Minimally Invasive Management of Inguinal Lymph Nodes in Penile Cancer: Recent Progress and Remaining Challenges.

The diagnosis of occult inguinal lymph node metastasis in clinically node-negative invasive penile squamous cell carcinoma (PSCC) has remained a challenge, with substantial perioperative complications. The recent refinements in the technique of dynamic sentinel lymph node biopsy (DSLNB) demonstrated high diagnostic accuracy with considerably lower morbidity compared to conventional open modified/superficial inguinal lymph node dissection (ILND). Although DSLNB, if available, has been endorsed as the preferred method for nodal staging in patients with invasive PSCC and no palpable inguinal lymphadenopathy in the recent penile cancer guidelines, its utilization has been quite limited so far. Laparoscopic and robotic-assisted ILND have emerged as alternatives for nodal staging in this patient population and are shown to improve the rate of wound infections and postoperative pain. For management of nodal metastasis in patients with clinically palpable inguinal lymph nodes, minimally invasive ILND has shown promising results as well. Nonetheless, given the rarity of PSCC and the absence of prospective studies and clinical trials, nodal staging and treatment of nodal metastasis in clinical practice will likely continue to vary across the medical centers in the following years. In this review, we first summarize the evolution of DSLNB and minimally invasive ILND and discuss the advantages and drawbacks of each management strategy. We further discuss the remaining challenges and future perspectives in the management of inguinal lymph nodes in patients with PSCC.

Molecular characterization of metastatic penile squamous cell carcinoma in developing countries and its impact on clinical outcomes: LACOG 2018 translational study.

BACKGROUND: Penile squamous cell carcinoma (PSCC) is a rare malignancy. However, in developing countries the incidence rate is higher. The understanding of molecular alterations is essential for evaluating possible targets for more effective systemic therapies. METHODS: We retrospectively collected clinical data of metastatic PSCC (mPSCC) patients who had received at least one prior systemic treatment from 3 Brazilian hospitals. Tumor samples were evaluated using the next-generation sequencing (NGS) Foundation One DX and immunohistochemistry (IHC). The objective was to identify and describe somatic genomic alterations known to be functional or pathogenic and their association with survival outcomes. RESULTS: Twenty-three patients were identified, 22 and 18 patients had tumor samples analyzed by IHC and NGS, respectively. PD-L1 expression (CPS ≥ 1%) was positive in 14 patients (63.6%). Regarding the genomic alterations, 16 patients (88.9%) had some clinically relevant genomic alterations. TP53, TERT, CDKN2A, PIK3CA, NOTCH1, and CDKN2B loss were identified in 66.7%, 50%, 50%, 33.3%, 27.8%, and 22.2% of the patients, respectively. No MSI or TMB high (≥10 mutations/MB) cases were identified. NOTCH1 mutation was identified only in HPV-negative patients and it was associated with worse OS (yes: 5.5 vs no: 12.8 months, P = .049) and progression-free survival (yes: 5.5 vs no: 11.7 months, P = .032). CONCLUSION: This study demonstrated that molecular alterations in mPSCC from developing countries are similar to those from developed countries. Predictive biomarkers for immunotherapy response such as TMB high or MSI were not identified. Specific gene mutations may identify patients with worse prognoses and open new avenues for therapeutic development.

Bladder-sparing Therapy for Bacillus Calmette-Guérin-unresponsive Non-muscle-invasive Bladder Cancer: International Bladder Cancer Group Recommendations for Optimal Sequencing and Patient Selection.

BACKGROUND AND OBJECTIVE: There has been a recent surge in the development of agents for bacillus Calmette-Guérin-unresponsive (BCG-U) non-muscle-invasive bladder cancer (NMIBC). Critical assessment of these agents and practical recommendations for optimal selection of patients and therapies are urgently needed, especially in the absence of randomized trials on bladder-sparing treatment (BST) options. METHODS: A global committee of bladder cancer experts was assembled to develop recommendations on BST for BCG-U NMIBC. Working groups reviewed the literature and developed draft recommendations, which were then voted on by International Bladder Cancer Group (IBCG) members using a modified Delphi process. During a live meeting in August 2023, voting results and supporting evidence were presented, and recommendations were refined on the basis of meeting discussions. Final recommendations achieved >75% agreement during the meeting, and some were further refined via web conferences and e-mail discussions. KEY FINDINGS AND LIMITATIONS: There is currently no single optimal agent for patients with BCG-U disease who seek to avoid radical cystectomy (RC). BST selection should be personalized, taking into account individual patient characteristics and preferences, tumor attributes, and efficacy/toxicity data for the agents available. For patients with BCG-U carcinoma in situ (CIS), gemcitabine/docetaxel (GEM/DOCE), nadofaragene firadenovec (NFF), and nogapendekin alfa inbakicept-pmln (NAI) + BCG are recommended; because of its systemic toxicity, pembrolizumab should only be offered after other options are exhausted. For patients with BCG-U papillary-only tumors, GEM/DOCE, NFF, NAI + BCG, single-agent chemotherapy, hyperthermic mitomycin C, and pembrolizumab are recommended. Given the modest efficacy of available options, clinical trial participation is encouraged. For unapproved agents with reported data, IBCG recommendations await the final results of pivotal trials. CONCLUSIONS AND CLINICAL IMPLICATIONS: The IBCG consensus recommendations provide practical guidance on BST for BCG-U NMIBC.

Urachal and Nonurachal Adenocarcinomas of the Urinary Bladder: A Comprehensive Genomic Profiling Study.

PURPOSE: Although both urachal (U) and nonurachal (NU) bladder adenocarcinomas (adenoCas) share several histologic similarities, they differ in location and sometimes in therapeutic options. We analyzed the differences in genomic alterations (GAs) between these tumor entities, with the aim of identifying potential therapeutic targets for clinical trials. MATERIALS AND METHODS: Overall, 133 U and 328 NU adenoCas were analyzed. Hybrid capture-based comprehensive genomic profiling (CGP) was performed to evaluate all classes of GA. Germline status of GA was predicted using a validated somatic-germline computational method. CGP was performed using the FoundationOne and FoundationOne CDx assays (Foundation Medicine, Inc). RESULTS: The most frequent GA in both U and NU cohorts included TP53 (86.5% v 81.1%) and KRAS (34.6% v 27.7%). GAs characteristic of colorectal adenoCa, such as SMAD4 (P = .069) and GNAS (P = .071), were more common in U versus NU. Conversely, TERT (P < .01) and RB1 (P = .071) were more prevalent in NU adenoCa. Notably, both U and NU adenoCas exhibited possibly targetable GA in PIK3CA (7.5% v 7.9%) and ERBB2 (6.8% v 7.6%). Biomarkers associated with potential benefit from anti-PD-1/L1 were infrequent. Median tumor mutational burden was 2.6 and 3.5 mutations per megabase for U and NU, respectively, and PD-L1 expression >1% was rare. Genomic ancestry and genomic signature distribution were similar in both tumor types. GAs were most commonly of somatic nature. Limitations include lack of clinical data, tumor heterogeneity, and retrospective nature. CONCLUSION: U and NU adenoCAs revealed differences in GA, with PIK3CA and ERBB2 being identified as putative therapeutic targets. Biomarkers of response to anti-PD-(L)1 were uncommon. Results highlight the potential of CGP to personalize treatment options of bladder adenoCa and inform clinical trial designs.

Testicular Germ Cell Tumors with Venous Tumor Thrombus: Prevalence, Presentation, and Management.

BACKGROUND AND OBJECTIVE: There are limited data on the prevalence and management of testicular germ cell tumor (TGCT) cases presenting with venous tumor thrombus (VTT). Our objectives were to describe the prevalence of TGCT with VTT, to identify a multicenter retrospective cohort, and to ascertain expert opinion regarding optimal management of this entity. METHODS: Using the IBM Marketscan database, we identified men with testicular cancer who underwent retroperitoneal lymph node dissection (RPLND) with concurrent VTT or inferior vena cava (IVC) tumor thrombectomy to estimate the prevalence of VTT in TGCT. To identify a multicenter retrospective cohort of patients, we surveyed surgeons and described the presentation, management, and outcomes for the cohort. KEY FINDINGS AND LIMITATIONS: The prevalence of TGCT with VTT in the IBM Marketscan database was 0.3% (n = 7/2517) when using stringent criteria and 3.1% (n = 79/2517) when using broad criteria. In response to our survey, 16 surgeons from ten centers contributed data for 34 patients. Most patients (n = 29, 85%) presented with nonseminomatous germ cell tumor. Surgical management was used for 93.9% (n = 31), including postchemotherapy tumor thrombectomy with primary cavorrhaphy in 63%. The Marketscan analysis was limited to insured individuals and did not include clinicopathological details, and use of billing codes may have included patients with stromal tumors. In addition, lack of responses to the anonymous survey limited data capture, and the RedCap survey did not address symptoms specific to IVC obstruction or allow central review of the imaging leading to VTT diagnosis. CONCLUSIONS AND CLINICAL IMPLICATIONS: VTT among males with TGCT is rare and requires complex multidisciplinary management, including venous tumor thrombectomy at the time of postchemotherapy RPLND. PATIENT SUMMARY: Using a medical database, we estimated that the frequency of testicular cancer cases in which the tumor extends into a blood vessel (called venous tumor thrombus, VTT) is just 0.3-3.1%. We carried out a survey of surgeons with experience of this condition. Our results indicate that although testicular cancers respond well to chemotherapy, VTT is less responsive and complex surgery is necessary for this rare condition.

Feasibility of a Smartphone Application for Education and Symptom Management of Patients With Renal Cell Carcinoma on Combined Tyrosine Kinase and Immune Checkpoint Inhibitors.

PURPOSE: Patients with advanced renal cell carcinoma (RCC) face significant challenges, stemming both from the complexities of the disease itself and the adverse effects of treatments. This study evaluated the feasibility and acceptability of a mobile health (mHealth) application tailored for education and symptom management of patients with advanced RCC receiving combined immune checkpoint inhibitor and tyrosine kinase inhibitor (ICI-TKI) therapy. METHODS: The primary end points were acceptability and feasibility. Acceptability was defined as the proportion of patients approached who consented to participate, setting a benchmark of at least 50% for this metric. Feasibility was gauged by the completion rate of the intervention among the participants; it required at least 50% of participants to fully complete the intervention and at least 70% to finish half of the administered questionnaires. The secondary end points included knowledge assessment and patient-reported outcomes (PROs). PROs were evaluated using validated instruments. To discern the changes between pre- and post-educational module quiz scores, we used the Wilcoxon signed-rank test. Time-course data of PROs were visualized using line plots and then compared using paired t-tests. RESULTS: From November 2022 to July 2023, 20 of 22 (90%) patients approached for the study consented and enrolled. Of the enrolled patients, 60% completed all questionnaires and knowledge assessments at every time point and 75% completed at least half of the surveys and questionnaires. Significant pre/post differences were noted in two of six quizzes in the knowledge assessment. This study population did not experience a significant change in PRO scores after starting therapy. CONCLUSION: The mHealth application designed for education and symptom management in patients with advanced RCC undergoing combination ICI-TKI has proven to be both acceptable and feasible, meeting previous research benchmarks.

Complications and adverse events in lymphadenectomy of the inguinal area: worldwide expert consensus.

BACKGROUND: Inguinal lymph node dissection plays an important role in the management of melanoma, penile and vulval cancer. Inguinal lymph node dissection is associated with various intraoperative and postoperative complications with significant heterogeneity in classification and reporting. This lack of standardization challenges efforts to study and report inguinal lymph node dissection outcomes. The aim of this study was to devise a system to standardize the classification and reporting of inguinal lymph node dissection perioperative complications by creating a worldwide collaborative, the complications and adverse events in lymphadenectomy of the inguinal area (CALI) group. METHODS: A modified 3-round Delphi consensus approach surveyed a worldwide group of experts in inguinal lymph node dissection for melanoma, penile and vulval cancer. The group of experts included general surgeons, urologists and oncologists (gynaecological and surgical). The survey assessed expert agreement on inguinal lymph node dissection perioperative complications. Panel interrater agreement and consistency were assessed as the overall percentage agreement and Cronbach's α. RESULTS: Forty-seven experienced consultants were enrolled: 26 (55.3%) urologists, 11 (23.4%) surgical oncologists, 6 (12.8%) general surgeons and 4 (8.5%) gynaecology oncologists. Based on their expertise, 31 (66%), 10 (21.3%) and 22 (46.8%) of the participants treat penile cancer, vulval cancer and melanoma using inguinal lymph node dissection respectively; 89.4% (42 of 47) agreed with the definitions and inclusion as part of the inguinal lymph node dissection intraoperative complication group, while 93.6% (44 of 47) agreed that postoperative complications should be subclassified into five macrocategories. Unanimous agreement (100%, 37 of 37) was achieved with the final standardized classification system for reporting inguinal lymph node dissection complications in melanoma, vulval cancer and penile cancer. CONCLUSION: The complications and adverse events in lymphadenectomy of the inguinal area classification system has been developed as a tool to standardize the assessment and reporting of complications during inguinal lymph node dissection for the treatment of melanoma, vulval and penile cancer.

Brachytherapy and external beam radiation in the management of primary penile cancer - Game changer for organ preservation?

OBJECTIVE: In squamous cell carcinoma of the penis (PeCa), treatment options for primary tumors vary by disease stage and may include surgery, radiation, topical chemotherapy, or laser excision. This review aims to highlight the current evidence on the value of radiotherapy as an organ-preserving strategy in primary PeCa. MATERIAL AND METHODS: Manuscripts on primary PeCa treatment with external beam radiotherapy (EBRT) and brachytherapy were evaluated via Scopus, PubMed/MEDLINE, and Web of ScienceTM (2013-2023) to assess their efficacy and safety. Animal studies, studies with <5 patients, and case reports were excluded. RESULTS: Radiotherapy offers the potential for organ preservation with tumor control rates comparable to radical surgery, while disease-specific survival rates up to 70 % were experienced with EBRT. Brachytherapy (BT) is the preferred method of irradiation for glans-limited tumors, whereas a higher relapse risk is expected for tumors >4 cm. BT shows 73 % amputation-free survival at 8-10 years and 81 % progression-free survival at 5-10 years. Compared with BT, total amputation significantly improves 5-year disease-free survival rate. BT offers a superior 5-year local control and penile preservation rates compared to EBRT. Common acute toxicities of brachytherapy include radiodermatitis, sterile urethritis, and urethral adhesions. The primary late adverse events of BT are soft tissue necrosis (0-31 %) and meatal stenosis (0-43 %). CONCLUSION: BT is a favorable radiation modality, offering an efficient and conservative approach. HDR BT is favored for its enhanced dose distribution and radiation protection. Collaboration between radiation oncologists and urologists is essential in order to provide an optimal patient selection and manage toxicities thus optimizing patient outcomes.

Cancer centers of excellence for the multidisciplinary management of urologic cancers The intersection between education, research, and healthcare.

Urologic cancers are among the leading causes of morbidity and mortality in the world, representing more than 10% of the total number of new cancer cases worldwide. These complex diseases are linked to several issues related to their diagnosis, management, monitoring, and treatment - issues that require multidisciplinary solutions that encompass and manage patients as complex entities. In response to this, the so-called cancer centers of excellence (CCEs) emerged, defined as multidisciplinary institutions specialized in the diagnosis, management, monitoring, and treatment of specific diseases, including cancer. Different institutions, such as the European Association of Urology (EAU), have proposed and encouraged its consolidation, especially for the management of prostate cancer. These institutions must be composed of three areas: healthcare, education, and research, which have complementary interactions and relationships, stimulating research and problem-solving from a multidisciplinary approach and also covering elements of basic science and mental health. The implementation of these CCEs has generated positive results; therefore, it is necessary to stimulate their implementation with a uro-oncologic approach.

Factors predictive of recurrence, metastasis and death in node-negative penile squamous cell carcinoma: A retrospective multicentre cohort study.

BACKGROUND: Penile squamous cell carcinoma (PSCC) carries significant morbidity and mortality. Literature is limited regarding prognostic factors, especially prognostic factors for development of metastasis. OBJECTIVES: To identify independent prognostic factors associated with poor outcomes, defined as local recurrence (LR), metastasis and disease-specific death (DSD) in clinically node-negative PSCC undergoing local therapy. METHODS: Thirty-two-year Retrospective Multicenter Cohort Study of 265 patients with histologically diagnosed PSCC at three tertiary care centres. Predictive models based on patient or tumour characteristics were developed. RESULTS: Local recurrence occurred in 56 patients, metastasis in 52 patients and DSD in 40 patients. In multivariable models, the following five factors were independent prognostic factors based on subhazard ratio (SHR): history of balanitis (LR SHR: 2.3; 95% CI 1.2-4.2), poor differentiation (metastasis SHR 1.9; 95% CI 1.0-3.6), invasion into the corpora (metastasis SHR: 3.0; 95% CI 1.5-5.8 and DSD SHR: 4.5; 95% CI 1.7-12.1), perineural invasion (PNI) (metastasis SHR: 2.8; 95% CI 1.4-5.5 and DSD SHR: 3.5; 95% CI, 1.6-7.8) and a history of phimosis (DSD SHR: 2.5; 95% CI 1.2-5.3). The 5-year cumulative incidence of metastasis was higher for tumours with PNI [cumulative incidence function (CIF) = 55%, 95% CI 38-75 vs. CIF 15%, 95% CI 11-22], corporal invasion (CIF: 35%, 95% CI 26-47 vs. 12%, 95% CI 7-19) and poorly differentiated tumours (CIF = 46%, 95% CI 31-64 vs. CIF 15%, 95% CI 11-22). CONCLUSIONS: History of balanitis, history of phimosis, PNI, corporal invasion and poor differentiation are independent risk factors associated with poor outcomes. Since poor differentiation and PNI currently constitute only T1b disease, prognostic staging can likely be improved.

The spectrum of cutaneous toxicities related to novel genitourinary cancer therapies.

CONTEXT: Genitourinary cancers (GUCs) encompass malignancies affecting the urinary and reproductive systems, including renal cell carcinoma (RCC), urothelial carcinoma (UC), and prostate cancer (PC). With the rapidly evolving therapeutic domain of these cancers, cutaneous adverse events (AEs) remain among the most observed toxicities. OBJECTIVE: To explore the dermatologic AEs linked to novel GUC treatments, their underlying pathophysiology, clinical presentations, and risk factors. EVIDENCE ACQUISITION: A narrative review of the literature from PubMed and Embase databases was conducted. The search strategy included dermatologic/cutaneous adverse events, risk factors, and pathophysiology in conjunction with the following classes of therapies; immune checkpoint inhibitors (ICIs), antiangiogenic therapies, enfortumab vedotin (EV), erdafitinib, and androgen receptor antagonists (ARAs). EVIDENCE SYNTHESIS: Maculopapular rash, pruritus, and alopecia are present among the five classes of therapies. ICIs demonstrate the highest incidence of severe drug AEs including Steven Johnson syndrome/toxic epidermal necrolysis. Unique cutaneous AEs present with specific therapies including hand-foot skin reaction and subungual splinter hemorrhage with antiangiogenic drugs, stomatitis/mucositis and onycholysis with erdafitinib. Incidence and type of cutaneous AE also differed within therapies in the same class as seen with apalutamide displaying the highest risk of cutaneous AEs within ARAs. Risk factors for development of cutaneous AEs can be general to therapies, or specific, and include age, immune status, BMI, and gender. CONCLUSIONS: Dermatologic AEs may impact patients' quality of life and increase the tendency to dose reduce, hold or discontinue life-saving therapies, underscoring the need for vigilant monitoring, early recognition, and collaborative management between medical oncologists, pharmacists, dermatologists and other specialists.

From Detection to Cure - Emerging Roles for Urinary Tumor DNA (utDNA) in Bladder Cancer.

PURPOSE OF REVIEW: This review sought to define the emerging roles of urinary tumor DNA (utDNA) for diagnosis, monitoring, and treatment of bladder cancer. Building from early landmark studies the focus is on recent studies, highlighting how utDNA could aid personalized care. RECENT FINDINGS: Recent research underscores the potential for utDNA to be the premiere biomarker in bladder cancer due to the constant interface between urine and tumor. Many studies find utDNA to be more informative than other biomarkers in bladder cancer, especially in early stages of disease. Points of emphasis include superior sensitivity over traditional urine cytology, broad genomic and epigenetic insights, and the potential for non-invasive, real-time analysis of tumor biology. utDNA shows promise for improving all phases of bladder cancer care, paving the way for personalized treatment strategies. Building from current research, future comprehensive clinical trials will validate utDNA's clinical utility, potentially revolutionizing bladder cancer management.

Current Status and Challenges in Rare Genitourinary Cancer Research and Future Directions.

PURPOSE OF REVIEW: In contemporary urological practice, managing rare genitourinary (GU) malignancies presents significant challenges, necessitating a comprehensive understanding of their unique characteristics and tailored treatment approaches. RECENT FINDINGS: Rare GU malignancies, whether per se, variants of common histologies, or common tumors in uncommon locations, often lack widely available clinical guidelines. Consequently, treatment decisions are frequently based on empirical evidence, risking suboptimal outcomes. However, recent advances in molecular profiling, targeted therapies, and immunotherapy offer promising avenues for improving management strategies and patient outcomes. This review provides a comprehensive overview of some rare GU malignancies encountered in clinical practice, including their distinct pathological features, current management approaches, and ongoing research directions. Understanding the complexities of these rare tumors and implementing multidisciplinary treatment strategies are essential for optimizing patient care and improving survival outcomes.

Management of Bulky Inguinal and Pelvic Lymph Nodes.

Penile cancer with bulky inguinal metastasis has a high probability of harboring pathologically involved lymph nodes best managed in a multidisciplinary care setting. Appropriate staging with cross-sectional imaging and fine-needle aspirate cytology of suspicious nodes guide decision-making for the use of platinum-based neoadjuvant chemotherapy followed by inguinal lymph node dissection. Surgical resection plays an important diagnostic, therapeutic, and guiding role in disease management. Patients with adverse pathologic features, especially those with extranodal disease extension, may derive additional benefit from adjuvant radiotherapy.

Overview of Systemic Therapies in Penile Cancer.

Penile cancer (PC), although rare, poses significant challenges in both diagnosis and treatment. Penile squamous cell carcinoma (PSCC) represents the most common histologic subtype of PC, accounting for approximately 95% of cases. With limited therapeutic options available, systemic therapies have emerged as critical components in the management of advanced PSCC. Recent developments in clinical research have revealed the effectiveness of new therapeutic strategies. By elucidating the mechanism of action and clinical evidence supporting these treatments, we strive to offer insights into optimizing treatment strategies and enhancing the quality of care for patients affected by this complex disease.

Immune-based Therapies for Penile Cancer.

This article reviews penile squamous cell carcinoma (PSCC), a rare genitourinary cancer that has been increasing in prevalence. It discusses emerging therapies, focusing on immunotherapy, vaccine therapy, and cell-based treatments, especially in the context of human papillomavirus-related PSCC. Factors influencing these therapies are discussed. These include the immune microenvironment, programmed cell death ligand-1 expression, and tumor immune cell infiltration. This article also highlights immune checkpoint inhibitors and related clinical trials. This review supports the use of personalized medicine in treating PSCC. It stresses the need for collaborative studies and data sharing to create specific treatment plans and achieve better outcomes.

NCCN Guidelines® Insights: Bladder Cancer, Version 3.2024.

Bladder cancer, the sixth most common cancer in the United States, is most commonly of the urothelial carcinoma histologic subtype. The clinical spectrum of bladder cancer is divided into 3 categories that differ in prognosis, management, and therapeutic aims: (1) non-muscle-invasive bladder cancer (NMIBC); (2) muscle invasive, nonmetastatic disease; and (3) metastatic bladder cancer. These NCCN Guidelines Insights detail recent updates to the NCCN Guidelines for Bladder Cancer, including changes in the fifth edition of the WHO Classification of Tumours: Urinary and Male Genital Tumours and how the NCCN Guidelines aligned with these updates; new and emerging treatment options for bacillus Calmette-Guérin (BCG)-unresponsive NMIBC; and updates to systemic therapy recommendations for advanced or metastatic disease.