Cyclin D1 expression in penile cancer.

The main goal of the present study was to analyze the expression profile of cyclin D1 in patients with PC, and to determine possible correlations with clinical and histopathological features. A survey was conducted with 100 patients diagnosed with PC, who were treated at two reference hospitals in São Luís, Maranhão, Brazil, between 2013 and 2017. A review of clinical, epidemiological, and histopathological data was performed, Human Papillomavírus (HPV) DNA was detected using polymerase chain reaction (PCR) and cyclin D1 expression analysis was performed using immunohistochemical techniques. The data revealed that the absence of cyclin D1 expression was significantly associated with HPV-positive histological subtypes (p = 0.001), while its expression was associated with high-grade tumors (p = 0.014), histological subtype (p = 0.001), presence of sarcomatoid transformation (p = 0.04), and perineural invasion (p = 0.023). Patients with cyclin D1 expression exhibited lower disease-free survival compared to the cyclin D1-negative group, although the difference was not statistically significant. The results suggest that cyclin D1 may be a potential biomarker for PC, especially for poorer prognosis.

The effects of HIV and oncogenic human papillomavirus on the tumor immune microenvironment of penile squamous cell carcinoma.

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

Antibodies against high-risk human papillomavirus proteins as markers for noncervical HPV-related cancers in a Black South African population, according to HIV status.

Human papillomavirus (HPV) proteins may elicit antibody responses in the process toward HPV-related malignancy. However, HPV seroepidemiology in noncervical HPV-related cancers remains poorly understood, particularly in populations with a high prevalence of human immunodeficiency virus (HIV). Using a glutathione S-transferase-based multiplex serology assay, antibodies against E6, E7 and L1 proteins of HPV16 and HPV18 were measured in sera of 535 cases of noncervical HPV-related cancers (anal (n = 104), vulval (n = 211), vaginal (n = 49), penile (n = 37) and oropharyngeal (n = 134)) and 6651 non-infection-related cancer controls, from the Johannesburg Cancer Study that recruited Black South African with newly diagnosed cancer between 1995 and 2016. Logistic and Poisson regression models were used to calculate adjusted odds ratios (aOR) and prevalence ratios (aPR) and 95% confidence intervals (CI) in cases versus controls. HPV16 E6 was more strongly associated with noncervical HPV-related cancers than HPV16 L1 or E7, or HPV18 proteins: anal (females (HPV16 E6 aOR = 11.50;95%CI:6.0-22.2), males (aOR = 10.12;95%CI:4.9-20.8), vulval (aOR = 11.69;95%CI:7.9-17.2), vaginal (aOR = 10.26;95%CI:5.0-21), penile (aOR = 18.95;95%CI:8.9-40), and oropharyngeal (females (aOR = 8.95;95%CI:2.9-27.5), males (aOR = 3.49;95%CI:1.8-7.0)) cancers. HPV16-E6 seropositivity ranged from 24.0% to 35.1% in anal, vulval, vaginal and penile cancer but was significantly lower (11.2%) in oropharyngeal cancer. After adjustment for HIV, prevalence of which increased from 22.2% in 1995-2005 to 54.1% in 2010-2016, HPV16 E6 seropositivity increased by period of diagnosis (aPR for 2010-2016 vs. 1995-2006 = 1.84;95%CI:1.1-3.0). Assuming HPV16 E6 seroprevalence reflects HPV attributable fraction, the proportion of certain noncervical-HPV-related cancers caused by HPV is increasing over time in South Africa. This is expected to be driven by the increasing influence of HIV.

A cross-sectional study of human papillomavirus genotype distribution and integration status in penile cancer among Chinese population.

Human papillomavirus (HPV) has been recognized as an important risk factor in penile cancer. This study aimed to investigate the HPV subtypes and integration status in Chinese patients. Samples were collected from 103 penile cancer patients aged 24-90 years between 2013 and 2019. We found that HPV infection rate was 72.8%, with 28.0% integration. The aging patients were more susceptible to HPV (p = 0.009). HPV16 was the most frequent subtype observed (52/75) and exhibited the highest frequency of integration events, with 11 out of 30 single infection cases showing integration positive. The HPV integrations sites in the viral genome were not randomly distributed, the breakpoints were enriched in the E1 gene (p = 0.006) but relatively scarce in L1, E6 and E7. Our research might provide some clues how HPV leads to the progression of penile cancer.

The routine use of LCD-Array hybridisation technique for HPV subtyping in the diagnosis of penile carcinoma compared to other methods.

BACKGROUND: Routine human papillomavirus (HPV) testing is performed in cervival cancer and is required for classification of some head and neck cancers. In penile cancer a statement on HPV association of the carcinoma is required. In most cases p16 immunohistochemistry as a surrogate marker is applied in this setting. Since differing clinical outcomes for HPV positive and HPV negative tumors are described we await HPV testing to be requested more frequently by clinicians, also in the context of HPV vaccination, where other HPV subtypes are expected to emerge. METHOD: Therefore, a cohort of archived, formalin-fixed paraffin embedded (FFPE) penile neoplasias was stained for p16 and thereafter tested for HPV infection status via PCR based methods. Additionally to Sanger sequencing, we chose LCD-Array technique (HPV 3.5 LCD-Array Kit, Chipron; LCD-Array) for the detection of HPV in our probes expecting a less time consuming and sensitive HPV test for our probes. RESULTS: We found that LCD-Array is a sensitive and feasible method for HPV testing in routine diagnostics applicable to FFPE material in our cohort. Our cohort of penile carcinomas and carcinomas in situ was associated with HPV infection in 61% of cases. We detected no significant association between HPV infection status and histomorphological tumor characteristics as well as overall survival. CONCLUSIONS: We showed usability of molecular HPV testing on a cohort of archived penile carcinomas. To the best of our knowledge, this is the first study investigating LCD-Array technique on a cohort of penile neoplasias.

The peri- and intratumoral immune cell infiltrate and PD-L1 status in invasive squamous cell carcinomas of the penis.

INTRODUCTION: Penile carcinomas are rare tumors throughout Europe. Therefore, little attention is drawn to this disease. That makes it important to study tumor-associated key metrics and relate these to known data on penile neoplasias. MATERIALS AND METHODS: A cohort of 60 well-defined penile invasive carcinomas with known human papillomavirus (HPV) infection status was investigated. Data on tumor type, grading and staging were recorded. Additionally, data on the peri- and intratumoral immune cell infiltrate in a semiquanititave manner applying an HE stain were assessed. RESULTS: Our study showed a significant correlation of immune cell infiltrate and pT stage with overall survival. Therefore, in a subset of tumors, PD-L1 staining was applied. For tumor proportion score (TPS), 26 of 30 samples (87%) were scored >0%. For the immune cell score (IC), 28 of 30 samples (93%) were defined as >0% and for CPS, 29 of 30 samples (97%) scored >0. PD-L1 expression was not associated with overall survival. CONCLUSION: PD-L1 is expressed in penile carcinomas, providing a rationale for targeted therapy with checkpoint inhibitors. We were able to show that immune reaction appears to be prognostically relevant. These data enhance the need for further studies on the immune cell infiltrate in penile neoplasias and show that PD-L1 expression is existent in our cohort, which may be a potential target for checkpoint inhibitor therapy.

Should men be exempted from vaccination against human papillomavirus? Health disparities regarding HPV: the example of sexual minorities in Poland.

INTRODUCTION: Social campaigns concerning vaccinations against human papillomavirus (HPV) in Poland are mainly addressed to women. In addition to cervical cancer, anal, penile, and oropharyngeal cancers can be caused by the virus, which clearly affects men as well. HPV vaccinations are voluntary and mostly not refunded in Poland. METHODS: A survey was published on social media's group gathering males and contained questions concerning epidemiological data, knowledge about HPV, and opinions of HPV vaccination. A questionnaire was enriched with educational note regarding HPV-dependent cancers and available vaccines against HPV in Poland. RESULTS: Because of age limitations, 169 males (115 heterosexuals, 48 homosexuals) aged 14-39 were chosen for the study. Seventyfive percent of straight and 88% of gay men were aware of HPV, but less than 4 and 17% (respectively) were vaccinated against the virus. Main sources of knowledge about HPV were the Internet (61%), media (28%) and relatives (27%). HPV infection was linked with the development of anal and oropharyngeal cancers by 28, and 37% of heterosexual males, compared with 56.3 and 43.8% of homosexual males. The majority of respondents (88%) indicated that all genders should be vaccinated, although only 57% were aware of HPV vaccination availability in Poland. CONCLUSIONS: The men are at risk of HPV-related cancers and the danger is poorly understood amongst Polish men. Despite awareness of HPV vaccines, the vaccination rate is low. Consequently, there is a serious need to broaden educational campaignes with a special attention to LGBTQ+ communities.

National trends and survival outcomes of penile squamous cell carcinoma based on human papillomavirus status.

BACKGROUND: There are no series evaluating penile squamous cell carcinoma (pSCC) based on human papillomavirus (HPV) infection. Herein, we present national registry data on clinical and survival outcomes for pSCC based on HPV status. METHODS: We performed a retrospective review of 1224 pSCC patients with known HPV staining from the National Cancer Database. Patients with cM1 disease, those who did not receive treatment, or had missing follow-up data were excluded. Logistic regression identified factors associated with locally aggressive disease. Univariable, multivariable, and inverse probability of treatment weighting (IPTW)-Cox proportional hazard modeling were used to assess hazard ratios (HR) associated with overall survival (OS). RESULTS: After exclusion criteria, we identified 825 cases of which 321 (38.9%) were HPV positive. The HPV-positivity rate did not significantly change by year. HPV-positive patients were younger, had lower Charlson-Deyo performance score, and resided in areas with both lower median household income and lower school education completion. HPV-positive tumors presented with lower American Joint Committee on Cancer clinical T-stage (cT), poorer differentiation, lower rates of lymphovascular invasion (LVI), but more node-positive disease (cN+). For those who underwent lymph node surgery, there were no differences in final pathologic stage, upstaging, or presence of extranodal extension. Only tumor differentiation, LVI, and performance score were independent predictors for locally aggressive disease. HPV status was not a predictor of OS (IPTW-HR:0.89, p = 0.13). CONCLUSIONS: In the largest series evaluating pSCC based on HPV status, HPV-positive tumors were associated with lower cT stages, less LVI, but more cN + disease. More studies on prognostic factors are needed, and time may still be immature to use HPV information for risk stratification.

Investigation of the Epithelial to Mesenchymal Transition (EMT) Process in Equine Papillomavirus-2 (EcPV-2)-Positive Penile Squamous Cell Carcinomas.

Equine penile squamous cell carcinoma (epSCC) is the most frequent tumor of the external male genitalia, representing 67.5% of equine genital cancers. epSCC is associated with papilloma virus (PV) infection and has been recently proposed as a model for human PV-induced squamous cell carcinomas. It has already been suggested that epSCC might undergo epithelial-to-mesenchymal transition (EMT). This work aims to investigate in detail this process and the possible role of PV oncoproteins in epSCC. For this purpose, 18 penile SCCs were retrospectively selected and tested for both EcPV2 presence and oncoproteins (EcPV2 E6 and EcPV2 E7) expression. Moreover, immunohistochemical EMT characterization was carried out by analyzing the main epithelial markers (E-cadherin, ß-catenin, and pan-cytokeratin AE3/AE1), the main mesenchymal markers (N-cadherin and vimentin), and the main EMT-related transcription factors (TWIST-1, ZEB-1). PCR analysis was positive for EcPV2 in 16 out of 18 samples. EMT was investigated in epSCC positive for EcPV2. The immunohistochemistry results suggested the presence of EMT processes in the neoplastic cells at the tumor invasive front. Moreover, the significant upregulation of RANKL, together with BCATN1, LEF1, and FOSL1 genes, might suggest a canonical Wnt pathway activation, similarly to what is reported in human penile squamous cell carcinomas.

p53 and p16ink4a As Predictive and Prognostic Biomarkers for Nodal metastasis and Survival in A Contemporary Cohort of Penile Squamous Cell Carcinoma.

BACKGROUND: Human papilloma virus (HPV) infection is implicated in a proportion of invasive squamous cell carcinoma of the penis (PC). A subset of PC involves dysregulation of the p53 pathway. HPV in situ hybridization (ISH) and p16ink4a positivity are surrogate markers for HPV infection, and p53 immunohistochemistry (IHC) denotes abnormality in the p53 pathway. There remains an ambiguity with regard to the contribution of both the pathways in the prognosis of PC. We sought to analyze the clinicopathologic characteristics of a cohort of Indian PC patients with respect to p16 ink4a and p53 expression. PATIENTS AND METHODS: A cohort of 123 PC patients was studied for p16ink4aand p53IHC and HPVISH. The results of these biomarkers were correlated with various clinicopathologic parameters. RESULTS: p16ink4a and HPV ISH were positive in 47% and 53% of the tumors, respectively. The proportion of warty, basaloid, or mixed warty-basaloid tumor subtypes showed significant p16ink4apositivity (P < .0001) compared to other subtypes. Twenty-eight patients were dual negative (p53- /p16ink4a-), 32 were dual positive (p53+/p16ink4a+), 38 were p53+/p16ink4a-, and 25 were p53-/p16ink4a +. In patients where p16ink4a was negative, a p53-positive phenotype had a higher propensity for lymph node metastases (OR, 5.42; 95% CI, 1.75-16.80; P = .003). Similarly, p53 positivity dictates nodal involvement in the p16ink4a-positive subset of tumors (OR, 5.00; 95% CI, 1.23-20.17; P = .024). On multivariate analyses, pathologic subtypes (warty, warty-basaloid, and basaloid) (P < .0001), p16ink4aexpression (P < .0001), and absence of nodal metastasis (P < .0001) were significant predictors of improved overall (OS) and cancer specific survival (CSS). In Kaplan-Meier analysis, the OS was significantly longer in patients with p16ink4a + tumors (P < .0001), as was the CSS (P < .0001). Patients with dual positive tumors had a significantly higher OS (P < .001) and CSS (P = .012), in the entire cohort. In the node positive patients, dual positivity was associated with significantly higher OS (P < .0001); however, the median CSS for p53+/p16ink4a+tumors were not significantly different compared to p53- /p16ink4a- tumors (P = .064), although there was a trend towards improved CSS. CONCLUSIONS: There is a strong concordance between p16ink4aIHC and HPV ISH results. p16ink4a status is an independent predictor of survival (OS and CSS) in our cohort of PCs. p53 is a predictor of nodal metastasis irrespective of p16 status. Dual positive tumors have a significantly better outcome in comparison to dual negative tumors.

Immunotherapy for the treatment of penile intraepithelial neoplasia associated with human papilloma virus type 16 using topical imiquimod and human papilloma virus vaccination.

Penile intraepithelial neoplasia (PeIN) is frequently associated with human papilloma virus (HPV). Three cases of PeIN associated with HPV-type 16 were successfully treated with topical imiquimod and concurrent HPV vaccination. Human papilloma vaccine protects against oncogenic human papilloma viruses. In New Zealand, a decline in incidence of PeIN is anticipated with the recent funding of human papilloma vaccine for boys and young men aged 9-26 years. Therefore, HPV vaccination may have a role for treatment of PeIN and prophylaxis.

HPV-associated penile cancer: Impact of copy number alterations in miRNA/mRNA interactions and potential druggable targets.

BACKGROUND: Penile cancer (PeCa) is a rare disease, but its incidence has increased worldwide, mostly in HPV+ patients. Nevertheless, there is still no targeted treatment for this carcinoma. OBJECTIVE: To predict the main signaling pathways involved in penile tumorigenesis and its potential drug targets. METHODS: Genome-wide copy number profiling was performed in 28 PeCa. Integration analysis of CNAs and miRNAs and mRNA targets was performed by DIANA-TarBase v.8. The potential impact of the miRNAs/target genes on biological pathways was assessed by DIANA-miRPath v.3.0. For each miRNA, KEGG pathways were generated based on the tarbase and microT-CDS algorithms. Pharmaco-miR was used to identify associations between miRNAs and their target genes to predict druggable targets. RESULTS: 269 miRNAs and 2,395 genes were mapped in cytobands with CNAs. The comparison of the miRNAs mapped at these cytobands and the miRNAs that were predicted to regulate the genes also mapped in these regions, resulted in a set of common 35 miRNAs and 292 genes. Enrichment pathway revealed their involvement in five top signaling pathways. EGFR and COX2 were identified as potential druggable targets. CONCLUSION: Our data indicate the potential use of EGFR and COX2 inhibitors as a target treatment for PeCa patients.

Screening for HPV-related oropharyngeal, anal, and penile cancers in middle-aged men: Initial report from the HOUSTON clinical trial.

BACKGROUND: The Human papillomavirus (HPV)-related Oropharyngeal and Uncommon Cancers Screening Trial of Men (HOUSTON) was designed to determine the prevalence of IgG antibodies to HPV type 16 E proteins (HPV16EAbs), to screen for persistence of HPV and/or detect HPV-related premalignancies and cancers, and to assess acceptance of screening among middle-aged men. METHODS: HOUSTON consists of a cross-sectional study and a longitudinal cohort study of men aged 50-64 years. Serologic HPV16EAb status and oral rinse HPV16 status were determined. All HPV16EAb-positive (HPV16EAb+) men and a matched cohort of HPV16EAb-negative (HPV16EAb-) men as well as all oral rinse HPV16-positive (HPV16+) men were included in the longitudinal study (blinded to their results) and underwent oropharyngeal screening every 6 months as well as one-time anal and penile screening. RESULTS: Of 553 men enrolled in the cross-sectional study, six (1.1%) were HPV16EAb+ (two were also oral rinse HPV16+), and 41 (7.4%) were HPV16EAb- but oral rinse HPV16+. These 47 men, along with five matched controls, were invited to participate in the longitudinal study, and 42 (81%) agreed and completed baseline in-person screening, with 93% and 90% completeing 6-month and 12-month follow-up visits. One HPV16EAb+ (also oral rinse HPV16+) man, who declined participation in the longitudinal study, presented 4 months after enrollment with an early-stage HPV16-related pharyngeal cancer. Additionally, one HPV16EAb+ (oral rinse HPV16-) man and two oral rinse HPV16+ (HPV16EAb-) men were diagnosed with oncogenic HPV-associated anal dysplasia. CONCLUSIONS: This biomarker panel deserves further prospective study to explore potential utility for HPV-related cancer screening among men.

TERT promoter mutations in penile squamous cell carcinoma: high frequency in non-HPV-related type and association with favorable clinicopathologic features.

PURPOSE: Penile carcinoma is a rare malignant neoplasm with a largely unknown molecular pathogenesis. Telomerase reverse transcriptase promoter (TERT-p) mutations have been detected in several types of human malignancies. The aim of this study was to investigate the presence of TERT-p mutations in penile squamous cell carcinomas (SCCs) and their associations with clinicopathologic features. METHODS: In this retrospective study, Sanger sequencing was performed to detect TERT-p mutations in formalin-fixed paraffin-embedded tissue samples from 37 patients with penile SCC, 16 patients with cutaneous SCC, and 4 patients with non-neoplastic penile/skin tissue. The expression of p16INK4a and Ki-67 was investigated via immunohistochemistry. Associations of TERT-p mutation with clinicopathological factors, immunohistochemical results, and clinical outcome were statistically analyzed. RESULTS: Recurrent TERT-p mutations were identified in 18 out of 37 (48.6%) penile SCCs, including all 3 carcinoma in situ cases. TERT-p mutations were significantly more frequent in non-human papilloma virus (HPV)-related penile SCC types than in non-HPV-related penile SCC based on both histologic classification and p16INK4a immunoreactivity. Furthermore, TERT-p mutation was associated with a low histologic grade, low mitotic count, absence of necrosis, low Ki-67/MIB-1 labeling index, and absence of lymph node or distant metastasis. CONCLUSION: Our study shows TERT-p mutations are the most frequent somatic mutations in penile SCC. In addition, TERT-p mutations are far more frequent in non-HPV-related penile SCC than in HPV-related penile SCC, indicating TERT-p mutations may have a role in tumorigenesis distinct from HPV-related penile SCC.

Expansion of tumor-infiltrating lymphocytes (TIL) from penile cancer patients.

Penile cancer is a rare but highly lethal cancer, and therapeutic options for patients presenting with lymph nodal disease are very limited. Adoptive cell therapy (ACT) using tumor-infiltrating lymphocytes (TIL) was shown to provide durable objective response in patients with metastatic melanoma and TIL have been expanded from solid tumors at rates between 70 and 90% depending on the specific diagnosis. We evaluated whether TIL could be expanded from surgical specimens of patients with penile cancer. Tumor samples from metastatic lymph nodes obtained at the time of inguinal lymph node dissection were collected, minced into fragments, placed in individual wells of a 24-well plate, and propagated in high dose IL-2 for four weeks. The phenotype of expanded TILs was assessed by flow cytometry and their anti-tumor reactivity was assessed by IFN-γ ELISA. TIL were expanded from 11 out of 12 (91.6%) samples of metastatic lymph nodes. Expanded TIL were predominantly CD3+ (mean 67.5%, SD 19.4%) with a mean of 46.8% CD8+ T cells (SD 21.1%). Five out of 11 samples (45.4%) from expanded TIL secreted IFN-γ in response to autologous tumor. TIL expansion and phenotype of expanded T cell lymphocytes were independent of previous HPV infection and treatment with neoadjuvant chemotherapy. This is the first report demonstrating successful expansion of tumor-reactive TIL from penile cancer patients, which support development of ACT strategies using TIL for the treatment of advanced and recurrent penile cancer.

Penile Lymphoepithelioma-Like Carcinoma: A Rare Case With PD-L1 Expression.

Most malignant tumors of the penis are squamous cell carcinomas (SCC), being divided in 2 groups, one human papillomavirus (HPV)-related and another non-HPV-related, with lymphoepithelioma-like carcinoma (LELC) being one of the rarest HPV-related SCC. In this article, we report a case of a 50-year-old man who presented testicular swelling and pain for the past 3 months. A penile mass was identified, and the patient was submitted to a total penectomy. The penectomy specimen showed an ulcerated lesion at the glans reaching the cavernous bodies. Microscopic examination showed undifferentiated epithelial cells with syncytial growth pattern mix with a dense lymphoplasmacytic infiltrate, consistent with LELC. The tumor cells expressed p16 and all 3 different clones of PDL1 (22C3, SP263, and SP142). The patient is alive and well with a follow-up of 3 months. To our knowledge, this is the third LELC of the penis reported in literature and the first case reported with PDL1 expression.

Management of penile cancer patients during the COVID-19 pandemic: An eUROGEN accelerated Delphi consensus study.

OBJECTIVES: To develop an international consensus on managing penile cancer patients during the COVID-19 acute waves. A major concern for patients with penile cancer during the coronavirus disease 2019 (COVID-19) pandemic is how the enforced safety measures will affect their disease management. Delays in diagnosis and treatment initiation may have an impact on the extent of the primary lesion as well as the cancer-specific survival because of the development and progression of inguinal lymph node metastases. MATERIALS AND METHODS: A review of the COVID-19 literature was conducted in conjunction with analysis of current international guidelines on the management of penile cancer. Results were presented to an international panel of experts on penile cancer and infection control by a virtual accelerated Delphi process using 4 survey rounds. Consensus opinion was defined as an agreement of ≥80%, which was used to reconfigure management pathways for penile cancer. RESULTS: Limited evidence is available for delaying penile cancer management. The consensus rate of agreement was 100% that penile cancer pathways should be reconfigured, and measures should be developed to prevent perioperative nosocomial transmission of COVID-19. The panel also reached a consensus on several statements aimed at reconfiguring the management of penile cancer patients during the COVID-19 pandemic. CONCLUSIONS: The international consensus panel proposed a framework for the diagnostic and invasive therapeutic procedures for penile cancer within a low-risk environment for COVID-19.

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.

The Incidence and Prevalence of Human Papilloma Virus-associated Cancers in IBD.

AIM: The human papilloma virus has been associated with anal, cervical, vaginal, and penile cancers. The primary aim of this population-based study is to determine whether HPV-associated cancers are more commonplace in patients with inflammatory bowel disease (IBD). METHOD: The Hospital Episode Statistics (HES) database from 1997 to 2012, linked with officer for age standardized rates (ASR), were calculated using population data, and Cox regression analysis was used to determine whether IBD patients have poorer survival compared with non-IBD patients. RESULTS: A total of 61,648 patients were included in this study; of these, 837 patients had a preexisting diagnosis of IBD (1.4%). Inflammatory bowel disease patients had a significantly higher ASR of anal cancers than the non-IBD population: 5.5 per 100,000 in the IBD group compared with 1.8 in the non-IBD group. The IBD group was also diagnosed with anal cancers at a younger age (60 years compared with 66 years in the non-IBD group, P < 0.001). The survival of IBD patients with anal cancer was also poorer than the non-IBD group (hazard ratio, 1.32; 95% confidence interval, 1.15-1.52; P < 0.001). On average, survival was significantly shorter in the IBD group with anal cancer (46 months) compared with the non-IBD group (61 months, P < 0.001). Age standardized rates for cervical cancer was significantly higher in the IBD group (5.2 of 100,000) compared with the non-IBD group (4.6 of 100,000 P = 0.042). CONCLUSION: Patients with IBD have a higher rate of anal cancer compared with the general population. Survival is also worse for anal cancers in the IBD group.

Penile intraepithelial neoplasia, penile cancer precursors and human papillomavirus prevalence in symptomatic preputium: a cross-sectional study of 351 circumcised men in Sweden.

OBJECTIVES: To investigate the prevalence of pathological disease and spectrum of human papillomavirus (HPV) types among symptomatic foreskin tissue. PATIENTS AND METHODS: Consecutively excised symptomatic foreskins from 351 men were sent for histopathological evaluation. During the surgical procedure, a fresh biopsy was taken for HPV analysis by modified general primer polymerase chain reaction. A medical questionnaire regarding medication, smoking habits, number of lifetime sexual partners, former diseases and surgery performed on penis was completed by all participants. RESULTS: The most common clinical diagnosis and cause for circumcision was phimosis, seen in 85.2%. Histopathologically inflammatory dermatological conditions were present in 87% of the men. The most common histopathological diagnosis was lichen sclerosus (LS) observed among 58.7%. Notably, penile intraepithelial neoplasia (PeIN) was present in 2% without former clinical suspicion. Overall, HPV was detected in 17.1% of the men and 28 different HPV types were found. High-risk (HR) HPV types were identified in 9.1% and HPV16 was present in 2.3%. Current smoking increased the risk of HPV (crude odds ratio [OR] 2.8, confidence interval [CI] 1.4-5.6; P = 0.005). Having >15 lifetime sexual partners increased the risk of HPV (crude OR 2.6, 95% CI 1.4-5.1; P = 0.003) and when adjusted for current smoking the OR was substantially increased (OR 6.0, 95% CI CI 2.2-16.8; P < 0001). CONCLUSIONS: Histopathological evaluation of circumcised symptomatic foreskin revealed PeIN in 2% of the men without any clinical suspicion of malignancy and that treatable dermatological conditions were present in 87%, LS being the most common. HR-HPV types were present in 9%. Due to risk of malignant development both in PeIN and in inflammatory skin diseases we recommend sending all excised foreskins from patients with symptoms for histopathological evaluation as guidance for further clinical management.