Prognostic factors for relapse in patients with clinical stage I testicular non-seminoma: A nationwide, population-based cohort study.

BACKGROUND: Approximately 30% of patients with clinical stage I non-seminoma (CSI-NS) relapse. Current risk stratification is based on lymphovascular invasion (LVI) alone. The extent to which additional tumor characteristics can improve risk prediction remains unclear. OBJECTIVE: To determine the most important prognostic factors for relapse in CSI-NS patients. DESIGN, SETTING, AND PARTICIPANTS: Population-based cohort study including all patients with CSI-NS diagnosed in Denmark between 2013 and 2018 with follow-up until 2022. Patients were identified in the prospective Danish Testicular Cancer database. By linkage to the Danish National Pathology Registry, histological slides from the orchiectomy specimens were retrieved. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Histological slides were reviewed blinded to the clinical outcome. Clinical data were obtained from medical records. The association between prespecified potential prognostic factors and relapse was assessed using Cox regression analysis. Model performance was evaluated by discrimination (Harrell's C-index) and calibration. RESULTS: Of 453 patients included, 139 patients (30.6%) relapsed during a median follow-up of 6.3 years. Tumor invasion into the hilar soft tissue of the testicular hilum, tumor size, LVI and embryonal carcinoma were independent predictors of relapse. The estimated 5-year risk of relapse ranged from < 5% to > 85%, depending on the number of risk factors. After internal model validation, the model had an overall concordance statistic of 0.75. Model calibration was excellent. CONCLUSION AND RELEVANCE: The identified prognostic factors provide a much more accurate risk stratification than current clinical practice, potentially aiding clinical decision-making.

Prognostic Factors for Relapse in Patients With Clinical Stage I Testicular Seminoma: A Nationwide, Population-Based Cohort Study.

PURPOSE: Approximately 20% of patients with clinical stage I seminoma relapse. Tumor size and rete testis invasion have been identified as risk factors for relapse. However, the level of evidence supporting the use of these risk factors in clinical decision making is low. Previous studies have been hampered by selection bias and variable pathology reporting that limit interpretation and generalization of results. We assessed prognostic factors for relapse in an unselected nationwide population-based setting with centralized pathology review. METHODS: Patients with clinical stage I seminoma diagnosed from January 2013 to December 2018 were identified in the prospective Danish Testicular Cancer database. By linkage to the Danish National Pathology Registry, histologic slides from the orchiectomy specimens were retrieved and reviewed blinded to the clinical outcome. Clinical data were obtained from medical records with follow-up until July 2022. The association between prespecified potential clinical and histopathologic prognostic factors and relapse was assessed by the use of Cox regression analysis. RESULTS: Of 924 patients included, 148 (16%) patients relapsed during a median follow-up of 6.3 years. Invasion of the testicular hilum (rete testis and hilar soft tissue), lymphovascular invasion, and elevated preorchiectomy levels of ß-human chorionic gonadotropin and lactate dehydrogenase were independent predictors of relapse. The estimated 5-year risk of relapse ranged from 6% in patients with no risk factors to 62% in patients with all four risk factors with tumor extension into the hilar soft tissue of the testicular hilum. After internal model validation, the prognostic model had an overall concordance statistic of 0.70. CONCLUSION: The provided prognostic factors could replace current risk factors in guidelines and be used in future studies investigating risk-adapted follow-up and treatment strategies.

A Validated Algorithm for Register-Based Identification of Patients with Relapse of Clinical Stage I Testicular Cancer.

Purpose: The Danish Testicular Cancer (DaTeCa) database aims to monitor and improve quality of care for testicular cancer patients. Relapse data registered in the DaTeCa database rely on manual registration. Currently, some safeguarding against missing registrations is attempted by a non-validated register-based algorithm. However, this algorithm is inaccurate and entails time-consuming medical record reviews. We aimed (1) to validate relapse data as registered in the DaTeCa database, and (2) to develop and validate an improved register-based algorithm identifying patients diagnosed with relapse of clinical stage I testicular cancer. Patients and Methods: Patients registered in the DaTeCa database with clinical stage I testicular cancer from 2013 to 2018 were included. Medical record information on relapse data served as a gold standard. A pre-specified algorithm to identify relapse was tested and optimized on a random sample of 250 patients. Indicators of relapse were obtained from pathology codes in the Danish National Pathology Register and from diagnosis and procedure codes in the Danish National Patient Register. We applied the final algorithm to the remaining study population to validate its performance. Results: Of the 1377 included patients, 284 patients relapsed according to the gold standard during a median follow-up time of 5.9 years. The completeness of relapse data registered in the DaTeCa database was 97.2% (95% confidence interval (CI): 95.2-99.1). The algorithm achieved a sensitivity of 99.6% (95% CI: 98.7-100), a specificity of 98.9% (95% CI: 98.2-99.6), and a positive predictive value of 95.9% (95% CI: 93.4-98.4) in the validation cohort (n = 1127, 233 relapses). Conclusion: The registration of relapse data in the DaTeCa database is accurate, confirming the database as a reliable source for ongoing clinical quality assessments. Applying the provided algorithm to the DaTeCa database will optimize the accuracy of relapse data further, decrease time-consuming medical record review and contribute to important future clinical research.

Exercise training to increase tumour natural killer-cell infiltration in men with localised prostate cancer: a randomised controlled trial.

OBJECTIVES: To explore the effects of preoperative high-intensity interval training (HIIT) compared to usual care on tumour natural killer (NK)-cell infiltration in men with localised prostate cancer (PCa), as NK-cell infiltration has been proposed as one of the key mechanisms whereby exercise can modulate human tumours. PATIENTS AND METHODS: A total of 30 patients with localised PCa undergoing radical prostatectomy (RP) were randomised (2:1) to either preoperative aerobic HIIT four-times weekly (EX; n = 20) or usual care (CON; n = 10) from time of inclusion until scheduled surgery. Tumour NK-cell infiltration was assessed by immunohistochemistry (CD56+ ) in diagnostic core needle biopsies and corresponding prostatic tissue from the RP. Changes in cardiorespiratory fitness, body composition, blood biochemistry, and health-related quality of life were also evaluated. RESULTS: The change in tumour NK-cell infiltration did not differ between the EX and CON groups (between-group difference: -0.09 cells/mm2 , 95% confidence interval [CI] -1.85 to 1.66; P = 0.913) in the intention-to-treat analysis. The total number of exercise sessions varied considerably from four to 30 sessions. The per-protocol analysis showed a significant increase in tumour NK-cell infiltration of 1.60 cells/mm2 (95% CI 0.59 to 2.62; P = 0.004) in the EX group. Further, the total number of training sessions was positively correlated with the change in NK-cell infiltration (r = 0.526, P = 0.021), peak oxygen uptake (r = 0.514, P = 0.035) and peak power output (r = 0.506, P = 0.038). CONCLUSION: Preoperative HIIT did not result in between-group differences in tumour NK-cell infiltration. Per-protocol and exploratory analyses demonstrate an enhanced NK-cell infiltration in PCa. Future studies are needed to test the capability of exercise to increase tumour immune cell infiltration.

Effects of acute exercise training on tumor outcomes in men with localized prostate cancer: A randomized controlled trial.

Postdiagnosis physical activity is associated with improved cancer outcomes, but biological mechanisms mediating anticancer effects remain unclear. Recent findings suggest that physiological adaptations to acute exercise comprise potential anticancer effects, but these remain poorly explored in clinical settings. The objective of this study was to explore the effects of a single exercise bout on tumor oxygenation and immune cell infiltration in patients with prostate cancer. Thirty patients with localized prostate cancer were randomized (2:1) to either one high-intensity interval training bout or no exercise on the day before radical prostatectomy. Immunohistochemical analyses were performed on prostatic tissue from surgery and assessed for tumor hypoxia, natural killer (NK) cell infiltration, and microvessel density (MVD). Acute systemic response in blood lymphocytes, epinephrine, norepinephrine, IL-6, tumor necrosis factor, cortisol, lactate, and glucose was also evaluated. We did not find between-group differences in tumor hypoxia (Mann-Whitney U test, U = 83.5, p = 0.604) or NK cell infiltration (U = 77.0, p = 0.328). Also, no significant correlation was found between MVD and tumor hypoxia or NK cell infiltration. One exercise bout is likely insufficient to modulate tumor hypoxia or NK cell infiltration. Future studies may elucidate if an accumulation of several exercise bouts can impact these outcomes (NCT03675529, www.clinicaltrials.gov).

PD-L1 expression and FGFR-mutations among Danish patients diagnosed with metastatic urothelial carcinoma: A retrospective and descriptive study.

Checkpoint inhibitors have changed the treatment landscape of advanced urothelial carcinoma (mUC), and recently, a fibroblast-growth-factor-receptor (FGFR) inhibitor has been introduced. This study aimed at estimating programmed death-ligand 1 (PD-L1) expression in primary tumors (PTs) and the PD-L1 expression concordance between PTs and paired metastases in 100 patients with UC managed in the real-world setting. Further, the aim was to investigate FGFR1-3 aberrations and the correlation between FGFR1-3 aberrations and PD-L1 expression. PD-L1 immunohistochemistry was performed on 100 formalin-fixed paraffin-embedded archival primary UC samples and 55 matched metastases using the 22C3 PD-L1 assay. PD-L1 expression was determined by the combined positive score, considered positive at ≥10. Targeted next-generation sequencing on the S5+/Prime System with the Oncomine Comprehensive Assay version 3 was used to detect FGFR1-3 aberrations in PTs. We found that 29 of 100 PTs had positive PD-L1 expression. The PD-L1 concordance rate was 71%. FGFR1-3 aberrations were observed in 18% of PTs, most frequently FGFR3 amplifications or mutations. We found no association between FGFR1-3 aberrations and PT PD-L1 expression (p = 0.379). Our data emphasize the need for further studies in predictive biomarkers.

RANKL regulates testicular cancer growth and Denosumab treatment has suppressive effects on GCNIS and advanced seminoma.

BACKGROUND: Testicular germ cell tumours (TGCTs) have a high sensitivity to chemotherapy and a high cure rate, although with serious adverse effects. In the search for tumour suppressive drugs, the RANKL inhibitor Denosumab, used to treat osteoporosis, came up as a candidate since RANKL signalling was recently identified in the testis. METHODS: Expression of RANKL, RANK and OPG, and the effects of RANKL inhibition were investigated in human TGCTs, TGCT-derived cell-lines, and TGCT-xenograft models. Serum RANKL was measured in TGCT-patients. RESULTS: RANKL, RANK, and OPG were expressed in germ cell neoplasia in situ (GCNIS), TGCTs, and TGCT-derived cell lines. RANKL-inhibition reduced proliferation of seminoma-derived TCam-2 cells, but had no effect on embryonal carcinoma-derived NTera2 cells. Pretreatment with Denosumab did not augment the effect of cisplatin in vitro. However, inhibition of RANKL in vivo reduced tumour growth exclusively in the TCam-2-xenograft model and Denosumab-treatment decreased proliferation in human GCNIS cultures. In TGCT-patients serum RANKL had no prognostic value. CONCLUSIONS: This study shows that the RANKL signalling system is expressed in GCNIS and seminoma where RANKL inhibition suppresses tumour growth in vitro and in vivo. Future studies are needed to determine whether RANKL is important for the malignant transformation or transition from GCNIS to invasive tumours.

A Nationwide Analysis of Risk of Prostate Cancer Diagnosis and Mortality following an Initial Negative Transrectal Ultrasound Biopsy with Long-Term Followup.

PURPOSE: Magnetic resonance imaging (MRI) targeted prostate biopsy has been shown to find many high-grade prostate cancers in men with concurrent negative transrectal ultrasound (TRUS) systematic biopsy. The oncologic risk of such tumors can be explored by looking at long-term outcomes of men with negative TRUS biopsy followed without MRI. The aim was to analyze the mortality after initial and second negative TRUS biopsy. MATERIALS AND METHODS: All men who underwent initial TRUS biopsies between January 1, 1995 and December 31, 2016 in Denmark were included. A total of 37,214 men had a negative initial TRUS biopsy and 6,389 underwent a re-biopsy. Risk of cause-specific mortality was analyzed with competing risks. Diagnosis of Gleason score ≥7 prostate cancer following negative biopsies was analyzed with multivariable logistic regression including time to re-biopsy, prostate specific antigen (PSA), age and digital rectal examination. RESULTS: The 15-year prostate cancer-specific mortality was 1.9% (95% CI: 1.7-2.1). Prostate cancer-specific mortality was 1.3% (95% CI: 0.9-1.6) and 4.6% (95% CI: 3.4-5.8) for men with PSA <10 and >20 ng/ml, respectively. Of the TRUS re-biopsies 12% were Gleason score ≥7 and risk of Gleason score ≥7 increased with longer time to re-biopsy (p <0.001). Mortality after re-biopsy was similar to after initial biopsy. CONCLUSIONS: Men with negative TRUS biopsies have a very low prostate cancer-specific mortality, especially with PSA <10 ng/ml. This raises serious questions about the routine use of MRI targeting for initial prostate biopsy and suggests that MRI targeting should only be recommended for men with PSA >10 ng/ml after negative biopsy.

Detection of Clinically Significant Prostate Cancer by Systematic TRUS-Biopsies in a Population-Based Setting Over a 20 Year Period.

OBJECTIVE: To assess the performance of systematic TRUS-biopsies in a population-based setting to detect clinically significant PCa (csPCa) in combination with age, clinical tumor category (cT), and prostate-specific antigen (PSA) in men referred for the first biopsy. METHODS: We identified all men referred for PCa work-up because of elevated PSA who underwent initial TRUS-biopsies in the nationwide Danish Prostate Cancer Registry (DaPCaR) between January 1st, 1995 and December 31st, 2016, in Denmark. Risk of histologic findings in initial TRUS-biopsies categorized as non-malignant, insignificant PCa, or significant PCa (csPCa). We defined csPCa as any biopsy containing Gleason score 3 + 4 or above as in the PRECISION trial. We assessed risk of csPCa with absolute risk, logistic regression model, and predicted risks. RESULTS AND LIMITATIONS: After exclusions, our cohort included 39,886 men. The diagnostic hit rate for csPCa was 40.8 %. Men with PSA > 20 ng/mL and ≥cT2 harbor a risk >75% for finding csPCa in the first TRUS biopsy-set. Men with cT1 tumors and PSA < 20 ng/mL have a risk of non-malignant histology of at least 58%. Limitations include the high number of exclusions based on missing information. CONCLUSION: The diagnostic accuracy of systematic TRUS-biopsies is high for men with palpable tumors and high PSA. Our data point to the fact that not all men need pre-biopsy MRI to find csPCa.

Pheochromocytoma induced cardiomyopathy in a young man: a case report.

Pheochromocytoma is a tumor arising from the adrenal medulla, most frequent benign and, due to the excretion of catecholamines, a rare cause of hypertension. The diagnosis of pheochromocytoma can be challenging because of its episodic nature, unspecific symptoms and rarity. Consequently, treatment can be delayed with serious consequences for the patient. We present a case report regarding a young man with episodes of severe hypertension over a period of at least 9 years. Ultimately, with a possible trigger effect from the intake of multiple energy drinks, the patient presented with severe hypertension, symptoms mimicking acute coronary syndrome, abnormal laboratory parameters and echocardiography suggestive of severe cardiomyopathy. The patient's pheochromocytoma was incidentally identified in a computed tomography scan during the initial workup. Although a rare condition, pheochromocytoma should be considered as a differential diagnosis, especially in young patients presenting with unexplained hypertension, chest pain and cardiac dysfunction.

AZGP1 Protein Expression in Hormone-Naïve Advanced Prostate Cancer Treated with Primary Androgen Deprivation Therapy.

Biomarkers for predicting the risk of castration-resistant prostate cancer (CRPC) in men treated with primary androgen deprivation therapy (ADT) are lacking. We investigated whether Zinc-alpha 2 glycoprotein (AZGP1) expression in the diagnostic biopsies of men with hormone-naïve prostate cancer (PCa) undergoing primary ADT was predictive of the development of CRPC and PCa-specific mortality. The study included 191 patients who commenced ADT from 2000 to 2011. The AZGP1 expression was evaluated using immunohistochemistry and scored as high or low expression. The risks of CRPC and PCa-specific mortality were analyzed using stratified cumulative incidences and a cause-specific COX regression analysis for competing risk assessment. The median follow-up time was 9.8 (IQR: 6.1-12.7) years. In total, 94 and 97 patients presented with low and high AZGP1 expression, respectively. A low AZGP1 expression was found to be associated with a shorter time to CRPC when compared to patients with a high AZGP1 expression (HR: 1.5; 95% CI: 1.0-2.1; p = 0.03). However, the multivariable analysis demonstrated no added benefit by adding the AZGP1 expression to prediction models for CRPC. No differences for PCa-specific mortality between the AZGP1 groups were observed. In conclusion, a low AZGP1 expression was associated with a shorter time to CRPC for PCa patients treated with first-line ADT but did not add any predictive information besides well-established clinicopathological variables.

Luteinizing Hormone Receptor Is Expressed in Testicular Germ Cell Tumors: Possible Implications for Tumor Growth and Prognosis.

Luteinizing hormone/choriogonadotropin receptor (LHCGR) regulates gonadal testosterone production and recent studies have suggested a growth-regulatory role in somatic cancers. Here, we established that LHCGR is expressed in a fraction of seminoma cells and germ cell neoplasia in situ (GCNIS), and the seminoma-derived cell line TCam2 released LHCGR into the medium. LH treatment induced proliferation of TCam2 cells in vitro, while hCG treatment induced a non-significant 51% increase in volume of tumors formed in a TCam2 xenograft model. A specific ELISA was used to detect a soluble LHCGR in serum. Serum concentrations of soluble LHCGR could not distinguish 4 patients with GCNIS and 216 patients with testicular germ cell tumors (TGCTs) from 297 infertile or 148 healthy young men. Instead, serum LHCGR levels were significantly higher in 112 patients with a seminoma > 5 cm or elevated serum lactate dehydrogenase (LDH) compared with men harboring smaller seminomas < 2 cm or normal LDH levels. Serum LHCGR levels in TGCT patients could not predict relapse irrespective whether determined pre- or post-orchiectomy. Combined, these novel findings suggest that LHCGR may be directly involved in the progression and growth of seminomas, and our retrospective pilot study suggests that serum LHCGR may have some prognostic value in men with seminoma.

[Tumour of the ureter surprisingly turned out to be localised amyloidosis].

Localised amyloidosis in the urinary tract is a rare and often benign condition, which is usually clinically mistaken for malignancy. I this case report, a 48-year-old man was referred to the hospital with left flank pain, and CT-urography showed a tumour with calcification in the distal ureter. During transurethral procedure, the tumour was resected macroscopically. Histology revealed the diagnosis of amyloidosis. Follow-up was without signs of systemic involvement or recurrence. This case underlines the significance of preoperative diagnostic biopsy, thus saving the patient from unnecessary major surgery.

Prognostic factors for relapse in patients with clinical stage I testicular cancer: protocol for a Danish nationwide cohort study.

INTRODUCTION: Approximately one-fourth of patients with clinical stage I testicular germ cell cancer will relapse within 5 years of follow-up. Certain histopathological features in the primary tumour have been associated with an increased risk of relapse. The available evidence on the prognostic value of the risk factors, however, is hampered by heterogeneity of the study populations included and variable reporting of the histopathological features. The aim of this study is to identify pathological risk factors for relapse in an unselected large nationwide cohort of patients with stage I disease. METHODS AND ANALYSIS: All incident cases of stage I testicular germ cell cancer diagnosed in Denmark between 2013 and 2018 will be identified using the nationwide prospective Danish Testicular Cancer (DaTeCa) database. Archived microscopic slides from the orchiectomy specimens will be retrieved through linkage to the Danish Pathology Data Bank and reviewed blinded to the clinical outcome. The DaTeCa database includes 960 stage I seminoma patients with expected 185 relapses and 480 patients with stage I non-seminoma with expected 150 relapses. A minimum follow-up period of 3 years of all patients will be ensured. Predefined prognostic variables will be investigated with regard to relapse in univariable and multivariable analysis using the Cox proportional hazards model. ETHICS AND DISSEMINATION: This study protocol has been approved by the Regional Ethics Committee (Region Zealand, Denmark) and the Danish Data Protection Agency. All data will be managed confidentially according to legislation. Study results will be presented at international conferences and published in peer-review journals.

Predictive value of AZGP1 following radical prostatectomy for prostate cancer: a cohort study and meta-analysis.

AIMS: Zinc-alpha 2-glycoprotein (AZGP1) is a promising tissue biomarker to predict outcomes in men undergoing treatment for localised prostate cancer (PCa). We aimed to examine the association between AZGP1 expression and the endpoints: risk of biochemical failure (BF), initiating castration-based treatment, developing castration-resistant PCa (CRPC) and PCa-specific mortality following radical prostatectomy (RP). METHODS: The study included a prospective cohort of 302 patients who underwent RP for PCa from 2002 to 2005. AZGP1 expression was analysed using immunohistochemistry on tissue microarray RP specimens and was scored semiquantitively as low or high expression. Risk of all endpoints was analysed using stratified cumulative incidences and cause-specific Cox regression, and validated with receiver operating curves, calibration and discrimination in competing-risk analyses. A meta-analysis was performed including previous studies investigating AZGP1 expression and risk of BF following RP. RESULTS: Median time of follow-up was 14.0 years. The cumulative incidence of all endpoints was significantly higher in patients with low AZGP1 expression compared with patients with high AZGP1 expression (p<0.001). In a multivariate analysis, low AZGP1 expression increases the risk of BF (HR 2.7; 95% CI 1.9 to 3.8; p<0.0001), castration-based treatment (HR 2.2; 95% CI 1.2 to 4.2; p=0.01) and CRPC (HR 2.3; 95% CI 1.1 to 5.0; p=0.03). Validation showed a low risk of prediction error and a high model performance for all endpoints. In a meta-analysis, low AZGP1 was associated with BF (HR 1.7; 95% CI 1.2 to 2.5). CONCLUSIONS: Low AZGP1 expression is associated with the risk of aggressive time-dependent outcomes in men undergoing RP for localised PCa.

5hmC Level Predicts Biochemical Failure Following Radical Prostatectomy in Prostate Cancer Patients with ERG Negative Tumors.

This study aimed to validate whether 5-hydroxymethylcytosine (5hmC) level in combination with ERG expression is a predictive biomarker for biochemical failure (BF) in men undergoing radical prostatectomy (RP) for prostate cancer (PCa). The study included 592 PCa patients from two consecutive Danish RP cohorts. 5hmC level and ERG expression were analyzed using immunohistochemistry in RP specimens. 5hmC was scored as low or high and ERG was scored as negative or positive. Risk of BF was analyzed using stratified cumulative incidences and multiple cause-specific Cox regression using competing risk assessment. Median follow-up was 10 years (95% CI: 9.5⁻10.2). In total, 246 patients (41.6%) had low and 346 patients (58.4%) had high 5hmC level. No significant association was found between 5hmC level or ERG expression and time to BF (p = 0.2 and p = 1.0, respectively). However, for men with ERG negative tumors, high 5hmC level was associated with increased risk of BF following RP (p = 0.01). In multiple cause-specific Cox regression analyses of ERG negative patients, high 5hmC expression was associated with time to BF (HR: 1.8; 95% CI: 1.2⁻2.7; p = 0.003). In conclusion, high 5hmC level was correlated with time to BF in men with ERG negative PCa, which is in accordance with previous results.

Prevalence of human papillomavirus DNA and p16INK4a in penile cancer and penile intraepithelial neoplasia: a systematic review and meta-analysis.

BACKGROUND: Although previous meta-analyses have examined human papillomavirus (HPV) DNA prevalence in penile cancer, none, to our knowledge, have assessed pooled HPV DNA prevalence in penile intraepithelial neoplasia or p16INK4a percent positivity in penile cancer and penile intraepithelial neoplasia. Therefore, we aimed to examine the prevalence of HPV DNA and p16INK4a positivity in penile cancer and penile intraepithelial neoplasia worldwide. METHODS: In this systematic review and meta-analysis, we searched PubMed, Embase, and the Cochrane Library until July 24, 2017, for English-language articles published from Jan 1, 1986, onwards reporting the prevalence of HPV DNA and p16INK4a positivity, either alone or in combination, in at least five cases of penile cancer or penile intraepithelial neoplasia. Only studies that used PCR or hybrid capture for the detection of HPV DNA and immunohistochemical staining or methylation for the detection of p16INK4a were included. Data were extracted and subsequently crosschecked, and inconsistencies were discussed to reach consensus. Using random-effects models, we estimated the pooled prevalence and 95% CI of HPV DNA and p16INK4a positivity in penile cancer and penile intraepithelial neoplasia, stratifying by histological subtype and HPV DNA or p16INK4a detection method. Type-specific prevalence of HPV6, HPV11, HPV16, HPV18, HPV31, HPV33, and HPV45 in penile cancer was estimated. FINDINGS: Our searches identified 1836 non-duplicate records, of which 73 relevant papers (71 studies) were found to be eligible. The pooled HPV DNA prevalence in penile cancer (52 studies; n=4199) was 50·8% (95% CI 44·8-56·7; I2=92·6%, pheterogeneity<0·0001). A high pooled HPV DNA prevalence was seen in basaloid squamous cell carcinomas (84·0%, 95% CI 71·0-93·6; I2=48·0%, pheterogeneity=0·0197) and in warty-basaloid carcinoma (75·7%, 70·1-81·0; I2=0%, pheterogeneity=0·52). The predominant oncogenic HPV type in penile cancer was HPV16 (68·3%, 95% CI 58·9-77·1), followed by HPV6 (8·1%, 4·0-13·7) and HPV18 (6·9%, 2·9-12·4). The pooled HPV DNA prevalence in penile intraepithelial neoplasia (19 studies; n=445) was 79·8% (95% CI 69·3-88·6; I2=83·2%, pheterogeneity<0·0001). The pooled p16INK4a percent positivity in penile cancer (24 studies; n=2295) was 41·6% (95% CI 36·2-47·0; I2=80·6%, pheterogeneity<0·0001), with a high pooled p16INK4a percent positivity in HPV-related squamous cell carcinoma (85·8%, 95% CI 72·1-95·4; I2=56·4%, pheterogeneity=0·0011) as compared with non-HPV-related squamous cell carcinoma (17·1%, 7·9-29·1; I2=78·3%, pheterogeneity<0·0001). Moreover, among HPV-positive cases of penile cancer, the p16INK4a percent positivity was 79·6% (95% CI 65·7-90·7; I2=89·9%, pheterogeneity<0·0001), compared with 18·5% (9·6-29·6; I2=89·3%, pheterogeneity<0·0001) in HPV-negative penile cancers. The pooled p16INK4a percent positivity in penile intraepithelial neoplasia (six studies; n=167) was 49·5% (95% CI 18·6-80·7). INTERPRETATION: A large proportion of penile cancers and penile intraepithelial neoplasias are associated with infection with HPV DNA (predominantly HPV16), emphasising the possible benefits of HPV vaccination in men and boys. FUNDING: None.

Human papillomavirus and squamous cell carcinoma of the urinary bladder: DaBlaCa-10 study.

OBJECTIVE: To evaluate a potential association between Human Papillomavirus (H.P.V.) and squamous cell carcinoma (S.C.C.) urinary bladder cancer (B.C.). Furthermore, the relation between p16INK4a, H.P.V. and B.C. was examined. PATIENTS AND METHODS: Patients were included and divided into three groups based on the histological diagnosis of B.C. SPECIMENS: An extensive exclusion was performed, including accepted casual risk factors for S.C.C. B.C., such as long-term use of catheters, cystolithiasis and Schistosoma hematobium infection. A total of 100 patients were included: 50 with pure S.C.C., 25 with urothelial carcinomas (U.C.) and 25 with squamous differentiation of U.C. (Sq.D.). The patients were operated at one of four major Danish hospitals in the period January 2005 to December 2016. Clinical information was collected from the medical records. Presence of H.P.V. was analyzed using the INNO-LiPA H.P.V. Genotyping Extra II. p16INK4a was analyzed using immunohistochemical (I.H.C.) staining. A p-value <0.05 was considered statistically significant. RESULTS: An overall H.P.V. prevalence of 12/100 (12%) was observed. H.P.V. was demonstrated in 9/50 (18%) of the S.C.C. PATIENTS: Overall, p16INK4a over-expression was observed in 52/100 (52%) patients. However, concomitant H.P.V. positivity and p16INK4a over-expression were observed in only 4/100 (4%) patients. CONCLUSION: The presence of H.P.V. in one fifth of patients with S.C.C. B.C. was demonstrated. H.P.V. infection could have a significant association with S.C.C. B.C. without other known casual risk factors for S.C.C. B.C.