Penile cancer: ESMO–EURACAN Clinical Practice Guideline for diagnosis, treatment and follow-up

•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