cancers Article Epidemiology, Diagnosis and Management of Penile Cancer: Results from the Spanish National Registry of Penile Cancer Ángel Borque-Fernando 1,† , Josep Maria Gaya 2, *, Luis Mariano Esteban-Escaño 3, * , Juan Gómez-Rivas 4 , Rodrigo García-Baquero 5 , Fernando Agreda-Castañeda 6 , Andrea Gallioli 2 , Paolo Verri 2 , Francisco Javier Ortiz-Vico 7 , Balig Fawwaz Amir-Nicolau 8 , Ignacio Osman-Garcia 9 , Pedro Gil-Martínez 1 , Miguel Arrabal-Martín 10 , Álvaro Gómez-Ferrer Lozano 11 , Felix Campos-Juanatey 12 , Félix Guerrero-Ramos 13 and Josè Rubio-Briones 14,†,‡ on behalf of Grupo Cooperativo de Registro Nacional Cáncer Pene (PIEM/AEU/2014/0002) 1 IIS-Aragón, Miguel Servet University Hospital, Universidad de Zaragoza, 50009 Zaragoza, Spain 2 Fundació Puigvert, Autonomus University of Barcelona, 08193 Barcelona, Spain 3 Applied Mathematics Department, Escuela Universitaria Politécnica de La Almunia, Universidad de Zaragoza, 50100 La Almunia de Doña Godina, Spain 4 Hospital Universitario La Paz, 28046 Madrid, Spain 5 Hospital Universitario Puerta del Mar, 11009 Cádiz, Spain 6 Hospital Germans Trias y Pujol, 08916 Badalona, Spain 7 Principe Asturias University Hospital, 28805 Alcala de Henares, Spain 8 Nuestra Señora de la Candelaria University Hospital, 38010 Santa Cruz de Tenerife, Spain 9 Virgen del Rocio University Hospital, 41013 Sevilla, Spain 10 Granada University Hospital, 18071 Granada, Spain 11 Instituto Valenciano de Urologia (IVO), 46009 Valencia, Spain 12 Marques de Valdecilla University Hospital, 39008 Santander, Spain 13 Hospital Universitario 12 de Octubre, 28041 Madrid, Spain 14 Clinica de Urología, Hospital VITHAS 9 de Octubre, 46015 Valencia, Spain Citation: Borque-Fernando, Á.; Gaya, * Correspondence: jmgaya@fundacio-puigvert.es (J.M.G.); lmeste@unizar.es (L.M.E.-E.); J.M.; Esteban-Escaño, L.M.; Tel.: +34-934-169-700 (J.M.G.); +34-976-600-813 (ext. 121) (L.M.E.-E.) † These authors contribute equally to this work. Gómez-Rivas, J.; García-Baquero, R.; ‡ Collaborators/Membership of the Group is provided in the Acknowledgments. Agreda-Castañeda, F.; Gallioli, A.; Verri, P.; Ortiz-Vico, F.J.; Amir-Nicolau, B.F.; et al. Simple Summary: Penile cancer is a rare malignant tumor mainly affecting adult/older men. Given Epidemiology, Diagnosis and the rarity of this disease, affecting 1/100,000 men every year, risk factors and diagnostic procedures Management of Penile Cancer: are often inadequately described. This is the first multicenter study to describe the approach to this Results from the Spanish National disease in Spain. The results highlight the need for the institution of referral centers and standardized Registry of Penile Cancer. Cancers diagnostic pathways for the optimal management of this disease. 2023, 15, 616. https://doi.org/ 10.3390/cancers15030616 Abstract: Introduction: Penile cancer (PC) is a rare malignancy with an overall incidence in Europe Academic Editor: Francesco Massari of 1/100,000 males/year. In Europe, few studies report the epidemiology, risk factors, clinical presentation, and treatment of PC. The aim of this study is to present an updated outlook on Received: 22 December 2022 the aforementioned factors of PC in Spain. Materials and Methods: A multicentric, retrospective, Revised: 11 January 2023 observational epidemiological study was designed, and patients with a new diagnosis of PC in 2015 Accepted: 17 January 2023 were included. Patients were anonymously identified from the Register of Specialized Care Activity Published: 19 January 2023 of the Ministry of Health of Spain. All Spanish hospitals recruiting patients in 2015 were invited to participate in the present study. We have followed a descriptive narration of the observed data. Continuous and categorical data were reported by median (p25th–p75th range) and absolute and Copyright: © 2023 by the authors. relative frequencies, respectively. The incidence map shows differences between Spanish regions. Licensee MDPI, Basel, Switzerland. Results: The incidence of PC in Spain in 2015 was 2.55/100,000 males per year. A total of 586 patients This article is an open access article were identified, and 228 patients from 61 hospitals were included in the analysis. A total of 54/61 distributed under the terms and (88.5%) centers reported ≤ 5 new cases. The patients accessed the urologist for visually-assessed conditions of the Creative Commons penile lesions (60.5%), mainly localized in the glans (63.6%). Local hygiene, smoking habits, sexual Attribution (CC BY) license (https:// habits, HPV exposure, and history of penile lesions were reported in 48.2%, 59.6%, 25%, 13.2%, creativecommons.org/licenses/by/ and 69.7%. HPV-positive lesions were 18.1% (28.6% HPV-16). The majority of PC was squamous 4.0/). Cancers 2023, 15, 616. https://doi.org/10.3390/cancers15030616 https://www.mdpi.com/journal/cancers Cancers 2023, 15, 616 2 of 12 carcinoma (95.2%). PC was ≥cT2 in 45.2% (103/228) cases. At final pathology, PC was ≥pT2 in 51% of patients and ≥pN1 in 17% of cases. The most common local treatment was partial penectomy (46.9% cases). A total of 47/55 (85.5%) inguinal lymphadenectomies were open. Patients with ≥pN1 disease were treated with chemotherapy in 12/39 (40.8%) of cases. Conclusions: PC incidence is relatively high in Spain compared to other European countries. The risk factors for PC are usually misreported. The diagnosis and management of PC are suboptimal, encouraging the identification of referral centers for PC management. Keywords: penile cancer; cancer; epidemiology; incidence 1. Introduction Penile cancer (PC) is a rare cancer globally, but great variation exists between countries. Its occurrence leads to strong physical and psychological consequences for the patient since surgical treatment includes the partial or total removal of the external genitalia. The overall incidence in Europe accounts for 1/100,000 males per year [1,2]. However, there is evidence that PC incidence has been increasing in recent years in Europe [3,4]. Although it can affect men of any age, it is usually diagnosed in the sixth and seventh decades [5]. Squamous cell carcinoma (SCC) comprises the vast majority of cases accounting for up to 95% of cases of PC [6], while other variants such as basaloid, warty, verrucous, papillary, and mixed carcinoma account for the residual percentage [7]. The European Association of Urology (EAU) guidelines for PC recommend treating the patient with a partial or total penectomy and a strict follow-up depending on TNM staging and grading [7]. Multiple risk factors have been identified and described, such as smoking, lack of circumcision, phimosis, obesity, poor hygiene, and lichen sclerosis [8]. The exposure to Human Papilloma Virus (HPV) is directly related to increased reporting, with HPV DNA prevalence in 50.8% of PC patients, as reported by Saraiya et al. in a meta-analysis based on 52 studies [9]. Methodological drawbacks have been proposed in the evaluation of the association between HPV and PC due to a limited number of reliable studies, different and/or unreliable detection methods, and confusing bias due to the inclusion of any anogenital warts as premalignant lesions. However, the pooled relative risks indicate up to a 4.5-fold increased risk between seropositivity for HPV infection and invasive PC [10]. The difference in HPV prevalence among geographical regions and the low socio-economic status linked to a lack of education and seeking medical treatment might influence the profile of patients with PC [11]. In fact, the incidence rates vary dramatically among different populations, with less developed nations having the highest incidence. Reports indicate the largest disease burden concentration in Brazil, with a recorded incidence of 2.8–6.8 per 100,000 and an incidence of 0.3–0.6 per 100,000 in the United States and the United Kingdom [12,13]. In Europe, few studies reported the epidemiology of PC in different countries, an- alyzing the incidence trends without focusing on risk factors, clinical presentation, and treatment of this rare disease. This lack of evidence translates into a disregard for the direct impact of PC in developed countries. Therefore, the aim of this study is to present an updated transversal outlook on the incidence, distribution per region, risk factor profile, and clinical management of PC in Spain. 2. Material and Methods 2.1. Patient Recruitment A multicentric, retrospective, observational epidemiological study was designed. Booth’s request for data extraction from the Register of Specialized Care Activity, including all patients diagnosed with PC in 2014 and 2015, was sent to the Ministry of Health, Social Services, and Equality of Spain. The International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) diagnostic codes were used to select potential Cancers 2023, 15, 616 3 of 12 candidates for the study; in particular, the codes 187.1 “Malignant Neoplasm of Prepuce”, 187.2 “Malignant neoplasm of glans penis”, 187.3 “Malignant neoplasm of body of penis”, 187.4 “Malignant neoplasm of penis, unspecified”, 222.1 “Benign neoplasm of penis”, 233.5 “Carcinoma in situ of penis” were used. The inclusion criteria were patients with a new diagnosis of PC in 2015 with hospital admission. According to the specific consultation carried out in the Health Activity In- formation and Statistics Area of the Institute of Health Information (Ministry of Health, Social Services, and Equality), 943 potential patients with a diagnosis of PC and hospi- tal admission in 2015 were identified, and 753 cases in 2014. After eliminating hospital readmission in 2015 of the same patient or previous admission and diagnosis in 2014, 586 patients were identified and were considered the potential target population of our study. From the Ministry of Health database, those patients could be located anonymously. The corresponding hospitals from the patients’ locations were invited by the investigators to fill out the electronic Case Report Form for each patient (Plataforma de Investigación de Estudios Multicéntricos de la Asociación Española de Urología, PIEM-AEU. https://piem. aeu.es/proyectos/RegNCaPene/ (accessed on 2 January 2019) through a pseudonymiza- tion procedure (Supplementary Materials). All 226 Spanish public and private centers were eligible to participate. The study protocol was approved by the Ethical Committee of Fundación Instituto Valenciano de Urología (protocol number: AEU/PIEM/2014/0002; date of approval, 27 September 2017). The study was conducted in accordance with the Declaration of Helsinki (1964) and the Guidelines for Best Clinical Practice. Patients with a clinical diagnosis of PC in 2015 without any histology were excluded from the study. Premalignant lesions treated on an outpatient basis were not taken into account as there were no reliable documented hospital admissions, and every hospital recorded them in a heterogeneous manner. 2.2. Objective The primary endpoint of the study was to evaluate the incidence of PC in a contempo- rary national series. The secondary endpoint was to describe the characteristics of the diagnosis of PC in Spain and to analyze therapeutic management and deviations from clinical practice guidelines. 2.3. Statistical Analysis The PC incidence rate was reported as cases per 100,000 persons. An incidence map shows differences between Spanish regions. The analyzed variables included demographic data, risk factors (phimosis, HPV, smoking status), sexual habits, primary lesion and lymph node status at first diagnosis, radiological and nuclear imaging, penile and sentinel lymph node biopsy histology, patho- logical stage according to TNM classification, and surgical treatment and complications. Pathological data were recruited following EAU recommendations. There was no central pathological review. The continuous variables were described using median and interquartile range (p25th–p75th), and categorical variables were reported by absolute and relative frequency. 3. Results The overall incidence of PC in Spain in 2015 was 2.55/100,000 male inhabitants per year. By autonomous regions, the higher incidence was observed in Castilla León, followed by Castilla La Mancha and Galicia. All three together were above the national average (Figure 1). The lowest incidence was in Cantabria, the Balearic Islands, and Extremadura. The median age at diagnosis was 72 years (interquartile range: 62–81 y.o.). or equal to 5 new cases in a year. The patients were sent to urologic consulta another specialist in 45.6% (104/228) cases and from the general practitione (75/228). Cancers 2023, 15, 616 4 of 12 Figure 1. Incidence rate of penile cancer in the Autonomous Communities of Spain. After an invitation to review the medical charts of the 586 patients identified, 61 centers answered, and 280 patients Figure 1.were properly Incidence registered rate of in the penile cancer in database. After aCommunities the Autonomous critical revision of Spain. of the patients entered into the database, 52 patients were excluded for protocol violations (namely, the first PC3.1. histologic Clinics diagnosis outside 2015). Only 2/61 (3.3%) hospitals reported more than 10 new patients, while 54/61 The patients (88.5%) accessed the centers urologistreported fewerassessed for visually than or penile equal tolesions (60 5 new cases in a year. The patients were sent to urologic consultation from another specialist puration (11.8%), pain (5.7%), and itching (6.1%) (Table 1). The lesions were lo in 45.6% (104/228) the cases and(63.6%), glans from thebalanic generalgroove practitioner (14%),inpreputial 32.9% (75/228). skin (9.7%), preputial muco penile skin (2.6%), and urethra (2.2%) (Figure 2). 3.1. Clinics The patients accessed Table 1. the urologist Patients’ for visually Baseline assessed Characteristics (n = penile 228). lesions (60.5%), suppu- ration (11.8%), pain (5.7%), and itching (6.1%) (Table 1). The lesions were localized at the glans (63.6%), balanic groove (14%), preputial skin (9.7%), preputial mucosa (7.5%), penile skin (2.6%), and urethra (2.2%) (Figure 2). Table 1. Patients’ Baseline Characteristics (n = 228). Median (IQR) or Number (%) Age, years 72 (62–81) Prior circumcision 70 (30.7) Prior HPV exposure Yes 2 (0.9) No 28 (12.3) Unknown 198 (86.8) Local hygiene Correct 62 (27.2) Poor 48 (21.1) Unknown 188 (51.7) Cancers 2023, 15, 616 5 of 12 Table 1. Cont. Median (IQR) or Number (%) Smoking habits Never 73 (32) Current 63 (27.6) Unknown 92 (40.4) Promiscuous sexual habits Yes 10 (4.4) No 47 (20.6) Unknown 171 (75) Prior penile lesion Yes 62 (27.2) No 97 (42.5) Unknown 69 (30.3) Referral to a urologist Specialist 104 (45.6) General practitioner 75 (32.9) Entourage 10 (4.4) Unknown 39 (17.1) Symptoms Visually assessed penile lesion 138 (60.5) Suppuration 27 (11.8) Pain 13 (5.7) Itching 14 (6.1) Unknown 36 (15.9) Phimosis at clinical presentation 103 (45.2) Tumor location Glans 145 (63.6) Balanic groove 17 (7.5) Preputial skin 22 (9.7) Preputial mucosa 32 (14) Penile skin 6 (2.6) Cancers 2023, 15, x FOR PEER REVIEWUrethra 5 (2.2) 6 of 12 Unknown 1 (0.4) Figure 2. Localization of penile cancer lesions. Figure 2. Localization of penile cancer lesions. Phimosis Phimosis waswas present present in 45.2% in 45.2% (103/228)(103/228) of patients,of patients, while while had 30.7% (70/228) 30.7% been(70/228) had been submitted submitted to to circumcision circumcision at a median at a median age of 60 age of years (35–74) 60 (35–74) years old. Local old.smoking hygiene, Local hygiene, smoking habits, sexual habits, HPV exposure, and history of penile lesions were reported in only 48.2%, 59.6%, 25%, 13.2%, and 69.7% of cases, respectively. Among patients who underwent risk factors assessment, 43.5% had poor local hygiene, 46.3% were smokers, 17.5% had promiscuous sexual habits, 7.1% reported HPV exposure, and 39% had a history of penile lesions. The tumors were known as HPV-positive in 28/155 (18.1%), 8/28 (28.6%) cases were HPV 16, 1 case of HPV 12, 24, 42, 51, 52, 53, 68, 70, or 82, and 11/28 Cancers 2023, 15, 616 6 of 12 habits, sexual habits, HPV exposure, and history of penile lesions were reported in only 48.2%, 59.6%, 25%, 13.2%, and 69.7% of cases, respectively. Among patients who underwent risk factors assessment, 43.5% had poor local hygiene, 46.3% were smokers, 17.5% had promiscuous sexual habits, 7.1% reported HPV exposure, and 39% had a history of penile lesions. The tumors were known as HPV-positive in 28/155 (18.1%), 8/28 (28.6%) cases were HPV 16, 1 case of HPV 12, 24, 42, 51, 52, 53, 68, 70, or 82, and 11/28 (39.3%) cases were HPV subtype unknown. 3.2. Histology and Staging Table 2 depicts the clinical and pathological features of PC. The vast majority of PC were SCC (95.2%), with only one case of melanoma (0.4%), one case of undetermined carcinoma (0.4%), and 9 cases of unknown nature (4%). The most frequent SqCCs were common (62.7%), verrucous (12.3%), condylomatous (i.e., warty) (4%), and basaloid (2.2%) variants. Less frequent variants were mixed (4 cases, 1.7%), papillary (2 cases, 0.9%), adenosquamous (2 cases, 0.9%), and sarcomatoid (1 case, 0.4%) carcinomas. In 34 cases (14.9%), no specific SqCC subtype was identified. At first biopsy, the grade of the lesion was not reported or Gx in 34% (78/228) patients, while there was a similar distribution between G1 and G2 lesions, diagnosed in 60 (26.3%) and 57 (25%) patients, respectively. All the aforementioned results were confirmed at final pathology, with the tumor grading being undetermined in 25% (57/228) of cases. Table 2. Staging and Pathological Features of Penile Cancer (n = 228). Median (IQR) or Number (%) Histology Squamous cell carcinoma (SCC) 217 (95.2) Undetermined carcinoma 1 (0.4) Melanoma 1 (0.4) Unknown 9 (4) SqCC subtype Common carcinoma 143 (62.7) Basaloid carcinoma 5 (2.2) Warty carcinoma 9 (4) Papillary carcinoma 2 (0.9) Verrucous carcinoma 28 (12.3) Sarcomatoid carcinoma 1 (0.4) Mixed carcinoma 4 (1.7) Adenosquamous carcinoma 2 (0.9) Unknown 34 (14.9) Clinical T stage cTx 23 (10.1) cT0 5 (2.2) cTis 22 (9.6) cTa 7 (3.1) cT1a 51 (22.4) cT1b 17 (7.5) cT2 (corpus spongiosum) 45 (19.7) cT2 (corpus cavernosum) 21 (9.2) cT3 28 (12.3) cT4 9 (3.9) Clinical N stage Nx 55 (24.1) N0 132 (57.9) N1 11 (4.8) N2 16 (7) N3 14 (3.1) Cancers 2023, 15, 616 7 of 12 Table 2. Cont. Median (IQR) or Number (%) Clinical M stage Mx 35 (15.3) M0 181 (79.4) M1 12 (5.3) Grade at biopsy Gx 78 (34.2) G1 60 (26.3) G2 57 (25) G3–G4 33 (14.5) Pathological T stage pTx 7 (3.1) pT0 3 (1.3) pTis 23 (10.1) pTa 7 (3.1) pT1a 54 (23.7) pT1b 17 (7.5) pT2 (corpus spongiosum) 50 (21.9) pT2 (corpus cavernosum) 22 (9.6) pT3 37 (16.2) pT4 8 (3.5) Pathological N stage pNx 98 (43) pN0 91 (39.9) pN1 12 (5.3) pN2 10 (4.4) pN3 17 (7.4) Grade in the final specimen Gx 57 (25) G1 72 (31.5) G2 64 (28.1) G3–G4 35 (15.4) Penile cancer presented as ≥cT2 in 45.2% (103/228) of cases, with the T2 stage involving more frequently the corpus spongiosum. At final pathology, the lesions were ≥pT2 in 51% (117/228) of patients with a high incidence of pT1a (54/228; 23.7%) tumors and 10.1% (23/228) pTis tumors. The patients had clinically positive inguinal lymph nodes in 18% (41/228) of cases. Out of 130 lymph node biopsies/lymphadenectomies, 39 (30%) cases were ≥pN1. A total of 12 (5%) patients had metastatic disease. The majority were lung (41.7%; 5/12) and cutaneous (16.7%; 2/12) metastasis. 3.3. Management The surgery for primary treatment was partial penectomy, wedge excision, glan- sectomy, and total penectomy in 46.9%, 21.1%, 14.9%, and 11.4% of cases, respectively. Nonetheless, in 27/228 (11.8%) cases, the surgical margin was positive. In fact, 21.7%, 11.8%, 4.7%, and 26.9% margins were positive in wedge excision, glansectomy, partial penectomy, and total penectomy, respectively. Topic therapy with 5-fluoracile/imiquimod was rarely used (5.3%), as for laser treatment with either CO2 or Nd:YAG (1.7%). A total of 55 inguinal lymphadenectomy procedures were performed (39 bilateral and 16 unilateral). Out of these, 8 (14.5%) were laparoscopic, and the remnant (85.5%) were open, with a median of excised lymph nodes of 12 (5–16) and positive nodes of 3 (IQR: 2–6). Pelvic lymphadenectomy was performed in 13/55 (23.6%) cases, with a median of 2 (IQR: 1–4) and 7 (IQR: 3–10) positive and excised lymph nodes. Cancers 2023, 15, 616 8 of 12 Patients with ≥pN1 disease were treated with neoadjuvant and adjuvant chemother- apy in 3/39 (7.7%) and 9/39 (23.1%) cases, respectively. Similarly, neoadjuvant and adjuvant radiotherapy was performed in 2/39 (5.1%) and 7/39 (17.9%) patients, respectively. 4. Discussion In the present study, the epidemiology and clinical management of PC was assessed in a European country. We found that the incidence of PC was 2.55/100,000 male inhabitants per year. The incidence varied significantly among different Spanish communities. There- fore, the incidence of PC in Spain is rare but relatively high compared to other countries of the European Union, as already reported in the literature [14,15]. Geographical dispar- ities in the incidence of PC are known, with high rates concentrated in the developing world (2.8–6.8/100,000), where neonatal circumcision is low and socio-economic conditions predispose patients to multiple risk factors. The lowest incidence, as low as 0.3/100,000, has been described in Western countries [8]. The incidence in Europe has been described between 0.45–1.7/100,000 [16], but a recent study reported an increase in incidence in the UK from 1.1 to 1.33 in 100,000 men between 1979 and 2009, probably related to the global sexual revolution and greater exposure to HPV and other sexually transmitted diseases [17]. The incidence of HPV infection may be influenced by the number of female partners throughout life and also by the age of first intercourse and history of sexually transmitted diseases [1]. The lack of information recorded on these issues is limiting and could explain the national and even regional differences found in the incidence of PC. Additionally, infection by the Human Immunodeficiency Virus (HIV) surely represents one of the factors to be considered in the development of this rare disease. In fact, patients affected by HIV have an increased risk of developing penile cancer, up to 11.1 times higher, with respect to the general population. Furthermore, there’s a faster progression from intraepithelial neoplasia to cancer (i.e., six years sooner) and increased cancer-specific mortality (i.e., four times higher). In addition, this review highlighted how coinfection by HPV is more frequent in this specific population, furtherly increasing the chance of developing penile cancer [18]. As estimated by Nunez et al. [19], up to 18% (95% CI 14.3–22.1%) of patients affected by HIV are unaware of it, regardless of being men who have sex with men (MSM) or heterosexuals. For privacy reasons, data regarding HIV status were not available for a non-negligible number of cases, so this aspect was not analyzed in this study. Given that numerous risk factors have been identified and many of them are modifi- able, knowing its incidence in our country could lead to public health campaigns focused on combating smoking trends, promoting better hygiene, and seeking a wide deployment of the vaccine against HPV [20]. This study represents a national registry of the diagnosis and management of PC stratified by Hospital origin in a European country and a contemporary scenario. In 2015, only 4 out of 17 communities reported more than 20 cases each, for a total of 61.8% (141/228) of new cases in Spain. Consequently, 88.5% of hospitals treated fewer than or equal to 5 new cases in a year. These results outline a worrisome national picture in the current management of PC, clearly confronting the current recommendations of EAU Guidelines [7]. Unfortunately, as observed in Table 1, the main classical risk factors mentioned in the literature for the occurrence of PC cannot be properly described. Many of them were not performed (HPV characterization and HIV status) or not reflected in the medical charts; therefore, the investigators could not translate them into the case report form. One of the suggestions we could make is that epidemiological prevention of PC should start with the proper registration and knowledge of the local incidence of risk factors in every country, mostly HPV relevance. In the majority of the communities, the patients’ access to hospitals for suspicion of PC can be considered sporadic. Since no referral centers have been identified by the national government, the treatment of PC depends on the experience of the center where the patient is accessed. This may translate into suboptimal management of the disease, either with Cancers 2023, 15, 616 9 of 12 diagnostic or curative intent [21]. Another important aspect we have to mention is that penile cancer is initially managed by general practitioners or dermatologists, referring them to a general urologist, who normally does not refer them to any referral centers as these are not predefined. For that, patients are not usually evaluated in multidisciplinary teams. As previously mentioned, the most important risk factors for PC were not systematically explored (13.2–69.7% of cases, depending on the risk factor). The grade of the lesion was undetermined in 34% of biopsies and 25% of lesions at final pathology. Despite the high rate of partial/total penectomy (58.3% of patients) in a population characterized by 48% of 20%). Concerning other treatment modalities (e.g., radiotherapy), the small sample did not allow any sub-analysis, although recent findings highlight the advantages of radiotherapy in organ-sparing approaches [25]. Interestingly, the role of circumcision is still an object of debate. Uncircumcised patients show a higher chance of harboring