Gunia S, Jain A, Koch S, et al.
Periostin expression correlates with pT-stage, grading and tumour size, and independently predicts cancer-specific survival in surgically treated penile squamous cell carcinomas.
J Clin Pathol. 2013; 66(4):297-301 [PubMed]

AIMS: Overexpression of periostin, a secreted cell adhesion molecule, has been reported to enhance invasion and angiogenesis in squamous cell carcinomas (SCCs) derived from different anatomic sites. We studied the so far neglected periostin expression profiles in penile SCCs and evaluated its association with pertinent clinicopathologic variables.
METHODS: Paraffin-embedded tissues from 89 patients with surgically treated penile SCCs were subjected to a central histopathologic review performed by one pathologist. Then, tissue microarray technique was employed for periostin immunostaining which was evaluated by two independent raters. Kappa (κ)-statistics were used to assess interobserver variability. Spearman correlations as well as uni- and multivariable Cox proportional hazards analysis were applied to assess the association between periostin expression and clinicopathologic parameters. Mean postsurgical follow-up was 31.5 months (IQR 6-66).
RESULTS: Periostin expression was recorded in 39/89 penile SCCs (44%). K-statistics disclosed substantial interobserver agreement for epithelial and stromal staining evaluation (K-values 0.76 vs 0.83, p values <0.001). High periostin expression in either stroma or tumour epithelia showed a significant positive correlation with tumour size, histologic grade and pT-stage. In the multivariable Cox models including pT-stage, pN status, grading and the patients' age at the time of surgery, periostin expression independently predicted cancer-specific survival (CSS).
CONCLUSIONS: Immunohistochemically, periostin is not infrequently expressed in penile cancer, and might become a valuable tool to independently predict CSS after surgical treatment. Further studies should clarify the so far unresolved usefulness of periostin to be employed as a possible molecular target in antineoplastic therapy in metastasised penile SCCs.

Do HT, Koriyama C, Khan NA, et al.
The etiologic role of human papillomavirus in penile cancers: a study in Vietnam.
Br J Cancer. 2013; 108(1):229-33 [PubMed] Article available free on PMC after 15/01/2014

BACKGROUND: We investigated the aetiologic role of human papillomavirus (HPV) in 120 penile squamous cell carcinomas (PSCCs) from Vietnam.
METHODS: Human papillomavirus DNA was detected by PCR using SPF10 primers and a primer set targeting HPV-16 E6. The INNO-LiPA HPV genotyping kit was used to determine genotype. Human papillomavirus-16 viral load and physical status were determined by real-time PCR. P16(INK4A) protein expression was investigated by immunohistochemistry.
RESULTS: Human papillomavirus DNA was detected in 27 of 120 (23%) PSCCs. The most frequently detected genotype was HPV-16 (24 of 27 cases, 89%). In 16 of 18 (89%) HPV-16-positive cases, the HPV DNA was considered to be integrated into the host genome. The geometric mean of the HPV-16 viral load was 0.4 copies per cell. P16(INK4A) overexpression was significantly related to PSCCs infected with high-risk HPV (P=0.018) and HPV-16 copy numbers (P<0.001).
CONCLUSION: Human papillomavirus-16 DNA integration and p16(INK4A) overexpression in high-risk HPV detected PSCCs suggested an aetiologic role of high-risk HPV in the development of PSCCs.

Olsen J, Jørgensen TR, Kofoed K, Larsen HK
Incidence and cost of anal, penile, vaginal and vulvar cancer in Denmark.
BMC Public Health. 2012; 12:1082 [PubMed] Article available free on PMC after 15/01/2014

BACKGROUND: Besides being a causative agent for genital warts and cervical cancer, human papillomavirus (HPV) contributes to 40-85% of cases of anal, penile, vaginal and vulvar cancer and precancerous lesions. HPV types 16 & 18 in particular contribute to 74-93% of these cases. Overall the number of new cases of these four cancers may be relatively high implying notable health care cost to society. The aim of this study was to estimate the incidence and the health care sector costs of anal, penile, vaginal and vulvar cancer.
METHODS: New anogenital cancer patients were identified from the Danish National Cancer Register using ICD-10 diagnosis codes. Resource use in the health care sector was estimated for the year prior to diagnosis, and for the first, second and third years after diagnosis. Hospital resource use was defined in terms of registered hospital contacts, using DRG (Diagnosis Related Groups) and DAGS (Danish Outpatient Groups System) charges as cost estimates for inpatient and outpatient contacts, respectively. Health care consumption by cancer patients diagnosed in 2004-2007 was compared with that by an age- and sex-matched cohort without cancer. Hospital costs attributable to four anogenital cancers were estimated using regression analysis.
RESULTS: The annual incidence of anal cancer in Denmark is 1.9 per 100,000 persons. The corresponding incidence rates for penile, vaginal and vulvar cancer are 1.7, 0.9 and 3.6 per 100,000 males/females, respectively. The total number of new cases of these four cancers in Denmark is about 270 per year. In comparison, the total number of new cases cervical cancer is around 390 per year. The total cost of anogenital cancer to the hospital sector was estimated to be 7.6 million Euros per year. Costs associated with anal and vulvar cancer constituted the majority of the costs.
CONCLUSIONS: Anogenital cancer incurs considerable costs to the Danish hospital sector. It is expected that the current HPV vaccination program will markedly reduce this burden.

Giraldi G, De Luca d'Alessandro E
The HPV infection in males: an update.
Ann Ig. 2012 Nov-Dec; 24(6):497-506 [PubMed]

The role of Human papillomavirus (HPV) in malignant and non-malignant genital diseases in females is well known and the corresponding epidemiological burden has been widely described, in males instead, less is known about the role of the virus in anal, penile and head and neck cancer, and the burden of malignant and non-malignant HPV-related diseases. There are many types of HPV that can infect the epithelium: some types can cause genital warts (low risk genotype), other types (high risk genotypes) can cause cancers of the penis, anus or oropharynx. Relative to females, males tend to be less knowledgeable about the infection: some may view its consequences as less likely and severe for themselves than for females, and thus could perceive vaccination as unnecessary. Including boys in the vaccination program generally exceeded conventional thresholds of good value for money, even under favorable conditions of vaccine protection and health benefits; however, uncertainty still exists in many areas that can either strengthen or attenuate the findings achieved.

Forman D, de Martel C, Lacey CJ, et al.
Global burden of human papillomavirus and related diseases.
Vaccine. 2012; 30 Suppl 5:F12-23 [PubMed]

The worldwide prevalence of infection with human papillomavirus (HPV) in women without cervical abnormalities is 11-12% with higher rates in sub-Saharan Africa (24%), Eastern Europe (21%) and Latin America (16%). The two most prevalent types are HPV16 (3.2%) and HPV18 (1.4%). Prevalence increases in women with cervical pathology in proportion to the severity of the lesion reaching around 90% in women with grade 3 cervical intraepithelial neoplasia and invasive cancer. HPV infection has been identified as a definite human carcinogen for six types of cancer: cervix, penis, vulva, vagina, anus and oropharynx (including the base of the tongue and tonsils). Estimates of the incidence of these cancers for 2008 due to HPV infection have been calculated globally. Of the estimated 12.7 million cancers occurring in 2008, 610,000 (Population Attributable Fraction [PAF]=4.8%) could be attributed to HPV infection. The PAF varies substantially by geographic region and level of development, increasing to 6.9% in less developed regions of the world, 14.2% in sub-Saharan Africa and 15.5% in India, compared with 2.1% in more developed regions, 1.6% in Northern America and 1.2% in Australia/New Zealand. Cervical cancer, for which the PAF is estimated to be 100%, accounted for 530,000 (86.9%) of the HPV attributable cases with the other five cancer types accounting for the residual 80,000 cancers. Cervical cancer is the third most common female malignancy and shows a strong association with level of development, rates being at least four-fold higher in countries defined within the low ranking of the Human Development Index (HDI) compared with those in the very high category. Similar disparities are evident for 5-year survival-less than 20% in low HDI countries and more than 65% in very high countries. There are five-fold or greater differences in incidence between world regions. In those countries for which reliable temporal data are available, incidence rates appear to be consistently declining by approximately 2% per annum. There is, however, a lack of information from low HDI countries where screening is less likely to have been successfully implemented. Estimates of the projected incidence of cervical cancer in 2030, based solely on demographic factors, indicate a 2% increase in the global burden of cervical cancer, i.e., in balance with the current rate of decline. Due to the relative small numbers involved, it is difficult to discern temporal trends for the other cancers associated with HPV infection. Genital warts represent a sexually transmitted benign condition caused by HPV infection, especially HPV6 and HPV11. Reliable surveillance figures are difficult to obtain but data from developed countries indicate an annual incidence of 0.1 to 0.2% with a peak occurring at teenage and young adult ages. This article forms part of a special supplement entitled "Comprehensive Control of HPV Infections and Related Diseases" Vaccine Volume 30, Supplement 5, 2012.

Longpre MJ, Lange PH, Kwon JS, Black PC
Penile carcinoma: lessons learned from vulvar carcinoma.
J Urol. 2013; 189(1):17-24 [PubMed]

PURPOSE: Penile carcinoma is rare in the developed world and treatment guidelines are often based on marginal clinical data. Prospective controlled studies are virtually absent and meta-analyses are rare. Vulvar carcinoma, on the other hand, has many parallels to penile carcinoma, and the level of evidence for diagnosis and treatment is more robust. Therefore, we assessed the body of literature on vulvar carcinoma to identify potential improvements in the care of patients with penile carcinoma.
MATERIALS AND METHODS: A literature review was performed on vulvar carcinoma and direct comparisons were made to a similar review of the literature on penile carcinoma.
RESULTS: Several aspects of vulvar carcinoma management are clearly established and deserve closer evaluation in penile carcinoma. For example, human papillomavirus is identified in a high percentage of patients with vulvar carcinoma but is understudied in penile carcinoma. Further study is of potential clinical value, especially with the development of human papillomavirus vaccines for prevention. Penile carcinoma TNM staging does not adequately stratify survival or risk of advanced disease. Staging of vulvar carcinoma is dependent on tumor size and depth of invasion measured in millimeters, as opposed to the invasion of underlying structures in penile carcinoma. Management of the inguinal nodes is more refined for vulvar carcinoma, where lymphatic mapping has been conducted and sentinel node biopsy has proven to be highly effective in multicenter trials. Finally, the efficacy of adjuvant radiation and chemotherapy has been tested in controlled trials or reported in meta-analyses for vulvar carcinoma, which are both lacking for penile carcinoma. Radiation after inguinal node dissection, for example, has been shown to enhance survival in patients with defined risk factors. Neoadjuvant chemoradiation is recommended before surgery for advanced vulvar carcinoma.
CONCLUSIONS: Evidence derived from studies on vulvar carcinoma can be extrapolated to penile carcinoma to help guide clinical trials and future research directions to enhance the treatment of these patients.

Baydar DE, Kulac I, Ozagari A, Guler Tezel G
Occurrence of dysplasia and human papilloma virus typing in penile condylomas.
Urology. 2013; 81(1):211.e9-15 [PubMed]

OBJECTIVE: To determine the incidence of dysplasia as a preneoplastic change and high-risk human papilloma virus (HPV) infection in penile condylomas, which are common HPV-related lesions and considered a risk factor for penile cancer.
METHODS: Histologic analysis was done of 58 consecutive penile condylomas with tissue diagnosis. An immunohistochemical panel that included stains for p53, Ki-67, and p16INK4a was also used. HPV typing was successfully performed in 43 lesions. Genotyping was accomplished through polymerase chain reaction and flow-through hybridization with an HPV GenoArray Diagnostic Test kit.
RESULTS: Dysplasia was observed in 13 of the 58 condylomas (22%). High-risk HPV DNA was detected in 5 of 10 dysplastic lesions (50%) for which tissue blocks were available for study. High-risk HPV was not detected in the nondysplastic lesions (P<.001). Ki-67≥20% above the basal layer of epithelium and p53-positive immunostaining occurred more frequently in dysplastic lesions than in nondysplastic lesions; however, the difference was not statistically significance. Staining for p16INK4a was not helpful.
CONCLUSION: Anogenital condylomas in men are usually treated using destructive methods or with medication. We suggest that at least a part of the lesion must be removed and sent for histopathologic examination. If the histologic result shows significant dysplastic alteration, the lesion should be further investigated to determine the subtype of infective virus, because 50% of such lesions are associated with high-risk HPV. When oncogenic pathogens are found, careful patient follow-up for recurrences and counseling for the patient and his sexual partner(s) may be warranted.

Kayes O, Shabbir M, Minhas S
Male genital premalignant dermatoses.
Curr Urol Rep. 2012; 13(6):488-95 [PubMed]

The spectrum of conditions affecting the penile skin is varied and ranges from simple, benign dermatoses to premalignant and malignant conditions. Recently, improved understanding of the aetiology and natural history of these conditions has shaped new treatment paradigms and a functional knowledge of dermatology, urology and genitourinary medicine is required to successfully diagnose and treat these men. In this article, we explore the common precancerous states that can lead to penile carcinoma and review the recent advances with regards to the molecular basis for these dermatoses and the treatments that may be most effective for these men.

Hedgire SS, Pargaonkar VK, Elmi A, et al.
Pelvic nodal imaging.
Radiol Clin North Am. 2012; 50(6):1111-25 [PubMed]

Detection of nodal metastases in men with pelvic urogenital malignancies is important for accurate staging and has therapeutic and prognostic implications. Knowledge of clinical anatomy of these nodes and the lymphatic pathways is critical for assigning the correct N or M staging and to assess the treatment response. Both computed tomography and magnetic resonance imaging use size and morphologic criteria for nodal characterization. The limitations of these criteria have formed basis newer functional imaging tools. This article focuses on the clinical anatomy, pathways of lymphatic spread of malignancies, current criteria, and newer advances in imaging of male pelvic nodes.

Gunia S, Koch S, May M
Is CDX2 immunostaining useful for delineating anorectal from penile/vulvar squamous cancer in the setting of squamous cell carcinoma with clinically unknown primary site presenting with histologically confirmed inguinal lymph node metastasis?
J Clin Pathol. 2013; 66(2):109-12 [PubMed]

AIMS: Penile, vulvar and anal squamous cell carcinomas (SCCs) share histomorphological overlap and are prone to lymphatic dissemination into inguinal nodes. Anal SCCs might derive from the anorectal zone (ARZ), anal transitional zone, squamous zone or from perianal skin. These anatomically distinct zones differ in terms of their embryological development. We sought to investigate the role of caudal-related homeobox 2 (CDX2), a homeobox gene implicated in the development and anterior/posterior pattern specification from duodenum to rectum including the ARZ, in terms of narrowing the possible sites of origin to be considered in the setting of SCC with unknown primary presenting with histologically confirmed inguinal lymph node metastasis.
METHODS: By immunohistochemistry (IHC) employing a panel of antibodies directed against CK5/6, CK7, CK20, p63, p16, CEA and CDX2, we compared 89 penile, 11 vulvar and eight anal SCCs with respect to their staining profiles. Moreover, anal SCCs were subjected to in situ hybridisation (ISH) for high-risk human papillomavirus (HPV) subtypes.
RESULTS: By IHC, CDX2 expression was observed in 2/8 anal SCCs (25%) while being absent from all penile and vulvar SCCs examined. High-risk HPV subtypes were detected by ISH in all anal SCCs examined, which were uniformly p16-positive by IHC.
CONCLUSIONS: CDX2 might be valuable in terms of narrowing the possible sites of origin to be considered in the setting of SCC with unknown primary presenting with inguinal lymph node metastasis. However, despite its favourable specificity, the diagnostic benefit achieved by this observation is limited by the low sensitivity.

Thuret R, Sun M, Abdollah F, et al.
Competing-risks analysis in patients with T1 squamous cell carcinoma of the penis.
BJU Int. 2013; 111(4 Pt B):E174-9 [PubMed]

OBJECTIVE: To quantify and compare cancer-specific mortality (CSM) and other-cause mortality (OCM) in individuals with stage T1G1-3 clinically node-negative (cN0) squamous cell carcinoma of the penis (SCCP) since there is no consensus regarding the need for an inguinal lymph node dissection (ILND) in patients with T1G2-3 cN0 SCCP.
METHODS: Relying on the Surveillance, Epidemiology and End Results database, we identified 655 patients diagnosed with primary SCCP between 1988 and 2006. Cumulative incidence plots were used to graphically depict the effect of CSM relative to OCM. Competing-risks regression analyses were used to quantify the risk of CSM or OCM after adjusting for age, race, tumour grade and surgery type.
RESULTS: The 5-year CSM rates after a primary tumour excision without ILND were 2.6%, 10.0% and 15.9% in patients with respectively T1G1, T1G2 and T1G3 cN0 SCCP. The 5-year OCM rates were 29.5%, 27.3% and 29.3% in patients with respectively T1G1, T1G2 and T1G3. Age failed to provide additional stratification.
CONCLUSIONS: The CSM rate was highest in T1G3 patients and appears to justify ILND. Conversely, the CSM rate was lowest in T1G1 patients, which justifies active surveillance in this patient subset. A moderate CSM rate at 5 years was recorded for T1G2 patients, which brings into question the benefits of ILND.

Masferrer E, Ferrándiz-Pulido C, Lloveras B, et al.
MYC copy number gains are associated with poor outcome in penile squamous cell carcinoma.
J Urol. 2012; 188(5):1965-71 [PubMed]

PURPOSE: We determined MYC gene numerical aberrations and protein expression at different stages of penile squamous cell carcinoma carcinogenesis. We correlated these findings with clinicopathological parameters and HPV infection.
MATERIALS AND METHODS: We evaluated 79 cases of penile squamous cell carcinoma, including 11 in situ and 68 invasive carcinomas. The MYC cytogenetic profile was evaluated by fluorescence in situ hybridization. HPV was detected by polymerase chain reaction amplification.
RESULTS: MYC gains were identified in 4 of 11 in situ carcinomas (36%) and 50 of 68 invasive penile squamous cell carcinomas (73%). A significant association between MYC gains, and tumor progression and poor outcome was demonstrated (p <0.05). HPV DNA was detected in 32 of 79 penile squamous cell carcinomas (39%). High risk type 16 was the most prevalent type. MYC numerical aberrations did not correlate with HPV status. A significant association between HPV and MYC protein over expression was noted. In HPV negative cases MYC gains correlated with MYC over expression.
CONCLUSIONS: MYC gains progressively increased during penile squamous cell carcinoma progression from in situ samples to metastases. MYC gains were an independent factor for poor prognosis. These findings were independent of HPV infection. MYC expression was increased in samples with HPV infection, probably reflecting direct activation of MYC.

Skeppner E, Andersson SO, Johansson JE, Windahl T
Initial symptoms and delay in patients with penile carcinoma.
Scand J Urol Nephrol. 2012; 46(5):319-25 [PubMed]

OBJECTIVE: This study aimed to assess initial symptoms and factors associated with patients' and doctors' delay in penile carcinoma.
MATERIAL AND METHODS: Fifty consecutive patients with penile carcinoma treated with an organ-sparing technique and nine with partial amputation were enrolled in a prospective study at the Department of Urology, Örebro University Hospital, between 2005 and 2009. Face-to-face structured interviews in combination with self-assessment forms were used for the patients' descriptions of clinical symptoms, treatment seeking and reasons for delay. Data were also extracted from the medical records confirming time-lag between GP assessment, specialist care and time for diagnosis.
RESULTS: Erythema, rash and eczema were the most common initial symptoms (35%). In total, 65% had a patients' delay of more than 6 months, and among these there was a small, but not statistically significant, predominance for pT1 and pTis tumours. Living with a stable partner did not affect the delay. The most common reason for patients' delay was the feeling of embarrassment over symptoms localized in a sexual body area. Nine patients had a doctors' delay of more than 3 months from first special visit to diagnosis. Eight of these patients consulted dermatologists and were subjected to repeated biopsies, leaving premalignant results.
CONCLUSIONS: A considerable proportion of the patients had a patients' delay of more than 6 months, perhaps due to benign initial symptoms as erythema, rash or eczema. Psychological factors such as embarrassment and denial may also be involved, as well as insufficient awareness or knowledge.

Di Lorenzo G, Buonerba C, Federico P, et al.
Cisplatin and 5-fluorouracil in inoperable, stage IV squamous cell carcinoma of the penis.
BJU Int. 2012; 110(11 Pt B):E661-6 [PubMed]

UNLABELLED: What's known on the subject? and What does the study add? Metastatic or locally advanced squamous cell carcinoma of the penis (SCCP) is generally incurable, but it can be palliated with systemic chemotherapy. Two retrospective studies, involving <10 patients each, showed that cisplatin plus continuous infusion of 5-fluorouracil (5-FU) may be effective and well tolerated. Cisplatin, methotrexate and bleomycin, cisplatin and irinotecan and taxanes can also play an important role for patients with locally advanced/metastatic SCCP. Finally, anti-EGFR therapy may also be effective in advanced SCCP. Although cisplatin plus continuous infusion of 5-FU is widely used in clinical practice for palliation of SCCP, toxicity and efficacy data regarding this schedule include a total of 14 patients with SCCP, treated more than two decades ago. In our retrospective study, cisplatin plus continuous infusion of 5-FU was used for palliative purposes in a homogenous sample of 25 patients with SCCP. Partial responses and stable disease were observed in 8 (32%) and 10 (40%) patients, respectively, with a median progression-free survival of 20 weeks. Neutropenia was the most important grade 3-4 side effect observed, occurring in 20% of patients. These data provide confirmation that such a combination regimen is moderately effective and well tolerated in patients with SCCP.
OBJECTIVE: • To investigate the activity and toxicity of 5-fluorouracil (5-FU) as a first-line treatment in metastatic squamous cell carcinoma of the penis (SCCP).
METHODS: • The medical records of 78 patients with SCCP treated between January 2000 and June 2011 at the four participating centres were reviewed. • Data regarding patients treated with first-line 5-FU were extracted. • Patients were included in the study if radiological reports were available for determination of response and progression-free survival (PFS) according to response evaluation criteria in solid tumours (RECIST) 1.1.
RESULTS: • Between January 2000 and June 2011, 25 patients were treated with i.v. cisplatin on day 1 followed by 5-FU as a continuous 24-h infusion for 4 days every 3 weeks until disease progression or unacceptable toxicity. Partial responses and stable disease were observed in eight (32%) and 10 (40%) patients, respectively, with a disease control rate of 72%. • Severe neutropenia was the most important grade 3-4 side effect observed, occurring in 20% of patients. • The median (interquartile range [IQR]) PFS was 20 (11-20) weeks and the median (IQR) overall survival (OS) was 8 (7-12) months.
CONCLUSION: • 5-FU is associated with a moderate response rate and is well tolerated in patients with metastatic SCCP.

Somers K, Iorizzo L, Scott G, Mercurio MG
Extramammary Paget disease of the penis as a manifestation of recurrent transitional cell carcinoma.
Dermatol Online J. 2012; 18(8):3 [PubMed]

Extramammary Paget disease (EMPD) mainly affects elderly women in areas with apocrine glands. Only 10 cases have been reported to involve the penis in patients with underlying transitional cell carcinoma of the bladder. Herein we report a patient with EMPD of the penis after radical cystectomy.

La-Touche S, Ayres B, Lam W, et al.
Trial of ligation versus coagulation of lymphatics in dynamic inguinal sentinel lymph node biopsy for staging of squamous cell carcinoma of the penis.
Ann R Coll Surg Engl. 2012; 94(5):344-6 [PubMed]

INTRODUCTION: The principal advantage of dynamic sentinel lymph node biopsy (DSNB) over modified inguinal node dissection is the lower complication rate. The aim of this study was to identify factors associated with short-term complications of DSNB in order to lower morbidity of the procedure.
METHODS: Retrospective and prospective cohort studies were performed on patients undergoing DSNB between April 2005 and March 2010. Patients were categorised into three groups of 50 (from a total of 250 patients on the database). The patients of Group A, on whom ligaclips were the lymphovascular control technique, were compared with those of Group B, in whom diathermy was used. Incision length, operative time, number of nodes removed, antibiotics and co-morbidities were recorded. A prospective study on Group C, using ligaclips, was also performed.
RESULTS: Groups A (88 groins), B (75 groins) and C (68 groins) were explored with complication rates of 5.7%, 24.0% (p =0.0018) and 8.8% (p =0.0277). Co-morbidities, antibiotics (co-amoxiclav 1.2g intravenous as per protocol) and the mean number of nodes removed were similar in all groups. The mean incision length was 4.1cm (standard deviation [SD]: 1.0 cm) for Group A, 5.6 cm (SD: 1.0 cm) for Group B (p =0.0001) and 5.6 cm (SD: 0.8 cm) for Group C (p =0.979). The mean operative times for Groups A, B and C were 15.8 (SD: 8.1), 19.3 (SD: 7.4) (p =0.0043) and 22.1 (SD: 7.7) (p =0.0301) minutes respectively.
CONCLUSIONS: Lymphovascular control with diathermy is associated with a statistically higher short-term complication rate compared with ligaclip usage (ie 'permanent' ligation). Lymphocoeles are the principal complication and can result in delayed wound infection and breakdown. A small but statistical increase in operative time and wound length is likely to be related to registrar training.

D'Hauwers KW, Depuydt CE, Bogers JJ, et al.
Human papillomavirus, lichen sclerosus and penile cancer: a study in Belgium.
Vaccine. 2012; 30(46):6573-7 [PubMed]

PURPOSE: The prevalence of penile cancer varies between 1.5 (industrialized countries) and 4.5 per 100,000 men (non-industrialized countries). Predominant histological subtype is squamous cell carcinoma (SCC). Human papillomavirus (HPV) is found in 40-46% of cases: penile cancer is considered to behave as vulvar cancer. Non HPV related risk factors are lack of circumcision, phimosis, chronic inflammation, and smoking. The role of lichen sclerosus (LS) is unclear. Clinical diagnosis is difficult and treatment often mutilating. Preventive measures can be taken since the risk factors are known: the use of the prophylactic HPV vaccines may contribute. We measured the prevalence of HPV and LS in penile cancer in Belgium.
MATERIALS AND METHODS: We found 76 samples of penile lesions in the archives of the departments of Histology of four university hospitals in Belgium. Real-time PCR of type-specific HPV DNA was performed targeting 18 HPV types.
PRINCIPAL RESULTS: Patients with penile intraepithelial neoplasia (PeIN) were 56.1 years of age: patients with invasive penile cancer (IPC) 68.5 (p=0.009). Fifty-five samples (55/76) were adequate for HPV targeting. Overall HPV DNA was 70.9%: 89.5% in samples of PeIN (n=19) and 61.1% in samples of IPC (n=36). Invasive penile cancer samples were less likely to be HPV infected (p=0.028). HPV 16 was most prevalent: 48.3%: 20% PeIN, and 28.3% IPC. HPV DNA of the types, included in the prophylactic vaccines, was found in 33% of PeIN and 31.7% of IPC samples. Thrice, low risk HPV (lrHPV) types 6 (1 IPC) and 11 (1 PeIN, 1 IPC) were solely present. There was no difference in the presence of LS between HPV positive and HPV negative samples (p=0.944).
CONCLUSIONS: Prevalence of HPV DNA in penile lesions in Belgium is high. However, the prophylactic vaccines may contribute to primary prevention of only a subset of cases. The role of LS remains unclear.

Kirrander P, Andrén O, Windahl T
Dynamic sentinel node biopsy in penile cancer: initial experiences at a Swedish referral centre.
BJU Int. 2013; 111(3 Pt B):E48-53 [PubMed]

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.

Tripoli M, Cordova A, Maggì F, Moschella F
Giant condylomata (Buschke-Löwenstein tumours): our case load in surgical treatment and review of the current therapies.
Eur Rev Med Pharmacol Sci. 2012; 16(6):747-51 [PubMed]

BACKGROUND: Buschke-Löwenstein tumour (BLT) or giant condyloma is a verrucous infiltrating lesion, due to a sexually transmitted virus infection, human papilloma virus subtypes 6 and 11. Poor hygiene, promiscuity, chronic irritation and cellular immunocompromised states are often implicated in its genesis. Typical treatment of giant condyloma includes imiquimod cream, podophillin resin, cryotherapy, laser surgery, tangential shave excision with electrocautery.
OBJECTIVE: The authors report their case load in the treatment of giant condyloma and the review of the modern therapies.
METHODS AND MATERIALS: 27 consecutive patients (18 men, nine women) underwent surgery for giant condylomata of perianal region and externa genitalia at the Department of Plastic Surgery of the University of Palermo, from October 2006 to December 2009. All the patients had been treated before with conservative therapies without significant results. We performed the radical excision with split-thickness skin graft in all the patients.
RESULTS: No significant complications have occurred in all the cases. The functional and aesthetic outcome were satisfying. No recurrence of disease were noticed in the follow-up.
CONCLUSION: the radical excision with split-thickness skin graft appears to be a successful option of treatment for Buschke-Löwenstein tumours. Compared to other methods it does not necessitate several stages of treatment, moreover it has the advantage of a lower risk of recurrence, it allows a complete histologic examination, the healing process is rapid, the improvement of quality of patients's life is significant.

Canter DJ, Dobbs RW, Jafri SM, et al.
Functional, oncologic, and technical outcomes after endoscopic groin dissection for penile carcinoma.
Can J Urol. 2012; 19(4):6395-400 [PubMed]

Penile cancer is a rare cutaneous malignancy that frequently spreads to the regional inguinal lymph nodes with a prolonged locoregional phase. An inguinal lymph node dissection may be both diagnostic and therapeutic, even in the setting of advanced disease. Despite its proven oncologic importance and efficacy, an inguinal lymphadenectomy remains underutilized, even with the publication of guidelines advocating its use. Failure to apply this modality is most likely due to the significant morbidity associated with a traditional open approach, including flap necrosis, wound infection and debilitating lymphedema. The risks and complications associated with an open inguinal lymph node dissection have driven several investigators to develop techniques for performing a minimally invasive endoscopic inguinal lymph node dissection that is oncologically equivalent to the 'gold standard' open approach, while potentially minimizing the complications traditionally seen with the open technique. In this report, we detail our technique for performing a minimally invasive endoscopic groin dissection with inguinal lymphadenectomy for penile carcinoma. We also present preliminary complication and short term oncologic data employing this surgical technique in an initial cohort of patients.

Ferrándiz-Pulido C, Masferrer E, de Torres I, et al.
Identification and genotyping of human papillomavirus in a Spanish cohort of penile squamous cell carcinomas: correlation with pathologic subtypes, p16(INK4a) expression, and prognosis.
J Am Acad Dermatol. 2013; 68(1):73-82 [PubMed]

BACKGROUND: Penile squamous cell carcinoma (PSCC) is a tumor with a high metastatic potential. In PSCC the attributable fraction to human papillomavirus (HPV) is not well established.
OBJECTIVE: We sought to provide novel data about the prevalence of HPV in a large series of penile intraepithelial neoplasia (PeIN) and invasive PSCC, correlating the results with the histologic subtype, p16(INK4a) immunostaining, and prognosis.
METHODS: A total of 82 PSCC were included in the study, 69 invasive and 13 PeIN. HPV detection was performed by polymerase chain reaction with SPF-10 broad-spectrum primers followed by DNA enzyme immunoassay and genotyping with a reverse hybridization line probe assay. P16(INK4a) immunohistochemical expression on tissue microarrays was also analyzed.
RESULTS: HPV DNA was identified in 31 of 77 (40.2%) PSCC (22 of 67 invasive and 9 of 10 PeIN). In 25 of 31 (80.6%) cases HPV-16 was identified. HPV detection was significantly associated with some histologic subtypes: most basaloid and warty tumors were high-risk HPV (hrHPV) positive, whereas only 15% of usual PSCC were hr-HPV positive. All hrHPV-positive PSCC had an adjacent undifferentiated PeIN. Strong p16(INK4a) immunostaining correlated with hrHPV infection. Most undifferentiated PeIN showed p16(INK4a) immunohistochemical overexpression. Both hrHPV-positive and p16(INK4a)-positive tumors showed a better overall survival without reaching statistical significance.
LIMITATIONS: This was a retrospective study.
CONCLUSIONS: Our results suggest that most hrHPV-positive PSCC develop from undifferentiated hrHPV-positive PeIN. P16(INK4a) immunostaining may be useful in identifying both etiologically related hrHPV-positive tumors and those with better outcome. The routine use of p16(INK4a) staining should be incorporated in histologic evaluation of PSCC.

Taib F, Mohamad N, Mohamed Daud MA, et al.
Infantile fibrosarcoma of the penis in a 2-year-old boy.
Urology. 2012; 80(4):931-3 [PubMed]

Fibrosarcoma is rare in the pediatric age group. It generally involves the extremities and the trunk but rarely involves the genital area. We report a case of a large fungating infantile fibrosarcoma of the penis in a 2-year-old Malay boy. Partial recovery of the penile structure was achieved after chemotherapy. The difficulty in managing the social and surgical aspect of this case is discussed in our report. To the best of our knowledge, this is the first case report of infantile fibrosarcoma involving the penis in an Asian region.

Held-Warmkessel J
Penile cancer.
Semin Oncol Nurs. 2012; 28(3):190-201 [PubMed]

OBJECTIVES: To review the risk factors, prevention, treatment, and management of the patient with penile cancer.
DATA SOURCES: Publications; clinical experience.
CONCLUSION: Penile cancer is a rare malignancy in the United States, but is more common in developing countries. The disease is so uncommon in the United States that there are oncology nurses who have never cared for a patient with this diagnosis.
IMPLICATIONS FOR NURSING PRACTICE: With significant psychosocial implications for the patient with penile cancer and partner, it is important that the nurse have an understanding of the diagnosis, treatment, and care of these patients.

Philippou P, Shabbir M, Malone P, et al.
Conservative surgery for squamous cell carcinoma of the penis: resection margins and long-term oncological control.
J Urol. 2012; 188(3):803-8 [PubMed]

PURPOSE: We assessed the oncological outcome of penile conserving surgery and identified parameters predicting local recurrence, including resection margins.
MATERIALS AND METHODS: A total of 179 patients with invasive penile cancer treated with organ sparing surgery at a tertiary center between 2002 and 2010 fulfilled our study criteria. Demographic, histopathological, management and followup data were recorded in a prospective database. Local, regional and distant recurrence rates, time to recurrence and survival rates were calculated. Survival analysis was performed by the Kaplan-Meier method. Multivariate analysis was used to identify predictors of local recurrence.
RESULTS: Mean followup was 42.8 months (range 4 to 107). Local, regional and distant metastatic recurrence developed in 16 (8.9%), 19 (10.6%) and 9 patients (5.0%) at a mean of 26.1, 26.8 and 11.7 months, respectively. The 5-year disease specific survival rate after recurrence was 54.7% (95% CI 46.1-63.3). For patients with isolated local recurrence the 5-year disease specific survival rate was 91.7% compared to 38.4% for those with regional recurrence. The overall 5-year local recurrence-free rate was 86.3% (95% CI 82.6-90.4). Tumor grade (p = 0.003), stage (p = 0.021) and lymphovascular invasion (p = 0.014) were identified as predictors of local recurrence on multivariate analysis.
CONCLUSIONS: Penile conserving surgery is oncologically safe and a surgical excision margin of less than 5 mm is adequate. Higher local recurrence rates are associated with lymphovascular invasion, and higher tumor stage and grade. Local recurrence has no negative impact on long-term survival.

Wu X, Chen Z, Ji H, et al.
Angiosarcoma of the penis: a case report and literature review.
Int Urol Nephrol. 2012; 44(5):1341-3 [PubMed]

We reported one case of penile angiosarcoma in a 49-year-old patient who had been misdiagnosed as syphilis. Based on our experience, we suggest that if sexually transmitted diseases and Peyronie's disease can be ruled out, diagnosis of the penile angiosarcoma be warranted if unexplained rash, ulceration on the penis, and induration in corpus cavernosum are observed. It should be noted that if the anti-inflammatory or anti-viral treatment is prescribed for some time but the lesion does not disappear or even gets worse, the penile angiosarcoma should be suspected and penile biopsy is necessary.

Figliuolo G, Maia J, Jalkh AP, et al.
Clinical and laboratorial study of HPV infection in men infected with HIV.
Int Braz J Urol. 2012 May-Jun; 38(3):411-8 [PubMed]

OBJECTIVES: To determine the prevalence of precursor lesions of penile cancer, to establish the concordance of diagnostic techniques (PCR, Hybrid Capture (HC) and peniscopy with acetic acid 5%) in the diagnosis of Human Papilloma Virus (HPV) of the penis of men infected with HIV and to evaluate the influence of the immune status.
PATIENTS, METHODS AND RESULTS: 276 men were studied, with a median age of 34.6 years. Prevalence of High Risk HPV, Low Risk HPV and infection with both, according to HC, was 43%, 32% and 22%, respectively. PCR showed 50% of positivity for HPV DNA. Peniscopy was positive in 27% of individuals. Peniscopy showed good specificity and low sensitivity for the detection of penile HPV, and low concordance with PCR. Men with white lesions had a 3.6 higher relative risk of positivity for HPV. The most common clinical lesion observed was vegetation, identified in 29% of patients. PCR and HC techniques showed high sensitivity for HPV DNA and there was an excellent correlation between them. Immunosuppressed individuals with CD4 < 200 cells/mm(3) had the highest prevalence of premalignant lesions that were observed in 10% of the studied individuals.
CONCLUSIONS: Peniscopy was important for identification and treatment of subclinical lesions. PCR and HC techniques were sensitive methods for the detection of HPV DNA with high concordance. Severely immunosuppressed individuals showed a higher prevalence of pre-malignant lesions of the penis.

Alei G, Letizia P, Sorvillo V, et al.
Lichen sclerosus in patients with squamous cell carcinoma. Our experience with partial penectomy and reconstruction with ventral fenestrated flap.
Ann Ital Chir. 2012 Jul-Aug; 83(4):363-7 [PubMed]

INTRODUCTION: The vast majority of penile malignant tumors are squamous cell carcinomas (SCCs). After histological diagnosis of penile carcinoma, when possible, more conservative procedures are performed, otherwise it is necessary to perform a total penectomy.
MATERIAL AND METHODS: Ten patients, from 2006 to 2008, underwent to partial penectomy and reconstruction with ventral fenestrated flap technique; five of these patients had lichen sclerosus. All tumors were staged as T2N0M0, involving the corpus spongiosum and cavernosum. Patients were evaluated both the aesthetical and the sexual satisfaction, the first one by patient aesthetical self-assessment score, the second one by the International Index of Erectile Function (IIEF). Patients underwent follow-up for forty months.
RESULTS: Of the ten patients, no one encountered severe complications. The average aesthetic satisfaction one month postoperatively was of 2 points, 40 months postoperatively it was of 3 points (scoring scale: 1= complete dissatisfaction, 5 = complete satisfaction). The average IIEF score in the preoperative period was 21.6 points, one month postoperatively it was 13 points, 40 months postoperatively it was 19.7 points (mild erectile dysfunction).
DISCUSSION: The technique we presented, compared to other techniques, allows a reduction in operating time and is a one step technique without risk of non-engraftment. The ventral fenestrated flap technique did not result in metal stenosis in our ten patients series.
CONCLUSIONS: The use of a ventral fenestrated flap in the closure of the defect due to partial penectomy has numerous advantages. Aesthetics is highly accepted by patients who are satisfied and report satisfactory sexual activity despite the reduction in penis length.

Brunasso AM, Bandelloni R, Massone C
Fast growing penis ulcer: an unusual coincidence.
Urology. 2012; 80(1):e9-10 [PubMed]

A 57-year-old man was seen with a 2-week history of progressive enlargement of an asymptomatic genital ulcer associated with bilateral inguinal lymphadenomegaly. Multiple unprotected heterosexual contacts were reported. The family doctor misdiagnosed primary syphilis with the following laboratory results: negative findings on the Venereal Disease Research Laboratory test, positive findings on the Treponema pallidum particle agglutination assay (titer 1:1280), and IgM negative on the Treponema pallidum particle agglutination assay. The patient was treated with penicillin G for the diagnosis of indeterminate latent syphilis and initially denied authorization for a skin biopsy. After 2 weeks, fast enlargement of the lesion was documented. He underwent skin biopsy, and the histopathologic examination revealed squamous cell carcinoma, and polymerase chain reaction for human papillomavirus 16 was positive.

Ishioka P, Yamada S, Michalany NS, Hirata SH
Dermoscopy of Bowen's disease: pigmented variant on the penis.
An Bras Dermatol. 2012 May-Jun; 87(3):482-4 [PubMed]

Pigmented Bowen's disease (PBD) is a variant of squamous cell carcinoma in situ and represents less than 2% of cases of Bowen's disease. It is characterized by a sharply demarcated, pigmented plaque with a scaly or crusted surface on intertriginous and genital areas. The authors describe a case of PBD on the penis and analyze the dermoscopic aspects of this type of lesion.

Herrel LA, Butterworth RM, Jafri SM, et al.
Bilateral endoscopic inguinofemoral lymphadenectomy using simultaneous carbon dioxide insufflation: an initial report of a novel approach.
Can J Urol. 2012; 19(3):6306-9 [PubMed]

Inguinal lymphadenectomy plays a critical role in the diagnosis and treatment of several neoplastic diseases. Frequently, bilateral lymphadenectomy is undertaken for staging and/or treatment of genitourinary cancers. Our objective was to determine if bilateral endoscopic lymphadenectomy could be performed simultaneously, in an effort to decrease overall anesthetic and operative time. This was accomplished by utilizing two carbon dioxide insufflators concurrently. This approach requires careful positioning of the patient, surgical team, and instrumentation, as well as special anesthetic considerations necessary to avoid severe hypercarbia. Simultaneous bilateral endoscopic inguinal lymphadenectomy is a technically feasible and efficient surgical approach.