Safety and efficacy of immune checkpoint inhibitors in advanced penile cancer: report from the Global Society of Rare Genitourinary Tumors.

BACKGROUND: Treatment options for penile squamous cell carcinoma are limited. We sought to investigate clinical outcomes and safety profiles of patients with penile squamous cell carcinoma receiving immune checkpoint inhibitors. METHODS: This retrospective study included patients with locally advanced or metastatic penile squamous cell carcinoma receiving immune checkpoint inhibitors between 2015 and 2022 across 24 centers in the United States, Europe, and Asia. Overall survival and progression-free survival were estimated using the Kaplan-Meier method. Objective response rates were determined per Response Evaluation Criteria in Solid Tumours 1.1 criteria. Treatment-related adverse events were graded per the Common Terminology Criteria for Adverse Events, version 5.0. Two-sided statistical tests were used for comparisons. RESULTS: Among 92 patients, 8 (8.7%) were Asian, 6 (6.5%) were Black, and 24 (29%) were Hispanic and/or Latinx. Median (interquartile range) age was 62 (53-70) years. In all, 83 (90%) had metastatic penile squamous cell carcinoma, and 74 (80%) had received at least second-line treatment. Most patients received pembrolizumab monotherapy (n = 26 [28%]), combination nivolumab-ipilimumab with or without multitargeted tyrosine kinase inhibitors (n = 23 [25%]), or nivolumab (n = 16 [17%]) or cemiplimab (n = 15 [16%]) monotherapies. Median overall and progression-free survival were 9.8 months (95% confidence interval = 7.7 to 12.8 months) and 3.2 months (95% confidence interval = 2.5 to 4.2 months), respectively. The objective response rate was 13% (n = 11/85) in the overall cohort and 35% (n = 7/20) in patients with lymph node-only metastases. Visceral metastases, Eastern Cooperative Oncology Group (ECOG) performance status of 1 or higher, and a higher neutrophil/lymphocyte ratio were associated with worse overall survival. Treatment-related adverse events occurred in 27 (29%) patients, and 9.8% (n = 9) of the events were grade 3 or higher. CONCLUSIONS: Immune checkpoint inhibitors are active in a subset of patients with penile squamous cell carcinoma. Future translational studies are warranted to identify patients more likely to derive clinical benefit from immune checkpoint inhibitors.

Atezolizumab With or Without Radiotherapy for Advanced Squamous Cell Carcinoma of the Penis (The PERICLES Study): A Phase II Trial.

PURPOSE: Patients with advanced penile squamous cell carcinoma have a poor prognosis (21% 2-year overall survival [OS] from diagnosis). We assessed the activity of atezolizumab (anti-PD-L1) in patients with advanced penile cancer, with or without radiotherapy (RT). PATIENTS AND METHODS: A single-center, nonrandomized phase II study with two treatment arms was conducted in 32 patients with histologically confirmed advanced penile cancer. All patients received atezolizumab (1,200 mg) once every 3 weeks. Twenty patients, who were expected to benefit from RT for locoregional disease control, received additional irradiation. The primary end point was 1-year progression-free survival (PFS) for the complete cohort and was reached if the actual 1-year PFS was at least 35%. Secondary end points included OS, objective response rate (ORR), and tolerability. Exploratory biomarker analyses were conducted in pretreatment specimens. RESULTS: Median follow-up was 29.1 months (IQR, 18.1-33.5). Grade 3-4 adverse events related to atezolizumab or RT were observed in 3/32 (9.4%) and 13/20 (65%) patients, respectively. One-year PFS was 12.5% (95% CI, 5.0 to 31.3), which did not meet the study's primary end point. Median OS was 11.3 months (95% CI, 5.5 to 18.7). In the objective response-evaluable population (n = 30; 93.8%), the ORR was 16.7% (95% CI, 6 to 35), including 2 (6.7%) complete responders and 3 (10%) partial responders. Improved PFS was observed in patients with high-risk human papillomavirus (hrHPV)-positive tumors (P = .003) and those with high infiltration of intratumoral CD3+CD8+ T cells (P = .037). CONCLUSION: Although the primary end point of 1-year PFS was not met, durable antitumor activity to atezolizumab was observed in a subset of patients. Biomarkers, such as hrHPV and intratumoral CD3+CD8+ T-cell infiltration, may help to better select responders.

Wound Complication Rates after Inguinal Lymph Node Dissection: Contemporary Analysis of the NSQIP Database.

BACKGROUND: Inguinal lymph node dissection (ILND) is used for diagnosis and treatment in penile cancer (PC), vulvar cancer (VC), and melanomas draining to the inguinal lymph nodes. However, ILND is often characterized by its morbidity and high wound complication rate. Consequently, we aimed to characterize wound complication rates after ILND. STUDY DESIGN: The NSQIP database was queried for ILND performed from 2005 to 2018 for melanoma, PC, or VC. Thirty-day wound complications included wound disruption and superficial, deep, and organ-space surgical site infection. Multivariable logistic regression was performed with covariates, including cancer type, age, American Society of Anesthesiologists score ≥3, BMI ≥30, smoking history, diabetes, operative time, and concomitant pelvic lymph node dissection. RESULTS: A total of 1,099 patients had an ILND with 92, 115, and 892 ILNDs performed for PC, VC, and melanoma, respectively. Wound complications occurred in 161 (14.6%) patients, including 12 (13.0%), 17(14.8%), and 132 (14.8%) patients with PC, VC, and melanoma, respectively. Median length of stay was 1 day (interquartile range 0 to 3 days), and median operative time was 152 minutes (interquartile 83 to 192 minutes). Readmission rate was 12.7%. Wound complications were associated with longer operative time per 10 minutes (odds ratio 1.038, 95% CI 1.019 to 1.056, p < 0.001), BMI ≥30 (odds ratio 1.976, 95% CI 1.386 to 2.818, p < 0.001), and concomitant pelvic lymph node dissection (odds ratio 1.561, 95% CI 1.056 to 2.306, p = 0.025). CONCLUSIONS: Predictors of wound complications after ILND include BMI ≥30, longer operative time, and concomitant pelvic lymph node dissection. There have been efforts to decrease ILND complication rates, including minimally invasive techniques and modified templates, which are not captured by NSQIP, and such approaches may be considered especially for those with increased complication risks.

The Acute Complications After Surgery for Penile Carcinoma and Strategies for Their Management: A Systematic Review of the Literature.

OBJECTIVES: To investigate the contemporary rates of 30-day complications after surgery for penile cancer and to discuss the currently used preventative and therapeutic practices aimed at mitigation of these postoperative adverse events. DATA SOURCES: A systematic review in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines was performed, and studies reporting on the contemporary rates, nature, or management of acute complications following primary penile surgery or inguinal lymph node dissection for penile cancer were abstracted. Medline (PubMed) and EMBASE libraries were used to retrieve the articles published between January 1984 and December 2021 (n = 170 articles). Ultimately, 38 articles were included. The primary outcome of interest was 30-day (acute) postoperative complications, stratified by those associated with treatment of the primary penile lesion and those with inguinal lymph node dissection. Risk of bias assessment was undertaken. Special attention was paid to studies reporting management strategies for these complications. CONCLUSION: This comprehensive review revealed that the quality of existing studies reporting on complications is poor and the risk of bias is high. Within these studies, the rates of acute complications following primary penile surgery and inguinal lymph node dissection ranged between 0% and 29.4% and 6% and 90%, respectively. More than 50% of these complications were wound related. Over the past two decades, several studies have reported on improved surgical techniques and protocolized postsurgical care pathways. Although the newer techniques have been associated with improved outcomes, the absolute rates of complications have remained high even in the most contemporary series. Therefore, there is an urgent need for health care providers and stakeholders to reach consensus regarding preoperative workup and medical optimization goals, stage appropriate therapies, and postoperative care pathways, as has been done for other malignancies associated with high morbidity. IMPLICATIONS FOR NURSING PRACTICE: Penile cancer is a disease of the elderly, and surgical management of the primary lesion or the groins is associated with a high rate of complications. Most complications are wound related. Meticulous surgical technique and careful postoperative monitoring with early intervention are keys to mitigating surgery-related morbidity. However, equally important is dissemination and adoption of these principles by all health care workers universally.

Distinct Patterns of Myeloid Cell Infiltration in Patients With hrHPV-Positive and hrHPV-Negative Penile Squamous Cell Carcinoma: The Importance of Assessing Myeloid Cell Densities Within the Spatial Context of the Tumor.

Comprehensive analysis of tumor infiltrating myeloid cells in the tumor microenvironment of penile squamous cell carcinoma (PSCC) is lacking. In this retrospective study, for the first time, PSCC resection specimens (N = 103) were annotated into the following compartments: intratumoral tumor (IT Tumor), intratumoral stroma (IT Stroma), peritumoral tumor (PT Tumor) and peritumoral stroma (PT Stroma) compartments. We then quantified CD14+, CD68+ and CD163+ myeloid cells within these compartments using an image analysis software and assessed their association with various clinical parameters, including high-risk human papillomavirus (hrHPV) status. In the total cohort, hrHPV status, grade of differentiation, age and tumor size were associated with myeloid cell densities. hrHPV+ tumors had higher infiltration rates of CD14+, CD68+ and CD163+ myeloid cells in the IT tumor compartment (p < 0.001, for all) compared to hrHPV- tumors. Furthermore, when examining the association between compartment-specific infiltration and differentiation grade, increased myeloid cell densities in the IT tumor compartment were associated with a more advanced histological grade (p < 0.001, for all). This association remained significant when the hrHPV- cohort (N = 60) was analyzed (CD14+ p = 0.001; CD68+ p < 0.001; CD163+ p = 0.004). Subgroup analysis in the hrHPV+ group (N = 43) showed that high infiltration rates of CD68+ and CD163+ cells in the PT tumor compartment were associated with lymph node (LN) metastasis (p = 0.031 and p = 0.026, respectively). Regarding the association between myeloid cell densities and disease-specific survival, the risk of death was found to decrease slightly as the number of myeloid cells in the IT tumor compartment increased (CD14+ p = 0.04; CD68+ p = 0.05; CD163+ p = 0.02). However, after adjusting for hrHPV, no independent association between myeloid densities and disease-specific survival were found. Altogether, these findings demonstrate the importance of assessing myeloid cell densities within the spatial context of the tumor. Further studies are needed to unravel the specific phenotype of myeloid cells residing in the different compartments, their effect on clinical parameters and the impact of hrHPV on the recruitment of myeloid cell populations in PSCC.

Penile cancer.

Penile squamous cell carcinoma (PSCC) is a rare cancer with orphan disease designation and a prevalence of 0.1-1 per 100,000 men in high-income countries, but it constitutes up to 10% of malignancies in men in some African, Asian and South American regions. Risk factors for PSCC include the absence of childhood circumcision, phimosis, chronic inflammation, poor penile hygiene, smoking, immunosuppression and infection with human papillomavirus (HPV). Several different subtypes of HPV-related and non-HPV-related penile cancers have been described, which also have different prognostic profiles. Localized disease can be effectively managed by topical therapy, surgery or radiotherapy. As PSCC is characterized by early lymphatic spread and imaging is inadequate for the detection of micrometastatic disease, correct and upfront surgical staging of the inguinal lymph nodes is crucial in disease management. Advanced stages of disease require multimodal management. Optimal sequencing of treatments and patient selection are still being investigated. Cisplatin-based chemotherapy regimens are the mainstay of systemic therapy for advanced PSCC, but they have poor and non-durable responses and high rates of toxic effects, indicating a need for the development of more effective and less toxic therapeutic options. Localized and advanced penile cancers and their treatment have profound physical and psychosexual effects on the quality of life of patients and survivors by altering sexual and urinary function and causing lymphoedema.

Penile Cancer: Managing Sexual Dysfunction and Improving Quality of Life After Therapy.

PURPOSE OF REVIEW: To review the most current literature on how the treatment for penile cancer can affect quality of life and to discuss current treatment options to overcome sexual dysfunction and ultimately improve patient wellbeing. RECENT FINDINGS: Multiple medical and surgical therapies exist to address the high incidence of sexual dysfunction following penile cancer treatment. Advancements and refinements in the neophalloplasty, penile prosthesis, and penile lengthening procedures have opened the door to improved long-term outcomes. Additionally, studies continue to highlight the severe psychological toll that penile cancer treatment can have on patients. We explore the potential options for addressing the inherent psychologic effects of these treatments and highlight the need for further research in this domain. Although rare, it is important for all urologists to be familiar with the treatments and post-treatment sequelae of penile cancer. Penile cancer is associated with dramatic decline in quality of life and sexual function. Multiple medical and surgical therapies exist that addresses these concerns. Additionally, urologists must also be mindful of the psychologic component regarding surgical disfigurement and the decline in sexual function.

Pathogenesis of Penile Squamous Cell Carcinoma: Molecular Update and Systematic Review.

Penile squamous cell carcinoma (PSCC) is a rare but aggressive neoplasm with dual pathogenesis (human papillomavirus (HPV)-associated and HPV-independent). The development of targeted treatment is hindered by poor knowledge of the molecular landscape of PSCC. We performed a thorough review of genetic alterations of PSCC focused on somatic mutations and/or copy number alterations. A total of seven articles have been identified which, overall, include 268 PSCC. However, the series are heterogeneous regarding methodologies employed for DNA sequencing and HPV detection together with HPV prevalence, and include, in general, a limited number of cases, which results in markedly different findings. Reported top-ranked mutations involve TP53, CDKN2A, FAT1, NOTCH-1 and PIK3CA. Numerical alterations involve gains in MYC and EGFR, as well as amplifications in HPV integration loci. A few genes including TP53, CDKN2A, PIK3CA and CCND1 harbor both somatic mutations and copy number alterations. Notch, RTK-RAS and Hippo pathways are frequently deregulated. Nevertheless, the relevance of the identified alterations, their role in signaling pathways or their association with HPV status remain elusive. Combined targeting of different pathways might represent a valid therapeutic approach in PSCC. This work calls for large-scale sequencing studies with robust HPV testing to improve the genomic understanding of PSCC.

Progress on Management of Penile Cancer in 2020.

OPINION STATEMENT: Management of penile cancer represents a challenge to urologic oncologists due to the disease's rarity and sparse data in the literature. Squamous cell carcinoma represents the most common histologic subtype of penile cancer. Penile cancer has a disastrous effect on patients' psychological and physical health. Penile cancer accounts for approximately 1% of cancer deaths in the USA annually. However, in recent years, the management of penile cancer has achieved marked progress in both diagnostic and therapeutic approaches with the intent to avoid radical surgeries. The traditional total penile amputation has been replaced by penile preserving procedures in many patients. Nowadays, total penile amputation (total penectomy) is preserved only for patients with proximal lesions. The introduction of minimally invasive surgical techniques in the management of penile cancer-infiltrated lymph nodes has been reported. Given the dismal prognosis with conventional cytotoxic therapies, new systemic therapies have been investigated in patients with locally advanced or metastatic penile cancer. Multiple studies have shown promising outcomes. All these efforts have resulted in a remarkable improvement in patient quality of life. The objectives of our review are to update clinicians on the advances in the management of penile cancer and to summarize the recent guidelines and recommendations.

Future directions in advanced penile cancer - mechanisms of carcinogenesis and a search for targeted therapy.

Penile squamous cell carcinoma (SCC) is a rare and aggressive urological malignancy. Advanced penile SCC requires multimodal management, including surgery and systemic therapy. Given its rarity, there have been few substantial advances in our understanding of the molecular and genomic drivers of penile SCC, especially for patients with relapsed or advanced disease. In this review, we discuss the molecular and genomic landscape of penile SCC, clinical trials in progress and implications for novel therapeutic targets. Future work should focus on preclinical models to provide a platform for investigation and validation of new molecular pathways for testing of therapeutics.

Presence of HPV with overexpression of p16INK4a protein and EBV infection in penile cancer-A series of cases from Brazil Amazon.

BACKGROUND: In Brazil, penile cancer (PC) is not uncommon. The highest incidence of PC is in the North and Northeast of the country. In addition to phimosis, the Human Papillomavirus (HPV) and Epstein-Baar Virus (EBV) infections are also related as risk factors for PC. The overexpression of p16INK4a is a surrogate sensitive marker of HPV infection in PC. OBJECTIVES: To correlate p16INK4a overexpression and HPV infection status with EBV infection in a series of PC patients from the Amazon region. METHODS: Tumor tissues from 47 PC cases were analyzed for the presence of HPV and EBV DNA by PCR. All PC patients were diagnosed between 2013 and 2018 at a public reference cancer center hospital in Manaus, Amazonas-Brazil. HPV was genotyped using E7 HPV16/HPV18 type-specific real-time PCR and the PapilloCheck® HPV-Screening assay. p16INK4a expression was evaluated by immunohistochemistry using the automated Ventana® BenchMark Ultra. RESULTS: The mean age of patients at the time of diagnosis was 57.4 years ±SD 17.8 ranging from 20 to 90 years old. Most of the patients (64%) came from rural areas of the Amazonas State. Thirty patients had phimosis (64%). Among the patients with phimosis, 43% (13/30) underwent circumcision, three during childhood and 10 in adulthood. 60% of the patients were smokers or ex-smokers. HPV infection was observed in 45% (21/47) of cases. HPV16 was detected in 13 patients (61%). Other HPV types detected were HPV 6, 11, 42, 51, 53, 68 and 44/55. EBV infection was observed in 30% (14/47) of the patients with PC. Co-infection with HPV and EBV was observed in 28% (6/21) cases. p16INK4a was only investigated in 26 samples. The p16INK4a overexpression was observed exclusively in HPV 16 positive cases and four HPV negative cases. In the survival analysis, the follow-up time was 35.4 months/patient. The mortality rate during the follow up time was 38%. CONCLUSIONS: p16INK4a positivity presented a high correlation to HPV 16 DNA detection, reinforcing its use as a surrogate marker for HPV-driven cancers. Infection with EBV was quite frequent and its role in epithelial penile oncogenesis needs to be demonstrated.

Risk factors and molecular characterization of penile cancer: impact on prognosis and potential targets for systemic therapy.

PURPOSE OF REVIEW: To provide a comprehensive summary of risk factors, molecular machinery as well as potential therapeutic targets with a particular focus on literature published in the last 2 years on prognosis and treatment of penile cancer (PeCa). RECENT FINDINGS: E2F, LAMC2, MAML2, ID1 and IGFBP2 proteins were demonstrated to play a critical role for aggressive tumor behavior and might predict poor survival in PeCa. PD-L1 axis was confirmed as a promising pathway to serve as a therapeutic target. A number of genetic alterations were illuminated. In clinical testing, pan-HER tyrosine kinase inhibitor dacomitinib provided promising results in chemo-naïve and EGFR monoantibody nimotuzumab in chemotherapy-failed PeCa patients. SUMMARY: Knowledge of prognosis-relevant altered molecular pathways in PeCa is expanding paving the way for identification of potential therapeutic targets. Multicenter clinical trials in the setting of centralized PeCa care are warranted to foster effective marker-based individualized treatment strategies.

Competing-risks model for predicting the prognosis of penile cancer based on the SEER database.

OBJECTIVES: This study performed a competing-risks analysis using data from the SEER database on penile cancer patients with the aim of identifying more accurate prognostic factors. METHODS: Data on patients with penile cancer were extracted from the SEER database. A univariate analysis used the cumulative incidence function and Gray's test, while multivariate analysis was performed using the Fine-Gray model. Cumulative hazards were compared with a competing-risks model constructed using Kaplan-Meier estimation. RESULTS: The multivariate Fine-Gray analysis indicated that being black (HR = 1.51, 95%CI: 1.10-2.07, P = .01), AJCC stage II (HR = 1.94, 95%CI: 1.36-2.77, P < .001), AJCC stage III (HR = 1.98, 95%CI: 1.34-2.91, P < .001), tumor size > 5 cm (HR = 2.23, 95%CI: 1.33-3.72, P < .05), and TNM stages N1 (HR = 2.49, 95%CI: 1.71-3.61, P < .001), N2 (HR = 3.25, 95%CI: 2.18-4.84, P < .001), N3 (HR = 5.05, 95%CI: 2.69-9.50, P < .001), and M1 (HR = 2.21, 95%CI: 1.28-3.84, P < .05) were statistically significant. The results obtained using multivariate Cox regression were different, while Kaplan-Meier curve analysis led to an overestimation of the cumulative risk of the patient. CONCLUSIONS: This study established a competing-risks analysis model for the first time based on the SEER database for the risk assessment of penile cancer patients. The results may help clinicians to better understand penile cancer and provide these patients with more appropriate support.

Awareness of human papillomavirus infection complications, cervical cancer, and vaccine among the Saudi population. A cross-sectional survey.

OBJECTIVES: To determine human papillomavirus (HPV) infection, cervical cancer, and vaccine awareness among the Saudi population. METHODS: This cross-sectional study of a convenience sample comprising 1033 participants (males and females) from different parts of Kingdom of Saudi Arabia was conducted between August 2018 and January 2019 using a web-based questionnaire. This self-administrated questionnaire was distributed to all participants. Collected data included age groups, cervical cancer, Papanicolaou (Pap) smear, and HPV vaccine awareness. RESULTS: The response rate was 95%. Approximately 50% of the participants were 15-22 years old, less than 3% were more than 46 years old, and less than 10% had heard of HPV. Awareness and previous knowledge of the Pap smear as a screening tool was variable with male (5.9%) and female (27.9%) participants, having knowledge of the test. There were no statistically significant differences (p more than 0.05) between males and females in their knowledge of HPV's role in cervical and penile cancers, the HPV vaccine availability in the hospital, its role in cervical cancer prevention, and suggestions that this vaccine should be provided to married and non-married women. CONCLUSION: There is a lack of knowledge and misinformation regarding cervical cancer, Pap smears, HPV, and HPV association with cervical cancer. These data can be used as a basis to formulate effective population awareness programs.

Penile Lymphangioma Secondary to Sclerosing Lymphangitis/Mondor's Disease in an HIV-Positive Patient.

A 34-year-old man presented with a painless lesion of the glans present for more than 4 years. The patient became HIV-positive in 2011, and he has been treated with tenofovir, emtricitabine, and efavirenz. A CD4 count performed 4 months prior was 570 cells/mL3; syphilis, hepatitis B, and hepatitis C serologies performed on the same date were non-reactive.