A comprehensive review of current knowledge on penile squamous cell carcinoma.

Neoplasm of the penis is relatively rare in most regions representing 0-2% of cancers worldwide. While the penis can be affected by sarcomas, basal cell carcinomas or even melanoma, Penile Squamous Cell Carcinoma (PSCC) represents approximately 95% of all penile neoplasms. Despite its rarity and most common presentation at later decades of life most individuals diagnosed with PSCC are faced with significant decrease in quality of life. The prevalence and incidence vary among different regions and populations, but a common trend is for diagnosis to occur late (stage 4). Underdeveloped countries are traditionally reported to have higher incidence rates; however, rates may vary significantly between urban and rural areas even in developed countries. Age adjusted rates are on the rise in some countries that used to have incidence rates of 1:100 000 or less. The list of associated risk factors is long and includes among others, lack of neonatal circumcision, poor genital hygiene, socioeconomic status, history of human papillomavirus (HPV) infection and penile intraepithelial neoplasia (PeIN). Many risk factors are widely debated among experts however HPV and PeIN are indisputable risk factors, and both also form part of the classification system for PSCC. Both conditions may have occurred in the past or be present at the time of diagnosis and identifying them plays a major role in management strategies. For such a rare condition PSCC can present in many different forms clinically making diagnosis no easy feat. Diagnosis of PSCC is done through clinical examination, including lymph node palpation, followed by a biopsy, which is essential for the classification. Lymph node involvement is a common finding at first presentation and investigation of spread to deep nodes is important and can be done with the aid of PET-CT. Treatment options for PSCC include surgery, chemotherapy, and radiation therapy. Surgical removal of the tumor is considered the most effective however can lead to severe decrease of quality of life. Chemotherapy is used in the case of fixed or bulky lymph nodes, where surgery is not indicated, and for distant metastasis. Radiation therapy is particularly effective in the case of HPV-positive PSCC.

Improving Quality of Life and Psychosocial Health for Penile Cancer Survivors: A Narrative Review.

Treatment of penile cancer (PC) focuses on organ preservation, employing various surgical and non-surgical approaches. These interventions may lead to disfigurement, impacting patients' functional outcomes and psychosocial well-being. We reviewed studies related to penile health and PC up to February 2024, limited to studies published in English. Studies employing health-related quality of life (HRQoL) assessments have identified a detrimental association between aggressive treatment and overall health status, physical functioning, and relationships. In contrast, organ-sparing demonstrates improved measures related to HRQoL and sexual function. Assessment through validated questionnaires reveals diverse voiding outcomes, and varying impacts on QoL and sexual activity, emphasizing the necessity for multidisciplinary personalized care. Studies highlight substantial variations in sexual function, with patients reporting adaptations, reduced satisfaction, and concerns about body image and sexual well-being. Furthermore, unmet needs include challenges in patient-clinician communication, obtaining information, and accessing psychosocial support. Patient experiences underscore the importance of timely diagnosis, treatment access, and addressing psychological consequences. Organ-sparing approaches have higher QoL preservation and sexual function. Individualized support, including sexual therapy, support groups, and family counseling, is essential for post-treatment rehabilitation. Timely diagnosis and comprehensive care are paramount in addressing the multifaceted impact of PC on patients and families.

Microbiome reveals inflammatory-related bacteria and putative functional pathways involved in human papillomavirus-associated penile squamous cell carcinoma.

BACKGROUND: Penile squamous cell carcinoma (PSCC) is a rare disease that is more prevalent in developing countries, such as Brazil, and is linked to poor genital hygiene, which promotes the proliferation of microorganisms. Dysbiosis has an effect on the local immune response, increases the risk of viral infection, and can generate inflammatory processes. Current knowledge of the microbiota found in penile tissues is limited, and the bacterial diversity of the PSCC remains unknown. In this investigation, the microbiota associated with penile cancer and its potential role in tumor development and progression were identified. METHODS: The 16S rRNA gene was analyzed by next-generation sequencing in 19 tumors and their respective non-tumor adjacent tissues to perform taxonomic classification, analysis of core microbiome, abundance, and diversity of amplicon sequence variants (ASVs) (QIIME2 v.2020.2), and in silico functional prediction (PICRUST2, p < 0.05). RESULTS: In both tissues, the phyla Proteobacteria and Firmicutes, and genera Alcaligenes and Fusobaterium, were the most prevalent. Tumors presented a greater relative abundance of Fusobacteriota, Campilobacteria, and Fusobacterium (p = 0.04, p = 0.04, and p = 0.039, respectively). In addition, the beta diversity analysis revealed a tendency for the formation of two distinct groups when only advanced tumors (pT2 and pT3) were considered. Further, the functional analysis identified the top 35 pathways, and 79.5% of PSCC samples contained pro-inflammatory microorganisms. CONCLUSION: We describe the first microbiome of penile carcinoma, which revealed an abundant and diverse microbiota as well as inflammatory-related taxa (the phyla Proteobacteria and Firmicutes, the genera Fusobacterium and Prevotella, and the species Finegoldia magma and Pseudomonas geniculata) and molecular pathways (chitin derivates degradation, the protocatechuic acid pathway, inositol metabolism, and the sucrose pathway), which have also been linked to inflammation and carcinogenesis. Moreover, we found specific and abundant ASVs in both tumor and non-tumor tissues. Our data encourage further study to better understand the role of these microorganisms in penile carcinogenesis, offering an opportunity for advances in diagnosis, prognosis, and early therapy.

MIR-376A-2-5P as a potential prognostic marker for advanced penile squamous cell carcinomas trough HPV-dependent pathways.

Penile cancer (PeCa) is a rare tumor, generally associated with socioeconomic conditions in low-income countries. Hence, a delay in diagnosis and treatment leads in more advanced tumors, to higher comorbidity, and mortality. Human papillomavirus (HPV) infection has been identified as one of the major risk factors for PeCa. In addition, viral integration sites have been related to copy number alterations, impacting miRNAs/mRNA interactions and, consequently, the molecular pathways related to them. Nonetheless, studies on differentially expressed miRNAs (miRDEs) in PeCa are still scarce, especially in PeCa associated with high-risk HPV (hrHPV). To investigate the role of these gene regulators in PeCa progression, 827 miRNAs (Nanostring Technologies™, Seattle, WA, USA) were evaluated in 22 hrHPV-associated penile squamous cell carcinomas and five non-tumor penile tissues. For functions of miRNAs/target genes and relationship with HPV we conducted an integrated analysis by Diana Tools, KEGG, HPVbase, and InterSPPI-HVPPI platforms. We found that 25 miRNAs of the most differentially expressed impact 43 top molecular pathways, of which the fatty acid biosynthesis pathway, prions, miRNAs in cancer and hippo signaling (P<1.0-325, for each) were the most statistically significant. Notably, 23 out of 25 are located at HPV integration sites (HPVis). MiR-1206, miR-376b-3p and miR-495-3p were downregulated and associated with perineural invasion. In addition, a comparison between advanced and early diseases revealed 143 miRDEs. ROC analysis of a single (miR-376a-2-5p), paired (miR-376a-2-5p, miR-551b-3p) or combination of five miRDEs (miR-99a-5p, miR-150-5p, miR-155-5p, let-7c-5p, miR-342-3p) showed robust discriminatory power (AUC = 0.9; P = 0.0114, for each). Strikingly, miR-376a-2-5p exhibited the highest values of sensitivity and specificity, with 100% and 83.3%, respectively, indicating this miRNA as a potential prognostic marker in hrHPV-penile carcinogenesis.

Racial differences in survival for early stage (T1) penile cancer: Analysis from the SEER database.

BACKGROUND: Penile cancer accounts for less than 1% of male cancers in the United States. Localized disease, particularly T1 tumors are potentially curable with local therapy. We present the racial differences in survival outcomes for T1, penile cancer from the SEER database. METHODS: From 2004 to 2016 all men with T1, N0, M0 penile cancer in the SEER-18 database were included. Kaplan-Meier analysis and multivariable Cox-Regression analysis were conducted to investigate prognostic variables for cancer specific survival (CSS). RESULTS: A total of 4,406 men were identified with penile cancer; 1,941 men had T1 disease. The Kaplan-Meier (KM) analysis showed those with primary site surgery had better 5-year CSS compared to those without primary site surgery (P <.0001) and a significant difference in CSS based on race (P= 0.0078). On multivariable analysis, Hispanic individuals had worse CSS (HR 1.92; P = 0.0057) compared to the White men. Black men were also found to have a poor CSS however this was not statistically significant (HR 1.53, P = 0.118). Men with penile cancer who had either penectomy (HR 0.45; P = 0.006) or penile preservation surgery (HR 0.25; P< 0.001) had improved CSS. CONCLUSION: Racial disparities in CSS exist among men with in early-stage penile cancer. KM analysis showed significant differences in CSS by race and in those receiving primary site surgery. On multivariable analysis, the CSS is worse in Hispanic compared to White men. There is a trend towards worse CSS in Black men however this was not statistically significant.

Abordaje quirúrgico primario en un paciente con eritroplasia de Queyrat / Primary surgical approach to a patient with erythroplasia of Queyrat

Presentación del caso. Paciente masculino de 52 años que se presentó a la consulta de urología con historia de dos años de notar una lesión en el glande y el prepucio, de color rojo brillante, pruriginosa y dolorosa con aumento progresivo del tamaño que no mejoró con tratamientos antibióticos y anti fúngicos. Intervención terapéutica. Se realizó una glandectomía parcial con injerto de piel de muslo. Evolución clínica. Luego de un mes, el injerto presentó un 95 % de acoplamiento. No se observó recurrencia local de cáncer. El estudio histopatológico reportó un carcinoma escamoso invasor en la lesión del prepucio y en la piel del glande, con todos los márgenes quirúrgicos, limites laterales y profundos, negativos a malignidad. Luego de ocho meses posquirúrgicos, se observó el recubrimiento del glande con un adecuado resultado estético, con apariencia similar a la cubierta natural

Case presentation. A A 52-year-old male patient presented to the urology office with a two-year history of noticing a bright red, pruritic, and painful lesion on the glans and foreskin with a progressive increase in size that did not improve with antibiotic and antifungal treatments. Treatment. Partial glandectomy with thigh skin graft was performed. Outcome. After After one month, the graft presented a 95 % of coupling. No local recurrence of cancer was observed. The histopathological study reported invasive squamous cell carcinoma in the lesion of the foreskin and glans skin, with all surgical margins, lateral and deep limits, negative for malignancy. After eight months post-surgery, the covering of the glans was observed with an appropriate esthetic result, with a similar appearance to the natural covering

Prognostic utility of SOX2, STAT3, and CD44high/CD24low expression in penile cancer.

PURPOSE: Penile cancer has a high incidence in developing countries. The standard treatment is removal of the primary tumor and, when necessary, inguinal lymphadenectomy. Currently, the most important prognostic factor is lymph node disease, however, the available staging methods are inaccurate, and the high morbidity rate of lymphadenectomy has stimulated the study of predictive biomarkers of lymph node metastasis for selecting the patients who need lymphadenectomy. SOX2, STAT3 and CD44high/CD24low were chosen because they have provided good predictive results in other squamous cell carcinoma (SCC), although there are no studies for penile cancer. Thus, the expression of SOX2, STAT3, CD24+, and CD44+ in the penile cancer tumor microenvironment was investigated for correlation with tumor behavior in SCC. METHODS: This observational, prospective, translational study included 34 men and investigated the expression of SOX2, STAT3, CD24+, and CD44+ in tumor tissue by flow cytometry. RESULTS: The median age of the 38 evaluated patients with penile cancer was 61 (37-80) years. Most patients presented a tumor located on the glans penis (82.3%), with the usual histological type (79.4%) and 61.7% of patients presented stage pT2. No metastasis was found in 85.3% of patients. The expression of SOX2, STAT3 and CD44high/CD24low in the microenvironment of penile SCC treated with lymphadenectomy was significantly associated with aggressive tumor behavior (p < 0.05). STAT3 expression shows discrepant points when evaluated in context of angiolymphatic vascular invasion. CONCLUSION: SOX2, STAT3 and CD44high/CD24low in penile SCC can be indicators of prognosis, allowing for selection of more aggressive treatment when necessary.

Overview and characterization of penile cancer content across social media platforms.

Background: Social media platforms (SMP) are an emerging resource that allows physicians, patients, and families to converse on cancer prevention, diagnosis, and treatment. We aimed to characterize penile cancer (PC) content shared on SMP. Methods: We searched PC posts on Twitter, Facebook, and Instagram from July 1st, 2021, through June 30th, 2022. Two independent, blinded reviewers analyzed the hashtags: #PenileCancer, #PenileCancerAwareness, and #PenileNeoplasm. Descriptive statistics were used for posts characterization, Pearson´s correlation coefficient for associations, and Cohen's weighted kappa coefficient for inter-rater agreement rate. Results: A total of 791 posts were analyzed, with Twitter accounting for 52%, Facebook for 12.2%, and Instagram for 35.5%, and. Most posts originated from high-income countries, such as the United Kingdom (48.8%). We found no correlation between the number of posts with PC incidence (p = 0.64) or users on SMP (p = 0.27). Most accounts were classified as "support and awareness communities" (43.6%) and "physicians and clinical researchers" (38.2%). Urology was the most common medical specialty to post (60.9%), followed by oncology (11.3%). Most posts were classified as "prevention and awareness for users" (45.1%). Global inter-reviewer agreement rate was almost perfect (k=0.95; p ≤ 0.01). On Twitter, "physicians and clinical researchers" shared more content on "treatment updates and medical papers published in medical journals," while on Facebook and Instagram, "support and awareness communities" focused on "personal and support comments." Conclusion: Overall, the number of PC posts was low compared to other neoplasms across the SMP evaluated in this study. "Physicians and clinical researchers" shared more content on Twitter, while "support and awareness communities" on Facebook and Instagram. Encouraging the use of a common SMP among the medical community and general users could lead to a more effective communication between physicians, patients, and support groups, and to increased awareness of PC.

Associação entre lesões de hpv e os carcinomas genitais e da cavidade oral: uma revisão narrativa / Association between hpv lesions and genital and oral cavity carcinomas: a narrative review / Asociación entre lesiones por vph y carcinomas genitales y de cavidad oral: una revisión narrativa

Os Papilomavírus Humano (HPVs) são membros da família Papilomaviridae. O vírus destaca-se pelo seu tropismo por células epiteliais, infectando exclusivamente mucosa epitelial e cutânea. O HPV-16 e HPV-18 são subtipos classificados como de alto risco, conhecidos por sua oncogenicidade, fortemente associados aos cânceres anais, genitais e de orofaringe. Lesões por HPV representam um grande grupo de doenças sexualmente transmissíveis. O objetivo do presente estudo consistiu em realizar uma revisão narrativa sobre a associação entre lesões por HPV e carcinomas genitais e da cavidade oral. Realizamos uma busca na base de dados eletrônicos PubMed, Lilacs, Scielo, Medline e Google Scholar, sendo utilizados artigos publicados entre os anos de 2017-2021, ao fim, foram selecionados 36 artigos. Grande parte das infecções por HPV são subclínicas, ou seja, não apresentam sintomatologia importante e tendem a desaparecer espontaneamente. Desta forma, faz-se necessário ter conhecimento a respeito dos aspectos clínicos e comportamentais dessas lesões, possibilitando o diagnóstico precoce, evitando a evolução para estágios mais invasivos, favorecendo um tratamento efetivo e melhor prognóstico.

Human Papillomaviruses (HPVs) are members of the Papilomaviridae family. The virus stands out for its tropism for epithelial cells, exclusively infecting epithelial and cutaneous mucosa. O HPV-16 and HPV-18 are subtypes classified as high risk, known for their oncogenicity, strongly associated with anal, genital and oropharyngeal cancers. HPV lesions represent a large group of sexually transmitted diseases. The objective of this study was to carry out a narrative review on the association between HPV lesions and genital and oral cavity carcinomas. We carried out a search in the electronic databases PubMed, Lilacs, Scielo, Medline and Google Scholar, using articles published between the years of 2017-2021, at the end, foram selected 36 articles. A large part of HPV infections are subclinical, or seem to, do not present significant symptoms and tend to disappear spontaneously. In this way, it is necessary to be aware of the two clinical and behavioral aspects of these injuries, enabling early diagnosis, avoiding evolution to more invasive stages, favoring effective treatment and better prognosis.

Los virus del papiloma humano (VPH) son miembros de la familia Papillomaviridae. El virus destaca por su tropismo por las células epiteliales, infectando exclusivamente mucosas epiteliales y cutáneas. El VPH-16 y el VPH-18 son subtipos clasificados como de alto riesgo, conocidos por su oncogenicidad, fuertemente asociados con cánceres anales, genitales y orofaríngeos. Las lesiones por VPH representan un gran grupo de enfermedades de transmisión sexual. El objetivo del presente estudio fue realizar una revisión narrativa sobre la asociación entre las lesiones por VPH y los carcinomas genitales y de cavidad oral. Realizamos una búsqueda en la base de datos electrónica PubMed, Lilacs, Scielo, Medline y Google Scholar, utilizando artículos publicados entre los años 2017-2021, al final se seleccionaron 36 artículos. La mayoría de las infecciones por VPH son subclínicas, es decir, no presentan síntomas importantes y tienden a desaparecer espontáneamente. Por lo tanto, es necesario tener conocimiento sobre los aspectos clínicos y conductuales de estas lesiones, que permitan un diagnóstico precoz, evitando la progresión a estadios más invasivos, favoreciendo un tratamiento eficaz y un mejor pronóstico.

HPV infection and 5mC/5hmC epigenetic markers in penile squamous cell carcinoma: new insights into prognostics.

BACKGROUND: Penile cancer is one of the most aggressive male tumors. Although it is preventable, the main etiologic causes are lifestyle behaviors and viral infection, such as human papillomavirus (HPV). Long-term epigenetic changes due to environmental factors change cell fate and promote carcinogenesis, being an important marker of prognosis. We evaluated epidemiological aspects of penile squamous cell carcinoma (SCC) and the prevalence of HPV infection using high-risk HPV (hrHPV) and p16INK4A expression of 224 participants. Global DNA methylation was evaluated through 5-methylcytosine (5mC) and 5-hydroxymethylcytosine (5hmC). RESULTS: The incidence of HPV was 53.2% for hrHPV and 22.32% for p16INK4a. hrHPV was not related to systemic or lymph node metastasis and locoregional recurrence, nor influenced the survival rate. P16INK4a seems to be a protective factor for death, which does not affect metastasis or tumor recurrence. Lymph node and systemic metastases and locoregional recurrence increase the risk of death. An increased 5mC mark was observed in penile SCC regardless of HPV infection. However, there is a reduction of the 5hmC mark for p16INK4a + (P = 0.024). Increased 5mC/5hmC ratio (> 1) was observed in 94.2% of penile SCC, irrespective of HPV infection. Despite the increase in 5mC, it seems not to affect the survival rate (HR = 1.06; 95% CI 0.33-3.38). CONCLUSIONS: P16INK4a seems to be a good prognosis marker for penile SCC and the increase in 5mC, an epigenetic mark of genomic stability, may support tumor progression leading to poor prognosis.

A comprehensive analysis of penile cancer in the region with the highest worldwide incidence reveals new insights into the disease.

BACKGROUND: Although penile cancer (PC) is uncommon in developed countries, it is widespread in developing countries. The state of Maranhão (Northeast, Brazil) has the highest global incidence recorded for PC, and, despite its socioeconomic vulnerability, it has been attributed to human papillomavirus (HPV) infection. This study aimed to determine the histopathological features, the prevalence of HPV infection, and the immunohistochemical profile of PC in Maranhão. METHODS: A retrospective cohort of 200 PC cases were evaluated. HPV detection was performed using nested-PCR followed by direct sequencing for genotyping. Immunohistochemistry (IHC) was performed using monoclonal antibodies anti-p16INK4a, p53, and ki-67. RESULTS: Our data revealed a delay of 17 months in diagnosis, a high rate of penile amputation (96.5%), and HPV infection (80.5%) in patients from Maranhão (Molecular detection). We demonstrated the high rate of HPV in PC also by histopathological and IHC analysis. Most patients presented koilocytosis (75.5%), which was associated with those reporting more than 10 different sexual partners during their lifetime (p = 0.001). IHC revealed frequent p16INK4a overexpression (26.0%) associated with basaloid (p < 0.001) and high-grade tumors (p = 0.008). Interestingly, p16 appears not to be a better prognostic factor in our disease-free survival analysis, as previously reported. We also demonstrated high ki-67 and p53 expression in a subset of cases, which was related to worse prognostic factors such as high-grade tumors, angiolymphatic and perineural invasion, and lymph node metastasis. We found a significant impact of high ki-67 (p = 0.002, log-rank) and p53 (p = 0.032, log-rank) expression on decreasing patients' survival, as well as grade, pT, stage, pattern, and depth of invasion (p < 0.05, log-rank). CONCLUSIONS: Our data reaffirmed the high incidence of HPV infection in PC cases from Maranhão and offer new insights into potential factors that may contribute to the high PC incidence in the region. We highlighted the possible association of HPV with worse clinical prognosis factors, differently from what was observed in other regions. Furthermore, our IHC analysis reinforces p16, ki-67, and p53 expression as important diagnosis and/or prognosis biomarkers, potentially used in the clinical setting in emerging countries such as Brazil.

Upregulated miRNAs on the TP53 and RB1 Binding Seedless Regions in High-Risk HPV-Associated Penile Cancer.

Cancer development by the human papillomavirus (HPV) infection can occur through the canonical HPV/p53/RB1 pathway mediated by the E2/E6/E7 viral oncoproteins. During the transformation process, HPV inserts its genetic material into host Integration Sites (IS), affecting coding genes and miRNAs. In penile cancer (PeCa) there is limited data on the miRNAs that regulate mRNA targets associated with HPV, such as the TP53 and RB1 genes. Considering the high frequency of HPV infection in PeCa patients in Northeast Brazil, global miRNA expression profiling was performed in high-risk HPV-associated PeCa that presented with TP53 and RB1 mRNA downregulated expression. The miRNA expression profile of 22 PeCa tissue samples and five non-tumor penile tissues showed 507 differentially expressed miRNAs: 494 downregulated and 13 upregulated (let-7a-5p, miR-130a-3p, miR-142-3p, miR-15b-5p miR-16-5p, miR-200c-3p, miR-205-5p, miR-21-5p, miR-223-3p, miR-22-3p, miR-25-3p, miR-31-5p and miR-93-5p), of which 11 were identified to be in HPV16-IS and targeting TP53 and RB1 genes. One hundred and thirty-one and 490 miRNA binding sites were observed for TP53 and RB1, respectively, most of which were in seedless regions. These findings suggest that up-regulation of miRNA expression can directly repress TP53 and RB1 expression by their binding sites in the non-canonical seedless regions.

Emerging Therapies in Penile Cancer.

Advances in the treatment of rare tumors like penile cancer were always hampered by the lack of deep comprehension of the molecular biology and genomic and epigenomic alterations involved in carcinogenesis and tumor progression, as well as by the difficulty in recruitment of patients for prospective clinical trials. Despite the high rates of cure in early localized penile cancers with surgery or other local procedures, locally advanced and metastatic tumors require systemic treatment, with chemotherapy being the current standard, but with high toxicity and no proven real impact on survival. Recent important findings of frequent genomic alterations and mutation signatures in penile cancer have motivated several trials in new modalities of systemic treatments, especially immunotherapy. This review aims to present the most recent advances and the prospect of new modalities of systemic therapies with ongoing studies in penile cancer.

Patterns of Treatment and Outcomes in Older Men With Penile Cancer: A SEER Dataset Analysis.

Purpose: To evaluate clinicopathologic and treatment characteristics from a population-based cohort of penile cancer, with an emphasis in older adults, due to incomplete evidence to guide therapy in this age subgroup. Materials and Methods: Patients with malignant penile tumors diagnosed 2004-2016 were identified in the Surveillance, Epidemiology and End Results Program (SEER)-18 dataset. Demographic and treatment characteristics were obtained. Population was analyzed by age at diagnosis (<65 vs ≥65 years). We examined univariate associations between age groups with Chi-square analysis. To study survival, we calculated Kaplan-Meier survival curves, but due to the high number of competing events, we also performed a univariate competing risk analysis using the cumulative incidence function, and a multivariate analysis using the Fine-Gray method. We also described competing mortality due to penile cancer and other causes of death. Results: We included 3,784 patients. Median age was 68 years, 58.7% were aged ≥65. Older patients were less likely to have received chemotherapy (p<0.001), primary site surgery (p = 0.002), or therapeutic regional surgery (p <0.001). Median overall survival (OS) in patients <65 years was not reached (95% CI incalculable) vs 49 months in those ≥65 years (95% CI 45-53, p <0.0001). On univariate analysis, age was associated with a lower incidence of penile cancer death. On multivariate analysis, stage at diagnosis, and receipt of primary site surgery were associated with a higher incidence of penile cancer death. Estimated penile cancer-specific mortality was higher in patients <65 years in stages II-IV. Estimated mortality due to other causes was higher in older patients across all stages. Conclusions: Older patients are less likely to receive surgery, chemotherapy and radiotherapy for penile cancer. Primary surgical resection was associated with better penile cancer-specific mortality on multivariate analysis. Competing mortality risks are highly relevant when considering OS in older adults with penile cancer. Factors associated with undertreatment of older patients with penile cancer need to be studied, in order to develop treatment strategies tailored for this population.

miRNA and mRNA Expression Profiles Associated with Lymph Node Metastasis and Prognosis in Penile Carcinoma.

Penile cancer (PeC) is a rare disease, and no prognostic biomarkers have been adopted in clinical practice yet. The objective of the present study was to identify differentially expressed miRNAs (DEmiRs) and genes (DEGs) as potential biomarkers for lymph node metastasis and other prognostic factors in PeC. Tumor samples were prospectively obtained from 24 patients with squamous cell carcinoma of the penis. miRNA microarray analysis was performed comparing tumors from patients with inguinal lymph node metastatic and localized disease, and the results were validated by qRT-PCR. Eighty-three gene expression levels were also compared between groups through qRT-PCR. Moreover, DEmiRs and DEGs expression levels were correlated with clinicopathological variables, cancer-specific (CSS), and overall survival (OS). TAC software, TM4 MeV 4.9 software, SPSS v.25.0, and R software v.4.0.2 were used for statistical analyses. We identified 21 DEmiRs in microarray analysis, and seven were selected for validation. miR-744-5p and miR-421 were overexpressed in tissue samples of metastatic patients, and high expression of miR-421 was also associated with lower OS. We found seven DEGs (CCND1, EGFR, ENTPD5, HOXA10, IGF1R, MYC, and SNAI2) related to metastatic disease. A significant association was found between increased MMP1 expression and tumor size, grade, pathological T stage, and perineural invasion. Other genes were also associated with clinicopathological variables, CSS and OS. Finally, we found changes in mRNA-miRNA regulation that contribute to understanding the mechanisms involved in tumor progression. Therefore, we identified miRNA and mRNA expression profiles as potential biomarkers associated with lymph node metastasis and prognosis in PeC, in addition to disruption in mRNA-miRNA regulation during disease progression.

Non-Coding RNA in Penile Cancer.

Penile cancer (PC) still presents a health threat for developing countries, in particular Brazil. Despite this, little progress has been made on the study of markers, including molecular ones, that can aid in the correct management of the patient, especially concerning lymphadenectomy. As in other neoplasms, non-coding RNAs (ncRNAs) have been investigated for penile cancer, with emphasis on microRNAs, piRNAs (PIWI-interacting small RNAs), and long non-coding RNAs (LncRNAs). In this context, this review aims to assemble the available knowledge on non-coding RNA linked in PC, contributing to our understanding of the penile carcinogenesis process and addressing their clinical relevance. ncRNAs are part of the novel generation of biomarkers, with high potential for diagnosis and prognosis, orientating the type of treatment. Furthermore, its versatility regarding the use of paraffin samples makes it possible to carry out retrospective studies.

Evolving insights into penile cancer pathology and the eighth edition of the AJCC TNM staging system.

The majority of penile malignant tumors are squamous cell carcinomas. They are pathologically defined as epithelial neoplasms originating in the squamous cells of the inner mucosal lining of the glans, coronal sulcus or foreskin. Tumor location and site of origin is preferentially in glans (70%) followed by foreskin (25%) and coronal sulcus (5%). Despite the variable geographic distribution, pathological features of penile carcinomas in areas of high- and low-risk are similar. Penile tumors are morphologically heterogeneous. A major advance, based on biological, etiological and prognostic factors, is the 2016 WHO classification separating epithelial penile neoplasia, precancerous and invasive, in non-HPV and HPV-related.

Disruption of miRNA-mRNA Networks Defines Novel Molecular Signatures for Penile Carcinogenesis.

Penile cancer (PeC) carcinogenesis is not fully understood, and no biomarkers are reported in clinical practice. We aimed to investigate molecular signatures based on miRNA and mRNA and perform an integrative analysis to identify molecular drivers and pathways for PeC development. Affymetrix miRNA microarray was used to identify differentially expressed miRNAs (DEmiRs) comparing 11 tumoral tissues (TT) paired with non-neoplastic tissues (NNT) with further validation in an independent cohort (n = 13). We also investigated the mRNA expression of 83 genes in the total sample. Experimentally validated targets of DEmiRs, miRNA-mRNA networks, and enriched pathways were evaluated in silico. Eight out of 69 DEmiRs identified by microarray analysis were validated by qRT-PCR (miR-145-5p, miR-432-5p, miR-487b-3p, miR-30a-5p, miR-200a-5p, miR-224-5p, miR-31-3p and miR-31-5p). Furthermore, 37 differentially expressed genes (DEGs) were identified when comparing TT and NNT. We identified four downregulated DEmiRs (miR-30a-5p, miR-432-5p, miR-487b-3p, and miR-145-5p) and six upregulated DEGs (IL1A, MCM2, MMP1, MMP12, SFN and VEGFA) as potential biomarkers in PeC by their capacity of discriminating TT and NNT with accuracy. The integration analysis showed eight dysregulated miRNA-mRNA pairs in penile carcinogenesis. Taken together, our findings contribute to a better understanding of the regulatory roles of miRNAs and altered transcripts levels in penile carcinogenesis.

Geometrical Model of Free Skin Graft for the Optimization of Glans Reconstruction after Partial Penectomy / Modelo geométrico de injerto de piel libre para la optimización de reconstrucción de glande tras penectomía parcial

Introduction and Objective The management of penile carcinoma is very disabling and mutilating, bur early treatment can be curative. Our group systematically performs oncological management with immediate penile reconstruction and preservation of the organ (partial penectomy, resurfacing, or glansectomy) when feasible. Due to the low incidence of penile carcinoma, it is difficult to achieve experience in penile reconstruction using free grafts in a standardized and reproducible way. Therefore, we herein present the results of the use of an inanimate model to identify the most efficient geometric way to procure and apply a free skin graft to reconstruct the penis. Methods A preclinical inanimate model of the penis was developed to simulate the surgical reconstruction using a free skin graft. Six different geometric skin-graft models were created and tested. For each of them, we measured graft's surface area as well as the discarded surface after placing the graft on the penis for reconstruction. We also measured the amount of suture lines required for reconstruction. All of these measurements in the six different models were compared. Results Based on the six models, we identified that the longitude of the graft must measure the same as the maximum perimeter of the glans in order to have a square that enables the complete coverage of the penile defect. The total graft area for the first 4 models was of 40 cm2; for models 5 and 6, it was of 60 cm2. The average discarded area of the graft was of 18.135 cm2 (range: 12 cm2 to 30 cm2). Models 4 years 6 were the ones with the least discarded tissue: 12 cm2. The average amount of suture lines to secure the different model grafts was 7.3 (range: 5 to 12). The models that required the least amount of suture lines were number 1 and 4, with a total of 5 suture lines. Conclusions The double trapezoid is the most efficient model to reconstruct the glans after organ-sparing oncological management. Our results contribute to establish a more standardized and predictable technique to reconstruct the penis.

Introducción y Objetivo El manejo del cáncer de pene es muy mutilante y discapacitante. Pero el manejo quirúrgico oportuno puede ser curativo. Nuestro grupo realiza de manera sistemática el manejo oncológico con reconstrucción inmediata del pene y preservación del órgano (penectomía parcial, desepitelización, o gladectomía) cuando sea viable. Como la incidencia de cancer de pene es baja, lograr obtener la experiencia en reconstrucción de pene con el uso de injertos libres de manera estandarizada y reproducible resulta difícil. Por lo tanto, presentamos en este artículo los resultados de un modelo inanimado para identificar la forma geométrica mas eficiente de obtener y aplicar un injerto de piel libre para reconstruir el pene. Materiales y Métodos Se desarrolló un modelo preclínico y inanimado del pene para que se simulara su reconstrucción quirúrgica con el uso de un ijerto de piel libre. Desarrollamos y evaluamos seis modelos geométricos de injerto de piel distintos. Para cada uno, medimos el area total del injerto y la del tejido desechado tras ponerlo en el pene para la recosntrucción. También medimos la cantidad de líneas de sutura necesarias para la recosntrucción. Comparamos todas las medidas entre los seis modelos distintos. Resultados De los 6 modelos diferentes, encontramos que la longitud del injerto debe tener la misma medida que el perímetro máximo del glande para que se tenga un cuadrado que nos permita cubrir todo el defecto del pene. El area total de los 4 modelos iniciales fue de 40 cm2, y el area de los modelos 5 y 6 fue de 60 cm2. El area promedio del tejido desechado en los injertos fue de 18,135 cm2 (rango: 12 cm2 a 30 cm2). Los modelos 4 y 6 fueron los que tuvieron la menor cantidad de tejido desechado: 12 cm2. El promedio de la cantidad de líneas de sutura para atar los distintos modelos de injerto fue de 7,3 (rango: 5 a 12). Los modelos con la menor cantidad de líneas de sutura fueron el 1 y el 4, con un total de 5 líneas. Conclusiones El modelo de doble trapezoide es el más eficiente para reconstruir el glande tras el majejo oncológico en que se preserva el órgano. Nuestros resultados contribuyen para establecer una técnica de reconstrucción del pene más estandarizada y previsible.