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Introduction: Radical surgery is the \"gold standard\" for treatment of invasive penile carcinoma but very poor aesthetic, functional and psychological outcomes have been reported. Our purpose was to assess the impact of organ potency-sparing surgery in locally confined carcinoma of the penis. Materials and Methods: We evaluated retrospectively 42 patients with early penile cancer (Ta,T1,T2), treated with glandulectomy and glanduloplasty with urethral mucosa and sparing of cavernosal apexes, or glandulectomy and limited apical resection in cases of Stage T2. Sexual function, ejaculation and libido were evaluated with an IIEF-15 questionnaire before the appearance of neoplasia (about three months before the surgery) and six months after surgery. Quality of life was evaluated by the Bigelow-Young questionnaire. The scores relating to two weeks prior to the surgery have been compared to those obtained six months after surgery. The statistical analysis was conducted using t-Student for repeated measures and analysis of variance. Results: Six months after surgery 73% of patients reported spontaneous rigid erections, 60% coital activity while 76% of the group treated with urethral glanduloplasty reported normal ejaculation and orgasm, regained an average of 35 days after surgery. The average IIEF-15 scores reported in the entire series in the domains of erection, libido and coital activity of the pre-cancer period were not statistically different than those recorded six months after surgery. In the group treated with glandular reconstruction, pre-and postoperative IIEF-15 mean scores related to ejaculation and orgasm domains were not significantly different. Mean scores of Bigelow-Young questionnaires related to sexual pleasure, familial, social and professional relationships showed significant improvement after surgery. Conclusions: Potency sparing-sparing surgical treatments have a positive impact on a wide spectrum of the patient′s life including family relationships, and social and working conditions.

Objective Our study tried to evaluate the prognostic utility of preoperative serum cyfra21-1 in patients with penile squamous cell carcinoma (PSCC). Methods This retrospective study analyzed data from 94 patients who underwent either partial or radical penectomy accompanied by bilateral inguinal or pelvic lymphadenectomy at our institution from 2010 to 2018. The median duration of follow-up was 66.5 months. Serum cyfra21-1 concentrations were quantified through enzyme-linked immunosorbent assay, with patients classified into two groups based on cyfra21-1 levels (≤ 3.30 ng/ml and > 3.30 ng/ml). The impact of cyfra21-1 levels on clinical outcomes was evaluated. Results Among the 94 patients, 68 (72.3%) had normal cyfra21-1 levels, while 26 (27.6%) exhibited elevated cyfra21-1 levels. During the follow-up period, 38 patients (40.4%) experienced relapse, and 35 patients (37.2%) died from PSCC. A significantly higher occurrence of advanced pathological grades was observed in the elevated cyfra21-1 group compared to the normal group ( P  = 0.029). Patients with elevated cyfra21-1 levels had significantly worse disease-free survival (DFS) and disease-specific survival (DSS) than those with normal levels ( P  < 0.001 and P  < 0.001, respectively). In multivariate analysis, cyfra21-1 (HR: 3.938, 95% CI: 1.927–8.049, P  < 0.001), lymph node involvement (HR: 8.277, 95% CI: 2.261–30.298, P  = 0.001), pathological grade (HR: 2.789, 95% CI: 1.110–7.010, P  = 0.029), and ECOG (Eastern Cooperative Oncology Group) performance status (HR: 1.751, 95% CI: 1.028–2.983, P  = 0.039) were independent predictors of worse DFS. Similarly, CYFRA 21 − 1 (HR: 3.000, 95% CI: 1.462–6.156, P  = 0.003), lymph node involvement (HR: 9.174, 95% CI: 2.010–41.862, P  = 0.003), and ECOG performance status (HR: 1.856, 95% CI: 1.053–3.270, P  = 0.032) were independent predictors of worse DSS. Conclusions High preoperative serum cyfra21-1 levels correlate with greater tumor aggressiveness and represent a novel, effective, and convenient prognostic biomarker for PSCC.

Penile cancer is an uncommon malignancy. Surgical treatment is inevitably mutilating. Considering the strong impact on patients＇ sexual life we want to evaluate sexual function and satisfaction after partial penectomy. The patients in this study （n = 25） represented all those who attended our institutions and were diagnosed and treated for penile cancer from October 2011 to November 2013. All patients underwent partial penectomy and followed-up （mean： 14 months; range： 12-25）. Sexual presurgical baseline was estimated using the International Index of Erectile Dysfunction 15 （IIEF-15）. Sexual outcomes of each patient were estimated considering four standardized and validated questionnaires. We analyzed the means and ranges of IIEF-15 including erectile function （IIEF-1-5 and -15）, orgasmic function （IIEF-9 and -10）, sexual desire （IIEF-11 and -12）, intercourse satisfaction （IIEF-6-8）, and overall satisfaction （IIEF-13 and -14）. Then, we also used Quality of Erection Questionnaire （QEQ）, Erectile Dysfunction Inventory of Treatment Satisfaction （EDITS） and Self-Esteem and Relationship （SEAR） to evaluate the sexual function and satisfaction of our patients. The final results showed that penile cancer leads to several sexual and psychosexual dysfunctions. Nevertheless, patients who undergo partial penectomy for penile cancer can maintain the sexual outcomes at levels slightly lower to those that existed in the period before surgery.

Introduction Obese patients with penile cancer may have more advanced disease. This study evaluated the association of obesity with penile cancer and the risk of lymph node metastases in patients who underwent inguinal lymphadenectomy. Methods We retrospectively reviewed the charts of 197 penile cancer (PC) patients from January 2000 to December 2011. Seventy underwent inguinal lymphadenectomy. For this subgroup, chi-square analysis evaluated the correlations of sociodemographic, clinical, and pathological variables with the presence of positive inguinal lymph nodes. Patients were divided into normal weight, overweight, and obese categories according to body mass index (BMI). The mean numbers of positive and resected lymph nodes were compared for each BMI category. Results The percentage of overweight men in the Brazilian population and among patients with PC was 52.6% and 42.8%, respectively. For patients who underwent lymphadenectomy, the mean BMIs were 25.9 ± 6. Most patients were white, married, had a lower education level, and had no history of smoking. Partial penectomy was the most frequently performed surgery; lymphovascular invasion occurred in 45.7%, and lymph node metastasis occurred in 52.9% of cases. The mean numbers of resected and positive lymph nodes for normal weight, overweight, and obesity were 21.1 and 2.2, 23.3 and 2.2, and 16.8 and 1.5, respectively. Conclusion Overweight and obesity were less frequently seen in patients with PC than in the Brazilian population. BMI was not a risk factor for developing lymph node metastasis; the only predictive factor for lymph node metastasis was the presence of lymphovascular invasion.

Penile squamous cell carcinoma (PSCC) occurs more frequently in some developing countries compared to developed countries. Infection with HIV and/or high-risk human papillomavirus (hrHPV) are risk factors for penile cancer development. The tumor microenvironment of PSCC may predict prognosis and may inform on the best targets for immunotherapy. We evaluated the immune microenvironment of penile tumors histologically, and determined whether and/or how HIV and/or hrHPV infections affect this tumor microenvironment. We conducted a prospective analytical cross-sectional study in which penile cancer tumors from 35 patients presenting at the University Teaching Hospital in Lusaka, Zambia were histologically staged and assessed for presence of tumor infiltrating immune cells and expression of immune checkpoints. Immunohistochemistry was used to evaluate immune checkpoints and infiltrating immune cells, while multiplex real-time polymerase chain reaction was used for hrHPV genotyping. The median age of all participants was 55 years. About 24% had advanced histological stage, 83% were HIV + , and 63% had hrHPV detected in their tumors using multiplex real-time polymerase chain reaction. PDL1 expression was significantly higher in HIV - participants than HIV + participants (p = 0.02). Tumors with multiple hrHPV infections had a significantly higher number of cells expressing TIM3 than those with one hrHPV (p = 0.04). High grade tumors had a significantly higher infiltrate of FoxP3 + cells (p = 0.02), CD68 + cells (p = 0.01), CD163 + cells (p = 0.01), LAG3 + cells (p = 0.01), PD1 + cells (p = 0.01) and TIM3 + cells (p = 0.03) when compared with low grade tumours. There was significant moderate to strong positive correlation of cells expressing PD1 and LAG3 (⍴ = 0.69; p = 0.0001), PD1 and TIM3 (⍴ = 0.49; p = 0.017) and TIM3 and LAG3 PDL1 (⍴ = 0.61; p = 0.001). In conclusion, the tumor microenvironment of penile squamous cell carcinoma seems to be affected by both HIV and HPV infections. TIM3 appears to be a potential therapeutic target in PSCC patients with hrHPV infections.

Key Points Patients with high-risk penile cancer tumours and without palpable lymphadenopathy benefit from inguinal lymph node dissection, as many of these men harbour occult metastasis Modified and superficial inguinal lymph node dissection and dynamic sentinel lymph node sampling, as well as minimally invasive techniques, have been developed to decrease the morbidity of traditional radical inguinal lymphadenectomy Patients with large or bulky nodal metastasis benefit from neoadjuvant chemotherapy before surgical intervention High-level evidence of a benefit of radiotherapy in patients with penile cancer with lymph node metastasis is currently lacking Targeted therapies that have demonstrated efficacy in squamous cell carcinomas of other sites might also be effective in treating men with penile cancer and nodal metastasis and advanced disease Leone et al . describe management strategies for patients with penile cancer and metastasis to regional lymph nodes. They review the prognostic factors, indications for lymphadenectomy, surgical techniques and the role of systemic chemotherapy, radiotherapy and new targeted and immunotherapeutic approaches. Penile cancer is a rare disease that causes considerable physical and psychological patient morbidity, especially at advanced stages. Patients with low-stage nodal metastasis can achieve durable survival with surgery alone, but those with extensive locoregional metastasis have overall low survival. Contemporary management strategies for lymph node involvement in penile cancer aim to minimize the morbidity associated with traditional radical inguinal lymphadenectomy through appropriate risk stratification while optimizing oncological outcomes. Modified (or superficial) inguinal lymph node dissection and dynamic sentinel lymph node biopsy are diagnostic modalities that have been recommended in patients with high-risk primary penile tumours and nonpalpable inguinal lymph nodes. In addition, advances in minimally invasive and robot-assisted lymphadenectomy techniques are being investigated in patients with penile cancer and might further decrease lymphadenectomy-related adverse effects. The management of patients with advanced disease has evolved to include multimodal treatment with systemic chemotherapy before surgical intervention and can include adjuvant chemotherapy after pelvic lymphadenectomy. The role of radiotherapy in the neoadjuvant or adjuvant setting remains largely unclear, owing to a lack of high-level evidence of possible benefits. New targeted therapies have shown efficacy in squamous cell carcinomas of other sites and might also prove effective in patients with penile cancer.

To determine the epidemiological, histopathological, and clinical characteristics of patients diagnosed with penile cancer in the Brazilian state of Maranhão, the region with the highest incidence worldwide. One hundred and sixteen penile cancer patients were interviewed from July 2016 to October 2018. The majority of patients lived in a rural area (57%), worked in farming (58%), had a low level of schooling or no schooling (90%), and were married or in a stable relationship (74%). The mean age was 60.4 ± 16.51 years (range, 23–93 years). Phimosis (66%), poor/moderate genital hygiene (73%), history of sexually transmitted infections (55%), and zoophilia (60%) were found in the majority of patients. Most patients had their first sexual encounter at 16.2 ± 2.8 years (range, 10–25 years), and 75% had >6 sexual partners. The most common initial symptom was pruritus (37%), and most patients waited to seek treatment (average time to treatment, 18.9 months; range, 2–84 months). Human papillomavirus (HPV)-related histologies were observed in 62% of patients. Most patients had histological grades II or III (87%), stage ≥T2 disease (84%), and lymphadenopathy at admission (42%). Penectomy was performed in 96% of patients. The population with penile cancer in the region of highest incidence in the world is marked by low socioeconomic status, high prevalence of HPV infection, and phimosis. The delay in seeking treatment is related to a very high rate of advanced cancer and aggressive surgical treatment. The high prevalence of young patients was also a striking feature.

Penile squamous cell carcinoma is a rare disease with very limited data to guide treatment decisions. In particular, there is minimal evidence for effective therapies in the metastatic setting. Here, we present a case of metastatic penile squamous cell carcinoma with response to the Nectin-4 inhibitor enfortumab-vedotin-ejfv (EV). EV was selected due to the evidence of the high expression of Nectin-4 in squamous cell carcinomas, including penile carcinoma. The patient had both radiographic and symptomatic improvement after two cycles of treatment, despite having been treated with multiple prior lines of traditional chemotherapy. This case provides support for the use of antibody–drug conjugates (ADC), including EV, in this disease with few other options in the advanced setting. Further studies examining Nectin-4 and ADCs in penile squamous cell carcinoma should be completed, as high-quality evidence is needed to guide treatment after initial progression for these patients.

The incidence of penile squamous cell carcinoma (PSCC) has increased in developed countries over the past decades owing to increased human papilloma virus (HPV) exposure. Despite successful surgical treatment of locoregional PSCC, effective treatment options for advanced disease are limited. The prognosis of patients with bulky nodal and metastatic PSCC is dismal and new management approaches are urgently needed. Genomic analyses have provided transformative knowledge on the genomic and molecular landscape and tumour microenvironment of PSCC. Around one-quarter of patients with metastatic PSCC have clinically actionable genomic alterations in mechanistic target of rapamycin, DNA repair and receptor tyrosine kinase pathways. These patients might benefit from combined and sequential targeted therapies. HPV vaccination might be another therapeutic option as PSCC is genetically similar to other HPV-driven cancers. In addition, 40–60% of PSCC tumours show strong PDL1 expression, and the frequency of mutational signatures suggestive of immunotherapy resistance is low, pointing to potential utility of immunotherapy for PSCC. Finally, identification of the composition of the penile microbiota and its biological role might lead to new cancer prevention and treatment strategies.In this Review, Aydin et al. discuss our current knowledge of the genomic, molecular and immunological make-up of penile squamous cell carcinoma and the findings of research studies to explore future therapeutic approaches in this disease.

Neoadjuvant chemotherapy (NAC) has shown promising results in patients with locally advanced penile cancer. However, no consensus exists on its applications for locally advanced penile cancer. Thus, it is unclear which kind of chemotherapy regimen is the best choice. Consequently, a systematic search of PubMed, Web of Science, and EMBASE was performed in March 2021 to assess the efficacy and safety of NAC for the treatment of patients with locally advanced penile cancer. The Newcastle-Ottawa Scale was used to assess the risk of bias in each study. This study synthesized 14 published studies. The study revealed that patients who achieved an objective response to NAC obtained a better survival outcome compared with those who did not achieve an objective response. In addition, the objective response rates (ORRs) and pathological complete response (pCR) rates were 0.57 and 0.11, respectively. The incidence of grade ≥3 toxicity was 0.36. Subgroup analysis found that the ORR and pCR of the taxane-platinum (TP) regimen group performed better than those of the nontaxane-platinum (NTP) regimen group (0.57 vs 0.54 and 0.14 vs 0.07, respectively). Moreover, the TP regimen group had more frequent toxicity than the NTP regimen group (0.41 vs 0.26). However, further studies were warranted to confirm the findings.