Inguinal lymph node density as a powerful predictor of cancer specific survival in patients with node-positive penile cancer.

INTRODUCTION: Penile cancer (PC) is an aggressive malignancy in which the most important prognostic factor for cancer specific survival (CSS) is the involvement of regional lymph nodes (LNs). Lymph node density (LND) could become a superior prognostic tool for CSS, by accounting for both extent of dissection and nodal disease burden. We aim to validate LND as a prognostic factor for CSS in a contemporary series of patients with PC treated and followed at a single high-volume center, treating more than 25 PC patients per year, over a 13-year period. METHODS: Clinical charts of all patients with PC who underwent surgical treatment between 2007 and 2020 were reviewed. Clinicopathological data was collected and analyzed retrospectively. We only included patients with ≥ 8 LNs removed in a unilateral ILND or ≥16 LNs when a bilateral approach was used. We attempted to find an optimal threshold for LND, capable of maximizing effect difference in terms of CSS and RFS between dichotomized groups. To determine this threshold, we used the chi-squared and the Mann-Whitney tests, and it was required to fulfill the proportional hazards assumption. We assessed different thresholds previously reported in the literature. In our study the optimal threshold for LND was determined to be ≤ 20% Descriptive statistics were used to summarize patient characteristics, CSS and RFS were graphically represented by Kaplan-Meier estimates. Harrell's C index for CSS and RFS were calculated for LND and pN stage, to determine which variable has a superior predictive capacity RESULTS: We identified 110 patients with PC who underwent ILND at our institution, of these, 87 were node-positive and were included in the final analysis. Overall estimates of CSS showed a 3-year CSS of 43% (95% CI: 32-54), the estimated 3-year CSS for the patients with a LND ≤ 20% was 69% (95% CI: 50-82) and 26% (95% CI: 14-39) in the group with a LND >20% (Log-rank P = 0.001). The estimated 3-year RFS for the patients with LND ≤ 20% was 61% (95% CI: 42-76) and 30% (95% CI: 16-44) in the group with a LND >20% (Log-rank P = 0.009). The results of univariate analysis indicate that in patients with a LND >20% the risk for cancer specific mortality was increased (HR 2.68; 95% CI: 1.45-4.98, P =  0.002) compared with LND ≤ 20%. In the and Cox multivariate analysis after Adjusting for age and pN stage the association increased (HR 2.73; 95%, CI 1.38-5.40, P = 0.004). Harrell´s C index for CSS was 0.63 for LND vs. 0.54 for pN stage, suggesting a 9% higher concordance for LND and CSS. CONCLUSIONS: Lymph node density stands as a promising tool for risk-stratifying patients with node-positive PC after ILND. In this retrospective study, LND was a significant predictor of CSS and RFS when using a LND >20% threshold, and also showed a superior predictive ability than pN stage. These results support the use of the LND parameter in clinical practice with a final goal to improve risk stratification, and individualized adjuvant treatment decision-making to patients with high-risk of cancer specific mortality.

Glans Resurfacing with Skin Graft for Penile Cancer: A Step-by-Step Video Presentation of the Technique and Review of the Literature.

INTRODUCTION: Glans resurfacing has been suggested as a treatment option for the surgical management of superficial penile cancer (Tis, Ta, T1aG1, T1aG2). In this article we describe in detail the glans resurfacing technique with skin graft for penile cancer in a video presentation and we review the current knowledge of the literature. MATERIAL AND METHODS: The procedure is described in a stepwise fashion. Initially the patient is circumcised. The glans is marked in quadrants and completely stripped by dissecting and removing the epithelium and subepithelium layer of the glans. Deep spongiosal biopsies are taken to exclude invasion. Each quadrant is sent separately for biopsy. The surface of the graft size needed is estimated. A partial thickness skin graft is harvested from the thigh with a dermatome. The skin graft is then fenestrated. The graft is rolled over the glans and quilted with multiple sutures. A silicone 16F Foley catheter and a suprapubic catheter are placed. The penis is dressed with multiple gauzes and compressed with an elastic band. RESULTS: The patient is discharged the next day. The dressing and Foley catheter are removed in 7 days. The patient continues to use the suprapubic catheter for 7 more days. The patient refrains from any sexual activity for 6 weeks and is closely followed. CONCLUSIONS: Glans resurfacing is an emerging new appealing surgical technique that is already a recommendation in the EAU guidelines for the treatment of premalignant and superficial penile lesions. The overall satisfaction rate and recovery of the sexual function are acceptable, and it can be considered an ideal procedure to treat superficial penile cancer.

Penile metastases of rectal adenocarcinoma after abdominoperineal resection: a case report.

BACKGROUND: Penile metastases are very rare and arise most frequently from genitourinary cancers. Penile metastases from rectal adenocarcinoma are less common. CASE PRESENTATION: We report the case of a 47-year-old North Afican man with penile metastases from a rectal adenocarcinoma, which was discovered 4 months after abdominoperineal resection. A penile biopsy was carried out and established the metastatic nature. He underwent palliative chemotherapy treatment. He was still alive 4 months after diagnosis of penile metastases. CONCLUSION: The prognosis of metastasis to the penis is very poor; the best results have been achieved with surgery but only for lesions where metastasis is limited to the penis.

The Role of Oncogenic DNA Viruses in Penile Cancer Development.

Penile cancer is a relatively rare neoplasia in developed countries, with significant morbidity and mortality in developing countries. Penile cancer can be subdivided into human papillomavirus (HPV)-positive and HPV-negative cases. Worldwide, the HPV prevalence in penile cancer samples is around 50%, and HPV16 is the most prevalent genotype. Although HPV is an important factor for cancer development, other oncogenic factors may be associated with carcinogenesis. Some of these factors can be infectious, such as the Epstein-Barr virus (EBV), as well as the Merkel cell polyomavirus (MCPyV). The prevalence rates of nearly 50% for both HPV and EBV infections indicate an important role of these viruses in penile tissue malignancy, reinforcing the idea of a multifactorial etiology of the disease. Although the HPV role is better understood, EBV is thought to facilitate persistence, integration, and mutations. Recent studies on the Merkel cell polyomavirus have not shown a relevant prevalence in penile cancer samples, but its presence indicates the opportunistic infectious potential of this virus. Regarding HPV-negative cases, the literature suggests a link with younger age and epigenetic alterations, mainly through the p16INK4a pathway. Recently, several biomarkers that might act as prognostic tools (e.g., Ki-67, squamous cell carcinoma antigen, among others) have been proposed, but the results remain controversial. In addition, other risk factors have also been associated with penile carcinogenesis, such as the presence of phimosis, noncircumcision, chronic inflammation, and number of sexual partners. Further studies are needed to develop tools for early detection and epidemiological surveillance of penile cancer.

Prognostic Significance of HPV and p16 Status in Men Diagnosed with Penile Cancer: A Systematic Review and Meta-analysis.

It has been shown that human papillomavirus (HPV) and p16 status has prognostic value in some HPV-associated cancers. However, studies examining survival in men with penile cancer according to HPV or p16 status are often inconclusive, mainly because of small study populations. The aim of this systematic review and meta-analysis was to examine the association between HPV DNA and p16 status and survival in men diagnosed with penile cancer. Multiple electronic databases were searched. Twenty studies were ultimately included and study-specific and pooled HRs of overall survival and disease-specific survival (DSS) were calculated using a fixed effects model. In the analysis of DSS, we included 649 men with penile cancer tested for HPV (27% were HPV-positive) and 404 men tested for p16 expression (47% were p16-positive). The pooled HRHPV of DSS was 0.61 [95% confidence interval (CI), 0.38-0.98], and the pooled HRp16 of DSS was 0.45 (95% CI, 0.30-0.69). In conclusion, men with HPV or p16-positive penile cancer have a significantly more favorable DSS compared with men with HPV or p16-negative penile cancer. These findings point to the possible clinical value of HPV and p16 testing when planning the most optimal management and follow-up strategy. Cancer Epidemiol Biomarkers Prev; 27(10); 1123-32. ©2018 AACR.

A Comparative study of two types of organ-sparing surgeries for early stage penile cancer: Wide local excision vs partial penectomy.

INTRODUCTION: Till date, there have been few reports of comparative studies on the outcomes of these different treatment modalities. In this study, we have aimed to comparatively evaluate the quality-of-life parameters, including sexual function, urinary function, and health-related quality of life (HRQOL), in patients with early stage penile cancers who underwent two different organ-sparing surgeries. MATERIAL AND METHODS: From March 2012 to March 2015, we enrolled 15 patients with early stage penile cancers who underwent either wide local excision or partial penectomy as organ-sparing surgical treatments. We assessed their sexual and urinary functions and their HRQOL, using the International Index of Erectile Function (IIEF-15), Self-Esteem and Relationship (SEAR), and Erectile Dysfunction Inventory of Treatment Satisfaction (EDITS) questionnaires and urodynamic determinations, and comparatively analyzed the outcomes of these patients who underwent either type of surgery. RESULTS: All patients who underwent these two types of surgeries experienced satisfactory outcomes. The patients who underwent wide local excision performed relatively better, in terms of their sexual functions, urinary functions, and HRQOL, but no statistically significant differences were observed in the data collected via the IIEF-15, SEAR, EDITS, and EORTC-QLQ-C30 questionnaires and urodynamic determinations (p > 0.05), except in the data corresponding to the orgasmic function (p = 0.033). CONCLUSION: Both types of organ-sparing surgeries assessed in this study achieved good outcomes, in terms of the aesthetics, sexual functions, urinary functions, and HRQOL in patients, without compromising the therapeutic effects of these surgeries. However, the observed decreases in orgasmic function will need to be addressed further.

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.

Sexual Function after Partial Penectomy: A Prospectively Study From China.

The Purpose of this study was to evaluate the sexual function after partial penectomy for penile carcinoma patients. Between January 2010 and May 2013, patients treated with partial penectomy at our institution were prospectively enrolled in this study. Sexual function (IIEF-15), age, body mass index, penile length in the flaccid state after partial penectomy (PL), treatment, having a partner and psychological factors (SAS scores and SDS scores) were assessed. Univariate and multivariate linear regression analyses were performed. 43 patients were included in our study. The median age was 56 years, and the median PL was 4 cm. The preoperative IIEF-15, SAS, SDS scores were significantly different from the postoperative scores. There was no statistically significant difference between the patients treated with partial penectomy and partial penectomy+ lymphadenectomy on IIEF-15 scores. Age was negatively associated with erectile function, sexual desire, and overall satisfaction; PL was positively associated with intercourse satisfaction; SAS score was negatively associated with erectile function, orgasmic function, sexual desire, and intercourse satisfaction. Our preliminary findings suggest that the sexual function after partial penectomy was significantly reduced. The sexual function was negatively affected by age and anxiety but positively affected by PL.

Establishment and characterization of primary cell lines of squamous cell carcinoma of the penis and its metastasis.

PURPOSE: We established cell lines from penile squamous cell carcinoma and its lymph node metastasis, and investigated the role of chemokines, chemokine receptors and podoplanin in cancer progression. MATERIALS AND METHODS: Tumor specimen of primary tumors, and lymph node and distant metastases were cultured in vitro and xenotransplanted in SCID beige mice. Specimens were analyzed by hematoxylin and eosin staining, and immunohistochemistry. Comparative screening for chemokines, chemokine receptors and podoplanin was done by polymerase chain reaction, fluorescence activated cell sorting and enzyme-linked immunosorbent assay. RESULTS: We established 2 cell lines from a primary tumor and its corresponding lymph node metastasis, respectively. Heterotopic xenotransplantation revealed reliable tumor growth in vivo. Morphological and immunohistological analysis showed comparable features for human tumors, cell lines in vitro and xenotransplanted tumors in mice regarding the primary tumor and metastasis. Comprehensive analysis of chemokines and chemokine receptors in the metastasis derived cell line and in the cell line originating from the primary tumor revealed the most pronounced changes for CXCL14. This pattern was confirmed on the protein level. Comparative analysis of podoplanin showed marked down-regulation in the metastatic variant on the mRNA and protein levels. CONCLUSIONS: To our knowledge we established the first pair of cell lines of a human primary penile tumor and the corresponding lymph node metastasis. These cell lines offer unique possibilities for further comparative functional investigations in in vitro and in vivo settings. They enable studies of new potential therapeutic agents and other assays to better understand the molecular mechanisms of penile cancer progression.

The role of annexins I, II and IV in tumor development, progression and metastasis of human penile squamous cell carcinomas.

PURPOSE: The outcome of patients with penile squamous cell carcinomas (PSCC) largely depends on occurrence of metastasis. Therefore, prognostic markers indicating the risk for tumor cell spreading would be useful. Since Annexins are potential prognostic markers in a variety of tumors, we immunohistochemically examined the expression of Annexins I, II and IV (ANX AI, ANX AII and ANX AIV) in PSCC. METHODS: Samples originated from 29 patients subjected to surgical resection of invasive PSCC. Immunohistochemistry was done on paraffin-embedded sections using monoclonal antibodies against ANX AI, ANX AII and ANX AIV. Expression of ANXs was compared with clinical data. RESULTS: ANX AI expression was found in conventional PSCC and was absent in basaloid and sarcomatoid subtypes. High ANX AI score was significantly associated with higher T stages (P = 0.006). Strong expression in the invasion front of carcinomas was significantly associated with the occurrence of lymph node metastasis (P = 0.001). ANX AIV expression was weak in conventional PSCC, while it was strong in basaloid and sarcomatoid subtypes. Strong expression of Annnexin IV in the invasion front also showed a significant association with metastasis (P = 0.019). CONCLUSION: Expression of ANXs was different in histologic subtypes of penile carcinomas. Strong expression of ANX AI and ANX AIV in the invasion front seems to indicate a higher risk of lymph node metastasis.

Activity and toxicity of paclitaxel in pretreated metastatic penile cancer patients.

The objective of this study was to evaluate the use of paclitaxel in patients with advanced squamous cell penile cancer previously treated with neoadjuvant cisplatin-based chemotherapy. This was a single-arm, phase II, multicenter study. Patients were treated with 175 mg/m paclitaxel at a 3-week interval, until disease progression or irreversible toxicity. The primary end point was the objective response rate. Secondary end points were safety, progression-free survival, and overall survival. Twelve patients were enrolled. Partial responses were observed in 25% (3 of 12) of patients (95% confidence interval: 12-40%). Grade 3 neutropenia and oral mucositis were the most common side effects, each noted in three patients. Median progression-free survival was 4 months (range 2-6 months) and median overall survival was 6 months (range 3-10 months). Paclitaxel is well tolerated and associated with promising efficacy. Further trials, also in a neoadjuvant setting, are needed to corroborate our preliminary findings.

La terapia fotodinámica en urología. Mecanismos de acción biológicos y patológicos / Photodynamic therapy in urology. Biologic and pathologic mechanisms of action

La Terapia Fotodinámica (TFD) es una modalidad terapéutica mínimamente invasiva y de extraordinaria utilidad. En Urología, la TFD, es muy útil y puede ser aplicada mediante endoscopia o directamente, habiéndose obtenido excelentes resultados en el diagnóstico y tratamiento de lesiones tumorales de vejiga, en el tratamiento de carcinoma de próstata y de sus recidivas y en el tratamiento de lesiones dermatológicas precancerosas y tumorales del pene. La TFD se fundamenta en el uso de compuestos fotosensibilizadores (FSs) que se acumulan selectivamente en los tejidos tumorales. La irradiación posterior de éstos tejidos con luz de longitud de onda apropiada (generalmente de la región del rojo del espectro visible λ > 600nm) produce la formación de especies reactivas de oxígeno (ROS) con efectos citotóxicos, que conducen a la muerte selectiva de las células neoplásicas y en consecuencia a la regresión del tumor. La principal ventaja de la TFD es que el daño celular queda restringido a la zona irradiada, con la consiguiente disminución de efectos secundarios sobre los tejidos sanos próximos al tumor, al contrario de lo que ocurre con otras terapias convencionales de algunos tumores del tracto urinario. Además, la TFD puede utilizarse en combinación con radioterapia y quimioterapia (AU)

Photodynamic Therapy (FDT) is a minimally invasive therapeutic modality extraordinarily useful. In urology, FDT is very useful and may be applied through endoscopes or directly, with excellent results obtained for the diagnosis and treatment of bladder tumors, in the treatment of prostate cancer and its recurrences, and in the treatment of dermatological premalignant lesions and carcinomas of the penis. FDT is founded on the use of photosensitizing products which selectively accumulate in tumor tissues. The irradiation of these tissues with a proper wavelength light (generally in the red region of the visible spectrum λ > 600nm) produces the formation of oxygen reactive species with cytotoxic effects leading to selective death of neoplastic cells, and tumor regression. The main advantage of FDT is the restriction of cellular damage to the irradiation area, with the associated decrease of secondary effects on healthy tissues near the tumor, on the contrary to what happen with other conventional therapies for some tumors of the urinary tract. Moreover, FDT may be used in combination with radiotherapy and chemotherapy (AU)

Multiple penile schwannomas.

The occurrence of penile schwannoma is very rare. A 41-year-old man presented with multiple penile tumors and pain on erection. The largest tumor causing pain was excised. Pathology was characteristic of benign schwannoma. We recommend that penile schwannomas be excised if the tumors cause pain or are malignant.

Metastatic penile carcinomas : a study of nine cases and review of the literature

Objective: Primary penile carcinoma is one of the rarest male genital tract tumors in Turkey; because circumcision is performed routinely. In general; metastatic carcinoma of the penis is the second most common penile tumor. Despite the fact that the penis is rarely affected by metastases; there have been 319 cases reported in the literature. This study was carried out to throw light on the main characteristics of the metastatic disease. Patients and Methods: Nine patients aged between 32 and 68 years (median 62.9 years) with metastatic tumors of the penis were the subject of this study. The clinical history of the cases was reviewed; and the patients' data were recorded including location; histology of the primary tumor; presence and location of other metastases; clinical findings; treatment and outcome. The microscopic preparations from both the primary tumor and the penile metastases were reviewed in our pathology department to confirm that the penile lesions showed the same histomorphological characteristics as the primary tumor. Results: The primary tumors were located in the genitourinary system in 7 / 9 patients(transitional cell carcinoma of the bladder); while in the remaining two patients the primary site was the lung (squamous cell carcinoma) and the bone marrow (lymphoblastic leukemia); respectively. Percutaneous needle aspiration cytology was performed in all cases and incisional biopsy in one case for diagnosis. Total penectomy was the treatment of choice in 7 cases and bilateral cavernotomy in the leukemia case. No treatment was given to one patient because of multiple metastases in other organs. Survival after treatment lasted from 4 months to 62 months; the longest survival (5 years) was found in the leukemia case. Conclusion: Metastatic penile carcinomas are relatively rare and present a challenging problem. Total penectomy and local excision of solitary nodules or distal penile involvement still represent the treatment of choice. However; because of the association of a penile metastatic lesion with advanced disease; survival rates are limited; and the majority of the patients die within one year

Invasive penile carcinoma: a review.

BACKGROUND: Penile carcinoma is an invasive epithelial tumor that may arise from penile skin or mucosa. OBJECTIVE: To review the pathogenesis and the clinical and histopathologic features of invasive penile carcinomas, with emphasis on current guidelines for their diagnosis and treatment. METHODS: Information available from the authors' clinical experience, review articles, case reports, clinical trials, and in vitro research studies identified from a computerized literature search on MEDLINE database and from Meetings' Abstract Books, including those from non-English literature, was considered. RESULTS: Penile cancer may develop de novo or in association with underlying factors. Conditions predisposing to the development of penile cancer are delineated. The diagnosis should be suspected by clinical findings and must be confirmed histologically. Imaging techniques may be useful for staging and planning therapy. Therapeutic options include excisional surgery, laser destruction, cryosurgery, radiotherapy, immunotherapy, and chemotherapy. CONCLUSIONS: Although there are no current guidelines for the treatment of penile carcinoma, surgical ablation probably represents the best option, as conservative treatments still deserve cautious evaluation because of the relatively small number of treated patients and the lack of good-quality comparative data. Regarding indications for lymph nodal dissection in patients showing no inguinal node enlargement, sentinel node mapping with targeted lymph node dissection is recommended for those with deeply invasive, high-grade tumors, whereas a watchful waiting may be advised for those with superficially invasive, low-grade tumors.