P. Malone

Epigenetics Markers of Metastasis and HPV-Induced Tumorigenesis in Penile Cancer

Purpose: Penile cancer is a rare malignancy in the developed world with just more than 1,600 new cases diagnosed in the United States per year; however, the incidence is much higher in developing countries. Although HPV is known to contribute to tumorigenesis, little is known about the genetic or epigenetic alterations defining penile cancer. Experimental Design: Using high-density genome-wide methylation arrays, we have identified epigenetic alterations associated with penile cancer. Q-MSP was used to validate lymph node metastasis markers in 50 cases. A total of 446 head and neck squamous cell carcinoma (HNSCC) and cervical squamous cell carcinoma (CESCC) samples were used to validate HPV-associated epigenetic alterations. Results: We defined 6,933 methylation variable positions (MVP) between normal and tumor tissue, which includes 997 hypermethylated differentially methylated regions associated with tumor supressor genes, including CDO1, AR1, and WT1. Analysis of penile cancer tumors identified a 4 gene epi-signature which accurately predicted lymph node metastasis in an independent cohort (AUC of 89%). Finally, we explored the epigenetic alterations associated with penile cancer HPV infection and defined a 30 loci lineage-independent HPV specific epi-signature which predicts HPV status and survival in independent HNSCC, CESC cohorts. Epi-signature–negative patients have a significantly worse overall survival [HNSCC P = 0.00073; 95% confidence interval (CI), 0.021–0.78; CESC P = 0.0094; HR = 3.91, 95% CI = 0.13–0.78], HPV epi-signature is a better predictor of survival than HPV status alone. Conclusions: These data demonstrate for the first time genome-wide epigenetic events involved in an aggressive penile cancer phenotype and define the epigenetic alterations common across multiple HPV-driven malignancies. Clin Cancer Res; 21(5); 1196–206. ©2014 AACR.

Genital lichen sclerosus/balanitis xerotica obliterans in men with penile carcinoma: a critical analysis

The European Association of Urology guidelines identify lichen sclerosus (LS) as a strong risk factor for penile squamous cell carcinoma (pSCC). However, this statement is based on the findings of case–control studies (Level of Evidence 2a) and a direct causal relationship between LS/balanitis xerotica obliterans (BXO) and pSCC remains to be established. Firm guidelines with respect to the appropriate follow‐up policy for LS/BXO are lacking, whereas the impact of synchronous LS/BXO on the prognosis of pSCC remains to be determined. The presence of histologically‐confirmed synchronous LS/BXO in patients diagnosed with pSCC is relatively high, although it is not associated with an increased risk of adverse histopathological features. LS/BXO can develop in extragenital skin grafts used for reconstruction after organ‐sparing surgery for pSCC.

Glansectomy and Split-thickness Skin Graft for Penile Cancer

BACKGROUNDnPenile cancer is a rare malignancy that is confined to the glans in up to four out of five cases. Although descriptions of glansectomy exist, there are no contemporary video explanations or large published single centre series.nnnOBJECTIVEnTo show the efficacy and safety of glansectomy and split-thickness skin graft (STSG) reconstruction.nnnDESIGN, SETTING, AND PARTICIPANTSnData were collected retrospectively for patients identified from surgical theatre diaries between February 2005 and January 2016. 177 patients with histologically proven squamous-cell carcinoma on the glans underwent glansectomy and STSG at a tertiary referral centre in the UK. The median follow-up was 41.4 mo.nnnSURGICAL PROCEDUREnThe skin is incised at the subcoronal level and deepened onto Bucks fascia. Dissection is performed over or under Bucks fascia, depending on suspicion of invasion or risk of disease. The glans is excised and a neoglans is created using a STSG.nnnMEASUREMENTSnLocal recurrence, cancer-specific survival, overall survival, and complications.nnnRESULTS AND LIMITATIONSnSixteen out of 172 patients (9.3%) experienced local recurrence during the follow-up period. Eighteen out of 174 (10.7%) patients died of penile cancer, while 29 patients in total died during the follow-up period. Of 145 patients, 9% required operative intervention for complications, including graft loss and meatal stenosis. Limitations include the retrospective data collection and the lack of functional and sexual outcomes.nnnCONCLUSIONSnGlansectomy and STSG comprise a safe procedure in terms of oncologic control and complications for patients with penile cancer confined to the glans penis. Further studies are required to assess functional and sexual outcomes in these patients.nnnPATIENT SUMMARYnWe report on the management of penile cancers confined to the head of the penis using glansectomy and a split-thickness skin graft to recreate the appearance of a glans. This technique is safe and effective, with limited complications.

Feasibility of performing dynamic sentinel lymph node biopsy as a delayed procedure in penile cancer

IntroductionPatients diagnosedxa0with penile cancer and clinically impalpable inguinal lymph nodes (cN0), normally undergo dynamic sentinel lymph node biopsy (DSNB) at thexa0same time as the primary penile surgery. The aim of this study is to investigate the diagnostic accuracy and clinical outcomes of performing DSNB in patients who have already undergone surgery for the primary penile cancer.MethodsNinety-two patients with unilateral or bilateral impalpable inguinal lymph nodes (LNs) who had already undergone primary resection of the penile tumour (stagexa0≥xa0T1G2) were included in this study. All patients underwent a preoperative USS of the groin(s) with fine needle aspiration cytology (FNAC). Provided that the FNAC was clear, DSNB was performed. Radical inguinal lymphadenectomy was performed if the histological analysis of the SLN confirmed the presence of micrometastatic disease.ResultsDSNB was undertaken in 165 groins with a nonvisualisation rate of 4.8xa0% (8/165 groins). The SLN was positive for micrometastatic disease in nine groins (5.5xa0%) from a total of eight patients (8.7xa0%). One patient developed regional recurrence in a prepubic LN after excision of bilateral negative SLN (1.1xa0%). The three-year disease-specific survival for patients with negative and positive SLN was 98.8 and 87.5xa0%, respectively (pxa0=xa00.042). Using DSNB, occult LN metastases in penile cancer can be detected with a sensitivity of 88.9xa0% and specificity of 100xa0%.ConclusionsWe have demonstrated that DSNB is feasible as a delayed procedure to localise the SLN. Surgical resection of the primary penile lesion does not appear to change the lymphatic drainage.

Management of non-visualization following dynamic sentinel lymph node biopsy for squamous cell carcinoma of the penis.

To review the management and clinical outcomes of uni‐ or bilateral non‐visualization of inguinal lymph nodes during dynamic sentinel lymph node biopsy (DSNB) in patients diagnosed with penile cancer and clinically impalpable inguinal lymph nodes (cN0), and to develop an algorithm for the management of patients in which non‐visualization occurs.

Zentralisierung der Harnröhre und Pseudoglansbildung nach partieller Penektomie

ZusammenfassungDie operative Therapie des Peniskarzinoms hat sich im letzten Jahrzehnt stark verändert. Die Gewissheit, maligne Läsionen mit einem schmaleren Sicherheitsabstand sicher im Gesunden resezieren zu können, hat zur Einführung organerhaltender Operationstechniken geführt und damit die funktionellen und kosmetischen Ergebnisse optimiert. Im Falle einer partiellen Penektomie (PP) beklagen die Patienten postoperativ jedoch die abnormale ventrale Lage der Harnröhre. Zudem besteht ein hohes Risiko für die Entstehung einer Meatusstenose. Wir beschreiben unsere Operationstechnik zur Zentralisierung der Harnröhre und Pseudoglansbildung nach partieller Penektomie, die das kosmetische Aussehen des Penis nach Spalthautdeckung aufrecht erhält und einen weiten Meatus schafft. Die beschriebene UCAPP-Technik („urethral centralisation after partial penectomy“) ermöglicht im Falle einer partiellen Penektomie die Wiederherstellung der normalen Harnröhren-Mündung und verbessert durch Pseudoglansbildung das gesamte kosmetische Erscheinungsbild und reduziert somit die psychische Morbidität Betroffener.AbstractThe management of penile cancer has altered dramatically over the last decade. Confidence to excise lesions safely with smaller margins has led to the adoption of penile-preserving techniques and in turn improved the functional and cosmetic results. Patients undergoing partial penectomy (PP) find that the urethral meatus is located in an abnormal ventral position. In addition, there is axa0high risk of meatal stenosis. We describe our novel technique that allows the urethral meatus to be centralised after PP and creation of axa0pseudo-glans and wide meatus and therefore maintain the cosmetic appearance of the penis after split thickness skin grafting. The UCAPP technique allows the restoration of the normal meatal location and creation of axa0pseudo-glans in case of partial penectomy and therefore can improve the overall cosmetic appearance and reduce the psychological morbidity.The management of penile cancer has altered dramatically over the last decade. Confidence to excise lesions safely with smaller margins has led to the adoption of penile-preserving techniques and in turn improved the functional and cosmetic results. Patients undergoing partial penectomy (PP) find that the urethral meatus is located in an abnormal ventral position. In addition, there is axa0high risk of meatal stenosis. We describe our novel technique that allows the urethral meatus to be centralised after PP and creation of axa0pseudo-glans and wide meatus and therefore maintain the cosmetic appearance of the penis after split thickness skin grafting. The UCAPP technique allows the restoration of the normal meatal location and creation of axa0pseudo-glans in case of partial penectomy and therefore can improve the overall cosmetic appearance and reduce the psychological morbidity.

PATIO-Repair zum Harnröhrenfistelverschluss

BACKGROUNDnUrethrocutaneous (UC) fistulae are common complications after hypospadias surgery and they have been axa0serious problem for surgeons since the repair was first attempted. We present the results of our multicentre retrospective study for repairing UC fistulae using the Patio (preserve the tract and turn it inside out) repair described by Malone.nnnMATERIALS AND METHODSnAxa0total of 16xa0boys (Eschweilerxa02, Lingenxa04, Readingxa010) at the ages of 1-10xa0years were treated for UC fistulae. Instead of excising the fistula tract, it is preserved and turned inside out, this creates a flap valve inside the urethral lumen. After axa0circumferential incision around the skin and meticulous dissection of the fistula tract, axa02/0 nylon suture is passed down the tract and brought out through the external urinary meatus. As axa0result, the fistula tract is inserted into the urethral lumen. In order to keep the fistula tract inverted, it is sutured to the tip of the external urinary meatus, or fixed by an angler lead (modification from Lingen). Due to the narrow base, the excess tissue atrophies postoperatively and leads to an appealing cosmetic result.nnnRESULTSnA total of 9xa0fistula repairs were performed on an outpatient basis without using axa0transurethral catheter; 7xa0boys were treated on an inpatient basis with an average length of stay in the hospital for 1-2xa0days with/without catheterization. During axa0mean follow-up of up to 4.5xa0years, only one fistula recurrence occurred; no other complications were observed.nnnCONCLUSIONnThe Patio repair for urethrocutaneous fistula is an outpatient, simply reproducible surgical technique without the necessity of transurethral catheterization. The short-term results are impressive; long-term results of axa0larger patient cohort will follow.ZusammenfassungEinleitungDie Harnröhrenfistel (HRF) ist eine typische Komplikation der Hypospadiekorrektur und stellt selbst in erfahrener Hand eine operative Herausforderung dar. Wir präsentieren die Ergebnisse einer retrospektiven, multizentrischen Studie zum Einsatz der PATIO-Technik (PATIO: „preserve the tract and turn it inside out“) nach Malone bei der HRF.Material und MethodenInsgesamt wurden 16xa0Jungen (Eschweilerxa02, Lingenxa04, Readingxa010) im Alter von 1–10xa0Jahren zum HRF-Verschluss vorgestellt. Bei der Operationstechnik wird der Fisteltrakt nicht exzidiert, sondern mobilisiert und in das Harnröhrenlumen im Sinne einer Inversionsplastik eingestülpt. Nach kreisförmigem Umschneiden und akribischer Präparation des Fistelgangs wird ein 2/0-Nylonfaden durch den Fisteltrakt zum Meatus ausgeleitet. Hierdurch wird der Fisteltrakt in das Harnröhrenlumen eingestülpt. Um den Fistelgang invertiert zu halten, wird er mit der äußeren Harnröhrenmündung vernäht und dann an der Penisschafthaut mittels Einzelknopfnaht oder in der Modifikation aus Lingen der Faden mittels Anglerblei fixiert. Aufgrund der schmalen Basis atrophiert das überschüssige Gewebe postoperativ und führt zu einem ansprechenden kosmetischen Resultat.Ergebnisse9xa0HRF-Korrekturen erfolgten ambulant ohne Verwendung eines transurethralen Katheters. Bei 7xa0Jungen betrug der stationäre Aufenthalt im Mittel 1–2xa0Tage mit/ohne Katheterisierung. Während eines mittleren Follow-up von 4,5xa0Jahren trat lediglich ein HRF-Rezidiv auf, keine anderen Komplikationen wurden beobachtet.SchlussfolgerungDer PATIO-Repair zum HRF-Verschluss ist eine ambulant durchführbare, einfach reproduzierbare Operationstechnik ohne zwingende Notwendigkeit der transurethralen Katheterisierung. Die Kurzzeitergebnisse sind beeindruckend. Langzeitergebnisse eines größeren Patientenkollektivs werden folgen.AbstractBackgroundUrethrocutaneous (UC) fistulae are common complications after hypospadias surgery and they have been axa0serious problem for surgeons since the repair was first attempted. We present the results of our multicentre retrospective study for repairing UC fistulae using the Patio (“preserve the tract and turn it inside out”) repair described by Malone.Materials and methodsAxa0total of 16xa0boys (Eschweilerxa02, Lingenxa04, Readingxa010) at the ages of 1–10xa0years were treated for UC fistulae. Instead of excising the fistula tract, it is preserved and turned inside out, this creates a flap valve inside the urethral lumen. After axa0circumferential incision around the skin and meticulous dissection of the fistula tract, axa02/0 nylon suture is passed down the tract and brought out through the external urinary meatus. As axa0result, the fistula tract is inserted into the urethral lumen. In order to keep the fistula tract inverted, it is sutured to the tip of the external urinary meatus, or fixed by an angler lead (modification from Lingen). Due to the narrow base, the excess tissue atrophies postoperatively and leads to an appealing cosmetic result.ResultsA total of 9xa0fistula repairs were performed on an outpatient basis without using axa0transurethral catheter; 7xa0boys were treated on an inpatient basis with an average length of stay in the hospital for 1–2xa0days with/without catheterization. During axa0mean follow-up of up to 4.5xa0years, only one fistula recurrence occurred; no other complications were observed.ConclusionThe Patio repair for urethrocutaneous fistula is an outpatient, simply reproducible surgical technique without the necessity of transurethral catheterization. The short-term results are impressive; long-term results of axa0larger patient cohort will follow.