•This ESMO CPG provides recommendations for diagnosis, staging, pathology, treatment and follow-up of penile cancer.•Algorithms for the management of primary penile tumours and inguinal lymph nodes are provided.•The author group encompasses a multidisciplinary group of experts from different institutions and countries in Europe.•Recommendations are based on available scientific data and the authors' collective expert opinion.•In clinical practice, all recommendations provided need to be discussed with patients in a shared decision-making approach. Penile cancer is a rare genital malignancy with an estimated global incidence of 36 068 new cases in 2020.1World Health OrganizationInternational Agency for Research on Cancer. Cancer today, 2022https://gco.iarc.fr/today/homeDate accessed: December 14, 2022Google Scholar In Western Europe and the United States, the age-adjusted incidence of penile cancer is 0.3-2.1 per 100 000.2Barnholtz-Sloan J.S. Maldonado J.L. Pow-sang J. et al.Incidence trends in primary malignant penile cancer.Urol Oncol. 2007; 25: 361-367Google Scholar Conversely, in countries where circumcision is routine practice due to religious or cultural reasons,3Bandini M. Ahmed M. Basile G. et al.A global approach to improving penile cancer care.Nat Rev Urol. 2022; 19: 231-239Google Scholar penile cancer is almost non-existent, whereas areas within South America, South Asia and Sub-Saharan Africa have the highest prevalence in the world (3-7 per 100 000 men).1World Health OrganizationInternational Agency for Research on Cancer. Cancer today, 2022https://gco.iarc.fr/today/homeDate accessed: December 14, 2022Google Scholar,4Christodoulidou M. Sahdev V. Houssein S. et al.Epidemiology of penile cancer.Curr Probl Cancer. 2015; 39: 126-136Google Scholar A number of aetiological factors have been linked with penile cancer and its geographical distribution. Among them, ethnicity, human papilloma virus (HPV), population age, social and cultural habits and prevalence of neonatal circumcision are the most important.3Bandini M. Ahmed M. Basile G. et al.A global approach to improving penile cancer care.Nat Rev Urol. 2022; 19: 231-239Google Scholar HPV infection has been reported in up to 50.8% [95% confidence interval (CI) 44.8% to 56.7%] of penile cancer cases and in up to 79.8% (95% CI 69.3% to 88.6%) of patients with penile intraepithelial neoplasia (PeIN).5Olesen T.B. Sand F.L. Rasmussen C.L. et al.Prevalence of human papillomavirus DNA and p16(INK4a) in penile cancer and penile intraepithelial neoplasia: a systematic review and meta-analysis.Lancet Oncol. 2019; 20: 145-158Google Scholar The predominant oncogenic HPV subtype in penile cancer is HPV 16, which is prevalent in up to 70% of HPV-positive penile cancers;6Backes D.M. Kurman R.J. Pimenta J.M. et al.Systematic review of human papillomavirus prevalence in invasive penile cancer.Cancer Causes Control. 2009; 20: 449-457Google Scholar other common HPV subtypes include HPV 6, 11, 18, 31 and 33.7Wendland E.M. Caierão J. Domingues C. et al.POP-Brazil study protocol: a nationwide cross-sectional evaluation of the prevalence and genotype distribution of human papillomavirus (HPV) in Brazil.BMJ Open. 2018; 8e021170Google Scholar Lichen sclerosus, a chronic inflammatory condition of unknown aetiology which mainly affects the anogenital area (85%-98%), has also been associated with the development of penile cancer. Lichen sclerosus is associated with up to 30% of penile cancer cases, and in particular those that are not HPV driven.8Perceau G. Derancourt C. Clavel C. et al.Lichen sclerosus is frequently present in penile squamous cell carcinomas but is not always associated with oncogenic human papillomavirus.Br J Dermatol. 2003; 148: 934-938Google Scholar,9Kravvas G. Shim T.N. Doiron P.R. et al.The diagnosis and management of male genital lichen sclerosus: a retrospective review of 301 patients.J Eur Acad Dermatol Venereol. 2018; 32: 91-95Google Scholar Other risk factors include smoking, poor penile hygiene and treatment with psoralen ultraviolet (UV)-A phototherapy (PUVA). The most common tumour affecting the penis is squamous-cell carcinoma (SCC). SCCs are predominantly exophytic lesions originating from the mucosal surface of the glans and inner prepuce as opposed to the keratinised skin of the penile shaft. Incisional or excisional biopsies of suspected penile cancer should be carried out to confirm a histological diagnosis. Penile cancer has an accepted stepwise lymphatic dissemination whereby it initially drains to the inguinal lymph nodes (LNs) followed by the pelvic LNs. A proposed algorithm for the diagnostic work-up of penile cancer is shown in Figure 1. Clinical assessment of the primary tumour should record the size, morphology and relationship to adjacent structures in order to plan penile-preserving surgery where possible. Lesions on the glans penis should be assessed for invasion into the distal corpus cavernosum. Where there is uncertainty, magnetic resonance imaging (MRI) or penile ultrasound (US) combined with an intracavernosal injection of prostaglandin E1 to induce an artificial erection can be helpful to stage the primary lesion.10Kirkham A. MRI of the penis.Br J Radiol. 2012; 85 (Spec No 1): S86-S93Google Scholar, 11Kayes O. Minhas S. Allen C. et al.The role of magnetic resonance imaging in the local staging of penile cancer.Eur Urol. 2007; 51 (discussion 1318-1319): 1313-1318Google Scholar, 12Bozzini G. Provenzano M. Romero Otero J. et al.Role of penile doppler US in the preoperative assessment of penile squamous cell carcinoma patients: results from a large prospective multicenter European study.Urology. 2016; 90: 131-135Google Scholar Evaluation of the LNs is critical as characteristics, such as the involvement of inguinal LNs, the number and site of metastatic nodes and extracapsular nodal involvement, provide the strongest prognostic factors for disease-specific survival (DSS).13Horenblas S. van Tinteren H. Squamous cell carcinoma of the penis. IV. Prognostic factors of survival: analysis of tumor, nodes and metastasis classification system.J Urol. 1994; 151: 1239-1243Google Scholar Clinically impalpable inguinal LNs (cN0) should undergo US imaging and fine-needle aspiration cytology (FNAC) of morphologically abnormal inguinal nodes. Palpable inguinal nodes are likely due to metastatic disease in >80% of cases; this can be confirmed by carrying out percutaneous FNAC or a biopsy of the LN. In cases of a negative biopsy and clinically suspicious nodes, a repeat FNAC or excisional biopsy of the node is advised.14Graafland N.M. Leijte J.A. Olmos R.A. et al.Repeat dynamic sentinel node biopsy in locally recurrent penile carcinoma.BJU Int. 2010; 105: 1121-1124Google Scholar In the presence of fungating primary lesions, lymphadenopathy can develop secondary to inflammatory changes. If nodes are palpable, US ± FNAC has a high sensitivity for detecting cancer, although it can still miss micrometastases in reactive nodes.15Senthil Kumar M.P. Ananthakrishnan N. Prema V. Predicting regional lymph node metastasis in carcinoma of the penis: a comparison between fine-needle aspiration cytology, sentinel lymph node biopsy and medial inguinal lymph node biopsy.Br J Urol. 1998; 81: 453-457Google Scholar MRI and computed tomography (CT) scanning can detect enlarged inguinal and pelvic LNs. CT is primarily used, despite the low sensitivity (36%). The use of [18F]2-fluoro-2-deoxy-d-glucose (FDG)–positron emission tomography (PET)–CT remains uncertain, although the sensitivity is reported as 96% for palpable nodes.16Sadeghi R. Gholami H. Zakavi S.R. et al.Accuracy of 18F-FDG PET/CT for diagnosing inguinal lymph node involvement in penile squamous cell carcinoma: systematic review and meta-analysis of the literature.Clin Nucl Med. 2012; 37: 436-441Google Scholar MRI or CT fusion PET probably has the highest sensitivity for detecting distant metastasis and can be used in high-risk cases. For routine staging at diagnosis and follow-up, however, CT of the chest, abdomen and pelvis is sufficient. Tumour staging must be carried out according to a recognised staging classification system—either the World Health Organization (WHO) 2022, the Union for International Cancer Control (UICC) eighth edition or the American Joint Committee on Cancer (AJCC) eighth edition.17Compérat E. Varinot J. Eymerit C. et al.[Comparison of UICC and AJCC 8th edition TNM classifications in uropathology].Ann Pathol. 2019; 39: 158-166Google Scholar, 18Paner G.P. Stadler W.M. Hansel D.E. et al.Updates in the eighth edition of the tumor-node-metastasis staging classification for urologic cancers.Eur Urol. 2018; 73: 560-569Google Scholar, 19Amin M.B. Edge S. Greene F. AJCC Cancer Staging Manual. Springer, New York, NY2017Google Scholar, 20Brierley J.D. Gospodarowicz M.K. Wittekind C. UICC TNM Classification of Malignant Tumours. 8th ed. Wiley-Blackwell, Oxford, UK2017Google Scholar, 21Moch H. Amin M.B. Berney D.M. et al.The 2022 World Health Organization classification of tumours of the urinary system and male genital organs-part A: renal, penile, and testicular tumours.Eur Urol. 2022; 82: 458-468Google Scholar The TNM (tumour–node–metastasis) clinical and pathological classification of penile cancer according to the UICC eighth edition is shown in Supplementary Table S1, available at https://doi.org/10.1016/j.esmoop.2024.103481. Staging of the primary lesion and regional LNs requires accurate knowledge of the penile anatomy. In the distal penis, three different epithelial mucosal compartments exist: glans, coronal sulcus and inner prepuce of the foreskin. Premalignant disease of the penis is termed PeIN. Here, the basement membrane remains intact but intraepithelial changes occur. PeIN is a recognised precursor of invasive SCC; it was integrated into the WHO 2016 classification22Moch H. Cubilla A.L. Humphrey P.A. et al.The 2016 WHO classification of tumours of the urinary system and male genital organs-part A: renal, renile, and testicular tumours.Eur Urol. 2016; 70: 93-105Google Scholar and is maintained in the WHO 2022 classification.21Moch H. Amin M.B. Berney D.M. et al.The 2022 World Health Organization classification of tumours of the urinary system and male genital organs-part A: renal, penile, and testicular tumours.Eur Urol. 2022; 82: 458-468Google Scholar Precursor lesions of SCC are outlined in Supplementary Table S2, available at https://doi.org/10.1016/j.esmoop.2024.103481. Two major subgroups of PeIN can be distinguished, as shown in Supplementary Table S3, available at https://doi.org/10.1016/j.esmoop.2024.103481. WHO 2022 has retained the classification of invasive penile cancer based on the association with HPV,23Cupp M.R. Malek R.S. Goellner J.R. et al.The detection of human papillomavirus deoxyribonucleic acid in intraepithelial, in situ, verrucous and invasive carcinoma of the penis.J Urol. 1995; 154: 1024-1029Google Scholar in line with the classification of precursor lesions, giving due importance to the pathogenesis.21Moch H. Amin M.B. Berney D.M. et al.The 2022 World Health Organization classification of tumours of the urinary system and male genital organs-part A: renal, penile, and testicular tumours.Eur Urol. 2022; 82: 458-468Google Scholar The most common histological subtype in this group is SCC usual type, which also includes the well differentiated pseudo-hyperplastic form. Grading of these lesions should be according to the WHO system.21Moch H. Amin M.B. Berney D.M. et al.The 2022 World Health Organization classification of tumours of the urinary system and male genital organs-part A: renal, penile, and testicular tumours.Eur Urol. 2022; 82: 458-468Google Scholar Other subtypes are verrucous carcinoma, which includes a low-grade entity called carcinoma cuniculatum,24Barreto J.E. Velazquez E.F. Ayala E. et al.Carcinoma cuniculatum: a distinctive variant of penile squamous cell carcinoma: report of 7 cases.Am J Surg Pathol. 2007; 31: 71-75Google Scholar papillary carcinoma, pseudoglandular carcinoma, mixed carcinoma, the rare sarcomatoid carcinoma and the extremely rare adenosquamous carcinoma (including mucoepidermoid carcinoma). The frequency and prognosis25Chaux A. Reuter V. Lezcano C. et al.Comparison of morphologic features and outcome of resected recurrent and nonrecurrent squamous cell carcinoma of the penis: a study of 81 cases.Am J Surg Pathol. 2009; 33: 1299-1306Google Scholar for each histological subtype are summarised in Supplementary Table S4, available at https://doi.org/10.1016/j.esmoop.2024.103481. HPV-associated SCC is related to high-risk HPV, such as HPV 16 and 18, and demonstrates p16 expression. Histological subtypes include basaloid SCC,26Cubilla A.L. Lloveras B. Alemany L. et al.Basaloid squamous cell carcinoma of the penis with papillary features: a clinicopathologic study of 12 cases.Am J Surg Pathol. 2012; 36: 869-875Google Scholar warty carcinoma,27Yorita K. Kuroda N. Naroda T. et al.Penile warty mucoepidermoid carcinoma with features of stratified mucin-producing intra-epithelial lesion and invasive stratified mucin-producing carcinoma.Histopathology. 2018; 72: 867-873Google Scholar,28Manipadam M.T. Bhagat S.K. Gopalakrishnan G. et al.Warty carcinoma of the penis: a clinicopathological study from South India.Indian J Urol. 2013; 29: 282-287Google Scholar clear-cell carcinoma,29Sanchez D.F. Rodriguez I.M. Piris A. et al.Clear cell carcinoma of the penis: an HPV-related variant of squamous cell carcinoma: a report of 3 cases.Am J Surg Pathol. 2016; 40: 917-922Google Scholar lymphoepithelioma-like carcinoma30Mentrikoski M.J. Frierson Jr., H.F. Stelow E.B. et al.Lymphoepithelioma-like carcinoma of the penis: association with human papilloma virus infection.Histopathology. 2014; 64: 312-315Google Scholar and mixed (previously termed warty-basaloid) carcinoma. The frequency and prognosis25Chaux A. Reuter V. Lezcano C. et al.Comparison of morphologic features and outcome of resected recurrent and nonrecurrent squamous cell carcinoma of the penis: a study of 81 cases.Am J Surg Pathol. 2009; 33: 1299-1306Google Scholar of each histological subtype are shown in Supplementary Table S5, available at https://doi.org/10.1016/j.esmoop.2024.103481. Invasive keratinising carcinoma without any special features and which cannot be tested for HPV is designated as SCC not otherwise specified (NOS). No established prognostic or treatment differences between HPV-associated and HPV-independent penile cancers currently exist. Some recent studies suggest, however, that HPV-associated SCC may respond better to radiotherapy (RT) or multimodality treatments.31Yuan Z. Naghavi A.O. Tang D. et al.The relationship between HPV status and chemoradiotherapy in the locoregional control of penile cancer.World J Urol. 2018; 36: 1431-1440Google Scholar,32Bandini M. Ross J.S. Zhu Y. et al.Association between human papillomavirus infection and outcome of perioperative nodal radiotherapy for penile carcinoma.Eur Urol Oncol. 2021; 4: 802-810Google Scholar Mandatory and recommended information to include in the pathology report for penile cancers is provided in Supplementary Table S6, available at https://doi.org/10.1016/j.esmoop.2024.103481. •Clinical assessment of the primary tumour should record size, morphology and relationship to adjacent structures [III, A].•The use of MRI or US combined with an intracavernosal injection of prostaglandin E1 is useful to assess the primary lesion [III, B].•FNAC should be used in clinically impalpable inguinal nodes when they are detected as morphologically abnormal on US [IV, A].•Clinicians should carry out percutaneous FNAC for palpable inguinal nodes and repeat the FNAC or carry out an excisional biopsy in case of negative findings for clinically suspicious nodes [III, A].•CT is advised in all cases for the assessment of distant metastases [III, A]. MRI or CT fusion PET can be used in patients with high-risk disease [IV, B].•The following are recommended for disease staging classification: WHO 2022, UICC eighth edition or AJCC eighth edition [I, A].•Pathological assessment should include HPV status, histological grade and tumour type [III, A].•The WHO system is recommended for disease grading [IV, A]. It is important to note that the treatment of penile cancer is based on non-randomised data largely derived from heterogeneous patient cohorts, typically from high-volume institutional series. No randomised studies have been undertaken in this disease that have suggested a survival benefit of one approach over another. The rarity of the disease makes large randomised trials unfeasible. According to the AJCC eighth edition, localised penile cancer includes stage I (T1a N0 M0) and stage II (T1b-T3 N0 M0) disease. For both stages, treatment should be carried out with curative intent with surgical resection or RT which includes brachytherapy and/or external beam RT (EBRT) in selected cases. Although brachytherapy is not widely available, it is potentially suitable for selected cases when the lesion is located in the distal penis and the patient does not want to undergo surgical intervention. A proposed algorithm for the management of primary penile tumours is shown in Figure 2. The primary aim of surgical intervention is to remove the tumour using penile-preserving techniques. Preservation of the aesthetic, sexual and urinary function is an important outcome to allow penetrative sexual intercourse and voiding standing up. Several organ-sparing surgery (OSS) options have been described to manage the primary penile cancer. Nonetheless, no randomised controlled trials or comparative studies are available to define the best OSS in patients with localised penile cancer. Thus, surgical options should be tailored according to the disease stage, patient willingness for reconstruction and clear surgical margins. In cases of biopsy-proven PeIN located on the glans or prepuce, circumcision is mandatory as the initial management. Following circumcision, any residual PeIN can be treated using topical agents, such as 5-fluorouracil (5-FU)33Alnajjar H.M. Lam W. Bolgeri M. et al.Treatment of carcinoma in situ of the glans penis with topical chemotherapy agents.Eur Urol. 2012; 62: 923-928Google Scholar or imiquimod. Alternatively, carbon dioxide (CO2) laser ablation (penetration is 2-2.5 mm) can be used. Following topical treatment, the response should be assessed clinically or with a repeat biopsy of any new lesions which may indicate progression to invasive disease. If topical treatment fails, wide local excision or glans resurfacing, whereby the mucosal layer is removed and replaced with a split-thickness skin graft (SSG), should be considered. The 5-year local recurrence rate after laser treatment is ∼50%34Tang D.H. Yan S. Ottenhof S.R. et al.Laser ablation as monotherapy for penile squamous cell carcinoma: a multi-center cohort analysis.Urol Oncol. 2018; 36: 147-152Google Scholar,35van Bezooijen B.P. Horenblas S. Meinhardt W. et al.Laser therapy for carcinoma in situ of the penis.J Urol. 2001; 166: 1670-1671Google Scholar which emphasises the importance of close clinical follow-up.34Tang D.H. Yan S. Ottenhof S.R. et al.Laser ablation as monotherapy for penile squamous cell carcinoma: a multi-center cohort analysis.Urol Oncol. 2018; 36: 147-152Google Scholar Vaccination against HPV in HPV-related PeIN has not been routinely used as the long-term efficacy is unclear, but in high-risk individuals, it is an option that can be discussed in unvaccinated men.36Harder T. Wichmann O. Klug S.J. et al.Efficacy, effectiveness and safety of vaccination against human papillomavirus in males: a systematic review.BMC Med. 2018; 16: 110Google Scholar Therefore, concomitant use of local treatment and nonavalent vaccine in HPV-related PeIN is an option but requires further validation. Patients with tumour localised to the foreskin can undergo a circumcision, which is often therapeutic. Wide local excision of the lesion with reconstruction using an SSG or advancement flap using penile shaft skin is preferable for small tumours located on the glans penis. Long-term follow-up, depending on the tumour stage, is mandatory for both procedures as recurrence rates can reach 15.4% according to contemporary evidence.37Philippou P. Shabbir M. Malone P. et al.Conservative surgery for squamous cell carcinoma of the penis: resection margins and long-term oncological control.J Urol. 2012; 188: 803-808Google Scholar Glans resurfacing is recommended for PeIN or T1a lesions with excellent oncological outcomes as well as aesthetic and functional outcomes.38O'Kelly F. Lonergan P. Lundon D. et al.A prospective study of total glans resurfacing for localized penile cancer to maximize oncologic and functional outcomes in a tertiary referral network.J Urol. 2017; 197: 1258-1263Google Scholar The local recurrence rate is up to 4.5%,39Chipollini J. Yan S. Ottenhof S.R. et al.Surgical management of penile carcinoma in situ: results from an international collaborative study and review of the literature.BJU Int. 2018; 121: 393-398Google Scholar but positive surgical margins (48%) and repeat surgery (28%) are common.40Shabbir M. Muneer A. Kalsi J. et al.Glans resurfacing for the treatment of carcinoma in situ of the penis: surgical technique and outcomes.Eur Urol. 2011; 59: 142-147Google Scholar Mohs micrographic surgery can be used for small, low-grade penile lesions (T1) but again there is a high recurrence rate (32%)41Shindel A.W. Mann M.W. Lev R.Y. et al.Mohs micrographic surgery for penile cancer: management and long-term followup.J Urol. 2007; 178: 1980-1985Google Scholar and the need for a more complicated clinical set-up, including a pathologist. Glansectomy, with or without distal urethrectomy, is the surgical treatment of choice for T2 tumours on the glans penis. An SSG is recommended to reconstruct a neo-glans from the preserved distal corporal tips. Surgical margins of >1 mm are now accepted, with the risk of local recurrence being low. According to a recent systematic review, local recurrence and positive surgical margin rates after glansectomy are 2.6%-16.7% and 2.9%-22.6%, respectively. The incidence of salvage penectomy for positive margins and/or recurrence is 1.2%-8.3%. The overall survival (OS) rate is 78.6%-91.9% and the DSS rate is 89%-96.6%. Good cosmetic outcomes are reported in 95%-100% and normal erectile function in 50%-100% of cases.42Pang K.H. Muneer A. Alnajjar H.M. Glansectomy and reconstruction for penile cancer: a systematic review.Eur Urol Focus. 2022; 8: 1318-1322Google Scholar Partial or total penectomy still remain valid alternatives whenever adequate surgical margins cannot be guaranteed or when the patient is unfit for reconstruction after OSS. Partial penectomy or total penectomy combined with a perineal urethrostomy are the treatments of choice when the cancer infiltrates proximally into the corpus cavernosum. The penile shaft length should be evaluated before surgery. In the presence of an adequate penile shaft length, partial penectomy with an SSG or urethral advancement43Belinky J.J. Cheliz G.M. Graziano C.A. et al.Glanuloplasty with urethral flap after partial penectomy.J Urol. 2011; 185: 204-206Google Scholar for neo-glans reconstruction are valid options. For shorter penile shaft lengths or where there is a buried penis, total penectomy with urinary diversion via a perineal urethrostomy is advised. Total phallic reconstruction can be considered following subtotal or total penectomy. Radial-artery free flaps44Falcone M. Blecher G. Anfosso M. et al.Total phallic reconstruction in the genetic male.Eur Urol. 2021; 79: 684-691Google Scholar and latissimus dorsi flaps45Perovic S.V. Djinovic R. Bumbasirevic M. et al.Total phalloplasty using a musculocutaneous latissimus dorsi flap.BJU Int. 2007; 100 (discussion 905): 899-905Google Scholar are the preferred options in patients with penile cancer. With more extensive disease, total penectomy with perineal urethrostomy is the recommended option. Toilet procedures with urinary diversion are also considered as palliative treatment in advanced cases when negative margins cannot be achieved. This allows easier wound management for patients in the community setting. The inguinal LNs represent the initial site for metastatic disease in patients with penile cancer due to the stepwise lymphogenic spread before any haematogenic spread. The presence of metastatic disease in the inguinal LNs is the most important prognostic indicator in patients with penile cancer, with 5-year survival rates dropping from 90% in localised disease to 50% when there is regional LN involvement.46Cancer.Net. Penile cancer: statistics.https://www.cancer.net/cancer-types/penile-cancer/statisticsDate: 2022Date accessed: December 14, 2022Google Scholar Thus, the clinical and pathological assessment of the inguinal LNs is pivotal in the management of patients diagnosed with penile cancer. A proposed algorithm for the management of inguinal LNs is shown in Figure 3. The management of the inguinal LNs depends on the clinical stage, which is still classified according to whether they are palpable or not. Accordingly, patients with impalpable inguinal LNs are classified as cN0 and those with uni- or bilateral palpable disease are classified as cN1-2. Cases of grossly enlarged or fungating inguinal LNs are classified as cN3. In patients with cN0 disease, no imaging technique has the desired sensitivity to detect micrometastatic disease. As such, the clinical management is often based on the disease characteristics of the primary tumour, such as pT stage, histological grade and the presence of lymphovascular invasion. Accordingly, cN0 patients are classified into low-, intermediate- and high-risk groups based on the aforementioned characteristics,47Winters B.R. Mossanen M. Holt S.K. et al.Predictors of nodal upstaging in clinical node negative patients with penile carcinoma: a National Cancer Database Analysis.Urology. 2016; 96: 29-34Google Scholar as shown in Supplementary Table S7, available at https://doi.org/10.1016/j.esmoop.2024.103481. Treatment options for patients with cN0 disease include clinical surveillance, dynamic sentinel LN biopsy (DSLNB) followed by radical inguinal lymphadenectomy where there is micrometastatic disease detected in the sentinel node or a superficial modified inguinal lymphadenectomy with frozen section or modified inguinal lymphadenectomy when DSLNB is unavailable. As the risk of micrometastatic disease is up to 25%, subjecting all patients with cN0 disease to an open lymphadenectomy procedure would be deemed as overtreatment. In patients with low-risk disease following observation, the 5-year crude inguinal relapse-free survival is 90%.48Nazzani S. Catanzaro M. Biasoni D. et al.Clinical outcomes in clinical N0 squamous cell carcinoma of the penis according to nodal management: early, delayed or selective (following dynamic sentinel node biopsy) inguinal lymph-node dissection.J Urol. 2021; 206: 354-363Google Scholar Given these considerations, patients with cN0 low-risk disease should be managed with clinical surveillance, whereas active treatment is recommended for patients with intermediate- and high-risk disease.49Woldu S.L. Ci B. Hutchinson R.C. et al.Usage and survival implications of surgical staging of inguinal lymph nodes in intermediate- to high-risk, clinical localized penile cancer: a propensity-score matched analysis.Urol Oncol. 2018; 36: 159.e7-159.e17Google Scholar DSLNB followed by radical inguinal lymphadenectomy is an option for patients with intermediate- or high-risk metastatic disease.50Zhu Y. Gu W.J. Xiao W.J. et al.Important therapeutic considerations in T1b penile cancer: prognostic significance and adherence to treatment guidelines.Ann Surg Oncol. 2019; 26: 685-691Google Scholar A proven protocol which relies on preoperative US combined with FNAC for morphologically abnormal LNs followed by sentinel node localisation using a combination of technetium-99m (99mTC) nanocolloid and patent blue dye has a false-negative rate of 10%.51Dell'Oglio P. de Vries H.M. Mazzone E. et al.Hybrid indocyanine green-(99m)Tc-nanocolloid for single-photon emission computed tomography and combined radio- and fluorescence-guided sentinel node biopsy in penile cancer: results of 740 inguinal basins assessed at a single institution.Eur Urol. 2020; 78: 865-872Google Scholar Colocalisation of the sentinel node with indocyanine green (ICG) has also been used.52Brunckhorst O. Ahmed K. Alnajjar H.M. et al.Sentinel lymph node biopsy using indocyanine green in penile cancer.Nat Rev Urol. 2020; 17: 541-542Google Scholar,53Vreeburg M.T.A. Azargoshasb S. van Willigen D. et al.Comparison of two hybrid sentinel node tracers: indocyanine green (ICG)-(99m)Tc-nanocolloid vs. ICG-(99m)Tc-nanoscan from a nuclear medicine and surgical perspective.Eur J Nucl Med Mol Imaging. 2023; 50: 2282-2291Google Scholar The most comprehensive meta-analysis on DSLNB in patients with cN0 disease pooled 28 studies and reported a sensitivity of 87%.54Sadeghi R. Gholami H. Zakavi S.R. et al.Accuracy of sentinel lymph node biopsy for inguinal lymph node staging of penile squamous cell carcinoma: systematic review and meta-analysis of the literature.J Urol. 2012; 187: 25-31Google Scholar Modified inguinal LN dissection (ILND) aims to decrease the morbidity associated with radical inguinal lymphadenectomy by limiting the surgical dissection to the superficial LNs above the fascia lata and reducing the boundaries of the femoral triangle. Despite the promising results and the lower morbidity rate, no randomised controlled trial has compared the false-negative rate of modified and radical ILNDs. Similarly, no randomised trial has compared modified ILND and DSLNB. Superficial modified inguinal lymphadenectomy reduces the boundary of disse

The following ESMO Clinical Practice Guideline (CPG) has been recently updated with new treatment recommendations and an updated algorithm for managing treatment-naive advanced or metastatic urothelial carcinoma (stage IV): Bladder cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up.1

Purpose:Patients with Ta low-grade (LG) nonmuscle-invasive bladder cancer (NMIBC) rarely develop metastases or die of it. Long-term data are scant and length of follow-up poorly defined.Materials and Methods:This retrospective study included 521 patients diagnosed with primary TaLG NMIBC (n = 491) or papillary urothelial neoplasm of low malignant potential (n = 30) from 1989 to 2019 at an academic center. Patient data were acquired using patient records chart review and a bladder cancer informatics registry at the center. Risk of recurrence and progression in stage to muscle invasion, metastases, and death due to bladder cancer (BC) were analyzed. RNAseq assessed the transcriptomic profiles of 4 TaLG NMIBCs that metastasized. Interobserver variability in pathological grading (WHO 2004/2022 and 1973, n = 80) was blindly assessed by 3 expert pathologists.Results:The median follow-up was 9.6 (95% CI: 8.6-10.2) years. Among 521 patients (73% men, median age 67.0 years), 350 recurred, 57 progressed in stage, 20 developed metastases, and 15 died of BC (median 9.6 years after diagnosis). Cancer-specific survival probabilities were 0.99, 0.98, and 0.96 at 5, 10, and 15 years, respectively. Fifty patients who were recurrence free for the first 5 years developed late recurrences and 2 of them died of BC. Metastatic TaLG NMIBC had more adverse transcriptomic findings in keeping with higher-grade tumors despite being phenotypically similar to indolent tumors. Grading concordance for the 2004/2022 system and WHO 1973 was 0.78 (95% CI: 0.65-0.90) and 0.41 (95% CI: 0.32-0.50), respectively.Conclusions:This study with long-term data challenges the assumption that primary TaLG NMIBC nearly never progresses to lethal disease if followed long enough. However, the risk of BC-related mortality is extremely low in patients who are recurrence free for the first 5 years. Minimizing variability in pathological grading remains an unmet need.

•This ESMO Clinical Practice Guideline provides key recommendations for managing renal cell carcinoma.•The guideline covers imaging and diagnosis, staging and risk assessment, treatment and follow-up.•Algorithms for the management of localised and advanced or metastatic disease are provided.•The authors comprise a multidisciplinary group of experts from different institutions and countries.•Recommendations are based on available scientific data and the authors' collective expert opinion. Renal cancer is the 14th most common malignancy worldwide, with >430 000 new cases diagnosed in 2020.1 The incidence varies geographically, with higher incidence in Europe and North America. Renal cell carcinoma (RCC) accounts for ∼90% of all renal cancers.1Bukavina L. Bensalah K. Bray F. et al.Epidemiology of Renal Cell Carcinoma: 2022 Update.Eur Urol. 2022; 82: 529-542Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar, 2Escudier B. Porta C. Schmidinger M. et al.Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2019; 30: 706-720Abstract Full Text Full Text PDF PubMed Scopus (724) Google Scholar, 3Huang J. Leung D.K. Chan E.O. et al.A Global Trend Analysis of Kidney Cancer Incidence and Mortality and Their Associations with Smoking, Alcohol Consumption, and Metabolic Syndrome.Eur Urol Focus. 2022; 8: 200-209Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar While incidence rates of renal cancer have been steadily increasing, including a slow rise over the past decade, mortality rates have slowly declined.1Bukavina L. Bensalah K. Bray F. et al.Epidemiology of Renal Cell Carcinoma: 2022 Update.Eur Urol. 2022; 82: 529-542Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar,2Escudier B. Porta C. Schmidinger M. et al.Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up.Ann Oncol. 2019; 30: 706-720Abstract Full Text Full Text PDF PubMed Scopus (724) Google Scholar This can be explained in part by increased rates of incidental diagnoses on abdominal imaging.1Bukavina L. Bensalah K. Bray F. et al.Epidemiology of Renal Cell Carcinoma: 2022 Update.Eur Urol. 2022; 82: 529-542Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar Improvements in treatments are also contributing to the declining mortality rates. There are several established risk factors for RCC such as smoking, obesity, hypertension and chemical exposures, which have been described previously.3Huang J. Leung D.K. Chan E.O. et al.A Global Trend Analysis of Kidney Cancer Incidence and Mortality and Their Associations with Smoking, Alcohol Consumption, and Metabolic Syndrome.Eur Urol Focus. 2022; 8: 200-209Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar An estimated 6%-9% of renal cancers have germline mutations in genes associated with cancer predisposition.1Bukavina L. Bensalah K. Bray F. et al.Epidemiology of Renal Cell Carcinoma: 2022 Update.Eur Urol. 2022; 82: 529-542Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar Several autosomal dominant syndromes have been described, including von Hippel–Lindau syndrome (VHL), hereditary leiomyomatosis and RCC (HLRCC) or fumarate hydratase (FH)-deficient RCC, hereditary papillary RCC, tuberous sclerosis complex, Birt–Hogg–Dubé syndrome and succinate dehydrogenase (SDH)-deficient RCC.1Bukavina L. Bensalah K. Bray F. et al.Epidemiology of Renal Cell Carcinoma: 2022 Update.Eur Urol. 2022; 82: 529-542Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar The initial presentation of RCC, based on the classic triad of flank pain, gross haematuria and palpable abdominal mass, has been largely replaced by incidental detection.1Bukavina L. Bensalah K. Bray F. et al.Epidemiology of Renal Cell Carcinoma: 2022 Update.Eur Urol. 2022; 82: 529-542Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar The recommended diagnostic investigations are summarised in Figure 1. Contrast-enhanced computed tomography (CT) of the chest, abdomen and pelvis is required for accurate staging of RCC for tumours of all stages. For advanced disease, neuroimaging [CT or magnetic resonance imaging (MRI)] and bone scan are desirable before starting systemic therapy. Positron emission tomography is not recommended for routine staging or assessment of RCC. Histopathological confirmation of RCC is mandatory for all patients before starting systemic treatment. Core biopsy of the renal tumour or metastatic site, or examination of the nephrectomy sample at surgery, provides histopathological confirmation with high sensitivity and specificity, and negligible risk of tumour seeding.4Leveridge M.J. Finelli A. Kachura J.R. et al.Outcomes of small renal mass needle core biopsy, nondiagnostic percutaneous biopsy, and the role of repeat biopsy.Eur Urol. 2011; 60: 578-584Abstract Full Text Full Text PDF PubMed Scopus (337) Google Scholar,5Volpe A. Kachura J.R. Geddie W.R. et al.Techniques, safety and accuracy of sampling of renal tumors by fine needle aspiration and core biopsy.J Urol. 2007; 178: 379-386Crossref PubMed Scopus (301) Google Scholar Histopathology assessment to establish the underlying subtype (clear-cell versus variant histology) and presence of sarcomatoid or rhabdoid differentiation using established criteria is strongly recommended due to prognostic and therapeutic implications.6Moch H. Amin M.B. Berney D.M. et al.The 2022 World Health Organization Classification of Tumours of the Urinary System and Male Genital Organs-Part A: Renal, Penile, and Testicular Tumours.Eur Urol. 2022; 82: 458-468Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar More recent classification based on molecular analysis techniques that are not currently widely available, while recommended, is not yet mandated. Patients with suspected metastatic relapse after nephrectomy for renal cancer do not necessarily need a repeat biopsy of the metastatic site, but the decision should be made on an individual basis, especially in the case of late relapse, which is common in RCC. The risk of relapse of the primary tumour and the interval between primary surgery and relapse are relevant in this decision. Laboratory assessment of serum creatinine, haemoglobin, leukocyte and platelet counts, lymphocyte to neutrophil ratio and serum-corrected calcium should be carried out. These tests are used in prognostic scoring systems and treatment selection for advanced disease, including the International Metastatic RCC Database Consortium (IMDC) score (see Staging and risk assessment section).7Ko J.J. Xie W. Kroeger N. et al.The International Metastatic Renal Cell Carcinoma Database Consortium model as a prognostic tool in patients with metastatic renal cell carcinoma previously treated with first-line targeted therapy: a population-based study.Lancet Oncol. 2015; 16: 293-300Abstract Full Text Full Text PDF PubMed Scopus (289) Google Scholar Clear-cell RCCs (ccRCCs) represent ∼80% of malignant renal tumours in adults. The remaining 20% consist of several subtypes with different histological, molecular and cytogenetic profiles. Papillary RCC (pRCC) is the most common of these.8Fernández-Pello S. Hofmann F. Tahbaz R. et al.A Systematic Review and Meta-analysis Comparing the Effectiveness and Adverse Effects of Different Systemic Treatments for Non-clear Cell Renal Cell Carcinoma.Eur Urol. 2017; 71: 426-436Abstract Full Text Full Text PDF PubMed Scopus (114) Google Scholar The fifth edition of the World Health Organization (WHO) classification of urogenital tumours, published in 2022, contains significant revisions.6Moch H. Amin M.B. Berney D.M. et al.The 2022 World Health Organization Classification of Tumours of the Urinary System and Male Genital Organs-Part A: Renal, Penile, and Testicular Tumours.Eur Urol. 2022; 82: 458-468Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar With increasing use of massive parallel sequencing to identify molecular alterations in renal tumours, the WHO has introduced a molecular-driven renal tumour classification with 11 subgroups.6Moch H. Amin M.B. Berney D.M. et al.The 2022 World Health Organization Classification of Tumours of the Urinary System and Male Genital Organs-Part A: Renal, Penile, and Testicular Tumours.Eur Urol. 2022; 82: 458-468Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar Molecular-defined renal tumours are those which show very heterogeneous morphological aspects and can therefore not be diagnosed by morphology alone. Such tumours include previously described molecular subtypes (such as microphthalmia transcription factor [MiT] family translocation carcinomas and SDH-deficient RCC), as well as new entities including SMARCB1-deficient medullary RCC, TFEB-altered RCC, ALK-rearranged RCC and ELOC-mutated RCC (Table 1).6Moch H. Amin M.B. Berney D.M. et al.The 2022 World Health Organization Classification of Tumours of the Urinary System and Male Genital Organs-Part A: Renal, Penile, and Testicular Tumours.Eur Urol. 2022; 82: 458-468Abstract Full Text Full Text PDF PubMed Scopus (218) Google ScholarTable 1New molecular-defined RCC entities defined by the WHO6Moch H. Amin M.B. Berney D.M. et al.The 2022 World Health Organization Classification of Tumours of the Urinary System and Male Genital Organs-Part A: Renal, Penile, and Testicular Tumours.Eur Urol. 2022; 82: 458-468Abstract Full Text Full Text PDF PubMed Scopus (218) Google ScholarRCC subtype (WHO)Genetic alterationCommentsEosinophilic solid and cystic RCCTSC mutation and activation of mTOR pathwayTypically clinically indolentResponses with use of mTOR inhibitors have been reportedELOC-mutated RCCELOC (TCEB1) mutationClear cells with abundant cytoplasm and presence of fibromuscular bandsBased on limited data, seem to behave indolently and are associated with good prognosisALK-rearranged RCCALK rearrangementsTypically morphologically very heterogenousResponses with use of ALK inhibitors have been reportedSMARCB1-deficient medullary RCCSMARCB1 lossHighly aggressive subtypeFrequently occurs in young patients with sickle cell trait (although not required for diagnosis)TFEB-altered RCCTFEB translocation and TFEB amplificationTFEB-translocated RCC is typically clinically indolentTFEB-amplified RCC is typically highly aggressive, tends to occur in older patientsFH-deficient RCCFH loss or mutationMay be associated with HLRCCALK, anaplastic lymphoma kinase; FH, fumarate hydratase; HLRCC, hereditary leiomyomatosis and renal cell carcinoma; mTOR, mammalian target of rapamycin; RCC, renal cell carcinoma; WHO, World Health Organization. Open table in a new tab ALK, anaplastic lymphoma kinase; FH, fumarate hydratase; HLRCC, hereditary leiomyomatosis and renal cell carcinoma; mTOR, mammalian target of rapamycin; RCC, renal cell carcinoma; WHO, World Health Organization. The incorporation of molecular-driven classification highlights a shift to using genome sequencing to identify actionable mutations for more personalised treatments. Testing for germline mutations is recommended for younger patients, those with multiple or bilateral lesions, those with first- or second-degree relatives who have had RCC, those with related disorders associated with known predisposing conditions and those who have exhausted standard therapeutic options. While molecular techniques are becoming more widely available, many laboratories still lack access to them, and most of the identified targets are not currently actionable. When genome sequencing is not available, pathologists should include comments regarding the possible molecular alterations in their diagnoses, along with a detailed morphological description.6Moch H. Amin M.B. Berney D.M. et al.The 2022 World Health Organization Classification of Tumours of the Urinary System and Male Genital Organs-Part A: Renal, Penile, and Testicular Tumours.Eur Urol. 2022; 82: 458-468Abstract Full Text Full Text PDF PubMed Scopus (218) Google Scholar Currently, the identification of ccRCC as opposed to pRCC or another established subtype (e.g. chromophobe, collecting duct, etc.) remains the priority. The identification of sarcomatoid features, which may be observed in any RCC subtype and are characterised by the presence of spindle or mesenchymal-like cells, has become increasingly important for the consideration of systemic therapy. The latest WHO classification no longer differentiates between type 1 and type 2 pRCC, reducing its importance. The clinical relevance of the new WHO subtypes remains uncertain. •Patients with suspected renal cancer should have appropriate investigations with cross-sectional imaging, histopathology analysis and laboratory tests [I, A].•Neuroimaging (CT or MRI) and a bone scan are desirable before starting systemic therapy for advanced disease [IV, B]•Histopathology analysis should be carried out to determine tumour subtype and results should be available before starting systemic treatment [I, A].•The recent WHO classification is not routinely required; instead, attention should be given to established subtypes with well-defined treatment algorithms, such as ccRCC and pRCC [IV, B].•Genetic assessment is recommended for younger patients, those with multiple or bilateral lesions, those with first- or second-degree relatives who have had RCC, those with related disorders associated with known predisposing conditions and those who have exhausted standard therapeutic options [IV, A]. Staging should follow the eighth edition of the Union for International Cancer Control (UICC) TNM (tumour–node–metastasis) system (Supplementary Tables S1 and S2).9Union for International Cancer Control. TNM Classification of Malignant Tumours. 8th ed. John Wiley & Sons, Ltd; 2017.Google Scholar Given the variable clinical course of RCC, the use of prognostic models is recommended in both localised and metastatic disease for the assessment of individualised risk. Localised disease. The approval of adjuvant pembrolizumab for high-risk RCC makes the TNM prognostic classification used in KEYNOTE-564 clinically relevant; this is now the preferred risk classification for operable disease. As per the trial protocol, intermediate-high risk is defined as pathological (p)T2, grade 4 or sarcomatoid, N0, M0, or pT3, any grade, N0, M0.10Choueiri T.K. Tomczak P. Park S.H. et al.Adjuvant Pembrolizumab after Nephrectomy in Renal-Cell Carcinoma.N Engl J Med. 2021; 385: 683-694Crossref PubMed Google Scholar High-risk disease is defined as pT4, any grade, N0, M0, or any pT, any grade, lymph node positive, M0. Other risk models testing pre- and post-operative scores can be used for prognostic purposes.11Leibovich B.C. Blute M.L. Cheville J.C. et al.Prediction of progression after radical nephrectomy for patients with clear cell renal cell carcinoma: a stratification tool for prospective clinical trials.Cancer. 2003; 97: 1663-1671Crossref PubMed Scopus (655) Google Scholar,12Patard J.J. Kim H.L. Lam J.S. et al.Use of the University of California Los Angeles integrated staging system to predict survival in renal cell carcinoma: an international multicenter study.J Clin Oncol. 2004; 22: 3316-3322Crossref PubMed Scopus (325) Google Scholar Advanced disease. The IMDC score, developed in the vascular endothelial growth factor receptor (VEGFR)-targeted therapy era, is a useful tool for predicting the prognosis of patients with advanced RCC. This scoring system uses six clinical and laboratory risk factors to produce three risk categories: favourable, intermediate and poor.7Ko J.J. Xie W. Kroeger N. et al.The International Metastatic Renal Cell Carcinoma Database Consortium model as a prognostic tool in patients with metastatic renal cell carcinoma previously treated with first-line targeted therapy: a population-based study.Lancet Oncol. 2015; 16: 293-300Abstract Full Text Full Text PDF PubMed Scopus (289) Google Scholar The risk category can be used to estimate prognosis and guide treatment decisions in first-line therapy and beyond.13Heng D.Y. Xie W. Regan M.M. et al.Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: results from a large, multicenter study.J Clin Oncol. 2009; 27: 5794-5799Crossref PubMed Scopus (1700) Google Scholar It should be noted, however, that this scoring system was validated in the era of VEGFR tyrosine kinase inhibitor (TKI) therapy and its predictive value with immune checkpoint inhibitor (ICI) therapy is less certain. Molecular prognostication and biomarkers. The introduction of the molecular-driven classification for RCC by the WHO highlights the prognostic implications of certain gene mutations, as discussed above. Gene expression panels can identify high-risk disease in operable cases and can potentially identify angiogenic versus immunogenic tumours in advanced disease;14McDermott D.F. Huseni M.A. Atkins M.B. et al.Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma.Nat Med. 2018; 24: 749-757Crossref PubMed Scopus (858) Google Scholar however, these are not applicable for routine use. Programmed death-ligand 1 (PD-L1) has been unreliable as a biomarker in renal cancer, and serum and urine biomarkers are experimental. •Staging should follow the eighth edition of the UICC TNM system [IV, B].•Prognostic scoring systems should be used to assess risk in operable disease (KEYNOTE-564 classification) and advanced disease (IMDC classification) [I, A]. T1 tumours (≤7 cm). Partial nephrectomy (PN) is the preferred option in organ-confined tumours measuring ≤7 cm (elective indication). This recommendation is based on a systematic review of multiple retrospective studies and a prospective, randomised controlled trial comparing radical nephrectomy (RN) with PN in solitary T1a-b N0 M0 renal tumours (<5 cm) with normal contralateral kidney function, which showed that PN was associated with significantly better preservation of renal function.15MacLennan S. Imamura M. Lapitan M.C. et al.Systematic review of oncological outcomes following surgical management of localised renal cancer.Eur Urol. 2012; 61: 972-993Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar PN can be carried out via open, laparoscopic or robot-assisted laparoscopic approaches. Conventional or robot-assisted laparoscopic RN is recommended if PN is not technically feasible. A nephron-sparing strategy, including PN, is the standard of care (SoC) in patients with compromised renal function, solitary kidney or bilateral tumours, with no tumour size limitation (imperative indication). Renal mass biopsy prior to surgery for clinical T1a tumours is recommended, as up to 30% are benign and may not need an intervention; however, a clear consensus has not been reached.16Widdershoven C.V. Aarts B.M. Zondervan P.J. et al.Renal biopsies performed before versus during ablation of T1 renal tumors: implications for prevention of overtreatment and follow-up.Abdom Radiol (NY). 2021; 46: 373-379Crossref Scopus (10) Google Scholar Radiofrequency ablation (RFA), stereotactic body radiotherapy (SBRT), microwave ablation and cryoablation (CA) are non-surgical options, particularly in patients with small cortical tumours. These may be especially appropriate for patients who are frail, present a high surgical risk, have a solitary kidney, compromised renal function, hereditary RCC or multiple bilateral tumours, or decline surgery. Preintervention biopsy is recommended to confirm malignancy and subtype in this setting.17Pierorazio P.M. Johnson M.H. Ball M.W. et al.Five-year analysis of a multi-institutional prospective clinical trial of delayed intervention and surveillance for small renal masses: the DISSRM registry.Eur Urol. 2015; 68: 408-415Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar Systematic reviews suggest a long-term cause-specific survival with RFA that is equal to PN, with a low metastasis rate but slightly higher local recurrence rate compared with PN and CA.15MacLennan S. Imamura M. Lapitan M.C. et al.Systematic review of oncological outcomes following surgical management of localised renal cancer.Eur Urol. 2012; 61: 972-993Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar The quality of the available evidence prevents definitive conclusions regarding morbidity and oncological outcomes for RFA and CA. Data from meta-analyses as well as prospective and retrospective studies support the efficacy and safety of SBRT, including favourable long-term outcomes.18Siva S. Ali M. Correa R.J.M. et al.5-year outcomes after stereotactic ablative body radiotherapy for primary renal cell carcinoma: an individual patient data meta-analysis from IROCK (the International Radiosurgery Consortium of the Kidney).Lancet Oncol. 2022; 23: 1508-1516Abstract Full Text Full Text PDF PubMed Scopus (38) Google Scholar Further randomised trials are needed to define its efficacy; SBRT cannot be strongly recommended without these data. Active surveillance is an option for those with a short life expectancy and for patients with small renal masses (≤4 cm); indeed, the growth rate of renal tumours is low in most cases (mean 3 mm/year) and progression to metastatic disease is reported in 1%-2% of patients.17Pierorazio P.M. Johnson M.H. Ball M.W. et al.Five-year analysis of a multi-institutional prospective clinical trial of delayed intervention and surveillance for small renal masses: the DISSRM registry.Eur Urol. 2015; 68: 408-415Abstract Full Text Full Text PDF PubMed Scopus (287) Google Scholar,19Jewett M.A. Mattar K. Basiuk J. et al.Active surveillance of small renal masses: progression patterns of early stage kidney cancer.Eur Urol. 2011; 60: 39-44Abstract Full Text Full Text PDF PubMed Scopus (393) Google Scholar In all cases, a risk–benefit discussion should occur with the patient. Minimally-invasive RN is the preferred option. Other approaches are likely to have similar oncological outcomes. Open RN remains the SoC for complex T3 and T4 tumours, although robotic and laparoscopic approaches can be considered. Routine adrenalectomy or lymph node dissection is not recommended when abdominal CT and intraoperative exploration show no evidence of adrenal or lymph node invasion.20Ljungberg B. Albiges L. Abu-Ghanem Y. et al.European Association of Urology Guidelines on Renal Cell Carcinoma: The 2022 Update.Eur Urol. 2022; 82: 399-410Abstract Full Text Full Text PDF PubMed Scopus (517) Google Scholar The evidence regarding management of venous tumour thrombus is based on retrospective studies.21Lardas M. Stewart F. Scrimgeour D. et al.Systematic Review of Surgical Management of Nonmetastatic Renal Cell Carcinoma with Vena Caval Thrombus.Eur Urol. 2016; 70: 265-280Abstract Full Text Full Text PDF PubMed Google Scholar Resection of venous thrombi is challenging and associated with a high risk of complications. Surgical intervention should be considered, but the most effective approach remains uncertain and outcomes depend on tumour thrombus level. There is no established role for neoadjuvant therapies. Unique considerations for VHL-associated RCC. VHL is a rare, autosomal dominant, hereditary disorder caused by germline pathogenic variants in the VHL gene. Approximately 70% of patients with VHL will develop RCC during their lifetime.22Jonasch E. Donskov F. Iliopoulos O. et al.Belzutifan for Renal Cell Carcinoma in von Hippel-Lindau Disease.N Engl J Med. 2021; 385: 2036-2046Crossref PubMed Scopus (262) Google Scholar Historic approaches to the management of RCC in this population have mostly relied on surgical or ablative approaches; however, given the propensity of patients with VHL to develop multiple RCCs, this often requires multiple procedures. Belzutifan is a novel hypoxia-inducible factor 2 alpha (HIF-2α) transcription factor inhibitor. A recent phase II, open-label, single-group trial of 61 patients investigated belzutifan in VHL-associated RCC.23Srinivasan R. Iliopoulos O. Rathmell W.K. et al.LBA69 Belzutifan, a HIF-2α Inhibitor, for von Hippel-Lindau (VHL) disease-associated neoplasms: 36 months of follow-up of the phase II LITESPARK-004 study.Ann Oncol. 2022; 33: S1433-S1434Abstract Full Text Full Text PDF Google Scholar The overall response rate (ORR) was 64% and there was a reduction in the need for subsequent intervention. Belzutifan appears to be well tolerated and should be recommended for patients who do not require immediate surgery. The phase III KEYNOTE-564 trial evaluated pembrolizumab (17 cycles of 200 mg three times weekly) versus placebo as adjuvant therapy in 994 patients with ccRCC with intermediate-high or high-risk disease (as defined by the trial protocol), or M1 and no evidence of disease (NED).10Choueiri T.K. Tomczak P. Park S.H. et al.Adjuvant Pembrolizumab after Nephrectomy in Renal-Cell Carcinoma.N Engl J Med. 2021; 385: 683-694Crossref PubMed Google Scholar After a median follow-up of 57.2 months, pembrolizumab was associated with improved overall survival (OS) [hazard ratio (HR) 0.62, 95% confidence interval (CI) 0.44-0.87, P = 0.005] and disease-free survival (DFS) (HR 0.72, 95% CI 0.59-0.87) versus placebo.24Choueiri T.K. Tomczak P. Park S.H. et al.Overall Survival with Adjuvant Pembrolizumab in Renal-Cell Carcinoma.N Engl J Med. 2024; 390: 1359-1371Crossref Scopus (2) Google Scholar This is the first adjuvant therapy with proven survival benefit in operable RCC and is recommended in patients with intermediate-high and high-risk (KEYNOTE-564 criteria) ccRCC, after careful patient selection and counselling regarding potential acute and long-term adverse events (AEs). If used, treatment should start within 12 weeks of surgery and continue for up to 1 year. The DFS and reported OS benefits observed in KEYNOTE-564 contrast with other trials of immunotherapy in the adjuvant setting (e.g. atezolizumab25Pal S.K. Uzzo R. Karam J.A. et al.Adjuvant atezolizumab versus placebo for patients with renal cell carcinoma at increased risk of recurrence following resection (IMmotion010): a multicentre, randomised, double-blind, phase 3 trial.Lancet. 2022; 400: 1103-1116Abstract Full Text Full Text PDF PubMed Google Scholar and ipilimumab–nivolumab26Motzer R.J. Russo P. Grünwald V. et al.Adjuvant nivolumab plus ipilimumab versus placebo for localised renal cell carcinoma after nephrectomy (CheckMate 914): a double-blind, randomised, phase 3 trial.Lancet. 2023; 401: 821-832Abstract Full Text Full Text PDF PubMed Google Scholar). Differences in trial design, duration of treatment, ICI activity or increased toxicity associated with the use of ipilimumab may offer explanations for the contrasting results. Biomarker data from these trials are also required. Adjuvant VEGFR-targeted therapies have demonstrated inconsistent benefit in phase III randomised trials.27Haas N.B. Manola J. Uzzo R.G. et al.Adjuvant sunitinib or sorafenib for high-risk, non-metastatic renal-cell carcinoma (ECOG-ACRIN E2805): a double-blind, placebo-controlled, randomised, phase 3 trial.Lancet. 2016; 387: 2008-2016Abstract Full Text Full Text PDF PubMed Google Scholar,28Ravaud A. Motzer R.J. Pandha H.S. et al.Adjuvant Sunitinib in High-Risk Renal-Cell Carcinoma after Nephrectomy.N Engl J Med. 2016; 375: 2246-2254Crossref PubMed Scopus (592) Google Scholar An algorithm for the treatment of local and locoregional RCC is shown in Figure 2. •Surgical resection remains the SoC for localised renal cancer [I, A] with either minimally invasive or open approaches preferred depending on tumour size and complexity.•Several nephron-sparing options, ranging from surveillance to PN, are recommended for small renal masses (T1 ≤4 cm) [III, B].•Belzutifan may avoid surgeries and can be considered for patients with germline VHL variants and localised renal cancer [III, A; ESMO-Magnitude of Clinical Benefit Scale (ESMO-MCBS) v1.1 score: 3; Food and Drug Administration (FDA) approved, not European Medicines Agency (EMA) approved].•Adjuvant pembrolizumab should be considered for patients with intermediate-high or high-risk operable ccRCC (as defined by the KEYNOTE-564 criteria) after careful patient counselling regarding potential long-term AEs [I, A; ESMO-MCBS v1.1 score: A]. Treatment should start within 12 weeks of surgery and continue for up to 1 year.•Adjuvant VEGFR-targeted therapies are not recommended [I, D]. Upfront cytoreductive nephrectomy (CN) is no longer considered the SoC in unselected patients with intermediate-risk asymptomatic primary ccRCC and all patients with poor-risk asymptomatic primary ccRCC in the advanced and metastatic setting.29Méjean A. Ravaud A. Thezenas S. et al.Sunitinib Alone or after Nephrectomy in Metastatic Renal-Cell Carcinoma.N Engl J Med. 2018; 379: 417-427Crossref PubMed Scopus (599) Google Scholar Due to the inclusion criteria and subset analysis from the CARMENA trial, CN may still be considered for patients with low-volume single-organ metastatic disease with a large primary tumour, or for patients who have had a near complete response (CR) to upfront systemic therapy.29Méjean A. Ravaud A. Thezenas S. et al.Sunitinib Alone or after Nephrectomy in Metastatic Renal-Cell Carcinoma.N Engl J Med. 2018; 379: 417-427Crossref PubMed Scopus (599) Google Scholar These patients may be candidates for observation rather than systemic therapy after CN, although data are limited regarding long-term outcomes in this setting. Metastasectomy, thermal ablation, stereotactic radiosurgery, SBRT, CyberKnife radiotherapy (RT) and hypofractionated RT can be considered for selected patients with low metastatic burden after multidisciplinary team (MDT) review, although randomised or robust prospective data to support their use is lacking.3

Dans le cancer de la prostate localisé, l’impact de l’hypogonadisme biochimique sur l’émergence et la progression du cancer est encore controversée. Notre objectif est de comparer les caractéristiques pathologiques et la récidive biologique (RB) à 5 ans après prostatectomie des patients atteints de cancer de la prostate (CaP) localisé en fonction du statut gonadique évalué par le total (TT) et la biodisponibilité (BT). Une étude de cohorte prospective de 1318 patients (âge 65,0, taille 174 cm, poids 81,5 kg, IMC 26,0 kg/m2, périmètre abdominal 100 cm) atteints de CaP localisé recrutés dans 4 centres urologiques en France, de 6/2013 à 6/2016 ayant tous un suivi de 5 ans postopératoire. Les paramètres du syndrome métabolique (MetS) ont été recueillis. Les dosages de TT, BT, DHT, E1 et E2 ont été réalisés par GC-MS. Un examen croisé centralisé des données pathologiques (grade de Gleason 4 prédominant (PrdGP4), stade) a été effectué. La survie sans RB a été évaluée selon Kaplan-Meier avec comparaisons par test de Log-rank. La cohorte a été divisée en 3 groupes ; le premier (n = 1067 ; 81 %) composé de patients eugonadiques dont la TT et la BT étaient normales (TT ≥ 3 ng/ml et BT ≥ 0,8 ng/ml), le deuxième (n = 251 ; 19 %) de ceux dont la TT et/ou la BT étaient diminuées et le troisième (n = 58 ; 4 %) de ceux dont la TT et la BT étaient diminuées. Les pourcentages de PrdGP4 et de pT ≥ 3 a étaient respectivement de 31 % et 30 % chez les eugonadiques et 41 % et 40 %, et 50 % et 51 % dans les deuxième et troisième groupe (différences significatives). 237 RB ont été observées (fréquence de 17 % chez les eugonadiques contre 21 % chez les hypogonadiques (différence non significative ; Fig. 1) du groupe 2 et 7 % (p = 0,017) chez ceux du groupe 3 (Fig. 1). Cette étude prospective démontre que l’hypogonadisme bioChimique a été associé à des CaP dont les caractéristiques histopathologiques sont plus fréquemment défavorables mais sans survenue significativement supérieure de RB dans les 5 ans après prostatectomie. Par conséquent, le statut gonadique biologique préopératoire des patients est utile pour la décision thérapeutique mais n’indique pas un suivi spécifique sur le plan oncologique.

Aim: The 46-gene Prolaris® cell cycle progression test provides information on the risk of prostate cancer progression. Here we developed and validated a 16-gene kit-based version. Methods: RNA was extracted from prostate cancer biopsy tissue. Amplification efficiency, minimum tumor content, repeatability, reproducibility and equivalence with the 46-gene test were evaluated. Results: Amplification efficiencies for all genes were within the acceptable range (90-110%), and samples with ≥50% tumor content were appropriate for the 16-gene test. Results were repeatable (standard deviation: 0.085) and reproducible (standard deviation: 0.115). Instrument, operator and kit lot had minimal impact on results. Cell cycle progression scores from the 46- and 16-gene tests were highly correlated (r = 0.969; bias = 0.217). Conclusion: The 16-gene test performs consistently and similarly to the 46-gene test.

Bien que l’expression de PD-L1 et PD-1 soit associée à un mauvais pronostic pour les tumeurs de vessie, les données sont plus rares et contradictoires pour les tumeurs de la voie excrétrice supérieure (TVES). L’objectif de cette étude était d’évaluer la valeur pronostique de l’expression de PD-L1 et PD-1 pour les TVEUS dans une large cohorte multicentrique française. Les blocs tumoraux de 283 patients traités par néphro-urétérectomie totale(NUT) pour une TVEUS ont été collectés dans 11 centres français afin d’évaluer l’expression de PD-L1 sur les cellules tumorales et PD-1 sur les lymphocytes infiltrant la tumeur en immunohistochimie à partir de Tissue Micro Arrays de 2 mm. Des modèles de Cox ajustés par des scores de propension basés sur la probabilité inverse d’exprimer soit PD-L1 ou PD-1 ont été utilisés pour comparer la survie sans récidive (SSR), spécifique (SS) et globale (SG) des patients PD-L1 ou PD-1 positif et négatif. Des analyses de sous-groupe ont été réalisées en fonction des résultats des tests d’interaction. Au total, 187 (66 %) et 96 (34 %) patients présentaient une expression respectivement positive et négative de PD-L1 alors que 65 (23. 0 %) et 218 (77. 0 %) patients présentaient une expression respectivement positive et négative de PD-1. L’analyse de Cox ajustée par score de propension montrait que l’expression positive de PD-L1 ou PD-1 n’avait pas d’impact significatif sur la SSR (HR = 1,77 ; 95 %CI = [0,89–1,54] ; p = 0,25 et HR = 1,11 ; 95 %CI = [0,84–1,45] ; p = 0,46, respectivement), la SS (HR = 1,14 ;95 %CI = [0,48–1,48] ; p = 0,30 et HR = 1,22 ; 95 %CI = [0,87–1,70] ; p = 0,25, respectivement), et la SG (HR = 1,14 ; 95 %CI = [0,48–1,48] ; p = 0,30 et HR = 1,01 ; 95 %CI = [0,78–1,32] ; p = 0,94, respectivement). Après les tests d’interaction, seule l’expression positive de PD-1 était associée à une diminution significative de la SSR (HR = 2,19 ; 95 %CI = [1,27–3,77] ; p = 0,01) et de la SS (HR = 2,38 ; 95 %CI = [1,27–4,44] ; p = 0,01) chez les patients ≤ pT1 alors qu’il n’y avait pas d’impact pronostic du statut PD-1 chez les patients ≥ pT2 (tous les p > 0,05). L’expression de PD-L1 et PD-1 ne semble pas avoir de valeur pronostique pour les TVEUS, à l’exception des lésions ≤pT1 pour lesquelles l’expression de PD-1 pourrait impacter les résultats oncologiques de la NUT. Cela est en cohérence avec les résultats contradictoires disponibles dans la littérature, et souligne l’importance d’évaluer les particularités immunologiques des TVEUS, indépendamment des tumeurs de vessie.

•This ESMO Clinical Practice Guideline provides key recommendations for diagnosis, staging and management of bladder cancer.•Recommendations for personalised medicine are also included.•All recommendations were compiled by a multinational and multidisciplinary group of experts.•Recommendations are based on the latest available scientific data and the authors’ expert opinions.•These recommendations are updated continuously in order to include results of the latest clinical trials.

Les progrès de l’imagerie par résonance magnétique multiparamétrique (IRMmp) prostatique et des systèmes de fusion d’images ont conduit au développement des biopsies ciblées pour le diagnostic du cancer de la prostate (CaP). L’objectif de cette étude était de réaliser une évaluation du taux de détection annuel du CaP dans une seule institution réalisant des biopsies ciblées depuis 10 ans. De janvier 2010 à novembre 2020, les données de tous les patients consécutifs ayant eu une IRM et une série de biopsies de prostate à l’aide du dispositif UroStation ou Trinity (Koelis) ont été recueillies de façon prospective. En cas de cible visible sur l’IRM (PIRADSv1 ou v2 > 2), des carottes ciblées (2 à 3 sur la cible index) et systématiques (12) ou uniquement ciblées étaient réalisées, selon le choix du praticien. En l’absence de cible, seules des carottes systématiques étaient réalisées. Les principaux critères d’évaluation étaient le taux annuel de détection global de CaP et de CaP cliniquement significatif (défini par un Gleason > 6). Parmi les 2942 patients inclus, 620 ont eu des carottes ciblées uniquement, 1782 ont eu des biopsies combinées (ciblées + systématiques) et 540 hommes ont eu uniquement des carottes systématiques. Vingt-neuf opérateurs différents ont effectué des biopsies chez des patients présentant un volume prostatique médian de 41 mL (IQR : 30–60) et un PSA médian de 7 ng/mL (IQR : 5–11). En 10 ans, le taux de détection du CaP est passé de 45 % à 73 % (p < 0,001) en suivant une progression régulière. Le taux de détection du CaP cliniquement significatif est passé de 23 % à 58 % (p < 0,001) et a donc été multiplié par 2,5. Cette augmentation linéaire sur les 10 ans a représenté la majorité CaP diagnostiqués après 2016 (cf. Fig. 1). Le taux de détection des CaP non significatifs a diminué sur l’ensemble de la période (p < 0,001). Dans cette étude menée sur 10 ans, la mise en œuvre d’un protocole de biopsies ciblées a conduit à améliorer notablement le taux de détection des CaP cliniquement significatifs sans augmenter le taux de détection des CaP non cliniquement significatif.

Les patients neuro-urologiques développent des tumeurs de vessie (TV) diagnostiquées à un stade tardif de la maladie après une longue évolution de la maladie neuro-urologique. Les caractéristiques épidémiologiques de ces TV restent mal connues. L’objectif de cette étude était de recenser les patients ayant eu une cystectomie pour TV sur vessie neurologique (VN) en France de janvier 2013 à décembre 2018, identifiés par une interrogation des urologues membres de l’AFU, et de les comparer à des patients ayant eu une cystectomie pour TV sur vessie non neurologique. Les données cliniques pré-opératoires, l’analyse anatomopathologique, la survie globale et spécifique ont été comparées entre les groupes VN et non VN (test du Chi2 pour les données qualitatives, test de Mann et Whitney pour les données quantitatives et test du Log Rank pour les survies). Entre 2013 et 2016, 54 patients avec cystectomie pour TV sur VN ont été identifiés en France à un âge moyen au diagnostic de 55,8 ± 11,2 ans (Tableau 1). La pathologie neurologique principale était une lésion médullaire et le mode mictionnel préférentiel l’autosondage. Comparés à un groupe de 215 TV sur vessie non neurologique (Tableau 2), les patients du groupe VN étaient significativement plus jeunes au moment du diagnostic et de la cystectomie (p < 0,001), avec une proportion de femmes plus importante. De plus, la proportion de carcinomes épidermoïdes dans le groupe VN était significativement plus importante (p < 0,001). La survie spécifique était significativement moins importante dans le groupe VN mais il n’existait pas de différence en survie globale entre les deux groupes (Fig. 1a et b). Les TV sur vessie neurologiques sont diagnostiquées à un âge plus précoce et la survie spécifique était moins longue que pour les TV sur vessie non neurologique. Une étude du profil protéomique de ces TV permettrait d’affiner leur connaissance.