Chris Protzel

EAU Guidelines on Penile Cancer: 2014 Update

CONTEXT Penile cancer has high mortality once metastatic spread has occurred. Local treatment can be mutilating and devastating for the patient. Progress has been made in organ-preserving local treatment, lymph node management, and multimodal treatment of lymphatic metastases, requiring an update of the European Association of Urology guidelines. OBJECTIVE To provide an evidence-based update of treatment recommendations based on the literature published since 2008. EVIDENCE ACQUISITION A PubMed search covering the period from August 2008 to November 2013 was performed, and 352 full-text papers were reviewed. Levels of evidence were assessed and recommendations graded. Because there is a lack of controlled trials or large series, the levels of evidence and grades of recommendation are low compared with those for more common diseases. EVIDENCE SYNTHESIS Penile squamous cell carcinoma occurs in distinct histologic variants, some of which are related to human papilloma virus infection; others are not. Primary local treatment should be organ preserving, if possible. There are no outcome differences between local treatment modes in superficial and T1 disease. Management of inguinal lymph nodes is crucial for prognosis. In impalpable nodes, invasive staging should be done depending on the risk factors of the primary tumour. Lymph node metastases should be treated by surgery and adjuvant chemotherapy in N2/N3 disease. CONCLUSIONS Organ preservation has become the standard approach to low-stage penile cancer, whereas in lymphatic disease, it is recognised that multimodal treatment with radical inguinal node surgery and adjuvant chemotherapy improves outcome. PATIENT SUMMARY Approximately 80% of penile cancer patients of all stages can be cured. With increasing experience in the management of penile cancer, it is recognized that organ-preserving treatment allows for better quality of life and sexual function and should be offered to all patients whenever feasible. Referral to centres with experience is recommended.

Lymphadenectomy in the Surgical Management of Penile Cancer

CONTEXT Uncertainty remains about the extent and indications for inguinal lymphadenectomy in penile cancer, a procedure known for relatively high morbidity. Several attempts have been made to develop strategies which can improve the diagnostic quality and reduce the morbidity of the management of inguinal lymph nodes in penile cancer. OBJECTIVE To analyse the existing published data on the surgical management of inguinal nodes in penile cancer regarding morbidity and survival. EVIDENCE ACQUISITION A Medline search was performed of the English-language literature (1966-September 2008) using the MeSH terms penile carcinoma, lymph node dissection, lymphadenectomy, and complications. EVIDENCE SYNTHESIS Lymph node metastases are frequent in penile cancer, even in early pT1G2 stages. Since the results of systemic treatment of advanced penile cancer are disappointing, complete dissection of all involved lymph nodes is highly recommended. The extent of lymph node dissection should be adapted to clinical stage, as this corresponds to metastatic spread. For low-risk patients (pTis, pTa, and pT1G1) without palpable lymph nodes and with good compliance, a surveillance strategy may be chosen. For all other patients without palpable lymph nodes (including intermediate risk pT1G2 disease), a modified bilateral lymphadenectomy is recommended. An alternative to this is a dynamic sentinel lymph node biopsy in specialised centres. All patients with histologically proven lymph node metastases should undergo radical inguinal lymphadenectomy. Pelvic lymph node dissection should be done in all patients with more than two metastatic inguinal lymph nodes. In case of fixed inguinal lymph nodes, neoadjuvant chemotherapy is recommended, followed by node resection. CONCLUSIONS Lymphadenectomy is an integral part of the management of penile cancer, since early dissection of involved lymph nodes improves survival.

Role of Human Papillomavirus in Penile Carcinomas Worldwide

BACKGROUND Invasive penile cancer is a rare disease with an approximately 22 000 cases per year. The incidence is higher in less developed countries, where penile cancer can account for up to 10% of cancers among men in some parts of Africa, South America, and Asia. OBJECTIVE To describe the human papillomavirus (HPV) DNA prevalence, HPV type distribution, and detection of markers of viral activity (ie, E6*I mRNA and p16(INK4a)) in a series of invasive penile cancers and penile high-grade squamous intraepithelial lesions (HGSILs) from 25 countries. A total of 85 penile HGSILs and 1010 penile invasive cancers diagnosed from 1983 to 2011 were included. DESIGN, SETTING, AND PARTICIPANTS After histopathologic evaluation of formalin-fixed paraffin-embedded samples, HPV DNA detection and genotyping were performed using the SPF-10/DEIA/LiPA25 system, v.1 (Laboratory Biomedical Products, Rijswijk, The Netherlands). HPV DNA-positive cases were additionally tested for oncogene E6*I mRNA and all cases for p16(INK4a) expression, a surrogate marker of oncogenic HPV activity. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS HPV DNA prevalence and type distributions were estimated. RESULTS AND LIMITATIONS HPV DNA was detected in 33.1% of penile cancers (95% confidence interval [CI], 30.2-36.1) and in 87.1% of HGSILs (95% CI, 78.0-93.4). The warty-basaloid histologic subtype showed the highest HPV DNA prevalence. Among cancers, statistically significant differences in prevalence were observed only by geographic region and not by period or by age at diagnosis. HPV16 was the most frequent HPV type detected in both HPV-positive cancers (68.7%) and HGSILs (79.6%). HPV6 was the second most common type in invasive cancers (3.7%). The p16(INK4a) upregulation and mRNA detection in addition to HPV DNA positivity were observed in 69.3% of HGSILs, and at least one of these HPV activity markers was detected in 85.3% of cases. In penile cancers, these figures were 22.0% and 27.1%, respectively. CONCLUSIONS About a third to a fourth of penile cancers were related to HPV when considering HPV DNA detection alone or adding an HPV activity marker, respectively. The observed HPV type distribution reinforces the potential benefit of current and new HPV vaccines in the reduction of HPV-related penile neoplastic lesions. PATIENT SUMMARY About one-third to one-quarter of penile cancers were related to human papillomavirus (HPV). The observed HPV type distribution reinforces the potential benefit of current and new HPV vaccines to prevent HPV-related penile neoplastic lesions.

SOX2 amplification is a common event in squamous cell carcinomas of different organ sites

Acquired chromosomal aberrations, including gene copy number alterations, are involved in the development and progression of human malignancies. SOX2, a transcription factor-coding gene located at 3q26.33, is known to be recurrently and specifically amplified in squamous cell carcinomas of the lung, the esophagus, and the oral cavity. In these organs, the SOX2 protein plays an important role in tumorigenesis and tumor survival. The aim of this study was to determine whether SOX2 amplification is also found in squamous cell carcinomas in other organs commonly affected by this tumor entity. In addition, we examined a large spectrum of lung cancer entities with neuroendocrine differentiation (ie, small cell cancers, large cell cancers, typical and atypical carcinoids) for SOX2 and TTF1 copy number gains to reveal potential molecular ties to squamous cell carcinomas or adenocarcinomas of the lung. Applying fluorescence in situ hybridization, we assessed squamous cell carcinomas of the cervix uteri (n = 47), the skin (n = 57), and the penis (n = 53) for SOX2 copy number alterations and detected amplifications in 28%, 28%, and 32% of tumors, respectively. Furthermore, we performed immunohistochemical SOX2 staining and found that SOX2 amplification is significantly associated with overexpression of the corresponding protein in squamous cell carcinomas (P < .001). Of the lung cancer entities with neuroendocrine differentiation, only small cell cancers and large cell cancers exhibited SOX2 or TTF1 amplifications at significant frequencies, indicating that at least a subset of these might be dedifferentiated forms of squamous cell carcinomas or adenocarcinomas of the lung. We conclude that SOX2 amplification and consequent SOX2 protein overexpression may represent important mechanisms of tumor initiation and progression in a considerable subset of squamous cell carcinomas.

Alterations in the tumor suppressor gene p16(INK4A) are associated with aggressive behavior of penile carcinomas.

Alterations in the p16/cyclinD1/Rb and ARF/Mdm2/p53 pathways are frequent events in the pathogenesis of squamous cell carcinomas. Different mechanisms of p16 regulation have been described for penile carcinomas so far. Therefore, expression of p16 and p53 was immunohistochemically detected with monoclonal antibodies in 52 primary invasive penile squamous cell carcinomas. The carcinomas were analyzed for allelic loss (LOH) in p16INK4A and p53, as well as for mutations in the p16INK4A and the p53 gene. In addition, we examined the promoter status of p16INK4A by methylation-specific PCR. The presence of human papilloma virus (HPV) 6/11, HPV 16 and HPV 18 DNA was analyzed by PCR. Data were compared to clinical data. Concerning p16, 26 (50%) tumors showed positive immunohistochemistry, 32 (62%) tumors showed allelic loss and 22 tumors (42%) showed promoter hypermethylation. All tumors with negative p16 immunohistochemistry showed LOH near the p16INK4A locus and/or hypermethylation of the p16INK4A promoter. HPV 16 DNA was detected in 17 tumors, ten of them with positive p16 immunostaining. The remaining seven tumors with negative p16 staining showed allelic loss and/or promoter hypermethylation. Evidence of lymph node metastasis was significantly associated with negative p16 immunohistochemistry as well as with combined LOH and promoter hypermethylation (p = 0.003 and p = 0.018, respectively). Allelic loss around p53 was found in 22 tumors (42%), and seven mutations of the p53 gene could be demonstrated in our tumors. No correlations could be found between any p53 alteration and clinical parameters.

Down-regulation of the metastasis suppressor protein KAI1/CD82 correlates with occurrence of metastasis, prognosis and presence of HPV DNA in human penile squamous cell carcinoma

In penile squamous cell carcinoma (PSCC), the outcome largely depends on early detection and resection of inguinal lymph node metastases. We investigated the role of metastasis suppressor protein kang ai 1 (KAI1)/cluster of differentiation 82 (CD82), which is known to be of prognostic significance for a wide variety of cancers. Moreover, we analysed the tumours for human papillomavirus (HPV) DNA and loss of heterozygosity at the 11p11.2 locus. Tissue samples of 30 primary PSCCs were investigated immunohistochemically using an anti-KAI1/CD82 polyclonal antibody. The expression was assessed according to the degree of KAI1/CD82-positive tumour cells as positive, decreased or negative. The presence of HPV6/11, HPV16 and HPV18 DNA was analysed by polymerase chain reaction. All patients with decreased or negative expression of KAI1/CD82 in primary lesions had lymph node metastases (p = 0.0002). Patients with positive KAI1/CD82 expression showed a significant better prognosis for survival compared to the other groups (p = 0.0042). Presence of HPV DNA was associated with decreased or negative KAI1/CD82 expression. Lacking or decreased expression of metastasis suppressor gene KAI1/CD82 appears to be a prognostic parameter for the occurrence of lymph node metastases in PSCC. Our study suggests an association of decreased KAI1/CD82 expression with tumour progression, development of metastases and disease-specific death.

Chemotherapy in patients with penile carcinoma.

The prognosis of patients with advanced penile carcinoma is poor. There are only few studies, mostly with a low number of patients, which show a low response rate with severe toxicity. While adjuvant and palliative chemotherapy for penile cancer is universally characterized by low efficacy, neoadjuvant approaches for patients with fixed lymph node metastases have shown some response. Overall, recent experiences with new chemotherapeutic approaches (i.e. taxane-based combinations) have shown some encouraging results. Therefore, these combinations should be investigated in larger and multi-center studies.

Predicting postoperative complications of inguinal lymph node dissection for penile cancer in an international multicentre cohort

To assess the potential complications associated with inguinal lymph node dissection (ILND) across international tertiary care referral centres, and to determine the prognostic factors that best predict the development of these complications.

Intrarenal artery superoxide is mainly NADPH oxidase-derived and modulates endothelium-dependent dilation in elderly patients

AIMS The present study was performed to investigate the contribution of NADPH oxidases (Nox) to superoxide formation in human renal proximal resistance arteries and to test whether superoxide formation contributes to acute vasoconstrictor responses and endothelium-dependent vasodilation in these vessels. METHODS AND RESULTS Arcuate and proximal interlobular artery segments were from patients who underwent nephrectomy because of a renal tumour. Vessels were dissected from tumour-free parts of the kidneys. Additional intrarenal arteries were obtained from rats. Superoxide formation was measured by lucigenin-enhanced chemiluminescence, expression of Nox isoforms was analysed by RT-PCR, and functional studies were performed by small vessel wire myography. Sixty per cent of superoxide formation in human arcuate and proximal interlobular arteries was due to Nox activity. mRNA expression analyses revealed the presence of Nox2 and Nox4 but not Nox1. Phenylephrine and endothelin-1 induced powerful concentration-dependent vasoconstrictions that were unaffected by superoxide scavengers. Vasopressin elicited small and variable vasoconstrictions with signs of tachyphylaxis. Endothelium-dependent vasodilation was blunted by tiron and Nomega-nitro-L-arginine methyl ester but not by superoxide dismutase or catalase. Exogenous hydrogen peroxide elicited vasoconstriction. CONCLUSION Nox activity is the major source of superoxide formation in renal proximal resistance arteries from elderly patients. Acute vasoconstrictor responses to alpha1-adrenoreceptor activation and to endothelin-1 do not depend on superoxide formation, while endothelium-dependent vasodilation in intrarenal arteries is reactive oxygen species-dependent.

Successful Sorafenib Treatment for Metastatic Renal Cell Carcinoma in a Case with Chronic Renal Failure

Treatment options for patients with end-stage renal disease (ESRD) and metastatic renal cell carcinoma (mRCC) are limited. We report the case of a 69-yr-old male who was treated with sorafenib after failure of immunotherapy. The treatment has resulted in remission with stable disease for 13 mo so far. Sorafenib seems to be a safe treatment option for patients with ESRD and mRCC, but further studies are required.