Incidence, Clearance and Persistence of Penile High-Risk Human Papillomavirus among Rwandan Men who have Sex with Men.

BACKGROUND: Little is known about penile high-risk HPV among MSM in low-and-middle income countries. We aimed to determine the incidence, clearance and persistence of penile hrHPV among Rwandan MSM. METHODS: We enrolled 350 MSM (345 with valid HPV results), aged ≥18 years, at each visit (6-12 months apart), we collected penile PreservCyt specimens and blood for HPV and HIV testing, socio-demographic and behavioral variables. HPV testing was performed using the Ampfire assay. Penile hrHPV incidence and clearance/1,000 person-months of follow-up (PMF), prevalent- and incident-persistence were computed and compared by HIV status. RESULTS: The mean age was 27.7 ± 6.7 years and 19.4% were living with HIV. Penile hrHPV incidence was 34.8 (95% CI: 29.1, 41.8)/1,000 PMF. HPV16 (11.7, CI 9.26, 14.9) and HPV59 (6.1, CI 4.52, 8.39) had the highest incidence rates. Prevalent- and incident-persistence were 47.5% and 46.6%, respectively. HPV66 (33.3%), HPV52 (30.8%) and HPV16 (29.2%) had the highest prevalent-persistence and HPV33 (53.8%), HPV31 (46.7%) and HPV16 (42.6%) the highest incident-persistence. No differences were found by HIV status except for HPV45 (higher in MSM with HIV). CONCLUSION: We found high incidence and prevalent/incident-persistence of penile hrHPV among Rwandan MSM. This highlights the importance of preventive strategies for HPV-associated anogenital cancers.

Prevalence of Human Papillomavirus (HPV) and HPV Type Distribution in Penile Samples in Young Men in Denmark: Results 10 Years After Implementation of a Girls-Only HPV Vaccination Program.

BACKGROUND: In Denmark, a girls-only human papillomavirus (HPV) vaccination program was initiated in 2008-2009. The study aim was to assess the HPV prevalence and type distribution in younger men prior to HPV vaccination in men. METHODS: The study population was younger men who attended information days regarding military service. At random days (2019-2020), 280 men were included. We collected questionnaire data regarding risk factors for HPV infection and a penile swab for HPV testing. We compared results in this study with those from a previous study of young men (2006-2007). RESULTS: The majority of participants (94%) were 18-20 years old. The median number of lifetime sexual partners was 4. Altogether, 130 men (46.4%) were HPV positive. No infections with HPV types 6, 11, 16, 18, 31, and 45 were detected. The most frequent type was HPV-51 (detected in 11.1%). Comparison showed that the odds of high-risk HPV type infection were higher in 2019-2020 (prevalence odds ratio [POR], 1.7 [95% confidence interval {CI}, 1.1-2.7]) compared with 2006-2007. In contrast, the odds were lower (POR, 0.3 [95% CI, .1-.6]) for HPV types targeted by the 9-valent HPV vaccine. CONCLUSIONS: The multicohort girls-only vaccination program has to a large degree protected young men against the HPV types included in the licensed vaccines. This does not speak against gender-neutral vaccination as the HPV prevalence is still high, although consisting largely of less carcinogenic HPV types.

Human papillomavirus infection affects treatment outcomes and the immune microenvironment in patients with advanced penile squamous cell carcinoma receiving programmed cell death protein 1 inhibitor-based combination therapy.

BACKGROUND: Penile squamous cell carcinoma (PSCC) is a human papillomavirus (HPV)-associated malignancy. Immunotherapy is emerging as a potential treatment for advanced PSCC. In this study, the authors analyzed the association of HPV status with outcomes and the immune microenvironment in patients with advanced PSCC undergoing programmed cell death protein 1 (PD1) inhibitor-based combination therapy (PCT). METHODS: HPV status was assessed using quantitative polymerase chain reaction in 87 patients with advanced PSCC treated with PCT. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) in the HPV+ and HPV- groups were compared. Additionally, bulk RNA sequencing was performed to investigate the potential impact of HPV on the immune microenvironment in advanced PSCC. RESULTS: Among patients receiving first-line PCT, ORR (91.7% vs. 64.6%, p = .014) and DCR (100.0% vs. 79.2%, p = .025) in the HPV+ group were higher compared to the HPV- group. Kaplan-Meier curves demonstrated that the HPV+ group exhibited superior PFS (p = .005) and OS (p = .004) for patients in the first-line setting. However, these advantages of HPV infection were not observed in multi-line PCT (p > .050). HPV status remained an independent prognostic factor for predicting better ORR (p = .024), PFS (p = .002), and OS (p = .020) in the multivariate analyses. Landmark analyses showed that the HPV-induced superiority of PFS occurred at an early stage (within 3 months) and OS occurred at a relatively late stage (within 9 months). Bioinformatic analyses identified potential immune-activated genes (GLDC, CYP4F12, etc.) and pathways (RAGE, PI3K/AKT, etc.), antitumor immune cell subtypes, and lower tumor immune dysfunction and exclusion scores in HPV+ tissues. CONCLUSIONS: HPV infection may confer treatment efficacy and survival benefits in patients with advanced PSCC receiving first-line PCT because of the possible stimulation of the antitumor immune microenvironment. PLAIN LANGUAGE SUMMARY: Human papillomavirus (HPV) infection may induce better objective response rate, progression-free survival (PFS), and overall survival (OS) for advanced penile squamous cell carcinoma (PSCC) patients receiving first-line programmed cell death protein 1 inhibitor-based combination therapy (PCT) instead of multi-line PCT. HPV infection-induced PFS advantage occurs at an early stage (within 3 months) whereas OS superiority occurs at a relatively late stage (within 9 months). Antitumor immune microenvironment could be stimulated by HPV infection in advanced PSCC tissues.

Molecular characterization of metastatic penile squamous cell carcinoma in developing countries and its impact on clinical outcomes: LACOG 2018 translational study.

BACKGROUND: Penile squamous cell carcinoma (PSCC) is a rare malignancy. However, in developing countries the incidence rate is higher. The understanding of molecular alterations is essential for evaluating possible targets for more effective systemic therapies. METHODS: We retrospectively collected clinical data of metastatic PSCC (mPSCC) patients who had received at least one prior systemic treatment from 3 Brazilian hospitals. Tumor samples were evaluated using the next-generation sequencing (NGS) Foundation One DX and immunohistochemistry (IHC). The objective was to identify and describe somatic genomic alterations known to be functional or pathogenic and their association with survival outcomes. RESULTS: Twenty-three patients were identified, 22 and 18 patients had tumor samples analyzed by IHC and NGS, respectively. PD-L1 expression (CPS ≥ 1%) was positive in 14 patients (63.6%). Regarding the genomic alterations, 16 patients (88.9%) had some clinically relevant genomic alterations. TP53, TERT, CDKN2A, PIK3CA, NOTCH1, and CDKN2B loss were identified in 66.7%, 50%, 50%, 33.3%, 27.8%, and 22.2% of the patients, respectively. No MSI or TMB high (≥10 mutations/MB) cases were identified. NOTCH1 mutation was identified only in HPV-negative patients and it was associated with worse OS (yes: 5.5 vs no: 12.8 months, P = .049) and progression-free survival (yes: 5.5 vs no: 11.7 months, P = .032). CONCLUSION: This study demonstrated that molecular alterations in mPSCC from developing countries are similar to those from developed countries. Predictive biomarkers for immunotherapy response such as TMB high or MSI were not identified. Specific gene mutations may identify patients with worse prognoses and open new avenues for therapeutic development.

Characterization of T cell receptor repertoire in penile cancer.

Tumor-infiltrating lymphocytes (TILs) play a key role in regulating the host immune response and shaping tumor microenvironment. It has been previously shown that T cell infiltration in penile tumors was associated with clinical outcomes. However, few studies have reported the T cell receptor (TCR) repertoire in patients with penile cancer. In the present study, we evaluated the TCR repertoires in tumor and adjacent normal tissues from 22 patients with penile squamous cell carcinoma (PSCC). Analysis of the T cell receptor beta-variable (TRBV) and joining (TRBJ) genes usage and analysis of complementarity determining region 3 (CDR3) length distribution did not show significant differences between tumor and matched normal tissues. Moreover, analysis of the median Jaccard index indicated a limited overlap of TCR repertoire between these groups. Compared with normal tissues, a significantly lower diversity and higher clonality of TCR repertoire was observed in tumor samples, which was associated with clinical characteristics. Further analysis of transcriptional profiles demonstrated that tumor samples with high clonality showed increased expression of genes associated with CD8 + T cells. In addition, we analyzed the TCR repertoire of CD4 + T cells and CD8 + T cells isolated from tumor tissues. We identified that expanded clonotypes were predominantly in the CD8 + T cell compartment, which presented with an exhausted phenotype. Overall, we comprehensively compared TCR repertoire between penile tumor and normal tissues and demonstrated the presence of distinct T cell immune microenvironments in patients with PSCC.

Prevalence and concordance of penile, anal, and oral human papillomavirus infections among sexually active heterosexual men in Ibadan, Nigeria.

BACKGROUND: The data on epidemiology of Human papillomavirus (HPV) infections in men are scarce relative to women generally, particularly among men engaging in heterosexual relationships. This study investigated the prevalence and risk factors for penile, anal, and oral HPV in men in two communities in Ibadan, Nigeria. METHODS: This was a cross-sectional survey involving a face-to-face interview, a clinical examination, and sample collection from participants. HPV genotyping was performed with Anyplex II 28 HPV assay. The prevalences and factors associated with HPV infections using multivariable models and concordance between sites. RESULTS: Of 316 men, the proportion of any HPV infection in the penile, anal, and oral sites was 40.5%, 9.7%, and 7.8%, respectively. The proportion of any high-risk HPV, low-risk HPV, and multiple HPV infections was highest in the penis followed by the anal and oral sites. Only 5/316 (1.6%) men had concordant HPV in all three sites, with the highest concordance in penile-anal sites relative to penile-oral and anal-oral sites. The odds of penile HPV were higher in men aged 25 years and above. Having penile HPV was associated with higher odds of detecting anal HPV and vice versa. Oral HPV was less likely in men not living with their sexual partners. CONCLUSION: Penile HPV is the most common infection followed by anal HPV and oral HPV infections among heterosexual Nigerian men. Concordant HPV infections was highest in penile-anal sites. Nigerian men, as in other settings, are a reservoir of HPV and it is important to conduct more robust studies to appreciate their role in HPV transmission, epidemiology, and prevention.

Creation of a Novel Classification System (PTNM) for Peyronie's Disease and Penile Curvature Using Evidence-Based Criteria.

PURPOSE: Our goal was to identify new Peyronie's disease (PD) subtypes, non-PD penile curvature classifications, and define active (acute) vs stable (chronic) phases of disease using evidence-based analyses. MATERIALS AND METHODS: A retrospective review was performed of 1098 men who presented with penile deformity, including subjective standardized and nonstandardized questionnaires and objective measures. A second cohort of 719 men who were sent a mailed survey was also utilized for the relapsing/remitting subtype. Statistical analyses were performed to identify clusters of disease characteristics representative of distinct PD and non-PD categorizations, including sensitivity/specificity analyses and subtype comparisons. RESULTS: Comparative analyses identified 4 distinct subtypes of PD: (1) classical and nonclassical, (2) calcifying-moderate/severe calcification, (3) progressive-subjective worsening following disease onset, and (4) relapsing/remitting-reactivation following ≥ 6 months of stability. Additional, non-PD categorizations included congenital (lifelong), maturational (developed around puberty), and trauma induced. Statistical analyses demonstrated unique profiles among each category. Penile pain was not found to be a reliable predictor for disease progression or stability. Stable phase disease (historically "chronic") was variably defined by subtype: classical (≥3 months); progressive, calcifying, or trauma induced (≥12 months + ≥3 months stable OR ≥6 months stable). Similarly, PD subtypes may be assigned at ≥ 3 months following disease onset. A PTNM staging system is proposed to help communicate disease states, in which P = PD component (Ca-calcifying, Cl-classical, P-progressive, R-relapsing/remitting, U-undifferentiated), T = trauma component (0-absent, 1-present), N = non-PD component (C-congenital, M-maturational, U-undifferentiated), and M = mode (0-stable, 1-active); for example, PClT1N0M0 = stable classical PD with prior trauma. CONCLUSIONS: The current study provides an evidence-based proposal for the establishment of new PD subtypes and non-PD curvature categorizations as well as a standardized definition for active vs stable phases of disease.

Total Margin Control Is Superior to Traditional Margin Assessment for Treatment of Low-Stage Penile Squamous Cell Carcinoma.

PURPOSE: Penile cancer is rare, with significant morbidity and limited literature assessing utility of peripheral and deep en face margin assessment (PDEMA) vs traditional margin assessment (vertical sections) on treatment outcomes. MATERIALS AND METHODS: This was a 32-year retrospective multicenter cohort study at 3 academic tertiary care centers. The cohort consisted of 189 patients with histologic diagnosis of in situ or T1a cutaneous squamous cell carcinoma of the penis at Brigham and Women's, Massachusetts General Hospital (1988-2020), and Memorial Sloan Kettering Cancer Center (1995-2020) treated with PDEMA surgical excision, excision/circumcision, or penectomy/glansectomy. Local recurrence, metastasis, and disease-specific death were assessed via multivariable Cox proportional hazard models. RESULTS: The cohort consisted of 189 patients. Median age at diagnosis was 62 years. Median tumor diameter was 1.3 cm. The following outcomes of interest occurred: 30 local recurrences, 13 metastases, and 5 disease-specific deaths. Primary tumors were excised with PDEMA (N = 30), excision/circumcision (N = 110), or penectomy/glansectomy (N = 49). Of patients treated with traditional margin assessment (non-PDEMA), 12% had narrow or positive margins. Five-year proportions were as follows with respect to local recurrence-free survival, metastasis-free survival, and disease-specific survival/progression-free survival, respectively: 100%, 100%, and 100% following PDEMA; 82%, 96%, and 99% following excision/circumcision; 83%, 91%, and 95% following penectomy/glansectomy. A limitation is that this multi-institutional cohort study was not externally validated. CONCLUSIONS: Initial results are encouraging that PDEMA surgical management effectively controls early-stage penile squamous cell carcinoma.

Human papillomavirus prevalence and genotype distribution in Liaocheng men between 2016 and 2022.

Human papillomavirus (HPV) infection can lead to HPV-related cancer in men, including the anus, penile, and oropharyngeal cancers and precancerous lesions. This study retrospectively investigated HPV prevalence and genotype distribution in Liaocheng men between 2016 and 2022. The total HPV positive rate was 64.87% (2388/3681, 95% confidence interval [CI]: 63.32%-66.40%), where high risk (HR)-HPV and low risk (LR)-HPV accounted for 42.49% (1564/3681, 95% CI: 40.90%-44.09%) and 69.71% (2566/3681, 95% CI: 68.20%-71.17%), respectively. The mixed HPV infection rate of two and more genotypes was 35.72%. The infection rate of HR-HPV increased with the number of positive cases annually from 2016 (16.91%) to 2022 (46.59%). The most common HR-HPV genotypes were HPV16 (11.60%), HPV52 (6.95%), and HPV59 (6.28%), whereas the least common HR-HPV was HPV26. The most common LR-HPV genotypes were HPV6 (56.99%), HPV11 (23.79%), and HPV43 (6.37%). The 9 v HPV vaccine preventable for LR-HPV and HR-HPV accounted for 80.78% and 30.40%, respectively, in this study. Most HPV-positive patients aged 1-86 were in the 30-39 age group. This study confirmed that HPV prevalence in Liaocheng men was common and diverse. HPV16, HPV52, and HPV59 are widely distributed in Liaocheng men, and the male HR-HPV infection rate remained high in this region. Regarding public health and cancer prevention, it is recommended and effective to include the HPV vaccination in the national vaccination program for men.

Radiotherapy Versus Partial Penectomy for T1 Squamous Cell Carcinoma of the Penis.

BACKGROUND: Radiotherapy (RT) represents an alternative treatment option for patients with T1 squamous cell carcinoma of the penis (SCCP), with proven feasibility and tolerability. However, it has never been directly compared with partial penectomy (PP) using cancer-specific mortality (CSM) as an end point. METHODS: In the Surveillance, Epidemiology, and End Results database (2000-2020), T1N0M0 SCCP patients treated with RT or PP were identified. This study relied on 1:4 propensity score-matching (PSM) for age at diagnosis, tumor stage, and tumor grade. Subsequently, cumulative incidence plots as well as multivariable competing risks regression (CRR) models addressed CSM. Additionally, the study accounted for the confounding effect of other-cause mortality (OCM). RESULTS: Of 895 patients with T1N0M0 SCCP, 55 (6.1%) underwent RT and 840 (93.9%) underwent PP. The RT and PP patients had a similar age distribution (median age, 70 vs 70 years) and more frequently harbored grade I or II tumors (67.3% vs 75.8%) as well as T1a-stage disease (67.3% vs 74.3%). After 1:4 PSM, 55 (100%) of the 55 RT patients versus 220 (26.2%) of the 840 PP patients were included in the study. The 10-year CSM derived from the cumulative incidence plots was 25.4% for RT and 14.4% for PP. In the multivariable CRR models, RT independently predicted a higher CSM than PP (hazard ratio, 1.99; 95% confidence interval, 1.05-3.80; p = 0.04). CONCLUSION: For the T1N0M0 SCCP patients treated in the community, RT was associated with nearly a twofold higher CSM than PP. Ideally, a validation study based on tertiary care institution data should be conducted to test whether this CSM disadvantage is operational only in the community or not.

[68Ga]Ga-FAPI-46 PET/CT for penile cancer - a feasibility study.

PURPOSE: Penile cancer is a rare entity and has a good prognosis in localized stage. Delayed surgical treatment of lymphatic disease is associated with poor overall survival but conventional imaging cannot detect occult lymph node metastasis sufficiently. Imaging cancer related fibroblasts has shown promising results as non-invasive staging tool in various tumor entities but has not yet been evaluated in penile cancer. METHODS: In this single-center pilot study, patients planned for surgical treatment for penile cancer underwent preoperatively [68Ga]Ga-FAPI-46 PET/CT. Post-operative histopathology was compared to [68Ga]Ga-FAPI-46 PET/CT results. RESULTS: From January 2022 to June 2022, a total number 11 patients with histopathologically proven penile cancer underwent surgery and received [68Ga]Ga-FAPI-46 PET/CT prior therapy. 8 primary tumor sites and 4 lymph node regions were analyzed. FAPI uptake was increased on primary tumor site (SUVmax 16.2 (9.1 - 25.8)). Histopathological proven lymph node regions showed highly increased FAPI uptakes (SUVmax 17.9 (16.4 - 23.5) on [68Ga]Ga-FAPI-46 PET/CT. CONCLUSION: In this first pilot cohort, there were no false-positive FAPI uptake which might allow the detection of occult lymph node metastasis by [68Ga]Ga-FAPI-46 PET/CT and might consequently lead to omitting lymph node regions during surgery that had no increased FAPI uptake pre-operatively.

New EAU/ASCO guideline recommendations on sentinel node biopsy for penile cancer and remaining challenges from a nuclear medicine perspective.

INTRODUCTION: The European Association of Urology (EAU) and the American Society of Clinical Oncology (ASCO) recently issued updated guidelines on penile cancer, emphasising dynamic sentinel node biopsy (DSNB) as the preferred method for surgical staging among patients with invasive penile tumours and no palpable inguinal lymphadenopathy. This paper outlines the rationale behind this new recommendation and describes remaining challenges, as well as strategies for promoting DSNB worldwide. MAIN TEXT: DSNB offers high diagnostic accuracy with the lowest postoperative complications compared to open or minimally invasive inguinal lymph node dissection (ILND), prompting its preference in the new guidelines. Nevertheless, despite its advantages, there are challenges hampering the widespread adoption of DSNB. This includes the false-negative rate associated with DSNB and the potential negative impact on patient outcome. To address this issue, improvements should be made in several areas, including refining the timing and interpretation of the lymphoscintigraphy and the single photon emission computed tomography/computed tomography images. In addition, the quantity of tracer employed and choice of the injection site for the radiopharmaceutical should be optimised. Finally, limiting the removal of nodes without tracer activity during surgery may help minimise complication rates. CONCLUSION: Over the years, DSNB has evolved significantly, related to the dedicated efforts and innovations in nuclear medicine and subsequent clinical studies validating its efficacy. It is now strongly recommended for surgical staging among selected penile cancer patients. To optimise DSNB further, multidisciplinary collaborative research is required to improve SN identification for better diagnostic accuracy and fewer complications.

Serum cyfra21-1 is a new prognostic biomarker of penile squamous cell carcinoma.

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.

Incidence, risk factors, and temporal trends of penile cancer: a global population-based study.

OBJECTIVES: To examine the global disease burden and country-specific trends of penile cancer incidence by age group and investigate its associations with several factors. MATERIALS AND METHODS: The Global Cancer Observatory database was interrogated for penile cancer incidence. The 10-year cancer incidence rates were collected from the Cancer Incidence in Five Continents Plus. The country-specific data were extracted from the World Health Organization Global Health Observatory and Global Burden of Disease databases for conducting risk factors analysis. The penile cancer incidence was presented using age-standardised rates. Its associations with various factors were examined by linear regression, while the incidence trend was estimated using joinpoint regression and presented as average annual percentage change with 95% confidence intervals in different age groups. RESULTS: There were an estimated 36 068 new cases of penile cancer in 2020. There was a considerable geographical disparity in the disease burden of penile cancer, with South America reporting the highest incidence. Overall, alcohol drinking, human immunodeficiency virus (HIV) infection, and unsafe sex were positively associated with a higher penile cancer incidence, while circumcision was found to be a protective factor. There has been a mixed trend in penile cancer incidence overall, but an increasing trend was found among younger males. CONCLUSIONS: There was a global variation in the penile cancer burden associated with prevalence of alcohol drinking, HIV infection, unsafe sex, and circumcision. The increasing penile cancer incidence in the younger population is worrying and calls for early detection and preventive interventions.

Penile intraepithelial neoplasia incidence, clinical classification, microenvironment and implications for imiquimod treatment.

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.

Efficacy of indocyanine green fluorescence-guided inguinal lymph node dissection for penile cancer: a randomised trial.

OBJECTIVES: To investigate the safety and efficacy of indocyanine green (ICG) fluorescence-guided inguinal lymph node dissection (ILND) in patients with penile cancer. PATIENTS AND METHODS: A prospective, single-blind, randomised controlled clinical trial (ChiCTR2100044584) was performed among patients with penile caner who underwent bilateral modified ILND at four centres in China between 1 April 2021 and 30 June 2022. Patients aged 18-80 years and diagnosed with squamous cell carcinomas were included. Each enrolled patient was randomly assigned to either ICG fluorescence-guided ILND by a laparoscopic or robot-assisted approach in one groin, with non-ICG fluorescence-guided ILND in the other groin acting as a control. The primary outcome was the number of retrieved ILNs. Secondary outcomes included complications according to the Clavien-Dindo classification and the ILN non-compliance (inadequate removal of ILNs) rate. RESULTS: A total of 45 patients were included in the intention-to-treat (ITT) analysis, and the 42 who completed the entire study were included in the per protocol (PP) analysis. There were no ICG-related complications in any of the patients. The results of the ITT and PP analyses indicated that the total number of unilateral ILNs retrieved was higher on the ICG side than on the non-ICG side (mean 13 vs 9 ILNs, difference 4 ILNs [95% CI 2.7-4.4], P = 0.007), and the number of unilateral deep and superficial ILNs was higher on the ICG side. Furthermore, the LN non-compliance rate was lower on the ICG side than on the non-ICG side. Additionally, there was no significant difference in local complications in the groins between the two sides (P > 0.05). CONCLUSION: An ICG fluorescence-guided ILND was safe for patients with penile cancer. This procedure can improve the number of ILNs retrieved and reduce the LN non-compliance rate without increased complications. ICG fluorescence-guided ILND is beneficial and recommended for selected patients with penile cancer.

Penile cancer care in the Netherlands: increased incidence, centralisation, and improved survival.

OBJECTIVE: To evaluate penile squamous cell carcinoma (PSCC) incidence and centralisation trends in the Netherlands over the past three decades, as well as the effect of centralisation of PSCC care on survival. PATIENTS AND METHODS: In the Netherlands PSCC care is largely centralised in one national centre of expertise (Netherlands Cancer Institute [NCI], Amsterdam). For this study, the Netherlands Cancer Registry, an independent nationwide cancer registry, provided per-patient data on age, clinical and pathological tumour staging, follow-up, and vital status. Patients with treatment at the NCI were identified and compared to patients who were treated at all other centres. The age-standardised incidence rate was calculated with the European Standard Population. The probability of death due to PSCC was estimated using the relative survival. Multivariable Cox regression analysis was performed to evaluate predictors of survival. RESULTS: A total of 3160 patients were diagnosed with PSCC between 1990 and 2020, showing a rising incidence (P < 0.001). Annual caseload increased at the NCI (1% in 1990, 65% in 2020) and decreased at other (regional) centres (99% to 35%). Despite a relatively high percentage of patients with T2-4 (64%) and N+ (33%) at the NCI, the 5-year relative survival was higher (86%, 95% confidence interval [CI] 82-91%) compared to regional centres (76%, 95% CI 73-80%, P < 0.001). Patients with a pathological T2 tumour were treated with glans-sparing treatment more often at the reference centre than at the regional centres (16% vs 5.0%, P < 0.001). After adjusting for age, histological grading, T-stage, presence of lymph node involvement and year of diagnosis, treatment at regional centres remained a predictor for worse survival (hazard ratio 1.22, 95% CI 1.05-1.39; P = 0.006). CONCLUSION: The incidence of PSCC in the Netherlands has been gradually increasing over the past three decades, with a noticeable trend towards centralisation of PSCC care and improved relative survival rate.

Trophoblast cell surface antigen-2: a promising new biomarker and potential therapeutic target in penile squamous cell carcinoma.

OBJECTIVE: To evaluate the potential utility of antibody-drug conjugates targeting trophoblast cell surface antigen-2 (TROP-2) in patients with primary penile squamous cell carcinoma (PSCC), patients with recurrence (REC cohort), and patient-matched distant metastases (MET cohort), and to assess the potential use of TROP-2 as a predictive non-invasive biomarker in PSCC. METHODS: A cohort comprising a PRIM (n = 37), REC (n = 5) and MET subcohort (n = 7), with MET including lymph node and lung metastases, was analysed using quantitative real-time PCR, ELISA and immunohistochemical staining with evaluation of H-score. RESULTS: TROP-2 mRNA and serum protein levels were significantly increased in primary and recurrent PSCC compared to cancer-free controls (both P < 0.001). Immunohistochemical analysis revealed that most of the PRIM cohort (n = 34/37, median H-score 260, interquartile range [IQR] 210-300), as well as all patients in the REC (median [IQR] H-score 200 [165-290]) and MET cohorts (median [IQR] H-score 280 [260-300]) exhibited moderate to strong membranous TROP-2 expression. Additionally, The H-score (membranous TROP-2 expression) was positively correlated with TROP-2 mRNA (ρ = 0.69, P < 0.0001, R2 = 0.70) and protein levels (ρ = 0.86, P < 0.0001, R2 = 0.59), indicating its potential as a non-invasive biomarker in PSCC. CONCLUSION: In summary, our results support further studies on TROP-2 as a diagnostic and therapeutic target in primary, recurrent and metastatic PSCC.

Fluorescence-guided surgery using cetuximab-800CW in patients with penile carcinoma.

OBJECTIVE: To investigate the feasibility of fluorescence molecular imaging (FMI), using cetuximab-800CW, as an intraoperative tool to determine surgical margins in penile squamous cell carcinoma (PSCC). PATIENTS AND METHODS: A total of 11 patients with PSCC received 75 mg cetuximab followed by 15 mg cetuximab-800CW 2 days before surgery. FMI of the whole excision specimen and tissue slices was performed. Fluorescence visualisation was correlated to histopathology. Based on tumour and healthy tissue regions of interest, mean fluorescence intensity was calculated for each individual patient. RESULTS: Significant differences between tumour and healthy mean fluorescence intensity were found with tumour-to-background ratios of a median (IQR) of 1.51 (0.99) and a mean (SD) of 1.51 (0.32) in the excision specimen and tissue slices, respectively. One patient showed a high relative fluorescence intensity with a signal-to-background ratio of 1.79, corresponding to a tumour-positive margin on fresh frozen sectioning. CONCLUSION: In this Phase I study we showed that cetuximab-800CW seems suitable to discriminate PSCC from background tissue. The tracer was well tolerated, and no false positive spots were seen.

Cosmetic penile enhancement procedures: an SMSNA position statement.

BACKGROUND: Penile cosmetic enhancement procedures have been performed for many years with varying success. However, they have historically been relegated to niche areas of sexual medicine, with limited data, and have not achieved mainstream adoption. More recently, the topic has been increasingly discussed within academic congresses due to availability of novel techniques, therapies, and procedures. Given their distinctive nature, the Sexual Medicine Society of North America (SMSNA) felt that it was pertinent to develop formal position statements to help guide both patients and sexual medicine providers on the current state of the scientific literature and to give recommendations for future research. AIM: The study sought to provide an evidence-based set of recommendations for injection and surgical procedures designed to lengthen, augment, or otherwise cosmetically enhance the penis. METHODS: A review was performed of all scientific literature listed in PubMed from inception through December 2023 relating to penile cosmetic enhancement procedures. Only invasive (injection/surgery) therapies were included due to their distinct risk-benefit profile compared with more conservative treatments (eg, vacuum erection devices, penile traction devices). Similar therapies were categorized, with pertinent data summarized and used to help create relevant position statements. All statements were expert opinion only and were based on analyses of the potential risks and benefits of the specific therapies. OUTCOMES: A total of 6 position statements were issued relating to 5 distinct sexual medicine cosmetic enhancement procedures. RESULTS: A consensus opinion was reached by SMSNA leadership on the state of injection/surgical penile cosmetic enhancement procedures as of 2024. Key topic areas addressed included injectable soft tissue fillers, suspensory ligament division, graft-and-flap procedures, silicone sleeve implants, and sliding/slicing techniques. Distinct recommendations were tailored to each therapy and were based solely on the current state of the literature. It is anticipated that future studies will further inform position statements and will lead to ongoing modifications. CLINICAL IMPLICATIONS: The current position statements provide both patients and clinicians evidence-based, expert recommendations on best practices relating to penile cosmetic enhancement procedures. STRENGTHS AND LIMITATIONS: Strengths include the use of an expert panel of sexual medicine clinicians, consensus design, and summary of existing literature. Limitations include expert opinion and limited research on the topic. CONCLUSION: The current SMSNA position statements provide evidence-based, consensus opinions on the appropriate role for penile augmentation and cosmetic procedures in 2024.