The role of histologic subtype, p16(INK4a) expression, and presence of human papillomavirus DNA in penile squamous cell carcinoma.

BACKGROUND: Up to 50% of penile squamous cell carcinomas (pSCC) develop in the context of high-risk human papillomavirus (HR-HPV) infection. Most of these tumours have been reported to show basaloid differentiation and overexpression of tumour suppressor protein p16(INK4a). Whether HPV-triggered carcinogenesis in pSCC has an impact on tumour aggressiveness, however, is still subject to research. METHODS: In tissue specimens from 58 patients with surgically treated pSCC between 1995 and 2012, we performed p16(INK4a) immunohistochemistry and DNA extraction followed by HPV subtyping using a PCR-based approach. The results were correlated with histopathological and clinical parameters. RESULTS: 90.4% of tumours were of conventional (keratinizing) subtype. HR-HPV DNA was detected in 29.3%, and a variety of p16(INK4a) staining patterns was observed in 58.6% of samples regardless of histologic subtype. Sensitivity of basaloid subtype to predict HR-HPV positivity was poor (11.8%). In contrast, sensitivity and specificity of p16(INK4a) staining to predict presence of HR-HPV DNA was 100% and 57%, respectively. By focussing on those samples with intense nuclear staining pattern for p16(INK4a), specificity could be improved to 83%. Both expression of p16(INK4a) and presence of HR-HPV DNA, but not histologic grade, were inversely associated with pSCC tumour invasion (p = 0.01, p = 0.03, and p = 0.71). However, none of these correlated with nodal involvement or distant metastasis. In contrast to pathological tumour stage, the HR-HPV status, histologic grade, and p16(INK4a) positivity failed to predict cancer-specific survival. CONCLUSIONS: Our results confirm intense nuclear positivity for p16(INK4a), rather than histologic subtype, as a good predictor for presence of HR-HPV DNA in pSCC. HR-HPV / p16(INK4a) positivity, independent of histological tumour grade, indicates a less aggressive local behaviour; however, its value as an independent prognostic indicator remains to be determined. Since local invasion can be judged without p16(INK4a)/HPV-detection on microscopic evaluation, our study argues against routine testing in the setting of pSCC.

Corpulence is the crucial factor: association of testosterone and/or obesity with prostate cancer stage.

OBJECTIVES: To evaluate whether low testosterone levels or obesity, or both, are directly associated with tumor stage/grade in patients with clinically localized prostate cancer. METHODS: Preoperative androgen serum levels (total and free testosterone), sex hormone-binding globulin, body mass index and waist circumference were assessed in 510 consecutive European Caucasian men treated with radical prostatectomy. Hormone levels and body mass index/waist circumference were correlated with patient- and tumor-specific characteristics using multivariable logistic regression analysis. RESULTS: Even though we confirmed an inverse correlation between bodyweight and testosterone levels, only overweight - but not low testosterone - was associated with advanced disease and poor differentiation of prostate cancer. Using multivariate analyses, both body mass index ≥30 kg/m(2) and waist circumference >110 cm were associated with high-grade disease (Gleason score ≥8). A waist circumference >110 cm also correlated significantly with lymph node metastasis. CONCLUSIONS: This is the first study showing that obesity, but not low serum testosterone levels, is significantly associated with high grade and metastatic disease in men diagnosed with clinically localized prostate cancer. The present findings suggest that low androgen levels at diagnosis, which used to be held responsible for the development of aggressive prostate cancer, is only an epiphenomenon of obesity rather than the cause of prostate cancer development and/or progression.

High CRP values predict poor survival in patients with penile cancer.

BACKGROUND: High levels of circulating C-reactive protein (CRP) have recently been linked to poor clinical outcome in various malignancies. The aim of this study was to evaluate the prognostic significance of the preoperative serum CRP level in patients with squamous cell carcinoma (SCC) of the penis. METHODS: This retrospective analysis included 79 penile cancer patients with information about their serum CRP value prior to surgery who underwent either radical or partial penectomy at two German high-volume centers (Ulm University Medical Center and Hannover Medical School) between 1990 and 2010. They had a median (mean) follow-up of 23 (32) months. RESULTS: A significantly elevated CRP level (>15 vs. ≤ 15 mg/l) was found more often in patients with an advanced tumor stage (≥pT2) (38.9 vs. 11.6%, p=0.007) and in those with nodal disease at diagnosis (50.0 vs. 14.6%, p=0.007). However, high CRP levels were not associated with tumor differentiation (p=0.53). The Kaplan-Meier 5-year cancer-specific survival (CSS) rate was 38.9% for patients with preoperative CRP levels above 15 mg/l and 84.3% for those with lower levels (p=0.001). Applying multivariate analysis and focusing on the subgroup of patients without metastasis at the time of penile surgery, both advanced local tumor stage (≥pT2; HR 8.8, p=0.041) and an elevated CRP value (>15 mg/l; HR 3.3, p=0.043) were identified as independent predictors of poor clinical outcome in patients with penile cancer. CONCLUSIONS: A high preoperative serum CRP level was associated with poor survival in patients with penile cancer. If larger patient populations confirm its prognostic value, its routine use could enable better risk stratification and risk-adjusted follow-up of patients with SCC of the penis.

Elevated C-reactive protein values predict nodal metastasis in patients with penile cancer.

BACKGROUND: The nodal status is a strong predictor for cancer specific death in patients with penile carcinoma, and the C-reactive protein (CRP) level at diagnosis has recently been shown to be associated with poor clinical outcome in various solid malignancies. Therefore, this retrospective study was performed to evaluate the association between preoperative CRP levels and the incidence of nodal metastasis in patients with squamous cell carcinoma (SCC) of the penis. METHODS: The analysis included 51 penile cancer patients who underwent either radical or partial penectomy for pT1-4 penile cancer between 1990 and 2010. The nodal status was correlated with patient and tumor specific characteristics. RESULTS: Sixteen (31%) patients had lymph node metastasis at the time of penile cancer surgery. Nodal status was associated with tumor stage but did not correlate significantly with tumor grade. In contrast, high presurgical CRP levels were significantly associated with the diagnosis of nodal involvement (p = 0.04). The optimal CRP cut-off value to predict lymph node metastasis was set at 20 mg/l based on ROC analysis. CONCLUSIONS: Since a high preoperative serum CRP level was closely correlated with nodal disease, it could be used as an additional marker to help identify patients with penile cancer who may benefit from inguinal lymph node dissection.

Capsulotomy for treatment of compartment syndrome in patients with post extracorporeal shock wave lithotripsy renal hematomas: safe and effective, but also advisable?

PURPOSE: To examine whether surgical decompression of hematomas by capsulotomy can help to improve long-term renal function following extracorporeal shock wave lithotripsy (SWL). MATERIALS AND METHODS: This study retrospectively identified 7 patients who underwent capsulotomy for post SWL renal hematomas between 2008 and 2012. The control group comprised 8 conservatively treated patients. The median follow-up time was 22 months. RESULTS: The two groups were comparable in age, gender, body mass index, risk factors for developing hematomas (renal failure, urinary flow impairment, indwelling ureteral stent and diabetes mellitus) and the selected SWL modalities. Hematoma size was also similar. However, significantly more patients in the surgical group had purely intracapsular hematomas (85.7% vs. 37.5%) without a potentially pressure-relieving capsular rupture. There were no significant differences in the post-interventional drop in hemoglobin, rise in retention parameters or drop in glomerular filtration rate (GFR). No capsulotomy-related complications were observed, but surgery required a significantly longer hospital stay than conservative management (median, 9 days vs. 5 days). The two groups also showed comparable recovery of renal function at long-term follow-up (median change in GFR from baseline, 97.1% and 97.8%, respectively). CONCLUSION: Since renal function did not differ between the two treatment groups, the conservative management remains the standard treatment for post-SWL renal hematoma.

Overexpression of p16(INK4a) in urothelial carcinoma in situ is a marker for MAPK-mediated epithelial-mesenchymal transition but is not related to human papillomavirus infection.

BACKGROUND: The role of human papillomavirus (HPV) in bladder carcinogenesis remains controversial. Overexpression of p16(INK4a), a surrogate marker for infection with oncogenic HPV in other tumours, has been described for urothelial carcinoma in situ (UCIS). Our goal was therefore to evaluate whether overexpression of p16(INK4a) is associated with HPV infection and to identify mechanisms of p16(INK4a) upregulation in UCIS. MATERIALS AND METHODS: In 60 tissue specimens from a total of 45 patients (UCIS and controls), we performed p16(INK4a) immunohistochemistry followed by detection and subclassification of HPV DNA. In a subset of samples, we tested for gene amplification of p16(INK4a) applying fluorescence in situ hybridization (FISH). RAS/MAPK signalling and epithelial-mesenchymal transition (EMT) was assessed using immunohistochemistry. Finally, we transfected urothelial carcinoma cells with KRAS and examined the expression of p16(INK4a) as well as markers of EMT. RESULTS: We found overexpression of p16(INK4a) in 92.6% of UCIS and in all cervical intraepithelial neoplasia (CIN) controls. In contrast, we detected high-risk HPV DNA in 80% of CIN, but none in UCIS. There was no gene amplification of p16(INK4a). High levels of phosphorylated kinases and urokinase plasminogen activator (uPA) and loss of membraneous E-cadherin were detected in UCIS. KRAS transfection of urothelial carcinoma cells led to upregulation of p16(INK4a) and uPA accompanied by loss of E-cadherin that could be inhibited by application of the kinase-inhibitor Sorafenib. CONCLUSIONS: Our results show that overexpression of p16(INK4a) in UCIS is neither associated with HPV infection nor p16(INK4a) gene amplification but is a consequence of enhanced RAS/MAPK signalling that promotes EMT, possibly due to Sorafenib-sensitive paracrine secretion of the EMT activator uPA. These findings might open a novel therapeutic option for localized but aggressive urothelial cancer.

The retrourethral transobturator sling suspension in the treatment of male urinary stress incontinence: results of a single institution experience.

Objective. To evaluate functional outcome of the retrourethral transobturator sling suspension (RTS) in the treatment of stress urinary incontinence (SUI) caused by prior prostate surgery. Methods. The RTS (AdVance male sling) was implanted in 32 patients who suffered from mild to severe postsurgical-treatment incontinence at the University Hospital Ulm from September 2010 to September 2011 including 10 patients with prior radiation therapy. Functional data (uroflowmetry, daily pad use, and postvoid residual urine) as well as quality of life with impact of urinary problems (ICIQ-UI SF) were prospectively assessed at baseline and during followup. Results. After a median followup of 9 months (range, 3-14) the incontinence cure rate (no pad usage) was 56.2% and the improvement rate (1-2 pads/day or ≥50% reduction) was 21.9%. No improvement was observed in 21.9%. Daily pad use and ICIQ-UI SF score improved significantly. No major perioperative complications occurred. Postoperatively, 15.6% of the patients exhibited transient acute urinary retention which resolved without further treatment after a maximum of 3 weeks. One patient underwent sling explantation due to dislocation and persistent perineal pain. Conclusions. The implantation of the RTS is a safe and effective procedure in selected patients with SUI resulting from prostate surgery.