Introduction and objective: Imiquimod (IQ) is an immunomodulator used in the management of penile intraepithelial neoplasia (PeIN) lesions. However, IQ treatment maybe associated with bothersome side effects (SEs). To date, studies reporting on this morbidity and evaluating predictors of response to IQ are scarce and included small cohorts. The primary objective of our study was to assess the response to IQ treatment, associated SEs, and potential predictors of response in the largest reported cohort to date. Methods: We conducted a collaborative retrospective study involving patients diagnosed with PeIN and treated with IQ between 2010 and 2022 in two high-volume centers in the Netherlands and Belgium. Eligible patients had a confirmed diagnosis of PeIN and a minimum of 6-mo follow-up. Response to IQ was categorized as a complete response (CR), partial response, or no response. Descriptive statistics were generated and statistical tests included the Mann-Whitney U test for age and Fisher's exact test for categorical variables. Key findings and limitations: The study included a total of 44 patients, with a median age of 65.4 yr (interquartile range 56-72). Of these patients, 28 (64%) achieved a CR, while 14 (32%) had a partial response and two (4.5%) had no response. In the CR subgroup, the 3-yr recurrence rate was 25%. No significant correlation was found between response status and age, human papillomavirus status, history of penile cancer, or circumcision before treatment. Among the patients, 50% reported SEs, mainly local pain, irritation, and bleeding, and 12% discontinued treatment because of SEs. There was no significant correlation between CR and the incidence or type of SE. Conclusions and clinical implications: Despite the high overall response rate to IQ, a significant number of patients experienced local recurrence within 3 yr, and approximately half of the patients reported SEs. Our results did not identify any clinical or pathological factors or local SEs predictive of the therapeutic response to IQ. Prospective studies are needed to help in predicting which patients are likely to respond to IQ so that those who will not benefit can be spared the SEs associated with this treatment. Patient summary: Our study looked at responses to imiquimod (IQ), an immune- based treatment in cream format, for precancerous lesions on the penis, called penile intraepithelial neoplasia. More than 95% of patients had a complete or partial response to IQ, but 50% reported side effects, and 25% of the group with a complete response had recurrence within 3 years. More research is needed to help in selecting patients who will benefit the most from IQ treatment. (c) 2024 The Authors. Published by Elsevier B.V. on behalf of European Associa tion of Urology. This is an open access article under the CC BY license (http://creativecom org/licenses/b mons. y/4.0/).

BACKGROUND AND OBJECTIVES:Penile cancer (PeCa) remains a challenge due to its rarity and the lack of prospective studies, leading to treatment challenges and controversies. Guidelines offer recommendations, but discrepancies with clinical practice persist. This study analyzed treatment practices among specialists managing high-risk PeCa in European reference centers. METHODS:A cross-sectional survey included 39 PeCa specialists from 13 European countries representing high-volume centers. Descriptive analysis assessed (neo)adjuvant therapy preferences, systemic regimen choices, immunotherapy use, and next-generation sequencing (NGS) integration. KEY FINDINGS AND LIMITATIONS:Variations in managing high-risk PeCa, especially in (neo)adjuvant therapy utilization, were noted among participants. The differences highlight the influence of professional backgrounds and variations in treatment approaches between participants. Systemic regimen preferences and immunotherapy utilization also varied. Limited NGS integration indicated gaps in precision medicine adoption. Limitations included sample size, self-reported data, and cross-sectional design. CONCLUSIONS AND CLINICAL IMPLICATIONS:This study offered insights into PeCa management by specialists in high-volume European reference centers, stressing the need for evidence-based recommendations, guideline adherence, and collaboration to enhance PeCa care. PATIENT SUMMARY:Managing PeCa is complex due to its rarity and treatment controversies. This study examined practices among specialists in European reference centers, revealing treatment variations. The findings emphasize the importance of evidence-based care and collaboration in optimizing PeCa management.

Surgery is the cornerstone of treatment for penile squamous cell carcinoma. Following surgical excision, reconstructive surgery is beneficial to restore aesthetics, functionality, and overall quality of life of these patients. In this mini-review, we discuss the use of skin grafts, perineal urethrostomy, phalloplasty, and vascularised flaps as reconstructive options following penile cancer treatment. Illustrated by videos, we highlight the surgical approach, indications, complications, and outcomes of these reconstructive strategies.Patient summaryReconstructive surgery is important to restore appearance, urinary function, and sexual function in patients who have been treated for penile cancer. We discuss the benefits and potential complications of various surgical reconstructive options, which are illustrated with videos.

OBJECTIVES:To provide an outline of the existing data on penile intraepithelial neoplasia (PeIN), as well as a narrative review on imiquimod (IQ; a toll-like receptor 7 agonist) treatment and immune microenvironment markers that may predict response to treatment. METHODS:A narrative review of the literature from 2000 to the present was conducted on PubMed, and we describe the most relevant data and cross references. RESULTS:The incidence of PeIN is increasing. Local therapy with IQ may offer an easy applicable treatment with complete response rates of up to 63% but can be associated with considerable side-effects. There is no conclusive data on the optimal treatment schedule for PeIN, but evaluation of treatment results for other human papillomavirus-related pre-malignancies suggest three times a week for a duration up to 16 weeks. There are no published studies concerning the PeIN immune microenvironment. However, findings from the few studies on penile cancer and pre-cancerous vulvar and cervical lesions imply that specific immune cell subpopulations can serve as future predictors for successful immunomodulation treatments such as IQ. CONCLUSIONS:Overall, limited data are available on IQ treatment for PeIN and no published data exists on the PeIN immune microenvironment. Further translational studies are warranted to gain more understanding on the pathophysiology of PeIN and potential predictors of progression and of response to topical treatments.

8 Background: TP53 mutations and Human papillomavirus (HPV) have been suggested to impact penile squamous cell carcinoma (pSCC) prognosis and may predict treatment outcomes. Insights in differences in tumor micro-environment at single cell resolution may benefit personalized therapeutic development and are currently unavailable. Methods: We performed single cell RNA sequencing and targeted next generation sequencing (for TP53 loss-of-function mutations; p53LOF) on primary HPV-associated and HPV-independent (HPV+/-) pSCC lesions or healthy control samples of the coronal sulcus skin. Cell clusters were annotated based on known marker genes. Gene Set Enrichment Analysis (GSEA) and slingshot trajectory analysis was performed using R/Seurat package. Results: Twenty-two samples were analyzed: 4 tumors harbored p53LOF mutations (1 HPV+ p53LOF, 3 HPV- p53LOF), 6 HPV- p53WT, 6 HPV+ p53WT and 6 healthy controls. A total of 84.394 cells was annotated and we identified 68 distinct cell subtypes in pSCC. In epithelial cells, two distinct pseudotime trajectories stemming from the basal cells were identified characterized by either signals of partial epithelial-mesenchymal transition (pEMT; TGFB, ZEB2, SNAI2) or cornification ( ELF3, KRT19, PPL). Whilst the pEMT trajectory was enriched in p53LOF samples, cornification was enriched in HPV+ p53WT. HPV- p53WT samples displayed increase in metabolic changes and stemness hallmarks ( SOX2, HEY1, ZEB1). GSEA confirmed these findings and showed upregulation of pEMT gene sets in p53LOF; fatty acid metabolism and xenobiotic metabolism in HPV- p53WT, and cornification in HPV+ p53WT. We observed an immune suppressive environment in p53LOF patients with higher regulatory T-cell abundancy, and this correlated with abundancy in the epithelial pEMT clusters. Pseudo-bulk analysis on all T-cell subsets demonstrated a higher expression of inhibitory immune checkpoints ( PD-1, CTLA4, TIM3 and LAG3) in p53LOF and HPV- p53WT while HPV+ p53WT patients displayed higher abundancy of immunomodulatory and cytotoxic natural killer (NK) cells. Conclusions: We established the first comprehensive pSCC transcriptomic atlas at single cell resolution and illustrate differences in molecular phenotypes of pSCC according to TP53 mutation- and HPV status. p53LOF tumors are characterized by pEMT, which is a known driver of invasiveness, therapy resistance and metastasis. HPV- p53WT display hallmarks of stemness, which is related to and may explain chemotherapy-resistance often observed in these patients. p53LOF and HPV- p53WT display immune-evasion and exhaustion, while HPV+ p53WT are characterized by abundant cytotoxic innate-like lymphocytes. These observations provide deeper insights into cancer biology that will help advancing pSCC diagnosis and therapy.

BACKGROUND AND OBJECTIVE:TP53 loss-of-function (TP53LOF) mutations might be a driver of poor prognosis and chemoresistance in both human papillomavirus (HPV)-independent (HPV-) and HPV-associated (HPV+) penile squamous cell carcinoma (PSCC). Here, we aim to describe transcriptomic differences in the PSCC microenvironment stratified by TP53LOF and HPV status. METHODS:We used single-cell RNA sequencing (scRNA-seq) and T-cell receptor sequencing to obtain a comprehensive atlas of the cellular architecture of PSCC. TP53LOF and HPV status were determined by targeted next-generation sequencing and sequencing HPV-DNA reads. Six HPV+ TP53 wild type (WT), six HPV- TP53WT, and four TP53LOF PSCC samples and six controls were included. Immunohistochemistry and hematoxylin-eosin confirmed the morphological context of the observed signatures. Prognostic differences between patient groups were validated in 541 PSCC patients using Kaplan-Meier survival estimates. KEY FINDINGS AND LIMITATIONS:Patients with aberrant p53 staining fare much worse than patients with either HPV- or HPV+ tumors and WT p53 expression. Using scRNA-seq, we revealed 65 cell subtypes within 83 682 cells. TP53LOF tumors exhibit a partial epithelial-to-mesenchymal transition, immune-excluded, angiogenic, and morphologically invasive environment, underlying their aggressive phenotype. HPV- TP53WT tumors show stemness and immune exhaustion. HPV+ TP53WT tumors mirror normal epithelial maturation with upregulation of antibody-drug-conjugate targets and activation of innate immunity. Inherent to the scRNA-seq analysis, low sample size is a limitation and validation of signatures in large PSCC cohorts is needed. CONCLUSIONS AND CLINICAL IMPLICATIONS:This first scRNA-seq atlas offers unprecedented in-depth insights into PSCC biology underlying prognostic differences based on TP53 and HPV status. Our findings provide clues for testing novel biomarker-driven therapies in PSCC. PATIENT SUMMARY:Here, we analyzed tissues of penile cancer at the level of individual cells, which helps us understand why patients who harbor a deactivating mutation in the TP53 gene do much worse than patients lacking such a mutation. Such an analysis may help us tailor future therapies based on TP53 gene mutations and human papillomavirus status of these tumors.

Organ-sparing surgery (OSS) is endorsed by the European Association of Urology (EAU) guidelines as the preferred treatment for distal primary penile cancer. The recommendation states that OSS should be used whenever possible, without exactly defining what constitutes "possible". This recommendation is based on findings showing that this approach has no detrimental impact on survival. At the same time, OSS results in preservation of quality of life (QoL) and of various functions of the penis. However, while narrow tumor-free margins (>1 mm) are deemed oncologically safe, there is a higher risk of local recurrence. Recent data have emerged that question the dogma that a local recurrence does not impact survival outcomes. In this mini review, we highlight areas of discrepancy in current guidelines and describe challenges for a surgical approach with a delicate balance between oncological safety on the one hand and maximal preservation of QoL and penile functions on the other. Patient summary: Organ-sparing surgery has been recommended as the preferred treatment for primary cancer of the penis, as quality of life and sexual function are maximally preserved. In this review we identify challenges and limitations in routinely adopting this approach. (c) 2023 European Association of Urology. Published by Elsevier B.V. All rights reserved.

BACKGROUND:Penile squamous cell carcinoma (PSCC) is characterised by stepwise lymphatic dissemination. Skip metastases (SkMs) are rare metastases in the corpus cavernosum or spongiosum without continuity to the primary tumour or its resection site. OBJECTIVE:To assess the distinct pattern of spread in SkM+ patients and the effect of SkM on prognosis. DESIGN, SETTING, AND PARTICIPANTS:We conducted a retrospective analysis of patients with SkM+ PSCC at ten high-volume international referral centres between January 2006 and May 2022. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:We evaluated histopathological data, primary lymph node (LN) staging, and metastatic spread. We included a cohort of patients matched for pT stage, LN status, and grade who did not have SkM (SkM-) to compare the SkM prognosis and predictive value for cancer-specific mortality (CSM). RESULTS AND LIMITATIONS:Among the 63 SkM+ patients who met our inclusion criteria, the SkM diagnosis was synchronous in 54.0% and metastases were mostly located in the corpus cavernosum. SkM was symptomatic in 14% of cases, was detected on imaging in 32%, and was found incidentally on pathological examination in 27%. Fifty-one patients (81%) presented with positive LNs and 28 (44%) developed distant metastases. Seven patients (11%) presented with or developed distant metastasis without displaying any LN involvement. The 2-yr cancer-specific survival estimates were 36% (95% confidence interval [CI] 25-52%) for SkM+ and 66% (95% CI 55-80%) for matched SkM- patients (p < 0.001). On multivariable Cox regression analysis, SkM presence was an independent predictor for higher CSM (hazard ratio 2.05, 95% CI 1.06-4,12; p = 0.03). CONCLUSIONS:PSCC-related SkM is associated with aggressive disease behaviour and poor survival outcomes. Palpation of the entire penile shaft is essential, and distant staging is recommended in patients suspected of having SkM owing to the tendency for distant metastatic spread. PATIENT SUMMARY:We investigated outcomes for patients with cancer of the penis who had metastases in the tissues responsible for erection. We found that metastases in this location were associated with poor prognosis, even in the absence of more typical spread of cancer via the lymph nodes.

Penile metastases are rare, with about 400 reported via case reports or small series. Under such circumstances coherent data about their behaviour may not be possible given vagaries of publication. For instance, one published meta‐analysis has proposed that malignant priapism contributes to worse survival, but this may be due to selection bias in published reports. We sought to evaluate clinical characteristics associated with survival in an international cohort of patients with metastases to the penis treated in major genitourinary cancer programmes.

Abstract Background Penile cancer is characterized by an early lymphatic dissemination. In intermediate and high-risk primary tumors without palpable inguinal lymph nodes, there is a 6–30% risk of micro-metastatic disease. Invasive lymph node staging in these patients is performed using dynamic sentinel lymph node biopsy (DSNB). In this study, the role of DSNB in cN0 penile cancer was studied, evaluating features of sentinel lymph node (SN) visualization and outcome parameters. Patients with penile cancer without inguinal lymph node metastases who were referred for DSNB at our center between January 2015 and May 2021 and had a follow-up period of at least 18 months, were retrospectively included. After injection of 85 ± 20 MBq [99mTc]Tc-nanocolloid peritumorally, dynamic, static planar and SPECT/CT imaging was performed. Primary endpoints were sensitivity of the diagnostic procedure, disease-free survival and DSNB-related adverse events. Secondary endpoints were SN detection rate, number of SNs and the number of counts of the most active SN. Results Seventy-seven penile DSNB procedures in 75 patients (67 ± 11 years) were included. The detection rate of DSNB was 91% and 96% per procedure and groin, respectively. Sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV) were 79%, 100%, 97% and 100%, respectively. More SNs were seen on SPECT/CT than on static planar imaging (1.33 vs. 1.17, p = 0.001). The mean counts per SN on static planar imaging was lower compared to SPECT/CT (1343 vs. 5008; p < 0.0001). There was a positive correlation between the total counts of the SN on the static planar image and the SPECT/CT (r = 0.79, p < 0.0001). Only one out of seventy-five patients (1%) experienced DSNB-related adverse events. After 18 months, 58 patients remained disease free (77%), 13 developed local recurrence (17%), and 4 developed lymphatic or distant metastases (5%). Conclusion DNSB is a safe diagnostic procedure with a good detection rate and in particular high negative predictive value. It can therefore prevent overtreatment of patients with negative inguinal groins on clinical examination and DSNB examination. Finally, DSNB enables an early detection of occult metastases which would not be visualized with standardized imaging modalities.

Surgery has always played a central role in the treatment of penile cancer. Historically, surgical excision of the primary tumour with a 2 cm margin was the gold standard. Although, reduction of penile length and loss of penile function cause significant reduction in the quality of life. The consequences of extensive surgery for penile cancer, including the inability to void standing and loss of sexual function, are debilitating. Consequently, the surgical treatment of penile cancer has shifted to less-invasive surgical strategies and organ-sparing surgery (OSS). Multiple studies have demonstrated that clear resection margins of less than 5 mm and even 1 mm are now deemed oncologically safe. Though, the use of OSS is associated with a higher risk of local recurrence. However, further research is needed to evaluate the role of local recurrence on overall survival and cancer specific survival, since studies report inconsistent results. Given that 80% of penile cancers develop on the prepuce and/or glans, many patients are eligible for OSS. However, a careful patient selection with respect to patient’s characteristics and tumour staging is crucial. This chapter aims to provide an overview of reconstructive surgical techniques, which can be used after surgical resection of primary tumours. Surgical techniques, grafts, common complications, functional and aesthetic outcomes are discussed.

BACKGROUND:Penile cancer (PeCa) represents a diagnostic and therapeutic challenge given the low patient volume, which may result in inadequate physician expertise and poor guideline adherence. Since 2015, we have developed a specific care pathway for PeCa in our tertiary referral center. OBJECTIVE:To evaluate the impact of a dedicated PeCa care pathway on patient management, the adequacy of pathological reporting, and oncological outcomes. DESIGN, SETTING, AND PARTICIPANTS:We retrospectively queried our institutional registry (S-66482) to identify patients who were surgically treated for PeCa between January 1989 and April 2022. The patient numbers were evaluated within a broader national context. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:We compared patient, surgery, tumor, and pathological data before and after 2015. Kaplan-Meier analysis was used to compare local and regional recurrence rates and cancer-specific survival (CSS). RESULTS AND LIMITATIONS:Overall, 313 patients were included, of whom 204 (65.1%) were surgically treated after 2015. The median number of patients treated yearly was significantly higher after 2015 (26 vs 5; p < 0.01). Patients treated after 2015 more frequently had no palpable lymph nodes at diagnosis, despite similar primary tumor stage. After adoption of the PeCa care pathway, organ-sparing surgery (OSS) was more commonly performed (79.9% vs 57.8%; p < 0.01) despite local staging being similar and without observing a significant increase in positive margins. Surgical staging in patients with European Association of Urology intermediate- or high-risk tumors was conducted more frequently after 2015 (90% vs 41%; p < 0.01). Pathology reporting was standardized, and there was more frequent reporting of p16 staining status (81.4% vs 8.3%; p < 0.01), lymphovascular invasion (93.8% vs 44.3%; p < 0.01), and perineural invasion (92.4% vs 44.3%; p < 0.01) following implementation. CONCLUSIONS:Implementation of a standardized care pathway for PeCa resulted in higher rates of OSS and pathological nodal staging and more complete pathology reports. Considering that these changes were associated with an increase in the number of patients treated, academic-driven centralization may play a role in optimizing the management of these patients. PATIENT SUMMARY:We evaluated the impact of a care pathway for patients with penile cancer on patient management, the completeness of pathology reporting, and cancer control. We found that implementation of this pathway was associated with an increase in the number of patients treated, higher rates of organ-sparing surgery and lymph node staging, and more complete pathology reports. Centralization of care may play a role in optimizing the management of penile cancer.

Objectives: Human papillomavirus (HPV) is the most common sexually transmitted infection globally, which causes nearly all cervix carcinomas and contributes to oropharyngeal, penile, vulva, vagina, and anal cancers. Despite the role of HPV in several preneoplastic and cancerous lesions in men, male vaccine coverage is low. This article aims to provide insights into the pathophysiology of HPV-related penile cancer and penile intrae-pithelial neoplasia (PeIN). Moreover, this review endeavors to outline the advantages of implementing HPV vaccination in male vaccination programs and the role of health care providers in this mission.Data Sources: This is a narrative review of relevant literature. A search on PubMed and Cochrane database was conducted. The following search terms were used: HPV vaccination, gender-neutral vaccination, male, genital warts, penile cancer, vaccine recommendations.Conclusion: HPV is responsible for 50.8% of penile cancers globally, 79.8% of PeIN, and 90% of genital warts. In 2009 the Food and Drug Administration licensed the quadrivalent HPV vaccine for use in males, with a potential efficacy of 90% and 77.5% to reduce genital warts and anal intraepithelial neoplasia, respectively. However, the uptake of HPV vaccination in men is low, and gender-neutral vaccination is estimated to be implemented only in 42 countries worldwide. Because data in penile cancer are lacking, further research is needed to study the efficacy of incorporation of HPV vaccines in male vaccination programs on preventing penile cancer and PeIN.Implications for Nursing Practice: Nurses and other members of the multidisciplinary team should take every opportunity to recommend HPV vaccination in adolescent men. Moreover, they play an important role in raising community awareness about the incidence of HPV and the related range of diseases. A practical approach is needed to incorporate HPV vaccines in vaccination programs and to optimize vaccination cover -age.(c) 2022 Elsevier Inc. All rights reserved.

Penile cancer (PC) is a rare disease with a prevalence of 0.1–1 in 100,000 men in Western countries. However, risk factors such as phimosis, low socioeconomic status, smoking and human papillomavirus (HPV) affect prevalence rates. Different histological subtypes of PC have been described and moreover, since 2016 the World Health Organization has stratified PC by HPV status as pathways of carcinogenesis strongly differ. Primary treatment of PC includes topical therapy, radiotherapy, laser therapy and surgical approaches. Historically, radical excision of localized disease with a 2 cm margin was the gold standard. Since radical surgery affects the ability to void in the upright position, sexual function and psychological wellbeing, a paradigm shift has occurred towards penile-sparing approaches. Organ-sparing surgery aims to minimize loss of penile function and to preserve patients’ quality of life, without compromising oncological outcome. Since PC is characterized by early lymphatic spread and as lymph node involvement is known as the most important predictor of survival in PC, in-depth and upfront lymph node staging is required. In advanced stages of disease, a multimodal approach is needed, including inguinopelvic lymphadenectomy followed by adjuvant chemotherapy. To date, Platinum- and Taxane-based chemotherapy is mainstay of systemic therapy, however burdened by poor response rates and early therapy resistance. Dealing with the diagnosis of PC and their appropriate treatments can have a substantial impact on psychological and physical wellbeing, by affecting sexual, esthetical, and urinary penile function.

The incidence of cancers driven by human papillomavirus (HPV) infection in men is increasing. Gender-neutral HPV vaccination and specific approaches to these cancers are needed.