positive lesions were con-
diagnosis of bone metastasis. Despite not being able to firmed by histology (often ethically or technically impossi-
demonstrate possible superiority of 18F-PSMA-11, the broad ble). Furthermore, the study was monocentric and the
inclusion criteria were chosen to better reflect reality. population heterogeneous. Among the major advantages
Positivity rates were between 65% and 73% for are the intraindividual comparison and the use of identical
18
F-PSMA-11 and 65% and 70% for 68Ga-PSMA-11 (depend- acquisition protocols for both tracers.
ing on the reader). These rates are similar to the positivity
rates reported in other prospective studies for 68Ga-PSMA 5. Conclusions
PET/CT, overall ranging from 65% to 75%, using wide PSA
ranges of >0.2–10 and 0.1–1154 ng/ml [18,19]. The esti- To date, the results of this largest prospective clinical trial
mated sensitivity in our trial was between 83% and 92% comparing 18F-PSMA-11 with 68Ga-PSMA-11 indicate that
18
for both tracers, depending on the reader. However, these F-PSMA-11 is a good and cost-efficient alternative in the
data are based only on 26 patients and need to be inter- detection and staging of prostate cancer. The trial demon-
preted with caution. Unfortunately, histopathological vali- strated noninferiority of 18F-PSMA-11 by all readers, as well
dation of imaging findings in patients with biochemical as superiority of 18F-PSMA-11 with regard to the miPSMA
recurrence is rarely available, impairing true test sensitivity. expression score by the reference reader. Additional
research in specific subpopulations is required to further References

explore superiority. Although, similar to other 18F-labelled
[1] Schwarzenboeck SM, Rauscher I, Bluemel C, et al. PSMA ligands for
radiotracers aimed at PSMA, more equivocal lesions were
PET imaging of prostate cancer. J Nucl Med 2017;58:1545–52.
detected with [18F]PSMA-11, inter-rater agreement (at [2] Awenat S, Piccardo A, Carvoeiras P, et al. Diagnostic role of 18F-
patient level) was fair to good and identical between the PSMA-1007 PET/CT in prostate cancer staging: a systematic review.
18
F-PSMA-11 and 68Ga-PSMA-11 scans. Diagnostics 2021;11:552.
[3] Treglia G, Annunziata S, Pizzuto DA, Giovanella L, Prior JO, Ceriani L.
Detection rate of18 F-labeled PSMA PET/CT in biochemical
recurrent prostate cancer: a systematic review and a meta-
Author contributions: Kathia De Man had full access to all the data in the
analysis. Cancers (Basel) 2019;11:710.
study and takes responsibility for the integrity of the data and the accu- [4] Lawhn-Heath C, Salavati A, Behr SC, et al. Prostate-specific
racy of the data analysis. membrane antigen PET in prostate cancer. Radiology
2021;299:248–60.
Study concept and design: De Man, Ost, De Vos. [5] Treglia G, Pereira Mestre R, Ferrari M, et al. Radiolabelled choline
versus PSMA PET/CT in prostate cancer restaging: a meta-analysis.
Acquisition of data: Schelfhout, Fendler, Lambert, Delrue.
Am J Nucl Med Mol Imaging 2019;9:127–39.
Analysis and interpretation of data: De Man, Van Laeken. [6] Morigi JJ, Stricker PD, Van Leeuwen PJ, et al. Prospective comparison
Drafting of the manuscript: De Man. of 18F-fluoromethylcholine Versus 68Ga-PSMA PET/CT in prostate
Critical revision of the manuscript for important intellectual content: All cancer patients who have rising PSA after curative treatment and
are being considered for targeted therapy. J Nucl Med
authors.
2015;56:1185–90.
Statistical analysis: Van Laeken, De Man. [7] Dietlein F, Kobe C, Neubauer S, et al. PSA-stratified performance of
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Administrative, technical, or material support: Van Laeken, Piron. prostate cancer. J Nucl Med 2017;58:947–52.
Supervision: Ost, Schelfhout, De Vos. [8] Piron S, De Man K, Van Laeken N, et al. Radiation dosimetry and
biodistribution of 18F-PSMA-11 for PET imaging of prostate cancer.
Other (recruitment of patients): Lumen, Decaestecker, Fonteyne, Ost.
J Nucl Med 2019;60:1736–42.
[9] Piron S, De Man K, Schelfhout V, et al. Optimization of PET protocol
and interrater reliability of 18F-PSMA-11 imaging of prostate
Financial disclosures: Kathia De Man certifies that all conflicts of interest, cancer. EJNMMI Res 2020;10:14.
including specific financial interests and relationships and affiliations rel- [10] Kersemans K, De Man K, Courtyn J, et al. Automated radiosynthesis
evant to the subject matter or materials discussed in the manuscript (eg, of Al[18F]PSMA-11 for large scale routine use. Appl Radiat Isot
employment/affiliation, grants or funding, consultancies, honoraria, stock 2018;135:19–27.
[11] Eiber M, Herrmann K, Calais J, et al. Prostate Cancer Molecular
Imaging Standardized Evaluation (PROMISE): proposed miTNM
received, or pending), are the following: Wolfgang P. Fendler reports fees classification for the interpretation of PSMA-ligand PET/CT. J Nucl
from SOFIE Bioscience (research funding), Janssen (consultant and speak- Med 2018;59:469–78.
ers’ bureau), Calyx (consultant), Bayer (consultant and speakers’ bureau), [12] Hofman MS, Lawrentschuk N, Francis RJ, et al. Prostate-specific
membrane antigen PET-CT in patients with high-risk prostate
and Parexel (image review), outside of the submitted work. Piet Ost
cancer before curative-intent surgery or radiotherapy (proPSMA): a
reports consultancies for Janssen, Bayer, Curium, Novartis, Telix, and Fer- prospective, randomised, multicentre study. Lancet
ring, and research grants from Bayer and Varian. The other authors report 2020;395:1208–16.
no conflict of interest. [13] Kuten J, Fahoum I, Savin Z, et al. Head-to-head comparison of 68Ga-
PSMA-11 with 18F-PSMA-1007 PET/CT in staging prostate cancer
using histopathology and immunohistochemical analysis as a
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[14] Pernthaler B, Kulnik R, Gstettner C, Salamon S, Aigner RM, Kvaternik
the Research Foundation-Flanders (FWO, TBM [T001517]). The sponsor
H. A prospective head-to-head comparison of 18F-fluciclovine with
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CT. Clin Nucl Med 2019;44:E566–73.
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Ethics statement: This study protocol was approved by the Ethics Com- individual blinded comparison of [18F]PSMA-1007 and [68Ga]Ga-
mittee of the Ghent University Hospital (2017/1294), and all patients PSMA-11 PET/CT imaging in patients with confirmed prostate
signed a written informed consent (EudraCT nr: 2017-003461-96). cancer. Eur J Nucl Med Mol Imaging 2022;49:763–76.
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1007 PET, and MRI for gross tumor volume delineation in primary
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Radiat Oncol 2021;11:202–11.
staff members and physicians of the Department of Radiotherapy and [17] dos Santos G, Rodriguez Taroco M, Giglio J, Savio E, Alonso O. Al18F-
Urology of Ghent University Hospital for the well-appreciated efforts to PSMA-HBED-CC as a novel tracer for the evaluation of prostate
recruit patients for the study and for filling out all paperwork. A special cancer patients with biochemical relapse: intraindividual
comparison with 68Ga-PSMA-HBED-CC. J Nucl Med 2020;61
word of thanks to the cyclotron team and nursing staff of the Department
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standing cooperation. The authors would also like to thank the Biostatis- clinical impact of gallium-68 prostate-specific membrane antigen
tics Unit of UGent for supporting the statistical analysis of this work. (PSMA) PET/CT imaging in early relapsed prostate cancer after
radical therapy: phase 3, prospective, multicenter study (IAEA-
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18 68
F-PSMA-11 as an Attractive Ga-PSMA-11 Alternative for Prostate
Cancer Imaging
Pim J. van Leeuwen a,*, Louise Emmett b

a
Department of Urology, Netherlands Cancer Institute, Amsterdam, The Netherlands; b Department of Theranostics and Nuclear Medicine, St.
Vincent’s Hospital, Sydney, Australia
Given the increasing importance of molecular imaging for their success in undertaking this important prospective
prostate cancer (PCa) staging, the challenge is to identify study. They found that 18F-PSMA-11 is not inferior to
68
good radiotracers for accurate detection of PCa metastases. Ga-PSMA-11 for detection of PCa and conclude that 18F-
Since its clinical introduction in 2011, prostate-specific PSMA-11 can be used as an effective alternative radiotracer.
membrane antigen (PSMA) positron emission tomogra- The choice of PSMA ligand is often limited in clinical
phy/computed tomography (PET/CT) imaging has been practice, with complexities surrounding which peptides
transforming the staging of both newly diagnosed and bio- have received approval, local laws regarding production,
chemically recurrent PCa. PSMA PET/CT has proven clearly and what PSMA ligands companies have progressed to local
superior in detecting PCa lesions at low prostate-specific registration. Fluorinated PSMA PET agents have the advan-
antigen levels in comparison to previous-generation cho- tage of a longer half-life that allows central manufacture
line-based tracers, and PSMA is the optimal cell target for for distribution to satellite centres, while the shorter half-
imaging of PCa [1]. As a cell-surface receptor with a propro- life of gallium imposes significant practical limitations, with
liferative role, PSMA has high sensitivity for detection of in-house and limited patient production often required. In
more aggressive PCa phenotypes and distant metastatic dis- addition, 18F PET has higher physical spatial resolution than
68
ease [2]. Initially evaluated in antibody form, the true Ga, potentially leading to better detection rates, and
potential of PSMA was realised on the development of small delayed imaging (easier with a longer half-life) with PSMA
urea PSMA ligands, in particular PSMA-11, which released PET agents may also lead to better detection of malignant
off-patent by the University of Heidelberg. Following exten- lesions [4]. For these reasons, the use of fluorinated PSMA
sive evaluation, 68Ga-PSMA-11 now has US Food and Drug radiotracers is appealing in PCa diagnostics. In light of these
Administration approval for both staging and detection of advantageous characteristics, comparative studies are
biochemical recurrence in localised PCa. A range of PSMA- needed to establish the role of the 18F-labelled PSMA radio-
based radiotracers are now available; the most frequently tracers currently available.
utilised is 68Ga-PSMA-11, followed by 18F-DCFPyL. How- Why does 18F-PSMA-11 sound like such a good idea?
ever, many other PSMA-based radiotracers (18F-PSMA- 68
Ga-PSMA-11 and 18F-DCFPyL, the two radiotracers most
1007, 18F-PSMA-11, 68Ga-PSMA-I&T, 68Ga-THP-PSMA, frequently used in the clinical setting, both have high speci-
64
Cu-PSMA-617, 18F-JK-PSMA-7) have been developed to ficity uniformly across all studies reported, with very good
address the unmet need to guide evidence-based decisions interobserver variability. Interobserver variability, defined
in selection of the optimal radiotracer. as the absence of consensus between nuclear medicine
In this issue of European Urology, De Man et al [3] evalu- physicians regarding oncological staging, gives an indica-
ate the diagnostic accuracy of 18F-PSMA-11 compared to tion of the reliability and reproducibility of the assessment
68
Ga-PSMA-11, the most frequently studied PSMA-based and is an essential indicator of the clinical value of PSMA
radiotracer. We would like to congratulate the authors on PET/CT scans. It is affected by the ability of nuclear medicine
DOI of original article: https://doi.org/10.1016/j.eururo.2022.05.010

* Corresponding author. Department of Urology, Netherlands Cancer Institute-Antoni van Leeuwenhoek Hospital, Plesmanlaan 121, Amsterdam 1066
CX, The Netherlands. Tel. +31 205121139.
E-mail addresses: [email protected] (P.J. van Leeuwen), [email protected] (L. Emmett).
68
physicians to recognise potential false-positive sources of Ga-PSMA-11 and 18F-DCFPyL. Good training in the inter-
uptake, such as false-positive bone findings, already fre- pretation of bone lesions with elevated 18F-PSMA-11 uptake
quently described with the use of PSMA radiotracers, espe- appears to be necessary. Further studies are needed to
cially 18F-PSMA-1007 [5]. Studies evaluating 18F-PSMA- assess the cost efficiency of 18F-PSMA-11 compared to
1007 have found nonspecific bone activity in approximately either 68Ga-PSMA-11 or 18F-DCFPyL, although the prospects
half of cases imaged. This led to a significant number of look promising.
extra imaging procedures and biopsies to exclude meta-
static PCa for equivocal cases. A health economics assess-
ment comparing 68Ga-PSMA-11 and 18F-PSMA-1007 found
that greater uncertainty and the false-positive rate, particu-
References
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1007 [6]. [1] Morigi JJ, Stricker PD, van Leeuwen PJ, et al. Prospective comparison
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bone lesions were visualised using 18F-PSMA-11 than with cancer patients who have rising PSA after curative treatment and are
68 being considered for targeted therapy. J Nucl Med 2015;56:1185–90.
Ga-PSMA-11 PET/CT resulting in higher interobserver vari-
[2] Kaittanis C, Andreou C, Hieronymus H, et al. Prostate-specific
ability for 18F-PSMA-11. According to the authors, discrep- membrane antigen cleavage of vitamin B9 stimulates oncogenic
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in lesions considered benign by the first reader and malig- 2018;215:159–75.
nant by the second. Furthermore, 18F-PSMA-11 PET/CT [3] De Man K, Van Laeken N, Fendler WP, et al. 18F-PSMA-11 versus
68Ga-PSMA-11 positron emission tomography/computed
detected nine additional bone lesions in comparison to tomography for staging and biochemical recurrence of prostate
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Ga-PSMA-11 PET/CT, resulting in (false-positive?) upstag- cancer: a prospective double-blind randomised cross-over trial. Eur
ing of the miTNM score for four patients (5%) [3]. One could Urol 2022;82:501–9.
argue that the nuclear medicine physicians in the study [4] Hoffmann MA, Buchholz HG, Wieler HJ, et al. Dual-time point [68Ga]
Ga-PSMA-11 PET/CT hybrid imaging for staging and restaging of
were more likely to misinterpret 18F-PSMA-11 PET/CT scans
prostate cancer. Cancers 2020;12:2788.
(ie, misinterpret the uptake in benign [skeletal] lesions as [5] Rauscher I, Krönke M, König M, et al. Matched-pair comparison of
being compatible with bone metastases) because of a lack 68
Ga-PSMA-11 PET/CT and 18F-PSMA-1007 PET/CT: frequency of
of experience with this tracer. This highlights the impor- pitfalls and detection efficacy in biochemical recurrence after radical
tance of sufficient training in interpretation of a specific prostatectomy. J Nucl Med 2019;61:51–7.
[6] Alberts I, Mingels C, Zacho HD, et al. Comparing the clinical
radiotracer (18F-PSMA-11) in clinical practice. Nevertheless, performance and cost efficacy of [68Ga]Ga-PSMA-11 and [18F]
the interobserver variability of 18F-PSMA-11 in the present PSMA-1007 in the diagnosis of recurrent prostate cancer: a Markov
study remains significantly better than that shown for chain decision analysis. Eur J Nucl Med Mol Imaging 2020;12.
18 https://doi.org/10.1007/s00259-021-05620-9, In press.
F-PSMA-1007 [7]. Furthermore, fewer bone lesions of
[7] Hagens MJ, Oprea-Lager DE, Vis A, et al. Reproducibility of PSMA PET/
benign cause were observed for 18F-PSMA-11 compared to
CT imaging for primary staging of treatment-naïve prostate cancer
the higher rates of equivocal bone abnormalities attributed patients depends on the applied radiotracer: a retrospective study. J
to a benign or physiological origin for 18F-PSMA-1007. Nucl Med 2022, In press.
In conclusion, it has been shown that 18F-PSMA-11 is a
good alternative to PSMA-based radiotracers such as
Platinum Priority – Brief Correspondence

Editorial by Tanya B. Dorff, Alicia K. Morgans on pp. 516–517 of this issue
Overall Survival Update for Patients with Metastatic Castration-

resistant Prostate Cancer Treated with Capivasertib and Docetaxel in
the Phase 2 ProCAID Clinical Trial
Simon J. Crabb a,*, Gareth Griffiths a, Denise Dunkley a, Nichola Downs a, Mary Ellis a, Mike Radford a,
Michelle Light a, Josh Northey a, Amy Whitehead a, Sam Wilding a, Alison J. Birtle b, Vincent Khoo c,
Robert J. Jones d
a
Southampton Clinical Trials Unit, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK; b Lancashire
Teaching Hospitals NHS Foundation Trust, University of Central Lancashire and University of Manchester, Preston, UK; c The Royal Marsden NHS
Foundation Trust, London, UK; d Beatson West of Scotland Cancer Centre, University of Glasgow, Glasgow, UK
Article history: The PI3K/AKT/PTEN pathway is frequently deregulated in metastatic castration-resistant

Accepted May 20, 2022 prostate cancer (mCRPC). ProCAID was a phase 2 trial assessing addition of the AKT1/2/3
inhibitor capivasertib to docetaxel for patients with mCRPC. We previously reported that
Associate Editor: capivasertib did not extend a composite progression-free survival primary endpoint but
James Catto did significantly improve the secondary endpoint of overall survival (OS). Here we present
OS data after 66% of events had occurred in the intent-to-treat population (n = 150). Median
OS was 25.3 mo for capivasertib plus docetaxel versus 20.3 mo for placebo plus docetaxel
Keywords: (hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.47–1.05; nominal p = 0.09). Receipt
AKT inhibitor of subsequent life-extending treatments was balanced between the treatment arms. The
Capivasertib OS benefit associated with capivasertib was maintained in a subset of patients previously
Docetaxel treated with abiraterone and/or enzalutamide (median OS 25.0 vs 17.6 mo; HR 0.57, 95% CI
Metastatic castration-resistant 0.36–0.91; nominal p = 0.02) but not in abiraterone/enzalutamide-naïve patients (median
prostate cancer OS 31.1 mo vs not reached; HR 1.43, 95% CI 0.63–3.23). We conclude that OS may be
PI3K/AKT/PTEN pathway extended by addition of capivasertib to docetaxel. Exploratory analysis revealed that the
Phase 2 trial OS benefit was maintained in a subset of patients previously exposed to androgen recep-
tor–targeted agents, which should be evaluated in prospective trials.
Patient summary: The ProCAID study examined whether adding the AKT inhibitor drug
capivasertib to docetaxel chemotherapy improves outcomes for patients with advanced
prostate cancer. Initial analysis of the ProCAID results suggested that capivasertib
improved overall survival benefit. This follow-up analysis suggests that capivasertib addi-
tion may be particularly beneficial for patients whose cancer was previously treated with
drugs that target the androgen receptor.
Urology. This is an open access article under the CC BY license (http://creativecommons.
org/licenses/by/4.0/).
* Corresponding author. Southampton Clinical Trials Unit, Centre for Cancer Immunology,
Southampton General Hospital, Southampton SO16 6YD, UK. Tel. +44 23 81205170; Fax: +44 844
7740621.
E-mail address: [email protected] (S.J. Crabb).
under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Several therapies improve the overall survival (OS) of group. One patient (0.67%) remained on the study treat-
patients with metastatic castration-resistant prostate can- ment. Median OS in this follow-up analysis was 25.3 mo
cer (mCRPC), including docetaxel as first-line chemotherapy for the capivasertib plus docetaxel group versus 20.3 mo
[1]. However, median survival from the point of mCRPC for the placebo plus docetaxel group (apparent difference
remains less than 3 yr, and most patients develop in OS between the treatment arms 5.0 mo; HR 0.70, 95%
chemotherapy resistance [2,3]. The PI3K/AKT/PTEN path- CI 0.47–1.05; nominal p = 0.09; Fig. 1A and Table 1). In total,
way is commonly aberrantly activated in prostate cancer
and has been associated with the development of resistance
to taxane chemotherapy in cell lines [4,5].
Capivasertib is a potent selective inhibitor of all three
AKT isoforms (AKT1/2/3). Preclinical, phase 1 and phase 2
studies have demonstrated capivasertib target engagement
and preliminary signs of clinical efficacy for several cancer
types [4,6]. Phase 1 of the ProCAID trial (NCT02121639)
established a recommended dose for capivasertib in combi-
nation with docetaxel for patients with mCRPC [7]. Phase 2
of ProCAID then examined whether addition of capivasertib
to docetaxel chemotherapy improved clinical outcomes [8].
Although the primary analysis found no difference in the
primary endpoint (composite progression-free survival;
cPFS), the prespecified secondary endpoint of OS was
extended in the capivasertib plus docetaxel arm in compar-
ison to placebo plus docetaxel (median 31.2 vs 20.3 mo;
hazard ratio [HR] 0.54, 95% confidence interval [CI] 0.34–
0.88; p = 0.01) [8]. The OS data were relatively immature
at the time of the primary analysis (72 deaths in the
intent-to-treat [ITT] population of 150 patients). Here we
report an updated OS analysis after extended follow-up in
the ITT population, as well as a subgroup analysis.
The design, methods, and primary analysis findings from
ProCAID have previously been reported [8]. In brief, the
study recruited 150 patients with progressive mCRPC (Sup-
plementary Table 1). Prior hormonal therapies were permit-
ted but not prior chemotherapy for mCRPC. Patients
received docetaxel and prednisolone according to local
practice. Patients were randomly assigned 1:1 to receive
either capivasertib 320 mg or matched placebo orally twice
daily using an intermittent dosing schedule (4 d on, 3 d off)
until disease progression according to Prostate Cancer
Working Group-2 criteria, need for new systemic therapy
for prostate cancer, development of unacceptable toxicities,
loss to follow-up, or withdrawal of consent. Patients and
investigators remained blinded to treatment allocation at
the point of this extended OS analysis, which was pre-
planned to occur after 65% OS events. OS was assessed
as the time from random assignment to death (with last
patient contact used as the censoring date). Analysis of
the ITT population was undertaken according to a Cox pro-
portional hazards model adjusted for minimisation factors
(presence of bone metastases, presence of visceral metas-
tases, investigational site, and prior treatment with an
androgen receptor–targeted agent [ARTA; abiraterone and/
or enzalutamide]).
At the time of this updated analysis, 99 patients in the
ProCAID ITT population (n = 150) had died (49 treated with
capivasertib, 50 treated with placebo), with 88 of these Fig. 1 – Kaplan-Meier estimates of overall survival by treatment arm
deaths due to prostate cancer (Supplementary Table 2). allocation for (A) the ITT population, (B) the subgroup that received prior
ARTA (abiraterone and/or enzalutamide) before entering ProCAID, and (C)
Median follow-up (obtained using the reverse Kaplan- the subgroup that had not received prior ARTA therapy. Tick marks denote
Meier method applied to the full patient cohort) was 35.0 censored patients. ARTA = androgen receptor-targeting agent; ITT = intent-
mo for the capivasertib group and 32.0 mo for the placebo to-treat.
Table 1 – Updated OS and subsequent treatments in the ITT population and subgroups who received and did not receive prior ARTA therapy before
entering the ProCAID study
ITT population Prior ARTA therapy No prior ARTA therapy

DOC + CAP DOC + placebo DOC + CAP DOC + placebo DOC + CAP DOC + placebo
(n = 75) (n = 75) (n = 51) (n = 50) (n = 24) (n = 25)
24-mo OS probability (95% CI) 0.54 (0.41–0.65) 0.40 (0.28–0.51) 0.51 (0.35–0.64) 0.27 (0.15–0.41) 0.61 (0.38–0.77) 0.65 (0.42–0.81)
36-mo OS probability (95% CI) 0.26 (0.14–0.39) 0.22 (0.11–0.35) 0.18 (0.07–0.32) 0.07 (0.01–0.23) 0.46 (0.23–0.67) 0.52 (0.28–0.72)
Median OS, mo (95% CI) 25.3 (20.1–31.2) 20.3 (17.5–24.2) 25.0 (17.7–31.1) 17.6 (14.4–20.3) 31.1 (20.1–41.1) NR (22.7–NR)
Subsequent LETs, n (%)
Yes (at least one treatment) 51 (68) 48 (64)
Abiraterone 8 (11) 7 (9.3)
Enzalutamide 21 (28) 14 (19)
Cabazitaxel 24 (32) 19 (25)
Radium-223 19 (25) 15 (20)
No 22 (29) 25 (33)
Unknowna 2 (2.7) 2 (2.7)
Subsequent treatments, n (%)
None/unknown 24 (32) 27 (36)
1 treatment 33 (44) 41 (55)
2 treatments 15 (20) 7 (9.3)
3 treatments 3 (4.0) 0 (0.0)
4 treatments 0 (0.0) 0 (0.0)
ARTA = androgen receptor–targeted agent; CAP = capivasertib; DOC = docetaxel; CI = confidence interval; ITT = intent-to-treat; LETs = life-extending treatments;
NR = not reached; OS = overall survival.
a
Information was not reported for four patients (two in each arm) because of withdrawal from the study.
99 patients (66%; 68% of the capivasertib arm, 64% of the demonstrated by the primary analysis, and an exploratory
placebo arm) had received at least one life-extending ther- analysis indicated that the OS benefit associated with capi-
apy (an ARTA, cabazitaxel, or radium-223) after discontinu- vasertib addition was confined to the subgroup of patients
ing the study treatment and the proportions were balanced who had previously received an ARTA. We had previously
between the treatment arms (Table 1). No clinically signifi- shown that there was no evident relationship between OS
cant differences from the previously reported safety out- and biomarker status for PI3K/AKT/PTEN pathway activa-
comes were seen on extended follow-up [8]. tion [8]. This update demonstrates that the apparent OS
Current treatment paradigms have evolved such that benefit associated with capivasertib does not appear to be
most patients with mCRPC would now have received an explained by imbalance in subsequent therapies. It remains
ARTA before docetaxel chemotherapy, typically while their unclear why the addition of capivasertib to chemotherapy
disease was hormone-sensitive [9,10]. As an exploratory improved OS but not the primary ProCAID endpoint of cPFS
analysis, we therefore investigated OS outcomes for the [8]. Larger trials are required to resolve this question and to
subgroup of 101 patients (67% of the ITT population) who confirm the OS benefit detected in ProCAID. The phase 3
had received an ARTA before entering the ProCAID study CAPItello-280 trial (NCT05348577) examining capivasertib
(Supplementary Tables 1 and 3), which had been included plus docetaxel for patients with mCRPC who have previ-
as a minimisation factor within the trial design. The median ously received an ARTA is positioned to provide these
OS benefit associated with capivasertib plus docetaxel ver- answers.
sus placebo plus docetaxel was 7.4 mo for the ARTA-
pretreated subgroup (median 25.0 vs 17.6 mo; HR 0.57,
Author contributions: Simon J. Crabb had full access to all the data in the
95% CI 0.36–0.91; p = 0.02; Fig. 1B and Table 1); the two
arms had similar baseline characteristics and similar fre-
quencies of life-extending treatments (Supplementary
Tables 1 and 4). By contrast, in the subgroup of 49 patients Study concept and design: Crabb, Birtle, Khoo, Jones.
(accepting that this analysis is underpowered) who had not Acquisition of data: Crabb, Griffiths, Dunkley, Radford, Ellis, Downs, Birtle,
received prior ARTA treatment, there was no difference in Khoo, Jones.
OS between the capivasertib and placebo cohorts (median Analysis and interpretation of data: Crabb, Griffiths, Light, Northey, White-
31.1 mo vs not reached; HR 1.43, 95% CI 0.63–3.23; head, Wilding, Birtle, Khoo, Jones.
Fig. 1C and Table 1). OS also appeared to be longer in this Drafting of the manuscript: Crabb, Griffiths, Dunkley, Downs, Ellis, Rad-
group than in the group with prior ARTA exposure, regard- ford, Light, Northey, Whitehead, Wilding, Birtle, Khoo, Jones.
less of treatment (Fig. 1C and Table 1). Critical revision of the manuscript for important intellectual content: Crabb,
In conclusion, this updated OS analysis provides further Griffiths, Birtle, Khoo, Jones.
evidence that addition of capivasertib to docetaxel Statistical analysis: Light, Northey, Whitehead, Wilding.
chemotherapy improves survival for patients with mCRPC Obtaining funding: Crabb, Griffiths, Jones.
in comparison to treatment with docetaxel alone. The dif- Administrative, technical, or material support: None.
ference in median OS between treatment arms in the ITT Supervision: None.
population had narrowed in comparison to that Other: None.
Financial disclosures: Simon J. Crabb certifies that all conflicts of interest, ending 3 yr after publication. Data sharing requests should be directed
including specific financial interests and relationships and affiliations rel- to Simon J. Crabb and Gareth Griffiths. The Southampton Clinical Trials
evant to the subject matter or materials discussed in the manuscript (eg, Unit (SCTU; University of Southampton, Southampton, UK) is committed
employment/affiliation, grants or funding, consultancies, honoraria, stock to the responsible sharing of clinical trial data and trial samples with the
ownership or options, expert testimony, royalties, or patents filed, wider research community. Data access is administered through the SCTU
received, or pending), are the following: Simon J. Crabb has received Data Release Committee. Requests for data access and sharing for SCTU
honoraria for speaking or advisory work from Astellas Pharma, AstraZe- trials should be e-mailed to the SCTU Data Release Committee Coordina-
neca, Bayer, EMD Serono, Janssen, MSD, Novartis, Roche, and Pfizer, and tor at [email protected].
research funding support from Astex Pharmaceuticals, AstraZeneca, Clo-
vis Oncology, and Roche. Alison J. Birtle has received advisory board Peer Review Summary
speaker fees and travel support from Astellas Pharma, AstraZeneca, Bayer,
EMD Serono, Janssen, Merck Serono, Pfizer, and Roche. Vincent Khoo has
received personal fees and nonfinancial support from Accuray, Astellas,
cle can be found online at https://doi.org/10.1016/j.eururo.
Bayer, Janssen, and Boston Scientific, and has received honoraria for
2022.05.019.
speaking work from Accuray, Astellas, Bayer, Boston Scientific, and Jans-
sen. Robert J, Jones has received research grants from AstraZeneca, Bayer,
References
Clovis, and Exelixis; lecture honoraria from Astella, Bayer, Bristol-Myers
Squibb, Ipsen, Merck Serono, MSD, Pfizer, and Roche; advisory board fees [1] Nuhn P, de Bono JS, Fizazi K, et al. Update on systemic prostate
from Astellas, Bayer, Bristol-Myers Squibb, Ipsen, Merck Serono, MSD, cancer therapies: management of metastatic castration-resistant
Novartis, Pfizer, and Roche; and data safety monitoring board fees from prostate cancer in the era of precision oncology. Eur Urol
2019;75:88–99.
Roche. The remaining authors have nothing to disclose.
[2] Petrylak DP, Tangen CM, Hussain MH, et al. Docetaxel and
estramustine compared with mitoxantrone and prednisone for
advanced refractory prostate cancer. N Engl J Med
Funding/Support and role of the sponsor: Funding was provided by Can-
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study was also supported by core funding from the Southampton Clinical mitoxantrone plus prednisone for advanced prostate cancer. N Engl
Trial Unit. University Hospital Southampton NHS Foundation Trust had J Med 2004;351:1502–12.
[4] Gasmi A, Roubaud G, Dariane C, et al. Overview of the development
roles in the design and conduct of the study; collection, management,
and use of Akt inhibitors in prostate cancer. J Clin Med 2021;11:160.
analysis, and interpretation of the data; and preparation, review, and [5] Liu Z, Zhu G, Getzenberg RH, Veltri RW. The upregulation of PI3K/
approval of the manuscript. AKT and MAP kinase pathways is associated with resistance of
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Acknowledgments: Capivasertib was discovered by AstraZeneca subse- [6] Coleman N, Moyers JT, Harbery A, Vivanco I, Yap TA. Clinical
quent to a collaboration with Astex Therapeutics (and its collaboration development of AKT inhibitors and associated predictive
biomarkers to guide patient treatment in cancer medicine.
with the Institute of Cancer Research and Cancer Research Technology
Pharmgenomics Pers Med 2021;14:1517–35.
Limited). We are most grateful to Cancer Research UK for funding of this [7] Crabb SJ, Birtle AJ, Martin K, et al. ProCAID: a phase I clinical trial to
study, the patients who participated in this clinical trial, their families, combine the AKT inhibitor AZD5363 with docetaxel and
and the nursing and medical staff at the ProCAID trial sites. The authors prednisolone chemotherapy for metastatic castration resistant
prostate cancer. Invest New Drugs 2017;35:599–607.
thank Claire Rooney and her team for helpful comments on the manu-
[8] Crabb SJ, Griffiths G, Marwood E, et al. Pan-AKT inhibitor
script and interpretation of data, and Rose Goodchild of Oxford capivasertib with docetaxel and prednisolone in metastatic
PharmaGenesis for medical writing assistance, which was funded by castration-resistant prostate cancer: a randomized, placebo-
AstraZeneca. We would also like to thank the independent data monitor- controlled phase II trial (ProCAID). J Clin Oncol 2021;39:190–201.
ing and ethics committee and trial steering committee. [9] Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with standard
first-line therapy in metastatic prostate cancer. N Engl J Med
2019;381:121–31.
[10] James ND, de Bono JS, Spears MR, et al. Abiraterone for prostate
Data sharing statement: Individual participant data can be made avail-
cancer not previously treated with hormone therapy. N Engl J Med
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in accordance with General Data Protection Regulation and following
authorisation from the sponsor organisation, starting immediately and

A Path to Precision Medicine in Prostate Cancer: Learning from

‘‘Negative’’ Trials of Targeted Therapies
Tanya B. Dorff a,*, Alicia K. Morgans b

a
Department of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA, USA; b Dana Farber Cancer
Institute, Boston, MA, USA
The Pi3K/AKT pathway is a driver of progression in prostate larger study investigating the combination of capivasertib
cancer, particularly when PTEN loss facilitates overactivity and docetaxel in patients with mCRPC who experience pro-
of this system [1]. It has been shown that Pi3K signaling is gression after prior ARTA treatment remains debatable.
enhanced after resistance to taxane chemotherapy has Targeting of molecular subsets is a different strategy for
developed [2]. Inhibition of signaling through AKT is phar- selecting patients with a greater likelihood of deriving ben-
macologically feasible and preclinically effective. However, efit from targeted therapies. The AKT inhibitor ipatasertib
understanding which patient subsets would experience was studied in combination with abiraterone acetate in
the greatest therapeutic impact from targeting the Pi3K/ patients with mCRPC in the IPATential150 trial, and
AKT pathway remains a challenge. although the overall study was not significantly positive,
In this issue of European Urology, the ProCAID investiga- the subset of patients with PTEN loss did appear to benefit
tors [3] report on their observation of a clinical signal that from the combination. Interestingly, the method for defin-
may shed light on one enriched patient population for ing PTEN loss, via immunohistochemistry versus next-gen-
future study of AKT-targeted treatment. In this study, the eration sequencing (NGS), mattered. NGS was better at
AKT inhibitor capivasertib was added to docetaxel for identifying those who experienced longer survival with
patients with metastatic castration-resistant prostate can- the combination of ipatasertib plus abiraterone acetate.
cer (mCRPC) in a randomized unselected design. While the Each of these studies of Pi3K/AKT inhibitors had a differ-
primary analysis was negative for the endpoint of progres- ent therapeutic partner, both of which were rationally
sion-free survival (PFS), there was a trend in favor of capi- selected. However, one could conceive of earlier prostate
vasertib for overall survival (OS) [4]. With longer follow- cancer disease states as being potentially more sensitive
up, the authors now report that OS is not significantly pro- to the effects of AKT inhibition, since it is felt that this path-
longed with the addition of capivasertib (hazard ratio [HR] way drives the development of castration resistance via
0.7, 95% confidence interval [CI] 0.47–1.05). However, the cross-talk with the AR [5]. Yet the current study found the
subset of patients previously treated with androgen recep- opposite, a potential greater benefit in patients with prior
tor–targeted agents (ARTAs) such as abiraterone acetate ARTA exposure. Serial assessment of circulating tumor
and enzalutamide experienced a statistically significant sur- DNA (ctDNA) may be a future method for better categoriza-
vival improvement with the addition of capivasertib com- tion of patients with mCRPC on the basis of their molecular
pared to docetaxel alone in first-line mCRPC (HR 0.57, 95% drivers and resistance mechanisms in ‘‘real time’’ rather
CI 0.36–0.91). Biologically this is plausible, as greater sup- than the basic clinical categorizations currently used (ie,
pression of AR signaling via ARTA treatment may drive after ARTA treatment). However, since it has been reported
heightened cancer cell dependence on alternative that truncal alterations such as PTEN loss were more con-
pathways, including Pi3K/AKT. Whether the benefit identi- cordant between archived tissue and ctDNA than other
fied in this subgroup in ProCAID is sufficient to prompt a molecular changes (such as AR alterations) [6], molecular

* Corresponding author. Department of Medical Oncology and Experimental Therapeutics, City of Hope Comprehensive Cancer Center, 1500 E. Duarte
E-mail address: [email protected] (T.B. Dorff).
selection for future enrichment of clinical trial populations exciting that prostate cancer continues to move in the
using AKT-targeted therapy could also be based on archival direction of precision medicine, even as the biologic
tissue. Regardless of the selection factors, the question complexity of castration resistance is yielding to one-size-
remains as to where AKT inhibitors would fit in the optimal fits-all combination approaches. It is up to us to innovate
sequence and/or combination with other therapeutics. daringly but proceed rationally to ensure that our next steps
Other combinations are being evaluated in first-line mCRPC toward precision medicine fall on more solid ground.
that may be more appealing to patients who wish to avoid
chemotherapy for as long as possible, including abiraterone
Conflicts of interest: Tanya B. Dorff has acted as a consultant for Astellas,
acetate in combination with olaparib, as assessed in the
AstraZeneca, Janssen, Pfizer, Exelixis, and SeaGen. Alicia K. Morgans has
PROpel trial, or with niraparib, as assessed in the MAGNI-
received consulting honoraria from AAA, Astellas, AstraZeneca, Bayer,
TUDE trial [7,8]. Further follow-up is needed to demonstrate
Lantheus, Janssen, Exelixis, Myovant, Myriad, Pfizer, Novartis, Sanofi,
whether the benefit seen with these combinations will be
and Telix; and has research collaborations with Astellas, Bayer, Myovant,
predominantly limited to patients with alterations in
Pfizer, Sanofi, and SeaGen.
homologous recombination repair genes, or is applicable
to a broader spectrum of patients. The data from PROpel
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Platinum Priority – Bladder Cancer

Editorial by Pooja Ghatalia, Elizabeth R. Plimack on pp. 527–528 of this issue
Phase 1 Study of Chemoradiotherapy Combined with

Nivolumab ± Ipilimumab for the Curative Treatment
of Muscle-invasive Bladder Cancer
Ben-Max de Ruiter a,b,1, Jons W. van Hattum a,b,1, Djoeri Lipman c, Theo M. de Reijke a,b,
R. Jeroen A. van Moorselaar b,d, Erik J. van Gennep e, A.H. Maartje Piet b,f, Mila Donker g,
Tom van der Hulle h, Jens Voortman b,i, Jorg R. Oddens a,b, Maarten C.C.M. Hulshof b,j,
Adriaan D. Bins b,k,*
a
Department of Urology, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands; b Cancer Center Amsterdam, Amsterdam,
The Netherlands; c Department of Radiation Oncology, Isala Hospital Zwolle, Zwolle, The Netherlands; d Department of Radiotherapy, Amsterdam UMC
location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands; e Department of Urology, Leiden University Medical Center, Leiden University,
Leiden, The Netherlands; f Department of Radiotherapy, Amsterdam UMC location Vrije Universiteit Amsterdam, Amsterdam, The Netherlands;
g
Department of Radiotherapy, Leiden University Medical Center, Leiden University, Leiden, The Netherlands; h Department of Medical Oncology, Leiden
University Medical Center, Leiden University, Leiden, The Netherlands; i Department of Medical Oncology, Amsterdam UMC location Vrije Universiteit
Amsterdam, Amsterdam, The Netherlands; j Department of Radiotherapy, Amsterdam UMC location University of Amsterdam, Amsterdam, The
Netherlands; k Department of Medical Oncology, Amsterdam UMC location University of Amsterdam, Amsterdam, The Netherlands
Article history: Background: Muscle-invasive bladder cancer (MIBC) has a poor prognosis.
Accepted July 14, 2022 Chemoradiotherapy (CRT) in selected patients has comparable results to radical cystec-
tomy. Results of neoadjuvant immune checkpoint inhibitors (ICIs) before radical cystec-
tomy are promising. We hypothesize that ICI concurrent to CRT (iCRT) is safe and may
improve treatment outcomes.
Objective: To determine the safety of iCRT for MIBC.
Design, setting, and participants: This multicenter, phase 1b, open-label, dose-escalation
study determined the safety of CRT with three ICI regimens in patients with non-
metastatic (T2-4aN0-1) MIBC. Twenty-six patients received mitomycin C/capecitabine
Keywords: and 20 2.75 Gy to the bladder. Tolerability was evaluated in a cohort of up to ten
Bladder cancer patients. If two or fewer out of the first six patients or three or fewer of ten patients
Chemoradiotherapy experienced dose-limiting toxicity (DLT), accrual continued in the next cohort.
Immune checkpoint inhibition Intervention: Patients received nivolumab 480 mg (NIVO480), nivolumab 3 mg/kg and
Bladder-sparing treatment ipilimumab 1 mg/kg (NIVO3 + IPI1), or nivolumab 1 mg/kg and ipilimumab 3 mg/kg
(IPI3 + NIVO1).
1
Both these authors contributed equally.
* Corresponding author. Department of Medical Oncology, Amsterdam University Medical Centers,
University of Amsterdam, De Boelelaan 1117, 1118, 1081 HV Amsterdam, The Netherlands. Tel. +31
20 566 9111.
E-mail address: [email protected] (A.D. Bins).
0302-2838/Ó 2022 The Authors. Published by Elsevier B.V. on behalf of European Association of Urology. This is an open access article
Outcome measurements and statistical analysis: The primary endpoint was safety.
Secondary objectives were response rate, disease-free survival, metastatic-free survival
(MFS), and overall survival (OS).
Results and limitations: In the NIVO480 cohort, no patients experienced DLT. The
NIVO3 + IPI1 2 patients experienced DLT, thrombocytopenia (grade 4), and asystole
(grade 5). IPI3 + NIVO1 was discontinued after three out of six patients experienced
DLT. Clinically significant adverse events (AEs) of grade 3 occurred in zero, three,
and five patients in the NIVO480, NIVO3 + IPI1, and IPI3 + NIVO1 groups, respectively.
The most common AEs were immune related and gastrointestinal. MFS and OS were
90% at 2 yr for NIVO480 and 90% at 1 yr for NIVO3 + IPI1. Limitations include the absence
of a centralized pathology and radiology review, and a lack of biomarker analysis.
Conclusions: In this dose-finding study of iCRT, the regimens of nivolumab monotherapy
and nivolumab 3 mg/kg with ipilimumab 1 mg/kg have acceptable toxicity.
Patient summary: We tested the safety of a new bladder-sparing treatment modality for
muscle-invasive bladder cancer patients, combining immune checkpoint inhibitors simul-
taneously with chemoradiotherapy. We report that two regimens, nivolumab monother-
apy and nivolumab 3 mg/kg with ipilimumab 1 mg/kg, are safe and can be used in phase 3
trials.
Ó 2022 The Authors. Published by Elsevier B.V. on behalf of European Association of
1. Introduction [20–22]. There are several active iCRT studies in MIBC

[23]. As yet, one trial investigating the anti–PD-L1 drug
Urothelial bladder cancer (UBC) is the ninth most prevalent atezolizumab has been published after premature termina-
cancer worldwide, with yearly over 500 000 new cases and tion due to toxicity [24]. This shows that careful evaluation
200 000 attributable deaths [1]. UBC, in which the tumor of iCRT in terms of ICI and CRT regimens is needed.
invades the detrusor muscle (muscle-invasive bladder can- To our knowledge, we present the first clinical trial
cer [MIBC]) contributes to approximately 30% of newly investigating the safety and feasibility of iCRT with nivolu-
diagnosed cases [2]. mab and ipilimumab for MIBC. We investigated three regi-
Despite intensive treatments such as radical mens: first anti–PD-1 monotherapy (nivolumab), followed
cystectomy (RC) with pelvic lymph node dissection or by anti–PD-1 + anti–CTLA-4 (ipilimumab) concurrent to
bladder-sparing chemoradiotherapy (CRT), the prognosis CRT with mitomycin C (MMC) and capecitabine to deter-
of MIBC remains poor, with 5-yr overall survival (OS) mine the maximally tolerable dose [25]. Additionally, we
of 50% [3,4]. The high mortality rate of MIBC is explained provide early oncological outcomes.
by the early development of micrometastases [5,6]. This
is supported by the fact that neoadjuvant chemotherapy
(NAC) before RC improves 5-yr OS by 5–8% [7]. A similar 2. Patients and methods
survival benefit of NAC on CRT has not been confirmed
2.1. Study design and patients
[8].
Recently, the use of immune checkpoint inhibitors The CRIMI trial (NCT038442556) is a multicenter, phase 1b–2, open-
(ICIs) has improved treatment outcomes in several can- label, dose-escalation study of MMC/capecitabine CRT combined with
cers [9–12]. ICI monotherapy targeted against pro- nivolumab monotherapy or nivolumab and ipilimumab as a curative
grammed death 1 (PD-1) or its ligand (PDL-1) has bladder-sparing treatment of nonmetastatic MIBC. Between January
produced clinically meaningful results and has already 2019 and December 2021, participants were sequentially enrolled in
gained a role in the treatment of metastatic UBC three academic hospitals in The Netherlands into three consecutive
[4,13,14]. Sharma et al [15] suggested that combined treatment regimens (IRB 2018_095#B202132).
treatment targeted against PD-1 and cytotoxic T lympho- The key eligibility criteria were 18 yr, Eastern Cooperative Oncol-
cyte antigen 4 (CTLA-4) improved treatment results with ogy Group performance status 1, and histologically confirmed urothe-
acceptable toxicity. In line with these developments, lial MIBC (>50% urothelial carcinoma, stage cT2-T4acN0-1M0 in
potential benefit of neoadjuvant ICIs before RC has been combination with adequate organ and bone marrow function). No con-
current extravesical UBC (ie, urethra and upper urinary tract), multifocal
demonstrated, with pathological response rates (RRs)
carcinoma in situ (CIS), and prior treatment for MIBC or pelvic radiother-
between 33% and 58% [16–19]. These outcomes warrant
apy was allowed. The eligibility criteria are described in the Supplemen-
further research of ICI combination therapy in the cura-
tary material.
tive treatment of MIBC patients.
The study protocol (Supplementary material) was approved by the
One such potential treatment is combining an ICI with
institutional review board of each participating center and was con-
CRT (iCRT). Both chemotherapy and radiotherapy influence
ducted in accordance with the Guidelines for Good Clinical Practice.
the tumor microenvironment by increasing immune cell Informed consent was obtained from participants. An independent data
infiltration and antigen presentation, which could lead to safety monitoring board was instituted and consulted at predefined
an enhanced immune response after ICI treatment stages throughout the study.
2.2. Study procedures and treatment Table 2 – Planning dose constraint radiotherapy
Organ at risk Dosimetric parameter Volume

Patients were staged by transurethral resection of the bladder tumor
(TURBT) prior to the start of study treatment and computed tomography Small bowel V55 <3 cc
Bowel bag V45 <300 cc
(CT) imaging of the chest, abdomen, and pelvis, and discussed in a mul- Rectum V50 <50%
tidisciplinary meeting. Fluorodeoxyglucose positron emission tomogra- Sigmoid V60 <3 cc
phy was optional following hospital guidelines. The study treatment Bladder V50 15%
Hip left <V50 NA
was administered in 12 wk (Table 1) and consisted of radiotherapy using
Hip right <V50 NA
volumetric modulated arc therapy or intensity-modulated radiotherapy
NA = not available; V55, V45, and V60 = percentages of volume receiving
(IMRT) with 40 Gy in 20 fractions of 2 Gy to the whole bladder and pelvic 55, 45, or 30 Gy.
lymph nodes up to the level of the common iliac arteries, with a simul-
taneous integrated focal boost (SIB) of 15 Gy in 20 fractions of 0.75 Gy to
the primary tumor area. Tumors were endoscopically demarcated using 4.03. Response was assessed by cystoscopy and CT scan of chest, abdo-
lipiodol or BioXmark injections for cone beam CT scan–based daily accu- men, and pelvis at 12 and 24 wk. Complete response was defined as
rate boost dose delivery, if possible [26,27]. On-line adaptive radiation absence of a tumor at cystoscopic evaluation without signs of metastasis
techniques were used in all patients, either with a library of plans or at CT. Bladder biopsies were not required unless there was a suspicion of
with online adaptive planning. Radiotherapy dose constraints are dis- residual tumor or recurrence. From week 24, cystoscopy and imaging
played in Table 2. Multifocal UBC was treated with whole bladder irradi- were conducted every 3 mo and used for tumor evaluation according
ation. Chemotherapy consisted of radiosensitizing MMC 12 mg/m2 to RECIST (response evaluation criteria in solid tumors) version 1.1.
intravenously on day 1 of radiation and capecitabine 750 mg/m2 twice Secondary objectives consisted of RR, disease-free survival (DFS)
daily on days of radiotherapy. defined as the absence of any recurrence, metastatic-free survival
The CRT treatment was combined with concurrent ICI therapy in (MFS), and OS per treatment regimen. Time-to-event analyses were cal-
three consecutive regimens. Patients were assigned to the next regimen culated from the start of treatment and censored at last hospital contact
when ten patients within one cohort were included: (OS), cystoscopy (DFS), or imaging (DFS and MFS).
1. NIVO480: nivolumab monotherapy at 480 mg fixed dose every 4 wk for

three doses on weeks 1, 5, and 9. 2.4. Statistical analysis
2. NIVO3 + IPI1: nivolumab 3 mg/kg and ipilimumab 1 mg/kg every 3 wk for
four doses on weeks 1, 4, 7, and 10. All analyses were conducted in R (R Foundation for Statistical Comput-
3. IPI3 + NIVO1: nivolumab 1 mg/kg and ipilimumab 3 mg/kg every 3 wk for
ing, Vienna, Austria). DFS, MFS, and OS intervals were defined as the time
four doses on weeks 1, 4, 7, and 10.
from the start of study treatment to the date of recurrence, progression,
and death, respectively. The Kaplan-Meier method was used to assess
After 12 wk, study participants could opt for fixed-dose adjuvant
survival probabilities. The sample size was based on clinical considera-
nivolumab 480 mg at intervals of 4 wk, from week 13 to week 52.
tions and toxicity data of nivolumab and ipilimumab in metastatic
Dose modifications of ICIs were not allowed; however, withholding
UBC [21]. We estimated 10% of patients to experience DLT in the first
infusions was allowed in case of adverse events (AEs), as judged by the
6 wk of treatment and the equivalent percentage in the context of
investigator. Dose reductions and discontinuation of capecitabine were
capecitabine/MMC-iCRT, based on previous CRT experience. We
allowed, with maximum discontinuation of 10 out of 20 d.
accepted a margin of 30% (up to 40% DLT) as equivalent in the dose esca-
lating safety evaluation phase. Ten patients were needed to be able to
2.3. Objectives and assessment
identify that the fraction of patients experiencing DLT with iCRT is
<30% different from the target, with at least 90% power in a one-
The primary endpoint was safety and identifying the maximal tolerable
sample equivalence test.
ICI regimen, determined by evaluating the rate of dose-limiting toxicity
(DLT) during the first 6 treatment weeks according to protocol-defined
criteria (Supplementary material). A regimen was deemed safe if two 3. Results
or fewer out of the first six patients or three of fewer out of ten patients
in a cohort experienced DLT. Patient enrolment followed a staggered 3.1. Patients
design.
AEs were monitored throughout the study and for up to 180 d after Between January 2019 and November 2021, 28 patients
the last ICI infusion, and graded according to National Cancer Institute were screened and 26 were enrolled in three hospitals on
Common Terminology Criteria for Adverse Events (CTCAE) version three consecutive regimens. Ten patients received NIVO480
Table 1 –
Regimen Treatment Week

1 2 3 4 5 6 7 8 9 10 11 12 13 17 21 25 29 33 37 41 45 49
Standard Radiotherapy 55 Gy U U U U
Capecitabine 750 mg bid U U U U
MMC 12 mg/m2 U
NIVO480 Nivolumab 480 mg U U U Optional: 10 nivolumab 480 mg
NIVO3 + IPI1 Nivolumab 3 mg/kg and ipilimumab 1 U U U U Optional: 10 nivolumab 480 mg
mg/kg
IPI3 + NIVO1 Nivolumab 1 mg/kg and ipilimumab 3 U U U U Optional: 10 nivolumab 480 mg
mg/kg
IPI3 + NIVO1 = nivolumab 1 mg/kg and ipilimumab 3 mg/kg; MMC = mitomycin C; NIVO480 = nivolumab 480 mg; NIVO3 + IPI1 = nivolumab 3 mg/kg and
ipilimumab 1 mg/kg.
Table 3 – Baseline characteristics
NIVO480 NIVO3 + IPI1 IPI3 + NIVO1

Patients (n) 10 10 6
Age (yr), median (IQR) 68 (61–75) 70 (66–75) 65 (61–67)
N % n % n %
Sex Male 9 90 9 90 4 66
Female 1 10 1 10 2 33
ECOG performance status 0 6 60 6 60 5 83
1 4 40 4 40 1 17
T stage T2 7 70 8 80 5 83
T3 3 30 2 20 1 17
N stage 0 10 100 8 80 5 83
1 2 20 1 17
Hydronephrosis at start of CRT Yes 1 10 0 0 1 17
TURBT histology 100% urothelial 10 100 10 100 4 67
>50% urothelial + squamous 1 17
>50% urothelial + sarcomatoid 1 17
Focality Unifocal 10 100 9 90 6 100
Multifocal 1 10
Concomitant CIS Yes 2 20 2 20 1 17
CIS = carcinoma in situ; CRT = chemoradiotherapy; ECOG = Eastern Cooperative Oncology Group; IPI3 + NIVO1 = nivolumab 1 mg/kg and ipilimumab 3 mg/kg;
IQR = interquartile range; NIVO480 = nivolumab 480 mg; NIVO3 + IPI1 = nivolumab 3 mg/kg and ipilimumab 1 mg/kg; TURBT = transurethral resection of a
bladder tumor.
and NIVO3 + IPI1, and six patients received IPI3 + NIVO1. AEs of grade 3 occurred in five (83%) patients and con-
The baseline characteristics are displayed in Table 3. At sisted of immune-related disorders (66%), colitis (50%), fati-
the data cutoff on February 4, 2022, the median follow-up gue (33%), and skin and urinary disorders (both 17%). Two
time was 89 (interquartile range [IQR] 50–109) wk. patients with colitis received additional infliximab.
Deteriorated laboratory results not requiring treatment
3.2. DLT and AEs were present in two (33%) patients.
Two regimens, NIVO480 and NIVO3 + IPI1, passed the dose 3.2.4. AEs after treatment regimen
evaluation phase. The maximally tolerated regimen was the After finishing the iCRT treatment regimen, 13 patients in
NIVO3 + IPI1 regimen with two cases of DLT in ten patients. total (six in the NIVO480, five in the NIVO3 + IPI1, and two
IPI3 + NIVO1 displayed unfavorable toxicity with three in the IPI3 + NIVO1 cohort) opted for 1-yr adjuvant nivolu-
cases of DLT in six patients. AEs during the first 12 wk of mab. AEs per regimen during the adjuvant nivolumab phase
treatment per treatment arm are displayed in Table 4. are displayed in Supplementary Table 1. AEs of grade 3
occurred in four out of 13 (31%) patients, of whom two
3.2.1. NIVO480 patients were in the NIVO480 cohort. One patient developed
No DLT or AE of grade 3 requiring intervention occurred in anemia leading to an episode of acute coronary syndrome
the NIVO480 cohort. Deteriorated laboratory results not and one developed grade 3 diarrhea due to pancreatitis. In
requiring treatment were present in one (10%) patient. both the NIVO3 + IPI1 and the IPI3 + NIVO1 cohort, one
patient experienced a grade 3 AE, pneumonitis, and
hydronephrosis of grade 3 after JJ stent removal. Immune-
3.2.2. NIVO3 + IPI1
related AEs (irAEs; pancreatitis and pneumonitis) resolved
Two out of ten patients in the NIVO3 + IPI1 regimen experi-
after nivolumab discontinuation and prednisone. AEs in
enced DLT. One thrombocytopenia grade 4, occurring dur-
patients who did not receive adjuvant nivolumab are pre-
ing week 4, normalized after ICI and capecitabine
sented in Supplementary Table 2. One patient (10%) in the
discontinuation. One patient, a 78-yr-old male with a his-
NIVO3 + IPI1 cohort developed hydronephrosis and a urinary
tory of atrial fibrillation, died (asystole) after 4 wk following
tract infection following disease progression.
hospitalization due to grade 3 hyponatremia and vomiting.
We were unable to attribute the death to a component of
3.3. Dose reductions
the study treatment.
AEs of grade 3 occurred in three (30%) patients and An overview of dose reductions is displayed in Figure 1. All
consisted of gastrointestinal (30%), hematological (20%), patients received the full radiotherapy and MMC dosages.
and cardiac (10%) disorders.
Deteriorated laboratory results not requiring treatment 3.3.1. NIVO480
were present in seven (70%) patients. All participants received all infusions. Capecitabine dose
reductions occurred in one out of ten (10%) patients due
3.2.3. IPI3 + NIVO1 to nausea.
Three out of six patients receiving IPI3 + NIVO1 experienced
DLT (colitis, pneumonitis, and hepatitis). DLT occurred in 3.3.2. NIVO3 + IPI1
patients with no prior medical history. All cases of DLT were Five out of ten patients received all ICI infusions. Two
treated by ICI discontinuation and prednisone. patients missed one infusion in week 7, due to grade 2 ele-
Table 4 – CTCAE-scored adverse events per regimen
Adverse events NIVO480 NIVO3 + IPI1 IPI3 + NIVO1

Grade, n (%) All 3 All 3 4 5 All 3 4
Any event 9 (90) 1 (10) 10 (100) 3 (30) 1 (10) 1 (10) 10 (100) 5 (50) 1 (10)
Gastrointestinal 8 (80) 9 (90) 2 (20) 1 (10) 6 (100) 3 (50)
Colitisa 3 (50) 3 (50)
Duodenal ulcer 1 (10) 1 (10)
Diarrhea 7 (70) 6 (60) 1 (10) 5 (50)
Vomiting 1 (10) 1 (10) 1 (10)
Flatulence 2 (20)
Abdominal pain 1 (10) 1 (10)
Constipation 2 (20) 1 (10) 2 (33)
Anorexia 2 (20) 2 (20)
Nausea 2 (20) 1 (10) 2 (33)
Rectal hemorrhage 1 (10)
Oral mucositis 1 (17)
GERD 1 (17)
Cardiac 1 (10) 1 (10) 1 (10)
Asystole 1 (10) 1 (10)
ACS 1 (10)
Immune system 0 3 (30) 4 (66) 4 (66)
Colitisa 3 (50) 3 (50)
Pneumonitisa 1 (17) 1 (17)
Hepatitis 1 (10) 1 (17) 1 (17)
Thyroiditis 2 (20)
Eye 0 0 2 (33)
Watering eyes 2 (33)
Hematological 1 (10) 4 (40) 1 (10) 1 (10) 0
Anemia 1 (10) 2 (20) 1 (10) 0
General 4 (40) 6 (60) 5 (83)
Fatigue 4 (40) 5 (50) 4 (66) 2 (33)
Weight loss 1 (10) 2 (33)
Fever 1 (17)
Renal and urinary 3 (30) 4 (40) 2 (33) 1 (17)
Bladder pain 3 (30) 2 (33) 1 (17)
Renal failure 1 (10) 1 (10)
Bladder spasm 1 (10)
Cystitis, noninfective 1 (10) 1 (10) 2 (33)
Urinary incontinence 1 (10) 1 (10)
Urinary retention 1 (10)
Urinary urge 1 (10) 2 (20)
Infectious 1 (10) 1 (17)
Urinary tract infection 1 (17) 1 (17)
Upper respiratory infection 1 (10)
Respiratory 1 (10) 1 (10) 2 (33) 1 (17)
Pneumonitisa 1 (17) 1 (17)
Hiccups 1 (17)
Cough 1 (10)
Skin disorders 8 (80) 5 (50) 3 (50) 1 (17)
Rash 7 (70) 4 (40) 3 (50) 1 (17)
Erythema multiforma 1 (10) 1 (17)
Pruritus 1 (10) 1 (10)
PPES 2 (20)
Endocrineb 1 (10) 3 (30) 0
Adrenal insufficiency 1 (10)
Hypothyroidism 1 (10)
Hyperthyroidism 2 (20)
Nervous system 1 (10) 3 (30) 1 (17)
Peroneal nerve injury 1 (10)
PMNP 1 (17)
Dysgeusia 1 (10) 3 (30)
Lab investigations 5 (50) 9 (90) 4 (66) 1 (17) 1(17)
Lymphocytes decreased 4 (40) 2 (20) 6 (60) 3 (50)
Lipase increased 3 (30) 2 (20) 1 (10)
Neutrophil count decreased 1 (10) 1 (10) 4 (40) 1 (10) 1 (17) 1(17)
Platelet count decreased 0 5 (50) 1 (10) 2 (33)
Amylase increased 0 2 (20) 1 (30)
Hypokalemia 0 1 (10) 1 (10)
Hyponatremia 2 (20) 2 (20)
Hypophosphatemia 1 (10) 1 (10)
ALT increased 1 (10)
WBC count decreased 1 (10) 4 (40) 1 (17) 1 (17)
ACS = acute coronary syndrome; AE = adverse event; ALT = alanine aminotransferase; CTCAE = National Cancer Institute Common Terminology Criteria for
Adverse Events; GERD = gastroesophageal reflux disease; IPI3 + NIVO1 = nivolumab 1 mg/kg and ipilimumab 3 mg/kg; NIVO480 = nivolumab 480 mg;
NIVO3 + IPI1 = nivolumab 3 mg/kg and ipilimumab 1 mg/kg; PMNP = peripheral motor neuropathy; PPES = palmar plantar erythodysthesia syndrome;
WBC = white blood cell; text in bold highlights >grade 2 adverse event.
a
Same adverse event.
b
More than one AE per participant.
Fig. 1 – An overview of infusions and dose reductions. AE = adverse event; Cape = capecitabine; CRT = chemoradiotherapy; DLT = dose-limiting toxicity;
ev. = evaluation; ICI = immune checkpoint inhibitor; IPI3 + NIVO1 = nivolumab 1 mg/kg and ipilimumab 3 mg/kg; irAE = immune-related adverse event;
NIVO480 = nivolumab 480 mg; NIVO3 + IPI1 = nivolumab 3 mg/kg and ipilimumab 1 mg/kg.
vated aspartate transaminase + alanine aminotransferase 3.4.2. NIVO3 + IPI1

and grade 2 diarrhea. Two patients received two infusions, No recurrences were observed at 12-wk follow-up. The DFS
one patient due to death, and one patient due to rash (grade and MFS probabilities at 1 yr were 0.89 (CI 0.71–1) and 1,
2) and an elevated lipase (grade 3). One patient received one respectively. The OS probability at 1 yr was 0.9 (CI 0.73–
infusion due to grade 4 thrombocytopenia. Dose reductions 1). The median follow-up of survivors was 83 (IQR 78–95)
of capecitabine occurred in seven out of ten (70%) patients wk. One patient experienced an intravesical high-grade
due to a low platelet count (40%), hyponatremia (10%), diar- noninvasive recurrence after 48 wk, and was treated with
rhea (10%), or a low neutrophil count (10%). TURBT and adjuvant BCG bladder instillations.
One patient who experienced DLT and received one ICI
infusion experienced a muscle-invasive recurrence with
3.3.3. IPI3 + NIVO1 simultaneous metastasis after 68 wk.
Two out of six (33%) patients received all ICI infusions. Four
out of six (66%) patients experienced irAEs, and ICI infusions 3.4.3. IPI3 + NIVO1
were discontinued. Dose reductions of capecitabine The median follow-up was 26 (IQR 14.6–29.8) wk. No recur-
occurred in four out of six (66%) patients due to low platelet rences were observed at 12-wk follow-up. One patient
counts (33%), colitis (17%), or nausea (17%). experienced an intravesical low-grade noninvasive recur-
rence after 32 wk, for which TURBT was performed, fol-
lowed by a single postoperative MMC bladder instillation.
3.4. Follow-up
Follow-up is displayed in Figure 2 and Supplementary 4. Discussion

Figure 1.
To our knowledge, this is the first safety analysis of nivolu-
mab monotherapy and combination therapy of nivolumab
3.4.1. NIVO480 and ipilimumab concurrent to MMC/capecitabine CRT for
No recurrences were observed at 12-wk follow-up. The DFS MIBC. NIVO3 + IPI1 in combination with CRT was the max-
probabilities at 1 and 2 yr are, respectively, 1 and 0.7 (con- imal tolerable dose. NIVO3 + IPI1 and NIVO480 showed an
fidence interval [CI] 0.47–1). The MFS probabilities at 1 and acceptable immune-related safety profile consistent with
2 yr are, respectively, 1 and 0.9 (CI 0.73–1). The OS probabil- iCRT in other tumor types [28–30]. IPI3 + NIVO1 iCRT led
ities at 1 and 2 yr are, respectively, 1 and 0.9 (CI 0.732–1). to unacceptable toxicity.
The median follow-up of survivors was 121 (IQR 109–123) The most common grade 3 hematological AEs (neu-
wk. Intravesical noninvasive CIS recurrences occurred in tropenia and thrombocytopenia) were consistent with AEs
two (20%) patients after 55 and 60 wk, and were treated typically observed with CRT [31]. The addition of ipili-
with TURBT and adjuvant bacillus Calmette-Guérrin (BCG) mumab leads to an increase of grade 3 laboratory abnor-
instillations. malities, with most prevalent low lymphocyte values. The
Fig. 2 – Follow-up of patients in the study. CT = computed tomography; IPI3 + NIVO1 = nivolumab 1 mg/kg and ipilimumab 3 mg/kg; NIVO480 = nivolumab 480
mg; NIVO3 + IPI1 = nivolumab 3 mg/kg and ipilimumab 1 mg/kg; NMIBC = non–muscle-invasive bladder cancer.
incidence of gastrointestinal and cardiac disorders was of DLT occurring in the NIVO3 + IPI1 regimen. Late onset
higher in the NIVO3 + IPI1 cohort than in the current CRT of AEs is common in ICI treatment [37]. The absence of early
literature. Trials in metastatic cancer show that ICIs are ICI toxicity during hypofractionated CRT provides a possible
the main drivers of toxicity. Sharma et al. [15] reported safeguard for concurrent iCRT schedules. Additionally,
the incidence of grade 3/4 AEs to increase with the ICI dose: recent literature shows that early ICI discontinuation due
26.9%, 30.8%, and 39.1% for NIVO, NIVO3 + IPI1, and to AEs does affect treatment outcomes in melanoma
IPI3 + NIVO1, respectively, a pattern similar to that patients [38]. Results of several multinational phase 2/3 tri-
observed in our study. Additionally, nivolumab combined als testing several ICI regimens for both N0 and N1 MIBC are
with ipilimumab is known to cause frequent grade 3 irAEs expected in the upcoming year, providing data for the tim-
in 39.1–59% of patients with metastatic disease [9,10,15], ing of ICI treatment in combination with CRT [23].
while in a recent phase 2 study of ICIs before RC, grade No histological analyses were performed following treat-
3 irAEs occurred in 55% [18]. ment due to the nature of bladder-sparing treatment. In
Interestingly, we report less toxicity with anti–PD-1 addition, central pathology and radiology reviews were
monotherapy compared with the results of the only pub- not done. Despite stringent follow-up, the absence of an
lished phase 1 trial on iCRT with atezolizumab for UBC exploratory biomarker analysis makes it impossible to
[24]. The most common grade 3 AE in that report was col- select responders. Additionally, oncological outcomes for
itis in four of eight patients, which we did not observe in our the complete study cohort are limited, which complicates
NIVO480 regimen. Several differences with our study may validation of biomarkers. However, with organ-sparing
account for this difference; The ICI regimen and dose differ, treatments, there is limited availability of tumor tissue, so
but differences in chemotherapy and radiotherapy may also researchers should be cautious in trying to validate ques-
play a role. We administered MMC/capecitabine chemosen- tionable biomarkers such as PD-L1 expression [39].
sitization in contrast to gemcitabine. Capecitabine is an oral Currently, we cannot determine the efficacy of iCRT for
prodrug of 5-flourouracil that avoids hospital admissions MIBC. Early oncological outcomes are promising. The results
and infusion-related events, and has shown similar onco- of iCRT in non–small cell lung and esophageal carcinoma
logical outcomes to 5-flourouracil when combined with are encouraging, with RRs between 30% and 70% [28,29].
MMC [25]. In our study, we used hypofractionated radio- In metastatic UBC, the increased toxicity of IPI3 + NIVO1
therapy using IMRT, online adaptive planning, and SIB, is deemed acceptable because of the higher RR [15]. A
which could have decreased intestinal radiation damage planned expansion cohort of NIVO3 + IPI1 to determine
[32–35]. A recent trial however suggested that large dose the efficacy will provide a solid basis for further randomized
fractions (6 Gy) in combination with immunotherapy might phase 3 trials.
cause increased toxicity [36].
An important factor when evaluating the toxicity is the 5. Conclusions
moment of onset of AEs. As shown by Marcq et al. [24],
the onset of grade 3 AEs was after completing CRT and This first-tested addition of nivolumab and ipilimumab to
at least two doses of ICIs, with the exception of two cases CRT for MIBC seems to be safe. The use of IPI3 + NIVO1 is
unadvised due to high toxicity. Future trials should focus on [5] van Hoogstraten LMC, van Gennep EJ, Kiemeney L, et al. Occult
lymph node metastases in patients without residual muscle-
the efficacy of both anti–PD-1 monotherapy and anti–PD-
invasive bladder cancer at radical cystectomy with or without
1 + anti–CTLA-4 combination iCRT regimens and their com- neoadjuvant chemotherapy: a nationwide study of 5417 patients.
parison with standard CRT alone. World J Urol 2022;40:111–8.
[6] Mertens LS, Meijer RP, Meinhardt W, et al. Occult lymph node
metastases in patients with carcinoma invading bladder muscle:
Author contributions: Ben-Max de Ruiter had full access to all the data in incidence after neoadjuvant chemotherapy and cystectomy vs after
the study and takes responsibility for the integrity of the data and the cystectomy alone. BJU Int 2014;114:67–74.
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accuracy of the data analysis.
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Voortman, Hulshof. invasive bladder cancer treated with neoadjuvant chemotherapy
followed by (chemo)radiotherapy in the BC2001 trial. Eur Urol
Acquisition of data: de Ruiter, van Hattum, van Gennep, Piet, Donker, van
2021;79:307–15.
der Hulle, Voortman, Oddens. [9] Hodi FS, Chiarion-Sileni V, Gonzalez R, et al. Nivolumab plus
Analysis and interpretation of data: de Ruiter, van Hattum, Bins. ipilimumab or nivolumab alone versus ipilimumab alone in advanced
Drafting of the manuscript: de Ruiter, van Hattum, Bins. melanoma (CheckMate 067): 4-year outcomes of a multicentre,
Critical revision of the manuscript for important intellectual content: de randomised, phase 3 trial. Lancet Oncol 2018;19:1480–92.
[10] Motzer RJ, Tannir NM, McDermott DF, et al. Nivolumab plus
Ruiter, van Hattum, de Reijke, van Moorselaar, van Gennep, Piet, Donker,
Ipilimumab versus Sunitinib in Advanced Renal-Cell Carcinoma. N
van der Hulle, Voortman, Oddens. Engl J Med 2018;378:1277–90.
Statistical analysis: de Ruiter. [11] Hellmann MD, Paz-Ares L, Bernabe Caro R, et al. Nivolumab plus
Obtaining funding: Bins, de Ruiter. ipilimumab in advanced non-small-cell lung cancer. N Engl J Med
2019;381:2020–31.
Administrative, technical, or material support: de Ruiter, van Hattum, van
[12] Choueiri TK, Powles T, Burotto M, et al. Nivolumab plus
Gennep, Donker, van der Hulle, Voortman. cabozantinib versus sunitinib for advanced renal-cell carcinoma.
Supervision: Bins, Oddens, de Reijke, Hulshof. N Engl J Med 2021;384:829–41.
Other: None. [13] Bellmunt J, Necchi A, Wit RD, et al. Pembrolizumab (pembro) versus
investigator’s choice of paclitaxel, docetaxel, or vinflunine in
recurrent, advanced urothelial cancer (UC): 5-year follow-up from
Financial disclosures: Ben-Max de Ruiter certifies that all conflicts of the phase 3 KEYNOTE-045 trial. J Clin Oncol 2021;39
(15_suppl):4532.
interest, including specific financial interests and relationships and affili-
[14] van der Heijden MS, Loriot Y, Duran I, et al. Atezolizumab versus
ations relevant to the subject matter or materials discussed in the manu- chemotherapy in patients with platinum-treated locally advanced
script (eg, employment/affiliation, grants or funding, consultancies, or metastatic urothelial carcinoma: a long-term overall survival
honoraria, stock ownership or options, expert testimony, royalties, or and safety update from the phase 3 IMvigor211 clinical trial. Eur
Urol 2021;80:7–11.
patents filed, received, or pending), are the following: Adriaan D. Bins
[15] Sharma P, Siefker-Radtke A, de Braud F, et al. Nivolumab alone and
received a research grant from the Dutch Cancer Society (13144/2020-1). with ipilimumab in previously treated metastatic urothelial
carcinoma: CheckMate 032 nivolumab 1 mg/kg plus ipilimumab 3
mg/kg expansion cohort results. J Clin Oncol 2019;37:1608–16.
Funding/Support and role of the sponsor: The work of Ben-Max de Ruiter [16] Necchi A, Anichini A, Raggi D, et al. Pembrolizumab as neoadjuvant
and Jons W. van Hattum is funded by the Cure for Cancer Foundation. therapy before radical cystectomy in patients with muscle-invasive
Ben-Max de Ruiter is cofunded by the Dutch Cancer Society. urothelial bladder carcinoma (PURE-01): an open-label, single-arm,
phase II study. J Clin Oncol 2018;36:3353–60.
[17] Powles T, Kockx M, Rodriguez-Vida A, et al. Clinical efficacy and
biomarker analysis of neoadjuvant atezolizumab in operable
Acknowledgments: The investigational products nivolumab (OPDIVO)
urothelial carcinoma in the ABACUS trial. Nat Med 2019;25:1706–14.
and ipilimumab (YERVOY) were provided by Bristol Myers Squibb. [18] van Dijk N, Gil-Jimenez A, Silina K, et al. Preoperative ipilimumab
plus nivolumab in locoregionally advanced urothelial cancer: the
NABUCCO trial. Nat Med 2020;26:1839–44.
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blockade in patients with cisplatin-ineligible operable high-risk
urothelial carcinoma. Nat Med 2020;26:1845–51.
[20] Schmid TE, Multhoff G. Radiation-induced stress proteins—the role
cle can be found online at https://doi.org/10.1016/j.eururo. of heat shock proteins (HSP) in anti-tumor responses. Curr Med
2022.07.009. Chem 2012;19:1765–70.
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Adding a Fourth Modality to Trimodal Therapy for Muscle-invasive

Bladder Cancer
Pooja Ghatalia *, Elizabeth R. Plimack

Department of Hematology/Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA
Trimodal therapy with maximal complete transurethral gens [3,4]. Likewise, chemotherapy has the potential to
resection of bladder tumor followed by radiation therapy enhance the antitumor effect of immunotherapy by priming
with sensitizing chemotherapy is a standard option for the tumor microenvironment following chemoradiation
muscle-invasive bladder cancer (MIBC). While this [5,6]. However, addition of immunotherapy to chemoradia-
approach has not been directly compared to neoadjuvant tion in MIBC is not a unique strategy. Previously, ate-
chemotherapy followed by radical cystectomy, a retrospec- zolizumab [7] and pembrolizumab [8] were also combined
tive series of 703 patients comparing cystectomy with with chemoradiation. In trial S1806, 432 patients were ran-
chemoradiation in MIBC showed comparable 5-yr metasta- domized to chemoradiation with or without atezolizumab
sis-free survival of 78% versus 73% [1]. for 6 mo. The chemotherapy regimen included cisplatin,
In this issue of European Urology, de Ruiter et al. [2] 5-fluorouracil/mitomycin C, or gemcitabine. In the safety
report results for addition of nivolumab ± ipilimumab to analysis of 73 patients, the combination was considered
chemoradiation for MIBC. The authors are commended for safe, with no increase in immune-related grade 3–4 AEs
conducting this study. This was a multicenter phase 1b/2, [7]. Similarly, pembrolizumab added to gemcitabine/radia-
open-label, dose-escalation trial of chemoradiation with tion in 54 patients showed good tolerability with expected
capecitabine/mitomycin C in combination with nivolumab toxicity (grade 3 AEs in four patients) [8].
monotherapy, nivolumab 3 mg/kg + ipilimumab 1 mg/kg For their trial combining nivolumab ± ipilimumab with
every 3 wk for four doses (NIVO3IPI1), or nivolumab 1 chemoradiation, de Ruiter et al. [2] conclude that nivolumab
mg/kg + ipilimumab 3 mg/kg every 3 wk for four doses and NIVO3IPI1 have acceptable toxicity and are safe to use
(NIVO1IPI3). After 12 wk, patients received adjuvant nivolu- with chemoradiation in future phase 3 trials. This conclu-
mab for up to 1 yr. The primary endpoint of the study was sion needs to be evaluated closely. Clearly, the toxicity of
safety and identification of the maximal tolerable nivolumab monotherapy was significantly less than that
immunotherapy regimen based on the rate of dose-limiting with the other two combinations even in this small 26-
toxicity during the first six treatment weeks. Ten patients patient study. However, with ten patients in the NIVO3IPI1
received nivolumab monotherapy, ten received NIVO3IPI1, arm and six in the NIVO1IPI3 arm, it may be too premature
and six received IPI3NIVO1. In this study, nivolumab to compare and draw any definitive conclusions about the
monotherapy and NIVO3IPI1 were considered tolerable reg- safety of these regimens. Since toxicities occurring only
imens, with one (10%) and five (50%) patients experiencing within the 6-wk treatment period were compared, and
grade 3 adverse events (AEs), respectively. NIVO1IPI3 was immune-related AEs are known to occur later, the early
considered intolerable, as six (100%) patients experienced comparison may not capture all events. Supplementary
grade 3 AEs. Table 2 [2] clearly indicates that even among patients not
The rationale for adding immunotherapy to chemoradia- receiving adjuvant nivolumab, late immune-related AEs
tion is based on possible synergistic effects via upregulation occur. In addition, given the short follow-up, no conclusions
of PD-L1 expression and cross-presentation of tumor anti- can be drawn about the efficacy of these regimens. In
DOI of original articles: https://doi.org/10.1016/j.eururo.2022.07.009

* Corresponding author. Department of Hematology/Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111, USA. Tel. +1 215
7282719; Fax: +1 215 7283639.
E-mail address: [email protected] (P. Ghatalia).
CheckMate032 comparing nivolumab alone to NIVO3IPI1 advisory for Astellas, AstraZeneca, BMS, EMD Serrono, Exelexis, IMV, Mer-
and NIVO1IPI3 in metastatic urothelial cancer, the overall ck, Natera, Pfizer, and Seattle Genetics, and has received grants for clinical
response rate was significantly higher in the NIVO1IPI3 research from Astellas, BMS, Genentech, and Merck.
arm than in the NIVO3IPI arm (42% vs 26%), making the
higher dose attractive despite higher toxicity. Such a risk- References
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with chemoradiation in MIBC is a first step in determining randomized trial of concurrent chemoradiotherapy with or without
the appropriate immunotherapy regimen and dose in com- atezolizumab in localized muscle-invasive bladder cancer: safety
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10.1200/JCO.2021.39.6_suppl.428.
number of patients and long-term safety and efficacy data
[8] Balar AV, Milowsky MI, O’Donnell PH, et al. Pembrolizumab (pembro)
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for muscle-invasive urothelial cancer of the bladder (MIBC): a
Conflicts of interest: Pooja Ghatalia has conducted clinical research for multicenter phase 2 trial. J Clin Oncol 2021;39(15 Suppl):4504.
BMS, Merck, and Genentech. Elizabeth Plimack has acted as a scientific 10.1200/JCO.2021.39.15_suppl.4504.
Review – Kidney Cancer
Epidemiology of Renal Cell Carcinoma: 2022 Update
Laura Bukavina a,b, Karim Bensalah c, Freddie Bray d, Maria Carlo e, Ben Challacombe f,
Jose A. Karam g, Wassim Kassouf h, Thomas Mitchell i, Rodolfo Montironi j, Tim O’Brien f,
Valeria Panebianco k, Ghislaine Scelo l, Brian Shuch m, Hein van Poppel n, Christopher D. Blosser o,
Sarah P. Psutka o,*
a
Division of Urologic Oncology, Fox Chase Cancer Center, Philadelphia, PA, USA; b University Hospitals Cleveland Medical Center, Case Western Reserve School
of Medicine, Cleveland, OH, USA; c Department of Urology, University of Rennes, Rennes, France; d Cancer Surveillance Section, International Agency for
Research on Cancer, Lyon, France; e Department of Medical Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; f Department of Urology,
Guy’s and St. Thomas Hospitals, London, UK; g Departments of Urology and Translational Molecular Pathology, The University of Texas MD Anderson Cancer
Center, Houston, TX, USA; h Division of Adult Urology, McGill University, Montreal, Canada; i Department of Urology, Wellcome Sanger Institute, Cambridge,
UK; j Molecular Medicine and Cell Therapy Foundation, Polytechnic University of the Marche Region, Ancona, Italy; k Department of Radiology, Sapienza
University of Roma, Rome, Italy; l International Agency for Research on Cancer, Lyon, France; m Department of Urology, University of California-Los Angeles, Los
Angeles, CA, USA; n Department of Urology, Catholic University of Leuven, Leuven, Belgium; o Department of Medicine, University of Washington and Seattle
Children’s Hospital, Seattle, WA, USA
Article history: Context: International variations in the rates of kidney cancer (KC) are considerable. An
Accepted August 16, 2022 understanding of the risk factors for KC development is necessary to generate opportu-
nities to reduce its incidence through prevention and surveillance.
Objective: To retrieve and summarize global incidence and mortality rates of KC and risk
factors associated with its development, and to describe known familial syndromes and
genetic alterations that represent biologic risk factors.
Keywords: Evidence acquisition: A systematic review was conducted via Medline (PubMed) and
Kidney cancer Scopus to include meta-analyses, reviews, and original studies regarding renal cell car-
Tumors of the kidney cinoma, epidemiology, and risk factors.
Epidemiology Evidence synthesis: Our narrative review provides a detailed analysis of KC incidence and
Risk factors mortality, with significant variations across time, geography, and sex. In particular, while
Renal cell carcinoma KC incidence has continued to increase, mortality models have leveled off. Among the
many risk factors, hypertension, obesity, and smoking are the most well established.
The emergence of new genetic data coupled with observational data allows for inte-
grated management and surveillance strategies for KC care.
Conclusions: KC incidence and mortality rates vary significantly by geography, sex, and
age. Associations of the development of KC with modifiable and fixed risk factors such as
obesity, hypertension, smoking, and chronic kidney disease (CKD)/end-stage kidney dis-
ease (ESKD) are well described. Recent advances in the genetic characterization of these
cancers have led to a better understanding of the germline and somatic mutations that
predispose patients to KC development, with potential for identification of therapeutic
targets that may improve outcomes for these at-risk patients.
Patient summary: We reviewed evidence on the occurrence of kidney cancer (KC) around
the world. Currently, the main avoidable causes are smoking, obesity, and high blood
* Corresponding author. Department of Urology, University of Washington, Seattle, WA, USA.

E-mail address: [email protected] (S.P. Psutka).
pressure. Although other risk factors also contribute, prevention and treatment of these
three factors provide the best opportunities to reduce the risk of developing KC at present.
Ó 2022 Published by Elsevier B.V. on behalf of European Association of Urology.
1. Introduction ferred Reporting Items for Systematic Reviews and Meta-

Analyses (PRISMA) criteria [6].
In 2020, there were an estimated 431 288 new cases of kid- Although the literature review was performed using a
ney cancer (KC) globally [1]. Although much of the epidemi- systematic search strategy, the results are presented as a
ologic data pertain to KC overall, histologically, renal cell narrative review without evaluation of heterogeneity or
carcinoma (RCC) accounts for the overwhelming majority bias among the studies.
(90%) of KC cases, predominantly including clear cell RCC
(ccRCC; 70%), papillary RCC (pRCC; 10–15%), and chromo- 3. Evidence synthesis
phobe RCC (5%) [2]. The remaining subtypes are rare (each
with total incidence of 1%) and are beyond the scope of 3.1. Epidemiology of KC
this review. Although it has been shown that histologic sub-
types differ in clinical features, outcomes, and genetic 3.1.1. Geography
determinants, granularity within epidemiologic data limits According to the Global Cancer Observatory, KC is the 14th
further descriptive analysis. most common malignancy globally, with an estimated
Here we present an updated synthesis of the epidemiologic 431 288 new cases in 2020 [1]. Owing to sexual dimorphism
data for KC in adults, with a primary focus on the epidemiol- with respect to incidence, KC is the ninth most common
ogy of RCC. We summarize and evaluate the contemporary cancer among men and the 14th most common among
epidemiologic data detailing geographic and temporal varia- women [1].
tions in disease incidence, risk factors for KC, and emerging KC incidence varies widely geographically, with gener-
research on somatic and germline genetic factors associated ally higher rates in Europe and North America (Fig. 2). As
with KC development. Although data highlighting risk factors seen in Figure 3, there is also significant geographic vari-
have already been well summarized [3], our narrative review ability in incidence by income: higher KC incidence is asso-
provides updated epidemiologic observations and a wider ciated with greater median income. However, it is
analysis of the previous RCC literature. hypothesized that this difference is largely due to higher
prevalence of small renal masses in settings where abdom-
inal imaging is more ubiquitous. Overall, Lithuania reported
2. Evidence acquisition the highest overall rate of KC in 2020, followed by Czechia,
with estimated age-standardized rates (ASRs) of
The primary objective of the current review was to retrieve 14.5/100 000 and 14.42/100 000, respectively. Overall, the
and summarize the most up-to-date data and recommenda- worldwide ASR reported in 2020 was 4.6/100 000, with
tions regarding KC epidemiology and risk factors. A system- lowest rates reported for Belize (0.26/100 000) and Solomon
atic review was conducted via Medline (PubMed) and Islands (0.12/100 000). To illustrate the cumulative risk of
Scopus. The search strategy included meta-analyses, KC diagnosis during an individual’s lifetime, a person living
reviews, and original studies on RCC, epidemiology, and risk in Czechia has a 2.83% chance of developing KC during their
factors from January 2015 to May 2022.The search used lifetime, compared to a risk of 0.02% for a person living in
medical subject heading (MeSH) terms and free text words: Comoros (Supplementary Table 1). Despite stable KC-
((‘‘kidney cancer*’’) [MeSH] OR (‘‘renal cell*’’)) AND ((‘‘renal associated mortality rates, the risk of developing KC has
tumour’’) [MeSH] OR (‘‘RCC’’)) AND ((‘‘renal tumor’’) [MeSH] been slowly rising over the past decade, largely attributable
OR (‘‘renal cancer’’)) AND ((‘‘*kidney tumour’’) [MeSH]) OR to an increase in abdominal imaging with increased rates of
(‘‘*renal cell’’)). incidental detection of otherwise asymptomatic small renal
In addition to standard MeSH terminology, articles were masses [7–9]. The classical KC triad of hematuria, flank pain,
screened on Elicit.org via natural language processing to and flank mass is seen infrequently in modern medicine
include the following ‘‘What are the risk factors for kidney (<15%), as the majority of KC cases are incidentally detected
cancer?’’ and ‘‘What is the incidence of kidney cancer?’’ Eli- on cross-sectional abdominal imaging obtained for other
cit is a generative pretrained transformer (GPT-3) search reasons before the development of symptoms [10].
engine that leverages deep learning search algorithms via The first worldwide ASR reported for KC was 7.1/100 000
natural language text [4]. The results from the MeSH termi- in 1975, which steadily increased to a peak of 16/100 000 in
nology and Elicit search were compiled into Rayyan- 2008. In contrast to most of the globe, Sweden and Israel
Intelligent Systematic Review [5]. A total of 477 retrieved have reported steady rates of detection, while the majority
articles were screened by title and abstract within Rayyan of other countries have seen an increase in diagnosis since
by the primary author (L.B.). Of these, 102 articles under- the early 2000s (Fig. 3). Although birth cohort and calendar
went full-text review by the primary author, with 59 arti- period both play an important role in increasing rates, coun-
cles finally included in the review. Figure 1 shows a tries such as Japan, Italy, and the USA have seen a steady
flowchart of the study selection process according to Pre- rise in ASR from 2000 to 2016 from 5.3, 12, and
Fig. 1 – PRISMA flow diagram demonstrating the search methodology for this systematic review.
Fig. 2 – Kidney cancer incidence across continents represented as a percentage of the total, and number of cases per region for 2020. Data obtained from the
International Agency for Research on Cancer/World Health Organization.
10.7/100 000 to 7.8, 13.7, and 13.3/100 000, respectively. sex, with the USA and Australia exhibiting highest discrep-
The UK alone has experienced an 88% increase in KC inci- ancy in incidence with ASR 16.1 vs 8.6 per 100,000 and 14.4
dence during this time [11]. vs 6.4 per 100,000, across men and women, respectively.
These differences are less pronounced in regions such as
3.1.2. Age, sex, and ethnicity Eastern Africa (1.9 vs 1.4), and Western Africa (1.8 vs 1.6).
KC incidence increases steadily with age, with a worldwide The geographical variation in incidence by sex suggests
median age at diagnosis of approximately 75 yr [12]. How- that, while biologic differences between men and women
ever, this largely depends on geographic region, as illus- exist, lifestyle as well as potential reporting of data, likely
trated by variations in the peak age at diagnosis among also contribute to observed disparities in incidence.
the USA (64 yr), UK (74 yr), India (67 yr), and China and Italy Comparison of KC incidence by ethnicity in the USA
(82 yr). revealed that KC diagnosis among Black individuals has
Regarding the differential risk of developing KC by sex, peaked at ASR 17.0/100 000, compared to 13.2/100 000
the incidence is approximately twofold higher for men than for White individuals, albeit with an identical mortality
for women, a pattern that appears stable over time and ASR of 3.2/100 000. In other words, while the Black popula-
across countries and age groups [13,14]. As seen in Figure 2, tion has a higher KC incidence rate in comparison to the
there are high fluctuations in the ASR among countries by White population, the mortality rate is largely unaffected.
Fig. 3 – Age standardized rate (ASR) for kidney cancer incidence and mortality by World Health Organization (WHO) region and continent in 2020. Results are
further stratified by sex. Data obtained from the International Agency for Research on Cancer/WHO.
3.1.3. Mortality patterns peaked at 3.8 in 2002 but then slowly trended down to
In 2020 there were 179 368 deaths worldwide from KC 3.1 in 2018. Countries such as Sweden have exhibited a
(115 600 men and 63 768 women), with a calculated global more pronounced decline in KC mortality, reaching a peak
ASR rate of 1.8/100 000. Regions with the highest age- in 1988 at 5.0/100,000, with most recent mortality rate
adjusted population mortality rate were Central and Eastern almost halved to 2.9 in 2018 (Fig. 4). Many novel
Europe (ASR 3.4), Western Europe (ASR 2.8), and Northern immunotherapy agents have contributed to a dramatic
Europe (ASR 2.7; Fig. 3). The lowest mortality rates were improvement in progression-free survival, and as such,
reported for South Central Asia (ASR 0.82), Melanesia (ASR may have contributed to the observed improvements in
0.72), and Middle Africa (ASR 0.73). Unlike rates of KC diag- survival globally [15,16]. The increasing incidence of KC
nosis which have been steadily increasing since early 1970s, with declining mortality rates in developed countries is a
rates of KC mortality have been slowly declining. Countries well-described phenomenon; it has been hypothesized that
such as Italy, Sweden, Japan, USA, and Australia, among this is because of overdiagnosis of small renal masses,
others, have demonstrated a steady decrease in mortality. which frequently demonstrate limited oncologic potential,
For example, in the USA, while KC incidence rose from as the utilization of cross-sectional abdominal imaging has
6.2/100,000 in 1975 to 13.3/100,000 in 2018, mortality increased [17,18].
Fig. 4 – Trends in the age-standardized rate for kidney cancer incidence (left) and mortality (right) in Israel, Italy, Sweden, Japan, France, USA, and Australia
from 1960 (data when available) to 2020.
3.2. Lifestyle risk factors that smoking cessation by KC patients even after diagnosis
may potentially lead to better survival outcomes [26]. The
KC incidence increases exponentially with age and is higher
exact mechanism for smoking-induced KC carcinogenesis
among men than among women. In the USA, predisposition
has not been fully delineated; however, it is thought that
by ethnicity has also been reported, with the highest rates
individual carcinogens such as polycyclic aromatic hydro-
observed for Native Americans, Indigenous Alaskans, and
carbons, aromatic amines, heterocyclic aromatic amines,
African Americans, and the lowest for Asian Americans
and N-nitrosamines play a substantial role [26,27].
and people of Pacific Island descent [19-21]. Previously
established risk factors for development of KC include
3.2.2. Excess body weight and insulin resistance
excess body weight, history of hypertension, and smoking,
Numerous epidemiologic studies have shown that obesity is
which are thought to contribute to up to 50% of KC patho-
a strong risk factor for a number of cancers [28]. A 2016
genesis [22,23].
report from the IARC Working Group on Body Fatness con-
cluded that there is sufficient evidence to support a causal
3.2.1. Smoking association between obesity and the risk of 13 cancers,
The International Agency for Research on Cancer (IARC) has including KC [29]. Nearly 20% of all KCs worldwide are
classified tobacco smoking as a moderate carcinogenic risk attributed to excess body weight, with the highest reported
factor for KC development [24]. According to a systematic association seen with higher central adiposity. The relation-
review of 56 studies, the risk of KC development is 39% ship is linear, with a 4% increase in KC risk for every 1-point
higher for current smokers. Furthermore, the authors increment in body mass index (BMI) [30]. Although excess
reported that KC risk is 20% higher for former smokers BMI is associated with KC development, the relationship is
and 26% higher for ever-smokers in comparison to never- less clear for KC survival. According to the ‘‘obesity para-
smokers. The relationship between smoking and KC risk is dox’’, while the risk of being diagnosed with KC increases
dose-dependent, with the risk sharply increasing for indi- with increasing BMI, higher BMI is associated with better
viduals smoking up to 30 cigarettes/d. The relative risk KC-specific survival [31,32]. In other words, obesity is a
(RR) was 1.18 (95% confidence interval [CI] 1.11–1.26), well-established risk factor for KC development but is actu-
1.36 (95% CI 1.22–1.52), 1.61 (95% CI 1.40–1.86), and 1.72 ally protective in the context of survival of patients with KC.
(95% CI 1.52–1.95) for individuals who smoked 5, 10, 20, Similar to localized disease, patients with metastatic renal
and 30 cigarettes/d, respectively. KC risk linearly decreases cell (mRCC) and high BMI generally experience better over-
with time since quitting cigarette smoking, with RR values all survival with targeted therapy [33]. Biologically, some
for former versus current smokers of 0.94 (95% CI 0.87– have argued that FASN pathway activation is associated
1.01), 0.88 (95% CI 0.76–1.02), and 0.82 (95% CI 0.66–1.02) with BMI and survival [33], suggesting an integral role for
at 10, 20, and 30 yr after quitting, respectively [25]. How- fatty acid metabolism in the prognosis of patients with
ever, it is notable that the RR does not ever return to the mRCC [34]. However, critics of the obesity paradox contend
same level observed for never-smokers (RR for never vs cur- that BMI is an inaccurate and nonspecific anthropologic
rent smokers 0.72, 95% CI 0.66–0.78) [25]. This observation measurement that does not reflect the presence of coexis-
is supported by additional studies showing that smoking tent sarcopenia [35], and have noted that studies are often
cessation for >10 yr is associated with significant benefits clouded by numerous unmeasured confounding factors.
in terms of lower KC incidence and disease-specific mortal- Indeed, residual confounding by tobacco smoking, which
ity. The results were applicable to both genders, implying is related to lower weight, may account for the inverse asso-
ciation observed between obesity and smoking-related KC risk reported that each 10-mm Hg increase in blood
malignancies such as KC [36]. pressure was associated with an additional 10–22% increase
The main pathways linking obesity and adiposity to KC in KC risk [54]. Conversely, other studies did not demon-
incidence include: (1) hyperinsulinemia or insulin resis- strate an association between hypertension and KC. For
tance and abnormalities of the IGF-1 system and signaling; example, in a cohort of 918 965 adolescent males, Leiba
(2) biosynthesis of sex hormones and the associated path- et al. [55] observed no association between an established
way; (3) subclinical chronic low-grade inflammation and diagnosis of hypertension and the risk of KC development
oxidative stress; and (4) alterations in the gut microflora after 17 yr of follow-up. Many critics contend that obesity
and toxic metabolites. may be the driver of KC development, with co-
The IGF pathway is a crucial and complex system com- development of hypertension in obese patients who are
posed of two growth factors (IGF-1 and IGF-2), along with already at elevated risk of KC. However, there is evidence
many additional cell-surface receptors and proteases. In suggesting that hypertension seems to be biologically inde-
vitro and animal studies have demonstrated IGF-1 receptor pendent from obesity, with a cumulative effect observed in
overexpression by KC cells [37-39]. Thus, a state involving patients presenting with both conditions [56]. Interestingly,
altered levels of serum IGFs and/or circulating levels of their the association between KC risk and hypertension was
binding proteins may potentiate neoplastic activity via pro- strongest for diastolic blood pressure (DBP) in a study of
motion of cell cycle progression and inhibition of apoptosis 289 135 Swedish construction workers. The authors
[40]. observed a dose-response relationship, whereby men with
Coupled with the pro-oncogenic state stimulated by dys- DBP of 90 mm Hg had double the risk of men with DBP
regulated IGF-1 production, the effects of obesity on the gut <70 mm Hg [56]. Treatment with antihypertensive therapy,
microflora warrant further discussion. Diets high in fat are particularly ace inhibitors and angiotensin II receptor block-
associated with changes in intestinal microbiome via the ers, was associated with 2% higher incidence of KC per year
production of deoxycholic acid, which suppresses p53 by of use (RR 1.02) in a recent meta-analysis [57]. However,
enhancing its degradation by the proteasome system [41]. these findings may reflect the increasing severity and dura-
Moreover, deoxycholic acid causes DNA damage via the for- tion of hypertension rather than risk related to the medica-
mation of reactive oxygen species. This cancer-promoting tion itself.
microenvironment, in conjunction with dysregulated IGF- Likewise, CKD and ESKD increase the risk of KC develop-
1 production, is associated with KC carcinogenesis and pro- ment by two- to threefold, particularly among African
gression [42]. American patients [58,59]. ESKD also increases the risk of
Obesity also represents a modifiable risk factor with mortality, with a standardized mortality ratio of 12.5 for
respect to cancer-specific mortality, with reductions in the patients on dialysis and 7.8 for kidney transplant recipients
risk of cancer-associated death of 40–50% observed for (KTRs) [60]. KTRs are more likely to present with KC in their
obese patients who have undergone bariatric surgery [43]. native kidney than in the transplanted kidney [61]. KC inci-
Similarly, it has been shown that tight glucose control with dence and outcomes for KTRs have not improved over the
metformin and lipid-lowering drugs such as statins reduce past 30 yr because of increased cancer risks and adverse
the risk of KC by 30%, highlighting the potential role of these effects of contemporary therapies, including immune-
drugs as cancer prevention agents [44,45]. Reversing related adverse events and rejection with immune check-
obesity-associated dysfunction via lifestyle interventions, point inhibitors [62,63]. Evidence suggests that some of
dietary modifications, or medical/surgical therapy could the increase in risk for ESKD patients may stem from
present a relevant public health contribution in decreasing acquired renal cystic disease, a common finding in ESKD
the risk of KC development and progression. patients on hemodialysis [64].
3.2.3. Hypertension and CKD 3.2.4. Physical exercise

There is strong evidence to suggest that hypertension Although no causal relationship between exercise and KC
increases the risk of KC development via dysregulation of risk has been demonstrated, research does show that
HIF, lipid peroxidation, and the formation of reactive oxy- improvements in lifestyle are associated with a reduction
gen species [46]. A recent meta-analysis identified 18 stud- in cancer incidence overall. In a pooled data set reported
ies that evaluated KC incidence among patients with by Moore et al. [65] that included 1.44 million participants,
hypertension, including ten with longitudinal analyses a higher level of physical activity during leisure time was
[47]. Of these ten studies, seven demonstrated an associa- significantly inversely associated with KC incidence (hazard
tion between severity of hypertension and development of ratio [HR] 0.77, 95% CI 0.70–0.85, 90th percentile vs 10th
KC. The largest of these studies, from Sweden (n = 855) percentile). Even after adjustment for BMI, the relationship
[48] and the USA (n = 759) [49], noted RR values of 1.2– was still present (HR 0.84, 95% CI 0.77–0.91) [65]. While this
2.2 in comparison to nonhypertensive control subjects study reported on the protective effects of physical exercise
[50]. While the majority of the studies evaluated hyperten- against KC development, many others have found little or
sion as a binary categorical variable, several evaluated the no difference [66]. This is probably because of the difficulty
severity of hypertension as a continuum of risk [51,52]. in quantifying physical activity across epidemiologic stud-
Although a history of hypertension, reported as a binary ies, as few measurement methods have been appropriately
measure, was associated with 67% higher risk of KC devel- validated, coupled with challenges in accounting for
opment [53], a meta-analysis evaluating hypertension and unmeasured confounding risk factors. While the data link-
ing physical activity to KC risk are still limited and conflict- ment and reporting, and variable geographic risk factors.
ing, physical activity is associated with reductions in body Nonetheless, it has been consistently proven that several
weight and adiposity, as well as improved blood pressure important chemicals are associated with KC development,
control and insulin sensitivity, all known risk factors for including perfluorinated chemicals and aristolochic acid
KC [67]. (AA) [78]. Furthermore, emerging research has shown that
micropalstic or nanoplastic particle exposure causes toxico-
3.2.5. Alcohol logic damage to the kidneys via oxidative stress and inflam-
The first exploratory study on the carcinogenic effect of mation [79].
alcohol dates back to the beginning of the 20th century, Trichloroethylene (TCE) and perchloroethelene (PCE) are
when an excess of cancer mortality due to alcohol con- two chlorinated solvents that are frequently used in indus-
sumption was reported [68]. Evidence indicating that alco- try as degreasers for metal parts and in dry-cleaning, among
hol use is a preventable risk factor for cancer has existed for other industrial applications [80]. In 2012 the IARC classi-
some time [69,70] and the World Health Organization fied TCE and PCE as carcinogenic to humans because of
deemed alcohol a carcinogen more than 30 yr ago [71]. known strong associations with the development of non-
Although alcohol has been linked to cancers of the oral cav- Hodgkin’s lymphoma, multiple myeloma, and KC [81].
ity, pharynx, esophagus, liver, and larynx, results for its Owing to their lipophilic nature, TCE and PCE rapidly accu-
association with KC have been conflicting [72-75]. mulate in the kidney, where they can be metabolized to
Unlike smoking, several prospective studies found that cysteine-S-conjugates, the metabolites thought to be
mild to moderate alcohol consumption was protective responsible for the carcinogenic effects. Prolonged high-
against KC development in a dose-response manner. Collec- level exposure to TCE or PCE is associated with a significant
tively, alcohol consumption of at least 15 g, equivalent to increase in the risk of KC development (odds ratio 1.78, 95%
slightly more than one drink per day, was inversely associ- CI 1.05–3.03) [82] and mortality. A recent epigenome-wide
ated with KC development, with an estimated 28% reduction association study in TCE-exposed workers highlighted ele-
[76]. An extensive meta-analysis by Bagnardi et al. [77] eval- vated genome-wide DNA methylation variation and differ-
uated alcohol consumption and the risk of cancer across 23 ential expression of genes involved in cell matrix adhesion
malignancies, noting a statistically significant inverse asso- and interferon subtypes, known to be related to cancer
ciation between KC and alcohol consumption. The authors development [83].
reported a lower risk across 24 studies, with RR of 0.92 Exposure to AA, typically via ingestion of Aristolochia
(95% CI 0.86–0.99) and 0.79 (95% CI 0.72–0.86) for light plants, has historically been linked to Balkan endemic
and moderate alcohol consumption, respectively (Fig. 5). nephropathy and carcinomas of the upper urinary tract
[13]. Studies have demonstrated a positive association
3.2.6. Environmental exposures between AA and many cancers, including KC. Shortly after
Despite increasing awareness of the contribution of pollu- AA-containing Chinese herbal products were banned in Tai-
tants and environmental exposures to human disease, the wan in 2000, the incidence of many urothelial cancers and
impact of many is difficult to assess in epidemiologic stud- KCs appeared to decrease [84]. The mechanism underlying
ies owing to competing exposures, challenges in measure- AA-induced carcinogenesis involves AA-DNA adducts, which
Fig. 5 – Schematic representation of modifiable and nonmodifiable risk factors contributing to the risk of kidney cancer development. VHL = von Hippel-
Lindau syndrome; HLRCC = hereditary leiomyomatosis and renal cell carcinoma; HPRC = hereditary papillary renal carcinoma; BHD = Birt-Hogg-Dubé
syndrome; tRCC = translocation renal cell carcinoma.
are typically repaired at high efficiency via the nucleotide cycle enzyme fumarate hydratase that catalyzes hydration
excision repair mechanism [85]. Cells deficient in this DNA of fumarate to malate [98]. Mutations shift glycolysis
repair pathway accumulate higher levels of AA-induced towards accumulation of fumarate, an oncometabolite,
DNA damage, leading to a higher risk of carcinogenesis [86]. leading to HIF accumulation or genome-wide methylated
status [99]. On loss of FH, fumarate further drives irre-
3.3. Genomic risk factors versible loss of mitochondrial respiration via inactivation
of several core enzymes. Despite restoration of FH status,
The genetic testing landscape in KC is continuing to evolve as
the inactivation is irreversible after the initial mitochondrial
we are better able to recognize germline and somatic muta-
insult. Thus, mitochondrial dysfunction ultimately forces
tions that predispose patients to KC development. It is esti-
metabolic remodeling in HLRCC tumors that favors anabolic
mated from The Cancer Genome Atlas analysis that nearly
pathways crucial for tumor growth and metastasis [100].
6–9% of KC cases submitted had a germline alteration identi-
Germline mutations across families are seen in 90% of
fied in a gene associated with cancer predisposition; how-
HLRCC cases, but biallelic somatic activation of FH has also
ever, owing to a lack of large population-wide studies, data
been reported in sporadic cases. KC, which is present in
on potentially strong autosomal recessive factors and poly-
approximately 15% of HLRCC patients, may be solitary or
morphisms that play a role in KC remain largely unknown
multifocal, with a strong propensity to metastases, even
[87].
with small primary tumors [97]. Given how common and
Several autosomal dominant inherited cancer syndromes
often asymptomatic manifestations of HLRCC are (uterine
predispose patients to KC development, including von Hip-
fibroids, cutaneous leiomyomas, and adrenal nodules), it is
pel Lindau (VHL) syndrome, hereditary leiomyomatosis and
thought that this syndrome is significantly underestimated
RCC (HLRCC), hereditary pRCC (HPRC), and Birt-Hogg-Dubé
in population studies. Although large population-wide stud-
(BHD) syndrome, caused by germline mutations in VHL, FH,
ies have estimated that HLRCC prevalence in the USA is
MET, and FLCN, respectively [87]. There is also a higher risk
0.024–0.181%, a recent analysis of germline records showed
of KC for patients with germline mutations in BAP1, SDHB,
that FH variants were detected in 1.3% of individuals [101].
SDHC, SDHD, TSC1, TSC2, and MITF [88-91]. Here we describe
Furthermore, unlike previously reported high disease pene-
established and several recently described hereditary syn-
trance results for life expectancy of 70 yr, Shuch et al. [102]
dromes associated with the development of KC.
reported lifetime penetrance ranging from 3.9% to 17.3%.
3.3.1. VHL syndrome
VHL is an autosomal dominant syndrome associated with 3.3.3. HPRC
multifocal ccRCC, renal cysts, central nervous system HPRC is a rare, autosomal dominant inherited disorder in
hemangioblastomas, pheochromocytomas, and other which affected individuals are at risk of developing bilateral,
tumors. The VHL gene is located on 3p25.3 and encodes multifocal type 1 pRCC [103]. Germline mutations in the MET
the VHL protein, an essential component of the VHL com- proto-oncogene are located at 7q31, which encodes for tyro-
plex, which targets HIF proteins for proteasomal degrada- sine kinase receptor. Mutations in MET lead to uncontrolled
tion via ubiquitination. This results in accumulation of activation of MET protein and aberrant cell growth [104].
HIF-1 and HIF-2 and their downstream targets, including HPRC has an estimated incidence of <1:1 500 000, and its rar-
VEGF, GLUT1, PDGFB, and TGFA. These factors, in turn, pre- ity is highlighted by the fact that only approximately 35
dispose to the development of KC. affected families have been reported worldwide. Despite the
Among patients with a VHL mutation, deregulation of rarity of the genetic mutation, it exhibits nearly 100% pene-
mTOR further correlates with both KC development and trance, with patients developing renal tumors between the
rapid progression. Recent work by Ganner et al. [92] points fifth and sixth decades of life [105] (Fig. 6).
to common dysregulation of mTOR1 signaling via rapid
degradation of RAPTOR, which promotes invasion and 3.3.4. BHD syndrome
metastasis [93]. Despite common loss of 3p, there is signifi- BHD syndrome is a rare genetic disorder caused by muta-
cant interpatient and intrapatient variability in somatic vari- tion in the FLCN gene located at 17p11.2 that causes the
ants and trinucleotide mutations among all the tumors, development of lung cysts, fibrofolliculomas, spontaneous
suggesting clonal independence following loss of VHL as pneumothorax, and renal tumors with various histologic
the trigger event [94]. Although VHL mutations exhibit high subtypes, including chromophobe RCC, hybrid oncocytic/
penetrance (70–87%), the maximum prevalence in a large chromophobe tumor, ccRCC, pRCC, and oncocytoma
national UK cohort was estimated at approximately [106,107]. It has been reported that bilateral, multifocal
1.4/100 000 [95]. The prevalence should be considered in renal tumors develop in 29–34% of BHD-affected patients
the context of hereditary predisposition within a population, during the fifth decade of life [108]. The overall prevalence
as many have reported much higher rates, such as national of BHD on the basis of the presence of a constellation of
estimates for Denmark of 1/46 000 individuals [96]. symptoms has recently been calculated as 2 per million
for men and 1.75 per million for women in a meta-
3.3.2. HLRCC analysis of national data [109]. Recent evaluation of dysreg-
HLRCC is an autosomal dominant syndrome associated with ulation leading to the formation of kidney cysts and cancer
higher risks of cutaneous and uterine leiomyomas and type has elucidated the role of activation of RagC and RagD
II papillary KC [97]. HLRCC is caused by mutations in the FH GTPases and mTORC1 kinase activity [110]. Napolitano
gene on chromosome 1p42.1, which encodes the Krebs et al. [111] suggested that the mTORC1 hyperactivity in
Fig. 6 – (A) Genomic risk factors, gene location, and prevalence of familial syndromes within the population. Other phenotypic manifestations and the RCC
risk are also described. (B) Representative distribution of histopathologic variants of kidney cancer and kidney cell origin; reproduced with permission from
Cell Trends in Cancer. CNS = central nervous system; RCC = renal cell carcinoma; HLRCC = hereditary leiomyomatosis and RCC; HPRC = hereditary papillary
renal carcinoma; ccRCC = clear cell RCC; pRCC = papillary RCC; chRCC = chromophobe RCC.
BHD syndrome (a key step in cystogenesis and tumorigene- ily noncoding mutations in the TERT promoter) [116]. Over-
sis) is not caused by a direct effect of FLCN on mTORC1 but all, the authors’ analysis of arm-level copy-number
rather by the substrates RagC and RagD (which are mutated alterations revealed that the most frequent translocations
in BHD). Phosphorylation of TFEB (a master regulator of are located on chromosomes 3p (28.6%), 9p (23.5%), 18
lysosomal biogenesis and autophagy) is strictly dependent (29.4%), and 22q (18.8%); they also noted a prevalent gain
on RagC and RagD and leads to mTORC1 hyperactivation on chromosome 17q (20.0%) [116,117]. Currently, there
[110]. Depletion of TFEB in kidneys rescues the disease phe- are no molecular therapies targeting tRCC specifically. Of
notype and associated lethality, while mTORC1 activity is note, additional post hoc analyses highlighted that a height-
normalized [111]. These findings not only identify a novel ened NRF2-driven antioxidant response in patients with
mechanism involving mTORC1 hyperactivation in BHD but tRCC was associated with significantly worse response to
also open a potential avenue for therapeutic targeting. VEGFR inhibitors in comparison to treatment with immune
checkpoint inhibitors [116].
3.3.5. Translocation RCC
Although inactivation of a single oncogene does not predis- 3.3.6. BAP1/PBRM1 cancer susceptibility
pose to KC development, double inactivation is a critical BAP1-associated RCC is an autosomal dominant inherited dis-
event triggering renal tumorigenesis [112]. Translocations order and patients are at risk of developing benign melanocy-
associated with KC development have been described tic tumors, malignant uveal and cutaneous melanoma,
across multiple chromosomes, with varying degrees of pen- malignant mesothelioma, and RCC. Similar to other com-
etrance and aggressiveness [105]. In general, translocation monly mutated genes: PBRM1 and SETD2, which are also
RCC (tRCC) is an aggressive subtype of non–clear-cell RCC located on chromosome 3, are chromatin modifiers contribut-
that accounts for up to 5% of all RCCs among adults and ing to DNA repair and transcriptional regulation [117]. BAP1
up to 50% among children [113]. The most common subtype is a nuclear-localized deubiquitinating enzyme with tumor
is characterized by Xp11.2 translocation, resulting in TFE3 suppressor abilities [118]. Studies have revealed a strong link
fusion with various partner genes (PRCC, MED15, and between BAP1 and HCF-1, a protein believed to regulate tran-
ASPSCR1, among others). Owing to the variety of fusion scription [119]. Loss of BAP1 leads to cell proliferation and
structures and genes, there is a high degree of tumor tumorigenesis via its interaction with HCF-1. Although
heterogeneity across genotypes and phenotypes at presen- BAP1 and PBRM1 are both considered chromatin modifiers,
tation. Specifically, while only 1–4% of adult RCCs have BAP1- and PBRM1-mutated tumors represent distinct gene
TFE3 translocation, the true population prevalence is expression signatures [120]. In comparison to PBRM1 mutant
unclear. Unlike ccRCC, tRCC is distinct and characterized tumors, BAP1 mutation is associated with necrosis on histol-
by younger age and advanced stage at presentation, as well ogy, higher Fuhrman grade, and worse survival [121]. This
as female predominance [114,115]. might partly explain the poor outcomes associated with sar-
A recently published genomic profile of 74 tRCCs comatoid and rhabdoid RCCs, as many harbor distinctive
revealed that the genes most commonly involved include molecular features, including BAP1 mutations [122].
DNA damage response genes (ATM, 8.1%; BRCA2, 8.1%; and
WRN, 4.4%), genes involved in ATP-dependent chromatin 3.3.7. Other hereditary syndromes with a higher risk of KC
remodeling via the switch/sucrose nonfermentable complex SDH, comprising SDHA, SDHAB, SDHC, and SDHD subunits,
(ARID1A, 5.4%; and SMARCA4, 5.4%), and TERT (6.8%; primar- is a ubiquitously expressed enzyme that acts as a tumor
suppressor via an unknown mechanism [123]. The impor- 3.3.8. Surveillance and treatment of familial KC syndromes
tance of SDH subunit mutations has been highlighted across In the hereditary RCC setting, young age at onset, bilateral/-
different malignancies, including KC, and a rare and aggres- multicentric tumors, and nonrenal manifestations of disease
sive subtype of RCC called SDH-deficient RCC has been iden- are well-recognized features and strong indications for
tified [124]. Typically, patients present with co-occurring genetic analysis. For patients with a high pretest probability
autonomic nervous system tumors (such as paragangiolo- of familial RCC, molecular testing will confirm the diagnosis,
mas) and pheochromocytoma [125]. The lifetime risk of particularly for well-characterized mutations such as VHL
RCC in SDH mutation carriers is not yet well defined, but [126]. As the mean age at diagnosis of symptomatic RCC in
it has been hypothesized that it is 10% [126]. Although it VHL is approximately 45 yr, germline mutation testing is gen-
is thought that the majority of tumors are indolent, approx- erally recommended for patients with sporadic RCC who are
imately one in three undergoes malignant transformation, younger than 46 yr. However, some centers have established
which is associated with a high risk of metastasis of up to a lower threshold (eg, age 40 yr) to minimize testing of
70% [127]. While the prevalence of hereditary SDH- patients with low clinical risk, which can often lead to diag-
deficient RCC is estimated to be anywhere between 0.05% nostic uncertainties because of identification of rare variants
and 0.5% of all kidney tumors, it is thought that underex- of uncertain molecular architecture and relevance [137].
pression of SDH subunits occurs in more than 80% of ccRCC The high likelihood of a detectable VHL mutation and
cases [128]. Recently published data evaluating SDH- well-defined genotype-phenotype has facilitated recom-
deficient RCC have highlighted that SDH downregulation mendations regarding surveillance for patients with VHL
is responsible not only for RCC pathogenesis but also for syndrome and asymptomatic family members. While
RCC progression [128]. The aggressive nature and risk of screening for nonrenal manifestations is generally recom-
rapid progression may be secondary to immune-cell exclu- mended within the first decade of life, magnetic resonance
sion and T-cell exhaustion [123]. imaging (MRI) of the abdomen is indicated annually at the
Similar to SDH-related inactivation of tumor suppressor age of 16 yr to allow early intervention for small renal
genes, germline mutations in TSC1 and TSC2 in tuberous tumors [137]. While patients with VHL-associated renal
sclerosis complex (TSC) allow for frequent MTOR pathway tumors are prioritized for a nephron-sparing approach and
activation and subsequent development of RCC in 4% of active surveillance, treatment of patients with FH-associate
patients [129,130]. Although angiomyolipoma and benign renal lesions in HLRCC is prompt, with wide-margin surgical
cysts are a more frequent manifestation of TSC, RCC can also excision and consideration of retroperitoneal lymph node
occur with a wide spectrum of histopathologic morpholo- dissection [138]. Individuals with a BAP1 mutation are
gies and a propensity for bilateral or multifocal lesions encouraged to undergo biannual abdominal surveillance
[131]. with ultrasound or MRI starting at age 30–35 yr [139].
A germline missense mutation in MITF confers genetic For many patients, especially those with no established
predisposition to melanoma and RCC [132,133]. While spo- family history or early manifestations of hereditary RCC, a
radic RCC mutations in MITF have been identified, this MITF diagnosis is only made after presentation with metastatic
variant is a germline alteration that increases susceptibility disease. Some patients can be managed with active surveil-
to multiple cancers. MITF is a master regular of melanocyte lance, particularly for individuals who remain asymp-
development, and Bertolotto et al. [134] reported that tomatic for extended periods of time. Reig Torras et al.
patients with the hereditary variant have a fivefold higher [140] recently explored the molecular genetic factors asso-
risk of melanoma and RCC incidence in comparison to the ciated with failure of active surveillance for patients with
general population. However, a recent meta-analysis has mRCC. The authors highlighted that while VHL was the most
questioned this early observation, noting that a common frequently mutated gene (72%), TP53, SMARCA4, and BAP1
polygenic background and shared environmental factors mutations were associated with worse prognosis and rapid
may have contributed, at least in part, to this higher risk. progression of disease without treatment. While VHL muta-
In fact, according to the Surveillance, Epidemiology and tions increase significantly from 64% in primary to 75% in
End Results database, the risk of developing secondary mel- metastatic disease, VHL mutation presence itself was not a
anoma is 2.31 times higher for patients with RCC than for marker of worse prognosis.
the general population, attributed to common putative risk Many of the benefits of surveillance protocols and surgi-
genes for RCC and melanoma, including BAP1, CDKN2B, and cal therapies are established according to decades of pheno-
MITF [135]. The rarity of MITF variants contributes to the typic data. However, continued development of novel
limited ability to characterize the relationship, limiting clin- diagnostic approaches in molecular testing will facilitate
ical utility at this time. deeper knowledge of inherited RCC gene products and the
In addition to single germline mutations in hereditary consequences of mutations, allowing for patient-centered
RCC, many studies are now focused on elucidating poly- and personalized surveillance and treatment approaches.
genic susceptibility to KC from genome-wide association
studies. Scelo et al. [136] identified single-nucleotide poly-
morphisms at six loci associated with risk of RCC for a pop- 4. Conclusions
ulation of European ancestry. As more KC susceptibility
alleles are discovered, deciphering the biologic basis of risk KC incidence and mortality rates vary significantly by geogra-
variants will provide further mechanistic approaches to KC phy, sex, and age. Associations between the development of
prevention, early detection, and intervention [136]. KC and modifiable and fixed risk factors such as obesity,
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Surgery in Motion
Long-term Follow-up of Detaenial Sigmoid Neobladder

Reconstruction for Paediatric Patients with Bladder and Prostate
Rhabdomyosarcoma: Technique and Results from a Single
High-volume Centre
Peng Xu a,1, Chunxiao Chen a,1, Binshen Chen a, Enguang Bi a,b, Wei Du a, Ning Jiang a, Zhe Liu a,
Hekui Lan c, Manming Cao d, Yazhen Liu a, Jingwen Huang a, Haiyan Shen a, Cunrong Liu a,
Chunxiao Liu a,*, Abai Xu a,*
a
Department of Urology, Zhujiang Hospital, Southern Medical University, Guangzhou, China; b Department of Biochemistry and Molecular Biology, School of
Basic Medical Science, Guangdong Provincial Key Laboratory of Single Cell Technology and Application, Southern Medical University, Guangzhou, China;
c
Department of Paediatrics, Zhujiang Hospital, Southern Medical University, Guangzhou, China; d Department of Oncology, Zhujiang Hospital, Southern
Medical University, Guangzhou, China
Article history: Background: Rhabdomyosarcoma (RMS) is the most common paediatric soft-tissue sar-
Accepted August 14, 2022 coma. Approximately 15–20% of RMS cases arise from the bladder and prostate (B/P).
The optimal treatment strategy for B/P RMS remains unclear.
Objective: To retrospectively evaluate the applicability of our procedure performed to
treat paediatric patients with B/P RMS.
Design, setting, and participants: This is a retrospective analysis from a single tertiary
Keywords: referral hospital. From August 2003 to March 2021, 62 children pathologically diagnosed
Rhabdomyosarcoma with B/P RMS underwent radical cystectomy and orthotopic detaenial sigmoid neoblad-
Paediatrics der reconstruction in our centre.
Radical cystectomy Surgical procedure: Surgical procedures included laparoscopic radical cystectomy and
Neobladder detaenial sigmoid neobladder reconstruction, which is demonstrated in the accompany-
ing video.
Measurements: Demographic, clinical, and follow-up data were collected. Perioperative
and long-term oncological and functional outcomes were reported. A logistic regression
analysis was also performed.
Results and limitations: All surgeries, including three intracorporeal laparoscopic surg-
eries, were completed successfully. Of the 62 patients, 54 were alive without evidence
of disease recurrence or metastasis at the last follow-up. Five of the 14 >12-yr-old boys
reported that they experienced erections. Two female patients >12 yr old reported that
1
These authors contributed equally to this work and are joint first authors.
* Corresponding authors. Department of Urology, Zhujiang Hospital, Southern Medical University,
253 Industrial Road, Haizhu District, Guangzhou, Guangdong, China. (Ch. Liu); Department of
Urology, Zhujiang Hospital, Southern Medical University, 253 Industrial Road, Haizhu District,
Guangzhou, Guangdong, China. Tel. +86 186 6562 6790; Fax: +86 20 616 432 56. (A. Xu).
E-mail addresses: [email protected] (C. Liu) [email protected] (A. Xu).
0302-2838/Ó 2022 The Authors. Published by Elsevier B.V. on behalf of European Association of Urology. This is an open access article
they menstruated. However, this was a retrospective study conducted at a single centre
with limited surgeon experience.
Conclusions: Our results confirmed the safety and feasibility of primary orthotopic sig-
moid neobladder reconstruction after radical cystectomy for paediatric patients with
B/P RMS. Good outcomes in terms of oncological control and functional recovery were
achieved. The high histocompatibility and tissue adaptability of children are inspiring.
Patient summary: We describe our stepwise technique of radical cystectomy and detae-
nial sigmoid neobladder reconstruction for paediatric patients with bladder and prostate
rhabdomyosarcoma. With this technique, we were able to achieve good functional
recovery without compromising cancer control and significantly increasing
complications.
Ó 2022 The Authors. Published by Elsevier B.V. on behalf of European Association of
1. Introduction
Table 1 – Preoperative characteristics
Rhabdomyosarcoma (RMS) accounts for 5% of all paediatric Variable Results
malignancies and is the most common paediatric soft-tissue Patients (n) 62
sarcoma [1]. Approximately 15–20% of all RMS cases arise Median age at surgery (mo) 46.9 ± 32.7
Gender (male/female) 53/9
from the genitourinary tract, most commonly in the bladder
Preoperative therapy, n (%)
and prostate (B/P) [2]. Multimodal therapy involving Chemotherapy 61 (98.4)
chemotherapy, extirpative surgery, and radiotherapy is Radiotherapy 18 (29.0)
Partial cystectomy 14 (22.6)
commonly used in combination or sequentially [3–5]. The
Cystectomy and ureterocutaneostomy 2 (3.2)
optimal treatment strategy remains unclear; however, Tumour size (cm), n (%)
extirpative surgery is considered to be an effective choice 5 41 (66.1)
>5 21 (33.9)
for tumour control, but postoperative functional outcomes
COG staging, n (%)
vary [6]. Stage 2 40 (64.5)
By 2000, our centre had started performing orthotopic Stage 3 22 (35.5)
detaenial sigmoid neobladder reconstruction with good COG = Children’s Oncology Group.
postoperative oncological and functional outcomes [7,8].
In 2003, we first applied this technique to a child with blad-
der RMS who had relapsed after chemotherapy. To date, we
have successively treated 62 patients with neobladder sur- node dissection. The peritoneum was incised laterally to the iliac artery.
gery in our single centre. The study aim was to retrospec- Organs in children are immature, but the corresponding anatomical
tively evaluate the applicability of our procedure landmarks are the same as those in adults. The field of dissection was
performed to treat paediatric patients with B/P RMS, and the same as that used in standard lymph node dissection for bladder
cancer [11]. The umbilical arteries on both sides were sealed and divided
evaluate the 18-yr oncological and functional outcomes
during dissection. The ureter was then identified and isolated to the
and prognostic factors.
ureterovesical junction. After clipping with Hem-o-lok, the ureter mar-
gin was sent for frozen inspection. The Douglas pouch was then incised
2. Patients and methods
to expose the vas deferens and seminal vesicles that were used as the
landmark for dissection. Separate bluntly along the Denonvillier’s fascia
From August 2003 to March 2021, 62 children pathologically diagnosed
to the posterior plane of underdeveloped prostate. The fat tissue on the
with B/P RMS underwent open/laparoscopic radical cystectomy and
anterior rectal surface is usually inconspicuous in children. For girls, the
orthotopic detaenial sigmoid neobladder reconstruction in our hospital
vaginal-wall integrity is important for preventing postoperative vaginal
(two patients underwent ureterocutaneostomy in other hospitals before
fistula. Thermal energy was used sparingly for treating lateral ligaments
admission). Patients were staged according to the Children’s Oncology
to prevent nerve damage, and nerve sparing was attempted in all
Group (COG; formerly the Intergroup Rhabdomyosarcoma Study Group)
patients. Absorbable clips and scissors were used to treat the lateral liga-
staging system [9]. Forty-seven patients came to our hospital because of
ments down to the endopelvic fascia. The next step was exposure of the
recurrence or disease persistence after multimodal treatments. General
anterior layer, which can be achieved easily by incision of the umbilical
information is shown in Table 1. This study was approved by the Medi-
ligaments. The Retzius space was expanded forward to the pubopro-
cine Institutional Review Board of Zhujiang Hospital of Southern Medical
static/pubovesical ligament and the endopelvic fascia, which was then
University, and informed consent was obtained from a parent or guar-
incised to expose the urethra. A ligation-free technique was used to con-
dian on behalf of the child.
trol the dorsal vascular complex in boys [12,13], and the periurethral tis-
2.1. Surgical procedure sue was dissociated until complete isolation of the membranous urethra.
After removal of the catheter, a Hem-o-lok clip was used routinely to
The surgical procedure is similar to that of adults, as we reported previ- close the stump before separating the urethra. Frozen sections of the
ously [7,10]. A five-port transperitoneal approach in dorsal lithotomy urethral stump were also taken to confirm that these had not been
with a steep Trendelenburg of 15–25° was used. Trocars were placed invaded. The specimen was placed in an Endo Catch bag (Metronics,
in a bow shape. Radical cystectomy started by performing a pelvic lymph Minneapolis, MN, USA) and brought out through a lower-abdomen
midline incision. Considering the child’s pelvic structure, six intermittent prethreading. Last but not least, side peritoneum petals were
stitches prethreaded at the lithotomy 10, 8, 12, 2, 4, and 6 o’clock posi- reperitonealised, which might be conductive to restore normal physio-
tions under laparoscopic monitoring were prepared for enterourethral logical structure and reduce postoperative complications. The surgical
anastomosis. Typically, 2-0 Monocryl with a UR-6 needle was used. process was detailed in Figures 1 and 2. A drainage tube was placed in
For neobladder reconstruction, an estimated 15–20 cm segment of the pelvis.
the sigmoid colon was isolated initially. A circular stapler was then used
in an end-to-end manner to restore intestinal continuity. The isolated
2.2. Follow-up
segment was irrigated repeatedly using a dilute iodine solution to elim-
inate impurities and arranged in a U-shape configuration without In the early stage, patients were hospitalised until the catheter and
detubularisation. We used a semicircular blade to delineate the detae- stents were all removed. In the past 5 yr, with the promotion of the con-
nial field by drawing an outline along the edge of the isolated sigmoid cept of enhanced recovery after surgery, children normally resumed
mesentery. The serosal layer was incised as deeply as the plane between bowel function and started oral feeding 5 d after surgery. After the
the smooth muscle and the submucosal layer. A circular area with a 1.5- removal of the drainage tube, the patient can be discharged with the
cm diameter at the centre and areas of 2 cm 1 cm at both ends of the catheter and stents. Cystography was performed to determine whether
free intestinal canal were preserved for enterourethral and ureteroen- the catheter and stents could be removed 1 mo after surgery.
teric anastomoses. The two colonic bands and the serosal muscle tissue The children received hospital follow-up every 3–6 mo in the first 2
between them were then detached from the submucosal layer and yr. As these children received different degrees of chemoradiotherapy at
removed continuously using the semicircular blade. The instant capacity a very young age, we paid more attention to bone development and cor-
and leak tightness were assessed by filling with 200 ml iodine solution. responding growth problems. During the follow-up period, the children
Neither of the ureters needs to be transposed below the sigmoid meso- received enhanced computed tomography and cystoscopy to determine
colon to the other side. After proper spatulation, two F6 single J stents whether there was a tumour recurrence or urinary tract disorder. Day-
were inserted upwards into the renal pelvis, and then each stent was and night-time urinary control was evaluated at each visit. Continence
passed through the neobladder and exteriorised. We used a modification was defined as the use of zero or one safety pad, whereas incontinence
of the Leadbetter and Clarke [14] method for complete ureteroenteric was defined as the use of more than one wet pad. Complications, defined
anastomosis with a 4-0 polyglactin suture. The ends of the intestinal according to the standardised criteria recommended by the European
canals on both sides were closed subsequently. Enterourethral anasto- Association of Urology guidelines, were reported and grouped in postop-
mosis was carried out at the corresponding position of the previous erative day periods of 0–30 and >30 d [15].
Fig. 1 – Step-by-step of radical cystoprostatectomy for B/P RMS. (A) Pelvic lymph node dissection; the field of dissection is the same as that of standard
dissection for bladder cancer. (B) Ureteral disconnection; the margin is sent for frozen inspection. (C) Separation of the Denonvillier’s fascia and
establishment of the posterior plane. (D) Treatment of the lateral ligaments and establishment of the lateral plane. (E) Dissection of the apex of the prostate
and urethra, and establishment of the anterior plane. (F) Prethreading under laparoscopic monitoring; six intermittent stitches are evenly distributed around
the urethra. (G) Interception of a sigmoid colon and placement of a U-shaped neobladder. (H and I) Intestinal continuity was restored by a circular stapler. B/P
RMS = bladder and prostate rhabdomyosarcoma.
Fig. 2 – Step-by-step configuration of a detaenial sigmoid neobladder for children. (A) Delineate the detaenial field by using a semicircular blade to draw an
outline along the edge of the isolated sigmoid mesentery. Areas at the centre and both ends of the free intestinal canal are preserved for enterourethral and
ureteroenteric anastomoses. (B and C) Two colonic bands and serosal muscle tissue between them are detached from the submucosal layer and removed
continuously. (D) After the stripping procedure, instant capacity and leak tightness are assessed. (E) After proper spatulation, a single J stent was inserted
upwards into the renal pelvis and fixed to the ureter. (F and G) Antireflux treatment (Leadbetter-Clarke method) is performed on the previously reserved
colon bands at both ends. (H) Mucosal-to-mucosal suture to avoid postoperative anastomotic stenosis and necrosis. (I) Enterourethral anastomosis is carried
out at the corresponding position of the previous prethreading.
2.3. Statistical analysis routine pouch irrigation after surgery. The mean hospital stay
was 21.5 d. Typically, single J stents and catheters were
IBM SPSS Statistics 22.0 (IBM Corp., Armonk, NY, USA) was used for the
removed 5 wk following surgery after confirmation of water-
statistical analysis. Descriptive statistics were mainly used. Continuous
tight healing by cystography. Details are shown in Table 2.
variables were presented as mean ± standard deviation, and categorical
variables were presented as ratios. The Kaplan-Meier method was used
3.1. Oncological outcomes
for the analysis of overall survival (OS), recurrence-free survival (RFS),
and continence rate. Univariate logistic regressions were performed to Of the 62 patients, 54 were alive without evidence of dis-
test the effect of baseline and perioperative characteristics on oncologi- ease recurrence or metastasis at the last follow-up. For
cal outcomes.
Table 2 – Perioperative characteristics
3. Results Variable Results

Total operative time (min) 386.9 ± 95.4
Estimated blood loss (ml) 136.5 ± 77.4
Approximately one-third of the patients were at stage 3 at the
Number of retrieved lymph nodes 13.2 ± 7.2
first visit to hospital. Nearly all patients had already received Preservation of uterus and uterine appendages, n (%) 4 (44.4)
chemotherapy, and 17 patients had received both COG grouping, n (%)
I 56 (90.3)
chemotherapy and radiotherapy (Table 1). All surgeries,
IIA 3 (4.8)
including three intracorporeal laparoscopic surgeries, were IIB 2 (3.2)
completed successfully without severe intraoperative com- IIC 1 (1.6)
Tumour resection status, n (%)
plications. Preservation of the reproductive system was per-
Microscopically complete 58 (93.5)
formed in four girls. The mean operative time was Microscopically incomplete 4 (6.5)
386.9 ± 95.4 min and the mean blood loss was 136.5 ± 77.4 Macroscopically complete 62 (100)
Hospital stay (d) 21.5 ± 12.6
ml. Lymph node metastases developed in three (4.8%) chil-
Catheter indwelling time (d) 37.8 ± 11.8
dren. Of 53 male patients, 21 (39.6%) developed prostate infil-
COG = Children’s Oncology Group.
tration. Unlike ileal neobladder, these children did not require
Fig. 3 – Kaplan-Meier estimates of (A) overall survival and (B) recurrence-free survival. Kaplan-Meier analyses depicting the (C) daytime and (D) night-time
continence rates.
the five deaths, four patients died of tumour recurrence and Table 3 – Oncological and functional outcomes
one died of pneumonia 2 mo after surgery. Two children
Variable Results
experienced recurrence and metastasis within 3 mo postop-
Follow-up (mo), median (range) 53.4 (1–223)
eratively, and one of the patients refused treatment. The
Oncologic outcomea (%)
other patient received further chemotherapy combined 1-yr OS 93
with targeted drug and had stable disease for 6 mo until 1-yr RFS 92
5-yr OS 92
progression was observed again. Salvage radiotherapy with
5-yr RFS 88
bilateral nephrostomy was administered, but the patient 10-yr OS 92
ultimately died of malnutrition 1 yr after radical cystec- 10-yr RFS 88
Sexual function (>12 yr old)
tomy. In addition, three relapsed patients are still on treat- Erectile functionb 5/14
ment. The 5-yr OS rate was 92%, with 88% RFS (Fig. 3A and B, Regular menstruationc 2/2
Table 3, and Supplementary Tables 1 and 2). To date, the Daytime continenced
3 mo (%) 32/60 (53.3)
longest follow-up time was 18 yr. The median follow-up 6 mo (%) 39/59 (66.1)
time was 53.4 mo (Table 3). Our univariate analysis showed 12 mo (%) 43/57 (75.4)
that tumour invasiveness, COG grouping, and lymph node Night-time continence
3 mo (%) 18/60 (30.0)
metastasis were potential predictors of a poor prognosis 6 mo (%) 24/59 (40.7)
(Table 4). 12 mo (%) 28/57 (49.1)
OS = overall survival; RFS = recurrence-free survival.
a
3.2. Functional outcomes Kaplan-Meier method was used.
b
Only boys are assessed.
c
Although three children developed varying degrees of post- Only girls with preserved the reproductive organs are assessed.
d
Continence was defined as the use of zero or one safety pad.
operative hydronephrosis, all 57 survivors exhibited normal
postoperative renal function (serum creatinine 44.3 ± 15.1
Table 4 – Evaluation of prognostic factors in B/P RMS Table 5 – Early and late complications
Variables OR 95% CI p value Variable Results

COG staging 5.6 1.0–31.7 0.052 Early complications (38.7%), n (%)
Ki67/10 1.5 1.0–2.5 0.070 Urinary tract infection 10 (16.1)
Lymph node metastasis 21.6 1.7–282.0 0.019 Pneumonia 3 (4.8)
Adjuvant chemotherapy 0.5 0.1–2.7 0.462 Surgical incision infection 5 (8.1)
Time to surgery (mo) 1.0 1.0–1.1 0.212 Fistula 2 (3.2)
Tumour shrinks 0.3 0.1–3.9 0.389 Urinary leak 2 (3.2)
Prostate invaded 2.3 0.5–11.4 0.318 Ileus 4 (6.5)
Positive margin 2.9 0.3–32.4 0.389 Late complications (37.1%)
Depth of tumour invasion 6.1 1.1–34.7 0.042 Urinary tract infection, n (%) 7 (11.3)
COG grouping above IIA 21.6 1.7–282.0 0.019 Enterourethral anastomotic stenosis, n (%) 9 (14.5)
6 cycles’ neoadjuvant chemotherapy 5.8 0.7–51.3 0.115 Ureteroenteric anastomotic stenosis, n (%) 3 (4.8)
Neobladder stones, n (%) 2 (3.2)
B/P RMS = bladder and prostate rhabdomyosarcoma. CI = confidence
Fistula, n (%) 4 (6.5)
interval; COG = Children’s Oncology Group; OR = odds ratio.
Urethrovaginal fistula 3/9
Tumour recurrence was the dependent variable.
Urethroscrotal fistula 1/53
Time to surgery: time from diagnosis to surgery.
Tumour shrinks: after neoadjuvant chemotherapy or/and radiotherapy.
Depth of tumour invasion: mucosa and submucosa versus muscle and
deeper. curing the patient. With the advent of new radiotherapeutic
modalities, brachytherapy combined with partial cystec-
lmol/l, estimated glomerular filtration rate 103.7 ± 26.6 ml/ tomy has gradually been recommended by researchers
min/1.73 m2). No severe metabolic disturbance was [19–21]. However, the bladder preservation reported in
observed in the survivors. The continence rates were the literature has mainly been performed for tumours that
75.4% (43/57) for the daytime and 49.1% (28/57) for the were not above the level of the bladder trigone and had
night-time 12 mo after surgery. Thereafter, the recovery of not infiltrated bladder vessels. Moreover, the recovery of
urinary control has been stabilised. Nevertheless, a small bladder function has been uneven after comprehensive
proportion of the children still experienced significant therapy, which reached only 40–60% [22]. Meanwhile, the
improvements (Fig. 3C and D). Five of the 14 >12-yr-old application of radiotherapy in China has lagged far behind
boys reported that they experienced erections. Two female the use of surgery. Doctors and patients both regard radio-
patients >12 yr old reported that they menstruated. therapy as an auxiliary treatment that does not have a dom-
inant role, and its adverse side effects are very obvious. Two
3.3. Complications of the patients in this group had received excessively heavy
dosages of radiation, which resulted in freezing of the pelvis
The major early complications included urinary tract infec- during the operation. Furthermore, among our follow-up
tion (16.1%), pneumonia (4.8%), and incisional infection patients, some had abnormal skeletal development caused
(8.1%). Especially, the first child who underwent the surgery by previous radiotherapy, which resulted in a serious delay
in 2003 suffered severe early complications; an additional in the growth stage. Lautz et al. [23] declared that surgical
surgery was performed to treat intestinal obstruction. For- complications are immediately measurable but that the full
tunately, she recovered uneventfully and was discharged impact of radiation therapy is often delayed by years.
home on day 34, without recurrences observed during the Children comprise a special group that will benefit
18-yr follow-up. Benign anastomotic stenosis was the most greatly from longer-term survival expectations. Complete
common late complication, which occurred in 12 children resection of the primary tumour is an important factor for
(including nine enterourethral anastomotic stenoses and prognosis [6]. Radical cystectomy is undoubtedly more reli-
three ureteroenteric anastomotic stenoses). For the patients able than partial resection in terms of oncological control.
with enterourethral anastomotic stenosis, continued antag- Hays et al [24] reported that 40% of patients without visible
onistic urethral dilation was necessary. Usually after three tumour cells at second surgeries experienced tumour
times of dilation, the patients can achieve a satisfactory uri- relapse, which indicated the malignancy and concealment
nation. For ureteroenteric anastomotic stenosis, we adopted of RMS. In the present group, six boys with negative frozen
dynamic monitoring of renal resistive index to evaluate section results developed recurrence with or without
obstruction [16,17]; the results did not show a significant metastasis during the follow-up. We thought that due to
increase. During the follow-up process, the hydrops gradu- the previous treatment, the activity of tumour cells and tis-
ally decreased without surgical intervention. Vaginal fistula sues may be hidden, but its invasive properties are main-
was another common complication that occurred in three tained. Nevertheless, given that no invasion of the uterus
out of nine girls. Overall, 24 (38.7%) and 23 (37.1%) children and appendages was found in the preoperative examina-
developed early (<30 d) and late (>30 d) complications, tion, also considering future endocrine function and repro-
respectively (Table 5). ductive function [3], we preserved the reproductive organs
in four girls, and none experienced a recurrence.
4. Discussion Orthotopic neobladder is undoubtedly the preferred
method of urinary diversion in children. Detubularised ileal
For B/P RMS, the COG reported that the 5-yr OS was 86% and spherical neobladders often require repeated folding and
the 5-yr event-free survival (EFS) was 79% [18]. Chemother- suturing, which is complicated and time consuming.
apy and radiotherapy are the preferred treatment strategies However, detaenial sigmoid neobladder only requires a
that are thought to preserve normal bladder function while 15–20 cm length of colon without potential adverse effects
on gastrointestinal absorption. By stripping the sion. Overall, about 35% children developed early and late
seromuscular tissue of the isolated colon, a large-capacity complications. Formation of neobladder stones occurred in
and low-pressure reservoir can be created. More two patients in the early stage. During the process of
importantly, routine neobladder irrigation is not required endoscopic lithotripsy, we found that both cases of neoblad-
after surgery. Long-term follow-up results showed no der stones were caused by the Hem-o-lok clips in the
overdistension of the neobladder and deteriorating renal neobladder. Clips’ erosion from the lateral ligament was
function. Postoperative recovery is faster and better in chil- highly suspected [26]. After the use of absorbable clips,
dren than in adults, which may depend on the high histo- neobladder stones were not observed subsequently.
compatibility and tissue adaptability of children. Previous studies from the COG found that the primary
Whether or not the neobladder should be reconstructed site, tumour size, tumour invasiveness, and positive lymph
primarily remains controversial [4]. Some authors have sug- nodes were important prognostic parameters for EFS and
gested that neobladder reconstruction should be delayed OS of patients with RMS (all sites) [27], and we obtained sim-
until the patient has achieved a durable disease-free status ilar results in the present study. Our previous immunohisto-
after radical cystectomy in case of tumour relapse [25]. How- chemistry results had shown that PD-L1–positive staining
ever, Castagnetti et al. [5] reported that none of the patients was observed in 47.1% of the patients; metastatic tumour
undergoing delayed Padua ileal neobladder reconstruction cells in the lymph nodes were positive for PD-L1 expression
after attaining disease-free status achieved autonomous uri- [28]. Thus, we speculated that PD-1/PD-L1 inhibitors may be
nation. Fibrostenosis might develop in the urethral stump potential therapeutic agents for patients with B/P RMS. We
and external sphincter after radical cystectomy. Conse- expect and are committed to develop very specific treat-
quently, the difficulty of second-stage surgery is greatly ments through technologies, such as genetic testing in the
increased, and physiological activities of the tissues around future.
the urethra and ureter are weakened, which are not con-
ducive to postoperative functional recovery. In the present 4.1. Limitations
study, detaenial sigmoid neobladder was constructed imme-
diately after radical cystectomy. Our results showed that Although the surgical cohort in this study comprised one of
single-stage neobladder reconstruction can provide patients the largest reported series of neobladder reconstructions
with good quality of life without significantly increasing for B/P RMS, the sample size was still small. The study
recurrence and complications. spanned a long time and the preoperative characteristics of
Functional recovery of the upper urinary tract is also the children varied greatly, which could have introduced a
associated with postoperative quality of life, which mainly bias in the analysis. Studies in larger samples would provide
depends on the ureteroenteric anastomosis. We used a results with a greater degree of reproducibility. Moreover,
modified Leadbetter and Clarke [14] method to accomplish this was a single-centre retrospective study with limited sur-
ureteroenteric anastomosis, which achieved extremely geon experience.
good results in the children. Only three children developed
varying degrees of postoperative hydronephrosis with nor-
5. Conclusions
mal renal function, which may be related to the high histo-
compatibility and tissue adaptability of children in general.
Our results confirmed the safety and feasibility of primary
Moreover, the design of the U-shaped neobladder can also
orthotopic sigmoid neobladder reconstruction after radical
enable a low-tension anastomosis and effectively protect
cystectomy for paediatric patients with B/P RMS. Good out-
the blood supply of the bowel and ureters.
comes in terms of oncological control and functional recov-
Children are too young to complete effective pelvic floor
ery were achieved. The high histocompatibility and tissue
muscle exercises, so urinary function recovery mostly
adaptability of children are inspiring. Individualised treat-
depends on precise intraoperative manipulation. Active
ment for B/P RMS may become possible after exploration
stimulation of the perianal muscles by a parent was also
of genetic testing in the future.
performed in some children. Our follow-up results showed
that the 3-mo daytime urinary continence rate was 53.3%
and reached as high as 75.4% at the 1-yr follow-up. On the Author contributions: Abai Xu had full access to all the data in the study
one hand, these results were influenced by the powerful and takes responsibility for the integrity of the data and the accuracy of
regenerative ability of children. On the other hand, our the data analysis.
results also depended on the effective protection of the
support structure during the operation, especially in the
Study concept and design: A. Xu, Ch Liu, P. Xu.
urethral stump and area around the neurovascular bundle.
Acquisition of data: C. Chen, Du, Z. Liu, Lan, Cao, Y. Liu, Huang, Shen, Cu
Moreover, we are currently conducting a study on the Liu.
neural remodelling mechanism of neobladder urination Analysis and interpretation of data: P. Xu, Ch Liu, A. Xu, C. Chen, B. Chen,
behaviour, and the initial results revealed that urinary con- Bi, Jiang, Du, Huang.
trol innervation of the sigmoid neobladder may resemble Drafting of the manuscript: P. Xu, C. Chen.
normal physiology more closely [10]. Critical revision of the manuscript for important intellectual content: P. Xu,
Children were more prone to postoperative complica- Ch Liu, A. Xu, C. Chen, B. Chen.
tions due to hypoimmunity caused by the history of Statistical analysis: C. Chen, Bi, Jiang, Z. Liu, Cu Liu.
chemoradiotherapy and surgical stress after urinary diver- Obtaining funding: P. Xu, Ch Liu, A. Xu.
Administrative, technical, or material support: A. Xu, Ch Liu, P. Xu, B. Chen, [10] Xu P, Chen B, Xu A, Yuan D, Zhang Y, Liu C. Initial experience with
Lan, Cao, Y. Liu, Shen. intracorporeal laparoscopic radical cystectomy and detaenial
sigmoid neobladder reconstruction. Eur Urol 2021;79:545–51.
Supervision: A. Xu, Ch Liu, B. Chen.
[11] Perera M, McGrath S, Sengupta S, et al. Pelvic lymph node dissection
Other: None. during radical cystectomy for muscle-invasive bladder cancer. Nat
Rev Urol 2018;15:686–92.
Financial disclosures: Abai Xu certifies that all conflicts of interest,
[12] Xu P, Xu A, Chen B, et al. Ligation-free technique for dorsal vascular
including specific financial interests and relationships and affiliations rel- complex control during laparoscopic radical prostatectomy: a single-
evant to the subject matter or materials discussed in the manuscript (eg, center experience from China. World J Urol 2017;35:395–402.
employment/affiliation, grants or funding, consultancies, honoraria, stock [13] Xu P, Chen B, Xu A, et al. Short-term outcomes and clinical efficacy
of ligation-free technique used in laparoscopic radical cystectomy.
World J Urol 2019;37(Suppl 1):81.
received, or pending), are the following: None. [14] Leadbetter WF, Clarke BG. Five years’ experience with uretero-
enterostomy by the combined technique. J Urol 1955;73:67–82.
[15] Mitropoulos D, Artibani W, Biyani CS, Bjerggaard Jensen J, Rouprêt
Funding/Support and role of the sponsor: This work was supported by M, Truss M. Validation of the Clavien-Dindo grading system in
the Sino-German Mobility Programme (grant no. M-0299) and the Medi- urology by the European Association of Urology Guidelines Ad Hoc
cal Science and Technique Foundation of Guangdong province of China Panel. Eur Urol Focus 2018;4:608–13.
[16] Patti G, Menghini ML, Todini AR, Marrocco G, Calisti A. The role of
(grant no. A2020241).
the renal resistive index ratio in diagnosing obstruction and in the
follow-up of children with unilateral hydronephrosis. BJU Int
Peer Review Summary 2000;85:308–12.
[17] Brkljacić B, Kuzmić AC, Dmitrović R, Rados M, Vidjak V. Doppler
sonographic renal resistance index and resistance index ratio in
Peer Review Summary and Supplementary data to this arti- children and adolescents with unilateral hydronephrosis. Eur
cle can be found online at https://doi.org/10.1016/j.eururo. Radiol 2002;12:2747–51.
[18] Saltzman AF, Cost NG. Current treatment of pediatric bladder and
2022.08.015. prostate rhabdomyosarcoma. Curr Urol Rep 2018;19:11.
[19] Michel J, Sauter L, Neunhoeffer F, et al. Sedation practices during
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Surgery in Motion
Single-port Robotic Transvesical Partial Prostatectomy for Localized

Prostate Cancer: Initial Series and Description of Technique
Jihad H. Kaouk a,*, Ethan L. Ferguson a, Alp Tuna Beksac a, Mahmoud Abou Zeinab a,
Aaron Kaviani a, Christopher Weight a, Samuel Haywood a, Mohamed Eltemamy a,
Andrei Purysko b, Jesse K. McKenney c, Eric Klein a
a
Glickman Urological & Kidney Institute, Cleveland Clinic, Cleveland, OH, USA; b Department of Radiology, Cleveland Clinic, Cleveland, OH, USA; c Department
of Pathology, Cleveland Clinic, Cleveland, OH, USA
Article history: Background: Partial prostatectomy has been described as an alternative to focal therapy
Accepted July 19, 2022 for the management of localized low- and intermediate-risk prostate cancer.
Objective: To describe early outcomes and technique for single-port (SP) transvesical
Associate Editor: partial prostatectomy.
Alexandre Mottrie Design, setting, and participants: A retrospective analysis was performed for nine
patients with low-volume, localized, low- to intermediate-risk prostate cancer
Keywords: (Gleason 7) undergoing SP transvesical partial prostatectomy replicating the inclusion
Focal therapy criteria for focal therapy by a single surgeon from November 2020 to March 2022.
Prostate cancer Surgical procedure: The daVinci SP access port was inserted percutaneously into the
Prostate imaging bladder and pnuemovesicum was achieved. The camera, robotic instruments, assistant
Subtotal prostatectomy port, and flexible suction tubing were introduced through the access port. The Koelis
Partial prostatectomy transrectal ultrasound with preoperative prostate magnetic resonance imaging fusion
Transvesical prostatectomy was used for intraoperative guidance.
Single port robotic Measurements: Demographic information, intraoperative variables, and postoperative
prostatectomy outcomes were collected in an institutional review board–approved database, and a
descriptive statistical analysis was performed.
Results and limitations: All cases were completed without requiring extra ports or con-
version. No intraoperative complications were noted, and all patients were discharged
on the day of surgery. Pathology showed Gleason scores of 3 + 3 = 6 in one case,
3 + 4 = 7 in seven cases, and 4 + 3 = 7 in one case, all with negative intraoperative margin
assessment. At 6 wk, the median prostate-specific antigen was 0.5 and the median
Sexual Health Inventory for Men score was 17.5 from 23 preoperatively. All patients
were continent at 6 wk. The limitations include a small number of patients, short
follow-up, and single-surgeon experience.
Conclusions: We demonstrated the feasibility of the SP robotic transvesical partial
prostatectomy. Early functional outcomes show impressive time to continence and erec-
tile function. Continued follow-up will evaluate long-term oncologic outcomes.
* Corresponding author. Glickman Urology and Kidney Institute, Cleveland Clinic, 9500 Euclid Ave,
Q10, Cleveland, OH 44195, USA. Tel. +1 (216) 444-2976; Fax: +1 (216) 636-4492.
E-mail address: [email protected] (J.H. Kaouk).
Patient summary: We performed partial prostatectomies in selected patients as an

alternative to focal therapy using a novel transvesical single-port approach. Our
approach was safe and feasible, with fewer complications and promising initial return
to continence and erectile function.
1. Introduction prostatectomy as safe and feasible, with removal of all but a

thin rim of tissue overlying the neurovascular bundle on the
Magnetic resonance imaging (MRI) combined with targeted contralateral side of the dominant lesion. In these patients,
prostate biopsy has improved detection and localization of a transperitoneal, anterior approach is utilized, similar to
clinically significant prostate cancer [1–3]. A transperineal traditional nerve-sparing prostatectomy.
approach to prostate biopsy possibly confers further The daVinci single-port (SP) robot has allowed for recent
improvement in diagnostic accuracy [4,5]. While whole- adaptation to a transvesical approach to radical prostatec-
gland treatments may be associated with treatment regret tomy and simple prostatectomy (Fig. 1) [12,13]. In our expe-
related to morbidity, many patients reach for therapeutic rience, the SP transvesical approach has been associated
options that minimize adverse effects [6]. with less overall morbidity, including decreased opioid pre-
Focal therapy in the form of high-intensity focused ultra- scription requirements, outpatient surgery, and shorter
sound (HIFU) has emerged as an acceptable treatment catheter duration [13]. Furthermore, the SP transvesical
option for appropriately selected men with localized low- approach allows for versatile access to the prostate gland
and intermediate-risk disease, and may have reduced the without disruption of the space of Retzius. In 2018, our
risk of post-treatment incontinence and impotence com- group published a preclinical study demonstrating technical
pared with radical prostatectomy [7]. By International Del- feasibility of SP transvesical partial prostatectomy [14].
phi Consensus, these men should have good life expectancy, In this manuscript, we describe a technique for partial
prostate MRI showing suspicious lesions with histologic prostate gland excision through a novel transvesical
confirmation, as well as MRI-visible Gleason 7 prostate approach and replicate the inclusion criteria for focal ther-
cancer localized to a treatable location [8]. apy. We report the initial perioperative outcomes in the first
While focal ablation has garnered significant interest in nine consecutive patients to undergo this procedure at our
the last decade, partial prostate excision for prostate cancer institution.
has been studied sparingly. Feasibility of partial prostatec-
tomy has been demonstrated in a single patient with a blad-
der neck paraganglioma with prostatic involvement [9]. 2. Patients and methods
Another series evaluated anterior partial prostatectomy in
2.1. Informed consent and preoperative counseling
patients with anterior prostate cancer not accessible to focal
ablation [10]. This study found that anterior partial prosta- Informed consent includes a thorough discussion of risks, benefits, and
tectomy was safe and feasible with good functional results, alternatives. Patients were informed of the novel nature of this proce-
although it was associated with a significant positive mar- dure, including the need for strict follow-up and possible need for fur-
gin rate of 53%. In 2021, Sood et al. [11] described precision ther treatments.
Fig. 1 – Single-port transvesical approach utilized for partial prostatectomy. The transvesical approach allows for direct access to the prostatic urethra,
facilitating hemigland excision of (A) the anterior prostate, (B) the lateral lobe, or (C) a specific tumor location.
2.2. Inclusion and exclusion criteria ation table. The ultrasound probe rotates automatically, allowing for
localization of the tumor intraoperatively in a three-dimensional display
The inclusion criteria were low- or intermediate-risk disease (Gleason (Fig. 2B).
7), organ-confined disease, and preoperative MRI without evidence of The Koelis software is utilized to fuse the preoperative digitally
locally advanced or metastatic disease. While the inclusion criteria tagged MRI and real-time intraoperative ultrasound images to identify
duplicated the HIFU prostate focal therapy program at our institution, the target lesion in real time, allowing for intraoperative guidance and
we expanded the inclusion criteria to include patients excluded from confirmation of complete excision of the targeted prostatic nodule
HIFU such as those with anteriorly located tumors, significant prostatic (Fig. 3).
calcifications, obliteration of prostatorectal junction, and prostate size A da Vinci SP surgical system (Intuitive Surgical, Sunnyvale, CA, USA)
larger than 80 cc on preoperative MRI. Patients were excluded if positive was utilized for all cases.
biopsy cores did not correspond to suspicious prostate MRI lesions.
Patients with bilateral positive biopsies, multiquadrant suspicious nod-
ules or signs of locally invasive disease on MRI, and >100 g prostate vol- 2.4. Incision and dissection
ume were excluded from this approach (Supplementary Table 1).
A 3 cm vertical incision is made about one to two finger breadths above
the pubic symphysis in the midline (Fig. 2C). The anterior rectus fascia is
2.3. Technical aspects identified and scored with cautery. The rectus muscles are split in the
midline and the transversalis fascia is incised.
Patients are positioned in the lithotomy position, and kept either flat or
in minimal Trendelenburg position based on body habitus (Fig. 2A). A
Foley catheter is inserted on the sterile field. 2.5. Cystotomy
The Koelis Trinity (Koelis Inc., Princeton, NJ, USA) is used for assis-
tance in localizing a target lesion intraoperatively. Prior to the operation, The bladder is filled via the Foley catheter with sterile irrigation. A 2 cm
a radiologist specialized in prostate MRI identifies, digitally tags, and vertical midline cystotomy is created, and stay sutures are placed at the
segments suspicious prostate nodules and the urethra. A transrectal apices of the cystotomy. All stay sutures utilized 2-0 Vicryl (Ethicon Inc.,
ultrasound probe is inserted and fixed into position attached to the oper- Cincinnati, OH, USA; Fig. 2D).
Fig. 2 – (A) Lithotomy position, (B) transrectal ultrasound guidance, (C) incision above the pubis, (D) cystotomy, (E) Alexis wound retractor insertion and (F) Da
Vinci access port assembly with insufflation, (G) SP robot docking, (H) partial prostatectomy specimen, and (I) final incision. SP = single port.
Fig. 3 – Examples of intraoperative guidance using preoperative MRI-fusion images and pre- and postoperative MRI. (A) The target lesion (shown here in red)
and the urethra (shown in yellow) are segmented from the preoperative prostate MRI. Real-time transrectal ultrasound images are shown here (B) before and
(C) after resection. (D) Preoperative prostate MRI compared with (E) postoperative MRI showing resection of the entire left lateral lobe of the prostate.
MRI = magnetic resonance imaging.
2.6. Docking and insufflation 2.8. Posterior dissection
A wound retractor is placed into the bladder (Fig. 2E). The daVinci SP For anteriorly located prostate tumors, dissection of posterior struc-
access port for small incisions (2.7–4 cm) is then attached to the wound tures and neurovascular bundles may not be necessary. For peripheral
retractor (Fig. 2F). An 8 mm AirSeal port is inserted through the access zone tumors, dissection of both the anterior and the posterior bladder
port with initial insufflation pressure of 10–12 mmHg. The SP robot is neck on the ipsilateral side of the target lesion is necessary. The con-
side docked on the patient’s left side, with the bedside assistant on the nective tissue attachments posterior to the bladder neck are incised
patient’s right (may be reversed based on the room setup; Fig. 2G). to reveal the vas and the seminal vesicle (SV) on the side of the lesion.
In the SP cannula partitioned into four channels, the camera is The vas deferens is retracted upward (anteriorly) and the vas is tran-
inserted at the 12:00, monopolar scissors at the 3:00, Maryland bipolar sected near the tip of the SV. Robotic applied 5 mm Hem-o-Lok clips
at the 6:00, and Cadier forceps at the 9:00 o’clock position. The robotic (Weck; Teleflex, Wayne, PA, USA) are used to clip the artery at the
scissors are exchanged for a robotic needle holder at the time of intrav- tip of the SV (Fig. 4B).
esical suturing. The robot is angled toward the pelvis (Fig. 2G).
A remotely operated suction and irrigation system (Vascular Tech-
nology, Nashua, NH, USA) is grasped and controlled by the robot console 2.9. Anterior dissection
surgeon, and is introduced through the 10 mm channel located at the top
Depending on the laterality of dissection, the bladder neck is incised at
of the access port.
the 10:00 (left) or 2:00 (right) o’clock position. For anterior lesions,
2.7. Bladder neck incision bilateral anterior dissection is performed. The endopelvic fascia is
incised, followed by the puboprostatic ligaments to reveal the dorsal
The bladder trigone, bilateral ureteral orifices, and anatomy of the pro- venous complex, which may be either completely ligated or partially
static base or median lobe are visualized. Depending on the location of ligated using a monofilament barbed suture (3-0 V-loc; Covidien,
the tumor, the mucosa is incised distal to the trigone, following the con- Mansfield, MA, USA). Apical dissection is performed to reveal the ure-
tour of the prostate. Care is taken to avoid injury to the ureteral orifices thra that is divided sharply, preserving as much urethral length as
(Fig. 4A). possible.
Fig. 4 – Intraoperative steps including (A) bladder neck incision, (B) seminal vesicle dissection, (C) left hemigland excision, (D) margin assessment, (E) bladder
neck reconstruction, and (F) final catheter insertion.
2.10. Pedicle ligation and nerve sparing 2.13. Vesicourethral anastomosis
While vascular pedicle dissection is not necessary for anterior gland A 3-0 monofilament barbed suture is used to perform the vesicourethral
excision, it is important for lateral gland excision. After the anterior anastomosis from the incised portion of the bladder neck to the urethral
and posterior extraprostatic dissections have been started, the interven- stump (Fig. 4E). The pnuemovesicum insufflation pressure is reduced to
ing posterolateral tissue contains the neurovascular bundles and the vas- 7–5 mmHg during this step to facilitate a tension-free anastomosis. Once
cular pedicle to the prostate. Cautery is minimized by using clips and/or complete, a new 20 French Foley catheter is inserted and 10–15 ml of
judicious bipolar electrocautery to control the vascular pedicle prior to sterile water is inserted into the retaining balloon (Fig. 4F).
dividing.
2.14. Bladder, fascia, and skin closure
2.11. Partial gland excision All robotic instruments are removed, the robot is undocked, and the
specimen is extracted. The access port is removed. Using an open
For anterior prostate gland excision, prostate tissue anterior to the ure-
approach, the cystotomy is closed in two layers—mucosal and detrusor
thra is incised. For lateral gland excision, the prostate is incised in the
muscle in a running fashion using 2-0 absorbable sutures. The fascia is
midline along the urethra (Fig. 4C). This preserves the mucosal strip of
closed with running 0 Vicryl or PDS sutures, and the skin is reapproxi-
the urethra and aids in mucosal approximation during the vesicourethral
mated with 4-0 absorbable sutures and covered with skin glue (Fig. 2I).
anastomosis. Once the specimen is free of all attachments, it is removed
into the bladder or into the access port (Fig. 2H). Hemostasis may be
2.15. Postoperative follow-up
obtained on the raw surface of the remaining prostate with either direc-
ted electrocautery or suture ligation. Patients are discharged with a Foley catheter after a short stay in the
Intraoperative real-time ultrasound imaging is imported into the pic- recovery room. The Foley catheter is removed, and a trial of void occurs
ture in picture mode on the robot console. After excision of the speci- on postoperative day 3. Prostate-specific antigen (PSA) was assessed at 6
men, ultrasound can assess disappearance of the prostatic nodule wk and then every 3 mo for 1 yr, along with assessments of voiding and
preoperative location (Fig. 3C). erectile function at each visit. Multiparametric prostate MRI is per-
formed at 1 yr followed by a transperineal prostate biopsy (Fig. 3E).
2.12. Prostatic excision margin assessment

3. Results
Margins status is assessed by using robotic scissors to remove thin sam-
ples of tissue from the apex, mid, and base at the medial and lateral 3.1. Patient characteristics
aspects of the excised prostatic surgical area. Biopsies are sent for intra-
operative frozen section, and results are obtained prior to the comple- All data were maintained in an institutional review board–
tion of the urethrovesical anastomosis (Fig. 4D). approved database. Data for baseline patient characteristics
of all nine patients are summarized in Table 1. The median Table 2 – Perioperative outcomes, pathology, and functional
outcomes
age and body mass index were 59 yr and 28.1 kg/m2,
respectively. The median PSA and prostate volumes were Outcome Result (N=9)
4.3 ng/ml and 32 cm3, respectively. Preoperative survey Operative time, min (median, IQR) 208 (199–211)
data showed a median International Prostate Symptom Console time, min (median, IQR) 141 (100–151)
EBL, mL (median, IQR) 50 (45–100)
Score of 3.8 and Sexual Health Inventory for Men score of Pain score at discharge (median, IQR) 3 (1–3)
23. The median follow-up duration was 8.7 mo. Opioids prescribed at discharge (n) 1/9
All patients underwent preoperative prostate MRI, with Length of Stay, hours (median, IQR) 3.8 (3.7–3.9)
Catheter duration, days (median, IQR) 3 (3–3)
six showing targeted lesions. Preoperative prostate biopsies Complications (n)
revealed Gleason score 3 + 3 = 6 in three of nine and Intraoperative 0
3 + 4 = 7 in six of nine patients. Two patients had low risk Postoperative 2 (catheter re-
insertion)
according to the National Comprehensive Cancer Network Readmission (n) 0
risk categories but had strong family histories of prostate Pathology details (n)
cancer, and the remaining seven patients had favorable Gleason 3+3 1/9
Gleason 3+4 7/9
intermediate risk. Gleason 4+3 1/9
Extracapsular extension 4/9
Seminal vesical invasion 0/9
3.2. Perioperative outcomes and postoperative data Positive intraoperative surgical margin 0/9
Laterality of excision (n)
The median operative time and estimated blood loss were Anterior 2
208 min and 50 ml, respectively (Table 2). Blood transfusion Left 5
Right 2
was not needed in any patient. No intraoperative complica- PSA, ng/ml (median, IQR)
tions were noted. There was no need for additional ports or 6 weeks (n = 8) 0.50 (0.32–1.3)
drains. No patients required an inpatient stay, with a med- 3 months (n = 2) 0.54 (0.38–0.69)
6 months (n = 4) 0.55 (0.25–0.86)
ian length of stay of 3.8 h. There were no readmissions. Pain 12 months (n = 2) 0.56 (0.42–0.71)
scores at discharge were low with a median of 3/10, and one Urinary control at 6 weeks, pads/day (median, 0 (0–0.2)
patient with a history of chronic pain medication use IQR)
SHIM score at 6 weeks (median, IQR) 17.5 (15–22)
required an opioid prescription at discharge. Foley catheters Change in score from preop (median, IQR) 2 ( 5.5–+2)
remained in place for 3 d, and all patients were able to void
EBL = estimated blood loss; IQR = interquartile range; PSA = prostate-
initially, though two patients required Foley catheter rein- specific antigen; SHIM = Sexual Health Inventory for Men.
sertion temporarily for 24 h and 72 h for hypercontinence
after which they were able to void normally.
Overlapped MRI and ultrasound images were utilized in
Doppler ultrasound was used to identify proximity to the
all cases to assess tumor locations intraoperatively. Further
neurovascular bundle.
intraoperative localization was facilitated by using the
Three patients had pathology upgrading, and the remain-
hyperechoic robotic instrument tip in real time. During
ing six patients showed concordance with their prostate
the nerve-sparing portion of the procedure, intraoperative
biopsy and surgical pathology. All patients had negative
margins of frozen sections and final pathology obtained
intraoperatively from the resection bed; however, the final
Table 1 – . Demographics and preoperative characteristics
report on the partial prostatectomy specimens revealed
Clinical data Result (N = 9) focally positive margins in four patients.
Age (median, IQR) 59.4 (55.1–61.7)
BMI (median, IQR) 28.1 (27.1–30.9)
ASA score (median, IQR) 3 (3–3)
4. Discussion
IPSS (median, IQR) 2 (0.5–6.5)
SHIM (median, IQR) 23 (15–25)
PSA, ng/ml (median, IQR) 4.3 (3.7–6.8)
In this study, we present our technique and initial outcomes
Prostate volume on MRI, cm3 (median, IQR) 32 (27–41)
PIRADS lesion (MRI) of SP transvesical partial prostatectomy. To our knowledge,
N/A 3 this is the first clinical report of this technique using the da
3 1
Vinci SP surgical platform and a transvesical approach,
4 2
5 3 which was previously shown to be technically feasible in
Gleason Score (N) a cadaver model [14]. The technique described here was
3+3 3
developed based on experience with the SP transvesical
3+4 6
NCCN risk category (N) radical prostatectomy and SP transvesical simple prostatec-
Low 1 tomy, both of which utilize a similar transvesical approach,
Intermediate–favorable 8
positioning, and equipment [13].
Median Follow-up, months (median, IQR) 8.7 (2.4–10.6)
Strict selection criteria are key in adopting this approach.
ASA = American Society of Anesthesiologists; BMI = body mass index;
IPSS = International Prostate Symptom Score; IQR = interquartile range; While we mirrored the inclusion criteria set for HIFU-
MRI = magnetic resonance imaging; NA = not applicable; NCCN = National eligible patients, we expanded our inclusion to patients
Comprehensive Cancer Network; PIRADS = Prostate Imaging Reporting otherwise not technically feasible for HIFU due to signifi-
and Data System; PSA = prostate-specific antigen; SHIM = Sexual Health
Inventory for Men. cant intraprostatic calcifications, anteriorly located pro-
static nodules, larger glands, and obliterated prostatorectal
junction. Prostates larger than 100 g remain a challenge for patients who are counseled thoroughly. Current data collec-
our intravesical approach due to limited surgical space. tion efforts and future studies will aim to evaluate func-
Our early experience with this procedure shows accept- tional and oncologic outcomes, as well as compare
able operative time and blood loss, no intraoperative com- outcomes with other focal and whole-gland therapies.
plications, no blood transfusions, and no readmissions. All
patients were discharged on the same day as the procedure, 5. Conclusions
and although one patient taking chronic pain medications
was prescribed opioids, all opioid-naïve patients did not This study suggests that a partial prostatectomy using a
require opioid prescriptions after discharge. All patients novel SP robotic transvesical approach is safe and feasible
maintained a Foley catheter for 3 d and were able to void in carefully selected patients with localized low- and
initially, although two patients required temporary Foley intermediate-risk prostate cancer. This technique provides
catheter reinsertion for hypercontinence. Hypercontinence advantages of Retzius sparing and accessing prostate nod-
may be related to periurethral edema in some patients ules selectively in various prostate locations. Although early
requiring a few more days of postoperative Foley drainage. perioperative and functional outcomes are impressive,
We plan to individualize our postoperative Foley catheter future studies of this patient population will be focused
duration to 2–5 d depending on the size of prostate partial on long-term oncologic outcomes.
excision.
To date, two patients in our cohort of partial prostatec-
tomy have completed a 1-yr postoperative follow-up. PSA Author contributions: Ethan L. Ferguson had full access to all the data in
values for these patients were 0.28 and 0.8 through 12 mo the study and takes responsibility for the integrity of the data and the
postoperatively, and were stable. Prostate MRI obtained at accuracy of the data analysis.
1 yr postoperatively showed no evidence of suspicious

Study concept and design: Kaouk.
lesions.
Acquisition of data: Ferguson, Beksac, Kaviani.
Benefits of this procedure shown here include limited
Analysis and interpretation of data: Ferguson, Zeinab.
perioperative pain, short recovery period with same-day
Drafting of the manuscript: Ferguson, Kaouk.
discharge, and a similar catheter duration to that of focal
Critical revision of the manuscript for important intellectual content: Kaouk,
ablation [7]. Intraoperative navigation using fused MRI
Purysko, Klein, Eltemamy, Haywood, McKenney, Weight.
and transrectal ultrasound imaging allows for precise local- Statistical analysis: Ferguson, Zeinab.
ization of prostate anatomy, like that of other focal thera- Obtaining funding: None.
pies [15]. Our cohort results are encouraging in terms of Administrative, technical, or material support: Purysko, McKenney.
the outpatient setting, low morbidity, and maintenance of Supervision: Kaouk, Klein, Weight.
functional outcomes. Long-term follow-up will clarify the Other: None.
oncologic control of this approach and define the role of this
minimally invasive approach as a focal treatment option.
Financial disclosures: Ethan L. Ferguson certifies that all conflicts of
We acknowledge that this approach may be controver-
interest, including specific financial interests and relationships and affili-
sial. There are a relatively narrow group of patients who
ations relevant to the subject matter or materials discussed in the manu-
may benefit from more treatment than active surveillance
script (eg, employment/affiliation, grants or funding, consultancies,
and yet less treatment than radical prostatectomy. A 2016
honoraria, stock ownership or options, expert testimony, royalties, or
editorial emphasized the importance of patient selection
patents filed, received, or pending), are the following: None.
when considering partial gland treatment in patients with
intermediate-risk disease [16]. Valid criticism directed
toward focal ablation may also apply to partial gland exci- Funding/Support and role of the sponsor: None.
sion—the multifocal nature of many prostate cancers, the
unknown of potentially untreated foci of cancer in the Peer Review Summary
remaining prostate gland, and how to follow PSA and inter-
pret MRI findings after treatment. Currently, there is no Peer Review Summary and Supplementary data to this arti-
consensus definition of biochemical recurrence in patients cle can be found online at https://doi.org/10.1016/j.eururo.
undergoing focal therapy [15]. Incidental prostate cancer 2022.07.017.
after holmium laser enucleation of the prostate with a PSA
nadir of <1 or a PSA density of <0.1 is considered reassuring References
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Prostate Cancer
Predicting the Need for Biopsy to Detect Clinically Significant

Prostate Cancer in Patients with a Magnetic Resonance Imaging–
detected Prostate Imaging Reporting and Data System/Likert 3
Lesion: Development and Multinational External Validation of the
Imperial Rapid Access to Prostate Imaging and Diagnosis Risk Score
Max Peters a,*, David Eldred-Evans b, Piet Kurver a, Ugo Giovanni Falagario c, Martin J. Connor b,
Taimur T. Shah b, Joost J.C. Verhoeff a, Pekka Taimen d, Hannu J. Aronen e, Juha Knaapila f,
Ileana Montoya Perez g, Otto Ettala f, Armando Stabile h, Giorgio Gandaglia h, Nicola Fossati h,
Alberto Martini h, Vito Cucchiara h, Alberto Briganti h, Anna Lantz i, Wolfgang Picker j,
Erik Skaaheim Haug k, Tobias Nordström l, Mariana Bertoncelli Tanaka b, Deepika Reddy b,
Edward Bass b, Peter S.N. van Rossum a, Kathie Wong m, Henry Tam b, Mathias Winkler b,
Stephen Gordon m, Hasan Qazi n, Peter J. Boström f, Ivan Jambor e, Hashim U. Ahmed b
a
Department of Radiotherapy, University Medical Center Utrecht, Utrecht, The Netherlands; b Department of Imperial Prostate, Imperial College London,
London, UK; c Department of Urology and Organ Transplantation, University of Foggia, Foggia, Italy; d University of Turku and Department of Pathology, Turku
University Hospital, Turku, Finland; e Department of Radiology, University of Turku, Turku, Finland; f Department of Urology, University of Turku and Turku
University hospital, Turku, Finland; g Department of Computing, University of Turku, Turku, Finland; h Urological Research Institute, IRCCS Ospedale San
Raffaele, Milan, Italy; i Department of Urology, Karolinska University Hospital, Solna, Sweden; j Department of Radiology, Aleris Cancer Center, Oslo, Norway;
k
Section of Urology, Vestfold Hospital Trust, Tønsberg, Norway; l Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm,
Sweden; m Department of Urology, Epsom and St. Helier’s University Hospital Trust, Surrey, UK; n Department of Urology, St. George’s Hospital NHS Foundation
Trust, London, UK
Article history: Background: Although multiparametric magnetic resonance imaging (MRI) has high
Accepted July 26, 2022 sensitivity, its lower specificity leads to a high prevalence of false-positive lesions requir-
ing biopsy.
Objective: To develop and externally validate a scoring system for MRI-detected Prostate
Imaging Reporting and Data System (PIRADS)/Likert 3 lesions containing clinically sig-
nificant prostate cancer (csPCa).
Keywords: Design, setting, and participants: The multicentre Rapid Access to Prostate Imaging and
Magnetic resonance imaging Diagnosis (RAPID) pathway included 1189 patients referred to urology due to elevated
Rapid Access to Prostate Imaging age-specific prostate-specific antigen (PSA) and/or abnormal digital rectal examination
and Diagnosis pathway (DRE); April 27, 2017 to October 25, 2019.
* Corresponding author. Room number Q01.1.110, Heidelberglaan 100, 3584 CX Utrecht, The
Netherlands. Tel. +31 (0) 887558800; Fax: +31 (0) 887555850.
E-mail address: [email protected] (M. Peters).
Imperial Rapid Access to Prostate Intervention: Visual-registration or image-fusion targeted and systematic transperineal
Imaging and Diagnosis risk score biopsies for an MRI score of 4 or 3 + PSA density 0.12 ng/ml/ml.
Clinically significant prostate Outcome measurements and statistical analysis: Fourteen variables were used in multi-
cancer variable logistic regression for Gleason 3 + 4 (primary) and Gleason 4 + 3, and PROMIS
definition 1 (any 4 + 3 or 6 mm any grade; secondary). Nomograms were created and
a decision curve analysis (DCA) was performed. Models with varying complexity were
externally validated in 2374 patients from six international cohorts.
Results and limitations: The five-item Imperial RAPID risk score used age, PSA density,
prior negative biopsy, prostate volume, and highest MRI score (corrected c-index for
Gleason 3 + 4 of 0.82 and 0.80–0.86 externally). Incorporating family history, DRE,
and Black ethnicity within the eight-item Imperial RAPID risk score provided similar out-
comes. The DCA showed similar superiority of all models, with net benefit differences
increasing in higher threshold probabilities. At 20%, 30%, and 40% of predicted Gleason
3 + 4 prostate cancer, the RAPID risk score was able to reduce, respectively, 11%,
21%, and 31% of biopsies against 1.8%, 6.2%, and 14% of missed csPCa (or 9.6%, 17%,
and 26% of foregone biopsies, respectively).
Conclusions: The Imperial RAPID risk score provides a standardised tool for the predic-
tion of csPCa in patients with an MRI-detected PIRADS/Likert 3 lesion and can support
the decision for prostate biopsy.
Patient summary: In this multinational study, we developed a scoring system incorpo-
rating clinical and magnetic resonance imaging characteristics to predict which patients
have prostate cancer requiring treatment and which patients can safely forego an inva-
sive prostate biopsy. This model was validated in several other countries.
1. Introduction 2. Patients and methods
2.1. Study population

In patients referred with an elevated prostate-specific anti-
gen (PSA), an area scoring of 3, 4, or 5 on magnetic reso- The development cohort used the Rapid Access to Prostate Imaging and
nance imaging (MRI) scoring systems is identifiable in the Diagnosis (RAPID) registry (RAPID-Online), funded by NHS England, in
majority who undergo multiparametric MRI (mpMRI) [1]. order to demonstrate the deliverability of a high-quality MRI-first path-
The level of suspicion can range from equivocal to highly way following the results of PROMIS [12,15]. All consecutive patients
suspicious [2]. Current guidelines recommend MRI- referred on the MRI-directed pathway were included. The RAPID pathway
targeted biopsy of these areas regardless of the suspicion involved straight-to-test mpMRI in patients referred by their primary care
score [3,4]. Performing prostate biopsies, without risk strat- physician to a urology department due to elevated age-specific PSA (2.5
ng/ml at 45–49 yr, 3 ng/ml at 50–69 yr, or PSA 5 ng/ml at 70 yr) and/
ification, would result in approximately half of MRI lesions
or abnormal digital rectal examination (DRE). Visual-registration or
being diagnosed either with benign histology or as clinically
image-fusion targeted and systematic transperineal biopsies were per-
insignificant prostate cancer (ciPCa) [5].
formed for an MRI score of 4 or 3 with PSA density 0.12 ng/ml/ml.
A risk-stratified MRI-directed pathway might allow a
We have previously reported that approximately 43% of patients avoided
more advantageous balance of risks from biopsy-related
immediate biopsy this way [16]. At analysis, three UK centres participated
complications and overdiagnosis of ciPCa against the risk
in RAPID-Online with a further eight centres currently. Initial analyses
of missing clinically significant prostate cancer (csPCa) [6].
have been described [17,18]. For this analysis, patients who received a
Several risk models incorporating MRI findings have biopsy needed prebiopsy mpMRI with a visible MRI lesion assessed using
recently been developed [7–11]. As different MRI scoring the PIRADS (version 2.0) or Likert scoring system [18]. To avoid a cluster-
systems such as Prostate Imaging Reporting and Data Sys- ing bias, the highest scoring lesion was selected for patients with multiple
tem version 2 (PIRADSv2) and Likert are used across various lesions [19]. MRI lesions with PIRADS or Likert 3 were included. We
healthcare settings, applying a scoring system based on only excluded patients with previous prostate cancer (PCa) or no MRI-
one system is limited [2,3]. Previous models no longer reflect directed targeted biopsy within 3 mo following MRI.
current practice, having been developed by incorporating
biopsies in patients with an MRI score of 1 or 2 [1,5,12,13].
Finally, models often lack external validation [14]. 2.2. Candidate predictor variables
A personalised risk score provided from a robustly devel-
A multidisciplinary panel of urologists, radiologists, and researchers
oped and externally validated risk model might allow
selected candidate predictors that were measurable, available, and reli-
patients, with both an mpMRI with score of 3 and a low
able based on existing evidence. Four classes were selected: demo-
risk of csPCa, to defer immediate biopsy. We aimed to
graphic (age, Black ethnicity, and family history of PCa), clinical (5-
design and externally validate a contemporary and more alpha reductase inhibitors, prior negative biopsy, and DRE), laboratory
representative risk prediction model for patients with (PSA and PSA density), and radiological (prostate volume, PIRADSv2
mpMRI-detected lesion(s) with a score of 3 than what is score, Likert score, combined MRI score, number of MRI lesions, and
present in the current literature. index lesion size; Supplementary material).
2.3. Data collection and data quality Multicollinearity was defined as a correlation coefficient r of >0.5.
Multiple imputation by chained equations was used for missing data,
All RAPID sites prospectively collected data using a customised Research generating 20 imputed datasets. The results were pooled with Rubin’s
Electronic Data Capture (REDCap) tool hosted at Imperial College Lon- [25] rules.
don. Training was conducted prior to the entry of each site into the reg- We created three models, decreasing clinical complexity in two steps
istry, to ensure adherence to a standardised protocol. Standardised data from the model with the lowest AIC value. First, DRE was removed
collection forms were used with detailed definitions and instructions for (model 2), and second, Black ethnicity (Gleason 3 + 4) or lesion size
each predictor variable. Quality assurance checks were performed (Gleason4 + 3) and family history of PCa were removed (model 1).
throughout the collection period. Any issues with data quality led to a We assessed whether this would reduce calibration, the C-statistic,
re-review of the primary health record by the coordinating centre and net benefit. We further compared the model with PSA density
(source data verification). against a model with PSA and prostate volume separately and with all
three variables (despite potential collinearity) included, to see which
2.4. Procedures combination provided the most parsimonious model.
Internal validation was performed using 2000 bootstrap resamples
2.4.1. MRI acquisition and reporting
The mpMRI scans were performed using a 1.5 T scanner with a pelvic from each imputed dataset, in which the modelling process was
phased-array coil in accordance with the European Society of Uroradiol- repeated. This provided correction of the final models’ b coefficients
ogy guidelines [20]. The sequences included T1-weighted, T2-weighted, and C-statistic. We assessed the models’ performance by evaluating dis-
and dynamic contrast-enhanced images, and multiple b values (for crimination (Harrell’s c-index, calibration plots) and plotting decision
apparent diffusion coefficient [ADC] maps and a high b value of 1500). curves to assess the clinical utility of the model in predicting csPCa com-
MRI scores were reviewed by a second reader in a weekly multidisci- pared with the approaches of a biopsy-in-all or a biopsy-in-none strat-
plinary tumour board. Any discordance was resolved by consensus. Radi- egy [26]. We further calculated the amount of missed csPCa against
ologists had over 3 yr of experience reporting >100 MRI scans per annum the number of biopsies prevented, given different model-predicted prob-
(Supplementary material) [21]. abilities of csPCa. Nomograms and an online risk calculator were created
to visually assess an individual patient’s risk.
2.4.2. Biopsy protocol For external validation, the predicted probabilities in the six external
Patients underwent a transperineal prostate biopsy according to a stan- cohorts on a per-patient basis were calculated using the complete mod-
dard operating procedure at all participating sites [17]. Targeting was els and compared with the observed probabilities in that population. The
performed with visual-registration or image-fusion software using a Delong test was used to compare C-statistics [27]. External validation
biopsy system that employs elastic image coregistration (Biopsee; Med- was conducted in a masked manner with no data pooling across cohorts;
Com GmbH, Darmstadt) [22]. Each MRI lesion was targeted under real- the RAPID investigators had no access to the data from the cohorts out-
time transrectal ultrasound guidance (using Hitachi Preirus device) side the UK. To assess temporal variation, the database was divided into
and potted individually. The minimum was three biopsy cores per lesion. a model-derivation set (years 2017–2018), which was subsequently val-
Additional nontargeted systematic sampling was performed [17]. Biop- idated in data from 2019.
sies were evaluated in accordance with the International Society of Uro- We additionally externally validated the model by Mehralivand et al
logical Pathology standards [23] by specialist uropathologists with 10 [8] on our RAPID-Online data and the external cohorts.
yr of experience. Pathologists were not blinded to other clinical Prediction modelling was adopted from the study of Steyerberg [28].
characteristics. Data were analysed with R studio version 4.1.2 (R Foundation, Vienna,
Austria) using packages rms, mice, psfmi, rmda, polycor, pROC, and
2.5. Validation cohorts ggplot2, among others, and STATA (version 15).
An extended description of the analysis is provided in the Supple-
The model was externally validated using six international cohorts from mentary material. The study follows the TRIPOD statement for reporting
four different countries including 154, 351, 324, 385, 570, and 590 multivariable prediction model development and validation (checklist in
patients (total 2374). The prevalence of Gleason 3 + 4 ranged from the Supplementary material) [29].
27% to 65%. These cohorts have been described previously, and represent
data from different settings encompassing single or multicentre clinical
trials and consecutive case series. The datasets incorporate a range of
2.8. Ethical considerations
MRI scanners. All MRI scans in the external validation cohorts were con-
temporary and performed between 2013 and 2019 (for details, see the Permission was granted by the institutional review board of each partic-
Supplementary material). ipating site either as consented research or as a continuous quality
improvement project depending on local ethics committee
2.6. Outcomes requirements.
The primary endpoint was any-length Gleason 3 + 4. This is a conser-

vative definition for csPCa, and its widespread availability allowed exter-
nal validation. Alternative models were constructed using the secondary 3. Results
endpoints any amount of Gleason 4 + 3 and PROMIS definition 1
(4 + 3 or any grade 6 mm).
The RAPID development cohort included 1189 patients with
an MRI-detected PIRADS/Likert 3 lesion who had MRI tar-
2.7. Statistical analysis
geted and systematic biopsies (April 27, 2017 to October 25,
Multivariable variable selection was done with a backward stepwise 2019). Gleason 3 + 4 was detected in 681 (57%) and
approach minimising the Akaike’s information criterion (AIC) [24]. Con- Gleason 4 + 3 in 378 (32%; Fig. 1 and Table 1). Only 64
tinuous variables were assessed for nonlinearity and transformed using (2.5%) patients were excluded due to not undergoing biop-
the natural logarithm when appropriate. sies within 3 mo.
Fig. 1 – Flowchart describing the study population. MRI = magnetic resonance imaging; PIRADS = Prostate Imaging Reporting and Data System.
Table 1 – Summary characteristics
Covariate Primary outcome

No PCa Gleason 3 + 4 cancer p value
(N = 508) (N = 681)
Age (yr) 64.3 (7.6) [42.3–83.5] 67.8 (7.7) [42.1–86.7] <0.001
PSA (ng/ml) 6.2 (4.7–8.9) [0.4–71] 8.4 (5.9–14.0) [1.5–1000] <0.001
PSA density 0.13 (0.09–0.19) [0.009–1.56] 0.22 (0.15–0.36) [0.02–26.3] <0.001
Black ethnicity 69 (14%) 76 (11%) 0.24
Family history of PCa 59 (12%) 89 (13%) 0.51
Prior prostate biopsy 42 (8.3%) 19 (2.8%) <0.001
5-ARIs 15 (3.0%) 17 (2.5%) 0.76
Abnormal DRE 116 (28%) 300 (53.0%) <0.001
Prostate volume 49 (35–67) [17–245] 38 (30–53) [12–150] <0.001
Lesion diameter 12 (9.0–18.2) [2–50] 15 (10–23) [3–58] <0.001
Number of lesions 0.01
1 373 (73%) 462 (68%)
2 126 (25%) 187 (28%)
3 8 (1.6%) 28 (4%)
4 1 (0.2%) 4 (0.6%)
Lesion score <0.001
3 184 (36%) 67 (9.8%)
4 234 (46%) 234 (34%)
5 90 (18%) 380.0 (56%)
5-ARI = 5-alpha reductase inhibitors; DRE = digital rectal examination; PCa = prostate cancer; PSA = prostate-specific antigen.
Summary statistics are presented as mean (±standard deviation) for continuous normally distributed data, median and interquartile range for skewed con-
tinuous variables, and n (%) for categorical data. Ranges are added in square brackets at the end. Differences were testes with a Student t test, Mann-Whitney U
test, and chi-square test for these data types, respectively.
3.1. Primary outcome: Gleason 3 + 4 eight variables remained in the full model (age, Black eth-
nicity, PSA density, family history of PCa, prior negative
3.1.1. Model development and performance
biopsy, prostate volume, positive DRE, and highest MRI
Eleven variables were used. PSA was excluded due to
score), with a C-statistic of 0.832 (AIC 1201.9; model 3).
collinearity with PSA density. After backward elimination,
Table 2 – Multivariable model coefficients for Gleason 3 + 4
Variable b (+SE), p value (model 1) b (+SE), p value (model 2) b (+SE), p value (model 3)
Intercept –1.851187 (0.655685), 0.005 –1.812339 (0.676587), 0.007 –1.929103 (0.685040), 0.005
Log(PSA density) 1.103418 (0.132386), <0.0001 1.134648 (0.133952), <0.0001 1.100873 (0.134728), <0.0001
Prior negative biopsy –1.020887 (0.334249), 0.002 –1.027477 (0.337287), 0.002 –0.890331 (0.337592), 0.008
MRI volume, by cc increase –0.008079 (0.003220), 0.01 –0.007505 (0.003227), 0.02 –0.007888 (0.003265), 0.02
MRI score 4 (ref. = 3) 0.933048 (0.184440), <0.0001 0.958390 (0.185986), <0.0001 0.951417 (0.187133), <0.0001
MRI score 5 (ref. = 3) 1.886100 (0.201489), <0.0001 1.915564 (0.202535), <0.0001 1.819472 (0.204162), <0.0001
Age, per year increase 0.052568 (0.009823), <0.0001 0.052062 (0.010005), <0.0001 0.050507 (0.010116), <0.0001
Black ethnicity –0.386964 (0.216905), 0.07 –0.381812 (0.216763), 0.08
Positive family history 0.394579 (0.214867), 0.07 0.394296 (0.216736), 0.07
DRE 0.570272 (0.152647), 0.0002
b = coefficient from model (the corresponding odds ratio can be calculated by e^b, where e = Euler’s number [2.71828]); DRE = digital rectal examination;
MRI = magnetic resonance imaging; PSA = prostate-specific antigen; ref. = reference; SE = standard error.
Coefficients in the table are the corrected coefficients after internal validation (correction factor 0.9544 and additional intercept correction of 0.00748) and are
used in all subsequent steps of the analyses.
Removal of DRE resulted in AIC increase (1215.4) with sim- 20%, 30%, and 40% of predicted Gleason 3 + 4 PCa, the
ilar C-statistic (0.826; model 2). The final model consisted of RAPID risk score was able to reduce, respectively, 11%,
five independent predictors (age, PSA density, prior nega- 21%, and 31% of biopsies against 1.8%, 6.2%, and 14% of
tive biopsy, prostate volume, and highest MRI score; model missed csPCa (or 9.6%, 17%, and 26% of foregone biopsies,
1). The C-statistic was 0.823 (AIC 1218.4; Table 2). The respectively).
models with PSA and prostate volume separately per-
formed worse (AIC 1233 vs 1218.4 of model 1) as well as 3.1.3. External validation
the model with all three variables included (AIC 1220.3 vs Temporal validation showed adequate calibration in the
1218.4). model developed based on the data from 2017 to 2018
applied to 2019, with minor deviations of the final model
3.1.2. Decision curve analysis and trade-offs coefficients from the original analysis. External validation
A decision curve analysis showed no difference between the of the Imperial RAPID risk score models for Gleason
three models regarding the net benefit over a range of 0– 3 + 4 on the six external cohorts showed a constant C-
40% threshold probabilities compared with recommending statistic/area under the curve (AUC) ranging from 0.80 to
biopsy for all (Fig. 2A). All three models were equally able 0.86 and stable calibration with a maximum of 10–15% mis-
to reduce biopsies for a range of predicted probabilities, calibration. The decision curve analysis predominantly
while minimising missed csPCa (Fig. 3A and Supplementary showed an increased net benefit over the range of threshold
Table 3). The difference in net benefit increased with higher probabilities compared with a biopsy-all strategy, especially
threshold probabilities, from 0.04 at 20% to 0.07 at 40%. At in populations with a lower incidence of Gleason 3 + 4.
Fig. 2 – Decision curve analysis of the three models with varying complexity for the primary outcomes of (A) Gleason 3 + 4 and (B) Gleason 4 + 3 over a
range of 0–60% threshold probabilities. The net benefit of the three models is depicted against a biopsy-all strategy (grey line) or biopsy-none strategy (black
line). Model 1: log(PSA density), prior negative biopsy, MRI prostate volume, MRI score, and age; model 2: model 1 + black ethnicity (Gleason 3 + 4) or lesion
size (Gleason 4 + 3) + positive family history; and model 3: model 2+ DRE. DRE = digital rectal examination; MRI = magnetic resonance imaging;
PSA = prostate-specific antigen; RAPID = Rapid Access to Prostate Imaging and Diagnosis.
Fig. 3 – Simulation of the reduction in biopsies attainable (lines for the three separate models for the left y axis) against the amount of missed (A) Gleason
3 + 4 and (B) Gleason 4 + 3 clinically significant prostate cancer (csPCa; bars of the three models for the right y axis). The x axis represents the predicted
probability of csPCa by the model. Example: when using model 1 on the RAPID database and filtering out the patients with 20% chance of Gleason 3 + 4
prostate cancer, you can reduce 10.5% of biopsies (or 105 per 1000 patients) while missing 1.76% (or 18 per 1000) Gleason 3 + 4 prostate cancers. Model 1: log
(PSA density), prior negative biopsy, MRI prostate volume, MRI score, and age; model 2: model 1 + black ethnicity (Gleason 3 + 4) or lesion size (Gleason
4 + 3) + positive family history; and Model 3: model 2+ DRE. AIC = Akaike’s information criterion; AUC = area under the curve; MRI = magnetic resonance
imaging; PSA = prostate-specific antigen; RAPID = Rapid Access to Prostate Imaging and Diagnosis.
External validation results of the five cohorts originating Long test model 1 vs models 2 and 3: p = 0.12 vs
outside the UK are depicted in Supplementary Figures 1 p = 0.02). Calibration of the model by Mehralivand et al
and 2, and Supplementary Table 1. External validation [8] showed an overestimation of predicted probabilities in
results of the UK cohort is depicted in Supplementary Fig- the RAPID database, which was corrected after recalibration
ure 3 (De Long test p = 0.61). of the intercept. Calibration on the external cohorts simi-
External validation of the Mehralivand et al’s [8] model larly showed an overestimation of the chance of csPCa
on the RAPID data (Supplementary Fig. 4) showed a (Gleason 3 + 4) of this model, which could be corrected
C-statistic of 0.812 (De Long test p = 0.02 vs model 1; De after recalibrating the intercept (Supplementary Fig. 1).
Fig. 4 – Nomogram from Gleason 3 + 4. The risk of clinically significant prostate cancer (csPCa; in this case Gleason 3 + 4) can be calculated by adding all
points from the upper horizontal bar per variable after which the risk can be read from the lowest bar. For example, a patient with a PSA density of 0.1 ng/ml/
ml (3 points), no previous biopsy (1 point), an MRI volume of 60 cc (1.5 points), an MRI score of 4 (1 point), and 70 yr of age (1.5 points) has a total of 8 points,
translating into a risk of 40% of Gleason 3 + 4 PCa. MRI = magnetic resonance imaging; PCa = prostate cancer; PSA = prostate-specific antigen.
3.1.4. Nomogram/risk calculator risk score showed consistency after external validation util-
Figure 4 shows the nomogram resulting from the simplified ising six datasets from multiple countries using different
model. An online risk calculator was created, available at MRI scoring systems and diverse reference standards. We
https://nomogramsumcu.shinyapps.io/RAPID_Gleason_3_4/. also examined the trade-off between avoided biopsy and
missed detection of csPCa if the model was deployed as a
3.2. Secondary outcomes: Gleason 4 + 3 and PROMIS decision tool in such patients. Such evaluation is vital in
definition 1 the process of gaining informed consent prior to recom-
mending a prostate biopsy or not.
3.2.1. Gleason 4 + 3
The prevalence of 57% of Gleason 3 + 4 is high in the
Results regarding Gleason 4 + 3 were largely concordant
RAPID dataset compared with the literature; consequently,
with Imperial RAPID risk score models for Gleason 3 + 4
the net benefit is increased most at higher threshold proba-
(Supplementary Table 2), with satisfactory calibration and
bilities compared with other models [1,12]. At lower thresh-
C-statistics of 0.814, 0.819, and 0.824 for models 1, 2, and
olds, for Gleason 3 + 4, the models’ net benefit is more
3, respectively. Temporal validation and external validation
modest in the RAPID database. For example, an overview
in the six external cohorts showed similar performance
of prediction models incorporating MRI shows an average
(Supplementary Fig. 5–7 and Supplementary Table 1). Lar-
of 20–50% of men not biopsied when a threshold probability
ger net benefit differences were obtained at lower threshold
of 20% is adopted [14], against 11% using the RAPID risk
probabilities than a biopsy-all strategy (Fig. 2B and 3B, and
score (125/1189). Missed csPCa accounts for 9.6% (12/125)
Supplementary Table 3).
of biopsies foregone, equivalent to the numbers found in
the literature (10%, range 1.5–15%), but lower when
3.2.2. PROMIS definition 1
looking relatively to all csPCa cases (1.8% of all Gleason
Models for PROMIS definition 1 were similar to the models
3 + 4 in RAPID, which compares favourably with the
for Gleason 3 + 4 and 4 + 3 with C-statistics of 0.826,
approximate 10% in the literature, ranging from 1% to
0.830, and 0.831 for models 1, 2, and 3, respectively. Tem-
12%). Although the net benefit in RAPID is achieved at
poral validation showed good calibration and minor devia-
higher threshold probabilities, the models are applicable
tions from the original model. For all outcomes, see the
to populations with a varying prevalence of the endpoint
Supplementary material for the statistical output, or
as well, as visible in the external validation sets (where
included code and anonymised data (upon request).
the incidence of Gleason 3 + 4 varied from 27% up to
65%). It is also clear that in these cohorts, the net benefit dif-
4. Discussion ference is more apparent at lower threshold probabilities. A
comprehensive externally validated model from the litera-
We report the development and external validation of a ture [8] showed overprediction across a wide range of prob-
contemporary risk tool to determine which patients with abilities including the RAPID data, indicating the better
suspicious MRI (score 3) might defer immediate biopsy, applicability of the RAPID risk score across populations.
given the probability of csPCa. Routinely collected clinical Additionally, for the endpoint with a lower incidence
factors were used, allowing for a broad clinical application. (Gleason 4 + 3), the models lead to a higher net benefit
We observed that the simplified five-item Imperial RAPID at lower threshold probabilities.
Our findings support the observations made by others As a result, we expect any risk calculator such as ours, in
that upfront risk stratification of patients with an MRI lesion this setting, to have an incremental impact. Indeed, given the
could reduce harms from biopsy [6]. Previous studies have higher prevalence of significant cancers in patients with sus-
developed models including MRI findings that have picious MRI, the rates of biopsy avoidance that can be
reported similar performance characteristics but use either achieved are in the order of 10%; such an incremental impact
a single MRI scoring system and/or transrectal biopsies as a contributes to the reduction in biopsy-related harms.
reference standard [7–11]. The Imperial RAPID risk score There are limitations to our study. RAPID-Online is an
overcomes the limitations of previous models developed observation cohort and not a clinical trial. Nonetheless, it
using a combination of PIRADSv2.0 or Likert scores, and val- has a standardised protocol for delivering the pathway
idated across multiple independent multinational external across multiple sites and reports outcomes of its large data-
datasets. The findings report high performance characteris- set in a uniform manner with all consecutive cases col-
tics across different csPCa prevalences during external vali- lected. Although the model was validated externally in
dation. To increase the reliability of MRI predictors, the cohorts from four different countries with varying preva-
protocol required MRI scans to be double reported. This lence of the target cancer endpoints, the results may not
was required in the RAPID pathway to address the widely be generalisable to all populations. The model is not valid
reported issue of interobserver mpMRI variability [30]. for the transrectal route of biopsy. We did not incorporate
We recognise that using MRI to develop risk scores is other descriptors of MRI lesions (eg, size, diffuse vs focal,
not new. Other groups have equally shown the possible capsular abutment, and ADC values). Rather than relying
clinical utility of a risk model incorporating MRI; an over- on individual radiological criteria that may not be represen-
view can be found in the study of Schoots and Roobol tative of the full diagnostic potential of the imaging tech-
[14]. The European Randomized study of Screening for nique, we utilised an MRI score (PIRADS or Likert) that
Prostate Cancer (ERSPC) risk calculator was added with combines multiple imaging findings.
MRI PIRADSv1 information (MRI-ERSPC-RC 3 and 4), There have been many previous validated nomograms
increasing the AUC to 0.84 and saving 33–48% of biopsies that have been published and made available for physicians
against 7–10% missed Gleason 3 + 4 [10] at a risk thresh- and the public. The impact that these models have on physi-
old of 20%. Radtke et al [7] also improved the ERSPC risk cians’ and patients’ decision-making process, or the overall
calculator from a single-centre retrospective cohort deter- impact these have on a healthcare service is unclear. To this
mining better accuracy using PIRADSv1.0 MRI scores. The end, we intend to prospectively evaluate the clinical utility
model was later validated externally [31]; however, predic- of the Imperial RAPID risk score regarding the decision on
tive accuracy varied, resulting in an overestimation/miscal- biopsy as an embedded randomisation within the IP3-
ibration when a lower csPCa prevalence was observed. PROSPECT study (ClinicalTrials.gov NCT04400656), which
Miscalibration is also frequently observed when the MRI- uses the cohort multiple randomised controlled study
ERSPC 3–4 risk calculators (and other models) are validated design [36]. Furthermore, we will evaluate model perfor-
externally [32,33], as was additionally seen when the mance and potentially adapt the model based on newly
model by Mehralivand et al [8] was applied to our data. acquired data from RAPID in the future. We encourage fur-
Uniquely, our study reports high performance characteris- ther validation on external cohorts.
tics for models developed using a combination of PIR-
ADSv2.0 and Likert scores, and validated across multiple
independent multinational external datasets. The Imperial 5. Conclusions
RAPID risk score appeared robust across different csPCa
prevalences during external validation. The Imperial RAPID risk score provides a standardised tool
Other models are developed using (transrectal ultra- for the prediction of different definitions of csPCa in
sonography–guided systematic) biopsies for patients with patients with an MRI-detected PIRADS/Likert 3 lesion,
nonsuspicious MRI, which are subject to spectrum and ver- and can support patients and physicians to make decisions
ification bias when comparing results with the RAPID risk regarding the need for prostate biopsy across a range of
score. We do not know in which direction model perfor- probabilities.
mance would change when a different reference test is
used. In case of a difference between these biopsy tech- Author contributions: Max Peters had full access to all the data in the
niques, as reported in the literature, transrectal biopsies study and takes responsibility for the integrity of the data and the accu-
often perform worse in detecting clinically significant dis- racy of the data analysis.
ease than MRI targeted and systematic transperineal biop- Study concept and design: Peters, Eldred-Evans, Winkler, Ahmed, Shah,
sies [34]. However, the effect on diagnostic accuracy can Connor, Reddy, Bass.
Acquisition of data: Peters, Eldred-Evans, Winkler, Ahmed, Shah, Connor,
vary in such cases [35]. The issue of a spectrum bias can
Reddy, Bass.
result in decreased applicability of the model in populations
Analysis and interpretation of data: Peters, Kurver, van Rossum, Eldred-
with less severe disease characteristics. The effect on diag-
Evans, Falagario.
nostic accuracy once again varies between studies [35].
Drafting of the manuscript: Peters, Eldred-Evans, Ahmed, Shah.
The Imperial RAPID risk score reflects clinical practice in
Critical revision of the manuscript for important intellectual content: All
many centres and countries, where patients with MRI
authors.
scores of 1 and 2 alongside those with an MRI score of 3
Statistical analysis: Peters, Kurver, van Rossum, Eldred-Evans, Falagario.
and a low PSA density are not biopsied immediately [13]. Obtaining funding: Ahmed, Winkler, Shah, Eldred-Evans.
Administrative, technical, or material support: Ahmed, Winkler, Connor, [3] NICE. NICE guidance—prostate cancer: diagnosis and management.
Reddy, Bass, Gordon, Qazi, Falagario, Taimen, Aronen, Knaapila, Perez, BJU Int 2019;124:9–26.
[4] Mottet N, Bellmunt J, Bolla M, et al. EAU-ESTRO-SIOG guidelines on
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prostate cancer. Part 1: screening, diagnosis, and local treatment
Picker, Haug, Nordström, Tanaka, Wong, Tam, Boström, Jambor. with curative intent. Eur Urol 2017;71:618–29.
Supervision: Ahmed, Winkler, Shah. [5] Kasivisvanathan V, Rannikko AS, Borghi M, et al. MRI-targeted or
Other: None. standard biopsy for prostate-cancer diagnosis. New Engl J Med
2018;378:1767–77.
[6] Schoots IG, Padhani AR, Rouvière O, Barentsz JO, Richenberg J.
Financial disclosures: Max Peters certifies that all conflicts of interest, Analysis of magnetic resonance imaging–directed biopsy strategies
for changing the paradigm of prostate cancer diagnosis. Eur Urol
including specific financial interests and relationships and affiliations rel-
Oncol 2020;3:32–41.
evant to the subject matter or materials discussed in the manuscript (eg, [7] Radtke JP, Wiesenfarth M, Kesch C, et al. Combined clinical parameters
employment/affiliation, grants or funding, consultancies, honoraria, stock and multiparametric magnetic resonance imaging for advanced risk
ownership or options, expert testimony, royalties, or patents filed, modeling of prostate cancer—patient-tailored risk stratification can
received, or pending), are the following: Martin J. Connor reports grant reduce unnecessary biopsies. Eur Urol 2017;72:888–96.
[8] Mehralivand S, Shih JH, Rais-Bahrami S, et al. A magnetic resonance
funding from University College Hospitals London (UCLH) Charity for
imaging–based prediction model for prostate biopsy risk
his prostate cancer research. Pekka Taimen reports research grant paid stratification. JAMA Oncol 2018;4:678.
to institution by Finnish Cancer Foundation; consulting fees from Faron [9] Perez IM, Jambor I, Kauko T, et al. Qualitative and quantitative
Pharmaceuticals; honoraria for lecture from Roche Finland; being a data reporting of a unique biparametric MRI: towards biparametric MRI-
based nomograms for prediction of prostate biopsy outcome in men
management committee member at ProScreen Prostate Cancer Screening
with a clinical suspicion of prostate cancer (IMPROD and MULTI-
Trial. Hannu J. Aronen reports novel MRI techniques for noninvasive IMPROD trials). J Magn Reson Imaging 2020;51:1556–67.
detection and characterisation of prostate cancer research grant from [10] Alberts AR, Roobol MJ, Verbeek JFM, et al. Prediction of high-grade
the Turku University Central Hospital. Otto Ettala reports academic grants prostate cancer following multiparametric magnetic resonance
from Finnish Cancer Society and Sakari Alhopuro Foundation. Alberto imaging: improving the Rotterdam European Randomized study of
Screening for Prostate Cancer risk calculators. Eur Urol 2019;75:310–8.
Martini reports grants from Intuitive Surgical (Sunnyvale, CA, USA).
[11] Distler FA, Radtke JP, Bonekamp D, et al. The value of PSA density in
Alberto Briganti reports academic grant from Italian Ministry of Health. combination with PI-RADS™ for the accuracy of prostate cancer
Tobias Nordström reports consulting fees from AstraZeneca; payment/ prediction. J Urol 2017;198:575–82.
honoraria from Ipsen; stock or stock options at A3P Biomedical. Deepika [12] Ahmed HU, Bosaily AE, Brown LC, et al. The PROMIS study: a paired-
cohort, blinded confirmatory study evaluating the accuracy of multi
Reddy reports funding for research from Prostate Cancer UK; funding for
parametric MRI and TRUS biopsy in men with an elevated PSA. J
attendance to conferences from Sonblate Corp and Imperial Healthcare Clin Oncol 2016;34:5000.
Charity. Peter J. Boström reports grant from Cancer Society of Finland; lec- [13] NICE. Prostate cancer: diagnosis and management; 2021. https://
ture fees from Astellas; being a member of the advisory board of Pfizer. www.nice.org.uk/guidance/ng131.
Hashim U. Ahmed reports support from Wellcome Trust; grants from [14] Schoots IG, Roobol MJ. Multivariate risk prediction tools including
MRI for individualized biopsy decision in prostate cancer diagnosis:
Cancer Research UK, National Institute of Health Research, Medical
current status and future directions. World J Urol 2020;38:517–29.
Research Council, the Urology Foundation, Prostate Cancer UK, the BMA [15] NHS England. Implementing a timed prostate cancer diagnostic
Foundation, Sophiris Biocorp, and Sonablate Corp; consulting fees for pathway; 2018. https://www.england.nhs.uk/wp-content/uploads/
teaching/training of HIFU prostate procedure from Sonablate Corp and 2018/04/implementing-timed-prostate-cancer-diagnostic-
pathway.pdf.
teaching/training of cryotherapy and Rezum prostate procedure from
[16] Bass E, Eldred-Evans D, Connor M, et al. MP13-06 The Rapid Access
Boston Scientific; payment/honoraria for teaching/training courses for Prostate Imaging and Diagnosis (RAPID) Pathway—a multicentre
HIFU from Sonablate Corp and teaching/training courses for Rezum from update of 1719 patients undergoing multi-parametric MRI as a
Boston Scientific; support for attending meetings and/or travels from Son- triage test. J Urol 2020;203:e186.
ablate Corp; participation for trial design in Francis Medical; chair at NCRI [17] Connor M, Eldred-Evans D, van Son M, et al. A multicentre study of
the clinical utility of non-targeted systematic transperineal
Prostate Research Group (unpaid); specialist adviser for NICE Diagnostics
prostate biopsies in patients undergoing pre-biopsy mpMRI. J
Assessment Panel on Transperineal Freehand Biopsy (unpaid). Urol 2020;204:1195–201.
[18] Khoo CC, Eldred-Evans D, Peters M, et al. Likert vs PI-RADS v2: a
comparison of two radiological scoring systems for detection of
Funding/Support and role of the sponsor: This work was supported by clinically significant prostate cancer. BJU Int 2020;125:49–55.
Wellcome Trust Senior Research Fellowship (ref: 204998/Z/16/Z) and [19] Gönen M, Panageas KS, Larson SM. Statistical issues in analysis of
NHS England Cancer Transformation Fund. The funders had no role in diagnostic imaging experiments with multiple observations per
patient. Radiology 2001;221:763–7.
any of the aspects of the conduction of the current study.
[20] Weinreb JC, Barentsz JO, Choyke PL, et al. PI-RADS prostate
imaging–reporting and data system: 2015, version 2. Eur Urol
2016;69:16–40.
Peer Review Summary and supplementary data [21] Brizmohun Appayya M, Adshead J, Ahmed HU, et al. National
implementation of multi-parametric magnetic resonance imaging
for prostate cancer detection—recommendations from a UK
Supplementary data to this article can be found online at consensus meeting. BJU Int 2018;122:13–25.
https://doi.org/10.1016/j.eururo.2022.07.022. [22] Khoo CC, Eldred-Evans D, Peters M, et al. A comparison of prostate
cancer detection between visual estimation (cognitive registration)
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interpreting decision curve analysis: a guide for investigators. Eur [33] Deniffel D, Healy GM, Dong X, et al. Avoiding unnecessary biopsy:
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Words of Wisdom
Re: Fragmentation of Stones by Burst Wave Lithotripsy in outcomes from BWL alone could not be assessed. Reducing
the First 19 Humans stones to <2 mm is a reasonable target, but the risk of ste-
instrasse, particularly when treating larger stones, remains
Harper JD, JE Lingeman, Sweet RM, et al.
pending a more thorough assessment of clinical outcomes.
While BWL may not challenge endoscopic and percuta-
J Urol 2022;207:1067–76 neous techniques as the gold standard for treating kidney
stones, this body of work underscores renewed interest in
noninvasive treatment strategies to reduce morbidity for
Experts’ summary:
patients with stones. The favorable side-effect profile and
Harper et al conducted a prospective feasibility study to
tolerability without requiring anesthesia are key features
evaluate the efficacy of burst wave lithotripsy (BWL) in
of BWL. These early results thus promise a future in which
patients with a stone. This technology was paired with ure-
treatment of small stones can be performed in emergency
teroscopy to allow visual assessment of the effects of litho-
departments or outpatient clinics, allowing for faster reso-
tripsy on the stone and surrounding urothelial tissues. The
lution of symptomatic stone events while easing the burden
primary purpose of the study was to assess the efficacy of
on operating rooms.
stone fragmentation across various stone types, sizes, and
locations while monitoring for adverse outcomes.
Nineteen subjects were recruited to this multi-institu- Conflicts of interest: Marshall Stoller is co-founder of Applaud Medical.
tional study. Treatment was delivered to stones <12 mm, Heiko Yang has nothing to disclose.
the upper limit for effective treatment according to acoustic
beam width. Most stones were in the kidney, except for two References
that were in the distal ureter. Stone density measured via
computed tomography had a wide range (205–2000 Houns- [1] Harper JD, Metzler I, Hall MK, et al. First in-human burst wave
lithotripsy for kidney stone comminution: initial two case studies. J
field units).
Endourol 2021;35:506–11.
The primary study outcome was stone comminution, [2] Zwaschka TA, Ahn JS, Cunitz BW, et al. Combined burst wave
which was defined as the percentage of fragments <2 mm lithotripsy and ultrasonic propulsion for improved urinary stone
as measured via ureteroscopy. The majority of stones fragmentation. J Endourol 2018;32:344–9.
[3] Ramesh S, Chen TT, Maxwell AD, et al. In vitro evaluation of urinary
reached complete or partial comminution within 10 min
stone comminution with a clinical burst wave lithotripsy system. J
of treatment. As expected, incomplete fragmentation was Endourol 2020;34:1167–73.
observed when the stone size or hardness was suboptimal. [4] Maxwell AD, Cunitz BW, Kreider W, et al. Fragmentation of urinary
Mild tissue trauma was visualized, mostly limited to the calculi in vitro by burst wave lithotripsy. J Urol 2015;193:338–44.
urothelium and renal papilla.
Heiko Yang *
Marshall Stoller
Experts’ comments:
Developed at the University of Washington, BWL is an Department of Urology,
emerging technology vying to be included in the repertoire University of California-San Francisco, San Francisco, CA, USA
for stone surgery in the near future [1]. This study provides
* Corresponding author. Department of Urology, University of California-
a visual demonstration of the ability of BWL to fragment San Francisco, 400 Parnassus Avenue, San Francisco, CA 94066, USA.
stones with minimal associated trauma to surrounding tis- E-mail address: [email protected] (H. Yang).
sues, building on prior proof-of-concept studies [2–4].
The potential for use of BWL as a monotherapy should, 0302-2838/Ó 2022 European Association of Urology. Published by
for now, be interpreted with caution. Like conventional Elsevier B.V. All rights reserved.
shockwave lithotripsy, the technology appears to be limited https://doi.org/10.1016/j.eururo.2022.07.012
by stone size and hardness. Moreover, since all study sub-
jects underwent concurrent ureteroscopy, stone clearance
Re: Development and Validation of the Metric-based – Response process: the extent to which the actions and
Assessment of a Robotic Dissection Task on an Avian thought processes of the survey responders demonstrate
Model that they understand the model and its procedure in the
Puliatti S, Amato M, Mazzone E, et al. same way as it was predefined by the research team.
While these parameters are increasingly used in adult

J Surg Res 2022;277:224–34
urology, it appears that the pediatric world is still lagging
behind. The Intuitive robotic platform is not made or
Experts’ summary: adapted for children. Nonetheless, for the benefit of our
With the advent of high-technology options such as patients, we work with it under pediatric conditions. The
robotic platforms, training is a major challenge. The authors Hugo RAS robotic platform has not (yet?) received a CE
developed a standardized objective teaching tool for robotic mark for pediatric cases [3]. The Versius platform is being
education that follows proficiency-based progression (PGP) evaluated in ‘‘boxes’’ regarding whether it will be suitable
principles and applied it to an avian model [1]. for pediatrics [4]. Help from these companies should be
A modified Delphi approach was used to assess the tool, expected in adapting their tools for children. Some of the
for which a panel was gathered that included novices and existing models for nonrobotic pediatric simulation are
experts. All the panelists completed two video-recorded acceptable, but standardization and availability remain
trials of predefined tasks, including dissection, suturing, poor. There is an urgent need for the development of speci-
knotting, and coagulation, with predetermined procedural fic training tools using PBP principles for technological
steps. Videos were independently reviewed by two innovations such as robotic platforms in pediatric and
reviewers. Scoring was performed using predefined parame- reconstructive subspecialties. Teaching has to become one
ters (tear/damage skin, camera off target, conflict of of the most important commitments in (pediatric) urology.
instruments). Ultimately, teaching is the best way to improve patient care
The authors conclude that this metric-based assessment on a large scale worldwide.
on an avian model is a good tool for evaluation of PGP in
predefined robotic surgical skills. Its place in training Conflicts of interest: The authors have nothing to disclose.
remains to be determined.
References
Experts’ comments: [1] Puliatti S, Amato M, Mazzone E, et al. Development and validation of
Over the past decades, the focus in teaching has the metric-based assessment of a robotic dissection task on an avian
clearly shifted. The historical ‘‘see one, do one, teach model. J Surg Res 2022;277:224–34. https://doi.org/10.1016/j.
jss.2022.02.056.
one’’ way of working is gradually being replaced by a
[2] Mazzone E, Puliatti S, Amato M, et al. A systematic review and meta-
more structured approach, with initial exercises ex vivo. analysis on the impact of proficiency-based progression simulation
However, it remains difficult to produce efficient tools training on performance outcomes. Ann Surg 2021;274:281–9.
that mimic the human body well enough to offer realis- [3] Ragavan N, Bharathkumar S, Chirravur P, Sankaran S, Mottrie A.
Evaluation of Hugo RAS system in major urologic surgery: our initial
tic training. Moreover, it is difficult to evaluate how effi-
experience. J Endourol 2022. https://doi.org/10.1089/end.2022.0015,
cient these tools are in improving trainees’ skills. A few In press.
concepts are defined to help us differentiate between [4] Kayser M, Krebs TF, Alkatout I, et al. Evaluation of the Versius robotic
the teaching tools available: surgical system for procedures in small cavities. Children
The PBP concept is based on step-by step teaching of 2022;9:199.
progressive models before reaching a living human model
Caroline Jamaer
[2]. To assess the validity of a model, a few parameters must
Anne-Françoise Spinoit *
be evaluated: Department of Urology, Ghent University Hospital, Ghent, Belgium
* Corresponding author. Department of Urology, Ghent University
– Face validity: does the model look similar enough to what it Hospital, Ghent, Belgium
mimics for novices? E-mail address: [email protected] (A.-F. Spinoit).
– Content validity: is there an expert consensus on whether
the model is a good replica? 0302-2838/Ó 2022 European Association of Urology. Published by
– Construct validity: for the procedure itself, is there sufficient Elsevier B.V. All rights reserved.
evidence accumulated to support interpretation of whether https://doi.org/10.1016/j.eururo.2022.07.026
the model is good enough?
Re: Artificial Intelligence for Diagnosis and Gleason automatically segment and report magnetic resonance
Grading of Prostate Cancer: The PANDA Challenge imaging scans, although the false positive rate needs to be
improved [3]. Likewise, MonaAI Label can segment prostatic
Bulten W, Karatasalo K, Cameron Chen P, et al zones and cancers, and produce a 3D image of the prostate,
sphincter, and neurovascular bundles that can be 3D
printed and taken to the operating room for ‘‘personalised
Nat Med 2022;28:154–63
surgery’’. There is also interest in automated performance
metrics, which may help with the training and performance
Expert’s summary: of the next generation of robotic surgeons [4]. Finally the
The Prostate Cancer Grade Assessment (PANDA) old idea of AI-driven automation has returned [5]. Although
challenge is currently the largest global histopathology a machine can perform certain steps of an operation such as
competition to date, joined by 1290 developers from 65 suturing more accurately than a human being, surgical
countries for Gleason grading using 10 616 digitised, pub- judgment is unlikely to be replaced by AI and automation
licly available prostate biopsies. The competition was open anytime soon. These advances should be good for our
to participants from April 21 to July 23, 2020 and was patients. In the meantime, the enthusiasm for AI needs to
hosted on the Kaggle platform. It isolated the developers be tempered with resposible research and innovation as
from independent evaluation of the algorithms’ perfor- well as ongoing social science studies involving health care
mance, thus reducing contamination. The study had two workers and patients to see whether they can trust AI over
phases: development and validation. A number of submit- human judgment [6].
ted algorithms performed as well as expert pathologists
on independent international cohorts, fully blinded to the
Conflicts of interest: The author has financial relationships with Proximie,
algorithm developers. On US and European external valida-
Jiva.ai, and MysteryVibe.
tion sets, the algorithms achieved agreement of 0.862 and
0.868, respectively, with expert pathologists. These results
References
are exciting as they can be generalised across different
laboratories and patient populations [1]. [1] Bulten W, Karatasalo K, Cameron Chen P, et al. Artificial intelligence
for diagnosis and Gleason grading of prostate cancer: the PANDA
challenge. Nat Med 2022;28:154–63.
Expert’s comments: [2] Hutson M. Artificial intelligence faces reproducibility crisis. Science
With increasing computational memory and speed, 2018;359:725–6.
artificial intelligence (AI) will have a significant influence [3] Mehta P, Antonella M, Singh S, et al. AutoProstate: towards
on health care. In urology, this impact will mainly be on automated reporting of prostate MRI for prostate cancer
assessment using deep learning. Cancers 2021;13:6138.
accurate diagnosis, prediction of outcomes, treatment plan- [4] Hung AJ, Ma R, Chen S, et al. Surgeon automated performance
ning, and evaluation of surgical skills. metrics as predictors of early urinary continence recovery after
The PANDA challenge, an open online data set of >10 000 robotic radical prostatectomy—a prospective bi-institutional study.
digitised prostate biopsies, shows that AI is as good as Eur Urol Open Sci 2021;27:65–72.
[5] Connor MJ, Dasgupta P, Ahmed HU, Raza A. Autonomous surgery in
human uro-pathologists for the diagnosis and Gleason
the era of robotic urology: friend or foe of the future surgeon? Nat
grading of prostate cancer. With robust external validation, Rev Urol 2020;17:643–9.
it reduces the difficulty that AI faces with reproducibility [6] https://www.practiceupdate.com/content/ai-for-diagnosis-and-gleason-
because of unpublished codes in >90% of articles published grading-of-prostate-cancer/130804; 2022.
[2].
Does this mean that AI will replace our friendly Prokar Dasgupta *
pathologists? I very much doubt it. AI will be an adjunct

King’s Health Partners, Guy’s Hospital, King’s College London, London, UK
to human reporting by improving accuracy and reducing
the variability among pathologists. I have spoken to a num- * King’s Health Partners, Counting House, Guy’s Hospital, King’s College
ber of leading pathologists who all feel that AI can be used London, London, UK.
as a triage tool to reduce their routine workload and instead E-mail address: [email protected].
allow experts to focus on the more difficult cases for which
an accurate pathological diagnosis would impact directly on 0302-2838/Ó 2022 European Association of Urology.. Published by
decision-making and patient care. Elsevier B.V. All rights reserved.
The other area in which AI is increasingly being used is in https://doi.org/10.1016/j.eururo.2022.07.028
surgical planning involving three-dimensional (3D) imaging
of organs and surrounding structures. AutoProstate can
Re: Active Surveillance Plus Enzalutamide Monotherapy vs Nonetheless, we also have to face the fact that AS is still
Active Surveillance Alone in Patients with Low-risk or not as impeccable as we want it to be. Around the globe,
Intermediate-risk Localized Prostate Cancer: The ENACT community uptake rates are insufficient and nearly one-
Randomized Clinical Trial
third of men opting for AS will undergo definitive treatment
Shore ND, Renzulli J, Fleshner NE, et al. within a few years, some of them even despite any disease
reclassification [2]. Thus, we should focus our energy on fur-
ther decreasing overdiagnosis of low-risk PCa and increas-
JAMA Oncol. In press. https://doi.org/10.1001/jamaoncol.2022.
ing educational and psychological efforts to improve the
1641
uptake of AS.
Human nature undoubtedly means that once diagnosed
Experts’ summary: with low-risk cancer, we would all prefer a ‘‘harmless’’ cure
In this open-label phase 2 trial, 227 patients were ran- over AS. However, as long as the available options are nei-
domized 1:1 to enzalutamide 160 mg for a 1-yr treatment ther proven to be ‘‘harmless’’ nor a cure, we should abstain
period or continued active surveillance (AS) alone [1]. The from targeting our patients’ Achilles heel and instead eval-
primary endpoint was time to pathological or therapeutic uate new therapies with curative potential in well-designed
prostate cancer (PCa) progression. Secondary endpoints neoadjuvant trials first.
included a negative biopsy, a rise in prostate-specific anti-
gen (PSA), and time to PSA progression. Enzalutamide
Conflicts of interest: Claudia Kesch has received consulting fees from
decreased the risk of pathological or therapeutic PCa pro-
Apogepha; has received research funding from Advanced Accelerator
gression by 46% (hazard ratio [HR] 0.54, 95% confidence
Applications (Novartis) and Curie Therapeutics; and has received com-
interval [CI] 0.33–0.89; p = 0.02) and delayed PSA pro-
pensation for travel from Janssen Pharmaceuticals. Boris A. Hadaschik
gression by 6 mo (HR 0.71, 95% CI 0.53–0.97; p = 0.03)
has served in advisory roles for ABX, Astellas, AstraZeneca, Bayer, Bris-
in comparison to AS alone. The odds for a negative biopsy
tol-Myers Squibb, Janssen R&D, Lightpoint Medical, and Pfizer; has
were significantly higher at 1 yr for the enzalutamide
received research funding from Astellas, Bristol-Myers Squibb, the Ger-
groups, but at 2 yr the difference between the groups
man Research Foundation, Janssen R&D, Novartis, and Pfizer; and has
was not statistically significant. Enzalutamide-related
received compensation for travel from Astellas, AstraZeneca, and Janssen
adverse events (AEs) were reported for 88.4% of the
R&D.
men, with 2.7% serious AEs and 7.1% leading to study
drug discontinuation. Patients in the treatment cohort
References
had a higher rate of AEs than patients on AS (92.0% vs
54.9%). The most commonly reported AEs during [1] Shore ND, Renzulli J, Fleshner NE, et al. Active surveillance plus
treatment with enzalutamide were fatigue (55.4%), enzalutamide monotherapy vs active surveillance alone in patients
gynecomastia (36.6%), nipple pain (30.4%), breast tender- with low-risk or intermediate-risk localized prostate cancer: the
ENACT randomized clinical trial. JAMA Oncol. In press. https://doi.
ness (25.9%), and erectile dysfunction (17.9%). The only
org/10.1001/jamaoncol.2022.1641.
AE that occurred in 5% of patients in the AS cohort [2] Kirk PS, Zhu K, Zheng Y, et al. Treatment in the absence of disease
was hypertension (7.1%). reclassification among men on active surveillance for prostate cancer.
Cancer 2022;128:269–74. https://doi.org/10.1002/cncr.33911.
Claudia Kesch *
Boris A. Hadaschik
This recent publication in JAMA Oncology caused a rarely
seen outrage on urology social media, including a twitter Department of Urology, West German Cancer Center, University of Duisburg,
storm and at least three critical podcast productions, a spot- Essen and German Cancer Consortium, University Hospital Essen, Essen,
light that even some level 1 practice-changing publications Germany
will never receive.
* Corresponding author. Department of Urology, West German Cancer
Indeed, a lot of the factual criticism, briefly summarized
Center, University of Duisburg-Essen and German Cancer Consortium,
below, is more than warranted: University Hospital Essen, Essen, Germany.
E-mail address: [email protected] (C. Kesch).
– AS plus a therapeutic intervention is by definition not AS but
is called active treatment. 0302-2838/Ó 2022 European Association of Urology. Published by
– It has yet to be proven that pathological progression is a Elsevier All rights reserved.
valid surrogate endpoint for long-term outcome in AS.
– Declaring a drug-related AE rate of 88.4% ‘‘well tolerated’’
may be justifiable if it results in significantly longer overall
survival, as observed in patients with metastatic disease,
but it is wide of the mark in the present context.
Re: Darolutamide and Survival in Metastatic, Hormone- the superiority of doublet ARTA versus triplet therapy.
sensitive Prostate Cancer Indeed, the hazard ratios obtained with both triplet combi-
Smith MR, Hussain M, Saad F, et al.
nations and with ARTA-based doublets are in the same
range.
An indirect comparison of triplet and doublet combina-
N Engl J Med 2022;386:1132–42 tions presented at the American Society of Clinical Oncology
2022 annual meeting revealed better outcomes with triplet
Experts’ summary:
combinations when compared to docetaxel-based doublet
The authors studied the overall survival (OS) benefit of strategies, but no differences between triplet combinations
adding darolutamide for patients with metastasic hor- and ARTA-based doublets [5].
mone-sensitive prostate cancer (mHSPC) treated with Taking all the information into consideration, for
androgen deprivation therapy (ADT) plus docetaxel in a patients with mHSPC for whom docetaxel is indicated, ARTA
phase 3 randomized, placebo-controlled trial. The trial addition is mandatory. However, the role of triplet therapy
included 1306 patients, most of whom had a Gleason score and the group of patients who will benefit the most still
8 (78.2%) and de novo metastatic disease (86.1%). Visceral need to be defined.
metastases were present in 17.5% of the patients.
The primary endpoint was met, with a 32.5% reduction in Conflicts of interest: The authors have nothing to disclose.
the risk of death in the darolutamide group (hazard ratio
0.68, 95% confidence interval 0.57–0.80; p < 0.001). On pre- References
specified subgroup analysis, the benefit was clearer for
patients with bone metastasis compared to visceral metas- [1] Chi KN, Agarwal N, Bjartell A, et al. Apalutamide for metastatic,
castration-sensitive prostate cancer. N Engl J Med 2019;381:13–24.
tasis, for de novo compared to recurrent metastasis, and for
https://doi.org/10.1056/NEJMoa1903307.
Gleason 8 compared to Gleason <8 disease. [2] Armstrong AJ, Szmulewitz RZ, Petrylak DP, et al. ARCHES: a
There were no differences in serious adverse events randomized, phase III study of androgen deprivation therapy with
between the two groups (44.8% darolutamide vs 42.3% enzalutamide or placebo in men with metastatic hormone-sensitive
placebo). prostate cancer. J Clin Oncol 2019;37:2974–86. https://doi.org/
10.1200/JCO.19.00799.
[3] Davis ID, Martin AJ, Stockler MR, et al. Enzalutamide with standard
first-line therapy in metastatic prostate cancer. N Engl J Med
2019;381:121–31. https://doi.org/10.1056/NEJMoa1903835.
The results from the ARASENS trial clearly support the [4] Fizazi K, Foulon S, Carles J, et al. Abiraterone plus prednisone added to
idea that androgen receptor–targeted agents (ARTAs) can androgen deprivation therapy and docetaxel in de novo metastatic
improve the results with docetaxel when there is indication castration-sensitive prostate cancer (PEACE-1): a multicentre, open-
for this in mHSPC. Still, we need to determine the appropri- label, randomised, phase 3 study with a 2 2 factorial design. Lancet
2022;399:1695–707. https://doi.org/10.1016/S0140-6736(22)00367-1.
ate group of patients who will benefit from this triplet
[5] Naqvi SAA, Bin Riaz Z, Riaz A, et al. Indirect comparisons of triplet
therapy. therapy as compared to novel hormonal therapy doublets in patients
While there is a continuous benefit of intensifying ADT with metastatic castration sensitive prostate cancer. J Clin Oncol
treatment with either docetaxel or ARTA among all studies, 2022;40(16 Suppl):5083.
with very similar hazard ratios, the benefit of adding doc-
Antoni Vilaseca
etaxel to ADT + ARTA is not as clear. For instance, neither
Maria J. Ribal *
the TITAN (apalutamide) nor the ARCHES (enzalutamide)
study showed a benefit of adding the study drug among Uro-oncology Unit, Hospital Clínic de Barcelona, Universitat de Barcelona,
patients who were previously treated with docetaxel [1,2]. Barcelona, Spain
Of note, the proportion of patients who received docetaxel
was small (11% and 18% respectively). In the ENZAMET * Corresponding author. Uro-oncology Unit, Hospital Clínic de Barcelona,
study, docetaxel was administered concurrently to Universitat de Barcelona, Barcelona, Spain.
E-mail address: [email protected] (M.J. Ribal).
enzalutamide in 45% of patients [3]. On subgroup analysis,
there was a progression-free survival (PFS) benefit but no
0302-2838/Ó 2022 European Association of Urology. Published by
OS benefit (immature data on OS). Finally, in the PEACE-1
Elsevier B.V. All rights reserved.
trial, a PFS improvement was seen among all the patients,
but an OS benefit was only observed among high-risk
patients (low-risk data immature) [4].
None of the triplet studies have a comparative third
ARTA-based doublet arm that would be key to establishing
Re: Novel Classification for Upper Tract Urothelial the current EAU risk groups by including tumor architecture
Carcinoma to Better Risk-stratify Patients Eligible for among the risk factors and by outlining a new intermediate
Kidney-sparing Strategies: An International Collaborative risk subcategory.
Study The authors should be commended for their valuable
Marcq G, Foerster B, Abufaraj M, et al. contribution to the ongoing debate with a large and hetero-
geneous cohort and extensive analyses of potential risk fac-
tors for muscle-invasive disease. However, the retrospective
Eur Urol Focus 2022;8:491–7 design of the study, as well as the exclusion of patients with
UTUC who received a primary KSS treatment, partly limits
Experts’ summary: the strength of these findings. Moreover, the authors did
In this retrospective multicenter study, the authors rec- not evaluate several recognized risk factors for UTUC, such
ommended a three-level risk-stratification algorithm for as tumor location [3] and prior bladder carcinoma [4],
patients with upper tract urothelial carcinoma (UTUC) which may influence the results.
according to the actual risk of muscle-invasive disease In summary, the present study should be interpreted as a
(pT2) according to the radical nephroureterectomy speci- remarkable starting point for additional research efforts in
men [1]. this field to identify the patients who might benefit the
On multivariable logistic analyses, the presence of non– most from KSS and those who deserve radical treatment.
organ-confined (nOC) disease on preoperative imaging
(odds ratio [OR] 5.40; p < 0.0001), hydronephrosis (OR Conflicts of interest: The authors have nothing to disclose.
1.93; p = 0.0003), high-grade biopsy (OR 1.76; p = 0.01),
high-grade cytology (OR 1.72; p = 0.004), sessile architec- References
ture (OR 2.63; p < 0.0001), and age at diagnosis (OR 1.02;
p = 0.03) were independent predictors of pT2 disease (area [1] Marcq G, Foerster B, Abufaraj M, et al. Novel classification for upper
under the receiver operating characteristic curve of 0.77). tract urothelial carcinoma to better risk-stratify patients eligible for
kidney-sparing strategies: an international collaborative study. Eur
Thus, high-risk was defined as the presence of any of the Urol Focus 2022;8:491–7. https://doi.org/10.1016/j.euf.2021.03.018.
following characteristics: nOC disease, hydronephrosis, [2] Rouprêt M, Babjuk M, Burger M, et al. European Association of
high-grade biopsy, high-grade cytology, sessile architecture, Urology guidelines on upper urinary tract urothelial carcinoma:
or tumor larger than 2 cm. Intermediate-risk was defined as 2020 update. Eur Urol 2021;9:80–1. https://doi.org/10.1016/j.
eururo.2020.05.042.
multifocal, 2 cm, low-grade disease, and low-risk as unifo-
[3] Chen XP, Xiong GY, Li XS, et al. Predictive factors for worse
cal, 2 cm, low-grade disease without a history of prior rad- pathological outcomes of upper tract urothelial carcinoma:
ical cystectomy for bladder carcinoma. Overall, the experience from a nationwide high-volume centre in China. BJU Int
estimated probability of muscle-invasive UTUC was 0.16, 2013;112:917–24. https://doi.org/10.1111/bju.12238.
0.34, and 0.49 for the low-, intermediate-, and high-risk cat- [4] Mullerad M, Russo P, Golijanin D, et al. Bladder cancer as a
prognostic factor for upper tract transitional cell carcinoma. J Urol
egories, respectively. 2004;172:2177–81. https://doi.org/10.1097/01.
ju.0000144505.40915.98.
Chiara Lonati *
The 2020 European Association of Urology (EAU) guide- Nazareno Suardi
lines [2] dichotomize UTUC into two risk groups according
to demographic and preoperative characteristics, reserving Urology Unit, ASST Spedali Civili di Brescia, Department of Medical and
kidney-sparing strategies (KSS) only for low-risk and select Surgical Specialties, Radiological Science and Public Health, University of
high-risk groups with mandatory indications. Although this Brescia, Brescia, Italy
two-level classification is routinely applied in the decision-
* Corresponding author at: ASST Spedali Civili di Brescia, piazzale Spedali
making process, it has not yet been validated.
Civili 1, Brescia, Italy.
Starting from these premises, Marcq et al. [1] recom- E-mail address: [email protected] (C. Lonati).
mended a three-level risk-stratification algorithm for
patients with UTUC and evaluated a cohort of 1214 patients 0302-2838/Ó 2022 European Association of Urology. Published by
who underwent preoperative cross-sectional imaging, ure- Elsevier B.V. All rights reserved.
teroscopy, and subsequent radical nephroureterectomy at https://doi.org/10.1016/j.eururo.2022.07.031
21 tertiary international referral centers. According to uni-
variable and multivariable analyses, the authors enhanced
EUROPEAN UROLOGY 82 (2022) e135–e136
Letter to the Editor
Re: Heng Li, Yucong Zhang, Dong Li, et al. Androgen preclinical validation. EPR15656 was generated to detect
Receptor Splice Variant 7 Predicts Shorter Response in (and is sensitive for) AR-V7, and has been used for detecting
Patients with Metastatic Hormone-sensitive Prostate AR-V7 protein in circulating tumour cells as a biomarker in
Cancer Receiving Androgen Deprivation Therapy. Eur Urol CRPC stratification [3,4]. However, we have previously
2021;79:879–86 AR-V7 is Rare in Hormone-sensitive
reported that EPR15656 detects off-target epitopes in AR-
Prostate Cancer
negative prostate cancer cells [5,10]. Thus, in response to
AR-V7 is Rare in Hormone-sensitive Prostate Cancer the findings by Li and colleagues and the potential clinical
implications, we performed an extensive analytical and
Expression of androgen receptor splice variant 7 (AR-V7), functional validation of these two AR-V7 antibodies
which lacks a canonical ligand-binding domain, is strongly (EPR15656 and RM7) for use in CSPC, with direct compar-
associated with resistance to endocrine therapies in ison to isoform-specific and splice junction–sensitive tran-
patients with metastatic castration-resistant prostate can- scriptome sequencing [11].
cer (CRPC) [1,2]. Therefore, positive detection of AR-V7 We found that EPR15656 was sensitive but not specific
has been nominated as a potential predictive biomarker for AR-V7, whereas the RM7 antibody clone was specific
for patient stratification to select AR-V7-positive patients for AR-V7. When assaying antibody specificity in CSPC, we
for treatment with taxane chemotherapy rather than fur- used splice junction–sensitive RNA-sequencing—specifi-
ther AR-targeting therapies [3,4]. Detection of AR-V7, as cally, mapping of sequence reads across the AR-V7 alterna-
well as its qualification as a biomarker, has frequently relied tive splice junctions—for determining whether a tumour
on antibody-based approaches for detection of AR-V7 pro- sample was positive or negative for AR-V7 expression. This
tein, but RNA-based methods (including isoform-sensitive approach demonstrated that AR-V7 mRNA expression is rare
reverse transcription polymerase chain reaction, in situ (if not absent) in the vast majority of CSPCs. Importantly, we
hybridisation, and splice-sensitive transcriptome sequenc- also found that methods that merely quantify the presence
ing) have also been used for quantifying transcript isoform of the AR-V7 cryptic exon, and not its splicing, overcall the
abundance [1–6]. Not surprisingly, the specific methods abundance of AR-V7. In CRPC, RM7 staining positively corre-
used for determining AR-V7 expression greatly impact find- lated with AR-V7 splice junction–positive mRNA abundance,
ings and remain an important consideration of any study. but both RM7 staining and AR-V7 mRNA were largely absent
We read with great interest the report by Li and col- in CSPC. Furthermore, in patients with CSPC who were trea-
leagues [7] in which the authors report that 64 out of 310 ted with neoadjuvant intense androgen deprivation ther-
patients with metastatic castration-sensitive prostate can- apy, this therapy did not immediately lead to substantial
cer (CSPC) demonstrated positive AR-V7 immunohisto- AR-V7 detectable at the RNA or protein level in post-treat-
chemical staining on diagnostic CSPC biopsies using clone ment prostate cancer tissue, and although there was a range
EPR15656 from Abcam. This contrasts with our own studies, of clinical outcomes, no patient had detectable AR-V7 at
using an alternative antibody (clone RM7 from RevMAb), baseline [11].
which demonstrated that <1% of CSPC samples had detect- Overall, our validation study does not support the use of
able AR-V7 [5]. Moreover, the authors reported that the EPR15656 antibody clone for AR-V7 detection in CSPC
patients with AR-V7-positive tumours had significantly and indicates that AR-V7 positivity, via both the RNA- and
shorter progression-free and overall survival, consistent antibody-based assays explored in these studies, has little
with their earlier studies [7,8]. If this were to be confirmed, utility as a predictive biomarker in CSPC. The contrast
it would have important clinical implications, supporting between these and other studies highlights the critical nat-
interrogation of AR-V7 positivity as a predictive biomarker ure of robust laboratory and clinical validation of predictive
in advanced CSPC, a setting in which doublet and triplet biomarkers before attempting patient stratification. As
therapy has now improved patient outcomes [9]. However, technologies rapidly evolve, if AR-V7 protein is sensitively
it is important to note that the study used a single antibody and specifically identified in CSPC, it will be important not
to detect AR-V7 (clone EPR15656) with limited analytical or only to analytically validate and clinically qualify these
0302-2838/Published by Elsevier B.V. on behalf of European Association of Urology.
e136 EUROPEAN UROLOGY 82 (2022) e135–e136
assays rigorously but also to understand the functional therapy resistance in high-risk castration-resistant prostate cancer:
the PROPHECY study. J Clin Oncol 2019;37:1120–9.
importance of AR-V7 in CSPC; AR-V7 in CRPC is believed
[2] Antonarakis ES, Lu C, Luber B, et al. Clinical significance of androgen
to drive resistance to AR-targeting therapies, and the major- receptor splice variant-7 mRNA detection in circulating tumor cells
ity of patients with CSPC initially respond to endocrine of men with metastatic castration-resistant prostate cancer treated
therapies. with first- and second-line abiraterone and enzalutamide. J Clin
Oncol 2017;35:2149–56.
[3] Scher HI, Graf RP, Schreiber NA, et al. Assessment of the validity of
Conflicts of interest: Johan S. de Bono has served on advisory boards and nuclear-localized androgen receptor splice variant 7 in circulating
received fees from many companies, including Amgen, AstraZeneca, tumor cells as a predictive biomarker for castration-resistant
Astellas, Bayer, Bioxcel Therapeutics, Boehringer Ingelheim, Cellcentric, prostate cancer. JAMA Oncol 2018;4:1179–86.
Daiichi, Eisai, Genentech/Roche, Genmab, GSK, Harpoon, ImCheck Ther- [4] Graf RP, Hullings M, Barnett ES, Carbone E, Dittamore R, Scher HI.
Clinical utility of the nuclear-localized AR-V7 biomarker in
apeutics, Janssen, Merck Serono, Merck Sharp & Dohme, Menarini/Silicon
circulating tumor cells in improving physician treatment choice in
Biosystems, Orion, Pfizer, Qiagen, Sanofi Aventis, Sierra Oncology, Taiho, castration-resistant prostate cancer. Eur Urol 2020;77:170–7.
Terumo, and Vertex Pharmaceuticals; is an employee of the Institute of [5] Sharp A, Coleman I, Yuan W, et al. Androgen receptor splice variant-
Cancer Research, which has received funding or other support for his 7 expression emerges with castration resistance in prostate cancer.
J Clin Invest 2019;129:192–208.
research work from AstraZeneca, Astellas, Bayer, Cellcentric, Daiichi,
[6] Zhu Y, Sharp A, Anderson CM, et al. Novel junction-specific and
Genentech, Genmab, GSK, Janssen, Merck Serono, MSD, Menarini/Silicon quantifiable in situ detection of AR-V7 and its clinical correlates in
Biosystems, Orion, Sanofi Aventis, Sierra Oncology, Taiho, Pfizer, and metastatic castration-resistant prostate cancer. Eur Urol
Vertex, and which has a commercial interest in abiraterone, PARP inhibi- 2018;73:727–35.
tion in DNA repair defective cancers, and PI3K/AKT pathway inhibitors [7] Li H, Zhang Y, Li D, et al. Androgen receptor splice variant 7 predicts
shorter response in patients with metastatic hormone-sensitive
(no personal income); is named as an inventor, with no financial interest,
prostate cancer receiving androgen deprivation therapy. Eur Urol
for patent 8,822,438 submitted by Janssen, which covers the use of abi- 2021;79:879–86.
raterone acetate with corticosteroids; and has been the Chief Investiga- [8] Li H, Wang Z, Xiao W, et al. Androgen-receptor splice variant-7-
tor/Principal Investigator of many industry-sponsored clinical trials. positive prostate cancer: a novel molecular subtype with markedly
worse androgen-deprivation therapy outcomes in newly diagnosed
Adam Sharp is an employee of the Institute of Cancer Research, which
patients. Mod Pathol 2018;31:198–208.
has a commercial interest in abiraterone, PARP inhibition in DNA repair [9] Davis ID. Combination therapy in metastatic hormone-sensitive
defective cancers, and PI3K/AKT pathway inhibitors (no personal prostate cancer: is three a crowd? Ther Adv Med Oncol
income); has received travel support from Sanofi and Roche-Genentech 2022;14:17588359221086827.
and speaker honoraria from Astellas Pharma; has served as an advisor to [10] Welti J, Nava Rodrigues D, Sharp A, et al. Analytical validation and
clinical qualification of a new immunohistochemical assay for
DE Research; and has been the Chief Investigator/Principal Investigator
androgen receptor splice variant-7 protein expression in metastatic
of industry-sponsored clinical trials. The remaining authors have noth- castration-resistant prostate cancer. Eur Urol 2016;70:599–608.
ing to disclose. [11] Sowalsky AG, Figueiredo I, Lis RT, et al. Assessment of androgen
receptor splice variant-7 as a biomarker of clinical response in
castration-sensitive prostate cancer. Clin Cancer Res 2022;28:
Acknowledgments: This work was supported by Prostate Cancer UK 3509–25.
(Research Funding to J.S. de Bono), the Prostate Cancer Foundation (Young
Investigator Award to A. Sharp; Challenge Awards to J.S. de Bono and A. Adam G. Sowalsky a,*
Stephen R. Plymate b,c
Sharp), the Intramural Research Program of the NIH, the National Cancer
Michael C. Haffner b,d
Institute, the Movember Foundation through the London Movember Cen- Johann S. de Bono e,f
tre of Excellence (CEO13 2-002 to J.S. de Bono), the Congressionally Direc- Adam Sharp e,f
ted Medical Research Program Prostate Cancer Research Program
a
(Translational Science Award to S.R. Plymate), the Wellcome Trust (Clin- Center for Cancer Research, National Cancer Institute, National Institutes of
ical Research Career Development Fellowship to A. Sharp), the NIHR Health, Bethesda, MD, USA
b
University of Washington, Seattle, WA, USA
Biomedical Research Centre, Cancer Research UK (Centre Programme c
Geriatrics Research, Education and Clinical Center, VAPSHCS,
and Experimental Cancer Medicine Centre grants to J.S. de Bono), the
Seattle, WA, USA
UK Department of Health, Biomedical Research Centre funding to the d
Fred Hutchinson Cancer Research Center, Seattle, WA, USA
e
Royal Marsden, the Doris Duke Charitable Foundation (Clinical Scientist Institute of Cancer Research, London, UK
f
Development Award to M.C. Haffner), the V Foundation (V Scholar Grant Royal Marsden NHS Foundation Trust, London, UK
to M.C. Haffner), the Veterans Affairs Research and Development Service
*Corresponding author. National Cancer Institute, 37 Convent Drive,
(VA BLRD 2101BX003324 to S.R. Plymate), and the Lopker Family Founda-
Bethesda, MD 20892, USA. Tel. +1 240 7607118.
tion (to S.R. Plymate). E-mail address: [email protected] (A.G. Sowalsky).
References June 25, 2022
[1] Armstrong AJ, Halabi S, Luo J, et al. Prospective multicenter

validation of androgen receptor splice variant 7 and hormone
Reply to Adam G. Sowalsky, Stephen R. Plymate, Michael C. results may also bring bias in the judgment of AR-V7 posi-
Haffner, Johann S. de Bono, and Adam Sharp’s Letter to the tive staining. The prognostic value of AR-V7 detection via
Editor re: Heng Li, Yucong Zhang, Dong Li, et al. Androgen IHC using different antibodies indeed needs further valida-
Receptor Splice Variant 7 Predicts Shorter Response in tion. As mentioned by the authors in their letter ‘‘As tech-
Patients with Metastatic Hormone-sensitive Prostate nologies rapidly evolve, if AR-V7 protein is sensitively and
Cancer Receiving Androgen Deprivation Therapy. Eur Urol specifically identified in CSPC [castration-sensitive prostate
2021;79:879–86: AR-V7 is Rare in Hormone-sensitive cancer], it will be important not only to analytically validate
Prostate Cancer and clinically qualify these assays rigorously but also to
understand the functional importance of AR-V7 in CSPC’’.
We read with concern the letter on with our article regard-
ing androgen receptor splice variant 7 (AR-V7) in patients Conflicts of interest: The authors have nothing to disclose.
with metastatic hormone-sensitive prostate cancer
(mHSPC) [1]. Sowalsky and colleagues carried out excellent References
work in characterizing the AR-V7 antibody RM7. They con-
[1] Li H, Zhang Y, Li D, et al. Androgen receptor splice variant 7 predicts
firmed the specificity of RM7 for detection of AR-V7 protein
shorter response in patients with metastatic hormone-sensitive
on immunohistochemical (IHC) staining and concluded that prostate cancer receiving androgen deprivation therapy. Eur Urol
AR-V7 is rare in HSPC. 2021;79:879–86.
To validate the accuracy of the AR-V7 antibody [2] Sharp A, Coleman I, Yuan W, et al. Androgen receptor splice variant-7
(EPR15656, ab198394) used in our study, we performed expression emerges with castration resistance in prostate cancer. J
Clin Invest 2019;129:192–208.
western blot, polymerase chain reaction, and RNA in situ [3] Welti J, Rodrigues DN, Sharp A, et al. Analytical validation and
hybridization assays. We also conducted IHC using RM7 clinical qualification of a new immunohistochemical assay for
on 12 prostate cancer tissue samples from patients with androgen receptor splice variant-7 protein expression in metastatic
mHSPC, and found no significant difference in IHC results castration-resistant prostate cancer. Eur Urol 2016;70:599–608.
[4] Kallio HML, Hieta R, Latonen L, et al. Constitutively active androgen
between EPR15656 and RM7. Our study found an AR-V7
receptor splice variants AR-V3, AR-V7 and AR-V9 are co-expressed in
positivity rate of approximately about 21% in our mHSPC castration-resistant prostate cancer metastases. Br J Cancer
cohort via IHC using EPR15656. We also found that AR-V7 2018;119:347–56.
expression in mHSPC is highly correlated with poor progno- [5] Qu Y, Dai B, Ye D, et al. Constitutively active AR-V7 plays an essential
sis and response after androgen deprivation therapy. role in the development and progression of castration-resistant
prostate cancer. Sci Rep 2015;5:7654.
As mentioned by the authors, previous studies indeed [6] Kaczorowski A, Chen X, Herpel E, et al. Antibody selection influences
reported that the IHC AR-V7 positivity rate in HSPC was rel- the detection of AR-V7 in primary prostate cancer. Cancer Treat Res
atively lower [2,3]. However, other studies have reported Commun 2020;24:100186.
relatively high AR-V7 positivity rates in mHSPC [4,5]. There [7] Li H, Wang Z, Xiao W, et al. Androgen-receptor splice variant-7-
positive prostate cancer: a novel molecular subtype with markedly
is substantial discrepancy in the frequency of AR-V7 posi-
worse androgen-deprivation therapy outcomes in newly diagnosed
tivity in HSPC detected via IHC, ranging from 1.6% to patients. Mod Pathol 2018;31:198–208.
91.8% [2–7]. Even for the same antibody, the AR-V7 positiv-
ity rates for patients with nonmetastatic HSPC in the three Heng Li a,b
studies were 1.6%, 21%, and 91.8% [2,4,6]. Among patients Yucong Zhang c
with mHSPC, the AR-V7 positivity rate was 21.2% using Hua Xu d,e,*
AG10008 [5] and 22% using ab198394 [7] for IHC, similar a
Department of Urology, Tongji Hospital of Tongji Medical College, Huazhong
to the rate for our data.
University of Science and Technology, Wuhan, China
In conclusion, AR-V7 positivity rates in mHSPC detected b
Institute of Urology of Hubei Province, Wuhan, China
on IHC vary for different populations, such as different races c
Department of Geriatrics, Tongji Hospital of Tongji Medical College,
and tumor stages. Different criteria for determining IHC Huazhong University of Science and Technology, Wuhan, China
d
Cancer Precision Diagnosis and Treatment and Translational Medicine Hubei
Engineering Research Center, Wuhan, China
e
Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan,
China
*Corresponding author. Department of Urology, Zhongnan Hospital of

Wuhan University, 169 Donghu Rd, Wuchang District, 430071 Wuhan,
China.
E-mail address: [email protected] (H. Xu).
August 10, 2022

Reply to Andreas Skolarikos’s Words of Wisdom re: Effect the 20 secondary outcomes. This is new information and
of Robot-assisted Radical Cystectomy with Intracorporeal new evidence that was not known beforehand and will lead
Urinary Diversion vs Open Radical Cystectomy on 90-Day to further research in this field.
Morbidity and Mortality Among Patients with Bladder 3. Finally, regarding the primary outcome, we agree that days
Cancer: A Randomized Clinical Trial. Eur Urol. In press alive out of hospital is a qualitative measure of recovery.
However, this as an objective measure that captures both
We write in response to the Words of Wisdom from Dr. patient recovery (including pain control, mobilization,
Skolraikos [1] regarding our report on the iROC (intracorpo- return to diet, and stoma management) and any significant
real robot assisted radical cystectomy versus open radical complications within 90 d of surgery. As most patients expe-
cystectomy) trial [2]. We thank the author for covering rience one or more complication after radical cystectomy,
our study and welcome the comments. Scientific discourse and those that are severe usually lead to delayed discharge
is one of the strengths of modern medicine. To correct the or readmission, length of stay and rates of severe complica-
debate, we would like to address a few of the points raised. tions and readmission have been suggested as metrics for
determining surgical quality [6] and are included in data
Dr. Skolarikos states that our primary outcome was
on patient-facing surgeon outcomes [7]. The 2-d difference
informed by ‘‘the lack of high-powered RCTs [randomized
represents a 20% relative reduction in hospital bed usage
controlled trials] on oncological outcomes’’. We politely dis-
and is equivalent to other transformational changes in the
agree. We believe that there are sufficient high-quality data
practice of modern surgery such as laparoscopy for colorec-
to show equivalence between the cancer outcomes [3].
tal cancer [8] and maintaining normothermia during surgery
Given that the surgery is performing the same exenteration, [9]. We believe that the better quality of recovery is valued
then differences would only arise through one approach by patients (less pain, less disability, and shorter hospital
having higher margin-positive rates, less complete lym- stays), clinical staff (fewer complication and faster recovery),
phadenectomies, or spillage of material (and peritoneal or and purchasers (less resource usage, lower total cost of care)
port-site recurrences). While early learning curve data did given the frequency and impact of complications and
question differences, recent RCTs and a meta-analysis have readmissions on the patient experience and health care
failed to show any difference [4,5]. We consider the RAZOR costs [10].
(robot-assisted radical cystectomy versus open radical cys-
tectomy in patients with bladder cancer) trial to be of high
quality and sufficiently powered for this outcome.
Dr. Skolarikos also states, ‘‘We believe that we should
carefully evaluate the outcome of this study, as in our opin-
ion, it was underpowered, adds no new evidence, and more References
importantly, the primary outcome is clinically insignifi-
[1] Skolarikos A. Re: Effect of robot-assisted radical cystectomy with
cant’’. There are three components to this statement, which intracorporeal urinary diversion vs open radical cystectomy on 90-
should be addressed separately. day morbidity and mortality among patients with bladder cancer: a
randomized clinical trial. Eur Urol. https://doi.org/10.1016/j.eururo.
1. First, the study was not underpowered. Before opening, we 2022.07.010.
calculated a sample size using national data. We recruited [2] Catto JWF, Khetrapal P, Ricciardi F, et al. Effect of robot-assisted
radical cystectomy with intracorporeal urinary diversion vs open
to this size and our analyses reached significance using a
radical cystectomy on 90-day morbidity and mortality among
predefined analytical plan. Therefore, the study was suffi- patients with bladder cancer: a randomized clinical trial. JAMA
ciently powered for our primary outcome. 2022;327:2092–103.
2. Second, this study is the first large multicentre prospective [3] Yuh B, Wilson T, Bochner B, et al. Systematic review and cumulative
RCT to show a benefit from robotic surgery (regardless of analysis of oncologic and functional outcomes after robot-assisted
the operation). We highlight the lower disability and supe- radical cystectomy. Eur Urol 2015;67:402–22.
[4] Parekh DJ, Reis IM, Castle EP, et al. Robot-assisted radical
rior recovery metrics, and that these disappear with time.
cystectomy versus open radical cystectomy in patients with
Differences favoring robot-assisted radical cystectomy with bladder cancer (RAZOR): an open-label, randomised, phase 3, non-
intracorporeal urinary diversion were seen for nearly all of inferiority trial. Lancet 2018;391:2525–36.
[5] Khetrapal P, Conroy S, Kelly JD, Catto JWF. Comparing open-radical

James W.F. Catto a,b,c,*
cystectomy and robot-assisted radical cystectomy: current status
Pramit Khetrapal c
and analysis of the evidence. Curr Opin Urol 2020;30:400–6.
Gareth Ambler d
[6] Tan WS, Leow JJ, Marchese M, et al. Defining factors associated with
high-quality surgery following radical cystectomy: analysis of the Norman R. Williams e
British Association of Urological Surgeons cystectomy audit. Eur Chris Brew-Graves f
Urol Open Sci 2021;33:1–10. John D. Kelly c
[7] Jefferies ER, Cresswell J, McGrath JS, et al. Open radical cystectomy
a
in England: the current standard of care – an analysis of the British Department of Oncology and Metabolism, University of Sheffield, Sheffield
Association of Urological Surgeons (BAUS) cystectomy audit and S10 2RX, UK
b
Hospital Episodes Statistics (HES) data. BJU Int 2018;121:880–5. Department of Urology, Sheffield Teaching Hospitals NHS Foundation Trust,
[8] Guillou PJ, Quirke P, Thorpe H, et al. Short-term endpoints of Sheffield, UK
conventional versus laparoscopic-assisted surgery in patients with c
Division of Surgery and Interventional Science, University College London,
colorectal cancer (MRC CLASICC trial): multicentre, randomised London, UK
controlled trial. Lancet 2005;365:1718–26. d
Department of Statistical Science, University College London, London, UK
[9] Kurz A, Sessler DI, Lenhardt R. Perioperative normothermia to e
Surgical and Interventional Trials Unit, Division of Surgery and Interventional
reduce the incidence of surgical-wound infection and shorten Science, University College London, London, UK
hospitalization. Study of Wound Infection and Temperature f
National Cancer Imaging Translational Accelerator, Division of Medicine,
Group. N Engl J Med 1996;334:1209–15.
University College London, London, UK
[10] Leow JJ, Cole AP, Seisen T, et al. Variations in the costs of radical
cystectomy for bladder cancer in the USA. Eur Urol
*Corresponding author. Department of Oncology and Metabolism, The
2018;73:374–82.
Medical School, University of Sheffield, Beech Hill Road, Sheffield S10
2RX, UK. Tel. +44 114 2261229; Fax: +44 114 2712268.
E-mail address: [email protected] (J.W.F. Catto).
July 25, 2022

Reply to Yuxuan Song, Yiqing Du, and Tao Xu’s Letter to germline alterations. We noted the lack of germline
the Editor re: Matthew Mossanen, Filipe L.F. Carvalho, sequencing as a limitation in the text [1], and we agree that
Vinayak Muralidhar, et al. Genomic Features of Muscle- future studies, especially prospective sequencing efforts,
invasive Bladder Cancer Arising After Prostate should strive to include matched germline and somatic
Radiotherapy. Eur Urol 2022;81:466–73 sequencing whenever possible.
Third, Song et al suggest application of an updated muta-
We thank Dr. Song and colleagues for their interest in our tional signature calling tool. Performing mutational signa-
work and for highlighting several unique aspects of the ture analysis from tumor exomes without matched
study and its findings. In the study, we performed whole- germline sequencing is challenging, so we used two differ-
exome sequencing of 22 muscle-invasive bladder cancers ent validated tools for mutational signature analysis (Signal
(MIBCs) from 19 patients who had previously received [7] and SigMA [8]). Reassuringly, both tools identified sim-
radiotherapy for prostate cancer [1]. We compared the ilar signatures in the cohort, and the signatures identified
genomic features of these radiation-associated MIBCs include those previously shown to be active in bladder can-
(RA-MIBCs) with features of non–radiation-associated cer, including APOBEC signatures (COSMIC v2 signatures 2
MIBCs and found both common features, such as a similar and 13) and age-related signatures (COSMIC v2 signatures
frequency of alterations in known BC driver genes, and 1 and 5). We chose to apply COSMIC v2 rather than COSMIC
some interesting differences, such as a higher frequency of v3 signatures because COSMIC v2 includes the most com-
short insertions and deletions (indels) in the RA-MIBC mon and best-characterized signatures, which we felt was
cohort. Higher indel frequency has also been identified in important given that we were working with tumor-only
other tumor types after radiation [2–4], and together these exome data. We agree that current and future data sets with
findings suggest that short indels are a common mutational matched germline and somatic whole-exome or genome
outcome following therapeutic radiation. data can be analyzed using expanded libraries of mutational
Dr. Song and colleagues raise several important consid- signatures such as COSMIC v3.
erations relevant to the interpretation of data from this Fourth, Dr. Song and colleagues note the interesting
and other clinical sequencing studies. First, they note that cases in which multiple tumor samples from the same
two of the 19 patients received neoadjuvant chemotherapy patient were sequenced. In one of these two cases, we iden-
before radical cystectomy. We agree this is an important tified shared driver alterations among the one MIBC and
detail and therefore noted this point in Table 1, Figure 1, two non-MIBC (NMIBC) tumor specimens, suggesting a
and the text [1]. Our group and others have analyzed shared common ancestor. However, in the second case,
whole-exome data from patient-matched tumor samples the MIBC and NMIBC tumor specimens showed no muta-
from before and after cisplatin-based chemotherapy and tional overlap, suggesting clonally independent tumors.
identified a significant proportion of chemotherapy- We agree with the authors that intraluminal seeding is a
induced subclonal mutations [5,6]. Because exome sequenc- possible mechanism for the development of multifocal clon-
ing was performed on the postchemotherapy radical ally related bladder tumors and that field carcinogenesis (ie,
cystectomy specimen in both cases, mutations identified cancer field effect) could lead to the development of sepa-
in these tumors reflect a contribution from chemotherapy- rate clonally unrelated tumors.
induced genomic evolution. In summary, we again thank Dr. Song and colleagues for
Second, Dr. Song and colleagues note that whereas two their interest in our work. We hope that our study can serve
of the five tumors with a homologous recombination as a basis for additional clinical and preclinical studies that
deficiency (HRD) mutation signature (COSMIC signature 3) are needed to further define the impact of previous radia-
harbored a BRCA1/2 alteration, the other three tumors tion exposure on tumorigenesis, clonality, tumor evolution,
lacked an obvious HRD gene defect. Although some germ- and therapy response in BC.
line alterations in genes such as BRCA1/2 may be identifiable
from tumor-only exome data, we agree with the authors
that matched sequencing of germline and tumor samples Conflicts of interest: Filipe L.F. Carvalho has nothing to disclose. Matthew
provides the greatest power for confident identification of Mossanen reports writing/editor fees from the Elsevier Practice Update
Bladder Cancer Center of Excellence. Eliezer M. Van Allen reports [6] Faltas BM, Prandi D, Tagawa ST, et al. Clonal evolution of
advisory/consulting activities for Tango Therapeutics, Genome Medical, chemotherapy-resistant urothelial carcinoma. Nat Genet
2016;48:1490–9.
Invitae, Enara Bio, Janssen, Manifold Bio, and Monte Rosa; research sup-
[7] Degasperi A, Dias Amarante T, Czarnecki J, et al. A practical
port from Novartis and BMS; equity in Tango Therapeutics, Genome Med- framework and online tool for mutational signature analyses show
ical, Syapse, Enara Bio, Manifold Bio, Microsoft, and Monte Rosa; travel inter-tissue variation and driver dependencies. Nat Cancer
reimbursement from Roche/Genentech; and interest in institutional 2020;1:249–63.
patents on chromatin mutations and immunotherapy response and meth- [8] Gulhan DC, Lee JJ, Melloni GEM, Cortes-Ciriano I, Park PJ. Detecting
the mutational signature of homologous recombination deficiency in
ods for clinical interpretation. Kent W. Mouw reports advisory board
clinical samples. Nat Genet 2019;51:912–9.
membership for Pfizer and EMD Serono; institutional research support
from Pfizer; writing/editor fees from UpToDate; speaker fees from Filipe L.F. Carvalho a
OncLive; and interest in an institutional patent on mutational signatures Matthew Mossanen a
of DNA repair deficiency. None of these are directly related to this work. Eliezer M. Van Allen c
Kent W. Mouw b,*
References a
Division of Urologic Surgery, Brigham & Women’s Hospital, Harvard Medical
[1] Mossanen M, Carvalho FLF, Muralidhar V, et al. Genomic features of School, Boston, MA, USA
b
muscle-invasive bladder cancer arising after prostate radiotherapy. Department of Radiation Oncology, Dana-Farber Cancer Institute, Brigham &
Eur Urol 2022;81:466–73. Women’s Hospital, Harvard Medical School, Boston, MA, USA
c
[2] Behjati S, Gundem G, Wedge DC, et al. Mutational signatures of Department of Medical Oncology, Dana-Farber Cancer Institute, Brigham &
ionizing radiation in second malignancies. Nat Commun Women’s Hospital, Harvard Medical School, Boston, MA, USA
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with a deletion signature that contributes to poor outcomes in Cancer Institute, 450 Brookline Avenue, Boston, MA 02215, USA.
patients with cancer. Nat Genet 2021;53:1088–96. Tel. +1 617 5829356.
[4] Lee CL, Mowery YM, Daniel AR, et al. Mutational landscape in E-mail address: [email protected] (K.W. Mouw).
genetically engineered, carcinogen-induced, and radiation-induced
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EUROPEAN UROLOGY 82 (2022) e143
Re: Kathia De Man, Nick Van Laeken, Vanessa Schelfhout, Therefore, we humbly suggest that the nuclear medicine
et al. 18F-PSMA-11 Versus 68Ga-PSMA-11 Positron and radiology community should recommend the need for
Emission Tomography/Computed Tomography for Staging contrast-enhanced CT while performing PSMA PET for PCa
and Biochemical Recurrence of Prostate Cancer: A patients.
Prospective Double-blind Randomised Cross-over Trial.
Eur Urol. 2022;82:501–509
We read with interest the article by De Man et al. [1]
reporting on a comparison between 18F-PSMA-11 and References
68
Ga-PSMA-11 in selected patients with prostate cancer
[1] De Man K, Van Laeken N, Schelfhout V, et al. 18F-PSMA-1versus 68Ga-
(PCa). The authors should be commended for diligently PSMA-1positron emission tomography/computed tomography for
completing a study that reassures clinicians about the staging and biochemical recurrence of prostate cancer: a prospective
safety and diagnostic accuracy of both tracers. We under- double-blind randomised cross-over trial. Eur Urol. 2022;82:501–9.
stand that contrast-enhanced computed tomography (CT) [2] Sheikhbahaei S, Afshar-Oromieh A, Eiber M, et al. Pearls and pitfalls
in clinical interpretation of prostate-specific membrane antigen
was used in this study as a morphological imaging tech- (PSMA)-targeted PET imaging. Eur J Nucl Med Mol Imaging
nique. In particular, CT may play an important role in the 2017;44:2117–36.
evaluation of benign prostate-specific membrane antigen [3] Hofman MS, Hicks RJ, Maurer T, Eiber M. Prostate-specific membrane
(PSMA)-positive bone lesions, such as PSMA ligand uptake antigen PET: clinical utility in prostate cancer, normal patterns,
pearls, and pitfalls. Radiographics 2018;38:200–17.
in healing bone fractures, degenerative changes, and fibro-
[4] Rauscher I, Krönke M, König M, et al. Matched-pair comparison of
cartilage lesions [2,3]. This issue can be partly resolved by 68
Ga-PSMA-11 PET/CT and 18F-PSMA-1007 PET/CT: frequency of
recognizing the corresponding findings on CT (eg, fracture pitfalls and detection efficacy in biochemical recurrence after radical
line or osteophytes) [4]. Similarly, immunohistochemistry prostatectomy. J Nucl Med 2020;61:51–7.
staining has shown that PSMA expression is not exclusive
to PCa cells, as it can be recognized in inflammation and Francesco Montorsi
Giorgio Gandaglia *
neovasculature. Discrimination between suggestive and
Daniele Robesti
unspecific PSMA ligand uptake in lymph nodes may Federico Dehò
challenging as well, but the shape and configuration of Alberto Briganti
PSMA-positive lymph nodes on CT images (eg, oval vs round
edges or the presence of a fatty hilum) may be helpful [4]. Urological Research Institute, San Raffaele Scientific Institute,
Notwithstanding this, the issue of a higher rate of University Vita-Salute San Raffaele, Milan, Italy
ambiguous bone lesions with 18F-PSMA-11 remained than
*Corresponding author. Urological Research Institute, San Raffaele
with the 68Ga-PSMA-11 tracer. We believe that interpreting Scientific Institute, University Vita-Salute San Raffaele, Via Olgettina 58,
the biological nature of these lesions could be even more Milan 20132, Italy. Tel. +1 514 5501074; Fax: +39 02 26437286.
difficult in everyday clinical practice when a CT scan at E-mail address: [email protected] (G. Gandaglia).
the time of positron emission tomography (PET) is very
often performed without any iodine-based contrast for July 21, 2022
practical reasons and because of potential costs.
Re: Sabrina H. Rossi, Grant D. Stewart. Re: Clinical Conflicts of interest: The author is a consultant for GRAIL.
Validation of a Targeted Methylation-based Multi-cancer
Early Detection Test Using an Independent Validation Set. References
Eur Urol. 2022;82:442–443
[1] Rossi SH, Stewart GD. Re: Clinical validation of a targeted
methylation-based multi-cancer early detection test using an
independent validation set. Eur Urol. 2022;82:442–3.
Understanding and Misunderstanding Multicancer Early Detection [2] Ahlquist DA. Universal cancer screening: revolutionary, rational, and
realizable. NPJ Precis Oncol 2018;2:23.
[3] Hackshaw A, Cohen SS, Reichert H, et al. Estimating the population
health impact of a multi-cancer early detection genomic blood test
By suggesting in their Words of Wisdom that multicancer early detection
to complement existing screening in the US and UK. Br J Cancer
(MCED) tests are not useful for screening for genitourinary malignancies, 2021;125:1432–42.
Rossi and Stewart [1] fundamentally misconstrue the purpose and advan- [4] Croswell JM, Kramer BS, Kreimer AR, et al. Cumulative incidence of
tages of these tests. Focusing only on cancers of a single organ system false-positive results in repeated, multimodal cancer screening. Ann
misses the point of MCEDs, in part because patients do not get to choose Fam Med 2009;7:212–22.
[5] Klein EA, Richards D, Cohn A, et al. Clinical validation of a targeted
which cancers they get. Compared to tests that screen for individual can-
methylation-based multi-cancer early detection test using an
cers, the benefits of MCEDs accrue at a population level because they independent validation set. Ann Oncol 2021;32:1167–77.
make screening more efficient by aggregating cumulative prevalence [6] Beer T, McDonnell CH, Nadauld L, et al. A prespecified interim
across all cancer types, resulting in a significantly higher positive predic- analysis of the PATHFINDER study: performance of a multi-cancer
early detection test in support of clinical implementation. J Clin
tive value and a significant reduction in the number needed to screen to
Oncol 2021;39(15 Suppl):3070.
find one cancer, and providing a cost-effective approach to early detection [7] Liu MC, Oxnard GR, Klein EA, Swanton C, Seiden MV, CCGA
of low-incidence cancers [2]. Current screening tests are calibrated for Consortium. Sensitive and specific multi-cancer detection and
high sensitivity, with a population-level false-positive rate estimated at localization using methylation signatures in cell-free DNA. Ann
7.5% per year [3] and a cumulative 10-yr real-world false-positive rate Oncol 2020;31:745–59. https://doi.org/10.1016/j.
annonc.2020.02.011.
observed in the PLCO trial of 40% for women and 50% for men [4]. By con-
[8] Hubbell E, Clarke CA, Aravanis AM, Berg CD. Modeled reductions in
trast, MCEDs are designed for high specificity to minimize false positives, late-stage cancer with a multi-cancer early detection test. Cancer
which have consistently been observed to be <1% [5–7]. Furthermore, Epidemiol Biomarkers Prev 2021;30:460–8.
MCEDs are able to detect early-stage lethal cancers for which screening [9] Clarke CA, Hubbell E, Ofman JJ. Multi-cancer early detection: a new
paradigm for reducing cancer-specific and all-cause mortality.
is currently unavailable or recommended against, detecting, for example,
Cancer Cell 2021;39:447–8.
60% of stage I and II ovarian and pancreatic cancers that effectively cur-
rently have an early detection rate of 0% [4]. Modeling studies suggest Eric A. Klein *
that MCED use in the general population can reduce overall cancer mor-
tality by 26% [8]; a slight increase in false positives over the baseline rate Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland, OH, USA
with existing screening tests seems like a reasonable tradeoff, especially
in light of the fact that current screening modalities miss 70% of all newly *Glickman Urological and Kidney Institute, Cleveland Clinic, Cleveland,
OH, USA.
diagnosed cancers [9], including those of the kidney and bladder. Finally,
E-mail address: [email protected] (E.A. Klein).
it is important to note that MCED tests are intended as an adjunct to cur-
rent screening tests, with all of their benefits and downsides remaining in July 14, 2022
place.
Re: Logan G. Briggs, Chanan Reitblat, Paul A. Bain, et al. (4) RCTs must report the full protocol for the exercise pro-
Prehabilitation Exercise Before Urologic Cancer Surgery: gram (cadence or range of motion, resistance or load,
A Systematic and Interdisciplinary Review. Eur Urol sets, repetitions, and total volume of physical effort)
2022;81:157–67 and strategies for dealing with errors during urologic
cancer surgery (possible surgical errors and how to solve
Recommendations for Experiments on Prehabilitation Exer- them).
cise Programs for Health Optimization Before Cancer (5) RCTs should add an economic evaluation of the proposed
Surgeries intervention as a topic, as this discussion is increasingly
I read with great interest the article by Briggs et al. [1]. The needed.
(6) RCTs should assess the effect size in outcome compar-
authors conducted a systematic review of the therapeutic
isons between groups; a p value has no clinical relevance
validity and efficacy of prehabilitation exercise programs
[2].
before urologic cancer surgery with the aim of informing
(7) Systematic reviews of primary studies on prehabilitation
discussion on the best practices for future interventions.
exercise programs before urologic cancer surgery should
The study has significant clinical relevance and will gener-
add two summaries of the evaluations: one that includes
ate new experimental studies (eg, clinical trials) on exercise all the articles, and a second summary that only includes
before urologic cancer surgery. Therefore, I have some sug- articles clearly reporting ethics approval.
gestions for the authors and other researchers who will use
these findings as a basis for further studies. I congratulate the authors on their publication as it pro-
Unfortunately, some randomized controlled trials (RCTs) vides a focus for discussion on the role of prehabilitation
on prehabilitation exercise programs before urologic cancer exercise programs before urologic cancer surgery in opti-
surgery make serious mistakes, including the absence of an mizing outcomes for our patients.
ethics approval number, the absence of an assessment of
the effect size, and only partial descriptions of the exercise
intervention, among others. The international representa- Conflicts of interest: The author has nothing to disclose.
tiveness of the study by Briggs et al [1] provides an oppor-
tunity for alerting researchers who will test new References
interventions in RCTs or perform other systematic reviews
[1] Briggs LG, Reitblat C, Bain PA, et al. Prehabilitation exercise before
in the future on exercise before urologic cancer surgery. urologic cancer surgery: a systematic and interdisciplinary review.
Therefore, I suggest seven points that are relevant for RCTs Eur Urol 2022;81:157–67. https://doi.org/10.1016/j.
and/or systematic reviews on this theme; furthermore, I eururo.2021.05.015.
would encourage the authors (who are experts on this [2] Pontes-Silva A. Statistical significance does not show clinical
relevance: we need to go beyond the p-value. J Clin Exp Hepatol
topic) to list other items. 2022. https://doi.org/10.1016/j.jceh.2022.04.017, In press.
(1) RCTs must clearly detail the procedure performed so that André Pontes-Silva a,b,*
a
it can be reproduced and use the CONSORT checklist Physical Therapy Post-Graduate Program (Ph.D.), Physical Therapy Depart-
(which seems a redundant point, but this is often ment, Universidade Federal de São Carlos, São Carlos, SP, Brazil
b
forgotten). Adult Health Post-Graduate Program (M.Sc.), Biological and Health Sciences
Center, Universidade Federal do Maranhão, São Luís, MA, Brazil
(2) RCTs must describe the experience of the professionals
involved in the prehabilitation exercise program before
*Universidade Federal de São Carlos, Programa de Pós-Graduação em
urologic cancer surgery as well as those performing the Fisioterapia, Departamento de Fisioterapia, Rod. Washington Luis, Km
surgery. 235, CEP 13565-905, São Carlos, SP, Brazil. Phone: +5598991188848;
(3) RCTs must report the ethics approval number (for some Author’s Twitter: @_psandre.
reason, several studies did not report this). E-mail address: [email protected] (A. Pontes-Silva).
July 21, 2022
Re: Sarah P. Psutka, Roman Gulati, Michael A.S. Jewett, represent a complex and heterogenous cohort harboring
et al. A Clinical Decision Aid to Support Personalized pT1a up to pT3a RCC in final pathology. Unfortunately,
Treatment Selection for Patients with Clinical T1 Renal the current study does not allow further insight into this
Masses: Results from a Multi-institutional Competing- issue, as final pathological stage and predictors of tumor
risks Analysis. Eur Urol 2022;81:576–85 complexity such as RENAL score characterstics score are
not reported for nephrectomy patients.
Finally, since the median follow-up for the study
We read with great interest the article by Psutka et al
cohort was 5.2 yr and only 12.5% of patients had fol-
[1] on a decision aid for patients with cT1 renal cell car-
low-up exceeding 8.7 yr, the 10-yr survival estimates
cinoma (RCC). The authors developed a risk calculator
may be associated with a certain degree of uncertainty.
that is clinically easily applicable for predicting cancer-
Moreover, the authors state that nonsurgical treatment
specific mortality (CSM), other-cause mortality (OCM),
has been increasing in popularity in recent years. Thus,
and 90-d complication rates after partial (PN), radical
median follow-up is shorter for patients who received
nephrectomy (PN), focal therapy (TA), or active surveil-
nonsurgical treatment in their cohort, potentially under-
lance (AS).
estimating the risk of CSM in this group of patients. This
While the authors need to be congratulated for develop-
underestimation needs to be considered, especially for
ing a predictive model with such a large sample size, their
patients favoring nonsurgical treatment and long life
study has limitations not specifically addressed within their
expectancy [5].
article.
Taken together, the risk calculator provides clinicians
First, owing to the retrospective nature of the cohort,
with important estimates regarding OCM and complica-
there is a selection bias resulting from allocation of
tion rates on the basis of a patient’s individual risk pro-
patients with higher oncological risk to surgical treat-
file. However, the CSM estimates should be interpreted
ment and patients with higher risk of OCM to nonsurgi-
with caution.
cal treatment. For example, tumor size—a strong proxy
for CSM—was 4.6 cm for the RN, 3.0 cm for the PN,
2.5 cm for the TA, and 1.9 cm for the AS group [2]. Con- Conflicts of interest: The authors have nothing to disclose.
versely, the proportion of patients with (American Soci-
ety of Anesthesiologists score) of 3–4 increased from References
55% and 43% in the RN and PN groups to 70% in the
TA and AS groups. Consequently, the observation that [1] Psutka SP, Gulati R, Jewett MAS, et al. A clinical decision aid to
support personalized treatment selection for patients with clinical
patients undergoing nephrectomy had a higher risk of
T1 renal masses: results from a multi-institutional competing-risks
CSM and lower risk of OCM cannot be solely attributed analysis. Eur Urol 2022;81:576–87. https://doi.org/10.1016/j.
to the treatment type. It is more likely that the CSM eururo.2021.11.002.
and OCM risks observed are intrinsically determined by [2] Rosiello G, Pecoraro A, Luzzago S, et al. Prognostic factors in patients
tumor characteristics and comorbidities. Therefore, the with small renal masses: a comparison between <2 vs. 2.1–4 cm
renal cell carcinomas. Cancer Causes Control 2021;32:119–26.
clinical applicability of the model described by Psutka https://doi.org/10.1007/s10552-020-01364-3.
et al should be interpreted with caution. [3] Nocera L, Stolzenbach LF, Ruvolo CC, et al. Predicting the risk of pT3a
In fact, within the heterogeneous cohort of cT1 RCC stage in cT1 clear cell renal cell carcinoma. Eur J Surg Oncol
patients, efforts should be focussed on patient identifica- 2021;47:1187–90. https://doi.org/10.1016/j.ejso.2020.10.040.
[4] Nocera L, Collà Ruvolo C, Stolzenbach LF, et al. Tumor stage and
tion with unfavorable pathology of RCC. For example,
substage predict cancer-specific mortality after nephrectomy for
Nocera et al [3] developed a model to predict pT3a nonmetastatic renal cancer: histological subtype-specific validation.
RCC in cT1 patients, relying on patient and radiographic Eur Urol Focus 2022;8:182–90. https://doi.org/10.1016/j.euf.2021.
tumor characteristics. These parameters offer precise pre- 02.009.
diction of unfavorable RCC pathology and therefore CSM [5] Würnschimmel C, Collà Ruvolo C, Nocera L, et al. Race/Ethnicity
Determines Life Expectancy in Surgically Treated T1aN0M0 Renal
[4]. Especially for AS or TA patients, it is crucial to iden- Cell Carcinoma Patients. Eur Urol Focus. 2022 Jan;8(1):191–9.
tify individuals with non–organ-confined disease pT3 to https://doi.org/10.1016/j.euf.2021.02.004, Epub 2021 Feb 18 PMID:
avoid undertreatment. Patients with cT1 RCC obviously 33610487.
EUROPEAN UROLOGY 82 (2022) e146–e147 e147
Mike Wenzel *
Felix K-H. Chun
Andreas Becker
Department of Urology, University Hospital Frankfurt, Goethe University

Frankfurt am Main, Frankfurt, Germany
*Corresponding author. Department of Urology, Goethe University

Hospital Frankfurt, Frankfurt am Main, Germany. Tel. +49 69
630183147; Fax: +49 69 630180069.
E-mail address: [email protected] (M. Wenzel).
June 25, 2022

Re: Sophie Knipper, Mehrdad Mehdi Irai, Ricarda Simon, Conflicts of interest: The authors have nothing to disclose.
et al. Cohort Study of Oligorecurrent Prostate Cancer
Patients: Oncological Outcomes of Patients Treated with References
Salvage Lymph Node Dissection via Prostate-specific
Membrane Antigen-radioguided Surgery. Eur Urol. In [1] Knipper S, Irai MM, Simon R, et al. Cohort study of oligorecurrent
press. https://doi.org/10.1016/j.eururo.2022.05.031 prostate cancer patients: oncological outcomes of patients treated with
salvage lymph node dissection via prostate-specific membrane
antigen-radioguided surgery. Eur Urol 2022. 10.1016/j.eururo.2022.
05.031, In press.
We read with great interest the article by Knipper et al [1] [2] Rigatti P, Suardi N, Briganti A, et al. Pelvic/retroperitoneal salvage
reporting on the impact of prostate-specific membrane lymph node dissection for patients treated with radical prostatectomy
antigen (PSMA)-radioguided lymph node (LN) dissection with biochemical recurrence and nodal recurrence detected by
[11C]choline positron emission tomography/computed tomography.
in prostate cancer patients with node-only recurrent dis-
Eur Urol 2011;60:935–43. 10.1016/j.eururo.2011.07.060.
ease. We wholeheartedly commend the authors—who are [3] Suardi N, Briganti A, Gandaglia G, Fossati N, Montorsi F. Salvage lymph
recognized international leaders in the field of prostate can- node dissection for node-only recurrence of prostate cancer: ready for
cer surgery—for diligently completing an innovative study. prime time? Eur Urol 2017;71:693–4. 10.1016/j.eururo.2016.12.001.
[4] Montorsi F, Gandaglia G, Fossati N, et al. Robot-assisted salvage
At our institution, we were the first to report on the novel lymph node dissection for clinically recurrent prostate cancer. Eur
concept of salvage LN dissection for node-only recurring Urol 2017;72:432–8. 10.1016/j.eururo.2016.08.051.
prostate cancer [2–4]. We embraced this experience with [5] Fossati N, Suardi N, Gandaglia G, et al. Identifying the optimal
candidate for salvage lymph node dissection for nodal recurrence of
genuine enthusiasm, but our enthusiasm has been tem-
prostate cancer: results from a large, multi-institutional analysis. Eur
pered over the years [5,6]. Urol 2019;75:176–83. 10.1016/j.eururo.2018.09.009.
Knipper at al [1] suggest that PSMA-radioguided surgery [6] Bravi CA, Fossati N, Gandaglia G, et al. Long-term outcomes of
is able to optimize the removal of diseased LNs and we are in salvage lymph node dissection for nodal recurrence of prostate
cancer after radical prostatectomy: not as good as previously
total agreement with this. At the same time, results thought. Eur Urol 2020;78:661–9. 10.1016/j.eururo.2020.06.043.
described after radioguided surgery—with 2-yr biochemical- [7] Suardi N, Gandaglia G, Gallina A, et al. Long-term outcomes of salvage
and therapy-free survival of 32% (95% confidence interval lymph node dissection for clinically recurrent prostate cancer: results
[CI]: 27–38%) and 58% (95%CI: 52–65%), respectively [1]— of a single-institution series with a minimum follow-up of 5 years.
Eur Urol 2015;67:299–309. 10.1016/j.eururo.2014.02.011.
are not that different from what was previously reported
for salvage LN dissection without radioligand guidance [6]. Francesco Montorsi a
For instance, the 3-yr androgen deprivation therapy–free Carlo Andrea Bravi a,b,c,*
survival in our cohort was 53% (95%CI: 45–60%) [6]. Thus, Giorgio Gandaglia a
we believe that an important focus for future investigations Alexandre Mottrie b,c
Alberto Briganti a
should be whether the improved LN removal allowed by
imaging-guided surgery might eventually translate into an a
Division of Oncology/Unit of Urology, Urological Research Institute, IRCCS
oncological benefit for patients. Among other interesting Ospedale San Raffaele, Milan, Italy
b
findings, Knipper and colleagues [1] identified selection cri- ORSI Academy, Ghent, Belgium
c
Department of Urology, Onze-Lieve-Vrouwziekenhuis Hospital, Aalst,
teria to avoid operating on patients who will inevitably
Belgium
experience treatment failure shortly after surgery; we com-
pletely agree with the list proposed by the authors, as it is *Corresponding author. Division of Oncology/Unit of Urology, Urological
identical to what we found early on [5,7]. Unfortunately, Research Institute, IRCCS Ospedale San Raffaele, Via Olgettina 60, Milan,
Italy.
the results reported by Knipper et al [1] are still oncologi-
E-mail address: [email protected] (C.A. Bravi).
cally disappointing and today we suggest that whenever a
patient is considered a candidate for radioguided salvage July 26, 2022
LN dissection, it should be carefully explained to him that
he should receive adjuvant systemic therapy. In other words,
we are no longer convinced that delaying the start of hor-
monal therapy represents treatment success; rather, we
believe that the ultimate success is overall survival.
Re: Christian Fuglesang S. Jensen, Dana A. Ohl, Mikkel vage mTESE was performed immediately after failed MNP-
Fode, et al. Microdissection Testicular Sperm Extraction TESA, which differs from the 6-mo interval used in previous
Versus Multiple Needle-pass Percutaneous Testicular studies [4]. Others have also raised questions about the
Sperm Aspiration in Men with Nonobstructive safety of MNP-TSEA. In the study by Jensen and colleagues,
Azoospermia: A Randomized Clinical Trial. Eur Urol.
MNP-TESA was applied by pushing an 18-gauge needle
2022;82:377–384
through the testis in various directions with 50–100 passes.
While the procedure seems harmless, it actually causes
We read the research reported by Jensen and colleagues [1] great injuries to the testis, as the multiple passages in differ-
with great interest. The authors conducted the first prospec- ent directions macerate the tissue and cause extensive
tive clinical trial to compare microdissection testicular intratesticular bleeding. The damage caused by this proce-
sperm extraction (mTESE) with multiple needle-pass percu- dure has been observed clinically: in 11% of cases in which
taneous testicular sperm aspiration (MNP-TESA) in men sperm were present during the first diagnostic TESA proce-
with nonobstructive azoospermia (NOA) with the aim of dure, no sperm were found during a repeat procedure [5]. A
evaluating the sperm retrieval rate (SRR), complications, study on the rat testis showed that TESA led to high serum
and changes in reproductive hormones. A total of 100 par- antisperm antibody levels, an increase in germ cell apopto-
ticipants were randomly assigned in a 1:1 ratio to either sis, and drastic and irreversible alterations in the testis
mTESE or MNP-TESA. In contrast to MNP-TESA, the authors [6].
found that mTESE had a significantly higher SRR with a sta- Another limitation of this randomized controlled trial
tistically significant rate difference of 0.21. Nevertheless, no (RCT) is that perioperative antibiotics were used for only
complications occurred in the group undergoing MNP-TESA, the last 30 procedures. The effect of perioperative antibiotic
while hematomas, infections, and de novo testosterone use on sperm motility and sperm retrieval success remains
deficiency were found after mTESE. In addition, the authors unknown. The use of antibiotics for 7 d after surgery may be
observed a statistically significant negative effect on repro- more appropriate for this study because the initial 70
ductive hormone levels in the mTESE group in comparison patients were not given antibiotics perioperatively.
to MNP-TESA at 3 and 6 mo after surgery. This study by Jenson et al. is the first prospective RCT to
Overall, the trial design, strict inclusion and exclusion assess the SRR of mTESE in comparison to MNP-TESA for
criteria, and complete follow-up data deserve to be com- patients with NOA. The trial results are consistent with
mended. However, we have some questions regarding the guideline recommendations and provide important evi-
indications and safety of MNP-TESA. According to the dence for decision-making by clinicians. Owing to its higher
2021 European Association of Urology guidelines on men’s success rate, mTESE may be a better choice for patients with
sexual and reproductive health [2], TESA should not be con- NOA, and the safety of TESA remains to be further evalu-
sidered the treatment of choice for patients with NOA given ated, in addition to postoperative complications and effects
the lower probability of positive sperm retrieval compared on reproductive hormones.
to conventional TESE and mTESE. Several retrospective
studies have proved that the SRR is significantly lower with Conflicts of interest: The authors have nothing to disclose.
TESA than with mTESE [3]. Moreover, testicular damage
caused by MNP-TESA is another concern, although the neg- References
ative effect of MNP-TESA on reproductive hormones is
much less than that of mTESE. In their study, Jensen et al [1] Jensen CFS, Ohl DA, Fode M, et al. Microdissection testicular sperm
found that sperm retrieval was successful in only four of extraction versus multiple needle-pass percutaneous testicular
sperm aspiration in men with nonobstructive azoospermia: a
38 patients with salvage mTSES, which appears to be a randomized clinical trial. Eur Urol. 2022;82:377–84.
low success rate. In a previous retrospective study, salvage [2] Minhas S, Bettocchi C, Boeri L, et al. European Association of Urology
mTESE had a sperm retrieval success rate of 46.5% [4]. The guidelines on male sexual and reproductive health: 2021 update on
male infertility. Eur Urol 2021;80:603–20.
possible reasons for this discrepancy are the time interval
[3] Bernie AM, Mata DA, Ramasamy R, Schlegel PN. Comparison of
between salvage mTESE and primary surgery and the inju- microdissection testicular sperm extraction, conventional testicular
ries caused by MNP-TESA. In the study by Jensen et al, sal- sperm extraction, and testicular sperm aspiration for nonobstructive
azoospermia: a systematic review and meta-analysis. Fertil Steril

Bo Li a,y
2015;104:1099–1103.e1–3.
Chen Duan a,y
[4] Kalsi JS, Shah P, Thum Y, et al. Salvage micro-dissection testicular
Xiangyang Yao c
sperm extraction; outcome in men with non-obstructive azoospermia
with previous failed sperm retrievals. BJU Int 2015;116:460–5. Xiaoliang Wu a
[5] Jensen CF, Ohl DA, Hiner MR, et al. Multiple needle-pass Hua Xu b,c,*
percutaneous testicular sperm aspiration as first-line treatment in
a
azoospermic men. Andrology 2016;4:257–62. Department and Institute of Urology, Tongji Hospital, Tongji Medical College,
[6] Prithiviraj E, Suresh S, Manivannan M, Prakash S. Impact of sperm Huazhong University of Science and Technology, Wuhan, China
b
retrieval [corrected] on testis and epididymis: an experimental study Cancer Precision Diagnosis and Treatment and Translational Medicine, Hubei
using Wistar albino rats. Syst Biol Reprod Med 2013;59:261–9. Engineering Research Center, Wuhan, China
c
Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan,
China
y
These authors contributed equally to this work.
*Corresponding author at: Department of Urology, Zhongnan Hospital of

Wuhan University, 169 Donghu Road, Wuhan, Hubei 430071, China.
Tel. +86 139 71051016.
E-mail addresses: [email protected] (H. Xu).
July 25, 2022

Reply to Bo Li, Chen Duan, Xiangyang Yao, Xiaoliang Wu, follow-up with systematic assessment of symptoms of low
and Hua Xu’s Letter to the Editor re: Christian Fuglesang S. testosterone; however, this is relevant for all methods of
Jensen, Dana A. Ohl, Mikkel Fode, et al. Microdissection surgical sperm retrieval and not specifically for TESA.
Testicular Sperm Extraction Versus Multiple Needle-pass Li et al highlight the low salvage mTESE SRR (11%) after
Percutaneous Testicular Sperm Aspiration in Men with unsuccessful MNP TESA. This might be because of tissue
Nonobstructive Azoospermia: A Randomized Clinical Trial. damage and bleeding when proceeding directly from MNP
Eur Urol. 2022;82:377–384 TESA to salvage mTESE. We did not observe this phe-
nomenon and the SRR from salvage mTESE was similar to
We thank Li and colleagues for their interest in our publica- our previous study [3], in which salvage mTESE was per-
tion [1] and for their comments. formed months after MNP TESA.
The authors question the choice of multiple needle pass We find it unlikely that perioperative antibiotics would
(MNP) percutaneous testicular sperm aspiration (TESA) in have an impact on sperm retrieval. Even if this were the case,
our trial as the 2021 European Association of Urology guide- the randomized design would counter any potential effects
lines on men’s sexual and reproductive health [2] argue that on sperm retrieval success from mTESE and MNP TESA.
TESA in men with nonobstructive azoospermia (NOA) is MNP TESA resulted in a statistically significantly lower
obsolete given the better sperm retrieval rate (SRR) from SRR in comparison to mTESE, while mTESE seems to have
microdissection testicular sperm extraction (mTESE). First, a higher complication rate. As stated by Li et al, we hope
our randomized trial was designed before this publication that our randomized clinical trial will help in clinical deci-
and, more importantly, no randomized clinical trials have sion-making and in providing evidence-based information
demonstrated the superiority of mTESE compared to other for patients undergoing surgical sperm retrieval.
surgical sperm retrieval procedures. Existing observational
studies include heterogeneous study populations without
clear definition of NOA, and specific procedure techniques
vary. Thus, it is difficult to assess the relative advantages References
and disadvantages of various approaches. With no level 1 [1] Jensen CFS, Ohl DA, Fode M, et al. Microdissection testicular sperm
evidence for sperm retrieval success, the least invasive extraction versus multiple needle-pass percutaneous testicular
option seemed a logical choice. We used a modified TESA sperm aspiration in men with nonobstructive azoospermia: a
procedure in which an 18-gauge needle is used to perform randomized clinical trial. Eur Urol 2022;82:377–84.
[2] Minhas S, Bettocchi C, Boeri L, et al. European Association of Urology
MNPs targeting the entire testis. This was thought to
guidelines on male sexual and reproductive health: 2021 update on
increase the amount of tissue retrieved and increase the male infertility. Eur Urol 2021;80:603–20.
sampling area of the testis to better target focal patchy sper- [3] Jensen CF, Ohl DA, Hiner MR, et al. Multiple needle-pass
matogenesis and possibly achieve a higher SRR. percutaneous testicular sperm aspiration as first-line treatment in
Li et al express concern regarding possible testicular azoospermic men. Andrology 2016;4:257–62.
damage resulting from this approach and conclude that
Christian Fuglesang S. Jensen *
the safety of TESA should be further evaluated. They state
Mikkel Fode
that MNP TESA causes great injury to the testis. We are Jens Sønksen
not aware of any study that has demonstrated worse clini-
a
cal complications from TESA in comparison to other sperm Department of Urology, Copenhagen University Hospital-Herlev and Gentofte
retrieval techniques. Li et al point out that mTESE in our Hospital, Herlev, Denmark
b
study was associated with more complications and a statis- Department of Clinical Medicine, University of Copenhagen, Copenhagen,
Denmark
tically significant negative effect on reproductive hormones
compared to MNP TESA. Furthermore, in a previous study *Corresponding author. Department of Urology, Copenhagen University
using the same MNP TESA technique we observed a low Hospital-Herlev and Gentofte Hospital, Borgmester Ib Juuls Vej 23A, DK-
complication rate [3]. 2730 Herlev, Denmark. Tel. +45 61702355.
We agree that potential complications from surgical E-mail address: [email protected] (C.F.S. Jensen).
sperm retrieval deserve further evaluation, including longer
August 25, 2022
Corrigendum
Corrigendum to ‘‘The Role of Stereotactic Ablative Body

Radiotherapy in Renal Cell Carcinoma’’ [Eur Urol 2022]
Muhammad Ali a,b,*, Jennifer Mooi c, Nathan Lawrentschuk d,e,f, Rana R. McKay g,
Raquibul Hannan h, Simon S. Lo i, William A. Hall j, Shankar Siva a,b
a
Department of Radiation Oncology, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia; b Sir Peter MacCallum Department of Oncology,
The University of Melbourne, Melbourne, Victoria, Australia; c Department of Medical Oncology, Northern Health, Melbourne, Victoria, Australia; d Department
of Urology, Royal Melbourne Hospital, Melbourne, Victoria, Australia; e Department of Surgery, Peter MacCallum cancer Centre, Melbourne, Victoria, Australia;
f
Department of Surgery, The University of Melbourne, Melbourne, Victoria, Australia; g University of California, San Diego, CA, USA; h Department of Radiation
Oncology, UT Southwestern Medical Centre, Dallas, TX, USA; i Department of Radiation Oncology, University of Washington, Seattle, WA, USA; j Department of
Radiation Oncology, Medical College of Wisconsin, WI, USA
The authors regret that Section 3.9, paragraph, In a prospective phase II clinical trial, Tang et al. [35] evaluated the feasibility
and efficacy of definitive intent radiotherapy in 30 mRCC patients with fewer than six lesions. Feasibility was defined as com-
pletion of SABR with <7 d of unplanned break, and efficacy was defined as 1-yr PFS of 70%. Patients received SABR for all
lesions and were maintained off systemic therapy. While the efficacy objective was not met, at a median follow-up of
17.5 mo, the trial demonstrated impressive 1-yr PFS and systemic therapy–free survival of 64% and 82%, respectively, with
two grade 3 and one grade 4 (hyperglycaemia) adverse events should read as follows:
‘‘In a prospective phase II clinical trial, Tang et al. [35] evaluated the feasibility and efficacy of definitive intent radiother-
apy in 30 mRCC patients with fewer than six lesions. Feasibility was defined as completion of SABR with <7 d of unplanned
break. Patients received SABR for all lesions and were maintained off systemic therapy. At a median follow-up of 17.5 mo, the
trial demonstrated impressive 1-yr PFS and systemic therapy–free survival of 64% and 82%, respectively, with two grade 3
and one grade 4 (hyperglycaemia) adverse events’’
Table 1 row (Correa et al.) column (Dose (Gy)/fraction) should read 26/1, 30–40/3–5.
The authors would like to apologise for any inconvenience caused.

* Corresponding author. 305 Grattan Street, Melbourne, Victoria 3000, Australia. Tel. +6138 5597 749.
E-mail address: [email protected] (M. Ali).
e153
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EDITOR EMERITUS (1975–2005) EDITOR EMERITUS (2006–2013)

Claude Schulman, Belgium Francesco Montorsi, Italy

STATISTICAL EDITOR STATISTICAL ASSOCIATE EDITOR STATISTICAL ASSOCIATE EDITOR

SURGERY IN MOTION EDITOR IMAGING EDITOR WORDS OF WISDOM EDITOR

MEDICAL ONCOLOGY EDITOR RADIATION ONCOLOGY EDITOR

MANAGING EDITOR EDITORIAL OFFICE ASSISTANT COPY EDITOR

Hashim Ahmed, UK Jack Elder, USA Valeria Panebianco, Italy

The Platinum Hall of Fame is online only at http://www.sciencedirect.com/science/journal/03022838/82/5

Best Scientific Paper Prizes 2000 to the Present 2006

2012 F. Porpigalia, M. Manfredi, F. Mele, M. Cossu, E. Bollito, A. Veltri,

2018 F.K.-H. Chun, M. Graefen, A. Briganti, A. Gallina, J. Hopp,

European Urology 2011;59:823–831 2016

2022 Platinum Award Winners 2018

Reviewer of the Year 2008 September: Sabine Brookman-May (Germany)

2016 Reviewers of the Month July: Adam Weiner (USA)

Platinum Opinion A Plea for Economically Sustainable Evidence-based Guidelines 449

Reviews Epidemiology of Renal Cell Carcinoma: 2022 Update 529

Re: Development and Validation of the Metric-based Assessment of a Robotic 570

Re: Darolutamide and Survival in Metastatic, Hormone-sensitive Prostate Cancer 573

Reply to Adam G. Sowalsky, Stephen R. Plymate, Michael C. Haﬀner, Johann S. de e137

Congress Calendar Congress Calendar e153

A Plea for Economically Sustainable Evidence-based Guidelines

Prostate Cancer Detection Percentages of Repeat Biopsy in Patients

Article info Abstract

EUROPEAN UROLOGY 82 (2022) 452–457

Review – Education – Platinum Priority Paper – Editor’s Choice

The 2022 World Health Organization Classification of Tumours of the

Article info Abstract

Table 1 – ICD-O coding of tumours of the kidney

Table 3 – ICD-O coding of tumours of the testis

Review – Prostate Cancer – Platinum Priority Paper – Editor’s Choice

The 2022 World Health Organization Classification of Tumors of the

Article info Abstract

The current edition of the WHO presents a detailed discus-

3.2. Noninvasive urothelial papillary neoplasms

Table 3 – The 2022 WHO classification of urinary tract tumors

attempt to quantitate the amount of different components

3.4. Urine cytology

The fifth edition fully endorses the adoption of the Paris

Table 5 – The Paris System for Reporting Cytology

Rodolfo Montironi a,*, Alessia Cimadamore b

1. Introduction resolved, so the 5th edition will be useful to and appreciated

DOI of original articles: https://doi.org/10.1016/j.eururo.2022.07.002; https://doi.org/10.1016/j.eururo.2022.06.016;

is a great departure from the previous two editions and

5. PCa grading, patient information, and patient

References [8] Lopez-Beltran A, Cimadamore A, Blanca A, et al. Immune checkpoint

Platinum Priority – Review – Prostate Cancer

Local Failure Events in Prostate Cancer Treated with Radiotherapy: A

Article info Abstract

1. Introduction randomized trials have shown that increased local control

Table 1 – Summary of trials included in study (by treatment categories)

Platinum Priority – Editorial

The Deep Blue of Prostate Cancer Metastasis Evolution: The

David Chang a,b, Pierre Blanchard c, Shankar Siva a,b,*

DOI of original articles: https://doi.org/10.1016/j.eururo.2022.07.011

Platinum Priority – Prostate Cancer

Article info Abstract

Article history: Background: Fluorine-18 (18F)-labelled prostate-specific membrane antigen (PSMA)

* Corresponding author. Department of Medical Imaging, Nuclear Medicine, Ghent University

The primary endpoint was any-length Gleason 3 + 4. This is a conser-

Table 2 – Multivariable model coefficients for Gleason 3 + 4