Real World Data of Penile Cancer Treatment at a High-Volume Center in South America: Insights and Survival Trends.

OBJECTIVE: To report survival trends and oncological outcomes of penile cancer surgically treated patients, at a high-volume center, treating more than 25 patients each year, in a high incidence country. METHODS: Clinical charts of all patients that underwent surgical management for penile cancer were reviewed. The primary end points were cancer specific survival (CSS), progression-free survival, and local recurrence free survival. Kaplan-Meier plots were used for survival analyses. Multivariate analysis was performed using cox proportional hazard age-adjusted models to determine the effect of pN, pT, lymphovascular invasion for CSS. RESULTS: A total of 209 patients were identified, with a median follow up of 96 months (IQR 49-133). Organ-sparing surgerywas performed in 72.7%, 56.9% underwent dynamic sentinel lymph node biopsy, 110 patients underwent inguinal lymph node dissection, and 45 (21.5%) pelvic lymph node dissection. A total of 75 (35.8%) of patients relapsed, median time to relapse of 12 months (IQR 6-25). Overall estimates of CSS showed an 8-year CSS of 68.9%. Eight-year CSS was 90.5% for N0, and 32.8% in pN3 (P <.001). The Cox proportional hazard model showed that pN1-3, pT2-4, lymphovascular invasion and positive dynamic sentinel lymph node biopsy were the variables associated with worse 8-year CSS. CONCLUSION: To the best of our knowledge, we report one of the largest cohorts on the survival outcomes of penile cancer surgical treatment, in a single institution, over a long period of time, were most patients are referred with high-risk, locally advanced or nodal disease.

Penile cancer trends and economic burden in the Brazilian public health system.

OBJECTIVE: To gather information on penile cancer epidemiologic trends and its economic impact on the Brazilian Public Health System across the last 25 years. METHODS: The Brazilian Public Health System database was used as the primary source of data from January 1992 to December 2017. Mortality and incidence data from the Instituto Nacional de Câncer José Alencar Gomes da Silva was collected using the International Classification of Diseases ICD10 C60. Demographic data from the Brazilian population was obtained from the last census by the Brazilian Institute of Geography and Statistics, performed in 2010 and its 2017 review. RESULTS: There were 9,743 hospital admissions related to penile cancer from 1992 to 2017. There was a reduction (36%) in the absolute number of admissions per year related to penile cancer in 2017, as compared to 1992 (2.7versus 1.7 per 100,000; p<0.001). The expenses with admissions related to this condition in this period were US$ 3,002,705.73 (US$ 115,488.68/year). Approximately 38% of the total amount was spent in Northeast Region. In 1992, penile cancer costed US$ 193,502.05 to the public health system, while in 2017, it reduced to US$ 47,078.66 (p<0.02). Penile cancer incidence in 2017 was 0.43/100,000 male Brazilian, with the highest incidence rate found in the Northeast Region. From 1992 to 2017, the mortality rates of penile cancer in Brazil were 0.38/100,000 man, and 0.50/100,000 man in the North Region. CONCLUSION: Despite the decrease in admissions, penile cancer still imposes a significant economic and social burden to the Brazilian population and the Public Health System.

Oncological and Functional Outcomes After Organ-Sparing Plastic Reconstructive Surgery for Penile Cancer.

OBJECTIVE: To describe oncological and functional outcomes in patients treated with reconstructive organ-sparing surgery (OSS) for squamous cell carcinoma of the penis. Plastic reconstructive OSS of the penis with a split thickness skin graft has been proposed as a treatment option for penile cancer, with the objective being preservation of physiological voiding and sexual function without comprising oncological control. MATERIALS AND METHODS: Multicenter study reporting clinicopathological data of 57 patients with malignant lesions of the penis treated with OSS and plastic reconstructive surgery with split thickness skin graft from 2007 to 2019. Health related quality of life (HRQoL) was assessed with EuroQoL-5D-3L, urinary symptoms with the International Consultation on Incontinence Modular Questionnaire for Male Lower Urinary Tract Symptoms, and erectile function with the International Index of erectile function (IIEF)-5. RESULTS: Fifty-seven patients underwent OSS reconstructive surgery. Twenty underwent glans resurfacing, 23 partial penectomy, and 14 glansectomy. Median age was 55.1 years (interquartile range [IQR] 29-90), median follow-up 55.7 months (3-149). At the time of data analysis, 6 patients had died of Squamous Cell Carcinoma (SCC) (12.5%) and 10 (17.8%) had progressed. Kaplan-Meier estimates showed a 5-year survival rate of 87.5% and a 5-year progression-free survival of 83%. We assessed HRQoL and functional outcomes in 32 patients. EuroQol 5D-3L showed a mean health status of 82.5%, median Voiding score of the ICIQ-MLTUS was 4 (IQR 1-15), and median IIEF-5 19 (IQR 10.75-25). CONCLUSION: OSS of the penis remains a safe and viable option for the treatment of SCC, ensuring a favorable appearance of the penis, preserving urinary and sexual function, with good HRQoL and without comprising oncological safety in selected cases.

Penile cancer trends and economic burden in the Brazilian public health system / Tendências e carga econômica do câncer de pênis no sistema público de saúde brasileiro

ABSTRACT Objective: To gather information on penile cancer epidemiologic trends and its economic impact on the Brazilian Public Health System across the last 25 years. Methods: The Brazilian Public Health System database was used as the primary source of data from January 1992 to December 2017. Mortality and incidence data from the Instituto Nacional de Câncer José Alencar Gomes da Silva was collected using the International Classification of Diseases ICD10 C60. Demographic data from the Brazilian population was obtained from the last census by the Brazilian Institute of Geography and Statistics, performed in 2010 and its 2017 review. Results: There were 9,743 hospital admissions related to penile cancer from 1992 to 2017. There was a reduction (36%) in the absolute number of admissions per year related to penile cancer in 2017, as compared to 1992 (2.7versus 1.7 per 100,000; p<0.001). The expenses with admissions related to this condition in this period were US$ 3,002,705.73 (US$ 115,488.68/year). Approximately 38% of the total amount was spent in Northeast Region. In 1992, penile cancer costed US$ 193,502.05 to the public health system, while in 2017, it reduced to US$ 47,078.66 (p<0.02). Penile cancer incidence in 2017 was 0.43/100,000 male Brazilian, with the highest incidence rate found in the Northeast Region. From 1992 to 2017, the mortality rates of penile cancer in Brazil were 0.38/100,000 man, and 0.50/100,000 man in the North Region. Conclusion: Despite the decrease in admissions, penile cancer still imposes a significant economic and social burden to the Brazilian population and the Public Health System.

RESUMO Objetivo: Reunir informações sobre as tendências epidemiológicas do câncer de pênis e seu impacto econômico no Sistema Único de Saúde nos últimos 25 anos. Métodos: O banco de dados de informações do Sistema Único de Saúde foi utilizado como fonte primária de dados de janeiro 1992 a dezembro 2017. Os dados demortalidade e incidência do Instituto Nacional de Câncer José Alencar Gomes da Silva foram coletados usando a Classificação Internacional de Doença CID10 C60. Os dados demográficos da população brasileira foram obtidos do último censo do Instituto Brasileiro de Geografia e Estatística, realizado em 2010, e em sua revisão, de 2017. Resultados: Ocorreram 9.743 internações relacionadas ao câncer de pênis de 1992 a 2017. Houve redução (36%) nas internações anuais absolutas em 2017 em comparação com 1992 (2,7 versus 1,7 por 100.000; p<0,001). Os gastos com internações neste período foram de US$ 3,002,705.73 (US$ 115,488.68/ano). Cerca de 38% do valor total foi gasto na Região Nordeste. Em 1992, o câncer de pênis custou US$ 193,502.05 ao sistema público, enquanto em 2017 reduziu para US$ 47,078.66 (p<0,02). A incidência em 2017 foi de 0,43/100.000 brasileiro do sexo masculino, com a maior taxa de incidência encontrada na Região Nordeste. De 1992 a 2017, as taxas de mortalidade por câncer de pênis foram de 0,38/100.000 homem, sendo 0,50/100.000 homem na Região Norte. Conclusão: Apesar da diminuição nas hospitalizações, o câncer de pênis ainda impõe uma carga econômica e social significativa à população brasileira e ao Sistema Único de Saúde.

Disparities in human papillomavirus-related cancer incidence and survival among human immunodeficiency virus-infected Hispanics living in the United States.

BACKGROUND: Human papillomavirus (HPV) causes 10% of cancers among human immunodeficiency virus (HIV)-infected people in the United States. Because Hispanics are disproportionally affected by the HIV epidemic and by infection-related cancers, this study compared incidence rates for HPV-related cancers and survival between Hispanics and non-Hispanic whites (NHWs) and non-Hispanic blacks (NHBs) in the HIV-infected US population. METHODS: Based on data from the HIV/AIDS Cancer Match Study, standardized incidence ratios (SIRs) were used to estimate cancer risk in HIV-infected Hispanics and the general US Hispanic population. Among HIV-infected people, cancer rates were compared with incidence rate ratios (IRRs), and survival was compared with hazard ratios between Hispanics and NHWs and NHBs. RESULTS: Five hundred two HPV-related cancers occurred in 864,067 person-years of follow-up among HIV-infected Hispanics. Except for oropharyngeal cancer, the risk of HPV-related cancers was higher among HIV-infected Hispanics than in the general population (SIR range, 3.59 [cervical cancer] to 18.7 [anal cancer in men]). Among HIV-infected females, Hispanics had higher cervical cancer rates than NHWs (IRR, 1.70; 95% confidence interval [CI], 1.19-2.43) but lower vulvar cancer rates than NHWs (IRR, 0.40; 95% CI, 0.24-0.67) and NHBs (IRR, 0.62; 95% CI, 0.41-0.95). Among HIV-infected males, Hispanics had higher penile cancer rates than NHWs (IRR, 2.60; 95% CI, 1.36-4.96) but lower anal cancer rates than NHWs (IRR, 0.54; 95% CI, 0.46-0.63) and NHBs (IRR, 0.65; 95% CI, 0.56-0.77). Among HIV-infected Hispanics, 5-year survival was greater than 50% across HPV-related cancer types, with no major differences by racial/ethnic group. CONCLUSIONS: HIV-infected Hispanics have an elevated risk for HPV-related cancers. Similarly to the general population, HIV-infected Hispanics have higher rates of cervical and penile cancer than NHWs and NHBs. HPV vaccination should be promoted among HIV-infected individuals to reduce the burden of HPV-related cancers.

Nuclear loss and cytoplasmic expression of androgen receptor in penile carcinomas: role as a driver event and as a prognosis factor.

Androgen receptor (AR) is a member of the steroid and nuclear family receptor that acts as transcription factor. AR signaling plays pivotal role in the development and progression of prostate cancer. However, the role of AR in penile cancer (PeCa) is poorly explored. Our previous molecular studies unveiled frequent AR mRNA loss in PeCa, which was further predicted as a major driver alteration in this neoplasm. Herein, we assessed the AR protein expression in 59 usual PeCa tissues and 42 surrounding normal tissues (SNT) by immunohistochemistry using a tissue microarray. In a paired analysis, we found a total absence of nuclear AR expression in PeCa while 95.2% of SNT samples presented strong nuclear AR expression (P < 0.001). Interestingly, 17 of 42 PeCa presented weak or moderate cytoplasmic AR staining, contrasting with 5 of 42 SNT (P = 0.008). Increased levels of AR cytoplasmic expression were related with poor prognosis features including advanced clinical staging (P = 0.044), compromised surgical margins (P = 0.005), and pathological inguinal node status (P = 0.047). Furthermore, AR cytoplasmic expression was also related with shorter overall survival (P = 0.032). In conclusion, the frequent loss of nuclear AR protein levels suggests a potential function in PeCa development. Based on this result, the androgen deprivation therapy is not indicated for PeCa patients. In addition, the AR cytoplasmic expression found in a significant number of cases (40.5%) showed prognostic value and pathways activated by the non-genomic AR signaling may represent a promising therapeutic strategy.

Human papillomavirus (HPV) genotype distribution in penile carcinoma: Association with clinic pathological factors.

BACKGROUND: Penile carcinoma (PC) is a rare, highly mutilating disease, common in developing countries. The evolution of penile cancer includes at least two independent carcinogenic pathways, related or unrelated to HPV infection. OBJECTIVES: To estimate the prevalence, identify HPV genotypes, and correlate with clinicopathological data on penile cancer. METHODS: A retrospective cohort study involving 183 patients with PC undergoing treatment in a referral hospital in Goiânia, Goiás, in Midwestern Brazil, from 2003 to 2015. Samples containing paraffin embedded tumor fragments were subjected to detection and genotyping by INNO-LiPA HPV. The clinicopathological variables were subjected to analysis with respect to HPV positivity and used prevalence ratio (PR), adjusted prevalence ratio (PRa) and 95% confidence interval (CI) as statistical measures. RESULTS: The prevalence of HPV DNA in PC was 30.6% (95% CI: 24.4 to 37.6), high-risk HPV 24.9% (95% CI: 18.9 to 31.3), and 62.5% were HPV 16. There was a statistical association between the endpoints HPV infection and HPV high risk, and the variable tumor grade II-III (p = 0.025) (p = 0.040), respectively. There was no statistical difference in disease specific survival at 10 years between the HPV positive and negative patients (p = 0.143), and high and low risk HPV (p = 0.325). CONCLUSIONS: The prevalence of HPV infection was 30.6%, and 80.3% of the genotypes were identified as preventable by anti-HPV quadrivalent or nonavalent vaccine. HPV infections and high-risk HPV were not associated with penile carcinoma prognosis in this study.

Multidimensional integrative analysis uncovers driver candidates and biomarkers in penile carcinoma.

Molecular data generation and their combination in penile carcinomas (PeCa), a significant public health problem in poor and underdeveloped countries, remain virtually unexplored. An integrativemethodology combin ing genome-wide copy number alteration, DNA methylation, miRNA and mRNA expression analysis was performed in a set of 20 usual PeCa. The well-ranked 16 driver candidates harboring genomic alterations and regulated by a set of miRNAs, including hsa-miR-31, hsa-miR-34a and hsa-miR-130b, were significantly associated with over-represented pathways in cancer, such as immune-inflammatory system, apoptosis and cell cycle. Modules of co-expressed genes generated from expression matrix were associated with driver candidates and classified according to the over-representation of passengers, thus suggesting an alteration of the pathway dynamics during the carcinogenesis. This association resulted in 10 top driver candidates (AR, BIRC5, DNMT3B, ERBB4, FGFR1, PML, PPARG, RB1, TNFSF10 and STAT1) selected and confirmed as altered in an independent set of 33 PeCa samples. In addition to the potential driver genes herein described, shorter overall survival was associated with BIRC5 and DNMT3B overexpression (log-rank test, P = 0.026 and P = 0.002, respectively) highlighting its potential as novel prognostic marker for penile cancer.

Human papillomavirus, Epstein-Barr virus, and methylation status of p16ink4a in penile cancer.

Little is known about penile carcinogenesis. The aim of this study was to evaluate the prevalence of HPV and EBV, and the methylation status of p16ink4a in penile cancer samples, and to contribute to the understanding of the mechanisms responsible for penile cancer development. HPV DNA was detected in 63.6% of 122 cases, with HPV16 being the most prevalent type. EBV DNA was detected in 47.7%, with EBV-1 being the most prevalent type. HPV/EBV co-infections were found in 27.3% of the cases. Hypermethylation in p16ink4a was detected in 64.5% of 110 tested cases. An association between the absence of HPV absence and p16ink4a hypermethylation was also found. Death and/or progressive disease was associated with grade (P = 0.001), T stage (P < 0.0001), and N stage (P < 0.0001). In the multivariable model, grade and N stage were independent risk factors for disease-free survival (P = 0.008 and P < 0.001, respectively). Patients without viral infection had a median age significantly lower than that of the HPV-infected patients. We suggest at least two pathways for penile carcinogenesis, one HPV-independent linked to epigenetic events, probably via p16ink4a inactivation; and another, dependent on HPV infection.

[Five-year survival analysis in patients with penile cancer]. / Análisis de supervivencia a cinco años en pacientes con cáncer de pene.

BACKGROUND: Short-term survival of penile cancer is poor. The objective was to describe the 5-years penile cancer survival. METHODS: Retrospective cohort study. We included patients with penile cancer managed surgically from 2010 to 2014. Descriptive statistics were used for socio-demographic variables and the Kaplan-Meier estimator for survival function. RESULTS: We studied 22 patients with a mean age of 64.95 years and a time of evolution of 25 months after the diagnosis. 68.2% of patients smoked or had human papillomavirus (HPV); they all presented phimosis; 72.7% had pain in the penis and the groin area; 81.8% had palpable lymph nodes and 45.5% lesions ≥ 3 cm; 86.3% were diagnosed in clinical stage IIIa. 59.1% underwent partial penectomy and 86.4% had squamous cell variety. 40.9% of patients died six months after the surgery. 66% of the smokers presented metastasis; all of the patients that smoked and had HPV infection had neurovascular invasion and died; 83.3% of the patients (n = 6) who underwent partial penectomy and positive lymph node dissection due to metastases died. The 5-years mortality of patients with penile cancer was 40.9%. CONCLUSION: Tobacco use and HPV increase morbidity and mortality in patients with penile cancer; lesions greater than 5 cm are more common in smokers. The size of the lesion increases with the delay in treatment.

Introducción: la sobrevida del cáncer de pene es pobre a corto plazo. El objetivo fue describir la supervivencia de pacientes con cáncer de pene a cinco años. Métodos: estudio de cohorte retrospectivo. Se incluyeron pacientes con cáncer de pene manejados quirúrgicamente durante el periodo de 2010 a 2014. La estadística fue descriptiva y se usó el estimador de Kaplan-Meier para analizar la función de supervivencia. Resultados: se estudiaron 22 pacientes, con edad media de 64.95 años y tiempo de evolución del cáncer al diagnóstico de 25 meses. El 68.2% era fumador o presentó VPH; todos tuvieron fimosis; 72.7% tuvo dolor en pene e ingle; 81.8% presentó ganglios palpables y 45.5% lesiones ≥ 3 cm. El 86.3% se diagnosticó en estadio clínico mayor de IIIa. Al 59.1% se le realizó penectomía parcial y 86.4% fue de variedad epidermoide. El 40.9% de los pacientes falleció a los seis meses después del tratamiento quirúrgico. El 66.6% de los fumadores presentó metástasis; todos los que presentaban tabaquismo más infección por VPH tuvieron invasión neurovascular y fallecieron. Al 83.3% (n = 6) de los pacientes a los que se les realizó penectomía parcial y disección ganglionar con ganglios positivos por metástasis fallecieron. La mortalidad fue de 40.9% a cinco años. Conclusión: el tabaquismo y el VPH aumentan la morbimortalidad en pacientes con cáncer de pene; las lesiones mayores de 5 cm se presentan más en fumadores. El tamaño de la lesión aumenta con la demora diagnóstica.

Epidermal growth factor receptor as an adverse survival predictor in squamous cell carcinoma of the penis.

Penile carcinoma (PC) is more frequent in underdeveloped countries, generally is diagnosed at an advanced stage when therapeutic options are restricted, and thus is associated with high morbidity/mortality rates. Recent studies have demonstrated clinical benefits with epidermal growth factor receptor (EGFR)-targeted therapy in patients with PC, although there is no test that provides accurate patient selection. The aim of the present study was to evaluate the prognostic value of EGFR gene and protein status in tumor samples from patients with primary penile squamous cell carcinoma. We assessed the expression of wild-type and 2 mutant EGFR isoforms (delA746-E750 and mL858R) by immunohistochemistry in 139 samples, of which 49 were also evaluated for EGFR copy number by fluorescence in situ hybridization (FISH). Positive immunohistochemical staining of wild-type and mutant EGFR was evidenced by complete and strong membranous staining. For FISH analysis, cases were considered unaltered, polysomic, or amplified, as determined by signals of the EGFR gene and chromosome 7. An independent cohort of 107 PC samples was evaluated for mutations in EGFR, KRAS, and BRAF. Protein overexpression was noted in nearly half of the cases and was associated with cancer recurrence (P=.004) and perineural invasion (P=.005). Expression of the 2 mutated EGFR isoforms was not observed. The FISH status was not associated with protein expression. Altered FISH (polysomy and gene amplification) was an independent risk factor for dying of cancer. Only 1 patient of 107 presented KRAS mutations, and no mutations of EGFR or BRAF were observed.

Tumor histologic grade is the most important prognostic factor in patients with penile cancer and clinically negative lymph nodes not submitted to regional lymphadenectomy

ABSTRACT Introduction: The presence and extension of inguinal lymph node metastasis are the main prognostic factors in patients with penile cancer. Physical exam and image exams are not adequate to evaluate inguinal lymph nodes and many patients are submitted to non-therapeutic lymphadenectomies. However, it is known that not all patients with clinically or histologically negative inguinal lymph nodes evolve favorably. Casuistic and Methods: the authors evaluated the clinical and pathologic characteristics of 163 patients with penile carcinoma and clinically negative inguinal lymph nodes followed for three or more years and their impact on global survival (GS) and cancer-specific survival (CSS) in the 10-year follow-up. Primary pathologic tumor stage (p=0.025) and the presence of high grade of tumor differentiation (p=0.018) were predictive of CSS. The presence of high grade tumor was an independent specific prognostic factor of death risk (RR 14.08; p=0.019). Conclusion: high histologic grade was an independent predictive factor of specific death risk in patients with penile carcinoma and clinically negative lymph nodes followed for three or more years.

Tumor histologic grade is the most important prognostic factor in patients with penile cancer and clinically negative lymph nodes not submitted to regional lymphadenectomy.

INTRODUCTION: The presence and extension of inguinal lymph node metastasis are the main prognostic factors in patients with penile cancer. Physical exam and image exams are not adequate to evaluate inguinal lymph nodes and many patients are submitted to non-therapeutic lymphadenectomies. However, it is known that not all patients with clinically or histologically negative inguinal lymph nodes evolve favorably. CASUISTIC AND METHODS: the authors evaluated the clinical and pathologic characteristics of 163 patients with penile carcinoma and clinically negative inguinal lymph nodes followed for three or more years and their impact on global survival (GS) and cancer-specific survival (CSS) in the 10-year follow-up. Primary pathologic tumor stage (p=0.025) and the presence of high grade of tumor differentiation (p=0.018) were predictive of CSS. The presence of high grade tumor was an independent specific prognostic factor of death risk (RR 14.08; p=0.019). CONCLUSION: high histologic grade was an independent predictive factor of specific death risk in patients with penile carcinoma and clinically negative lymph nodes followed for three or more years.

Pattern of invasion is the most important prognostic factor in patients with penile cancer submitted to lymph node dissection and pathological absence of lymph node metastasis.

OBJECTIVES: To identify prognostic factors in a cohort of patients with penile carcinoma with pathological absence of lymph node metastasis (pN0), as penile carcinoma is a rare neoplasm in European countries, in which the presence of lymph node metastasis is the most important prognostic factor but few studies have examined patients with penile carcinoma with histologically negative nodes (pN0). PATIENTS AND METHODS: Of patients with penile carcinoma, 101 met the inclusion criteria; 47 (46.5%) underwent bilateral inguinal lymph node dissection (LND) and 54 (53.5%) underwent bilateral inguinopelvic LND. Variables that had a prognostic impact on survival rates in univariate analysis were selected for multivariate survival analysis. RESULTS: The cohorts cancer-specific survival (CSS) and overall survival (OS) rates were 88.1% and 52.5%, respectively. Histological grade and pattern of invasion were the only features to significantly impact survival rates in the univariate analysis. The CSS and OS rates in patients with 'pushing' vs 'infiltrating' patterns of invasion were 98.0% vs 78.4% (P = 0.003) and 70.0% vs 35.3% (P = 0.005), respectively. Pattern of invasion was the only independent predictor of survival. Patients with infiltrating invasion had a higher probability of death from cancer (hazard ratio [HR] 11.5, P = 0.019) and overall death (HR 2.3, P = 0.007) compared with those with a pushing invasion pattern. CONCLUSIONS: The presence of an infiltrating pattern of invasion is the most important predictor of survival in patients with penile carcinoma. We encourage other centres to confirm our findings that the pattern of invasion is an important prognostic factor in patients with penile carcinoma and pN0 disease.

Pathological factors, behavior, and histological prognostic risk groups in subtypes of penile squamous cell carcinomas (SCC).

Pathologists' contribution in the determination of prognosis in invasive penile squamous cell carcinoma is crucial. The TNM staging system is based on the identification of pathological data. There are multiple pathologically based factors believed to be important in relation to the rates of regional inguinal lymph node and specific cancer death. Among them are tumor site, size, histological subtypes, thickness or anatomical level of invasion, tumor front, and vascular or perineural invasion. The identification of these factors determines the prognostic profile of patients with penile cancer. These factors are used for the construction of pathological risk groups, prognostic index, or nomograms and are helpful in the prediction of nodal metastasis or patients' outcome. This review will describe in detail the influential pathological prognostic factors present in each tumor category emphasizing the impact of especial histological subtypes in tumor spread and final outcome. There are few studies comprehensibly addressing the relation of tumor morphology and prognosis according to histological types. We are summarizing findings of prognostic factors in 3 different series for the most common types and individual series in more recently described tumor entities. We had found a broad correlation of special subtypes of penile squamous cell carcinomas that made regional nodal status and final outcome predictable according to histological features of the tumor. These findings permitted grouping special subtypes of squamous cell carcinomas into prognosis risk groups of low, intermediate, and high. In the first category of excellent prognoses are the usual grade I, verrucous, papillary NOS, pseudohyperplastic and cuniculatum carcinomas. In the second group, there are the grade II usual, mixed and warty carcinomas. The third category of tumors, with the worst prognosis is composed of high grade usual, basaloid, warty-basaloid, papillary basaloid, and sarcomatoid carcinomas. We found that subtyping of penile squamous cell carcinoma is important to determine risk for nodal metastasis and patients' survival.

Genomic profiling of human penile carcinoma predicts worse prognosis and survival.

The molecular mechanisms underlying penile carcinoma are still poorly understood, and the detection of genetic markers would be of great benefit for these patients. In this study, we assessed the genomic profile aiming at identifying potential prognostic biomarkers in penile carcinoma. Globally, 46 penile carcinoma samples were considered to evaluate DNA copy-number alterations via array comparative genomic hybridization (aCGH) combined with human papillomavirus (HPV) genotyping. Specific genes were investigated by using qPCR, FISH, and RT-qPCR. Genomic alterations mapped at 3p and 8p were related to worse prognostic features, including advanced T and clinical stage, recurrence and death from the disease. Losses of 3p21.1-p14.3 and gains of 3q25.31-q29 were associated with reduced cancer-specific and disease-free survival. Genomic alterations detected for chromosome 3 (LAMP3, PPARG, TNFSF10 genes) and 8 (DLC1) were evaluated by qPCR. DLC1 and PPARG losses were associated with poor prognosis characteristics. Losses of DLC1 were an independent risk factor for recurrence on multivariate analysis. The gene-expression analysis showed downexpression of DLC1 and PPARG and overexpression of LAMP3 and TNFSF10 genes. Chromosome Y losses and MYC gene (8q24) gains were confirmed by FISH. HPV infection was detected in 34.8% of the samples, and 19 differential genomic regions were obtained related to viral status. At first time, we described recurrent copy-number alterations and its potential prognostic value in penile carcinomas. We also showed a specific genomic profile according to HPV infection, supporting the hypothesis that penile tumors present distinct etiologies according to virus status.

Mortality trends and prediction of HPV-related cancers in Brazil.

Estimation of the size of a cancer group, either through number of cases or extrapolation of past observed trends, is indispensable to the planning of effective assistance measures. The aim of this study was to analyze the mortality trends of human papillomavirus-related cancers in Brazil by sex, in the period 1996-2010, and make predictions until the year 2025. All deaths registered as being a result of cervical cancer (ICD-10 code: C53), as well as those caused by vulvar and vaginal (C51 and C52), anal (C21), penile (C60), and oropharyngeal (C02, C09, C10) cancers, were registered. Adjusted rate calculations for each year were used to study the trends through the regression program 'Joinpoint'. Predictions were made using the Nordpred program, utilizing the age-period-cohort model. When analyzing separately by location, it was observed that penile and anal cancers in men presented an increasing trend for the entire period with a statistically significant annual percentage change of 4% for anal cancer and 1.4% for penile cancer. Predictions indicate a reduction in the risk of death due to oropharyngeal cancer in men and cervical, vulvar, and vaginal cancers in women. It was observed that the increase in the number of deaths occurs mainly because of population changes (size and age structure). In terms of risk, an increase is predicted for anal and penile cancers in men and consequently an increase in mortality rates is observed for these types of cancers, unlike what is expected for human papillomavirus-related cancers in women.

A clinical, pathologic, and molecular study of p53 and murine double minute 2 in penile carcinogenesis and its relation to prognosis.

Penile carcinoma constitutes up to 16% of male malignancies in developing countries. Changes in the p53 and murine double minute 2 pathway are important events in various cancers. Associate alterations in murine double minute 2 and p53 expression were evaluated by molecular techniques, with the clinical data of 297 cases of penile carcinoma. Automated immunohistochemistry was performed for murine double minute 2 and p53 using the primary antibodies SPM14 and DO7, respectively. Fluorescent in situ hybridization was performed using the probes murine double minute 2 at 12q15 and TP53 at 17p13.1. Slides were digitalized, and bright-field and fluorescent images were analyzed. TP53 was sequenced in 16 cases. The expression of p53 was higher in poorly differentiated, infiltrative border, corpus spongiosum, corpora cavernosa, and invasive urethral carcinomas. Patients who died of disease also expressed higher levels of p53. p53-negative tumors were associated with higher overall survival. Murine double minute 2 showed no difference of expression in any group of tumors, no correlation with p53 expression. No alterations in genes or chromosomes were observed. Mutations in TP53 were observed in 4 of 16 cases: p.T170M, p.L252P, p.C176Y, and the novel c.803_810del8; these changes correlated with p53 expression by immunohistochemistry. Murine double minute 2 is not useful in the prognosis of penile carcinoma by immunohistochemistry. Additional studies on the transcriptional, posttranscriptional, and epigenetic aspects are necessary to understand the interactions between p53 and murine double minute 2 because we did not observe any numeric alterations by fluorescent in situ hybridization. Examining p53 is helpful in identifying patients with more aggressive tumors and may be crucial in selecting the most suitable surgical procedure.

Metastatic tumors to the penis: a report of 17 cases and review of the literature.

This study presents clinicopathologic and outcome features of 17 patients with metastatic tumor to the penis. Primary sites and histological types were as follows: 6 urothelial carcinomas of urinary bladder, 4 prostatic carcinomas (2 adenocarcinomas and 2 adenosquamous carcinomas), 2 colorectal adenocarcinomas, 2 pulmonary carcinomas (1 squamous cell carcinoma and 1 small cell carcinoma), 1 squamous cell carcinoma of base of the tongue, 1 cutaneous malignant melanoma, and 1 acute myeloid leukemia. Literature review revealed similar distribution of organ sites in 437 cases. Most of our tumors were metachronous. Interval between primary and penile metastasis ranged from 3 to 60 months (mean 16 months). Most of the patients presented with a penile mass. Priapism was observed in 4 patients. The shaft was the commonest anatomical site involved (12 cases). Tumor emboli were usually found in the erectile tissues (14 cases), mainly corpora cavernosa. A total of 14 patients died of disseminated disease. Time interval between primary tumor and penile metastasis ranged from 3 to 60 months (mean 19 months) and between diagnosis of penile metastasis and death ranged from 0.25 to 18 months (mean 6 months), significantly shorter (P = .0058). Patients presented a median survival of 18 months from primary treatment and 5 months after diagnosis of penile metastasis. None of the patients who died of disseminated cancer lived more than 18 months after pathological diagnosis. Clinical evidence of penile involvement in a patient with a known malignancy is an ominous sign and should alert the clinicians to the dismal prognosis.