Predictors of local recurrence and its impact on survival after glansectomy for penile cancer: time to challenge the dogma?

OBJECTIVES: To identify predictive pathological factors for local recurrence (LR) and to study the impact of LR on survival in patients treated with glansectomy for penile squamous cell carcinoma (pSCC). PATIENTS AND METHODS: We retrospectively studied patients treated with glansectomy at international, high-volume reference centres. We analysed histopathological predictors of LR, stratified patients into risk groups based on the number of risk factors present, and studied the impact of LR on survival outcomes using Kaplan-Meier survival analysis and stepwise Cox proportional hazards regression models. Subsequently, we performed sensitivity analyses excluding margin-positive cases, pT3 disease, and cN+ disease, or all of these factors. RESULTS: Across nine institutions, 897 patients were included, of whom 94 experienced LR. On multivariable analysis, presence of high-grade disease and pT3 stage were independent predictors of LR. LR-free survival rates significantly differed according to the number of risk factors present, with a hazard ratio (HR) of 1.90 (95% confidence interval [CI] 1.17-3.07; P = 0.01) for the intermediate-risk group (one risk factor) and 6.11 (95% CI 3.47-10.77; P < 0.001) for the high-risk group (two risk factors), using the low-risk group (no risk factors) as reference. Patients who experienced LR had significantly worse overall survival (OS; HR 2.89, 95% CI 2.02-4.14; P < 0.001) and cancer-specific survival (CSS; HR 5.64, 95% CI 3.45-9.22; P < 0.001). LR (HR 3.82, 95% CI 2.14-6.8; P < 0.001), lymphovascular invasion and cN status were significant predictors of decreased CSS. LR remained a strong predictor of both OS and CSS in all sensitivity analyses. CONCLUSIONS: Pathological T3 stage and presence of high-grade disease were independent histopathological predictors of LR after glansectomy for primary pSCC, which allowed risk stratification into three groups with significantly different risk of developing LR. Additionally, LR is related to poor OS and CSS, indicating that LR is a manifestation of underlying aggressive disease and clearly challenging the dogma of using organ-sparing surgery whenever possible since survival is unaffected by higher LR rates.

Penile cancer: potential target for immunotherapy?

PURPOSE: Penile cancer (PeCa) is a rare malignancy with a poor prognosis in advanced disease. There is still a limited understanding of the biological mediators that are important in the prognosis and therapy of the disease. This review aims to provide a summary of the immune micro-environment, molecular oncogenesis and the role of HPV in the disease applying to the potential of the use of immunotherapy. METHODS: Narrative, non-systematic review based on publications retrieved by PubMed and EMBASE search. RESULTS: The molecular mechanisms underlying penile carcinogenesis are complex, and human papillomavirus (HPV) infection is a well-characterized driver of penile cancer. Up to 50% of the penile carcinomas are HPV related. There is potential to improve prevention, treatment and follow-up strategies pertaining to the role of HPV in penile cancer. Immune response modifiers such as toll-like receptor agonists are being used in a topical fashion for penile intraepithelial neoplasia while immune checkpoint inhibitors are currently under clinical investigation for its application in penile cancer. CONCLUSIONS: The knowledge of prognosis-relevant biological pathways in penile cancer is expanding. HPV plays an important role in the carcinogenesis. This can lead to the identification of therapeutic targets which could significantly influence the prognosis of advanced penile cancer. Clinical trials are being conducted to pave the way for immune-modifying treatment modalities.

Making surgery safer by centralization of care: impact of case load in penile cancer.

PURPOSE: Penile cancer is a rare but aggressive disease, often requiring a rapid and extensive surgical treatment of the primary tumor and staging or treatment of the inguinal lymph node basins. Current management and guidelines of the disease are mainly based on retrospective data, as there is a lack of controlled trials or large series. The purpose of this work is to review contemporary data on the impact of centralization and formation of rare disease networks on penile cancer care and outcomes. METHODS: This narrative, non-systematic review is based on publications retrieved by a PubMed and EMBASE search and on the current guidelines of the European Association of Urology, the National Institute for Health and Care Excellence, and the National Comprehensive Cancer network. RESULTS: The low case load, particularly in non-specialized centres, combined with limited evidence regularly results in a disparity between the treatment strategy and the guidelines. The suboptimal guideline adherence is specifically the case for organ-sparing surgery and surgical staging of the groin areas in selected cases. Treatment of the disease in high-volume referral centres has been shown to improve the use of organ-sparing surgery, the utilization of invasive lymph node staging in high-risk patients, and finally has resulted in increased survival rates. CONCLUSIONS: The management of penile cancer in disease networks and in countries where centralized healthcare is offered positively influences functional and oncological outcomes. We propose that governments and health care providers should be encouraged to centralize healthcare for rare tumors such as penile cancer.

Risk factors and molecular characterization of penile cancer: impact on prognosis and potential targets for systemic therapy.

PURPOSE OF REVIEW: To provide a comprehensive summary of risk factors, molecular machinery as well as potential therapeutic targets with a particular focus on literature published in the last 2 years on prognosis and treatment of penile cancer (PeCa). RECENT FINDINGS: E2F, LAMC2, MAML2, ID1 and IGFBP2 proteins were demonstrated to play a critical role for aggressive tumor behavior and might predict poor survival in PeCa. PD-L1 axis was confirmed as a promising pathway to serve as a therapeutic target. A number of genetic alterations were illuminated. In clinical testing, pan-HER tyrosine kinase inhibitor dacomitinib provided promising results in chemo-naïve and EGFR monoantibody nimotuzumab in chemotherapy-failed PeCa patients. SUMMARY: Knowledge of prognosis-relevant altered molecular pathways in PeCa is expanding paving the way for identification of potential therapeutic targets. Multicenter clinical trials in the setting of centralized PeCa care are warranted to foster effective marker-based individualized treatment strategies.

Organ-sparing surgical and nonsurgical modalities in primary penile cancer treatment.

PURPOSE OF REVIEW: To provide an overview of the current state of literature on organ-sparing approaches in penile cancer. Surgical as well as nonsurgical approaches can be adapted in the right setting, in an effort to spare patients from the burden of total or subtotal penectomy wherever possible. In this review, we focus on surgical approaches. RECENT FINDINGS: Narrower surgical margins do not seem to affect overall survival rates, neither do local recurrences. This has allowed a paradigm shift towards more sparing approaches locally. Contrary to what was previously thought, margins of a few millimetres suffice for adequate local cancer control. This allows laser therapy, wide local excisions, partial glansectomy and other surgical techniques to be performed in an organ-sparing fashion. Ablative techniques such as brachytherapy and external beam radiotherapy also provide adequate local cancer control. These sparing approaches have an important effect on psychological and functional outcomes; however, they are insufficiently adapted even in larger referral centres. SUMMARY: Organ-sparing techniques should be used in penile cancer surgery whenever possible. Patient selection for the most appropriate technique is key to provide good cosmetic and functional results while remaining oncologically safe.

Impact of the Standardization of Penile Cancer Care on the Quality of Care, Outcomes, and Academic-driven Centralization in a Single eUROGEN Referral Center.

BACKGROUND: Penile cancer (PeCa) represents a diagnostic and therapeutic challenge given the low patient volume, which may result in inadequate physician expertise and poor guideline adherence. Since 2015, we have developed a specific care pathway for PeCa in our tertiary referral center. OBJECTIVE: To evaluate the impact of a dedicated PeCa care pathway on patient management, the adequacy of pathological reporting, and oncological outcomes. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively queried our institutional registry (S-66482) to identify patients who were surgically treated for PeCa between January 1989 and April 2022. The patient numbers were evaluated within a broader national context. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We compared patient, surgery, tumor, and pathological data before and after 2015. Kaplan-Meier analysis was used to compare local and regional recurrence rates and cancer-specific survival (CSS). RESULTS AND LIMITATIONS: Overall, 313 patients were included, of whom 204 (65.1%) were surgically treated after 2015. The median number of patients treated yearly was significantly higher after 2015 (26 vs 5; p < 0.01). Patients treated after 2015 more frequently had no palpable lymph nodes at diagnosis, despite similar primary tumor stage. After adoption of the PeCa care pathway, organ-sparing surgery (OSS) was more commonly performed (79.9% vs 57.8%; p < 0.01) despite local staging being similar and without observing a significant increase in positive margins. Surgical staging in patients with European Association of Urology intermediate- or high-risk tumors was conducted more frequently after 2015 (90% vs 41%; p < 0.01). Pathology reporting was standardized, and there was more frequent reporting of p16 staining status (81.4% vs 8.3%; p < 0.01), lymphovascular invasion (93.8% vs 44.3%; p < 0.01), and perineural invasion (92.4% vs 44.3%; p < 0.01) following implementation. CONCLUSIONS: Implementation of a standardized care pathway for PeCa resulted in higher rates of OSS and pathological nodal staging and more complete pathology reports. Considering that these changes were associated with an increase in the number of patients treated, academic-driven centralization may play a role in optimizing the management of these patients. PATIENT SUMMARY: We evaluated the impact of a care pathway for patients with penile cancer on patient management, the completeness of pathology reporting, and cancer control. We found that implementation of this pathway was associated with an increase in the number of patients treated, higher rates of organ-sparing surgery and lymph node staging, and more complete pathology reports. Centralization of care may play a role in optimizing the management of penile cancer.