Hospitalization burden associated with anus and penis neoplasm in Spain (2016-2020).

In 2020, there were approximately 50,865 anal cancer cases and 36,068 penile cancer cases worldwide. HPV is considered the main causal agent for the development of anal cancer and one of the causal agents responsible for the development of penile cancer. The aim of this epidemiological, descriptive, retrospective study was to describe the burden of hospitalization associated with anal neoplasms in men and women and with penis neoplasms in men in Spain from 2016 to 2020. The National Hospital Data Surveillance System of the Ministry of Health, Conjunto Mínimo Básico de Datos, provided the discharge information used in this observational retrospective analysis. A total of 3,542 hospitalizations due to anal cancer and 4,270 hospitalizations due to penile cancer were found; For anal cancer, 57.4% of the hospitalizations occurred in men, and these hospitalizations were also associated with significantly younger mean age, longer hospital stays and greater costs than those in women. HIV was diagnosed in 11.19% of the patients with anal cancer and 1.74% of the patients with penile cancer. The hospitalization rate was 2.07 for men and 1.45 for women per 100,000 in anal cancer and of 4.38 per 100,000 men in penile cancer. The mortality rate was 0.21 for men and 0.12 for women per 100,000 in anal cancer and 0.31 per 100.000 men in penile cancer and the case-fatality rate was 10.07% in men and 8,26% in women for anal cancer and 7.04% in penile cancer. HIV diagnosis significantly increased the cost of hospitalization. For all the studied diagnoses, the median length of hospital stays and hospitalization cost increased with age. Our study offers relevant data on the burden of hospitalization for anal and penile cancer in Spain. This information can be useful for future assessment on the impact of preventive measures, such as screening or vaccination in Spain.

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.

Penile carcinoma: A retrospective analysis of 93 patients at a tertiary care center in Jakarta, Indonesia.

OBJECTIVES: Penile carcinoma (PC) is a rare disease with considerable physical and psychological impact. To date, there is no data regarding PC prevalence and characteristics in Indonesia. This study aimed to analyze the characteristics of patients with PC in Indonesia and determine cumulative survival rates and time to disease progression. METHODS: This was a retrospective study of all patients diagnosed with PC at Cipto Mangunkusumo General Hospital from 1995 to 2014, with a minimum of 1 year follow-up. The outcomes of the study were cumulative survival rates and time-to-disease progression. RESULTS: Ninety-three subjects were recruited, with a mean age of 49.44 ± 13.62. Inguinal lymph node dissection (ILND) was performed in 49 (53%) patients. The mean survival in the ILND group was better compared to the non-ILND group (80.7 months vs. 67.1 months; p = 0.032). Time-to-progression in the ILND group was significantly longer than in the non-ILND group (71.7 months vs. 54.3 months; p = 0.022). No significant difference in survival between the total and partial penectomy (PP) groups was observed (p = 0.701). Time-to-progression in total penectomy (TP) was significantly longer than in PP (68 months vs. 56.0 months; p = 0.023). In Cox-regression analysis, after adjustment of other variables, history of ILND, higher stage of cancer, and older age were found to affect the survival of patients. CONCLUSION: ILND in PC led to better survival and reduced disease progression. The type of penectomy is only associated with progression but not survival. TP had a longer time to disease progression compared to PP.

Risk and predictors of penile cancer in US Veterans with HIV.

OBJECTIVES: People with HIV (PWH) may have an increased burden of penile cancer. We aimed to evaluate the risk of penile cancer in PWH compared with that of the general population. DESIGN: We conducted a nationwide retrospective matched cohort study of penile cancer incidence among veterans with HIV (VWH) compared with veterans without HIV. METHODS: We compared penile cancer incidence rates in 44 173 VWH to those of veterans without HIV ( N  = 159 443; 4 : 1 matched in age). We used Cox regression models to estimate hazard ratios and 95% confidence intervals (CIs) for associations with HIV infection and for penile cancer risk factors. RESULTS: HIV positivity was associated with an increased risk of penile cancer, with adjusted hazard ratios of 2.63 (95% CI 1.64-4.23) when adjusting for age, race/ethnicity, baseline BMI, smoking and alcohol use, economic means test, and history of condyloma. The risk increased to hazard ratio = 4.25 (95% CI 2.75-6.57) when adjusting for all factors except history of condyloma. Risk factors for penile cancer in VWH included lower nadir CD4 + count, less than 50% of follow-up time with undetectable HIV viral load, and history of condyloma. CONCLUSION: VWH - particularly those with low CD4 + counts, detectable HIV viral loads, or history of condyloma - are at increased risk of penile cancer, suggesting the penile cancer prevention activities are needed in this population.

Soft tissue tumours of the penis. The 30-year Istituto Nazionale Tumori di Milano experience.

Objective: Small series and individual cases of penile soft tissue tumours are reported in the literature: these are rare tumours that represent less than 5% of all penile tumours. Methods: Penile soft tissue tumours were collected from the archive of the Department of Pathology at the Istituto Nazionale dei Tumori of Milan between January 1990 and October 2021. All available medical records were retrieved and reviewed to obtain clinical information. Results: Our series refers to the 30-year experience of highlighting the heterogeneity in the presentation and microscopic features of these rare sarcomas. 18 penile soft tissue tumours are described, 4 benign and 14 malignant. The mean age at diagnosis was 58.2 years (range 24-96 years) and 53.6 years among malignancies (range 24-89). The most frequent histotype was Kaposi's sarcoma (nr = 4) and very unusual histotypes were observed, namely low-grade fibromyxoid sarcoma, synovial sarcoma, proximal type epithelioid sarcoma and the first reported case of dedifferentiated liposarcoma of the penis. Conclusions: Among sarcomas of the genitourinary tract, tumours of the soft tissues of the penis are the rarest. Penile sarcomas can present at a young age. Kaposi's sarcoma in HIV-negative patients has a favorable outcome, while deep sarcomas have an aggressive behavior and poor prognosis.

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.

[Lichen sclerosus in clinically relevant phimosis: incidence, risk factors, and association with squamous cell carcinoma of the penis]. / Lichen sclerosus bei klinisch relevanter Phimose: Häufigkeit, Risikofaktoren und Assoziation mit Plattenepithelkarzinomen des Penis.

BACKGROUND: Lichen sclerosus et atrophicus (LSA) is a chronic inflammatory skin disease. It is frequently diagnosed following circumcision. Diabetes mellitus (DM) is a known risk factor in men. Malignant pathology is more common in patients with LSA. Data on LSA in men are very limited. OBJECTIVE: This study investigated the incidence of LSA in men who had undergone circumcision. Risk factors and likelihood of malignancy were captured. MATERIALS AND METHODS: Data of 215 patients were retrospectively analyzed. As potential risk factors, age, body mass index (BMI), DM, coronary heart disease (CHD) and arterial hypertension were identified. Data were analyzed and displayed graphically as spike histograms. Logistic regression was applied. Age and BMI were transformed using cubic spline function. RESULTS: Mean age of patients was 37 years (±â€¯22 years). Mean BMI was 26.4. In all, 24% of the patients had a BMI > 30. Of the patients, 11% had DM, 5.1% had CHD, and 19% had arterial hypertension. Pathology revealed LSA in 47% of patients. Malignant disease was apparent in 3.3% of patients (2.7% without concomitant LSA, 4% with concomitant LSA). Age (55 vs 20 years, odds ratio [OR]: 3.210 [1.421, 7.251]) was a significant risk factor for LSA. BMI (30 vs 22 kg/m2, OR 1.059 [0.614, 1.828]) and DM (OR: 0.42 [0.148, 1.192]) elevated the risk for LSA. CONCLUSION: We saw high rates of LSA in patients had undergone circumcision. Higher age represents a significant risk factor. In 3.3%, final pathology revealed squamous cell carcinoma of the penis. Therefore, pathologic work-up of circumcision specimen is mandatory.

Association between HPV infection and penile cancer and penile intraepithelial neoplasia: A retrospective observational study.

BACKGROUND: Penile cancer is rising in most European countries. Several risk factors have been identified, namely human papillomavirus (HPV) infection. However, the exact role of HPV in penile cancer carcinogenesis is still unknown. Clarifying the contribution of HPV in penile cancer is crucial as it may improve prevention and treatment strategies. OBJECTIVE: To describe the characteristics of patients with penile cancer and penile intraepithelial neoplasia (PeIN), evaluate the prevalence of HPV-DNA in tumour tissue and identify differences between patients with and without HPV-DNA. METHODS: A retrospective observational study including patients with histological diagnosis of penile squamous cell carcinoma (SCC) or PeIN between 2012 and 2021 in a university hospital was carried out. HPV analysis was performed using Anyplex™ II HPV28 Detection that detects and identifies 28 HPV types. (sensitivity of 95.9%). RESULTS: A total of 25 patients were included. Most of the tumours identified were invasive SCC (n = 11) and SCC in situ (PeIN 3) (n = 8). PeIN1/2 was found in the remaining six patients. HPV-DNA was tested in all tissue specimens and was detected in 18 of them. High risk HPV DNA was identified in all positive HPV samples, except one. HPV types included in the nonavalent HPV vaccine were identified in 16 of the 18 samples positive for HPV-DNA. Stratifying patients according to HPV-DNA detection, we found that patients with HPV-DNA were younger (57.5 years vs. 70 years, p = 0.047), less likely to have phimosis (5.8% vs. 42.9%, p = 0.022) and more likely to have PeIN lesions than invasive SCC (85.7% vs. 27.8%, p = 0.025). CONCLUSION: This study shows a prevalence of HPV-DNA in penile SCC and premalignant lesions of 45.5% and 92.9%, respectively. Identifying HPV involvement in SCC and PeIN pathology has the potential to guide treatment and enhance follow-up strategies.

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.

Epidemiological study of penile cancer in a northeastern state - Brazil.

OBJECTIVE: to trace the clinical and epidemiological profile of penile cancer in Rio Grande do Norte/Brazil and relate them to data published in the literature. METHODS: a cross-sectional study was conducted with 94 patients diagnosed with penile cancer in 2011-2018, treated at the Liga Norte Riograndense Contra o Cancer. RESULTS: all patients were diagnosed with squamous cell carcinoma, mainly aged over 50 years, from the states interior, brown, illiterate, or with incomplete primary education. At diagnosis, 68% of patients were classified as having tumors =T2, and 30% had lymph node involvement. Distant metastases were detected in 2.1% of patients at diagnosis. Most patients received the diagnosis in the initial phase of the disease, but 20.2% were diagnosed in stage IV. Partial penectomy was the most performed surgery, and 10% of patients relapsed, mainly in the lymph nodes (87.5%). The mean follow-up of the patients was 18 months, with an estimated overall survival at five years of 59.1%. However, 25% of patients were followed up for up to 3 months, losing follow-up. CONCLUSION: the State of Rio Grande do Norte has a high incidence of penile cancer with a high frequency of locally advanced tumors at diagnosis and in younger patients younger than 50. Furthermore, socioeconomic factors interfere with early diagnosis and hinder access to specialized services.

Regional differences in penile cancer patient characteristics and treatment rates across the United States.

INTRODUCTION: We tested for regional-specific differences in patient, tumor and treatment characteristics as well as cancer-specific mortality (CSM) of squamous cell carcinoma of the penis (SCCP) patients, across the Surveillance, Epidemiology, and End Results (SEER) registries. METHODS: The SEER database (2000-2018) was used to tabulate patient (age at diagnosis, race/ethnicity), tumor (stage, grade, N-stage) and treatment characteristics (proportions of primary tumor surgery, local lymph node surgery, systemic therapy), according to 12 SEER registries. Multinomial regression models, as well as multivariable Cox regression models tested for CSM differences, adjusting for patient, tumor and treatment characteristics. RESULTS: In 5395 SCCP patients, registry-specific patient counts ranged from 2060 (38 %) to 64 (1 %). Differences across registries existed for race/ethnicity, stage, grade and N-stage. Additionally, in stage I-II SCCP patients, proportions of local tumor destruction (LTD) ranged from 19 % to 39 % and from 33 % to 61 % for partial penectomy. In stage III-IV SCCP patients, proportions of partial penectomy ranged from 40 % to 59 % and from 17 % to 50 % for radical penectomy. Local lymph node surgery ranged from 8 % to 24 % and proportions of systemic therapy ranged from 3 % to 14 %. Significant inter-registry differences remained, after adjustment for treatment proportions. Unadjusted five-year CSM ranged from 19 % to 32 %. In multivariable analyses, one registry exhibited significantly higher CSM (SEER registry 10, Hazard Ratio [HR] 1.48), relative to the largest reference registry (SEER registry 1, n = 2060). CONCLUSION: Important regional differences including patient, tumor and treatment characteristics exist for SCCP patients across SEER registries. After multivariable adjustment, no differences in CSM were recorded, with the exception of one registry.

[Are there any volume-related effects on treatment options for patients with penile cancer? Results of a survey among university hospitals in Germany and Austria]. / Gibt es fallzahlabhängige Effekte auf Behandlungsangebote für Patienten mit einem Peniskarzinom? Ergebnisse einer Umfrage an Universitätsklinika in Deutschland und Österreich.

BACKGROUND: Currently, 959 men in Germany and 67 in Austria are diagnosed with penile cancer each year, with an increase of approximately 20% in the last decade [RKI 2021, Statcube.at 2023]. Despite the rising incidence, the number of cases per hospital remains low. The median annual number of penile cancer cases at university hospitals in the DACH region was 7 patients (IQR 5-10) in 2017 [E-PROPS group 2021]. The compromised institutional expertise due to low case numbers is compounded with inadequate adherence to penile cancer guidelines, as shown in several studies. The centralization, which is rigorously implemented in countries such as the UK, enabled a significant increase in organ-preserving primary tumor surgery and stage-adapted lymphadenectomies, as well as improved patient survival in cases of penile cancer, resulting in a claim for a similar centralization in Germany and Austria. The aim of this study was to determine the current effects of case volume on penile cancer related treatment options at university hospitals in Germany and Austria. MATERIALS AND METHODS: In January 2023, a survey was sent to the heads of 48 urological university hospitals in Germany and Austria, including questions regarding case volume in 2021 (total number of inpatient and penile cancer cases), treatment options for primary tumors and inguinal lymphadenectomy (ILAE), the availability of a designated penile cancer surgeon, and the professional responsibility for systemic therapies in penile cancer. Correlations and differences related to case volume were statistically analyzed without adjustments. RESULTS: The response rate was 75% (n=36/48). In total, 626 penile cancer patients were treated at the 36 responding university hospitals in 2021, representing approximately 60% of the expected incidence in Germany and Austria. The annual median total number of cases was 2807 (IQR 1937-3653), and for penile cancer, it was 13 (IQR 9-26). There was no significant correlation between the total inpatient and penile cancer caseloads (p=0.34). The number of organ-preserving therapy procedures for the primary tumor, the availability of modern ILAE procedures, the presence of a designated penile cancer surgeon, and the responsibility for systemic therapies were not significantly influenced by the total inpatient or penile cancer case volume of the treating hospitals, regardless of whether the case volumes were dichotomized at the median or upper quartile. No significant differences between Germany and Austria were observed. CONCLUSION: Despite a significant increase in the annual number of penile cancer cases at university hospitals in Germany and Austria compared to 2017, we found no case volume-related effects on structural quality with respect to penile cancer therapy. In the light of the proven benefits of centralization, we interpret this result as an argument for the necessity of establishing nationally organized penile cancer centers with even higher case volumes compared to the status quo, in light of the proven benefits of centralization.

Penile cancer: long-term infectious and thromboembolic complications following lymph node dissection - a population-based study (Sweden).

PURPOSE: To assess the long-term risks of infectious and thromboembolic events following inguinal (ILND) and pelvic (PLND) lymph node dissection in men with penile cancer. MATERIAL AND METHODS: A total of 364 men subjected to ILND with or without PLND for penile cancer between 2000 and 2012 were identified in the Swedish National Penile Cancer Register. Each patient was matched based on age and county of residence with six penile cancer-free men. The Swedish Cancer Register and other population-based registers were used to retrieve information on treatment and hospitalisation for selected infectious and thromboembolic events. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox proportional hazard models with multiple imputation. RESULTS: The risk of infectious events remained increased for more than five years postoperatively in men with penile cancer compared with matched controls. The palpable nodal disease was the only predictor of these events, with risk increasing with the cN stage. The HR at one, three and five years and six months postoperatively was 8.60 (95% CI 5.16-14.34), 4.02 (95% CI 2.65-6.09) and 1.93 (95% CI 1.11-3.38), respectively. An increased risk of thromboembolic events persisted for three years postoperatively. The HR at one and three years postoperatively was 13.51 (95% CI 6.53-27.93) and 2.12 (95% CI 1.07-4.20). The results correspond well with the over-prescription of anticoagulants observed during this period. An association with bulky disease (cN3) was observed. CONCLUSIONS: Lymph node dissection for penile cancer is associated with an increased risk of infectious and thromboembolic events. The findings of this population-based study show that the risks of these events remain increased more than five years for infectious and three years for thromboembolic events. Improved awareness of long-term complications following ILND is of importance both among patients and care givers to ensure early detection and treatment.

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.

Increased prevalence of human papillomavirus in fresh tissue from penile cancers compared to non-malignant penile samples: a case-control study.

BACKGROUND: HPV has been detected in approximately 50% of invasive penile cancers but with a large span between 24 and 89%, most likely due to different types of tumors and various methods for HPV analysis. Most studies of HPV in penile cancer have been performed using paraffin-embedded tissue, argued to be at risk for contaminated HPV analysis. Viral activity of HPV, by the use of HPV mRNA expression is well studied in cervical cancer, but seldom studied in penile cancer. The aim was to determine prevalence of HPV types in fresh tissue of penile cancers compared to non-malignant age-matched penile controls. Additional aims were to analyze the viral expression and copy numbers of HPV16-positive tumors and 10 mm adjacent to the tumor. METHODS: Fresh tissue from penile cancer cases was biopsied inside the tumor and 10 mm outside the tumor. Controls were males circumcised for non-malignant reasons, biopsied at surgery. PCR and Luminex assays were used for identification of HPV types. HPV16-positive samples were investigated for copy numbers and expression of HPV16-mRNA. RESULTS: Among tumors (n = 135) and age-matched controls (n = 105), HPV was detected in 38.5% (52/135) and 11.4% (12/105), respectively (p < 0.001), adjusted odds ratio 12.8 (95% confidence interval 4.9-33.6). High-risk HPV types were found in 35.6% (48/135) of tumors and 4.8% (5/105) of controls (p < 0.001). Among tumors and controls, HPV16 was present in 27.4% (37/135) and 1% (1/105), respectively (p < 0.001). Among HPV16-positive penile cancers, mean HPV16 viral copy/cell was 74.4 (range 0.00003-725.4) in the tumor and 1.6 (range 0.001-14.4) 10 mm adjacent from the tumor. HPV16-mRNA analysis of the tumors and 10 mm adjacent from the tumors demonstrated viral activity in 86.5% (32/37) and 21.7% (5/23), respectively. CONCLUSIONS: The prevalence of HPV was significantly higher in penile cancer (38.5%) than among age-matched non-malignant penile samples (11.4%). HPV16 predominates (27.4%) in penile tumors. HPV16 expression was more common in penile cancer than in adjacent healthy tissue, strongly suggesting an etiological role for HPV16 in the development of penile cancer.

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.

Global Pattern and Trends in Penile Cancer Incidence: Population-Based Study.

BACKGROUND: Penile cancer is a relatively rare genital malignancy whose incidence and mortality are rising in many countries. OBJECTIVE: This study aims to assess the recent incidence and mortality patterns and incidence trends of penile cancer. METHODS: The age-standardized incidence and mortality rates (ASIR and ASMR, respectively) of penile cancer in 2020 were estimated from the Global Cancer Registries (GLOBOCAN) database. Incidence trends of penile cancer from 1973 to 2012 were assessed in 44 populations from 43 countries using the Cancer Incidence in Five Continents plus (CI5plus) and the Nordic Cancer Registries (NORDCAN) databases. Average annual percentage change was calculated to quantify trends in ASIR using joinpoint regression. RESULTS: Globally, the estimated ASIR and ASMR of penile cancer were 0.80 (per 100,000) and 0.29 (per 100,000) in 2020, equating to 36,068 new cases and 13,211 deaths in 2020, respectively. There was no significant correlation between the ASIR (P=.05) or ASMR (P=.90) and Human Development Index. In addition, 15 countries saw increasing ASIR for penile cancer, 13 of which were from Europe (United Kingdom, Lithuania, Norway, Estonia, Finland, Sweden, Cyprus, Netherlands, Italy, Croatia, Slovakia, Russia, and the Czech), and 2 from Asia (China and Israel). CONCLUSIONS: Although the developing countries still bear the higher incidence and mortality of penile cancer, the incidence is on the rise in most European countries. To mitigate the disease burden resulting from penile cancer, measures to lower the risk for penile cancers, including improving penile hygiene and male human papillomavirus vaccination, may be warranted.

Ecologic Analysis of Correlates of Cervical Cancer Morbidity and Mortality in Sub-Saharan Africa.

BACKGROUND: Cervical cancer is the fourth leading cause of death among women worldwide, with 85% of the burden falling on low- to middle- income countries. We studied the correlates of cervical cancer incidence and mortality, and case-fatality in Sub-Saharan Africa. METHODS: Country-level data on 16 putative cervical cancer correlates for 37 Sub-Saharan African countries were collected from publicly available data sources. We performed univariate and multiple (stepwise) linear regression analyses to identify correlates of cervical cancer incidence and mortality, and case-fatality. RESULTS: In univariate analyses, incidence and mortality rates were significantly correlated with contraceptive use, penile cancer incidence, and human immunodeficiency virus prevalence. Incidence rates were also correlated with literacy rates, whereas mortality rates were correlated with the proportion of rural population and screening coverage. Multiple regression analyses showed contraceptive use (P = 0.009) and penile cancer incidence (P = 0.004) as associated with cervical cancer incidence. Penile cancer incidence (P = 9.77 × 10-5) and number of medical doctors (P = 0.0433) were associated with mortality. The goodness of fit of the incidence and mortality models was moderate at best, explaining 49% and 37% of variability in the data, respectively. However, the case-fatality model had the best fit explaining most of the variation (adjusted R2 = 0.948; P = 6.822 × 10-16). CONCLUSIONS: To reduce the burden of cervical cancer in Sub-Saharan Africa, it would be important to design multimodal interventions that not only target screening and HPV vaccination, but also focus on cervical cancer correlates. IMPACT: Identifying contextual factors associated with cervical cancer in this region could inform targeted interventions.