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.

International case series of metastasis to penis.

Objectives: To evaluate clinical characteristics associated with survival in patients with metastases to the penis. Methods: After approval by the IRB, records of collaborating centres in Leuven, London, Rostock, Amsterdam and Tampa were screened for men presenting with metastatic disease to penis. Multivariate logistic regression analyses were used to identify covariables associated with survival. We analysed clinical data on 34 patients. Results: Primary sites were most frequently prostate (n = 14, 41%) and bladder (n = 9, 26%). Twenty-eight of 34 (82%) presented with metachronous penile metastases, and 11 (32%) patients had penile metastases as the sole metastatic site. Penile metastatic locations were most frequently in the corpora (n = 18; 53%). Seven (21%) patients with penile metastases had priapism on presentation. Systemic therapy was frequent and variable (chemotherapy n = 12; immunotherapy n = 5; hormones n = 3). Local management included either surgery (n = 10) or RT (n = 8). Twelve- and 24-month overall survival rate were 67% and 35%, respectively. No clinical parameter including primary histology, synchronous or metachronous metastases or priapism showed statistical survival benefit or detriment. Conclusion: Metastasis to penis arises most frequently from pelvic primaries. Priapism does not appear to correlate with survival in this large, well-defined series.

Corporal Skip Metastases in Penile Squamous Cell Carcinoma: An Unknown and Distinct Pattern of Spread with Poor Prognosis.

BACKGROUND: Penile squamous cell carcinoma (PSCC) is characterised by stepwise lymphatic dissemination. Skip metastases (SkMs) are rare metastases in the corpus cavernosum or spongiosum without continuity to the primary tumour or its resection site. OBJECTIVE: To assess the distinct pattern of spread in SkM+ patients and the effect of SkM on prognosis. DESIGN, SETTING, AND PARTICIPANTS: We conducted a retrospective analysis of patients with SkM+ PSCC at ten high-volume international referral centres between January 2006 and May 2022. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We evaluated histopathological data, primary lymph node (LN) staging, and metastatic spread. We included a cohort of patients matched for pT stage, LN status, and grade who did not have SkM (SkM-) to compare the SkM prognosis and predictive value for cancer-specific mortality (CSM). RESULTS AND LIMITATIONS: Among the 63 SkM+ patients who met our inclusion criteria, the SkM diagnosis was synchronous in 54.0% and metastases were mostly located in the corpus cavernosum. SkM was symptomatic in 14% of cases, was detected on imaging in 32%, and was found incidentally on pathological examination in 27%. Fifty-one patients (81%) presented with positive LNs and 28 (44%) developed distant metastases. Seven patients (11%) presented with or developed distant metastasis without displaying any LN involvement. The 2-yr cancer-specific survival estimates were 36% (95% confidence interval [CI] 25-52%) for SkM+ and 66% (95% CI 55-80%) for matched SkM- patients (p < 0.001). On multivariable Cox regression analysis, SkM presence was an independent predictor for higher CSM (hazard ratio 2.05, 95% CI 1.06-4,12; p = 0.03). CONCLUSIONS: PSCC-related SkM is associated with aggressive disease behaviour and poor survival outcomes. Palpation of the entire penile shaft is essential, and distant staging is recommended in patients suspected of having SkM owing to the tendency for distant metastatic spread. PATIENT SUMMARY: We investigated outcomes for patients with cancer of the penis who had metastases in the tissues responsible for erection. We found that metastases in this location were associated with poor prognosis, even in the absence of more typical spread of cancer via the lymph nodes.

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.

Minimally invasive evaluation of the clinically negative inguinal node in penile cancer: Dynamic sentinel node biopsy.

The presence of lymph node metastasis is the most important prognostic factor in penile cancer (PeCa). Due to limited sensitivity of currently available imaging modalities, invasive staging approaches remain indispensable for adequate nodal staging. As an alternative to radical inguinal lymphadenectomy and with the aim to reduce morbidity, staging strategies such as modified lymphadenectomy and dynamic sentinel node biopsy (DSNB) have been introduced. Over the years, DSNB evolved into a safe and reliable staging technique when performed in high volume centers. Recent enhancements of the procedure such as Single-photon emission computed tomography/computed tomography (SPECT/CT) and the introduction of hybrid tracers have improved pre- and intraoperative sentinel node (SN) visualization. Other technologies such as superparamagnetic iron oxide nanoparticles could have a potential future role to further refine DSNB. Future efforts should be aimed at optimizing diagnostic accuracy whilst minimizing perioperative morbidity.

The role of fluorescent and hybrid tracers in radioguided surgery in urogenital malignancies.

The increasing availability of new imaging technologies and tracers has enhanced the application of nuclear molecular imaging in urogenital interventions. In this context, preoperative nuclear imaging and radioactivity-based intraoperative surgical guidance have become important tools for the identification and anatomical allocation of tumor lesions and/or suspected lymph nodes. Fluorescence guidance can provide visual identification of the preoperatively defined lesions during surgery. However, the added value of fluorescence guidance is still mostly unknown. This review provides an overview of the role of fluorescence imaging in radioguided surgery in urogenital malignancies. The sentinel node (SN) biopsy procedure using hybrid tracers (radioactive and fluorescent component) serves as a prominent example for in-depth evaluation of the complementary value of radio- and fluorescence guidance. The first large patient cohort and long-term follow-up studies show: 1) improvement in the SN identification rate compared to blue dye; 2) improved detection of cancer-positive SNs; and 3) hints towards a positive effect on (biochemical) recurrence rates compared to extended lymph node dissection. The hybrid tracer approach also highlights the necessity of a preoperative roadmap in preventing incomplete resection. Recent developments focus on receptor-targeted approaches that allow intraoperative identification of tumor tissue. Here radioguidance is still leading, but fluorescent and hybrid tracers are also finding their way into the clinic. Emerging multiwavelength approaches that allow concomitant visualization of different anatomical features within the surgical field may provide the next step towards even more refined procedures.

Defining the Tumor Microenvironment of Penile Cancer by Means of the Cancer Immunogram.

Current chemotherapeutic treatment for advanced penile squamous cell carcinoma has substantial side effects and no randomized data to support an overall survival benefit. Immunotherapy with checkpoint blockade is currently being tested in penile cancer patients in clinical trials. The high PD-L1 expression and CD8+ T-cell infiltration in penile cancer represent a promising prospect for immunotherapy response in the treatment of locally advanced disease. For efficacious immunotherapy treatment, a better understanding of the tumor microenvironment (TME) is critical. Here we use the structure revealed by cancer immunograms to define current knowledge of the penile cancer TME as a backbone for future research. PATIENT SUMMARY: Advanced penile cancer has a poor prognosis with a need for more effective therapy. In this manuscript we describe the potential of immunotherapy as a new treatment modality in penile cancer.