Detection of inguinal lymph node involvement in penile squamous cell carcinoma by 18F-fluorodeoxyglucose PET/CT: a prospective single-center study.

BACKGROUND: The extent of lymph node involvement is the most relevant prognostic factor in patients with penile cancer. OBJECTIVE: To prospectively analyze the diagnostic accuracy of 18F-FDG-PET/CT-scan in the assessment of inguinal lymph node involvement in patients with invasive penile carcinoma. PATIENTS AND METHODS: Thirty-five patients with invasive penile carcinoma were staged prospectively by 18F-FDG-PET/CT-scan, and blindly evaluated by 2 nuclear medicine physicians. In total, lymph node involvement was assessed in 70 inguinal groins. Reference standard was either histology or clinical follow-up with a minimum of 31 months (mean: 48.4 months; range: 31-68 months). RESULTS: 18-FDG-PET/CT showed a sensitivity of 88.2% and a specificity of 98.1%. Positive predictive value (PPV) was 93.8%, while negative predictive value (NPV) was 96.3%. In two groins, metastasis of 5 and 7 mm were missed by PET/CT scan. CONCLUSION: 18F-FDG-PET/CT is a promising staging tool in assessing the inguinal lymph node involvement of patients with penile carcinoma. Integration of PET/CT scanning into preoperative staging algorithms may avoid surgical staging in selected patients.

Fluorescence-guided laser therapy for penile carcinoma and precancerous lesions: long-term follow-up.

OBJECTIVES AND AIMS: Laser therapy for penile carcinoma is commonly used despite high recurrence rates of up to 48%. The aim of our study was to investigate the long-term recurrence rate of patients treated by fluorescence-guided laser therapy for penile carcinoma and its impact on oncologic outcome. PATIENTS AND METHODS: Between 1999 and 2005, a total of 26 patients with premalignant carcinoma in situ (Tis) (n = 11) or invasive penile carcinoma (n = 15) were treated by fluorescence-guided laser therapy in our center. The mean follow-up was 71.1 months (range 41-104 months). Recurrence rate, time to recurrence, and impact on survival was investigated for Tis patients and penile carcinoma patients separately. RESULTS: No patient died tumor-associated recurrence during follow-up. No local progression of T stage was observed in patients with Tis tumor. In the group with invasive penile cancer, there were 4 (15.4%) local recurrences. However, 3 of them occurred after more than 3 years and, therefore, are more likely to be considered as "de novo" carcinoma. No intra- or perioperative side effects of photodynamic diagnosis (PDD) were observed. CONCLUSIONS: Local recurrence rate of laser therapy can be reduced by fluorescence guidance without impairing cosmetic or functional results. The necessary equipment is available in many centers that perform PDD for urothelial bladder cancer. PDD, therefore, can be considered to be cost-effective and easy to perform. Prospective multi-center studies to directly compare recurrence rates between white light and fluorescence-guided laser therapy for penile carcinoma are required.

Intermediate-differentiated invasive (pT1 G2) penile cancer--oncological outcome and follow-up.

OBJECTIVES AND AIMS: Due to the low prevalence of penile cancer, little evidence exists on the metastatic potential and the ideal treatment strategies in intermediate-differentiated invasive (pT1 G2) penile cancer. The current study aimed to analyze the oncologic outcome of patients with penile carcinoma with long-term follow-up in a single-center study. PATIENTS AND METHODS: In this retrospective study, 38 patients with histologically proven T1 G2 squamous cell carcinoma of the penis were included. Only the 'classic' subtype was analyzed. Treatment of the primary tumor was Nd:YAG laser-therapy, excision, or partial amputation. Follow-up was performed according to EAU guidelines (2004). RESULTS: Mean follow-up was 78.1 months (range: 9-285 months). Local recurrence was seen in 12 patients (31.6%), but was not correlated with disease related death (P = 0.7944). Rate of local recurrence was not dependent on treatment modality (P = 0.3481); 13 patients died, accounting for a disease related survival rate of 81.6% during observation period. Positive lymph nodes were seen in 28.9% of patients and were significantly correlated with disease related death (P = 0.00004). Clinically enlarged inguinal lymph nodes were not correlated with histologically confirmed positive lymph nodes (P = 0.5785). CONCLUSIONS: For patients with T1 G2 penile cancer, organ preserving therapy appears to be a suitable treatment option. In our series, nearly one third of patients developed inguinal lymph node metastases, which highlights the potential benefit of surgical staging. Larger prospective multicenter studies are needed to define the best treatment strategy for intermediate-differentiated invasive penile cancer.

Organ-preserving neodymium-yttrium-aluminium-garnet laser therapy for penile carcinoma: a long-term follow-up.

OBJECTIVE: To retrospectively analyse the long-term follow-up of 54 patients treated with organ-preserving laser therapy for penile carcinoma, as such therapy provides excellent cosmetic and functional results, but recurrence rates are high, which might impair the oncological outcome and worsen tumour-related survival. PATIENTS AND METHODS: Between 1979 and 2008, 54 patients with penile carcinoma were treated with the neodymium-doped yttrium-aluminium-garnet (Nd:YAG) laser at our institution; 11 were classified as having carcinoma in situ (Tis), 39 as T1 and four as T2. RESULTS: There was local recurrence in 16 patients (42%); the mean (range) time to local recurrence was 53 (9-132) months. In half the patients the time to local recurrence was >53 months, with the latest recurrence at 132 months after initial therapy of primary tumour. There was no statistically significant difference in recurrence rates with Tis or invasive penile carcinoma. In lymph-node-negative patients at initial presentation, there were no newly developed positive lymph nodes during the follow-up. CONCLUSIONS: Organ-preserving laser therapy showed a relatively high recurrence rate in patients with a long-term follow up, but the oncological outcome and survival were not compromised by local recurrence. Therefore, laser therapy appears to be appropriate for treating premalignant lesions and early stages of penile carcinoma. Patients should be informed about the potential for late recurrence.

Adenocarcinoma of the bladder following nephrogenic adenoma: a case report.

INTRODUCTION: Nephrogenic adenomas are generally considered to be benign lesions, but there remains a risk for malignant transformation. Patients with immunosuppression in particular appear to be at a higher risk of malignant disease. We report a case of post-traumatic nephrogenic adenoma in a young patient without immunosuppression, which transformed into an adenocarcinoma of the bladder. CASE PRESENTATION: A 25-year-old man had a traumatic bladder perforation caused by a car accident. After physical recovery from the accident, he developed a neurogenic bladder and recurrent urinary tract infections. He presented with nephrogenic adenoma of the bladder 18 months after the accident. The adenoma was treated repeatedly with transurethral resections. The initial pathologic findings were benign, however, the last resection revealed that the former benign adenoma had transformed into a moderately differentiated adenocarcinoma of the bladder (tumor present but no invasion, multifocal, no lymph nodes involved, no metastasis, grade 2). He subsequently underwent radical cystectomy and has remained tumor-free for the last 4 years. CONCLUSION: Nephrogenic adenoma is a rare disease with some potential for malignant transformation. However, patients with nephrogenic adenoma under immunosuppression and patients with neurogenic bladder dysfunction appear to be at a higher risk of developing bladder cancer.

Squamous cell carcinoma antigen correlates with tumor burden but lacks prognostic potential for occult lymph node metastases in penile cancer.

OBJECTIVES: In penile cancer, radical groin dissection is the reference standard for lymph node staging, but it is associated with high morbidity. Prognostic markers for lymphatic spread would be helpful to select patients for a surveillance program. Squamous cell carcinoma (SCC) antigen is a well-known marker for various carcinomas. Our aim was to evaluate the value of the SCC antigen in terms of lymph node staging and treatment control. METHODS: From 1994 to 2004, the serum levels of SCC antigen were analyzed in 54 men with penile carcinoma at different disease stages. The SCC antigen values were compared in patients without evidence of tumor, with a primary tumor only, with nodal metastases, and with progressive metastatic disease. In 13 patients, repeated SCC antigen measurements correlated with the treatment effects. RESULTS: Once lymph node metastases occurred, a trend was found toward increased SCC antigen levels and at the stage of organ metastases, the SCC antigen levels had risen significantly (P <0.01). In cases of repeated measurements, a correlation was found between SCC antigen values and treatment effect. A response to treatment occurred, even if the values were within normal limits. CONCLUSIONS: The SCC antigen levels seemed to correlate with tumor burden in patients with penile carcinoma. However, it is of limited value in the primary prediction of occult lymph node metastases because the SCC antigen levels increased significantly only after massive lymph node involvement or metastatic disease has occurred. However, the SCC antigen could be used as a marker for treatment control in penile carcinoma.

Seven years' experience with 5-aminolevulinic acid in detection of transitional cell carcinoma of the bladder.

OBJECTIVES: Photodynamic diagnosis (PDD) using 5-aminolevulinic acid has proved to be a procedure with an outstanding sensitivity for the detection of transitional cell carcinoma of the bladder, in particular in the detection of flat urothelial lesions. We report on our clinical results with 875 patients (1713 PDD procedures) between March 1995 and March 2002. METHODS: A total of 1713 PDD procedures were done in 875 patients. Fluorescence imaging was performed 2 to 3 hours after instillation of 50 mL of a 3% solution of 5-aminolevulinic acid into the bladder by an incoherent light source. In total, specimens from 4630 lesions (2.7 lesions/PDD) were taken. RESULTS: In 34.8% of all biopsies, the histologic finding was malignant; 23.7% of these biopsies had been taken only because of positive fluorescence. In 28.5% of the positive biopsies, flat lesions had been identified. Also, 43.4% of carcinoma in situ and 30.7% of dysplasia II degrees were detected only by positive fluorescence. Of all tumor lesions, 92.0% were detected by PDD compared with 76.3% detected by white light endoscopy. CONCLUSIONS: PDD has proved to be an effective detection device for superficial bladder cancer.

Risk stratification in penile carcinoma: 25-year experience with surgical inguinal lymph node staging.

OBJECTIVES: In penile carcinoma, the most reliable staging method for lymph node involvement remains radical dissection with its associated high morbidity. However, the patient's prognosis is closely associated with lymph node status, and radical dissection is potentially curative. We report our experience with surgical lymph node staging and evaluate which group of patients could be assigned to a wait-and-see strategy or dynamic sentinel node biopsy and which group should undergo groin dissection. METHODS: From 1979 to 2004, 56 consecutive patients with penile cancer underwent surgical inguinal lymph node staging. On the basis of the histopathologic results, we defined risk stratification into low, high, and intermediate-risk groups according to the clinical examination findings, stage, and grade. RESULTS: Tumor stage (P = 0.019) and tumor grade (P <0.001) correlated significantly with lymph node status. Stratification into low (pT1G1, pT1G2), high (all G3 tumors), and intermediate-risk (all others) groups found 7.7% of low-risk patients with metastases. In the intermediate and high-risk groups, 28.6% and 75.0% had nodal metastases, respectively. Correlation with nodal involvement according to risk group was R2 = 0.608 (P <0.001). CONCLUSIONS: Risk stratification might enable a modified staging strategy for lymph node status according to stage, grade, and clinical examination findings. Highly motivated low-risk patients could be included in a surveillance program; however, high-risk patients should undergo bilateral inguinal dissection. Dynamic sentinel lymph node biopsy might be encouraged for intermediate-risk patients in the future.

Simultaneous bilateral laser Doppler fluxmetry and electrophysiological recording during middle cerebral artery occlusion in rats.

Laser Doppler fluxmetry (LDF) and electrocorticography (ECG) are techniques used to indicate successful occlusion of the middle cerebral artery (MCAO) in the intraluminal filament model of ischemic stroke. However, each method has several advantages and drawbacks. This article describes a simple technique to simultaneously and continuously monitor LDF and ECG over both cerebral hemispheres. We investigated the potential of this method to improve the reliability of the filament model. Thirty male Sprague-Dawley rats were subjected to transient MCAO under three different experimental conditions (n=10 each group): MCAO in [A] normothermic animals, in [B] animals treated with hypothermia and in [C] animals receiving barbiturate for induction of burst suppression. Cortical blood flow was continuously recorded bilaterally by LDF and the electrocorticogram was continuously recorded over both hemispheres. The results show that monitoring of cortical electrophysiological activity by ECG allows detection of subarachnoid hemorrhage (SAH) during normal electrophysiological status and provides continuous control of barbiturate induced burst suppression as well as information about postischemic electrophysiological recovery. ECG did not detect MCAO, premature reperfusion, or SAH during burst suppression induced by barbiturates. In contrast, MCAO, SAH and premature reperfusion were rapidly indicated by LDF. Our findings suggest that simultaneous bilateral LDF and ECG during MCAO are of complementary value, in particular if barbiturates are investigated.

18F-FDG PET/CT for staging of penile cancer.

UNLABELLED: The value of PET or PET/CT with (18)F-FDG for the staging of penile cancer has yet to be determined. The objective of this study was to investigate the pattern of (18)F-FDG uptake in the primary malignancy and its metastases and to determine the diagnostic value of (18)F-FDG PET/CT in the staging and restaging of penile cancer. METHODS: Thirteen patients (mean +/- SD age, 64 +/- 14.0 y) with suspected penile cancer or suspected recurrent disease were examined with a Gemini PET/CT system (200 MBq of (18)F-FDG). The reference standard was based on histopathologic findings obtained at biopsy or during surgery. RESULTS: Both the primary tumor and regional lymph node metastases exhibited a pattern of (18)F-FDG uptake typical for malignancy. Sensitivity in the detection of primary lesions was 75% (6/8), and specificity was 75% (3/4). On a per-patient basis, sensitivity in the detection of lymph node metastases was 80% (4/5), and specificity was 100% (8/8). On a nodal-group basis, PET/CT showed a sensitivity of 89% (8/9) in the detection of metastases in the superficial inguinal lymph node basins and a sensitivity of 100% (7/7) in the deep inguinal and obturator lymph node basins. The mean +/- SD maximum standardized uptake value for the 8 primary lesions was 5.3 +/- 3.7, and that for the 16 lymph node metastases was 4.6 +/- 2.0. CONCLUSION: According to our results, the main indication for (18)F-FDG PET in the primary staging or follow-up of penile cancer patients may be the prognostically crucial search for lymph node metastases. With the use of a PET/CT unit, the additional information provided by CT may be especially useful for planning surgery. Implementing (18)F-FDG PET and PET/CT in future staging algorithms may lead to a more precise and stage-appropriate therapeutic strategy. Furthermore, invasive procedures with a high morbidity rate, such as general bilateral lymphadenectomy, may be avoided.

Use of argon plasma coagulation in endourology: in vitro experiments.

OBJECTIVES: To investigate different parameters influencing argon plasma coagulation (APC) in a fluid medium with regard to endourologic procedures. APC is a novel therapeutic modality of noncontact electrocoagulation that applies high-frequency current by way of ionized argon gas. Recent modifications for endoscopic application of APC have helped to establish new indication in various surgical fields. METHODS: Standardized experiments using an endoscopic APC device were performed on fresh bovine skeletal muscle in different fluid media. The effects of the power setting, gas flow rates, and treatment duration on the coagulation zones and tissue ablation were evaluated. RESULTS: The coagulation zones were remarkably uniform. The depths of coagulation increased significantly with augmented power settings and APC duration but were not dependent on gas flow rates. Likewise, tissue removal increased with greater power and longer application times but was not affected by flow rates. Tissue ablation in general was moderate. Different fluid media generated varying performances. CONCLUSIONS: Using a laboratory model, we demonstrated that APC performed in a fluid medium is feasible. The power setting, treatment duration, and different fluid media were interdependent factors affecting the performance of APC in a fluid milieu. However, before application of APC in endourologic procedures in humans, additional studies concerning safety issues are mandatory.

Autofluorescence and 5-aminolevulinic acid induced fluorescence diagnosis of penile carcinoma -- new techniques to monitor Nd:YAG laser therapy.

Nd:YAG laser coagulation is possible for superficial tumors of the penis. The value of photodynamic diagnosis (PDD) and autofluorescence imaging (AF) in detecting malignant lesions on the penis was evaluated. Twelve patients with biopsy-confirmed squamous cell cancer (SCC) of the penis were examined with PDD and AF. For the PDD and AF the penis was illuminated with the blue excitation light from a xenon arch lamp. Biopsies were taken from suspicious lesions detected by PDD or AF and then treated with Nd:YAG laser coagulation. Neoplastic lesions presented with a positive red fluorescence under PDD or a diminished appearance under AF. The HPV-analysis was positive in eight of the 12 lesions. Fluorescence diagnosis is used for the detection of neoplastic lesions. It assists the urologist in detecting neoplastic and preneoplastic lesions, ensuring a more reliable destruction of all tumor material in penile sparing surgery.

Role of 5-aminolevulinic acid in the detection of urothelial premalignant lesions.

BACKGROUND: The authors evaluated the role of 5-aminolevulinic acid (5-ALA)-induced fluorescence endoscopy (AFE) in the detection of flat urothelial lesions in light of the suggestions made for flat neoplastic lesions within the 1999 World Health Organization (WHO) classification of urinary bladder tumors. METHODS: From 1995 to 2000, 713 patients underwent 1414 AFE procedures for the detection of transitional cell carcinoma of the bladder (TCCB). Fluorescence imaging was performed with an incoherent light source (D-light; 380-440 nm) that was filtered for efficient protoporphyrin IX excitation and with cystoscopes partially blocking reflected excitation light to enable fluorescence evaluation by a red/blue color contrast 2-3 hours after 50 mL of a 3% solution of 5-ALA was instilled into the bladder. In total, 3834 biopsy specimens (mean, 2.7 specimens per AFE procedure) were taken. RESULTS: Malignant disease was found in 1250 (32.6%) of all biopsies, with 304 biopsies (24.3%) showing carcinoma in situ (cis) and dysplasia II degrees (dys II) according to the previous diagnostic criteria of the WHO. Under prior conventional white-light endoscopy, 30.3% of specimens with dys II and 52.8% of specimens with cis had been missed. CONCLUSIONS: The current results suggest that 5-ALA may be more effective in the detection of flat urothelial lesions than the current diagnostic devices.

Occurrence of chromosome 9 and p53 alterations in multifocal dysplasia and carcinoma in situ of human urinary bladder.

To define the genetic changes of flat urothelial lesions, carcinoma in situ (CIS) and moderate dysplasias (DII) were investigated for alterations in the two chromosomal regions most frequently involved in bladder cancer. Overall, 33 CIS and 16 DII from 21 patients were used to microdissect urothelium. Dual color fluorescence in situ hybridization (FISH) using gene locus probes of 9q22 (FACC), 9p21 (CDK), 17p13 (p53), and related centromeric probes was applied on interphase nuclei. In parallel, preamplified DNA of these samples was used for loss of heterozygosity (LOH) analyses with eight microsatellite markers on chromosomes 9p, 9q and 17p, and for sequencing of exons 5-9 of p53. Data indicated nearly identical deletion frequencies for chromosomes 9 and 17 for CIS (chromosome 9, 86%; p53, 84%). DII showed a lower deletion rate in comparison with CIS (chromosome 9, 75%; p53, 53%). A very high correlation between the results of FISH and LOH analyses was found. p53 mutations were detected in 12 of 15 patients (CIS, 72%; DII, 67%). In three of 16 patients with multifocal tumors, oligoclonal lesions were identified by LOH analyses, a finding further supported by sequencing of p53, by which two different p53 deletions were detected in two cases. In conclusion, data from microdissected flat urothelial lesions indicate that chromosome 9 deletions cannot be regarded as indicators of papillary growth, because they are found frequently in both types of flat lesions of the urothelium: those associated with papillary tumors and those that are not. The similar distribution and lower amount of genetic changes in DII render DII a possible precursor lesion of CIS.