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.

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.

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.

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.

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.

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.

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.

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.

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.

Determination of telomerase activity in squamous cell carcinoma of the penis.

Telomerase activity was studied in 51 penile carcinomas, and detected in all samples from 3 patients with verrucous carcinoma, in 85.4% (41/48) of invasive carcinomas, in 81.8% (9/11) of adjacent non-cancerous skin and in 80% (8/10) of adjacent non-cancerous corpus cavernosum. All skin and corpus cavernosum samples from patients with prostatic carcinoma were found to be telomerase negative. Our results indicate a correlation between frequency of telomerase activity and grade of penile carcinoma. The finding of telomerase activity in skin and corpus cavernosum samples adjacent to tumor suggests that unidentified local factors may modulate telomerase activity in normal tissues.

Inguinal lymphadenectomy and primary groin reconstruction using rectus abdominis muscle flaps in patients with penile cancer.

OBJECTIVES: The use of deep inferior epigastric artery (DIEA) rectus abdominis muscle flaps in conjunction with inguinal lymphadenectomy to treat patients with squamous cell carcinoma (SCC) of the penis having high-volume inguinal lymph node metastases causing skin breakdown and secondary infection is described. METHODS: Three patients with invasive SCC of the penis who had extensive unilateral inguinal nodal metastases with skin breakdown and secondary infection underwent pelvic lymphadenectomy and attempted wide resection of the superficial and deep inguinal lymph nodes. One patient had unresectable deep inguinal metastases and received postoperative radiation therapy. A DIEA rectus abdominis muscle flap was utilized to close the resulting groin defect. RESULTS: Pathologic analysis demonstrated no pelvic lymph node metastases in any of the patients, superficial inguinal lymph node metastases in 1, and superficial and deep inguinal lymph node involvement in 2. All wounds healed well. The 2 patients with deep inguinal metastases experienced local disease progression. One patient died 7 months postoperatively of complications from chronic renal failure but had no evidence of tumor recurrence or wound problems. Another patient died of recurrent disease. CONCLUSIONS: A rectus abdominis muscle flap may be a useful adjunct for managing certain patients with penile cancer and extensive suppurative inguinal lymph node metastases.

[Erectile function and ablative surgery of penile tumors]. / Funzione erettile e chirurgia demolitiva nei tumori del pene.

The Authors try to show the possibility to combine radical excision with minimal invasiveness in the surgery of penile cancer. The focal point of every therapeutic decision is correct clinical staging. Unfortunately there's some confusion in the two international staging systems (TNM and Jackson's classification). In fact it's not clear the anatomical difference between epithelioma of the glans infiltrating corpus spongiosum and subcoronary epithelioma of the shaft infiltrating the corpora cavernosa. It's obvious that the infiltration of the corpora cavernosa is a far more aggressive oncological manifestation than that of tumour infiltrating the corpus spongiosum. So we consider Jackson's classification more congenial. In terms of surgery this anatomical independence makes it easy to consider the corpora cavernosa as a distinct entity, so they remain perfectly functional when separated from the glandulo-spongio-urethral unit with its vasculo-nervous bundle. This makes conservation of the erectile function, when clinical staging show us that the tumour is not infiltrating the corpora cavernosa. The Authors show their results, which seem to be rather good.

Counseling after resection of the penis.

Surgery is the most effective means of controlling or curing cancer of the penis, but management of a patient with penile cancer encompasses more than excising the lesion. Anticipatory guidance and counseling are required components of total patient care. An integral part of counseling is psychotherapy, including marital and sex therapy. This comprehensive management program is best provided by a team of health care professionals including the family physician.