Penile cancer: long-term infectious and thromboembolic complications following lymph node dissection - a population-based study (Sweden).

PURPOSE: To assess the long-term risks of infectious and thromboembolic events following inguinal (ILND) and pelvic (PLND) lymph node dissection in men with penile cancer. MATERIAL AND METHODS: A total of 364 men subjected to ILND with or without PLND for penile cancer between 2000 and 2012 were identified in the Swedish National Penile Cancer Register. Each patient was matched based on age and county of residence with six penile cancer-free men. The Swedish Cancer Register and other population-based registers were used to retrieve information on treatment and hospitalisation for selected infectious and thromboembolic events. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox proportional hazard models with multiple imputation. RESULTS: The risk of infectious events remained increased for more than five years postoperatively in men with penile cancer compared with matched controls. The palpable nodal disease was the only predictor of these events, with risk increasing with the cN stage. The HR at one, three and five years and six months postoperatively was 8.60 (95% CI 5.16-14.34), 4.02 (95% CI 2.65-6.09) and 1.93 (95% CI 1.11-3.38), respectively. An increased risk of thromboembolic events persisted for three years postoperatively. The HR at one and three years postoperatively was 13.51 (95% CI 6.53-27.93) and 2.12 (95% CI 1.07-4.20). The results correspond well with the over-prescription of anticoagulants observed during this period. An association with bulky disease (cN3) was observed. CONCLUSIONS: Lymph node dissection for penile cancer is associated with an increased risk of infectious and thromboembolic events. The findings of this population-based study show that the risks of these events remain increased more than five years for infectious and three years for thromboembolic events. Improved awareness of long-term complications following ILND is of importance both among patients and care givers to ensure early detection and treatment.

Nationwide Data Support Centralised Decision-making in Penile Cancer Care: A Before-and-After Study on Guideline Adherence and Disease-specific survival for Patients with an Indication for Perioperative Oncological Treatment.

Background: The benefit of perioperative oncological treatment in men with penile cancer is uncertain. In 2015, treatment recommendations were centralised in Sweden and treatment guidelines were updated. Objective: To evaluate if the use of oncological treatment in men with penile cancer increased after the introduction of centralised recommendations, and whether such therapy is associated with better survival. Design setting and participants: This was a retrospective cohort study including a total of 426 men diagnosed with penile cancer with lymph node or distant metastases in Sweden during 2000-2018. Outcome measurements and statistical analysis: We first assessed the change in the proportion of patients with an indication for perioperative oncological treatment who actually received such treatment. Second, we used Cox regression to calculate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for disease-specific mortality associated with perioperative treatment. Comparisons were made for both all men without perioperative treatment and for those who did not receive treatment but who lacked apparent contraindications for treatment. Results and limitations: The use of perioperative oncological treatment increased from 2000 to 2018, from 32% of patients with an indication for treatment during the first 4 yr to 63% during the last 4 yr. In comparison to patients potentially eligible for oncological treatment who did not receive it, those who were treated had a 37% lower risk of disease-specific death (HR 0.63, 95% CI 0.40-0.98). Stage migration because of improvements in diagnostic tools over time may have inflated the more recent survival estimates. An influence of residual confounding due to comorbidity and other potential confounders cannot be excluded. Conclusions: The use of perioperative oncological treatment increased after the centralisation of penile cancer care in Sweden. Although the observational study design precludes causal inference, the findings suggest that perioperative treatment in patients with penile cancer eligible for treatment may be associated with better survival. Patient summary: In this study, we looked at the use of chemotherapy and radiotherapy for men with penile cancer and lymph node metastases in Sweden during 2000-2018. We found an increase in the use of cancer therapy and an increase in survival for patients who received such therapy.

Sentinel Node Identification with Hybrid Tracer-guided and Conventional Dynamic Sentinel Node Biopsy in Penile Cancer: A Prospective Study in 130 Patients from the Two National Referral Centres in Sweden.

BACKGROUND: Studies suggest that a hybrid indocyanine green (ICG)-99mTc-nanocolloid tracer improves sentinel node (SN) identification compared to conventional dynamic sentinel node biopsy (DSNB). OBJECTIVE: To investigate hybrid tracer-guided SN identification in a multicentre setting and determine false-negative (FN) and complication rates. DESIGN, SETTING, AND PARTICIPANTS: A total of 130 patients with penile cancer scheduled for DSNB were prospectively included between February 2016 and December 2017 at two national Swedish referral centres. ICG-99mTc-nanocolloid hybrid tracer was used in the standard DSNB protocol. INTERVENTION: SNs were identified intraoperatively using radioguidance, fluorescence imaging, and blue dye. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The number of SNs identified by each tracer and the rates of complications and nodal recurrence during median follow-up of 34 mo were recorded. Differences in proportions between groups were compared using χ2 and McNemar's tests. RESULTS AND LIMITATIONS: Overall, 453 SNs were identified preoperatively via single-photon emission computed tomography/computed tomography. Among the 425 SNs excised, radioguidance, fluorescence, and blue dye identified 414 (97%), 363 (85%), and 349 (82%), respectively. Fluorescence imaging helped to detect six SNs that were negative using the other tracers, two of which were from the same patient and contained metastases. Histopathological examination detected 33 metastatic SNs in 20/130 patients (15%). The FN rate was 12% per groin (95% confidence interval 8-16%). CONCLUSIONS: Identification of SNs in patients with penile cancer relies mainly on radioguidance, while fluorescence (ICG) and blue dye methods for optical SN identification are comparable. However, the value of fluorescence imaging should be further evaluated in studies with long-term follow-up. PATIENT SUMMARY: In this study, we investigated addition of a dye called indocyanine green (ICG) for assessment of lymph nodes in patients with cancer of the penis. ICG did not improve the rate of detection of nodes most likely to harbour cancer because of their location in the drainage pathway for lymphatic fluid, but did help in identifying additional metastases.

Risk of second HPV-associated cancers in men with penile cancer.

PURPOSE: The aim of this study was to examine the risk of HPV-associated oral cavity, oropharyngeal or anal cancer in men with penile cancer to test the hypothesis of an increased risk to develop a second HPV-associated cancer later in life. MATERIAL AND METHODS: We conducted a population-based register study including all men in Sweden diagnosed with penile cancer between 2000 and 2012. For each patient, six men without penile cancer were matched based on age and county of residence. Data were retrieved from Swedish cancer and population registers, to assess the risk of oral cavity, oropharyngeal or anal cancer in patients with penile cancer. Cox proportional hazard models were used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs). Risks in men with penile cancer were also compared with the background Swedish male population by use of standardized incidence ratios. RESULTS: In total, 1634 men with and 9804 without penile cancer were included in the study. Among men with penile cancer, four men were subsequently diagnosed with oral cavity cancer, one with oropharyngeal cancer and one with anal cancer. Corresponding numbers among the penile cancer-free men were ten, two and three, respectively. There was evidence of an increased risks of all three cancers under study with an HR of 2.84 (95% CI 0.89-9.06) for oral cavity cancer, 3.66 (95% CI 0.33-40.39) for oropharyngeal cancer and 2.34 (95% CI 0.24-22.47) for anal cancer. When comparing the incidence of these malignancies between penile cancer patients and the background population, the patterns of association were similar. CONCLUSIONS: Our findings indicate that men with penile cancer are at an increased risk of a second HPV-associated cancer of the oral cavity, oropharynx and anal canal. Considering that our study was based on small numbers reflecting the rarity of these cancers, larger studies are needed to confirm our findings.

Oncological therapy to Swedish men with metastatic penile cancer 2000-2015.

BACKGROUND: Penile cancer is an uncommon disease with poor prognosis when spread to more than one inguinal lymph node. Recommendations on chemo- and radiotherapy in treatment guidelines are based on low-grade evidence. There are to our knowledge no described population-based cohort with detailed information on given oncological treatment and survival data. The aim of this study is to investigate in detail how men with metastatic penile cancer have been treated with chemotherapy and radiotherapy over time, and how survival varies with N-stage and given treatment. MATERIAL AND METHODS: For this observational cohort study all men in Sweden diagnosed with penile cancer with lymph node- or distant metastases 2000-2015 were identified through the Swedish National Penile Cancer Register (NPECR). Medical records were retrieved and 325 men were confirmed to have metastatic penile cancer (Tany, c or pN1-3 and/or M1). Information on treatments was collected. Causes of death were retrieved from the National Cause of Death Register (CDR). RESULTS: Chemotherapy and/or radiotherapy were given to 172 (53%) of all men. The use of oncological treatments with curative intent increased significantly during the study period, from 30% of men with c/pN2-3 diagnosed 2000-2003 compared with 57% of men diagnosed 2012-2015. Ninety-three (29%) men received oncological treatments with curative intent of whom 85/93 (91%) had stage c/pN2-3M0. Survival decreased with higher N-stage, M1-stage, and absence of oncological treatment with curative intent. For men with c/pN3-stage, the engagement of pelvic lymph nodes was entailed with lower survival than pN3 based on extra-nodal extension (ENE). CONCLUSION: The use of oncological treatment was below recommendations in guidelines but increased during the study period. Treatment was given predominantly to men with c/pN2-3 and M1-disease. Survival was higher among men treated with curative intent; this could be due to patient selection bias.

PD-L1 Expression in Men with Penile Cancer and its Association with Clinical Outcomes.

BACKGROUND: It has been hypothesized that PD-L1 expression in tumor cells and tumor-infiltrating immune (TII) cells may contribute to tumor progression by inhibiting antitumor immunity. OBJECTIVE: To investigate the association between PD-L1 expression in tumor cells and TII cells and clinical outcomes in penile cancer. DESIGN, SETTING, AND PARTICIPANTS: A cohort of 222 men treated for penile squamous cell carcinoma (SqCC) at Örebro University Hospital between 1984 and 2008 with long-term follow-up (median 34 mo) was evaluated for PD-L1 expression in tumor cells and TII cells via immunohistochemistry. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Association between clinicopathological features and PD-L1 expression was estimated using χ2 and Fisher's exact tests. For survival analyses, Kaplan-Meier curves with log-rank tests and multivariate Cox proportional hazards regression models were used. RESULTS AND LIMITATIONS: We found that 32.1% of the tumors and 64.2% of the TII cells expressed PD-L1. Our data demonstrate that penile SqCC patients with PD-L1-positive tumor cells or TII cells are at significant risk of lower cancer-specific survival and that the prognostic value of PD-L1 expression was strongest for tumor cell positivity. The use of tissue microarrays rather than whole sections may be viewed as a limitation. CONCLUSIONS: Tumor PD-L1 expression independently identifies penile SqCC patients at risk of poor clinical outcomes. PATIENT SUMMARY: We investigated how many patients with penile cancer had tumors that manufactured PD-L1, a protein that decreases the ability of the immune system to fight cancer. We found that up to one-third of penile tumors make this protein. Patients whose tumors make PD-L1 have more aggressive penile cancer and worse clinical outcomes.

Socioeconomic factors and penile cancer risk and mortality; a population-based study.

OBJECTIVE: To investigate possible associations between socioeconomic status (SES) and penile cancer risk, stage at diagnosis, and mortality. PATIENTS/SUBJECTS AND METHODS: A population-based register study including men in Sweden diagnosed with penile cancer between 2000 and 2012 (1676 men) and randomly chosen controls (9872 men). Data were retrieved from the National Penile Cancer Register (NPECR) and several other population-based healthcare and sociodemographic registers. Educational level, disposable income, marital status, and number of individuals in the household, were assessed as indicators of SES. The risk of penile cancer and penile cancer death in relation to SES were estimated using logistic regression and proportional hazards models, respectively. Cumulative cause-specific mortality (CSM) estimates by SES were calculated using the Kaplan-Meier method. RESULTS: A low educational level and low disposable income were associated with an increased risk of invasive penile cancer. Furthermore, low educational level was associated with more advanced primary tumour stage. Divorced and never married men had a generally increased risk of penile cancer and were diagnosed with more advanced primary tumour stages. However, neither educational level nor marital status was associated with lymph node or distant metastases. Also, men in single-person households had an increased risk of both non-invasive and invasive disease. In men with invasive penile cancer, there were no significant associations of indicators of SES and CSM. CONCLUSIONS: Low educational level, low disposable income, being divorced or never married, and living in a single-person household, all increase the risk of advanced stage penile cancer, but not lymph node or distant metastases. The assessed indicators of SES did not influence penile CSM. In conclusion, our findings indicates that SES influences the risk and stage of penile cancer, but not survival.

Swedish National Penile Cancer Register: incidence, tumour characteristics, management and survival.

OBJECTIVES: To assess penile cancer incidence, stage distribution, adherence to guidelines and prognostic factors in a population-based setting. PATIENTS AND METHODS: The population-based Swedish National Penile Cancer Register (NPECR) contains detailed information on tumour characteristics and management patterns. A total of 1 678 men with primary squamous cell carcinoma of the penis identified in the NPECR between 2000 and 2012 were included in the study. RESULTS: The mean age-adjusted incidence of penile cancer was 2.1/100 000 men, remaining virtually unchanged during the study period. At diagnosis, 14 and 2% of the men had clinical N+ and M+ disease, respectively. Most men were staged pTis (34%), pT2 (19%), or pT1 (18%), while stage information was unavailable for 18% of the men. Organ-preserving treatment was used in 71% of Tis-T1 tumours. Of men with cN0 and ≥pT1G2 disease, 50% underwent lymph node staging, while 74% of men with cN1-3 disease underwent lymph node dissection. The overall 5-year relative survival rate was 82%. Men aged ≥40 years and those with pT2-3, G2-3 and N+ tumours had worse outcomes. CONCLUSIONS: The incidence of penile cancer in Sweden is stable. Most men presented with localized disease, and the proportion of non-invasive tumours was high. During the period under study, adherence to guidelines was suboptimum. The overall 5-year relative survival rate was 82%. Older age, increasing tumour stage and grade, and increasing lymph node stage were associated with poorer survival.

Organ-sparing reconstructive surgery in penile cancer: initial experiences at two Swedish referral centres.

OBJECTIVE: The aim of this study was to present early outcome data for patients treated for penile cancer with organ-sparing reconstructive surgery at two referral centres in Sweden. MATERIAL AND METHODS: Oncological, cosmetic and functional outcome and complications were analysed retrospectively during the period 2011-2013. Twelve patients with non-invasive penile cancer were treated with glans resurfacing (GR), while 15 patients with invasive penile cancer underwent total glansectomy with neoglans reconstruction (TGN). RESULTS: The 12 patients treated with GR had a median age of 66 years (range 35-83 years) and a median follow-up time of 16 months (range 4-40 months). All patients showed carcinoma in situ and negative surgical margins in the final pathology report. The 15 patients treated with TGN had a median age of 71 years (range 37-78 years) and the median follow-up time was 10 months (range 1-25 months). All patients had invasive penile cancer and the surgical margins were negative in all cases except one. Complications occurred in five of the 27 patients (18%), and in most cases these were minor and infection related. No recurrences were seen in either group during follow-up, and all patients except one, who had undergone GR, were satisfied with the functional and cosmetic results. CONCLUSIONS: GR and TGN seem to be oncologically safe procedures for treating carefully selected patients with penile cancer, and the functional and cosmetic results are promising. Based on these findings, the authors recommend that penile amputation should only be carried out in patients who are not suitable for organ-sparing reconstructive surgery.

Dynamic sentinel node biopsy in penile cancer: initial experiences at a Swedish referral centre.

UNLABELLED: Study Type - Therapy (case series) Level of Evidence 4 What's known on the subject? and What does the study add? According to the current European Association of Urology Guidelines, dynamic sentinel node biopsy is the recommended approach to assess lymph node status in men with cN0 intermediate and high risk penile cancer. Nevertheless, most encouraging results derive from a limited number of studies. The present study shows a false-negative rate of 15%, comparable with or better than several previous studies. Nevertheless, the aim should be a false-negative rate of no more than 5%. We conclude that increased overall experience and the use of the complete modern dynamic sentinel node biopsy protocol are paramount to improve results. OBJECTIVE: • To evaluate the false-negative rate and complication rate of dynamic sentinel node biopsy (DSNB) in penile cancer. PATIENTS AND METHODS: • In this retrospective study, 58 unilaterally or bilaterally clinically lymph node negative (cN0) patients with penile cancer (57 squamous cell carcinomas and one malignant melanoma), scheduled for DSNB at the Örebro University Hospital, Sweden, between 1999 and 2011, were analysed. • Preoperative ultrasonography and fine-needle aspiration cytology of suspicious nodes were not introduced until 2008. • Patients were assessed by lymphoscintigraphy using (99m) technetium nanocolloid on the day before surgery and the dissection of sentinel nodes was aided by the lymphoscintigraphic images and intraoperative detection of radiotracer and patent blue dye. • The false-negative rate and complication rate were calculated per groin. RESULTS: • Of the 58 patients, 32 (55%) underwent preoperative ultrasonography. • Two patients had positive fine-needle aspiration cytology and discontinued further DSNB protocol. Of the remaining 56 patients, all but one were bilaterally cN0 and hence 111 cN0 groins were assessed by lymphoscintigraphy. • In the 55 bilaterally cN0 patients, lymphoscintigraphy visualized a bilateral sentinel node in 34 (62%). • At surgery, all excised sentinel nodes were radioactive while 43% were additionally blue. In total, at least one sentinel node was harvested in 96 (86%) of the DSNB staged groins. • A positive sentinel node was found in 11 groins (bilaterally in three patients). During a median follow-up of 21 months, two false-negative cases emerged, producing a false-negative rate of 15%. Both false-negative cases occurred during the first half of the study. The complication rate was 10%. The majority of complications were minor and transient. CONCLUSIONS: • DSNB is a minimally invasive staging tool in men with cN0 penile cancer, enabling early detection of metastatic disease and thus optimal care. • Our false-negative rate of 15% is comparable or even favourable in comparison with several previous studies, but far from the 5% or less that we aim for. The complication rate found is somewhat higher than previously reported. • With increased overall experience and the continued use of the complete DSNB protocol, we believe our results will improve and the complication rate will decrease.

Human papillomavirus prevalence, distribution and correlation to histopathological parameters in a large Swedish cohort of men with penile carcinoma.

OBJECTIVE: • To analyse the overall and type-specific human papillomavirus (HPV) prevalence and distribution in penile carcinoma and determine the correlation to histopathological parameters. PATIENTS AND METHODS: • In this retrospective study, we analysed HPV status in 241 patients with penile carcinoma, treated at Örebro University Hospital, Örebro, Sweden, between 1984 and 2008. Age and date at diagnosis was recorded. • The tumour specimens were categorized according to the UICC 2002 TNM classification. A subset of patients was operatively staged with regard to lymph node status. • A commercially available Real Time PCR was used to detect 13 different types of HPV (6,11,16,18,31,33,35,45,51,52,56,58 and 59). RESULTS: • We excluded 25 patients due to low DNA quality. Of the remaining 216, 179 (82.9%) tumour specimens were HPV infected. The majority of cases positive for HPV (70.4%) were infected by a single-type. The most frequent type was HPV 16 followed by HPV 18. • No significant association between HPV status and pathological tumour stage, grade or lymph node status was found. CONCLUSION: • The HPV prevalence found is higher than in most other studies, further strengthening HPV as an etiological agent in penile carcinoma. Furthermore, the high prevalence of HPV 16 and 18 raises the question of what potential impact current HPV vaccines that target these specific HPV types might have on penile carcinoma. No significant association between HPV status and histopathological parameters was found in the present study. Additional investigations are needed to draw final conclusions on the prognostic value of HPV status in penile carcinoma.

Recurrence patterns of squamous cell carcinoma of the penis: recommendations for follow-up based on a two-centre analysis of 700 patients.

BACKGROUND: Current follow-up recommendations for patients with penile carcinoma are based on small numbers of patients. OBJECTIVES: To give further insight into the recurrence patterns of penile carcinoma in different treatment settings and provide recommendations for follow up. DESIGNS, SETTING, AND PARTICIPANTS: In this retrospective study, we analysed 700 patients from two referral centres for penile carcinoma for recurrences. MEASUREMENTS: Recurrences were categorized as local, regional, or distant. The rate of local recurrences was compared between patients undergoing penile-preserving treatments and partial/total amputation. Regional recurrences were compared between patients surgically staged as pN0 or pN+ and clinically node-negative (cN0) patients subjected to a wait-and-see policy. The total recurrence rate, type of recurrence, time to recurrence, and survival were calculated. RESULTS AND LIMITATIONS: 205 out of 700 patients (29.3%) had a recurrence, consisting of 18.6% local, 9.3% regional, and 1.4% distant recurrences. Of the recurrences, 92.2% occurred within 5 yr after primary treatment. All regional and distant recurrences occurred within 50 and 16 mo, respectively. The local recurrence rate was 27.7% after penile-preserving therapy and 5.3% after amputation. The regional recurrence rate was 2.3% in patients staged as pN0, 19.1% in patients staged as pN+, and 9.1% in patients undergoing a wait-and-see policy. The 5-yr disease-specific survival was 92% after a local recurrence and 32.7% after a regional recurrence. All patients with a distant recurrence died within 22 mo. Although the number of analysed patients is substantial, the results do not necessarily reflect those of other centres using different techniques for the management of penile carcinoma. CONCLUSIONS: Patients undergoing penile-preserving therapy, patients surgically staged as pN+, and those undergoing a wait-and-see policy for the nodal status are at high risk of developing a recurrence. Follow-up recommendations are provided based on the risk and impact on survival of a recurrence.

PIK3CA, HRAS and KRAS gene mutations in human penile cancer.

PURPOSE: The knowledge of somatic mutations that arise in penile cancer is limited. We examined the dysregulation of components in the phosphatidylinositol 3-kinase and Ras pathways. MATERIALS AND METHODS: Using single stranded conformational analysis and direct sequencing we performed mutational analysis of the PIK3CA, PTEN, HRAS, KRAS, NRAS and BRAF genes in 28 penile tumors. RESULTS: We identified somatic missense mutations in 11 of the 28 penile cancer samples (39%). In the PIK3CA gene 8 mutations (29%) were identified that were E542K or E545K. In the HRAS gene a G12S and a Q61L mutation were found (7%). The KRAS gene contained 1 mutation (3%), that is a G12S change. PIK3CA mutations were found in all grades and stages, whereas HRAS and KRAS mutations were found in larger and more advanced tumors. The mutations were mutually exclusive, suggesting that dysregulation of either pathway is sufficient for the development and progression of penile carcinoma. CONCLUSIONS: The high frequency of mutations in the PIK3CA, HRAS and KRAS genes leads us to believe that dysregulation of the phosphatidylinositol 3-kinase or Ras pathway is significant for the development and progression of penile carcinoma.