Clinical Outcomes and Prognostic Factors in Patients With Penile Carcinoma: A Sub-Analysis From Meet-URO 23 (I-RARE) Registry Study.

INTRODUCTION: Penile squamous cell carcinoma (PSCC) is a rare tumor with an aggressive behavior. The Meet-URO 23/I-RARE registry includes rare genitourinary malignancies. We extracted patients with PSCC to conduct a retrospective study aimed at assessing clinical outcomes and prognostic factors. PATIENTS AND METHODS: Primary endpoints were overall survival and progression-free survival. Prognostic factors for OS and PFS were analyzed using univariate and multivariate analysis. From the Meet-URO 23/I-RARE database, we extracted 128 patients with diagnosis of PSCC. About 48% of patients underwent first-line of therapy. RESULTS: In the overall population, median OS from diagnosis was 34.6 months. Significant differences in median OS were observed according to ECOG PS at diagnosis (57.3 months vs. 8.3 months; P < .001), and median age (≤77y 88.8 months vs. >77y 26 months; P = .013). At multivariate analysis, ECOG PS 2-4 at diagnosis (HR 3.04) and lymph node metastases (HR 2.49) were independently associated with a higher risk of death. Among patients undergoing first-line therapy (n = 61), median OS was 12.3 months, and a statistically significant difference was found according to type of response to first-line (DCR 24.4 months vs. PD 7.1 months; P < .001). Multivariate analysis showed that only age >77 years was associated with a worse OS (HR 2.16). A statistically significant difference in PFS was found according to platinum plus 5-fluorouracil versus platinum plus taxane (4.9 vs. 3.4 months; P = .036) and regimens with 2 versus 3 drugs (3.4 vs. 8.6 months; P = .019). At the multivariate analysis only regimens with platinum plus taxane were associated with worse PFS (HR 2.83). CONCLUSION: In our registry study, PSCC is confirmed to be an aggressive disease. Poor ECOG PS, presence of lymph node metastases, and higher age at diagnosis appear to be associated with worse survival outcomes.

Clinical Profile and Outcomes of Carcinoma Penis Patients Receiving Systemic Therapy at an Indian tertiary care Center: A Retrospective Observational Study.

BACKGROUND: Penile cancer is a rare malignancy with scant data on the impact of systemic therapy on outcomes. METHODS: Retrospective observational study of patients with a histological diagnosis of carcinoma penis treated with systemic therapy at the Tata Memorial Centre (Mumbai, India) between August 2010 and February 2018. Primary objective was overall survival (OS); secondary objectives included assessment of clinical characteristics, treatment approaches, and toxicity profiles. RESULTS: We included 91 patients with penile carcinoma who received systemic therapy at our center. Intent of therapy was curative in 71 patients (78%), and palliative in 20 (22%). Median age was 57 years (interquartile range [IQR], 50-65.5) for curatively treated patients and 58.5 years (IQR, 44-65.2) for those with advanced disease. Common presenting symptoms were lumps (70%), and pain (57%). Neoadjuvant chemotherapy (NACT) with paclitaxel + platinum was administered to 19 patients (20.9%), of which 7 (37%) attained complete or partial response. Six patients (31.5%) underwent R0 surgery post-NACT. All 71 patients underwent primary surgery; 47 (66.2%) undergoing partial penectomy. Of the 20 patients treated with palliative first-line chemotherapy, 4(20%) attained a partial response. Median OS of patients treated in curative and palliative settings was 33.8 months (95% CI, 17.2-not recorded) and 11.4 months (95% CI, 9.53-23.3), respectively. CONCLUSIONS: Patients with penile cancer treated with systemic therapy have poor outcomes. Little over a third of the patients respond to neoadjuvant chemotherapy and those with advanced disease have poor survival despite systemic therapy, emphasizing the need for early detection and optimum management of primary and nodal disease.

Insights into the management of penile squamous cell carcinoma: from conventional approaches to emerging novel therapies.

INTRODUCTION: Penile squamous cell carcinoma (PSCC), a rare genitourinary cancer, is associated with poor outcomes due to limited treatment effectiveness, especially in advanced stages. AREAS COVERED: While chemotherapy and/or surgery remain the standard of care, emerging therapies like immunotherapy, targeted therapy, and human papillomavirus (HPV) directed therapies show promise. Key to advancing treatment is understanding the immune microenvironment to gain insights into tumor resistance mechanisms and potential therapeutic targets. The scarcity of data on PSCC is a major obstacle in advancing research for this rare cancer. EXPERT OPINION: Future research should prioritize collaborative efforts across various research centers and countries. Enhancing data sharing and pooling resources can lead to a more comprehensive understanding of PSCC, ultimately supporting the development of precision medicine strategies tailored to this specific cancer type. This collaborative approach is essential for making significant strides in PSCC treatment and care.

Penile Cancer Mortality in Brazil: Are We Making Progress?

PURPOSE: This study aims to analyze the trends in mortality rates from penile cancer (PeC) and the treatment modalities adopted in Brazil over recent years. MATERIALS AND METHODS: Death records for PeC cases (International Classification of Diseases, version 10 C60) and treatment modalities were extracted from the DATASUS database. A joinpoint regression analysis was conducted to examine the data. RESULTS: A total of 7,848 deaths due to PeC were recorded in Brazil between 1996 and 2020. Increasing mortality trends were observed, with an average annual percentage change (AAPC) of 0.91 (0.6-1.2; P < .001). The North and Northeast regions had the highest age-standardized mortality rates (ASMRs) and AAPCs. From 2008 to 2020, the ASMR in the Northeast region remained stable, whereas the North region surpassed it. The Southeast region exhibited a significant downward trend, with an AAPC of -0.91 (-1.3 to -0.5; P < .001). Penile biopsies declined and were more frequent in the southeastern region. A total of 8,498 penile amputations were performed, with 39.4% and 29.1% conducted in the Southeast and Northeast regions, respectively. CONCLUSION: Brazil has experienced increasing mortality trends in PeC over the past 2 decades. Low schooling, married, and young men from the North or Northeast regions represent the majority of deaths. Urgent efforts are needed to enhance the diagnosis and treatment of PeC to prevent and reduce mortality rates in the country.

Penile cancer care in the Netherlands: increased incidence, centralisation, and improved survival.

OBJECTIVE: To evaluate penile squamous cell carcinoma (PSCC) incidence and centralisation trends in the Netherlands over the past three decades, as well as the effect of centralisation of PSCC care on survival. PATIENTS AND METHODS: In the Netherlands PSCC care is largely centralised in one national centre of expertise (Netherlands Cancer Institute [NCI], Amsterdam). For this study, the Netherlands Cancer Registry, an independent nationwide cancer registry, provided per-patient data on age, clinical and pathological tumour staging, follow-up, and vital status. Patients with treatment at the NCI were identified and compared to patients who were treated at all other centres. The age-standardised incidence rate was calculated with the European Standard Population. The probability of death due to PSCC was estimated using the relative survival. Multivariable Cox regression analysis was performed to evaluate predictors of survival. RESULTS: A total of 3160 patients were diagnosed with PSCC between 1990 and 2020, showing a rising incidence (P < 0.001). Annual caseload increased at the NCI (1% in 1990, 65% in 2020) and decreased at other (regional) centres (99% to 35%). Despite a relatively high percentage of patients with T2-4 (64%) and N+ (33%) at the NCI, the 5-year relative survival was higher (86%, 95% confidence interval [CI] 82-91%) compared to regional centres (76%, 95% CI 73-80%, P < 0.001). Patients with a pathological T2 tumour were treated with glans-sparing treatment more often at the reference centre than at the regional centres (16% vs 5.0%, P < 0.001). After adjusting for age, histological grading, T-stage, presence of lymph node involvement and year of diagnosis, treatment at regional centres remained a predictor for worse survival (hazard ratio 1.22, 95% CI 1.05-1.39; P = 0.006). CONCLUSION: The incidence of PSCC in the Netherlands has been gradually increasing over the past three decades, with a noticeable trend towards centralisation of PSCC care and improved relative survival rate.

Case report of penile squamous cell carcinoma continuous treatment with BRCA2 mutation.

BACKGROUND: Penile squamous cell carcinoma (PSCC) is a highly aggressive malignancy with a poor prognosis. BRCA1/2 mutations are associated with impaired DNA double-strand break repair and are among the common mutations in penile cancer, potentially paving the way for poly ADP-ribose polymerase inhibitor therapy. CASE PRESENTATION: We report a 65-year-old male with PSCC who progressed to thigh metastasis at 10 months after partial penectomy. Next-generation sequencing showed that the penis primary lesion and metastatic thigh lesion harboured a BRCA2 mutation. Chemotherapy plus immunotherapy was used for treatment, and the thigh metastasis was found to involve no tumour. Progression-free survival (PFS) lasted for 8 months until the appearance of lung metastasis. Afterwards, the patient benefited from second-line therapy of olaparib with pembrolizumab and anlotinib, and his disease was stable for 9 months. The same BRCA2 was identified in the lung biopsy. Given the tumour mutation burden (TMB, 13.97 mutation/Mb), the patient received third-line therapy with nivolumab plus ipilimumab, but PFS only lasted for 3 months, with the appearance of right frontal brain metastasis. Then, the patient was treated with radiation sequential fluzoparib therapy as fourth-line treatment, and the treatment efficacy was evaluated as PR. Currently, this patient is still alive. CONCLUSIONS: This is the first report of penile cancer with BRCA2 mutation, receiving a combination treatment with olaparib and experiencing a benefit for 9 months. This case underscores the pivotal role of BRCA2 in influencing treatment response in PSCC, providing valuable insights into the application of targeted therapies in managing recurrent PSCC with BRCA2 alterations. This elucidation establishes a crucial foundation for further research and clinical considerations in similar cases.

SPP1 is associated with adverse prognosis and predicts immunotherapy efficacy in penile cancer.

BACKGROUND: The effect of SPP1 in squamous cell carcinoma of the penis (PSCC) remained unknown. We attempted to clarify the function of the SPP1 gene in PSCC. METHOD: Eight paired penile cancer specimens (including penile cancer tissue, paracancerous tissue, and positive lymph node tissue) subjected to whole transcriptome sequencing were analysed to identify differentially expressed genes. We used immunohistochemistry to detect the expression of SPP1 protein and immune cell related proteins in penile cancer tissue. Then, we performed weighted gene coexpression network analysis (WGCNA) to identify the genes related to SPP1 in penile cancer tissue and positive lymph node tissue. Based on the GSE57955 dataset, the CIBERSORT and ssGSEA algorithms were carried out to investigate the immune environment of PSCC. GSVA analysis was conducted to identify the signaling pathways related to SPP1 subgroups. Enzyme-linked immunosorbent assay (ELISA) method was adopted to detect SPP1 level in the serum of 60 patients with penile cancer. RESULTS: Differential analysis indicated that SPP1 was the most differentially upregulated gene in both penile cancer tissues and positive lymph node tissues. Survival analysis suggested that the prognosis of the low-SPP1 group was significantly poorer than that of the high-SPP1 group. Subsequently, immune-related bioinformatics showed that SPP1 was significantly associated with B cells, CD8 + T cells, CD4 + T cells, macrophages, helper T cells, neutrophils and dendritic cells. The immunohistochemical results showed that the high-SPP1 group was characterized by relatively high expression of CD16 and relatively low expression of CD4. GSVA analysis indicated that high-SPP1 group was significantly associated with immune-related pathways such as PD-L1 expression and the PD-1 checkpoint pathway in cancer and the TNF signaling pathway. ELISA demonstrated that the serum level of SPP1 in patients with positive lymph node metastasis of penile cancer was significantly higher than that in patients with negative lymph node metastasis of penile cancer. CONCLUSION: Our study shows that the SPP1 gene might be an effective biomarker for predicting the prognosis and the efficacy of immunotherapy in PSCC patients.

Centralizing Penile Cancer Care in Germany and Austria: Just a Dream or a Fast-Approaching Reality? Results of a Survey Study among Urological Department Chairs and Modeling of Real Treatment Numbers of Penile Cancer Patients.

INTRODUCTION: In countries characterized by a centralization of therapy management, patients with penile cancer (PeCa) have shown improvements in guideline adherence and ultimately, improved carcinoma-specific survival. Germany and Austria (G + A) have no state-regulated centralization of PeCa management, and the perspectives of urological university department chairs (UUDCs) in these countries, who act as drivers of professional and political developments, on this topic are currently unknown. METHODS: Surveys containing 36 response options, including specific questions regarding perspectives on PeCa centralization, were sent to the 48 UUDC in G + A in January 2023. In addition to analyzing the responses, closely following the CROSS checklist, a modeling of the real healthcare situation of in-house PeCa patients in G + A was conducted. RESULTS: The response rate was 75% (36/48). 94% and 89% of the UUDCs considered PeCa centralization meaningful and feasible in the medium term, respectively. Among the UUDCs, 72% estimated centralization within university hospitals as appropriate, while 28% favored a geographically oriented approach. Additionally, 97% of the UUDCs emphasized the importance of bridging the gap until implementation of centralization by establishing PeCa second-opinion portals. No country-specific differences were observed. The median number of in-house PeCa cases at the university hospitals in G + A was 13 (interquartile range: 9-26). A significant positive correlation was observed between the annual number of in-house PeCa cases at a given university hospital and the perspective of the UUDCs that centralization as meaningful by its UUDC (0.024). Under assumptions permissible for modeling, the average number of in-house PeCa cases in academic hospitals in G + A was approximately 30 times higher than in nonacademic hospitals. CONCLUSION: This study provides the first data on the perspectives of UUDCs in G + A concerning centralization of PeCa therapy management. Even without state-regulated centralization in G + A, there is currently a clear focusing of PeCa treatments in university hospitals. Further necessary steps toward a structured PeCa centralization are discussed in this manuscript.

[Clinical characteristics and prognostic factors of distant metastatic penile cancer].

OBJECTIVE: To investigate the clinical features of distant metastatic penile cancer (DMPC) and the factors influencing its prognosis. METHODS: We searched the Surveillance, Epidemiology and End Results Database for cases of DMPC diagnosed between 2004 and 2019, analyzed their clinical characteristics and the cancer-specific survival (CSS) rates relating to different factors using the Kaplan-Meier method and the differences among the variables by log-rank test. We determined the variables independently associated with CSS by Cox regression analysis. RESULTS: According to the inclusion criteria, 108 cases of DMPC were identified. The patients were mainly married White people, with a median CSS of 9 months, and 1-, 2- and 3-year CSS rates of 36.4%, 17.8% and 13.5%, respectively. Pairwise comparison showed no statistically significant differences in the median overall CSS among the patients in the surgery, chemotherapy and surgery + chemotherapy groups (8 mo vs 9 mo vs 13 mo, P > 0.05). Race was an independent factor affecting the prognosis of CSS. CONCLUSION: Distant metastatic penile cancer is a rare malignancy with poor prognosis, for which there have been no existing ideal treatment options.

Regional differences in penile cancer patient characteristics and treatment rates across the United States.

INTRODUCTION: We tested for regional-specific differences in patient, tumor and treatment characteristics as well as cancer-specific mortality (CSM) of squamous cell carcinoma of the penis (SCCP) patients, across the Surveillance, Epidemiology, and End Results (SEER) registries. METHODS: The SEER database (2000-2018) was used to tabulate patient (age at diagnosis, race/ethnicity), tumor (stage, grade, N-stage) and treatment characteristics (proportions of primary tumor surgery, local lymph node surgery, systemic therapy), according to 12 SEER registries. Multinomial regression models, as well as multivariable Cox regression models tested for CSM differences, adjusting for patient, tumor and treatment characteristics. RESULTS: In 5395 SCCP patients, registry-specific patient counts ranged from 2060 (38 %) to 64 (1 %). Differences across registries existed for race/ethnicity, stage, grade and N-stage. Additionally, in stage I-II SCCP patients, proportions of local tumor destruction (LTD) ranged from 19 % to 39 % and from 33 % to 61 % for partial penectomy. In stage III-IV SCCP patients, proportions of partial penectomy ranged from 40 % to 59 % and from 17 % to 50 % for radical penectomy. Local lymph node surgery ranged from 8 % to 24 % and proportions of systemic therapy ranged from 3 % to 14 %. Significant inter-registry differences remained, after adjustment for treatment proportions. Unadjusted five-year CSM ranged from 19 % to 32 %. In multivariable analyses, one registry exhibited significantly higher CSM (SEER registry 10, Hazard Ratio [HR] 1.48), relative to the largest reference registry (SEER registry 1, n = 2060). CONCLUSION: Important regional differences including patient, tumor and treatment characteristics exist for SCCP patients across SEER registries. After multivariable adjustment, no differences in CSM were recorded, with the exception of one registry.

Evaluation of Health-Related Quality of Life in Patients Receiving Treatment for Penile Cancer: A Single-Center Cross- Sectional Study.

INTRODUCTION: Penile cancer is one of the uncommon types of cancer in men. The treatment could significantly impact a patient's quality of life (QOL), leading to difficulties in fulfilling life functions. METHODS: This descriptive observational study aimed to describe a situation using a cross-sectional design objectively. The population of this study was all patients with a diagnosis of penile cancer who underwent therapy at the Haji Adam Malik Hospital from September 2020 to September 2021. Quality of life was assessed using EORTC QLQ-C30. RESULTS: The respondents' mean age and standard deviation were 54.44 and 8.647 years, respectively. The youngest was 38 years, while the oldest age was 64 years. Most respondents had no history of circumcision (55.6%). All respondents had a poor QOL based on the 28 components in the questionnaire. This study showed that erectile function, changes in sexual function, and overall sexual function were correlated with health-related quality of life (HRQoL) post-treatment. In general, lack of sexual activity is the primary factor responsible for decreasing HRQoL in penile cancer patients. It has been reported that 70% of patients experienced a negative impact on sexuality post-treatment. CONCLUSION: The quality of life in patients receiving treatment for penile cancer at RSUP H. Adam Malik, Medan, was poor. It is associated with a lack of sexual activity.

A Prospective Study of Chemoradiotherapy as Primary Treatment in Patients With Locoregionally Advanced Penile Carcinoma.

PURPOSE: Neoadjuvant chemotherapy followed by surgery for locoregionally advanced penile carcinoma (LAPSCC) is associated with severe toxicity and a 1-year survival probability of ∼50%. We aimed to evaluate the safety and efficacy of chemoradiotherapy (CRT) as the primary treatment for LAPSCC and the association of high-risk human papillomavirus (hrHPV) with the outcome. METHODS AND MATERIALS: This was a prospective, single-center, single-arm study of CRT in LAPSCC, defined as a large/inoperable primary tumor, large palpable nodes, suspicion of extranodal extension or pelvic nodal involvement, and no distant metastases. CRT consisted of 49.5 Gy (33 × 1.5 Gy) on affected inguinal and pelvic areas combined with intravenous mitomycin C on day 1 and capecitabine on radiation days. Primary tumors and positron emission tomography/computed tomography-positive deposits received a boost of 59.4 Gy (33 × 1.8 Gy). The response was evaluated by 18F-fluorodeoxyglucose positron emission tomography/computed tomography. If feasible, patients with residual/recurrent disease underwent salvage surgery. The primary endpoint was 1-year progression-free survival (PFS), reached when 1-year PFS was ≥50%. Other endpoints were 2-year PFS, overall survival, and toxicity rates. Kaplan-Meier survival curves were compared using the log-rank test. RESULTS: Thirty-three patients were included: 29 (88%) with stage IV disease (T4 any-N M0 and/or any-T N3 M0) and 8 (24%) with hrHPV-positive disease. Median follow-up was 41 months. Thirty-two completed CRT. Eleven (33%) experienced ≥1 grade 3 treatment-related adverse event. There were no grade 4 or 5 treatment-related events. Twenty-four patients (73%) responded, including 13 (39%) complete responses. Nine patients (27%) underwent salvage surgery, and an additional 8 patients underwent later surgery (together 52%). One- and 2-year PFS were 34% and 31%, respectively. One- and 2-year overall survival were 73% and 46%, respectively. No significant difference between patients with hrHPV-positive and -negative tumors was observed. CONCLUSIONS: CRT is a viable treatment option for LAPSCC with acceptable toxicity. CRT can result in an enduring response. If patients have residual tumor, salvage surgery is feasible. HrHPV status was not associated with outcomes.

European Association of Urology-American Society of Clinical Oncology Collaborative Guideline on Penile Cancer: 2023 Update.

CONTEXT: Penile cancer is a rare disease but has a significant impact on quality of life. Its incidence is increasing, so it is important to include new and relevant evidence in clinical practice guidelines. OBJECTIVE: To provide a collaborative guideline that offers worldwide physician and patient guidance for the management of penile cancer. EVIDENCE ACQUISITION: Comprehensive literature searches were performed for each section topic. In addition, three systematic reviews were conducted. Levels of evidence were assessed, and a strength rating for each recommendation was assigned according to the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) methodology. EVIDENCE SYNTHESIS: Penile cancer is a rare disease but its global incidence is increasing. Human papillomavirus (HPV) is the main risk factor for penile cancer and pathology should include an assessment of HPV status. The main aim of primary tumour treatment is complete tumour eradication, which has to be balanced against optimal organ preservation without compromising oncological control. Early detection and treatment of lymph node (LN) metastasis is the main determinant of survival. Surgical LN staging with sentinel node biopsy is recommended for patients with a high-risk (≥pT1b) tumour with cN0 status. While (inguinal) LN dissection remains the standard for node-positive disease, multimodal treatment is needed in patients with advanced disease. Owing to a lack of controlled trials and large series, the levels of evidence and grades of recommendation are low in comparison to those for more common diseases. CONCLUSIONS: This collaborative penile cancer guideline provides updated information on the diagnosis and treatment of penile cancer for use in clinical practice. Organ-preserving surgery should be offered for treatment of the primary tumour when feasible. Adequate and timely LN management remains a challenge, especially in advanced disease stages. Referral to centres of expertise is recommended. PATIENT SUMMARY: Penile cancer is a rare disease that significantly impacts quality of life. While the disease can be cured in most cases without lymph node involvement, management of advanced disease remains challenging. Many unmet needs and unanswered questions remain, underlining the importance of research collaborations and centralisation of penile cancer services.

2022 European guideline for the management of balanoposthitis.

BACKGROUND: This guideline is an update to the 2014 edition of the European guideline for the management of balanoposthitis. Balanoposthitis describes inflammation of the glans penis and prepuce and is caused by a range of disparate conditions including infection, dermatoses and premalignancy. OBJECTIVE: The main objectives of this guideline are to aid recognition of the symptoms and signs and complications of penile skin conditions and to offer recommendations on the diagnostic tests and treatment for a selected group of these conditions. METHODS: The previous guideline was updated following a literature review and priority was given to randomized controlled trial and systematic review evidence. RESULTS: The updated guideline includes amended management for infective balanitis to provide clear guidance for Group A streptococcal infections, management of on going Lichen sclerosus (to include circumcision and supportive management to reduce the recurrence of genital herpes and warts), additional regimens for Zoonoid change, use of calcineurin inhibitors in management and risk of premalignancy and change of nomenclaturefrom Premalignant conditions to Penile Intraepithelial neoplasia (PeIN). CONCLUSION: Balanoposthitis has a widerange of causes high quality evidence specific to the management of penile disease is not available for all the conditions described.

Melanoma of glans penis and urethra: A case report and systematic review of the literature of a rare and complex neoplasm.

OBJECTIVE: To evaluate the features and prognosis of melanoma of glans penis and urethra, with the presentation of a significant case report. MATERIALS AND METHODS: A systematic literature review was performed using the MEDLINE (PubMed) and Cochrane Libraries databases to identify all cases of male mucosal melanoma reported. RESULTS: Two hundred fifty-two patients with male mucosal primary melanoma were found. Glans penis and fossa navicularis as primary site includes the 81.6% of all lesions considered. Median Breslow's depth is 2.1 mm, whereas nine in situ melanomas have been reported. At the diagnosis, the disease was at a non-localized stage in 21.4% for glans penis melanomas and 11.7% urethral lesions, respectively. The 2 and 5-year survival for glans melanoma is 62.5% and 38.4%; higher rates were observed in the 2012-2020 period (76% and 58.8%, respectively). Two-year survival for urethral melanomas is 66.7%, while 5-year survival is 12.5%. 22 patients survived over 5 years with a Breslow's depth reported always < 3.3 mm. CONCLUSION: Melanoma of the glans penis and urethra is a rare neoplasm associated with a poor prognosis, however recent reports show higher survival rates. Surgery remains the mainstay for a localized disease. Taking into account the small number of cases reported, topical imiquimod seems to be a valid non-surgical alterative for melanoma in situ. The use of immunotherapy and targeted therapy should be considered only in an adjuvant setting according to the recommendations of cutaneous melanoma; however, additional clinical data on male mucosal melanoma are needed to draw definitive conclusions.