Search Results (93)

Background/Objectives: Penile malignant tumors are rare neoplasms, and both clinicopathologic features and prognoses remain unclear in Japanese patients. Here, we investigated the prognoses of penile malignant tumors in Japan using the nationwide hospital-based cancer registry (HBCR) database. Methods: The 2015 HBCR database cohort was queried to identify patients with penile malignant tumors. Moreover, we investigated age, pathology, tumor–node–metastases classification, first-course treatment, and overall survival in these patients. Results: A total of 269 patients were analyzed from the 2015 cohort (149 squamous cell carcinoma [SCC] patients and 56 extramammary Paget disease [EMPD] patients). The median ages at diagnosis in both SCC and EMPD patients were 76.0 and 76.5 years. The median observation period was 53 months in the present study. The 5-year overall survival (OS) rates of SCC and EMPD were 56.8% and 78.5%. The 5-year OS rates of clinical stages 0–I, II, III, and IV were (respectively) 68.0%, 70.1%, 38.5%, and 11.9% in SCC patients and (respectively) 83.7%, 83.3%, not evaluated, and 0% in patients with EMPD. Conclusions: We revealed the OS of Japanese patients with penile SCC and EMPD in a large population-based study for the first time. Patients with clinical stage IV penile SCC and EMPD had extremely poor prognoses, highlighting a need for improved disease management in these patients. Full article

Penile squamous cell carcinoma (PSCC) is a rare malignancy with limited therapeutic options in advanced and recurrent diseases. Advanced PSCC is typically managed with multimodal therapy, including neoadjuvant chemotherapy or chemoradiation followed by surgery; however, durable responses remain uncommon, and outcomes after recurrence are poor. Cancer vaccines represent a promising immunotherapeutic strategy, as these treatments induce tumor-specific immunity and heightened immune surveillance against penile cancer cells. While therapeutic cancer vaccines have not yet demonstrated consistent clinical efficacy as monotherapy in PSCC, their integration with complementary immune-modulating approaches, particularly immune checkpoint blockade, represents a rational strategy to enhance antitumor immunity. This review summarizes the rationale for vaccine development in PSCC, with emphasis on HPV-derived antigens, neoantigens, and emerging tumor-associated targets. We examine major vaccine platforms, including viral-vector, peptide-based, nucleic acid, and dendritic cell-based approaches. We also discuss how spatial transcriptomics, single-cell RNA sequencing, artificial intelligence-assisted antigen prediction, and nanotechnology-enhanced delivery systems may support future personalized vaccine development. Overall, therapeutic vaccines remain investigational in PSCC but may become relevant within biomarker-driven, combination-based immunotherapy strategies. Full article

Neutrophil extracellular traps (NETs) are web-like structures composed of decondensed DNA, histones, and proteins released by activated neutrophils. Originally identified as an innate defense mechanism against pathogens, NETs have since been implicated in cancer progression and immune evasion. Within the tumor microenvironment (TME), NETs suppress anti-tumor immunity through multiple mechanisms, including the physical exclusion of CD8⁺ cytotoxic T lymphocytes from the tumor interior and upregulation of exhaustion markers via checkpoint ligands. This review synthesizes current preclinical and clinical evidence on the interplay between NETs and CD8⁺ T cells across multiple malignancies, including non-small cell lung cancer, pancreatic ductal adenocarcinoma, cholangiocarcinoma, colorectal cancer, bladder cancer, hepatocellular carcinoma, skin cancer, and penile cancer. Cancer-specific mechanisms of NET-mediated immune suppression are discussed, including IL-8, IL-17, CXCL6, and TGF-β-driven NETosis pathways. Clinical data consistently demonstrate that elevated NET levels correlate with reduced CD8⁺ T cell infiltration, T cell dysfunction, and worse patient outcomes. Emerging therapeutic strategies targeting this axis are reviewed, including DNase I-mediated NET degradation, Peptidyl arginine deiminase 4 (PAD4) inhibition, CXCR2 blockade, and combination approaches with immune checkpoint inhibitors. These interventions have shown promise in restoring CD8⁺ T cell cytotoxicity and overcoming immunotherapy resistance in preclinical models. Collectively, the evidence supports the NET-CD8⁺ T cell axis as a promising prognostic and therapeutic target warranting further clinical investigation. Full article

Background/Objectives: Penile squamous cell carcinoma (SCC) is a rare but aggressive malignancy in which survival declines sharply once regional lymph nodes are involved. Neoadjuvant therapy is recommended for clinically node-positive disease to improve resectability and address micro-metastatic spread; however, the supporting evidence remains limited. We systematically reviewed contemporary data on neoadjuvant strategies for penile SCC, including cytotoxic chemotherapy, radiotherapy, immunotherapy, and molecularly targeted agents. Methods: A systematic search of MEDLINE, EMBASE, ClinicalTrials.gov, and CENTRAL was conducted from inception to January 2026 in accordance with MECIR guidance. Eligible studies included patients with histologically confirmed penile cancer treated with neoadjuvant intent prior to curative surgery. Primary outcomes were objective response rate (ORR), pathological complete response (pCR), progression-free survival (PFS), and overall survival (OS). Data were synthesised narratively by treatment modality. Results: Forty-two studies met the inclusion criteria (32 chemotherapy, five radiotherapy, five immunotherapy, three targeted therapy). The evidence base was dominated by retrospective cohorts with limited prospective phase II data and no completed randomised trials. Across chemotherapy studies, the median reported ORR was 50% (range 29–90%), with pCR/ypN0 rates ranging 10–25%. Median reported PFS and OS were approximately 11 and 18 months, respectively, with durable survival concentrated among responders undergoing complete surgical consolidation. Radiotherapy data were sparse and heterogeneous. Early-phase immunotherapy combinations reported higher short-term response and pCR signals than historical chemotherapy, though the results were based on small single-arm cohorts. Molecularly targeted systemic monotherapy demonstrated modest activity. Conclusions: Neoadjuvant taxane–platinum-based chemotherapy remains the guideline-supported standard for cN2-3 penile SCC, supported by phase II and retrospective data but limited by methodological heterogeneity and absence of randomised evidence. Emerging combination immunotherapy strategies show promising efficacy signals and warrant prospective validation within biomarker-informed trial frameworks. Full article

Background/Objectives: Optimal surgical margin management in penile squamous cell carcinoma remains debated because organ-preserving surgery must balance oncological control with functional preservation. Historically, wide excision margins have been recommended; however, subsequent evidence has challenged this threshold, shifting practice towards narrower margins without a demonstrated increase in local recurrence. We evaluated whether invasive positive surgical margins and minimal negative margin widths were associated with local recurrence and survival after surgery for penile squamous cell carcinoma. Methods: We retrospectively analysed 157 consecutive men who underwent surgical treatment at a single centre between 2011 and 2024. Time-to-event analyses were performed in 131 patients with invasive non-metastatic disease after excluding those with penile intraepithelial neoplasia (PeIN)-only lesions (n = 23) and distant metastases (n = 3) at diagnosis. The margins were classified as either invasive-negative or invasive-positive. Among histologically negative-margin cases, minimal margin width was grouped a priori as <2 mm, 2–5 mm, and >5 mm. Results: The median follow-up was 25 months (interquartile range [IQR], 10–52). In the invasive (M0) cohort, 101/131 patients had invasive-negative margins and 30/131 had invasive-positive margins; local recurrence occurred in 42/131 patients. Margin status was not independently associated with recurrence-free, overall, or cancer-specific survival rates. Non-sparing surgery was associated with a lower hazard of local recurrence, whereas grade 3 (G3) histology independently predicted worse recurrence-free, overall, and cancer-specific survival. Advanced stage according to the Tumour, Node, Metastasis (TNM) classification independently predicted worse cancer-specific survival. Conclusions: Among patients with histologically negative margins, outcomes did not differ significantly across the predefined margin-width categories. These findings support tissue-preserving surgery aimed at histologically negative margins within a structured surveillance framework. Full article

Background: Penile squamous cell carcinoma is an uncommon neoplasm that arises via two carcinogenic pathways, one linked to HPV infection and the other to chronic inflammation and p53 alterations. Objective/Methods: We assessed the distribution of HPV genotypes in penile tumors and subsequent inguinal metastases in a cohort of 343 patients, analyzing their concordance with p16 stain and histological subtype, as well as the predictive significance of HPV tumor status and the immunohistochemical expression of p16 and p53 in inguinal lymph node metastasis (ILNM). Results: The overall prevalence of HPV in primary penile tumors was 42.9%, with high-risk HPV genotypes detected in 95.2% of HPV-positive cases. HPV16 was the most prevalent genotype identified in both primary tumors and metastases. However, other genotypes, including the low-risk HPV82, were also found in metastatic disease. We observed good concordance between HPV tumor status and histological subtype and very good concordance between HPV tumor status and p16 staining, with Cohen’s kappa (κ) values of 0.80 (p-value < 0.001) and 0.83 (p < 0.001), respectively. Conclusions: In most HPV-positive metastatic cases, the same HPV genotypes were detected in both the metastasis and the penile tumor. Both p16 staining and histological subtype can serve as surrogates for molecular HPV testing in lower resourced settings. In this dataset, no significant association was found between HPV status, p16 expression, or p53 expression and the presence of ILNM, suggesting their limited utility as predictive markers for ILNM in penile cancer. Full article

Background/Objectives: Penile squamous cell carcinoma (PSCC) is a rare malignancy with a potential major impact on survival. Prognostic assessment remains challenging, particularly in underrepresented eastern European populations, where region-specific evidence is lacking. This paper aimed to identify independent predictors of overall survival in surgically treated patients with PSCC from a Romanian high-volume tertiary center. Methods: This retrospective cohort study analyzed 60 patients who were surgically treated for PSCC between October 2020 and December 2024. Univariate and multivariate Cox proportional hazards regression analyses were performed to identify independent prognostic factors. Results: The mean patient age was 62 ± 12 years. T-stage distribution showed 30% pT1, 35% pT2, 31.67% pT3, and 3.33% pT4, with 55% of patients presenting with nodal metastases. Univariate analyses demonstrated significant associations between lymphovascular invasion (p < 0.001), perineural invasion (p = 0.022), and positive surgical margins (p = 0.030) and risk of death. Multivariate analysis identified three independent prognostic factors: absence of histologically documented urethral invasion (HR 0.32; p = 0.027), T3–T4 disease (HR 8.26; p = 0.005 vs. T1), and N3 stage (HR 3.53; p = 0.030 vs. N0–N1). Patients without urethral invasion demonstrated significantly longer median overall survival (63 months vs. 11 months). The final three-variable prognostic model demonstrated good discrimination (C-index 0.78), providing a potential practical risk stratification tool. Conclusions: Urethral invasion, advanced T-stage, and N3 disease independently predict poor survival in surgically treated PSCC. The identification of urethral invasion as an independent prognostic factor warrants consideration in clinical practice. This is the first study of a Romanian cohort to provide critical data for risk-adapted treatment strategies in underrepresented eastern European populations. Full article

Penile squamous cell carcinoma (PSCC) is rare, but a biologically aggressive malignancy. Recent comprehensive genomic profiling (CPG) efforts revealed the underlying genomic landscape of PSCC, identifying TP53, TERT, CDKN2A, PIK3CA, NOTCH1, and FAT1 as frequently altered genes with potential roles in penile oncogenesis. In addition, recurrent mutations encoded in the GPS1 gene have been observed in 7.4% of cases in a particular PSCC cohort. Functional studies demonstrated loss of function due to GPS1 Exon 9 missense mutations, proposing a possible role for these alterations as oncogenic driver events in PSCC. However, no other study confirmed the occurrence of GPS1 gene mutations in PSCC. To elucidate the biological function of GPS1 exon 9 mutations in PSCC pathogenesis, we utilized a comprehensive in-house cohort of 106 PSCC cases to explore their frequency and occurrence. Albeit, the previously reported GPS1 mutations p.D382H and p.M384I were not observed in this large cohort of PSCC cases; this analysis, however, revealed two novel GPS1 alterations in exon 9 in two (1.9%) of the analyzed cases: p.S372F (c.1115C>T) and p.A375D (c.1124C>A). This observation suggests that GPS1 exon 9 sequence is a target of genetic alteration during PSCC pathogenesis. However, the non-recurrent nature of these alterations indicates that they are unlikely to represent oncogenic drivers in this disease. Full article

Background and Objectives: Paraneoplastic hypercalcemia represents a rare but clinically significant complication of penile squamous cell carcinoma (PSCC); however, limited information is available for this condition. Therefore, this systematically conducted narrative review aimed to comprehensively evaluate the pathophysiological mechanisms, clinical presentation, therapeutic strategies and prognostic outcomes of tumor-induced hypercalcemia in PSCC. Methods: A comprehensive literature search was conducted across PubMed/MEDLINE and Scopus databases from their inception to December 2024. Cases were included if they documented histopathologically confirmed PSCC with biochemically verified hypercalcemia and objective evidence of paraneoplastic etiology. Data extraction included tumor characteristics, severity of hypercalcemia, mechanistic classification, therapeutic interventions and survival outcomes. The search methodology followed PRISMA 2020 guidelines adapted for narrative synthesis. Given the absence of comparative studies for this rare condition, all study types were eligible for inclusion, resulting in an evidence base that consisted exclusively of case reports and case series. Results: Twelve published cases spanning six decades (1965–2024) met the inclusion criteria. The median age at presentation was 56 years, with 91.6% of patients presenting with advanced disease. Severe hypercalcemia (≥14 mg/dL) occurred in 66.7% of cases, with a median calcium level of 15.45 mg/dL. Two established pathophysiological mechanisms were identified: PTHrP-mediated humoral hypercalcemia and bone metastasis-associated hypercalcemia. By contrast, three cases with unmeasured PTHrP levels had an undetermined mechanism. Despite biochemical correction, median overall survival was 9 weeks following diagnosis of hypercalcemia. Conclusions: Paraneoplastic hypercalcemia in PSCC represents a rare metabolic emergency. While aggressive management can achieve biochemical correction, the occurrence of hypercalcemia uniformly indicates advanced tumor biology with limited survival benefit. Early recognition and prompt multidisciplinary intervention remain essential for symptomatic relief and preserving quality of life. Reporting future cases and collaborating with international registries will be necessary to improve understanding of this rare paraneoplastic entity. Full article

Kidney transplantation is the optimal treatment for end-stage kidney failure. However, after successful kidney transplantation, patients require long-term immunosuppression. Due to immunosuppressive therapy, the development of malignancies is more common in solid organ transplant recipients than in the general population. Because renal transplantation has been performed for many decades—much longer than other solid organ transplants—data on malignancies in kidney allograft recipients are the most comprehensive. Malignancies are the third most common cause of death in kidney allograft recipients, after cardiovascular disease and infections. In kidney allograft recipients, malignancies may develop de novo, be transmitted with the transplanted organ, or arise from previously present but undiagnosed cancers in the recipient. Over 90% of malignancies in renal allograft recipients are de novo. In this review, we first present the epidemiology of malignancies after kidney transplantation. Subsequently, the most common urinary tract malignancies, along with their diagnosis, treatment, and screening, are discussed. We also outline the limitations of the published data, propose research priorities, and identify existing gaps and unmet needs. Full article

Background/Objectives: Penile squamous cell carcinoma (PSCC) is a rare malignancy with poor prognosis in advanced and recurrent disease, and therapeutic options remain limited. Increasing evidence suggests that the tumor immune microenvironment (TIME), including immune cell composition and spatial organization, plays a critical role in tumor progression and survival outcomes. This study aimed to characterize immune cell density and geospatial clustering patterns within the TIME of PSCC and to evaluate their associations with clinical outcomes. Methods: Multiplex immunofluorescence (mIF) was performed on tumor samples from 57 patients with PSCC using a panel of immune markers to identify lymphoid and myeloid cell populations. Immune cell densities were quantified within tumoral and stromal compartments. Spatial relationships among immune cells and between immune cells and tumor cells were analyzed using point pattern analysis. Survival outcomes, including overall survival (OS), recurrence-free survival (RFS), and cancer-specific survival (CSS), were assessed using Kaplan–Meier methods and Cox proportional hazards models, with analyses stratified by nodal and human papillomavirus (HPV) status. Results: Higher intratumoral and stromal densities of pro-immunogenic M1 macrophages were associated with improved OS. Increased densities of CD3⁺CD4⁺ helper T cells in both compartments were also associated with favorable survival outcomes. In contrast, close clustering of pro-tumorigenic M2 macrophages with tumor cells and with one another was associated with worse OS, RFS, and CSS. Bivariate clustering of helper T cells with tumor cells was associated with improved OS, including among patients with node-positive disease. Survival outcomes did not differ significantly by HPV status in patients with high helper T cell clustering. Conclusions: Immune cell density and spatial organization within the TIME are associated with survival outcomes in PSCC. Favorable patterns involving helper T cells and M1 macrophages correlate with improved survival, whereas clustering of M2 macrophages is associated with poorer outcomes, supporting the relevance of spatial immune profiling in this disease. Full article

Background/Objectives: Penile squamous cell carcinoma (PSCC) is rare but aggressive. Systemic chemotherapy plays a crucial role in the management of node-positive or metastatic cases; however, the supporting evidence predominantly originates from small, non-randomized studies. This review provides a narrative analysis of the cytotoxic classes and regimens employed in PSCC and compares major clinical guidelines to facilitate informed decision-making in practice. Methods: English-language reports were identified in PubMed/Scopus/Google Scholar without date limits. Selection prioritized objective response, survival and toxicity outcomes, and guidance statements across neoadjuvant, adjuvant, and palliative settings. Results: Bleomycin-containing triplet regimens demonstrated efficacy but were associated with unacceptable pulmonary toxicity, leading to their discontinuation in clinical recommendations. Currently, cisplatin/taxane-based combinations remain fundamental in treatment protocols. The paclitaxel–ifosfamide–cisplatin (TIP) regimen achieves approximately 40–50% objective responses in phase II studies and may enable curative surgery, while taxane–cisplatin–5-fluorouracil (TPF) shows comparable efficacy with higher toxicity. For less fit patients, cisplatin–5-fluorouracil (PF) or carboplatin–taxane doublets are pragmatic alternatives. Single-agent taxanes or vinflunine offer modest second-line benefits. Although EAU–ASCO 2023, ESMO–EURACAN 2024, and NCCN v2.2025 are broadly in consensus, recommendations differ regarding eligibility thresholds and regimen preferences. Overall, the quality of the evidence remains low. Conclusions: TIP remains the reference neoadjuvant option for chemotherapy-fit patients with bulky nodal disease; doublets are reasonable when cisplatin fitness is limited; and bleomycin should be avoided. Harmonized eligibility criteria, biomarker-enriched studies, and coordinated multicenter trials are needed to improve outcomes in this rare malignancy. Full article

Background: Magnetic resonance imaging (MRI) plays an increasingly important role in the evaluation of scrotal and penile disorders, complementing ultrasonography in cases where findings are equivocal or complex. With its superior soft-tissue contrast, multiplanar capability, and advanced functional sequences, MRI provides unparalleled anatomic and tissue characterization across a wide range of male genital pathologies. Summary: This review summarizes current clinical applications of MRI in scrotal and penile imaging and discusses its diagnostic value, protocol optimization, and interpretive features. In scrotal pathology, MRI accurately differentiates torsion, trauma, infection, and neoplasms, aiding in the distinction between benign and malignant testicular lesions and supporting testis-sparing management. Quantitative diffusion and perfusion metrics further refine lesion characterization. In andrology, MRI biomarkers such as apparent diffusion coefficient (ADC), magnetization transfer ratio (MTR), and proton spectroscopy serve as promising non-invasive indicators of spermatogenic activity in male infertility. In penile imaging, MRI enables precise local staging of carcinoma, assessment of plaque morphology and activity in Peyronie’s disease, evaluation of tissue viability in priapism, and detection of prosthesis-related complications. Conclusions: MRI has become an essential problem-solving tool in the assessment of scrotal and penile diseases, enhancing diagnostic confidence and surgical planning. Future directions include protocol standardization, quantitative parameter validation, and the integration of radiomics and artificial intelligence to improve reproducibility and clinical impact. Full article

Penile cancer (PeCa) is a rare malignancy with few validated tissue biomarkers to guide prognosis and treatment, despite growing evidence for a key role of inflammation in its biology. This retrospective study evaluated whether the immuno-expression of selected pro-inflammatory cytokines is associated with disease progression and cancer-specific survival (CSS) in PeCa. Immunohistochemistry (IHC) analysis of eight cytokines (IL-1A, IL-1B, IL-2, IL-6, IL-12, TGF-β1, TNF-α and IFN-γ) was performed in paired tumour tissues and corresponding negative surgical margins from 94 patients with penile squamous cell carcinoma. Compared with surgical margins, tumour tissues showed a characteristic inflammatory shift, with markedly increased IL-1β and IL-6 and relatively reduced TNF-α, IFN-γ, IL-12 and IL-2. Receiver Operating Characteristic (ROC) analysis indicated that TNF-α, IL-6 and IL-12 had the strongest ability to discriminate tumour from normal tissue and provided data-driven cut-offs for subsequent analyses. Within tumour samples, high IL-1α, IL-12 and TGF-β1 immuno-expression was significantly associated with advanced UICC TNM prognostic stage and lymph node involvement. Importantly, in contrast to the classically anti-tumour role of IL-12 described in many other solid cancers, increased IL-12 immuno-expression in tumour tissues in our cohort was independently associated with poorer CSS in multivariable Cox regression (HR 2.42, 95% CI: 1.08–5.41, p = 0.031), alongside advanced TNM stage (HR 5.03, 95% CI: 2.12–11.95, p = 0.0002). These findings highlight IL-1α, IL-12 and TGF-β1 as promising tissue biomarkers of aggressive PeCa and support a central role for cytokine-driven immune dysregulation in penile cancer. The prognostic value of IL-12 should be considered exploratory and warrants validation in larger, multicentre cohorts. Full article

Introduction: Penile cancer is rare but rising in incidence. Any optimal treatment must balance oncologic control with preservation of sexual and urinary function. Objectives: To evaluate sexual function, patient satisfaction, and oncologic outcomes after carbon dioxide (CO₂), neodymium-doped yttrium aluminum garnet (Nd:YAG), and thulium-doped yttrium aluminum garnet (Tm:YAG) laser therapies for penile cancer. Methods: A systematic review was conducted in accordance with PRISMA 2020. We searched PubMed, Embase, Scopus, Google Scholar, ScienceDirect, ClinicalTrials.gov, and conference proceedings from January 2000 to 5 February 2025 for observational studies reporting sexual function after laser therapy. Risk of bias was assessed with the Newcastle–Ottawa Scale (NOS) and certainty of evidence with Grading of Recommendations Assessment, Development, and Evaluation (GRADE). Results: Eleven studies comprising 593 patients were included, mostly carcinoma in situ or T1. Local recurrence occurred in 6–19% of patients with Tis/T1 and 17–42% in ≥T2. Across laser types, 59–72% of patients retained erectile function, 50–100% reported sexual satisfaction, and 80–100% reported satisfaction with the cosmetic outcomes, with some degree of variation. Reports on libido and orgasm were heterogeneous and generally unvalidated. General patient satisfaction was high but often assessed using non-validated instruments. Conclusions: Laser therapy is a reasonable penile-sparing option for Tis/T1 disease, but mandates strict surveillance. Data are insufficient to support its use for ≥T2 tumors. Laser therapy generally preserves sexual function, but heterogeneous and non-standardized reporting limits firm conclusions. Prospective studies with standardized patient-reported outcome measures are needed. Full article