Short-term Changes in Health-related Quality of Life of Patients Undergoing Radical Surgery for Upper Urinary Tract Urothelial Carcinoma: Results from a Prospective Phase 2 Clinical Trial.

Background and objective: The possible negative impact of radical surgery on patients' health-related quality of life (HRQoL) plays an important role in preoperative counseling. Here, we analyzed the HRQoL of patients treated for upper urinary tract urothelial carcinoma (UTUC) in the context of a single-arm phase 2 multicenter study, in which the safety and efficacy of a single preoperative intravesical instillation with mitomycin C were investigated. Our objective was to investigate early changes in HRQoL in patients undergoing radical surgery for UTUC and identify factors associated with these outcomes. Methods: Patients with pTanyN0-1M0 UTUC were prospectively included. HRQoL was assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire C30 (EORTC QLQ-C30) questionnaire at baseline, and at 1 and 3 mo after surgery. A linear mixed model was used to evaluate the changes in HRQoL over time and identify the variables associated with these outcomes. The clinical effect size was used to assess the clinical impact and level of perceptibility of HRQoL changes for clinicians and/or patients based on given thresholds. Key findings and limitations: Between 2017 and 2020, 186 patients were included. At baseline, 1 mo after surgery, and 3 mo after surgery, response rates were 91%, 84%, and 78%, respectively. One month after surgery, a statistically significant and clinically relevant deterioration was observed in physical, role, and social functioning, and for the included symptom scales: constipation, fatigue, and pain. An improvement in emotional functioning was observed. At 3 mo, HRQoL returned to baseline levels, except emotional functioning, which improved at 1 mo and persisted to be better than that before surgery. Age >70 yr was associated with worse physical functioning, but better social and emotional functioning. Male patients reported better emotional functioning than females. Postoperative complications were negatively associated with social functioning. Conclusions and clinical implications: UTUC patients treated with radical surgery experienced a significant, albeit temporary, decline in HRQoL. Three months following surgery, HRQoL outcomes returned to baseline levels. This information can be used to counsel UTUC patients before undergoing radical surgery and contextualize recovery after surgery. Patient summary: We investigated the changes in quality of life as reported by patients who underwent surgery for upper tract urothelial carcinoma (UTUC). We found that patients experienced a decline in quality of life 1 mo after surgery, but this was temporary, with full recovery of quality of life 3 mo after surgery. These findings can help doctors and other medical staff in counseling UTUC patients before undergoing radical surgery.

Human papillomavirus prevalence in invasive penile cancer and association with clinical outcome.

PURPOSE: The incidence of penile cancer is increasing, and is suggested to be explained by changes in sexual practice and increased exposure of men to sexually transmitted high risk human papillomavirus infection. In penile cancers from a Dutch population treated in 1963 to 2001 we found a high risk human papillomavirus prevalence of about 30%. In this study we assessed the prevalence of high risk human papillomavirus-DNA in a more recent, contemporary penile cancer cohort and its association with patient survival. MATERIALS AND METHODS: High risk human papillomavirus-DNA presence was assessed by GP5+6+ polymerase chain reaction in 212 formalin fixed, paraffin embedded invasive penile tumor specimens of patients treated between 2001 and 2009. The 5-year disease specific survival was calculated using the Kaplan-Meier method with the log rank test and Cox regression. RESULTS: High risk human papillomavirus-DNA was detected in a subset of penile cancer cases (25%, 95% CI 19-31). HPV16 was the predominant type, representing 79% (42 of 53) of all high risk human papillomavirus infections. The 5-year disease specific survival in the high risk human papillomavirus negative group and the high risk human papillomavirus positive group was 82% and 96%, respectively (log rank test p=0.016). Adjusted for stage, grade, lymphovascular invasion and age, human papillomavirus status was still prognostic for disease specific survival (p=0.030) with a hazard ratio of 0.2 (95% CI 0.1-0.9). CONCLUSIONS: High risk human papillomavirus-DNA was observed in a quarter of penile cancer cases. No relevant increase in high risk human papillomavirus prevalence in recent decades was observed. The presence of high risk human papillomavirus-DNA in penile cancer confers a survival advantage.

Probability of downsizing primary tumors of renal cell carcinoma by targeted therapies is related to size at presentation.

OBJECTIVE: To evaluate the probability of downsizing primary renal tumors by targeted therapy in correlation to size. METHODS: A literature search was conducted and our own data were pooled with data of retrospective series and prospective trials in which patients were treated with tyrosine kinase inhibitors (TKIs) and in which tumor sizes before and after treatment were reported. Included were 89 primary clear cell renal tumors, including 34 from our institutes. The longest diameter of the primary tumors before and after treatment was obtained. Primary tumor size at presentation was divided in 4 categories: <5 cm (n=10), 5 to 7 cm (n=21), 7 to 10 cm (n=31), and >10 cm (n=27). Pearson correlation and t test were used for statistical analysis. RESULTS: The TKI was sorafenib in 21 tumors and sunitinib in the remaining 68. Smaller tumor size was related to more effective downsizing (P=0.01). Median downsizing was 32% (-46% to 11%) in the first group (<5 cm) and 11% (-55% to 16%) in the second group (5-7 cm); however, 8 of 21 (38%) in this group reduced to a range of 2.3 to 4.7 cm in which ablative techniques are feasible and nephron-sparing surgery may benefit from the reduced size. Median downsizing was 18% (-39% to 2%) in tumors of 7 to 10 cm and 10% (-31% to 0%) in those>10 cm. CONCLUSION: The smaller the primary tumor, the greater the likelihood and the more effective the downsizing. A potential benefit of neoadjuvant treatment to downsize the primary tumor for ablative techniques or nephron-sparing surgery may exist, particularly in tumors sized 5 to 7 cm.

Lymph node metastasis in intermediate-risk penile squamous cell cancer: a two-centre experience.

BACKGROUND: The risk of lymph node (LN) metastasis in G2T1 penile cancer has been previously reported as 0-50% and is classified as "intermediate" in the European Association of Urology (EAU) guidelines. The management of impalpable regional nodes in this cohort of patients remains contentious and varies among treatment centres depending on tumour factors and local resources. OBJECTIVES: To establish the risk of LN metastasis in G2T1 disease. DESIGN, SETTINGS, AND PARTICIPANTS: We interrogated the databases of two referral centres for penile cancer. MEASUREMENTS: Out of 902 patients, 117 (13%) patients were identified with G2T1 cancers. Those with palpable inguinal nodes (cN1) underwent early inguinal LN dissection (iLND). Those with clinically node negative (cN0) inguinal basins were either observed or surgically staged with iLND or by dynamic sentinel LN biopsy (DSLNB). Median follow-up was 44 mo, with minimum follow-up of 6 mo. RESULTS AND LIMITATIONS: Fifteen of 117 (13%) patients with G2T1 cancer had LN metastasis at initial staging or during follow-up. Six of 12 (50%) cN1 patients had histologically proven LN metastasis on iLND. One hundred five patients were cN0 at presentation. Ten cN0 patients had prophylactic iLND, none of which yielded LN metastasis; 5 of 64 (8%) cN0 patients who had DSLNB had tumour-positive LNs, and 4 of 31 (13%) cN0 patients who were observed developed LN metastasis during follow-up. In cN0 patients, the risk of LN metastasis at initial staging or during surveillance was 9%. CONCLUSIONS: We consider that in cN0 patients with G2T1 penile cancer, the risk of developing metastases during surveillance warrants surgical and potentially curative staging. However, the morbidity of prophylactic bilateral iLND is too great to justify a detection rate of 9%. Less morbid alternatives such as DSLNB are advisable in G2T1 disease.

Two-center evaluation of dynamic sentinel node biopsy for squamous cell carcinoma of the penis.

PURPOSE: Sentinel node biopsy is used to evaluate the nodal status of patients with clinically node-negative penile carcinoma. Its use is not widespread, and the majority of patients with clinically node-negative disease undergo an elective inguinal lymph node dissection. Reservations about the use of sentinel node biopsy include the fact that most current results come from one institution and the supposedly long learning curve associated with the procedure. The purpose of this study was to address these issues by analyzing results from two centers and by evaluating the learning curve. PATIENTS AND METHODS: All patients undergoing sentinel node biopsy for penile carcinoma at two centers were included. The sentinel node identification rate, false-negative rate, and morbidity of the procedure were calculated. RESULTS: from the first 30 procedures were assessed for a potential learning curve. Results A total of 323 patients with penile squamous cell carcinoma, which included 611 clinically node-negative groins, were scheduled for sentinel node biopsy. A sentinel node was found in 572 of the 592 groins (97%) that proceeded to sentinel node biopsy. In 79 groins, a sentinel node was positive for tumor. Six inguinal node recurrences occurred after a negative sentinel node procedure, all within 15 months after sentinel node biopsy. The combined false-negative rate was 7%. Complications occurred in 4.7% of explored groins. None of the false-negative procedures occurred in the initial 30 procedures. CONCLUSION: Sentinel node biopsy is a suitable procedure to stage clinically node-negative penile cancer, and it has a low complication rate. No learning curve was demonstrated in this study.

Microarray gene-expression profiling to predict lymph node metastasis in penile carcinoma.

OBJECTIVE: To determine the value of gene-expression profiling as a predictor of the status of the regional nodes in patients with penile carcinoma. PATIENTS AND METHODS: Tumour samples of 56 patients with penile squamous cell carcinoma were analysed for the gene expression on 35 k oligoarrays; 32 were from patients with histopathologically confirmed lymph node metastases and 24 from those with no lymph node involvement. The 56 patients were divided into a training and validation set. For the training set, 15 patients with histopathologically confirmed nodal metastases and 15 without were selected. The validation set consisted of the remaining 26 patients, containing 17 node-positive and nine with no nodal metastases. RESULTS: A 44-probe classifier had the best performance within the training set; this classifier correctly assigned 29 of 30 specimens in the training set to the two outcome groups. In the validation set of 26 tumours, the classifier correctly assigned 14 of the 26 (54%) specimens to the two outcome groups. Of the 17 specimens with histologically confirmed nodal involvement, 12 were classified as node-positive and five as node-negative, resulting in a sensitivity of 71%. Of the nine specimens from node-negative patients, two were correctly classified as node-negative and seven as node positive, resulting in a specificity of 22%. CONCLUSIONS: In this series, gene expression profiling did not produce a useful classifier to predict nodal involvement in patients with penile carcinoma.

Pelvic lymph node dissection for penile carcinoma: extent of inguinal lymph node involvement as an indicator for pelvic lymph node involvement and survival.

PURPOSE: We identified pathological parameters of inguinal lymph node involvement with the aim of predicting pelvic lymph node involvement and survival. MATERIALS AND METHODS: A total of 308 patients with penile carcinoma and adequate followup were included in this study. The outcome of 102 patients who underwent lymphadenectomy for lymph node metastases was analyzed further. Histopathological characteristics of the regional lymph nodes were reviewed including unilateral or bilateral involvement, the number of involved nodes, pathological tumor grade of the involved nodes, and the presence of extracapsular growth. RESULTS: Tumor grade of the involved inguinal lymph nodes (OR 6.0, 95% CI 1.2-30.3) and the number of involved nodes (2 or less vs more than 2) (OR 12.1, 95% CI 3.0-48.1) were independent prognostic factors for pelvic lymph node involvement. Extracapsular growth (OR 2.3, 95% CI 1.1-4.8), bilateral inguinal involvement OR 3.4, 95% CI 1.2-9.4) and pelvic lymph node involvement (OR 3.1, 95% CI 1.4-6.6) were independent prognostic factors for disease specific survival. CONCLUSIONS: Patients with only 1 or 2 inguinal lymph nodes involved without extracapsular growth and no poorly differentiated tumor within these nodes are at low risk of pelvic lymph node involvement and have a good prognosis with a 5-year survival rate of approximately 90%. Pelvic lymph node dissection seems to be unnecessary in these cases.

Reliability and safety of current dynamic sentinel node biopsy for penile carcinoma.

OBJECTIVES: Dynamic sentinel node biopsy (DSNB) has been performed at our department since 1994 to assess status of inguinal lymph nodes of clinically node-negative (cN0) patients with penile carcinoma. Over time, several modifications were made to reduce the false-negative rate and thus increase sensitivity. We compared the false-negative and complication rates of the current procedure, as performed at our institute since 2001, with the prior procedures. MATERIALS AND METHODS: The patients who underwent DSNB for penile carcinoma in the period from 1994 until July 2004 were divided into two cohorts: cohort A: patients treated from 1994 until 2001; cohort B: patients treated from 2001 until 2004. Cohort A consisted of 92 patients, in whom 157 groins were explored. Cohort B consisted of 58 patients, with a total of 105 explored groins. Medians for follow-up in cohorts A and B were 83 (range: 24-130) and 30 (range: 24-49) mo, respectively. The false-negative and complication rates were determined in both cohorts. RESULTS: In cohort A, 21 of 157 explored groins contained tumour-positive sentinel nodes, and five false-negative procedures were encountered, resulting in a false-negative rate of 19.2%. In cohort B, 20 of 105 explored groins contained tumour-positive sentinel nodes, and one procedure was false-negative. The false-negative rate was 4.8%. The rate of complications dropped from 10.2% in cohort A to 5.7% in cohort B. All complications were minor and transient. CONCLUSIONS: The false-negative and complication rates of DSNB have decreased since the procedure was modified. The current procedure has false-negative and complication rates of 4.8% and 5.7%, respectively. DSNB has matured into a reliable and safe method for assessing status of lymph nodes in cN0 penile carcinoma patients.

Size of metastasis in the sentinel node predicts additional nodal involvement in penile carcinoma.

PURPOSE: The majority of patients with penile cancer with a tumor positive sentinel node do not benefit from complementary lymph node dissection because of absent additional involved nodes. We analyzed factors that may determine the involvement of additional nodes. MATERIALS AND METHODS: A total of 158 patients with clinically node negative penile carcinoma underwent sentinel node biopsy. Complementary inguinal lymph node dissection was performed when the sentinel node was tumor positive. The size of the sentinel node metastasis was measured and classified as micrometastasis--2 mm or less, or macrometastasis--more than 2 mm. Sentinel and dissection specimen nodes were step-sectioned. Factors were analyzed for their association with additional nodal involvement, including stage, diameter, grade, absence or presence of vascular invasion of the primary tumor, and sentinel node metastasis size. RESULTS: Tumor positive sentinel nodes were found in 46 groins and complementary lymph node dissection was performed. Nine of these 46 groins (20%) contained additional involved lymph nodes. On univariate and multivariate analyses the size of the sentinel node metastasis proved to be the only significant prognostic variable for additional lymph node involvement (each p = 0.02). None of the 15 groins with only micrometastasis in the sentinel node contained additional involved nodes. CONCLUSIONS: In penile carcinoma additional nodal involvement was related to the size of the metastasis in the sentinel node. Sentinel node micrometastasis was not associated with other involved lymph nodes. This finding suggests that these patients can be spared complementary lymph node dissection.

Presence of high-risk human papillomavirus DNA in penile carcinoma predicts favorable outcome in survival.

There is evidence that a subset of penile carcinomas is caused by infection with high-risk human papillomavirus (HPV). However, extensive studies on the possible influence of HPV infection on clinical outcome of penile cancer are lacking. This investigation is aimed to examine the prevalence of high-risk HPV in a large series of penile squamous-cell carcinomas (SCCs) and to determine the relationship between HPV and survival. Formalin-fixed, paraffin-embedded tumor specimens of 171 patients with penile carcinoma were tested for high-risk HPV DNA presence by GP5+/6+-PCR. The clinical course of the patients and the histopathological characteristics of the primary tumors were reviewed. High-risk HPV DNA was detected in 29% of the tumors, with HPV 16 being the predominant type, accounting for 76% of high-risk HPV containing SCCs. Disease-specific 5-year survival in the high-risk HPV-negative group and high-risk HPV-positive group was 78% and 93%, respectively (log rank test p = 0.03). In multivariate analysis, the HPV status was an independent predictor for disease-specific mortality (p = 0.01) with a hazard ratio of 0.14 (95% CI: 0.03-0.63). Our results indicate that the presence of high-risk HPV (29%) confers a survival advantage in patients with penile carcinoma.

Reproducibility of lymphoscintigraphy for lymphatic mapping in patients with penile carcinoma.

PURPOSE: We evaluated the reproducibility of lymphoscintigraphy in the assessment of the location and number of sentinel nodes in patients with penile carcinoma. MATERIALS AND METHODS: A total of 20 patients were prospectively included in analysis. Lymphoscintigraphy was performed after intradermal injection of technetium nanocolloid around the tumor or excision scar. We performed 10-minute anterior dynamic imaging, and static anterior and lateral images were obtained at 30 minutes and 2 hours. The following day scintigraphy was repeated after a second injection of the radiolabeled colloid given in an identical fashion, preceded by acquisition of a starting image. An observer evaluated the paired images and count rates were calculated from the images. RESULTS: At least 1 sentinel node was visualized in all patients on the first lymphoscintigram. A total of 56 sentinel nodes were seen in 38 basins. Drainage to both groins was seen in 18 patients. In 1 of these patients drainage to the prepubic area was also observed. There were 2 patients with drainage to 1 groin. The second lymphoscintigram revealed the same drainage pattern in all patients- the same number of nodal basins and number of sentinel nodes were visualized at identical locations. All hotspots that were visualized during the first lymphoscintigram showed an unequivocal increase in radioactivity after repeat injection. Thus, the reproducibility of penile lymphoscintigraphy was 100% (95% CI 85%-100%). The Pearson correlation coefficient of the paired count rates was 0.69 (p <0.0001). CONCLUSIONS: Results of lymphoscintigraphy in patients with penile carcinoma are highly reproducible for assessment of the number and location of sentinel nodes.

Prepubic sentinel node location in penile carcinoma.

An unusual sentinel node location in a patient with penile carcinoma is described. The preoperative lymphoscintigram showed a prepubic sentinel node. The node could be harvested during surgery. This case illustrates one of the advantages of lymphatic mapping in penile carcinoma: preoperative lymphoscintigraphy can identify lymph nodes outside the usual nodal basins.

Non-visualization of sentinel lymph nodes in penile carcinoma.

PURPOSE: The purpose of this study was to analyse the incidence and cause of non-visualization of sentinel lymph nodes on preoperative lymphoscintigrams for penile cancer and its implications for further management. METHODS: Preoperative lymphoscintigraphy was performed after injection of (99m)Tc-labelled nanocolloid in 123 clinically node-negative penile carcinoma patients. Anterior dynamic lymphoscintigraphy was performed during 20 min immediately after tracer injection. Subsequently, 5-min anterior and lateral static images were obtained 30 min and 2 h post injection. RESULTS: Lymphatic drainage to both groins was seen in 98 patients (79%), unilateral drainage in 23 patients (19%) and no drainage at all in two patients (2%). Thus, in 27 (11%) of 246 groins, no sentinel node was visualized. The amount of administered tracer dose was associated with non-visualization (p=0.01). Unilateral drainage was initially interpreted as a normal physiological phenomenon. After the occurrence of a tumour-positive node in a non-visualized groin, we explore non-visualized groins by blue dye mapping and intraoperative palpation. Sentinel nodes were retrieved in four out of eight such groins, of which one contained metastasis. CONCLUSION: In penile carcinoma patients, preoperative lymphoscintigraphy visualizes a sentinel node in 89% of groins. Visualization depends on the administered tracer dose. It is worthwhile to explore non-visualized groins. Sentinel nodes can be intraoperatively identified in more than half of these cases.

Dynamic sentinel node biopsy in penile carcinoma: evaluation of 10 years experience.

PURPOSE: The aim of this study was to evaluate the results of 10 years dynamic sentinel node biopsy experience in penile carcinoma at our institute. PATIENTS AND METHODS: 140 patients with clinically node-negative groins were prospectively included. Lymphoscintigraphy was performed after injection of 99mTechnetium-nanocolloid around the primary tumour. The sentinel node was intraoperatively identified with the aid of patent blue dye and a gamma ray detection probe. Lymph node dissection was performed only if sentinel node metastasis was found. Median follow-up was 52 months (range 5-129). RESULTS: Lymphoscintigraphy visualized at least 1 sentinel node in 138 patients. Sentinel node metastasis was found in 37 inguinal regions of 31 patients. The sentinel node was the only tumour-positive node in 78% (29/37) of the dissection specimens. Complications occurred in 8% (17/206) of the operated groins. False-negative results were encountered in 6 patients resulting in a false-negative rate of 16% (6/37 patients). 5-year disease-specific survival was 96% and 66% for patients with a tumour-negative sentinel node and tumour-positive sentinel node, respectively (p=0.001). CONCLUSION: Dynamic sentinel node biopsy in penile carcinoma is of important diagnostic, prognostic, and therapeutic value at the cost of only minor morbidity.

Ultrasonography-guided fine-needle aspiration cytology before sentinel node biopsy in patients with penile carcinoma.

OBJECTIVE: To assess the accuracy of ultrasonography (US)-guided fine-needle aspiration cytology (FNAC) for detecting occult lymph node metastases in patients with squamous cell carcinoma of the penis. PATIENTS AND METHODS: Forty-three patients with 83 clinically node-negative inguinal regions were assessed with US and FNAC. The results were compared with histology from subsequent dynamic sentinel-node biopsy (DSNB) or inguinal lymph node dissection. RESULTS: Thirty-four groins in 27 patients were considered to be suspicious by US and the lymph nodes were aspirated. Nine nodes contained tumour cells and this was confirmed by subsequent lymph node dissection. The sensitivity and specificity of US-guided FNAC were 39% (nine of 23) and 100% (60 of 60), respectively. The number of groins requiring DSNB was reduced by 11% (nine of 83). CONCLUSION: US-guided FNAC can be used as the initial investigation in clinically node-negative groins. If tumour is confirmed then therapeutic inguinal lymph node dissection can be earlier and fewer DSNBs are required.

Contemporary management of penile squamous cell carcinoma.

Squamous cell carcinoma (SCC) is the most common tumor of the penis. The natural history and its proclivity to spread via regional lymphatics has been well defined. Laser ablation of the primary tumor has a prominent role in patients with a superficial tumor as a penis-conserving approach. Patients with deeper infiltrating tumors, should undergo (partial) penile amputation. For patients presenting with proven metastatic nodes complete (ilio-) inguinal lymphadenectomy should be performed. During the last two decades, the management of penile carcinoma patients with impalpable regional lymph nodes has improved due to better knowledge of risks for metastases, the introduction of modified lymphadenectomy, and sentinel node biopsy. Future perspectives in penile cancer comprises continuing research to reduce mutilation without jeopardizing clinical outcome.