To Örebro University

OBJECTIVES: The objective of this study is to compare the use of lymph node surgery and complication rates before and after centralization of penile cancer (PeCa) surgery in Sweden. In January 2015, curative surgical care for PeCa was centralized to the Skåne University Hospital in Malmö and the Örebro University Hospital in Örebro.

PATIENTS AND METHODS: All 1079 patients with invasive PeCa in the Swedish National Penile Cancer Register (NPECR) diagnosed between 2009 and 2020 were included, 458 before and 621 after centralization. The proportion of patients subjected to lymph node surgery 2009-2014 versus 2015-2020 was compared using Pearson's Chi-squared test. Odds ratios (ORs) for complications were calculated using a logistic regression model adjusting for age, nodal stage and extent of penile surgery. Continuous variables were presented as medians and compared using Wilcoxon's rank sum test.

RESULTS: Before centralization, 270/458 (59%) of patients were subjected to lymph node surgery compared to 474/621 (76%) after 2014. Overall complication rate for patients undergoing such surgery was unaltered before and after centralization. The incidence of any complications increased after Dynamic Sentinel Lymph Node Biopsy from 18% (22/122) to 36% (91/256), corresponding to an adjusted OR of 1.89 (95% confidence interval [CI] 1.09-3.27). For lymphocele, lymphedema or infection after modified or radical inguinal or pelvic lymphadenectomy, the adjusted OR was 0.47 (95% CI 0.29-0.75) after centralization. The register-based setting is a study limitation.

CONCLUSIONS: The proportion of men undergoing lymph node surgery increased, and the risk of lymphocele, lymphedema and infection after inguinal and pelvic lymph node surgery decreased after centralization of PeCa care.

Introduction & Objectives: Penile cancer (PeCa) surgery was in 2015 centralized to two hospitals in Sweden. This study compares the use of lymph node surgery and complication rates before and after centralization.

Materials & Methods: All 1079 patients with invasive PeCa in the Swedish National Penile Cancer Register (NPECR) diagnosed between 2009 and 2020 were included, 458 before and 621 after centralization. The proportion of patients subjected to lymph node surgery 2009-2014 vs 2015-2020 was compared using Pearson’s Chi-squared test. Odds ratios (OR) for complications were calculated using a logistic regression model adjusting for age, nodal stage, and extent of penile surgery. Continuous variables were presented as medians with inter quartile ranges and compared with Wilcoxon’s rank sum test.

Results: Before centralization 270/458 (59 %) of patients were subjected to lymph node surgery compared to 474/621 (76 %) after 2014. Overall complication rate for patients undergoing such surgery was unaltered (35 %) before and after centralization. Complications after Dynamic Sentinel Lymph Node Biopsy increased from 17 % (22/126) to 32 % (91/288), corresponding to an adjusted OR of 1.89 (95 % confidence interval (CI) 1.09-3.27). For lymphocele, lymphedema or infection after modified or radical inguinal or pelvic lymphadenectomy, the adjusted OR was 0.47 (95 % CI 0.29-0.75) after centralization. The register-based setting is a study limitation.

Conclusions: The proportion men undergoing lymph node surgery increased, and risk of lymphocele, lymphedema and infection after inguinal and pelvic lymph node surgery decreased after centralization of PeCa care.

The aim of this thesis is to optimise the clinical management and prognostic evaluation of penile cancer (PeCa) by investigating its long-term consequences and treatment-related morbidity, as well as by evaluating current surgical strategies and novel biomarker-based approaches for accurate lymph node staging.

In Paper I, nationwide register data demonstrated that patients with PeCa face a two- to threefold increased risk of developing second HPV-associated malignancies in the oral cavity, oropharynx, and anal canal, highlighting the need for improved surveillance and preventive measures. In Paper II, population-based analyses demonstrated that morbidity following lymph node dissection remains substantial overtime, with significantly elevated risks of infectious complications persisting for more than five years and thromboembolic events for up to three years postoperatively, underscoring the importance of long-term complication awareness. In Paper III, an evaluation of a panel of 14 soluble immune checkpoint proteins (sICs) for predicting lymphnode metastases (LNM) revealed limited clinical utility due to low sensitivity and modest accuracy. However, four inhibitory sICs (IDO,TIM-3, CD80, and CTLA-4) were significantly elevated in patients with PeCa compared to cancer-free controls, suggesting tumour-induced systemic immunosuppression. In Paper IV, dynamic sentinel node biopsy (DSNB) was shown to effectively detect LNM while maintaining favourable morbidity, although a false-negative rate of 14.5% was observed during a median follow-up of 34 months. Complications, predominantly mild to moderate, occurred in 14.8% of groins and were directly associated with higher lymph node yields, emphasizing the critical importance of precise and targeted excision of true sentinel nodes.

BACKGROUND: Penile cancer (PeCa) is a rare but aggressive disease where lymph node metastases (LNM) represent the most significant prognostic factor. Accurate identification of LNM remains a clinical priority, but traditional imaging and clinical parameters often fail to detect occult LNM. Soluble immune checkpoint proteins (sICs) have recently emerged as potential non-invasive biomarkers in various malignancies, although unexplored in PeCa. The primary aim of this study was to explore the value of a panel of 14 sICs for predicting LNM in PeCa. The secondary aim was to compare plasma sIC levels between PeCa patients and cancer-free controls.

METHODS: Using ProcartaPlex immunoassays, BTLA, IDO, LAG-3, HVEM, PD-1, PD-L1, PD-L2, TIM-3, CD80, CTLA-4, GITR, CD27, CD28, and CD137 were measured in plasma from 284 PeCa patients and 45 cancer-free controls. PeCa patients were divided into a training set (n=202) and a test set (n=82). A prediction model for LNM was created using logistic regression.

RESULTS: Overall accuracy of the prediction model reached 77.5% (95% CI: 70.9 - 83.3) for the training set, yielding 8.9% sensitivity and 99.3% specificity in predicting LNM. Upon validation using the test set, the accuracy decreased to 62.2% (95% CI: 50.8-72.7) with 17.9% sensitivity and 85.2% specificity. When comparing PeCa patients and cancer-free controls, four inhibitory sICs (IDO, TIM-3, CD80, and CTLA-4) were found at significantly higher levels in the PeCa group. Due to the rarity of the disease, the main limitation of the study is the small number of patients with LNM.

CONCLUSION: Our study provides no evidence that sICs can predict LNM in PeCa, although four inhibitory sICs were significantly elevated in PeCa patients compared to cancer-free controls, suggesting systemic immunosuppression associated with tumor presence, consistent with findings in other malignancies. Studies with larger cohorts are warranted to clarify the prognostic significance of sICs in PeCa.

BACKGROUND: Dynamic sentinel node biopsy (DSNB) is the currently preferred staging method of high-risk penile cancer (PeCa) patients with cN0 disease. Recently, there have been advancements in the surgical approach and techniques. This study aims to compare the contemporary DSNB practice and techniques amongst European referral centers.

MATERIALS AND METHODS: An online survey was sent to members of the EAU YAU Penile and Testis Cancer working group. These questions delved into various facets of DSNB, encompassing imaging techniques, tracers, surgical approaches, and postoperative patient care. Participating centers were also required to provide video-recorded DSNB procedures in a standardized manner for a comparative analysis of technical nuances.

RESULTS: Responses were received from twelve Urologists from nine European centers. Overall, 83% and 42% of surgeons performed >10 and >50 DSNB procedures per year, respectively. There is a broad consensus on the technique and site of tracer injections. Conversely, 50% of centers use lymphoscintigraphy, 17% use SPECT/CT, while 33% utilize both imaging modalities. The predominant choice of dye is Patent V/blue, but 25% of centers use Indocyanine Green (ICG). Notable variability exists in surgical incision sites and lymphatic ligation techniques. The consensus is leaning towards not leaving a wound drain. Overall, 83% of centers adopt antibiotic surgical prophylaxis, with 83% discontinuing it postoperatively. A quarter of centers would advocate for patients to be discharged with thromboprophylaxis, either using low molecular weight heparin or thromboembolic deterrent stockings. On average, the postoperative length of stay in hospital is 1 day.

CONCLUSIONS: Variation exists in procedural aspects and postoperative management among centers performing DSNB for PeCa. Newer technologies like fluorescence imaging and SPECT/CT are used in some European centers, but high-quality evidence is sparse, highlighting the need for extensive multicenter research into surgical outcomes and emerging technologies.

Introduction: Curative penile cancer (PeCa) surgery was in 2015 centralized to two hospitals in Sweden. This study compares the use of lymph node surgery and complication rates before and after the centralization.

Method: All 1079 patients with invasive PeCa in the Swedish National Penile Cancer Register (NPECR) diagnosed between 2009 and 2020 were included, 458 before and 621 after centralization. Proportion of patients subjected to lymph node surgery 2009-2014 vs 2015-2020 was compared with Pearson’s Chi-squared test. Odds ratios (OR) for complications were calculated using a logistic regression model adjusting for age, nodal stage, and extent of penile surgery. Continuous variables were presented as medians with inter quartile ranges (IQR) and compared with Wilcoxon’s rank sum test.

Results: Before centralization 270/458 (59%) of patients were subjected to lymph node surgery compared to 474/621 (76%) after 2014. Overall complication rate for patients undergoing such surgery was similar (35%) before and after centralization. After Dynamic Sentinel Node Biopsy (DSNB) overall complications increased from 17% (22/126) to 32% (91/288) after centralization corresponding to an adjusted OR of 1.89 (95% confidence interval (CI) 1.09-3.27). For lymphocele, lymphedema or infection after modified or radical inguinal lymphadenectomy or pelvic lymphadenectomy, the adjusted OR was 0.47 (95% CI 0.29-0.75) after centralization. The register-based setting is a study limitation.

Conclusion: The proportion men receiving lymph node surgery increased and risk of lymphedema, lymphocele and infection after inguinal and pelvic lymph node surgery decreased after centralization of PeCa care. 

Introduction & Objectives: Immune checkpoint proteins are recognized as critical regulators of the immune system and play an important role in the defence against cancer. Unfortunately, cancer cells evade the immune destruction by overexpressing inhibitory checkpoint proteins, hence creating a favourable tumour microenvironment. Recently, it has been proposed that immune checkpoint proteins can be detected in soluble form in body fluids. This is important since a blood sample is less invasive than a tissue sample and hypotheticall yhas the potential to be more representative. The aim of the study was to evaluate the concentrations of soluble immune inhibitory checkpoint proteins (sICs) in men with and without penile cancer.

Materials & Methods: The circulating levels of ten soluble immune inhibitory checkpoint proteins (TIM-3, CD152, HVEM, IDO, LAG-3, BTLA, CD80, PD-1, PD-L1 and PD-L2) were assessed in plasma of 206 men with penile cancer (cases) and 46 men free from penile cancer (controls) using a multiplex Luminex assay. Mean concentrations of sICs were calculated and bootstrap resampling together with Welch's t-tests were used to assess differential expression and distribution of sICs between cases and controls.

Results: HVEM was detectable in 87% of the samples. PD-L1 was only detectable in 43.3% and therefore excluded from further analyses. The remaining markers were detectable in all samples. When comparing the mean concentrations of soluble immune inhibitory checkpoint proteins, nine sICs were found in higher concentrations in cases compared to controls, out of which seven reached statistical significance (Table 1).

Conclusions: Our study indicates that men with penile cancer have higher concentrations of soluble immune inhibitory checkpoint proteins in plasma compared to penile cancer-free men. Further studies are needed to evaluate their prognostic value

OBJECTIVE: The Swedish national guidelines on penile cancer were first published in 2013. The objective of the present study is to present the 2023 update of these guidelines and highlight the differences to the European Association of Urology (EAU) / American Association of Clinical Oncology (ASCO) guidelines on penile cancer.

MATERIAL AND METHODS: A review of the literature and a comparison to the EAU / ASCO guideline on penile cancer was performed. Differences between the EAU / ASCO guidelines and the Swedish national guidelines are highlighted.  

Results: The Swedish national guidelines on penile cancer emphasized the consultation of a national multidisciplinary treatment conference for all patients diagnosed with both primary and recurrent penile cancer or penile intraepithelial neoplasia (PeIN). Clinically lymph node negative patients diagnosed with >pT1G1 are offered dynamic sentinel node biopsy (DSNB). In the EAU / ASCO guidelines the DSNB is optional for T1aG2 patients. Penile cancer surgery is centralized to two hospitals. Perioperative chemotherapy is offered to patients with ≥N2. In the EAU / ASCO guidelines the use of perioperative chemotherapy for N2 patients is optional. A structured follow-up program is advocated to find recurrences at an early stage.

CONCLUSIONS: The Swedish national guidelines on penile cancer have been updated and compared to the EAU / ASCO guidelines. The national multidisciplinary treatment conference, centralization of surgery, the use of perioperative chemotherapy and a structured follow-up are the cornerstones of the Swedish national guidelines on penile cancer.

OBJECTIVE: The National Penile Cancer Register (NPECR) in Sweden was initiated in year 2000 and currently contains more than 3,900 men diagnosed with penile cancer. The aim of this study was to evaluate data quality in the NPECR in terms of completeness, timeliness, comparability, and validity.

MATERIAL AND METHODS: Completeness was assessed by cross-linkage to the Swedish Cancer Register. Timeliness, defined as time from date of diagnosis to date of reporting in the NPECR, was calculated. Comparability was evaluated by reviewing and comparing coding routines in the NPECR with national and international guidelines. To assess validity, medical records of 375 men with a penile cancer diagnosis in the NPECR between 2017 and 2020 were reviewed and selected variables were re-abstracted and compared with previously registered data.

RESULTS: Completeness was high (93%). Timeliness was in median 4.6 (Inter Quartile Range 2.6-8.8) months. Comparability was good with coding routines and the registration forms were in compliance with current guidelines. Overall, the validity was high. The majority of variables showed an exact agreement exceeding 90%.

CONCLUSION: Data quality in the Swedish NPECR is generally high with respect to completeness, timeliness, comparability, and validity. Hence, the NPECR represents a reliable data source for monitoring the quality of penile cancer care and research. Data quality can be further improved by revision of reporting forms and manuals, training of reporting staff, and by organizational adjustments.