RESUMO
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.
Assuntos
Biomarcadores Tumorais , Ciclina D1 , Neoplasias Penianas , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Pessoa de Meia-Idade , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/genética , Brasil/epidemiologia , Ciclina D1/metabolismo , Ciclina D1/genética , Intervalo Livre de Doença , Imuno-Histoquímica , Infecções por Papillomavirus/virologia , Infecções por Papillomavirus/metabolismo , Neoplasias Penianas/genética , Neoplasias Penianas/patologia , Neoplasias Penianas/virologia , PrognósticoRESUMO
Rare sarcomas present significant treatment challenges compared to more prevalent soft tissue sarcomas due to limited treatment options and a poor understanding of their biology. This study investigates a unique case of penile sarcoma, providing a comprehensive morphological and molecular analysis. Through the creation of experimental patient-derived models-including patient-derived xenograft (PDX), 3D, and monolayer primary cultures-we successfully replicated crucial molecular traits observed in the patient's tumor, such as smooth muscle actin and CD99 expression, along with specific mutations in genes like TSC2 and FGFR4. These models are helpful in assessing the potential for an in-depth exploration of this tumor's biology. This comprehensive approach holds promise in identifying potential therapeutic avenues for managing this exceedingly rare soft tissue sarcoma.
Assuntos
Sarcoma , Animais , Humanos , Masculino , Camundongos , Mutação , Neoplasias Penianas/genética , Neoplasias Penianas/patologia , Sarcoma/genética , Sarcoma/patologia , Proteína 2 do Complexo Esclerose Tuberosa/genética , Pessoa de Meia-IdadeRESUMO
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.
Assuntos
Carcinoma de Células Escamosas , Neoplasias Penianas , Masculino , Humanos , Pessoa de Meia-Idade , Neoplasias Penianas/epidemiologia , Neoplasias Penianas/cirurgia , Neoplasias Penianas/patologia , Brasil/epidemiologia , Estudos Transversais , Carcinoma de Células Escamosas/epidemiologia , Carcinoma de Células Escamosas/cirurgia , Estudos Retrospectivos , Estadiamento de NeoplasiasRESUMO
OBJECTIVE: To report outcomes from the largest multicenter series of penile cancer patients undergoing video endoscopic inguinal lymphadenectomy (VEIL). MATERIALS AND METHODS: Retrospective multicenter analysis. Authors of 21 centers from the Penile Cancer Collaborative Coalition-Latin America (PeC-LA) were included. All centers performed the procedure following the same previously described standardized technique. Inclusion criteria included penile cancer patients with no palpable lymph nodes and intermediate/high-risk disease and those with non-fixed palpable lymph nodes less than 4 cm in diameter. Categorical variables are shown as percentages and frequencies whereas continuous variables as mean and range. RESULTS: From 2006 to 2020, 210 VEIL procedures were performed in 105 patients. Mean age was 58 (45-68) years old. Mean operative time was 90 minutes (60-120). Mean lymph node yield was 10 nodes (6-16). Complication rate was 15.7%, including severe complications in 1.9% of procedures. Lymphatic and skin complications were noted in 8.6 and 4.8% of patients, respectively. Histopathological analysis revealed lymph node involvement in 26.7% of patients with non-palpable nodes. Inguinal recurrence was observed in 2.8% of patients. 10y- overall survival was 74.2% and 10-y cancer specific survival was 84.8%. CSS for pN0, pN1, pN2 and pN3 were 100%, 82.4%, 72.7% and 9.1%, respectively. CONCLUSION: VEIL seems to offer appropriate long term oncological control with minimal morbidity. In the absence of non-invasive stratification measures such as dynamic sentinel node biopsy, VEIL emerged as the alternative for the management of non-bulky lymph nodes in penile cancer.
Assuntos
Neoplasias Penianas , Cirurgia Vídeoassistida , Idoso , Humanos , Masculino , Pessoa de Meia-Idade , Canal Inguinal/cirurgia , Canal Inguinal/patologia , Excisão de Linfonodo/métodos , Linfonodos/patologia , Neoplasias Penianas/cirurgia , Neoplasias Penianas/patologia , Resultado do Tratamento , Cirurgia Vídeoassistida/métodos , Estudos RetrospectivosRESUMO
There are few pathologic or molecular studies of penile precancerous lesions, and the majority refers to lesions associated with invasive carcinomas. Penile Intraepithelial Neoplasia (PeIN) is classified in two morphologically and distinctive molecular groups, non-HPV and HPV-related with special subtypes. The primary purpose of this international series was to classify PeIN morphologically, detect HPV genotypes and determine their distribution according to PeIN subtypes. A secondary aim was to evaluate the p16INK4a immunostaining as a possible HPV surrogate for high-risk HPV infection in penile precancerous lesions. Samples consisted of 84 PeIN cases, part of a retrospective cross-sectional analysis of 1095 penile carcinomas designed to estimate the HPV DNA prevalence in penile cancers using PCR and p16INK4a immunostaining. Penile Intraepithelial Neoplasia (PeIN) was classified in HPV-related (basaloid, warty-basaloid, warty, hybrid, and mixed subtypes) and non-HPV-related (differentiated), the former being the most frequent. PeIN subtypes were differentiated (non-HPV-related) and basaloid, warty-basaloid, warty, hybrid and mixed (HPV-related). Basaloid PeIN was the most commonly diagnosed subtype, and HPV16 was the most frequent HPV genotype detected. Warty-basaloid and warty PeIN showed a more heterogeneous genotypic composition. Most HPV genotypes were high-risk but low-risk HPV genotypes were also present in a few cases (4%). A single HPV genotype was detected in 82% of HPV positive cases. In contrast, multiple genotypes were detected in the remaining 18% of cases. The findings in this study support the paradigm that penile in situ neoplasia, like its invasive counterparts, is HPV dependent or independent and has distinctive morphological subtypes readily identified in routine practice. Considering that HPV16 is clearly the predominant type, and that the three available vaccines have HPV16, all of them will be suitable for vaccination programs; the price of the vaccines will be probably the main determinant to choose the vaccine.
Assuntos
Carcinoma in Situ , Carcinoma de Células Escamosas , Papiloma , Infecções por Papillomavirus , Neoplasias Penianas , Lesões Pré-Cancerosas , Neoplasias Cutâneas , Masculino , Humanos , Neoplasias Penianas/patologia , Inibidor p16 de Quinase Dependente de Ciclina/genética , Carcinoma in Situ/patologia , Estudos Transversais , Estudos Retrospectivos , Carcinoma de Células Escamosas/patologia , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/patologia , Neoplasias Cutâneas/complicações , Genótipo , Papillomaviridae/genéticaRESUMO
PURPOSE: Penile cancer has a high incidence in developing countries. The standard treatment is removal of the primary tumor and, when necessary, inguinal lymphadenectomy. Currently, the most important prognostic factor is lymph node disease, however, the available staging methods are inaccurate, and the high morbidity rate of lymphadenectomy has stimulated the study of predictive biomarkers of lymph node metastasis for selecting the patients who need lymphadenectomy. SOX2, STAT3 and CD44high/CD24low were chosen because they have provided good predictive results in other squamous cell carcinoma (SCC), although there are no studies for penile cancer. Thus, the expression of SOX2, STAT3, CD24+, and CD44+ in the penile cancer tumor microenvironment was investigated for correlation with tumor behavior in SCC. METHODS: This observational, prospective, translational study included 34 men and investigated the expression of SOX2, STAT3, CD24+, and CD44+ in tumor tissue by flow cytometry. RESULTS: The median age of the 38 evaluated patients with penile cancer was 61 (37-80) years. Most patients presented a tumor located on the glans penis (82.3%), with the usual histological type (79.4%) and 61.7% of patients presented stage pT2. No metastasis was found in 85.3% of patients. The expression of SOX2, STAT3 and CD44high/CD24low in the microenvironment of penile SCC treated with lymphadenectomy was significantly associated with aggressive tumor behavior (p < 0.05). STAT3 expression shows discrepant points when evaluated in context of angiolymphatic vascular invasion. CONCLUSION: SOX2, STAT3 and CD44high/CD24low in penile SCC can be indicators of prognosis, allowing for selection of more aggressive treatment when necessary.
Assuntos
Carcinoma de Células Escamosas , Neoplasias Penianas , Masculino , Humanos , Pessoa de Meia-Idade , Idoso , Idoso de 80 Anos ou mais , Prognóstico , Neoplasias Penianas/cirurgia , Neoplasias Penianas/patologia , Estudos Prospectivos , Receptores de Hialuronatos/metabolismo , Biomarcadores , Carcinoma de Células Escamosas/patologia , Antígeno CD24 , Microambiente Tumoral , Fator de Transcrição STAT3/metabolismo , Fatores de Transcrição SOXB1/metabolismoRESUMO
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.
Assuntos
Infecções por Papillomavirus , Neoplasias Penianas , Anticorpos Monoclonais/metabolismo , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Humanos , Incidência , Antígeno Ki-67/genética , Antígeno Ki-67/metabolismo , Masculino , Papillomaviridae/metabolismo , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/epidemiologia , Neoplasias Penianas/epidemiologia , Neoplasias Penianas/patologia , Prognóstico , Estudos Retrospectivos , Proteína Supressora de Tumor p53/genéticaRESUMO
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.
Assuntos
Alphapapillomavirus , Carcinoma de Células Escamosas , Infecções por Papillomavirus , Neoplasias Penianas , Masculino , Humanos , Neoplasias Penianas/genética , Neoplasias Penianas/epidemiologia , Neoplasias Penianas/patologia , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/genética , Infecções por Papillomavirus/epidemiologia , Inibidor p16 de Quinase Dependente de Ciclina/genética , Prognóstico , 5-Metilcitosina , Metilação de DNA , Recidiva Local de Neoplasia/genética , Papillomaviridae/genética , Carcinoma de Células Escamosas/metabolismo , Alphapapillomavirus/genética , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Epigênese Genética , DNA ViralRESUMO
Penile cancer (PeC) is a rare disease, and no prognostic biomarkers have been adopted in clinical practice yet. The objective of the present study was to identify differentially expressed miRNAs (DEmiRs) and genes (DEGs) as potential biomarkers for lymph node metastasis and other prognostic factors in PeC. Tumor samples were prospectively obtained from 24 patients with squamous cell carcinoma of the penis. miRNA microarray analysis was performed comparing tumors from patients with inguinal lymph node metastatic and localized disease, and the results were validated by qRT-PCR. Eighty-three gene expression levels were also compared between groups through qRT-PCR. Moreover, DEmiRs and DEGs expression levels were correlated with clinicopathological variables, cancer-specific (CSS), and overall survival (OS). TAC software, TM4 MeV 4.9 software, SPSS v.25.0, and R software v.4.0.2 were used for statistical analyses. We identified 21 DEmiRs in microarray analysis, and seven were selected for validation. miR-744-5p and miR-421 were overexpressed in tissue samples of metastatic patients, and high expression of miR-421 was also associated with lower OS. We found seven DEGs (CCND1, EGFR, ENTPD5, HOXA10, IGF1R, MYC, and SNAI2) related to metastatic disease. A significant association was found between increased MMP1 expression and tumor size, grade, pathological T stage, and perineural invasion. Other genes were also associated with clinicopathological variables, CSS and OS. Finally, we found changes in mRNA-miRNA regulation that contribute to understanding the mechanisms involved in tumor progression. Therefore, we identified miRNA and mRNA expression profiles as potential biomarkers associated with lymph node metastasis and prognosis in PeC, in addition to disruption in mRNA-miRNA regulation during disease progression.
Assuntos
Carcinoma de Células Escamosas , MicroRNAs , Neoplasias Penianas , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Perfilação da Expressão Gênica/métodos , Regulação Neoplásica da Expressão Gênica , Humanos , Metástase Linfática , Masculino , MicroRNAs/genética , MicroRNAs/metabolismo , Neoplasias Penianas/genética , Neoplasias Penianas/patologia , RNA Mensageiro/genéticaRESUMO
ABSTRACT Purpose: To determine independent predictors of inguinal lymph node (ILN) metastasis in patients with penile cancer. Patients and methods: We retrospectively analyzed all patients with penile cancer who underwent surgery at our medical center in the last ten years (n=157). Using univariate and multivariate logistic-regression models, we assessed associations with age, medical-history, phimosis, onset-time, number and maximum diameter of involved ILNs measured by imaging, pathological T stage, degree of tumor differentiation and/or cornification, lymphatic vascular infiltration (LVI), nerve infiltration, and ILN metastases. Interaction and stratified analyses were used to assess age, phimosis, onset time, number of ILNs, cornification, and nerve infiltration. Results: A total of 110 patients were included in the study. Multiple logistic regression analysis showed that the following factors were significantly correlated with ILN metastasis: maximum diameter of enlarged ILNs, T stage, pathological differentiation, and LVI. Among patients with a maximum ILN diameter ≥1.5cm, 50% had lymph node metastasis whereas 30.6% patients with a maximum ILN diameter <1.5cm showed LNM. Among 44 patients with stage Ta/T1, 10 showed ILN metastases, while 47.0% patients with stage T2 showed ILN metastases. Among 40 patients with highly differentiated penile-cancer, eight showed ILN metastasis, while 47.1% patients with low-to-middle differentiation showed ILN metastases. The rate of LNM was 33.3% in the LVI-free group and 64.3% in the LVI group. Conclusion: Our single-center results suggested that maximum ILN diameter, pathological T stage, pathological differentiation, and LVI were independent risk factors for ILN metastases.