Textbook of Penile Cancer
Asif Muneer • Manit Arya • Simon Horenblas Editors
Textbook of Penile Cancer
Editors Asif Muneer, B.Sc. (Hons.), M.B., Ch.B., FRCS (Ed.), FRCS (Eng.), M.D., FRCS (Urol.) Department of Urology University College London Hospital London UK
Simon Horenblas, M.D., Ph.D. Department of Urologic Oncology Netherlands Cancer Institute - Antoni van Leeuwenhoek Hospital Amsterdam The Netherlands
Manit Arya, M.B.Ch.B., M.D., FRCS (Urol.) Division of Minimally Invasive Interventional Therapy University College London Hospital London UK
ISBN 978-1-84882-878-0 e-ISBN 978-1-84882-879-7 DOI 10.1007/978-1-84882-879-7 Springer London Dordrecht Heidelberg New York British Library Cataloguing in Publication Data A catalogue record for this book is available from the British Library Library of Congress Control Number: 2011937713 © Springer-Verlag London Limited 2012 Apart from any fair dealing for the purposes of research or private study, or criticism or review, as permitted under the Copyright, Designs and Patents Act 1988, this publication may only be reproduced, stored or transmitted, in any form or by any means, with the prior permission in writing of the publishers, or in the case of reprographic reproduction in accordance with the terms of licenses issued by the Copyright Licensing Agency. Enquiries concerning reproduction outside those terms should be sent to the publishers. The use of registered names, trademarks, etc., in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant laws and regulations and therefore free for general use. Product liability: The publisher can give no guarantee for information about drug dosage and application thereof contained in this book. In every individual case the respective user must check its accuracy by consulting other pharmaceutical literature. Printed on acid-free paper Springer is part of Springer Science+Business Media (www.springer.com)
Preface
Penile cancer is a malignancy often associated with a long delay until diagnosis. This may be due to shame, fear, and ignorance. The geographical distribution shows that the malignancy is rare in developed countries but much more common in areas of South America, Africa, and Southeast Asia. Over recent years, there have been new developments in the surgical treatment options available to patients such that the functional and cosmetic results following surgery are now much better. However, the prognosis for patients with metastatic disease is still poor and there is still uncertainty regarding prognostic indicators and controversy with regards to the management of inguinal and pelvic lymph nodes. This edition of Textbook of Penile Cancer is the first textbook covering all the areas of molecular biology, radiological imaging, pathology as well as the management of penile cancer. The contributors are themselves international experts in the field of penile cancer and uro-oncology. The color photographs and detailed explanation of the surgical techniques are aimed at providing a reference for surgeons managing penile cancer. The book also provides a comprehensive text for all healthcare professionals involved in caring for patients diagnosed with penile cancer. Asif Muneer Manit Arya Simon Horenblas
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Acknowledgements
We would like to thank all of our contributors for their valuable time and effort in helping us to complete this textbook. A special thanks to the publishing team at Springer for overseeing this project. Finally to all our family and friends – thank you for your patience.
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About the Editors
Asif Muneer, B.Sc. (Hons.), M.B., Ch.B., FRCS (Ed.), FRCS (Eng.), MD, FRCS (Urol.) Asif Muneer is a consultant urological surgeon with a specialist interest in andrology and men’s health. After completing a research degree at the Wolfson Institute, University College London, he went on to complete his higher surgical training in Oxford and was awarded the Intercollegiate Gold Medal. After completing a further fellowship, he was appointed as a consultant based at University College London Hospital as well as Honorary Senior Lecturer at University College London. He is now part of one of the largest penile cancer teams in the UK. Asif has been actively involved in the diagnosis and management of penile cancer for a number of years. His other areas of interest are priapism, erectile dysfunction, penile reconstructive surgery and male infertility. Outside of work he is a keen cricketer and footballer. Asif is married to Iaisha and has two children.
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About the Editors
Manit Arya, M.D., FRCS (Urol.) Manit Arya has an interest in minimally invasive uro-oncology and is based at University College London Hospital. He has published extensively throughout the urology literature, particularly in the field of uro-oncology, as well as editing eight textbooks. He has completed a research degree investigating the theory of metastatic disease. He completed his higher surgical training in London, and has since organised a number of national educational courses for both medical students and trainees. Manit is married to Nitika and has two children.
About the Editors
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Simon Horenblas, M.D., Ph.D., FEBU Simon Horenblas trained as a urological surgeon in The Netherlands and was appointed at the Netherlands Cancer Institute in 1988. He became chief of the department of urology in 1993 and professor of urologic oncology in 2000. His clinical work focussed solely in the field of uro-oncology. His research has centred around tissue preservation and early detection of metastases. He has been at the forefront of developing sentinel lymph node biopsy in urologic cancers, bladder preservation, and prostate sparing cystectomy. He has authored more than 150 peer reviewed papers and has written a number of chapters in oncology textbooks. He is a keen ice skater, snowboarder, and alpinist. Simon is married to Irene and has a daughter and a son.
Contents
1
Epidemiology and Etiology of Penile Cancer . . . . . . . . . . . . . . . . . . . Maaike C.G. Bleeker, Daniëlle A.M. Heideman, Peter J.F. Snijders, Simon Horenblas, and Chris J.L.M. Meijer
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2
Molecular Biology of Penile Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . Daniëlle A.M. Heideman, Maaike C.G. Bleeker, Hashim Uddin Ahmed, Manit Arya, Simon Horenblas, Peter J.F. Snijders, and Chris J.L.M. Meijer
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3
Diagnosis and Pathology of Penile Cancer . . . . . . . . . . . . . . . . . . . . Alcides Chaux and Antonio L. Cubilla
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4
Radiological Imaging in Penile Cancer . . . . . . . . . . . . . . . . . . . . . . . . Alex P.S. Kirkham
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5
Premalignant Lesions of the Penis . . . . . . . . . . . . . . . . . . . . . . . . . . . . Majid Shabbir, Nicholas A. Watkin, and Asif Muneer
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6
Management of Penile Cancer Using Penile-Preserving Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Paul Hadway, Peter R. Malone, Suks Minhas, and Asif Muneer
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Management of Locally Advanced and Metastatic Penile Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Asif Muneer, Afshin Mosahebi, Vijay Sangar, and Suks Minhas
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8
Cancer of the Male Urethra . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Raj Nigam, Usama Ahmed, Alex Freeman, Suks Minhas, and Asif Muneer
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9
Management of Lymph Nodes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Niels M. Graafland and Simon Horenblas
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10
Prognostic Indicators in Penile Cancer . . . . . . . . . . . . . . . . . . . . . . . . Vincenzo Ficarra, Giacomo Novara, Guido Martignoni, and Filiberto Zattoni
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12
Contents
Phallic Reconstruction Following Surgery for Penile Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . David J. Ralph The Role of Chemotherapy and Radiotherapy in the Treatment of Penile Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . Jan M. Kerst, Luc M.F. Moonen, Niels M. Graafland, Andries M. Bergman, Floris J. Pos, and Simon Horenblas
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13
Nanotechnology and the Implications for Penile Cancer . . . . . . . . . . Ammar Hameed, Iqbal S. Shergill, and Manit Arya
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14
Follow-Up of Patients with Penile Cancer . . . . . . . . . . . . . . . . . . . . . . Niels M. Graafland and Simon Horenblas
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15
Living with Penile Cancer: Effects on Psychology and Quality of Life. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Ian Eardley and Victor Palit
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Future Directions in Penile Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . Paul K. Hegarty and Curtis A. Pettaway
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Appendix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
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Contributors
Hashim Uddin Ahmed, MRCS(Ed), B.M., B.Ch., B.A. (Hons.) Division of Surgery and Interventional Sciences, University College London, London, UK Usama Ahmed, B.Sc. (Hons.) Division of Surgery and Interventional Science, Royal Free Hospital, University College London, London, UK Manit Arya, M.B.Ch.B., M.D., FRCS (Urol.) Division of Minimally Invasive Interventional Therapy, University College London Hospitals, London, UK Andries M. Bergman, M.D., Ph.D. Department of Internal Medicine, Netherlands Cancer Institute, Amsterdam, The Netherlands Maaike C.G. Bleeker, M.D., Ph.D. Department of Pathology, Free University Medical Center, Amsterdam, The Netherlands Alcides Chaux, M.D. Department of Pathology, Instituto de Patologia e Investigacion, Asuncion, Paraguay Antonio L. Cubilla, M.D. Department of Pathology, Instituto de Patologia e Investigacion, Asuncion, Paraguay Ian Eardley, M.A., M.Chir., FRCS (Urol.), FEBU Pyrah Department of Urology, St. James University Hospital, Leeds, West Yorkshire, UK Vincenzo Ficarra, M.D. Department of Surgical and Ocological Sciences, Urologic Unit, University of Padua, Padua, Italy Alex Freeman, M.B.B.S., M.D., FRCPath Department of Pathology, University College London Hospitals NHS Foundation Trust, London, UK Niels M. Graafland, M.D., Ph.D. Department of Urologic, The Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands xv
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Contributors
Paul Hadway, M.B.B.S., MRCS., MSc. FRCS (Urol.) Department of Urology, Churchill Hospital, Oxford, Oxfordshire, UK Ammar Hameed M.B.Ch.B., MRCS., MSc. Registrar Urology, Department of Urology, Peterborough City Hospital, Peterborough, UK Paul K. Hegarty, FRCS (Urol.), M.Ch., M.B.A. Department of Urology, Guys Hospital, London, UK Daniëlle A.M. Heideman, Ph.D. Department of Molecular Pathology, VU University Medical Center, Amsterdam, The Netherlands Simon Horenblas, M.D., Ph.D. Department of Urologic Oncology, Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands Jan M. Kerst, M.D., Ph.D. Department of Medical Oncology, The Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands Alex P.S. Kirkham, FRCS, FRCR Department of Radiology, University College London Hospital, London, UK Peter R. Malone, M.B.B.S., FRCS, M.S., FEBU Harold Hopkins Department of Urology, Royal Berkshire Hospital, Reading, Berkshire, UK Guido Martignoni, M.D. Department of Pathology, University of Verona, Verona, Italy Chris J.L.M. Meijer, M.D., Ph.D. Department of Pathology, Free University Medical Center, Amsterdam, The Netherlands Suks Minhas, M.D., FRCS (Urol.) Department of Urology and Andrology, University College London Hospital, London, UK Luc M.F. Moonen, Ph.D. Radiotherapy Department, Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands Afshin Mosahebi, M.B.B.S., FRCS, FRCS (Plast.), Ph.D., M.B.A. Department of Plastic Surgery, Royal Free & University College London, London, UK Asif Muneer, B.Sc. (Hons.), M.B., Ch.B., FRCS (Eng.), FRCS (Ed.), M.D., FRCS (Urol.) Department of Urology, University College London Hospital, London, UK Raj Nigam, M.B.B.S., M.D. (Lon.), FRCS (Eng.), FRCS (Urol.), FEBU Department of Urology, Royal Surrey County Hospital, Guildford, Surrey, UK Giacomo Novara, M.D. Department of Surgical and Oncological Sciences, Urologic Unit, University of Padua, Padua, Italy
Contributors
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Victor Palit, M.S., FRCS (Urol.) Pyrah Department of Urology, St. James University Hospital, Leeds, West Yorkshire, UK Curtis A. Pettaway, M.D. Department of Urology/Surgery Division, The University of Texas M.D. Anderson Cancer Center, Houston, TX, USA Floris J. Pos, M.D., Ph.D. Department of Radiotherapy, Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands David J. Ralph, M.B.B.S., M.S., FRCS (Urol.) Department of Urology, Institute of Urology, University College Hospital, London, UK Vijay Sangar, M.B.Ch.B., FRCS (Urol.), M.D. Department of Urology, Christie Hospital, Manchester, UK Majid Shabbir, M.B.B.S., M.D., FRCS (Urol.) Department of Urology, Institute of Urology, University College London Hospital, London, UK Iqbal S. Shergill, B.Sc. (Hons.), MRCS (Eng.), FRCS (Urol.) Department of Urology, Wrexham Maelor Hospital, Wrexham, Clwyd, Wales, UK Peter J.F. Snijders, Ph.D. Department of Molecular Pathology, VU University Medical Center, Amsterdam, The Netherlands Nicholas A. Watkin, M.A., FRCS Department of Urology, St. George’s Hospital, London, UK Filiberto Zattoni, M.D. Oncological and Surgical Sciences, Urology Clinic, University of Padua, Padua, Italy
Chapter 1
Epidemiology and Etiology of Penile Cancer Maaike C.G. Bleeker, Daniëlle A.M. Heideman, Peter J.F. Snijders, Simon Horenblas, and Chris J.L.M. Meijer
1.1
Introduction
Penile cancer is a rare malignancy and a potentially mutilating disease for men. In recent years, a better understanding has been gained into the pathogenesis of the tumor, the risk factors associated with penile cancer, and the clinical and histological precursor lesions associated with the disease.
1.2
Epidemiology of Penile Cancer
Penile cancer occurs predominantly in elderly men although the disease may also occasionally present in young men. The mean age at diagnosis of patients with penile cancer is 60 years and the age-related incidence is highest at 70 years. The incidence has remained stable over recent years with an age-standardized incidence of 0.3–1.0 per 100,000 in Western Europe and the United States, accounting for 0.4–0.6% of all malignancies in this part of the world.1,2 The incidence is significantly higher is some areas of Asia, Africa, and South America, where the disease can constitute up to 10% of malignant disease in men with incidence rates of 4.2 and 4.4 per 100,000 in Paraguay and Uganda, respectively.3,4 In terms of the annual number of penile cancers occurring globally, a total penile cancer burden of about 26,000 cases has been estimated.5 The substantial worldwide variation in penile cancer incidences is most likely due to the differences in socio-economic conditions and religious practices.6
M.C.G. Bleeker (*) Department of Pathology, Free University Medical Center, Amsterdam 1081 HV, The Netherlands A. Muneer et al. (eds.), Textbook of Penile Cancer, DOI 10.1007/978-1-84882-879-7_1, © Springer-Verlag London Limited 2012
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2
M.C.G. Bleeker et al.
1.3
Risk Factors
A number of risk factors have been identified for penile cancer. The common risk factors associated with penile cancer are: s s s s s s s s
Phimosis HPV infection Smoking Age Psoralen-UV-A photochemotherapy Penile injury Genital warts HIV infection
1.3.1
Noncircumcision
The most important risk factor for penile cancer is non-circumcision of the penis. Penile cancer is rarely seen in populations who routinely practice circumcision during the neonatal or childhood period.7-10 The protective effect of circumcision has also been found in developing countries with a high incidence of penile cancer, such as Nigeria and India. In these countries the disease is rare in subpopulations that ritually practice circumcision after birth.10 The positive effect of circumcision is mainly explained by preventing conditions such as poor penile hygiene, smegma retention, and phimosis, which have been reported as risk factors for penile cancer.7,10,11 Phimosis (or narrowness of the opening of the foreskin) leads invariably to retention of the normally desquamated epidermal cells and urinary products (smegma) resulting in conditions of chronic irritation with or without bacterial inflammation of the prepuce and the glans. The frequency of phimosis in men with penile carcinoma is between 44% and 85% and in case–control studies a 65-fold increased relative risk for penile cancer was recorded among males with phimosis.10,11 When performing statistical analyses after exclusion of phimosis as a risk factor, the presence of a foreskin did not increase the risk of penile cancer.11 Although carcinogenesis has been attributed to chronic inflammation due to the irritating effects of smegma, to date a carcinogenic agent has not been identified and isolated within smegma.12,13 Inflammation appears to be a critical component for the development of penile cancer as these cancers commonly arise at sites of infection, chronic irritation, or injury. The inner prepuce of uncircumcised men consists of a mucosal surface which may be more vulnerable to infection by the human papillomavirus (HPV). The glans and prepuce of circumcised men is covered by keratinized stratified squamous epithelium which provides more resistance to viral entry.
1
Epidemiology and Etiology of Penile Cancer
1.3.2
3
Human Papillomavirus
A major risk factor for penile cancer is linked to infection with human papillomavirus (HPV). The risk factors for HPV infection includes; number of sexual partners, history of genital warts, or other sexually transmitted diseases.11 Sexual history and a self-reported history of condyloma is associated with a three- to fivefold increase in penile cancer risk. Moreover, the HPV prevalence is lower in circumcised men compared to those who have not been circumcised.14,15 Several studies have shown that an infection with genital high-risk (hr) or socalled “oncogenic” HPV is involved in the pathogenesis of a subset of penile carcinoma.4,16-18 The reported proportion of penile carcinomas carrying hrHPV DNA ranges from 30% to 100%, depending on the methods of HPV detection, population studied, and histological subtype.4,7,16 In systematic reviews, 40–48% of penile cancers are HPV-associated, with HPV-16 being the predominant viral subtype (found in 60–63% of the cases).5,10,19 The association of HPV-16 infection with penile cancer has been consistently supported by several epidemiological studies, including prospective studies.10,20 Seropositivity to HPV-16 is strongly associated with penile cancer as it is with cervical cancer and the association has been remarkably consistent in many case-controlled studies over the years.10,17,21-23 In addition to this hrHPV18 has been reported in 6–13% of penile cancer cases.19 A small subset of penile cancers with low-risk HPV types has also been suggested24,25 and the DNA of the cutaneous HPV-8 has occasionally been detected in penile lesions.26 In a recent review on HPV prevalence in invasive penile cancer, an HPV-6 prevalence of 6.7% has been reported.19 However, whether mucosal low-risk or cutaneous HPV types are etiologically involved in the pathogenesis of penile cancer is still unclear.17
1.3.3
Smoking
Another factor which has been studied in association with penile cancer is smoking, which shows a dose-dependent association with penile cancer. The use of tobacco in any form as a risk factor for penile cancer has been described in several studies.7,11,27 Maden et al. found an elevated risk for penile cancer in current cigarette smokers with an increase in risk with the number of pack-years. The risk of penile cancer among men who smoked at diagnosis was 2.8 times that of men who never smoked.7 Although an association with smoking has been repeatedly observed for penile cancer, the exact role that smoking plays in the development of this disease is not yet known. Similarly chewing tobacco is a significant risk factor for penile cancer and a combination of cigarette smoking and chewing tobacco carries an even higher risk.28 Tobacco may act either through one of its metabolites or directly after systemic absorption.28
4
1.3.4
M.C.G. Bleeker et al.
Psoralen-UV-A Photochemotherapy
Patients with psoriasis undergoing treatment with Psoralen-UV-A photochemotherapy are at an increased risk of penile cancer although there are limited studies which have reported this.29 In a cohort of 892 men who were treated with oral methoxsalen (8-methoxypsoralen) and ultraviolet A photochemotherapy (PUVA), a total of 14 patients (1.6%) with 30 genital neoplasms were identified. In patients exposed to high levels of PUVA, the incidence of invasive squamous-cell carcinoma was 286 times that of the general population and 16.3 times that in patients exposed to low levels of PUVA indicating a dose-dependent risk. Patients treated for psoriasis using immunosuppressive drugs also appear to have an increased risk of developing penile cancer and therefore a genital examination is mandatory in these patients.
1.3.5
Penile Injury
Maden et al.7 found that a history of small tears or small abrasions to the penis was associated with a risk of 3.9 relative to men without such a history. Daling et al.11 also reported an increased risk of penile cancer in men with a penile injury or penile tear. Further studies have suggested that a history of balanitis was also more common in men with penile cancer.27
1.3.6
Genital Warts and HIV Infection
The risk of penile cancer in men with a history of genital warts has been reported as 5.9 times that of men who have no history of warts.7 Similarly there is an eightfold increased risk of penile cancer in patients with HIV although this may be related to the higher incidence of HPV among men with HIV.30 However, Poblet et al.31 have suggested that HIV-1 could synergize with HPV resulting in progression of penile lesions into invasive cancer.
1.4 1.4.1
Penile Cancer and Its Precursor Lesions Penile Cancer and Adjacent Lesions
Penile cancers are thought to arise from the progression of precursor lesions and can be subdivided into HPV-positive and HPV-negative cases. The HPV prevalence differs significantly by histological subtype. Similar to vulvar and head and neck carcinomas, squamous cell carcinoma of the basaloid and warty type display the
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Epidemiology and Etiology of Penile Cancer
5
strongest association with hrHPV (ranging from 66% to 100%) and their etiological relationship with hrHPV infection is most plausible.4,19,32,33 The remaining penile squamous cell carcinomas demonstrate about 30% positivity for hrHPV DNA.4,7,17,18,34,35 Verrucous penile carcinoma seems to have a weaker association with HPV positivity, showing a prevalence of 22.4%.19 Despite the similarities between penile and vulvar cancer including the presence of HPV (mainly HPV-16) and their precursor lesions, the clear bimodal age distribution that is found for vulvar cancer is not clearly seen for penile cancer.36 Cubilla et al. observed a lower age for patients (average age 55 years) diagnosed with basaloid or warty types of cancer compared to other types of penile squamous cell carcinomas.33,37,38 However, in another study, no age difference was found between HPV-positive and -negative cases (i.e., average age 64 years).39 Cubilla et al.37 presented cross-sectional data of almost 300 cases of invasive penile cancers and studied the presence of associated epithelial lesions. Histological evaluation showed that histological hyperplastic epithelial alterations and low-grade penile intraepithelial neoplasia (PIN) were more commonly found in usual squamous, papillary, and verrucous squamous cell carcinomas than in cases with warty or basaloid carcinomas. Conversely, high-grade PIN was present in two thirds of the warty, basaloid, or mixed warty-basaloid tumor subtypes but absent in papillary and verrucous tumors. In fact, despite the lack of a clear identification of the clinical counterparts, corresponding histopathologic features between the precursor lesion and its associated tumor type were shown. Apparently, non-dysplastic or mildly dysplastic lesions may directly progress into invasive cancer in at least a substantial subset of the penile cancer cases. In conclusion, although there are several clear-cut differences between the subtypes of penile squamous cell carcinoma and their precursor lesions (i.e., histomorphological features and HPV status), their clinical distinction and the underlying molecular pathogenesis for progression into invasive cancer is not clear-cut and merits further investigation.
1.4.2
Characteristics of HPV-Related Precursor Lesions
Characteristics of HPV-related precursor lesions are presented in Fig. 1.1. Genital Bowen’s disease, erythroplasia of Queyrat (EQ), and Bowenoid papulosis (BP) are clinical presentations of high-grade PIN. Bowen’s disease and EQ are usually found in elderly men, being present on the follicle bearing skin and the mucosa of the penis (i.e., glans or prepuce), respectively. Bowen’s disease presents as a single, scaly plaque, located on keratinized genital skin. EQ usually presents as one or more red, moist plaque on the mucosal surface of the glans, which may spread to the inner aspect of the prepuce. Multiple studies have consistently shown that there is a high prevalence of HPV in PIN (60–100%) corresponding with reported prevalences of 43–100% in Bowen’s disease and EQ.26,40-43 HPV-16 is the most common type found in Bowen’s disease, being present in 43–88% of the cases.26,42,43 Bowen’s disease and EQ, corresponding with histologically identified high-grade PIN
6
M.C.G. Bleeker et al.
MIB-1
p16
HPV related high grade intraepithelial neoplasia of the penis, showing strong nuclear and cytoplasmic staining with p16 and strong MIB-1 positivity over the full thickness of the epithelium.The lesion tested HPV-16 positive.
HPV related low-grade intraepithelial neoplasia of the penis, showing multiple acetowhite spots, partly with a punctuated pattern on the frenulum at penoscopy. Histologically the lesions show mild dysplasia and convincing viral alterations. The lesion tested HPV-16 positive.
Fig. 1.1 Characteristic HPV-related lesions of the penis
lesions, may progress to penile cancer.26,44,45 Progression into penile cancer is more common in EQ, occurring in approximately 30% of the cases.26 It is unclear whether there is a differential outcome for either HPV-positive or negative cases of Bowen’s disease or EQ. BP has been considered as a predominantly transient and self-limiting hrHPVrelated disease in young men (usually under 40 years of age).41,46,47 This disease clinically presents as multiple, small, well-demarcated papules or small patches on the penile shaft, glans, or foreskin. BP is usually positive for hrHPV, mainly HPV-16. BP is highly contagious, presenting a high risk for cervical intraepithelial neoplasia (CIN) in female patients with BP on the vulva and in female sex partners of male patients with BP on the penis.48 The mean duration of the disease is less than 3 months and progression into penile cancer occurs in less than 1%, though persistent lesions may progress to Bowen’s disease or EQ.46,48,49 Other hrHPV-associated penile lesions include flat penile lesions (FPL), which are also known as acetowhite lesions.40,50-52 Similar to the high-grade penile lesions
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Epidemiology and Etiology of Penile Cancer
7
described above, FPL are predominantly found at the mucosal site of the penis. Histological evaluation of FPL generally shows mild changes such as squamous hyperplasia or low-grade PIN. High-grade PIN is uncommon, being present in about 5% of the cases. FPL are found in about 50–70% of the male sexual partners of women with CIN versus about 10–20% in men who do not have a partner with CIN.40,50-53 In young male populations, not selected on the basis of a prevalent CIN lesion in the partner, prevalences of up to 36% have been reported.54,55 These data indicate that FPL have a much higher prevalence compared to Bowen’s disease, EQ, or BP. Besides the association with HPV, it is important to realize that, in cases of HPV positivity, FPL display relatively high viral load levels. The presence of high viral loads in these lesions is clinically relevant as it indicates a potential increased risk for HPV transmission, similar to that which has been shown for other HPVrelated lesions such as genital warts or BP.48,53,56 The clinical course of FPL is generally benign, showing healing of the majority of the cases within 2 years.53 However, a small proportion remains persistently HPV-positive and does not heal.53 Although not proven in clinical studies, it is plausible to assume that some of these persistent HPV positive FPL might progress to high-grade PIN and subsequent penile cancer. Low-risk HPV (lrHPV)-associated condylomata acuminata do not have a malignant potential although in some cases, long-lasting giant condylomata acuminata (Buschke-Löwenstein tumor) might become malignant, showing invasion in 30% to 56% of cases.57 Although in the literature these tumors are sometimes classified as verrucous carcinomas, it seems best to consider this type of carcinoma as a separate entity which is supported by distinct clinicopathological characteristics like the presence of lrHPV (i.e., HPV-6 and 11), its relative young age at presentation, and their condylomatous appearance (both clinically and histopathologically).57-59 Yet, the role of lrHPV types in penile carcinogenesis needs further investigation especially considering the clinical behavior of lrHPV-positive penile carcinomas (i.e., its potential to metastasize).
1.4.3
Characteristics of Non-HPV-Related Precursor Lesions
Characteristics of non-HPV-related precursor lesions are presented in Fig. 1.2. Lichen sclerosus (LS) is a chronic inflammatory atrophic condition of unknown etiology, which most commonly affects the anogenital area (85–98%), especially in women.60,61 Because the epithelium is not always atrophic, the term LS is preferred over that of LS et atrophicus. In men, LS affects most commonly the foreskin and to a lesser extent the glans of the penis where it gives symptoms of pruritus, burning, and soreness. Clinical evaluation shows areas of pale atrophic and sclerotic plaques (patches).62 Histopathological evaluations show either an hyperplastic or an atrophic epithelium without cytonuclear atypia, a variable degree of interface dermatitis, homogenization of the underlying stroma, mild vasocongestion, and a variable infiltrate.
8
M.C.G. Bleeker et al. MIB-1
p16
Lichen sclerosis showing typically an atrophic epithelium with homogenisation of the underlying stroma,multiple blood vessels and a variable lymphocytic infiltrate. MIB-1 positive nuclei are only found at the basal layer and the lesions are p16 negative.
Fig. 1.2 Characteristic non-HPV-related lesions of the penis
The association between LS with vulvar cancer is well established. Studies of large groups of women with vulvar LS have shown that the risk of vulvar SCC is 4–5%.61,63 In view of the resemblance of penile and vulvar cancer, LS is likely to be a risk factor of penile cancer as well. Indeed, cumulative evidence suggests that LS indeed reflects a precancerous condition for penile SCC, preceding up to 30% of the penile carcinomas, particularly those unrelated to HPV.38,62,64,65 A 10-year follow-up study of 86 men with LS reported that nearly 6% of the patients developed penile cancer, very similar to that of carcinomas occurring in vulvar LS patients.66 Although the vast majority of LS cases are negative for HPV, the prevalence of hrHPV is higher in LS patients compared to controls.66 In addition, LS might co-exist with conditions of Bowen’s disease or EQ.41
1.5
Conclusion
Although rare, penile cancer is a disease with a high morbidity and mortality. Insight into its precursor lesions and risk factors offers measures for prevention. Careful monitoring of men with both HPV-related genital Bowen’s disease, erythroplasia of Queyrat and Bowenoid papulosis and non-HPV related lichen sclerosus seems useful either to prevent penile cancer or to recognize penile cancer at an early stage, thereby offering conservative therapeutic options. Special attention is given to flat penile lesions, which contain high numbers of HPV and are highly prevalent in the male population. Their role in HPV transmission to sexual partners is highlighted, but their potential to transform as a precursor lesion into penile cancer has been explored unsatisfactorily. To date, the etiology of penile cancers is not completely understood and additional research is necessary to fully delineate the sequence of molecular events involved in HPV, non-HPV, and common (both HPV and non-HPV) mediated pathways leading to penile cancer (see Chap. 2). Options for prevention of penile cancer include (neonatal) circumcision thereby negating the effects of phimosis, limitation of penile HPV infections (either by prophylactic vaccination or condom use), and smoking cessation.
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9
References 1. Parkin DM, Muir CS. Cancer incidence in five continents. Comparability and quality of data. IARC Sci Publ. 1992;120:45-173. 2. Jemal A, Siegel R, Ward E, Murray T, Xu J, Thun MJ. Cancer statistics, 2007. CA Cancer J Clin. 2007;57(1):43-66. 3. Wabinga HR, Parkin DM, Wabwire-Mangen F, Nambooze S. Trends in cancer incidence in Kyadondo County, Uganda, 1960–1997. Br J Cancer. 2000;82(9):1585-1592. 4. Rubin MA, Kleter B, Zhou M, et al. Detection and typing of human papillomavirus DNA in penile carcinoma: evidence for multiple independent pathways of penile carcinogenesis. Am J Pathol. 2001;159(4):1211-1218. 5. Parkin DM, Bray F. Chapter 2: The burden of HPV-related cancers. Vaccine. 2006; 24(Suppl 3):S3-11-S3-25. 6. Barnholtz-Sloan JS, Maldonado JL, Pow-sang J, Giuliano AR. Incidence trends in primary malignant penile cancer. Urol Oncol. 2007;25(5):361-367. 7. Maden C, Sherman KJ, Beckmann AM, et al. History of circumcision, medical conditions, and sexual activity and risk of penile cancer [See comments]. J Natl Cancer Inst. 1993;85(1): 19-24. 8. Moses S, Bailey RC, Ronald AR. Male circumcision: assessment of health benefits and risks. Sex Transm Infect. 1998;74(5):368-373. 9. Schoen EJ, Oehrli M, Colby C, Machin G. The highly protective effect of newborn circumcision against invasive penile cancer. Pediatrics. 2000;105(3):E36. 10. Dillner J, von Krogh G, Horenblas S, Meijer CJ. Etiology of squamous cell carcinoma of the penis. Scand J Urol Nephrol Suppl. 2000;205:189-193. 11. Daling JR, Madeleine MM, Johnson LG, et al. Penile cancer: importance of circumcision, human papillomavirus and smoking in in situ and invasive disease. Int J Cancer. 2005; 116(4):606-616. 12. Baruah IK, Reddy DG. Carcinogenic action of human smegma. Arch Pathol. 1963;75: 414-420. 13. Misra S, Chaturvedi A, Misra NC. Penile carcinoma: a challenge for the developing world. Lancet Oncol. 2004;5(4):240-247. 14. Castellsague X, Bosch FX, Munoz N, et al. Male circumcision, penile human papillomavirus infection, and cervical cancer in female partners. N Engl J Med. 2002;346(15):1105-1112. 15. Nielson CM, Schiaffino MK, Dunne EF, Salemi JL, Giuliano AR. Associations between male anogenital human papillomavirus infection and circumcision by anatomic site sampled and lifetime number of female sex partners. J Infect Dis. 2009;199(1):7-13. 16. McCance DJ, Kalache A, Ashdown K, et al. Human papillomavirus types 16 and 18 in carcinomas of the penis from Brazil. Int J Cancer. 1986;37(1):55-59. 17. Heideman DA, Waterboer T, Pawlita M, et al. Human papillomavirus-16 is the predominant type etiologically involved in penile squamous cell carcinoma. J Clin Oncol. 2007;25(29): 4550-4556. 18. Gregoire L, Cubilla AL, Reuter VE, Haas GP, Lancaster WD. Preferential association of human papillomavirus with high-grade histologic variants of penile-invasive squamous cell carcinoma. J Natl Cancer Inst. 1995;87(22):1705-1709. 19. Backes DM, Kurman RJ, Pimenta JM, Smith JS. Systematic review of human papillomavirus prevalence in invasive penile cancer. Cancer Causes Control. 2009;20(4):449-457. 20. Bjorge T, Dillner J, Anttila T, et al. Prospective seroepidemiological study of role of human papillomavirus in non-cervical anogenital cancers. BMJ. 1997;315(7109):646-649. 21. Carter JJ, Madeleine MM, Shera K, et al. Human papillomavirus 16 and 18 L1 serology compared across anogenital cancer sites. Cancer Res. 2001;61(5):1934-1940. 22. Van Doornum GJ, Korse CM, Buning-Kager JC, et al. Reactivity to human papillomavirus type 16 L1 virus-like particles in sera from patients with genital cancer and patients with carcinomas at five different extragenital sites. Br J Cancer. 2003;88(7):1095-1100.
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23. Newton R, Bousarghin L, Ziegler J, et al. Human papillomaviruses and cancer in Uganda. Eur J Cancer Prev. 2004;13(2):113-118. 24. Dorfman S, Cavazza M, Cardozo J. Penile cancer associated with so-called low-risk human papilloma virus. Report of five cases from rural Venezuela. Trop Doct. 2006;36(4):232-233. 25. Senba M, Kumatori A, Fujita S, et al. The prevalence of human papillomavirus genotypes in penile cancers from northern Thailand. J Med Virol. 2006;78(10):1341-1346. 26. Wieland U, Jurk S, Weissenborn S, Krieg T, Pfister H, Ritzkowsky A. Erythroplasia of queyrat: coinfection with cutaneous carcinogenic human papillomavirus type 8 and genital papillomaviruses in a carcinoma in situ. J Invest Dermatol. 2000;115(3):396-401. 27. Hellberg D, Valentin J, Eklund T, Nilsson S. Penile cancer: Is there an epidemiological role for smoking and sexual behaviour? Br Med J (Clin Res Ed). 1987;295(6609):1306-1308. 28. Harish K, Ravi R. The role of tobacco in penile carcinoma. Br J Urol. 1995;75(3):375-377. 29. Stern RS. Genital tumors among men with psoriasis exposed to psoralens and ultraviolet A radiation (PUVA) and ultraviolet B radiation. The Photochemotherapy Follow-up Study. N Engl J Med. 1990;322(16):1093-1097. 30. Engels EA, Pfeiffer RM, Goedert JJ, et al. Trends in cancer risk among people with AIDS in the United States 1980–2002. AIDS. 2006;20(12):1645-1654. 31. Poblet E, Alfaro L, Fernander-Segoviano P, Jimenez-Reyes J, Salido EC. Human papillomavirusassociated penile squamous cell carcinoma in HIV-positive patients. Am J Surg Pathol. 1999;23(9):1119-1123. 32. Cubilla AL, Reuter VE, Gregoire L, et al. Basaloid squamous cell carcinoma: a distinctive human papilloma virus-related penile neoplasm: a report of 20 cases. Am J Surg Pathol. 1998;22(6):755-761. 33. Cubilla AL, Velazques EF, Reuter VE, Oliva E, Mihm MC Jr, Young RH. Warty (condylomatous) squamous cell carcinoma of the penis: a report of 11 cases and proposed classification of “verruciform” penile tumors. Am J Surg Pathol. 2000;24(4):505-512. 34. Bezerra AL, Lopes A, Santiago GH, Ribeiro KC, Latorre MR, Villa LL. Human papillomavirus as a prognostic factor in carcinoma of the penis: analysis of 82 patients treated with amputation and bilateral lymphadenectomy. Cancer. 2001;91(12):2315-2321. 35. Ferreux E, Lont AP, Horenblas S, et al. Evidence for at least three alternative mechanisms targeting the p16INK4A/cyclin D/Rb pathway in penile carcinoma, one of which is mediated by high-risk human papillomavirus. J Pathol. 2003;201(1):109-118. 36. Canavan TP, Cohen D. Vulvar cancer. Am Fam Physician. 2002;66(7):1269-1274. 37. Cubilla AL, Velazquez EF, Young RH. Epithelial lesions associated with invasive penile squamous cell carcinoma: a pathologic study of 288 cases. Int J Surg Pathol. 2004;12(4):351-364. 38. Cubilla AL, Velazquez EF, Young RH. Pseudohyperplastic squamous cell carcinoma of the penis associated with lichen sclerosus. An extremely well-differentiated, nonverruciform neoplasm that preferentially affects the foreskin and is frequently misdiagnosed: a report of 10 cases of a distinctive clinicopathologic entity. Am J Surg Pathol. 2004;28(7):895-900. 39. Lont AP, Kroon BK, Horenblas S, et al. Presence of high-risk human papillomavirus DNA in penile carcinoma predicts favorable outcome in survival. Int J Cancer. 2006;119(5):1078-1081. 40. Barrasso R, De BJ, Croissant O, Orth G. High prevalence of papillomavirus-associated penile intraepithelial neoplasia in sexual partners of women with cervical intraepithelial neoplasia. N Engl J Med. 1987;317(15):916-923. 41. Porter WM, Francis N, Hawkins D, Dinneen M, Bunker CB. Penile intraepithelial neoplasia: clinical spectrum and treatment of 35 cases. Br J Dermatol. 2002;147(6):1159-1165. 42. Hahn A, Loning T, Hoos A, Henke P. Immunohistochemistry (S 100, KL 1) and human papillomavirus DNA hybridization on morbus Bowen and bowenoid papulosis. Virchows Arch A Pathol Anat Histopathol. 1988;413(2):113-122. 43. Ikenberg H, Gissmann L, Gross G, Grussendorf-Conen EI, zur HH. Human papillomavirus type-16-related DNA in genital Bowen’s disease and in Bowenoid papulosis. Int J Cancer. 1983;32(5):563-565. 44. Kaye V, Zhang G, Dehner LP, Fraley EE. Carcinoma in situ of penis. Is distinction between erythroplasia of Queyrat and Bowen’s disease relevant? Urology. 1990;36(6):479-482.
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45. Gross G, Pfister H. Role of human papillomavirus in penile cancer, penile intraepithelial squamous cell neoplasias and in genital warts. Med Microbiol Immunol. 2004;193(1): 35-44. 46. von Krogh G, Horenblas S. Diagnosis and clinical presentation of premalignant lesions of the penis. Scand J Urol Nephrol Suppl. 2000;205:201-214. 47. Hogewoning CJ, Bleeker MC, van den Brule AJ, et al. Pearly penile papules: still no reason for uneasiness. J Am Acad Dermatol. 2003;49(1):50-54. 48. Obalek S, Jablonska S, Beaudenon S, Walczak L, Orth G. Bowenoid papulosis of the male and female genitalia: risk of cervical neoplasia. J Am Acad Dermatol. 1986;14(3):433-444. 49. Ammin BA, Tamboli P, Cubilla AL. Penis and scrotum. In: Weidner N, Cote RJ, Suster S, Weiss LM, eds. Modern Surgical Pathology. Philadelphia: Elsevier Science; 2003:1197-1214. 50. Barrasso R. Latent and subclinical HPV external anogenital infection. Clin Dermatol. 1997;15(3):349-353. 51. Hippelainen M, Yliskoski M, Saarikoski S, Syrjanen S, Syrjanen K. Genital human papillomavirus lesions of the male sexual partners: the diagnostic accuracy of peniscopy [See Comments]. Genitourin Med. 1991;67(4):291-296. 52. Bleeker MC, Hogewoning CJ, van den Brule AJ, et al. Penile lesions and human papillomavirus in male sexual partners of women with cervical intraepithelial neoplasia. J Am Acad Dermatol. 2002;47(3):351-357. 53. Bleeker MC, Snijders PF, Voorhorst FJ, Meijer CJ. Flat penile lesions: the infectious “invisible” link in the transmission of human papillomavirus. Int J Cancer. 2006;119(11): 2505-2512. 54. Kataoka A, Claesson U, Hansson BG, Eriksson M, Lindh E. Human papillomavirus infection of the male diagnosed by Southern-blot hybridization and polymerase chain reaction: comparison between urethra samples and penile biopsy samples. J Med Virol. 1991;33(3):159-164. 55. Hippelainen M, Syrjanen S, Hippelainen M, et al. Prevalence and risk factors of genital human papillomavirus (HPV) infections in healthy males: a study on Finnish conscripts. Sex Transm Dis. 1993;20(6):321-328. 56. Campion MJ, Singer A, Clarkson PK, McCance DJ. Increased risk of cervical neoplasia in consorts of men with penile condylomata acuminata. Lancet. 1985;1(8435):943-946. 57. Chu QD, Vezeridis MP, Libbey NP, Wanebo HJ. Giant condyloma acuminatum (BuschkeLowenstein tumor) of the anorectal and perianal regions. Analysis of 42 cases. Dis Colon Rectum. 1994;37(9):950-957. 58. Trombetta LJ, Place RJ. Giant condyloma acuminatum of the anorectum: trends in epidemiology and management: report of a case and review of the literature. Dis Colon Rectum. 2001;44(12):1878-1886. 59. Grussendorf-Conen EI. Anogenital premalignant and malignant tumors (including BuschkeLowenstein tumors). Clin Dermatol. 1997;15(3):377-388. 60. Powell JJ, Wojnarowska F. Lichen sclerosus. Lancet. 1999;353(9166):1777-1783. 61. Meffert JJ, Davis BM, Grimwood RE. Lichen sclerosus. J Am Acad Dermatol. 1995;32(3): 393-416. 62. Velazquez EF, Cubilla AL. Lichen sclerosus in 68 patients with squamous cell carcinoma of the penis: frequent atypias and correlation with special carcinoma variants suggests a precancerous role. Am J Surg Pathol. 2003;27(11):1448-1453. 63. Carli P, Cattaneo A, De MA, Biggeri A, Taddei G, Giannotti B. Squamous cell carcinoma arising in vulval lichen sclerosus: a longitudinal cohort study. Eur J Cancer Prev. 1995;4(6): 491-495. 64. Perceau G, Derancourt C, Clavel C, et al. Lichen sclerosus is frequently present in penile squamous cell carcinomas but is not always associated with oncogenic human papillomavirus. Br J Dermatol. 2003;148(5):934-938. 65. Powell J, Robson A, Cranston D, Wojnarowska F, Turner R. High incidence of lichen sclerosus in patients with squamous cell carcinoma of the penis. Br J Dermatol. 2001;145(1):85-89. 66. Nasca MR, Innocenzi D, Micali G. Penile cancer among patients with genital lichen sclerosus. J Am Acad Dermatol. 1999;41(6):911-914.
Chapter 2
Molecular Biology of Penile Cancer Daniëlle A.M. Heideman, Maaike C.G. Bleeker, Hashim Uddin Ahmed, Manit Arya, Simon Horenblas, Peter J.F. Snijders, and Chris J.L.M. Meijer
2.1 Introduction: Molecular Concept of Penile Carcinogenesis Penile cancer is a rare disease, particularly in developed countries.1 Large case series for molecular studies are relatively limited. Only a few, albeit important, studies evaluating the molecular etiopathogenesis of penile carcinoma have been published to date. Based on these studies, a model of penile carcinogenesis describing the molecular alterations that accumulate during the pathogenesis of penile carcinoma has been proposed.2 In this molecular concept, the etiology of penile carcinoma is recognized to be heterogeneous in nature with evidence pointing to at least two independent carcinogenic routes, i.e., virus and nonvirus induced. About half of penile cancers are caused by an infection with high-risk (often also referred to as “oncogenic”) human papillomavirus (hrHPV), mainly type HPV-16. 3-8 The remaining penile cancers arise independent of hrHPV infection. A similar division has also been described for vulvar and head and neck carcinomas.9 Although the molecular routes of disruption differ in multiple ways – particularly related to the early genetic events and the activity of the known viral oncogenes E6 and E7 – common cellular pathways are disrupted at initial and later stages during penile carcinogenesis in both virus and nonvirus-induced modes. Penile cancers are likely to be initiated by interference with the cellular p14ARF/MDM2/p53 and/or p16INK4a/ cyclin D/Rb pathways, either by viral (i.e., HPV) or nonviral (i.e., mutation, gene promoter hypermethylation, etc.) mechanisms. This may lead to uncontrolled cell division and reduced apoptosis, and may trigger a state of chromosomal instability that further drives the carcinogenic process. More common molecular events in late(r) stage penile carcinogenesis include altered expression of genes involved in disease progression, invasion, angiogenesis, and metastasis.
D.A.M. Heideman (*) Department of Molecular Pathology, VU University Medical Center, Amsterdam, 1081 HV, The Netherlands A. Muneer et al. (eds.), Textbook of Penile Cancer, DOI 10.1007/978-1-84882-879-7_2, © Springer-Verlag London Limited 2012
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Carcinogenic route
HPV-induced
Non-virus induced
Early molecular events
leading to and Late(r) molecular disruption of resulting in events
Viral oncogenes hrHPV E6 and hrHPV E7
Altered expression of genes involved in disease progression, p16 / CyclinD/ CDK / Rb immortalisation uncontrolled invasion, angiogenesis and angiogenesis cell division invasion and reduced metastasis metastasis a.o. ras apoptosis p14 / MDM2 myc / p53 telomerase E-cadherin MMPs PGE2 synthase COX (epi) genome
Oncogeneactivating and/or TSG-inactivating mechanisms, like - gene promoter methylation - gene mutation - gene overexpression
resulting in
Fig. 2.1 Molecular concept of penile carcinogenesis. Schematic overview of molecular events during early and late(r) stages of penile carcinogenesis according to mode of pathogenesis, i.e., virus or nonvirus induced
An overview of the molecular pathogenesis of penile cancer is presented in Fig. 2.1, and will be further discussed in this chapter.
2.2
HPV-Mediated Penile Carcinogenesis
HPV is associated with anogenital tumor formation and is an important factor in the development of in-situ and invasive epithelial tumors. Our understanding of HPV DNA integration into the human genome has resulted from research investigating SCC of the cervix and from the development of an HPV-specific quadrivalent vaccine. HrHPV-associated penile cancers are thought to arise from the progression of precursor lesions caused by an hrHPV infection. HrHPV infections have a strong association with anogenital tumor formation, particularly cervical cancer. HPV is a family of epitheliotropic, small double-stranded DNA viruses of approximately 8,000 bp. Sexual transmission is the most common route for viral infection, although oral and vertical transmission are also possible.10 Epidemiologic research has classified 15 genotypes of HPV as high-risk, based on their association with cervical cancer, i.e., HPV16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, and 82, and three types as probably high-risk, i.e., HPV 26, 53, and 66.11 Recent literature reviews of data available for Europe, North America, South America, and Asia, reported an overall HPV prevalence in penile carcinomas of approximately 47%.3,8 The contribution of the different HPV types among HPV-positive penile cancers varies as follows: HPV-16 (60.23%), HPV-18 (13.35%), HPV-6/11 (8.13%), HPV-31 (1.16%), HPV-45 (1.16%), HPV-33 (0.97%), HPV-52 (0.58%), other types (2.47%).3
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The viral genome contains early (E) regions encoding proteins for replication, regulation, and modification of the host cytoplasm and nucleus, and late (L) regions that encode capsid proteins. Studies on the viral proteins E6 and E7 revealed their binding to and inactivation of the cellular p53 and Rb tumor suppressor gene products, respectively,12,13 thereby controlling cellular proliferation and apoptosis. The E6 and E7 gene products of the oncogenic HPV types have an initiating role in the transformation process, but are also relevant for the maintenance of the transformed phenotype of the infected cells, as interference with their expression may trigger senescence and apoptosis. Knowledge from cervical cancer development, a tumor for which hrHPV infection is a necessary cause, indicates that a persistent infection with hrHPV is the initiating causative event. There is no indication that this would be different for hrHPV-associated penile cancers. In fact, functional evidence for an initiating role of hrHPV in the transformation process comes partly from studies that used penile foreskin keratinocytes as a model system.14 Although essential, the hrHPV infection is not sufficient to induce frank cancer. Subsequent genetic and epigenetic alterations in the host cell are necessary for an hrHPV-infected cell to become fully malignant. As such, hrHPVassociated penile carcinogenesis is considered to be mechanistically equivalent to hrHPV-mediated cervical carcinogenesis.14 Following infection of the mucosal epithelium by hrHPV, it is assumed that generally productive viral infections arise in which the viral life cycle and virion production are strongly coupled to the differentiation program of the infected epithelium. Only when this tight regulation becomes lost, by a mechanism not yet fully understood, uncontrolled expression of the viral oncogenes E6 and E7 may occur in proliferating basal and parabasal epithelial cells, a phenomenon that distinguishes the process of cell transformation from a productive viral infection. By disturbance of the p14ARF/MDM2/p53 and p16INK4a/cyclin D/Rb pathways in the (para)basal cells, oncogenic HPV types interfere with control of the cell division cycle and apoptosis. A strong immunostaining for p16INK4A in HPV-associated penile cancers, consistent with an active role for HPV in interfering with the retinoblastoma pathway (i.e., functional inactivation of pRb by hrHPV E7 protein, which results in free E2F and the reciprocal overexpression of p16INK4a), has been described.15,16 The disturbance of cell division and apoptosis triggers a state of chromosomal instability and further drives the carcinogenic process. The subsequent host-cell genetic and epigenetic events involved in hrHPV-induced penile carcinogenesis are not extensively studied to date, but are likely to be similar to those involved in other hrHPV-associated anogenital cancers, e.g., telomerase activation, and gene promoter hypermethylation (see below). Based on similar prevalences of HPV (mainly HPV-16) and their precursor lesions,2 etiological similarities have been suggested between tumors from the vulva and the penis. Yet, differences should be taken into account. Vulvar cancer tends to have a bimodal age distribution. HPV-associated cancers manifest at an earlier age than HPV-unrelated cancers (i.e., seventh or eighth decade of life).17,18 For penile cancer these data are contradictory. Cubilla et al.19-21 reported an age difference between HPV-positive and negative cases, while another study found similar peak
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incidence for both HPV-mediated and non-HPV-associated penile cancers (i.e., average 64 years).22 From a molecular point of view, HPV-dependent carcinogenesis of the penis has been suggested to resemble that of the cervix.2,23 Despite a likely common ground based on the shared causative agent, differences between hrHPV-associated penile and cervical carcinoma should also be considered. First, the worldwide incidence of HPV-associated penile carcinoma is very rare as compared to cervical cancer, whereas penile and cervical hrHPV infections are equally common.24,25 Second, the peak incidence of penile cancer is approximately 20–30 years later than that of cervical cancer.22 These observations suggest tissue and/or hormone-specific variables influencing the clinical course of an hrHPV-infection and the potential accompanied oncogenic process. The penile epithelium likely comprises a less favorable environment for virus-induced transformation than the cervical transformation zone, in which cervical cancer arises. Thus, despite penile carcinogenesis sharing some specific genetic and epigenetic alterations which are known to be involved in hrHPV-mediated carcinogenesis at different anatomical sites including those related to cervical and vulvar cancer, these should be interpreted with caution in relation to penile carcinogenesis. Further research is warranted to reveal the precise role of these molecular events in HPVassociated penile carcinogenesis.
2.3
HPV-Independent Penile Carcinogenesis
Penile carcinomas that are not associated with hrHPV are thought to arise from the progression of precursor lesions at sites of chronic irritation or injury, such as lichen sclerosus. Although the causative agent of these lesions has not been completely elucidated, inflammation is recognized as a critical component of tumor development or progression in these cases.2 Studies evaluating the molecular biology of non-HPV associated penile cancer have suggested that, in general, gene alterations (i.e., p53 alterations, gene promoter methylation) are more frequent in non-HPV-associated penile carcinomas as compared to their HPV-mediated counterparts.26 Although these data should be interpreted with care as only small case series were compared, the phenomenon would be in line with studies on head and neck carcinomas.27 In head and neck carcinomas, HPV-associated cancers are characterized by the disruption of the pRb and p53 pathways by the viral oncoproteins and were found to be genetically different from those that did not contain HPV. The latter required alternative genetic damage to disrupt similar cellular pathways, including p53 gene mutations and methylation of tumor suppressor and tumor-related genes. Indeed, several studies have identified nonviral mechanism(s) leading to the disturbance of the p14ARF/MDM2/p53 and/or p16INK4a/cyclin D/Rb pathways as critical components of HPV-independent penile carcinogenesis.4,28,29 Inactivation of p16INK4a by methylation of the CpG-rich gene promoter region has been described in 15–26%
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of non-HPV associated penile cancers.15,26 Another plausible mechanism by which the p16INK4a /cyclin D/Rb pathway can be disrupted during penile carcinogenesis in the absence of hrHPV is overexpression of the polycomb group (PcG) gene BMI-1, which targets the CDKN2A locus (which encodes both p16INK4a and p14ARF). Overexpression of BMI-1 has been reported in 10% of hrHPV-negative cases.15 Mechanisms by which the p14ARF/MDM2/p53 pathway becomes inactivated in nonHPV-associated penile cancers include somatic mutations of the p53 gene. An inverse relation between the presence of mutations of the p53 gene or p53 stabilization, a feature of mutated, inactive p53, and HPV presence has been reported for penile carcinoma,26,30-32 although there is some contradictory evidence regarding the relation between p53 expression and HPV infection.29 Another mechanism by which the p14ARF/MDM2/p53 pathway can be disrupted during penile carcinogenesis in the absence of hrHPV is overexpression of the MDM2 gene product, a negative regulator of p53.33 Taken together, these studies show that the two carcinogenic routes, i.e., virus and nonvirus induced, can differ but do have similarities also. In other words, virus and nonvirus-induced modes may differ in their manner of disrupting cellular pathways by activity of the known viral oncogenes E6 and E7, or more direct, oncogeneactivating /tumor suppressor gene (TSG)-inactivating mechanisms, respectively. Nonetheless, similar cellular targets are hit during the early genetic events in penile carcinogenesis in both pathways. A few studies have been performed in which survival was correlated with the HPV status of the primary tumor with differing results. Some showed no survival difference between HPV-positive and -negative tumors,34,35 while others suggest a survival benefit for penile cancer patients with hrHPV-positive tumors over those with HPV-negative tumors.22,36 Though highly speculative, if the latter findings holds true, hrHPV-positive penile tumors may comprise a distinct molecular and clinical entity of which a survival benefit may be related to a lower degree of gross genetic alterations, as previously found in head and neck cancer,27 or increased immune surveillance due to the presence of viral epitopes.
2.4
Molecular Events Following Initial Disruption of P14ARF/ MDM2/P53 and/or P16INK4A/Cyclin D/RB Pathways
Following the initial disruption of p14ARF/MDM2/p53 and/or p16INK4a/cyclin D/Rb pathways by either viral or nonviral mechanisms, several additional molecular alterations have been reported in penile cancers. These molecular events include alterations in the activity and/or expression of genes involved in disease progression, invasion, angiogenesis, and metastasis. They will be discussed in further detail below. Some factors have been found to be of prognostic value and/or predictive value for lymph node metastases and will be indicated as such.
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2.4.1
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Chromosomal Aberrations
Whole genome studies on penile cancer are scarce. DNA ploidy studies suggest the frequency of DNA aneuploidy to be correlated with histological type of invasive squamous cell carcinoma of the penis37,38 and patients with DNA diploid cancer to have a better survival rate than patients with aneuploid cancer.39 Preliminary analysis suggests that patients with a high DNA index may be at increased risk of disease progression and metastatic involvement.38,40 Karyotype analysis has been reported in a very small set of penile cancers (n = 4), of which three of the four presented with a variety of cytogenetic anomalies.41-43 The tumors with cytogenetic abnormalities seem to have a more aggressive component, though clearly further data linking chromosomal abnormalities to biological behavior and outcome are necessary to state this firmly. In a comparative genomic hybridization study of 26 cases,44 DNA copy number alterations were present in 23 cases (89%). The CGH analysis using metaphase spreads showed aberrations in all chromosomes, at varying frequencies. The most common copy number gains were found in 8q24, 16p11–12, 20q11–13, 22q, 19q13, and 5p15, and the most common deletions were detected in 13q21–22, 4q21–32, and along the X chromosome. These alterations were similar to those detected in other SCC types, such as oral and esophageal SCC. No clear correlation between tumor grade and chromosome aberrations could be detected, but there was a tendency for lower copy number alterations being associated with shorter survival times. It would be worthwhile to extend these CGH studies and combine chromosomal patterns of various HPV-positive versus negative cancers, including those of other anatomical sites such as vulva and oropharynx, to determine both unique patterns and common denominators in HPV-mediated and HPVunrelated carcinogenesis.
2.4.2
RAS
The 21 kD ras protein has intrinsic GTPase activity, which is regulated by other protein factors, and acts as a focal point for several signal transduction pathways. Point mutations have been identified that result in constitutive ras activity. Mutations in ras genes are suggested to be late events in carcinogenesis, and are linked to disease progression. Data on ras mutation in penile cancer are limited.45,46 A recent study reported somatic missense mutations in three of the 28 penile cancer samples, including one mutation (3%) in KRAS and two mutations in HRAS (7%). HRAS and KRAS mutations were found in larger and more advanced tumors. In addition, in the PIK3CA gene eight mutations (29%) were identified. The mutations in ras and PIK3CA were mutually exclusive, suggesting that dysregulation of either the phosphatidylinositol 3-kinase or ras pathway would be sufficient for the development and progression of penile carcinoma.46
2 Molecular Biology of Penile Cancer
2.4.3
19
Myc
Myc activation, triggered by the insertion of HPV DNA sequences, has been suggested to be an important genetic event in HPV-associated oncogenesis.47 Studies on the pattern of genomic integration of HPV DNA in penile cancer using the cell line IC248,49 have demonstrated the integration of HPV-16 localized to sites containing c-myc (8q24.1) proto-oncogene. These results warrant further investigation on larger cases series.
2.4.4
Telomerase
There has been very little research looking at telomerase activity in penile cancer.50,51 Telomerase is an enzyme that adds specific DNA sequence repeats (“TTAGGG” in all vertebrates) to the 3c end of DNA strands in the telomere regions, which are found at the ends of eukaryotic chromosomes. The telomeres contain condensed DNA material, conferring stability to the chromosomes. The enzyme is a reverse transcriptase that carries its own RNA, which is used as a template when it elongates telomeres. Telomeres are normally shortened after each replication cycle and telomerase provides a compensatory mechanism. In cancer, increased telomerase activity could possibly overcome programmed cell death, immortalizing the cell and leading to indefinite replication capacity. This mechanism might be linked to an increased probability of developing chromosomal changes and aneuploid populations. Alves and coworkers50 describe detectable telomerase activity in 85–100% of penile carcinoma, but also in adjacent noncancerous skin and corpus cavernosum. Further studies are necessary to evaluate the relevance of these findings.
2.4.5
Epigenetic Events
Methylation of CpG-rich islands in or near the promoter region of genes has been associated with transcriptional inactivation of tumor-suppressor and tumor-related genes in human cancers. So far, a few studies have searched for DNA methylation of cellular genes in penile carcinoma. Yanagawa et al.26,52 revealed frequencies of methylation as follows: 27% for DAPK, 88% for FHIT, 19% for MGMT, 23% for RAR-beta, 12% for ras association domain family 1A (RASSF1A), and 42% for RUNX3. The high frequency of methylation of the FHIT gene promoter is noteworthy. FHIT gene promoter hypermethylation was associated with absence of FHIT expression.52 FHIT has a role in the regulation of apoptosis and the cell cycle, which may be lost upon promoter hypermethylation. In general, methylation of the above markers was observed more frequently in HPV-negative than in
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HPV-positive patients, though data should be interpreted with care as only 3 HPVpositive patients were included in the study.26 Another study reports methylation status in the promoter region of thrombospondin-1 (TSP-1) and RASSF1A in 46% and 42% of the tumors, respectively. The epigenetic inactivation of TSP-1 and RASSF1A genes was found associated with pathological variables (i.e., unfavorable histological grade, vascular invasion, and shorter overall survival for TSP-1; and T1 tumors for RASF1A). Both methylation markers seemed to be of prognostic significance in penile cancer, yet with opposite roles, i.e., TSP-1 promoter methylation was associated with shorter 5-year disease-free survival and overall survival, while RASSF1A hypermethylation seemed to be associated with a more prolonged-disease free survival.36
2.4.6
Cell Proliferation Markers
Factors involved in cell cycle regulation that, in addition to p14ARF/MDM2/p53 and/or p16INK4a/cyclin D/Rb (see above), have been investigated in penile cancer include proliferation cell nuclear antigen (PCNA) and Ki-67. PCNA is a protein found in the nucleus of cells and is a cofactor of DNA polymerase delta. PCNA is important for both DNA synthesis and DNA repair. Expression of PCNA has been evaluated in penile cancer with different results.28,53,54 Both no correlation between PCNA immuno-expression and prognosis, and PCNA as an independent factor for the presence of lymph node metastasis have been reported. It is likely that these findings are related to a difference in execution and interpretation of PCNA immunostaining, e.g., tissue fixation, antibody dilution, and cut off points. Accordingly, the application of PCNA as a prognostic factor must be evaluated with care. Ki-67 is a nuclear protein encoded by the MKI67 gene and a cellular marker for proliferation. Ki-67 expression has been found correlated with tumor type, with the highest expression in basaloid carcinomas and the lowest in verrucous carcinomas.55-58 Despite the fact that Ki-67 immunostaining results are more consistent as for PCNA, also Ki-67 findings in relation to penile cancer are diverse. Reports vary from an inverse relation between Ki-67 expression and lymph node metastasis to no relationship with biologic behavior or lymph node metastasis to positive correlation between tumor stage, progression, and lymph node metastasis.54,59-63 Clearly, these findings need further evaluation.
2.4.7
E-Cadherin
E-cadherins are cell adhesion molecules whose decrease in expression is involved in the mechanisms of metastasis. Low E-cadherin immunoreactivity has been reported in 35–45% of penile cancer cases, and has been correlated with a greater risk of lymph node metastases in penile carcinoma.60
2 Molecular Biology of Penile Cancer
2.4.8
21
Matrix Metallo-Proteinases (MMP-2, MMP-9)
Matrix metalloprotease MMP-2 and MMP-9 are part of a group of enzymes that degrade type IV collagen in the basal membrane and are involved in the tumor invasion mechanism. High expression of MMP-2 and MMP-9 have been reported in 72% and 26–47% of penile carcinoma cases, respectively.60,64 An increase in immunoreactivity of MMP-9 has been correlated with a greater risk for disease recurrence in penile cancer patients64
2.4.9 Cyclo-Oxygenase-2 (COX) and Prostaglandin E2 Synthase Prostaglandin E2 (PGE2) has been identified as a bioactive compound stimulating cell proliferation, inhibiting apoptosis, modulating angiogenesis, participating in cell-to-cell signaling, and suppressing immune surveillance. The synthesis of PGE2 from arachidonic acid requires two enzymes that act in sequence. Cyclooxygenase (COX) catalyzes the synthesis of PGH2, which is converted, in turn, by microsomal prostaglandin E synthase (mPGES-1) to PGE2. There are two isoforms of COX designated COX-1 and COX-2, respectively. In general, COX-1 is constitutively expressed and COX-2 is only expressed following induction by cytokines, growth factors, oncogenes, and tumor promoters. Elevated levels of COX-2 and mPGES-1 have been detected in a small set of premalignant and malignant tissue of the penis.65 Given the small case series examined in each above-described study, the trustworthiness of findings is relatively low and meaningful conclusions on the prognostic value of the individual biomarkers are difficult to make. It would be useful to explore a potential cumulative role of the individual biomarkers in a combined approach. The role of a combined panel of biomarkers can potentially increase the predictability of disease progression. This combined approach should be evaluated in a well-structured large scale multicentre study.
2.4.10
Squamous Cell Carcinoma Antigen (SCC Antigen)
SCC antigen (TA-4) is a 43 kDa glycoprotein which has been utilized in the diagnosis and management of SCC in various tissues as a result of its release into the serum. A few studies have investigated its role in penile cancer. Wishnow et al.66 studied serum levels of SCC antigen in 23 men with carcinoma of the penis and observed that levels correlated with disease progression and were increased in those patients with metastatic disease. Laniado et al.67 investigated 11 men – seven had histological evidence of nodal disease. The sensitivity of raised serum SCC antigen in detecting nodal disease was 57% and the specificity was 100%. Touloupidis et al.68
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sequentially measured SCC antigen in 16 men with penile cancer. This study once again demonstrated a possible role for SCC antigen in detecting nodal disease and response to treatment. The largest study has been performed by Hungerhuber et al.69 and consisted of 54 patients with penile cancer. SCC antigen levels correlated with tumor burden, increased significantly with extensive lymph node involvement or metastatic disease but did not predict microscopic nodal involvement. Currently, the role of SCC antigen as a prognostic marker is still limited. However, it may be used as an adjunct to sentinel lymph node biopsy in patients placed on surveillance or as a marker for disease response following chemotherapy.
2.5
Future Perspectives
Due to the relative rarity of penile cancer, fine-tuning of the molecular concept of penile carcinogenesis (see Fig. 2.1) is pending. Additional research to further delineate the sequence of molecular events underlying the development and progression of penile cancer and its precursor lesions is necessary to aid preventive, early detection, prognosis prediction and (targeted) therapeutic strategies for this highly mutilating disease. Particularly, the prognostic/therapeutic potential of investigating the expression of metastasis-promoting and metastasis suppressor genes would be interesting. Established metastasis-promoting genes include Ezrin (liver, ovary, prostate), S100A4 (breast, colon/rectum, prostate), and IGF-1 (breast, colon) and known metastasis-suppressor genes are annexin-7 (prostate) and KAI-1 (prostate, breast).However, with the advances in microarray Comparative Genomic Hybridization (maCGH), expression (mRNA/microRNA) array and deep-sequencing techniques, and initiatives to combine worldwide collections of tumors and (putative) precursor lesions within tumor registries and biobanks, it is hoped for that the molecular biology of penile cancer will be better understood within the next decade in order to facilitate improved outcomes for those men who suffer from the disease.
References 1. Hernandez BY, Barnholtz-Sloan J, German RR, et al. Burden of invasive squamous cell carcinoma of the penis in the United States, 1998–2003. Cancer. 2008;113(10 Suppl):2883-2891. 2. Bleeker MCG, Heideman DAM, Snijders PJF, Horenblas S, Dillner J, Meijer CJLM. Penile cancer: epidemiology, pathogenesis and prevention. World J Urol. 2009;27(2):141-150. 3. Miralles-Guri C, Bruni L, Cubilla AL, Castellsagué X, Bosch FX, de Sanjosé S. Human papillomavirus prevalence and type distribution in penile carcinoma. J Clin Pathol. 2009;62(10):870-878. 4. Rubin MA, Kleter B, Zhou M, et al. Detection and typing of human papillomavirus DNA in penile carcinoma: evidence for multiple independent pathways of penile carcinogenesis. Am J Pathol. 2001;159(4):1211-1218.
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5. McCance DJ, Kalache A, Ashdown K, et al. Human papillomavirus types 16 and 18 in carcinomas of the penis from Brazil. Int J Cancer. 1986;37(1):55-59. 6. Heideman DA, Waterboer T, Pawlita M, et al. Human papillomavirus-16 is the predominant type etiologically involved in penile squamous cell carcinoma. J Clin Oncol. 2007;25(29): 4550-4556. 7. Gregoire L, Cubilla AL, Reuter VE, Haas GP, Lancaster WD. Preferential association of human papillomavirus with high-grade histologic variants of penile-invasive squamous cell carcinoma. J Natl Cancer Inst. 1995;87(22):1705-1709. 8. Backes DM, Kurman RJ, Pimenta JM, Smith JS. Systematic review of human papillomavirus prevalence in invasive penile cancer. Cancer Causes Control. 2009;20(4):449-457. 9. Parkin DM, Bray F. Chapter 2: the burden of HPV-related cancers. Vaccine. 2006;24(Suppl 3): S3/11-S3/25. 10. Trottier H, Burchell AN. Epidemiology of mucosal human papillomavirus infection and associated diseases. Public Health Genomics. 2009;12:291-307. 11. Munoz N, Bosch FX, de Sanjose S, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med. 2003;348(6):518-527. 12. zur Hausen H. Papillomaviruses and cancer: from basic studies to clinical application. Nat Rev Cancer. 2002;2(5):342-350. 13. Scheffner M, Romanczuk H, Munger K, Huibregtse JM, Mietz JA, Howley PM. Functions of human papillomavirus proteins. Curr Top Microbiol Immunol. 1994;186:83-99. 14. Snijders PJ, Steenbergen RD, Heideman DA, Meijer CJ. HPV-mediated cervical carcinogenesis: concepts and clinical implications. J Pathol. 2006;208(2):152-164. 15. Ferreux E, Lont AP, Horenblas S, et al. Evidence for at least three alternative mechanisms targeting the p16INK4A/cyclin D/Rb pathway in penile carcinoma, one of which is mediated by high-risk human papillomavirus. J Pathol. 2003;201(1):109-118. 16. Prowse DM, Ktori EN, Chandrasekaran D, Prapa A, Baithun S. Human papillomavirusassociated increase in p16INK4A expression in penile lichen sclerosus and squamous cell carcinoma. Br J Dermatol. 2008;158(2):261-265. 17. Sturgeon SR. In situ and invasive vulvar cancer incidence trends (1973 to 1987). Am J Obstet Gynecol. 1992;166(5):1482-1485. 18. Canavan TP, Cohen D. Vulvar cancer. Am Fam Physician. 2002;66(7):1269-1274. 19. Cubilla AL, Reuter VE, Gregoire L, et al. Basaloid squamous cell carcinoma: a distinctive human papilloma virus- related penile neoplasm: a report of 20 cases. Am J Surg Pathol. 1998;22(6):755-761. 20. Cubilla AL, Velazques EF, Reuter VE, Oliva E, Mihm MC Jr, Young RH. Warty (condylomatous) squamous cell carcinoma of the penis: a report of 11 cases and proposed classification of “verruciform” penile tumors. Am J Surg Pathol. 2000;24(4):505-512. 21. Cubilla AL, Velazquez EF, Young RH. Pseudohyperplastic squamous cell carcinoma of the penis associated with lichen sclerosus. an extremely well-differentiated, nonverruciform neoplasm that preferentially affects the foreskin and is frequently misdiagnosed: a report of 10 cases of a distinctive clinicopathologic entity. Am J Surg Pathol. 2004;28(7):895-900. 22. Lont AP, Kroon BK, Horenblas S, et al. Presence of high-risk human papillomavirus DNA in penile carcinoma predicts favorable outcome in survival. Int J Cancer. 2006;119(5):1078-1081. 23. Kalantari M, Villa LL, Calleja-Macias IE, Bernard H-U. Human papillomavirus-16 and −18 in penile carcinomas: DNA methylation, chromosomal recombination and genomic variation. Int J Cancer. 2008;123:1832-1840. 24. Franceschi S, Castellsague X, Dal Maso L, et al. Prevalence and determinants of human papillomavirus genital infection in men. Br J Cancer. 2002;86(5):705-711. 25. Bleeker MC, Hogewoning CJ, Berkhof J, et al. Concordance of specific human papillomavirus types in sex partners is more prevalent than would be expected by chance and is associated with increased viral loads. Clin Infect Dis. 2005;41(5):612-620. 26. Yanagawa N, Osakabe M, Hayashi M, Tamura G, Motoyama T. Detection of HPV-DNA, p53 alterations, and methylation in penile squamous cell carcinoma in Japanese men. Pathol Int. 2008;58:477-482.
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27. Braakhuis BJ, Snijders PJ, Keune WJ, et al. Genetic patterns in head and neck cancers that contain or lack transcriptionally active human papillomavirus. J Natl Cancer Inst. 2004;96(13):998-1006. 28. Martins AC, Faria SM, Cologna AJ, Suaid HJ, Tucci S Jr. Immunoexpression of p53 protein and proliferating cell nuclear antigen in penile carcinoma. J Urol. 2002;167(1):89-92. 29. Kayes O, Ahmed HU, Arya M, Minhas S. Molecular and genetic pathways in penile cancer. Lancet Oncol. 2007;8(5):420-429. 30. Castren K, Vahakangas K, Heikkinen E, Ranki A. Absence of p53 mutations in benign and pre-malignant male genital lesions with over-expressed p53 protein. Int J Cancer. 1998;77(5):674-678. 31. Muneer A, Kayes O, Ahmed HU, Arya M, Minhas S. Molecular prognostic factors in penile cancer World J Urology 2009;27(2):161-167 32. Pilotti S, Donghi R, D’Amato L, et al. HPV detection and p53 alteration in squamous cell verrucous malignancies of the lower genital tract. Diagn Mol Pathol. 1993;2(4):248-256. 33. Ouban A, Dellis J, Salup R. Immunohistochemical expression of Mdm2 and p53 in penile verrucous carcinoma. Ann Clin Lab Sci. 2003;33:101-106. 34. Bezerra AL, Lopes A, Santiago GH, Ribeiro KC, Latorre MR, Villa LL. Human papillomavirus as a prognostic factor in carcinoma of the penis: analysis of 82 patients treated with amputation and bilateral lymphadenectomy. Cancer. 2001;91(12):2315-2321. 35. Wiener JS, Effert PJ, Humphrey PA, Yu L, Liu ET, Walther PJ. Prevalence of human papillomavirus types 16 and 18 in squamous-cell carcinoma of the penis: a retrospective analysis of primary and metastatic lesions by differential polymerase chain reaction. Int J Cancer. 1992;50(5):694-701. 36. Guerrero D, Guarch R, Ojer A, et al. Hypermethylation of the thrombospondin-1 gene is associated with poor prognosis in penile squamous cell carcinoma. BJU Int. 2008;102(6):747-755. 37. Masih AS, Stoler MH, Farrow GM, Wooldridge TN, Johansson SL. Penile verrucous carcinoma: a clinicopathologic, human papillomavirus typing and flow cytometric analysis. Mod Pathol. 1992;5(1):48-55. 38. Ornellas AA, Mendes Campos M, Ornellas MH, Wisnescky A, Koifman N, Cabral Harab R. [Penile cancer: flow cytometry study of ploidies in 90 patients]. Prog Urol. 2000;10(1): 72-77. 39. Yu DS, Chang SY, Ma CP. DNA ploidy, S-phase fraction and cytomorphometry in relation to survival of human penile cancer. Urol Int. 1992;48(3):265-269. 40. Hoofnagle RF Jr, Kandzari S, Lamm DL. Deoxyribonucleic acid flow cytometry of quamous cell carcinoma of the penis. W V Med J. 1996;92(5):271-273. 41. Xiao S, Feng XL, Shi YH, Liu QZ, Li P. Cytogenetic abnormalities in a squamous cell carcinoma of penis. Cancer Genet Cytogenet. 1992;64:139-141. 42. Ornellas AA, Ornellas MH, Simões F, et al. Cytogenetic analysis of an invasive, poorly differentiated squamous cell carcinoma of the penis. Cancer Genet Cytogenet. 1998;101(1):78-79. 43. Ornellas AA, Ornellas MH, Otero L, et al. Karyotypic findings in two cases of moderately differentiated squamous cell carcinomas of the penis. Cancer Genet Cytogenet. 1999;115(1):77-79. 44. Alves G, Heller A, Fiedler W, et al. Genetic imbalances in 26 cases of penile squamous cell carcinoma. Genes Chromosome Cancer. 2001;31(1):48-53. 45. Leis PF, Stevens KR, Baer SC, Kadmon D, Goldberg LH, Wang XJ. A C-rasHa mutation in the metastasis of a human papillomavirus (HPV)-18 positive penile squamous cell carcinoma suggests a cooperative effect between HPV-18 and C-rasHa activation in malignant progression. Cancer. 1998;83(1):122-129. 46. Andersson P, Kolaric A, Windahl T, Kirrander P, Söderkvist P, Karlsson MG. PIK3CA, HRAS and KRAS gene mutations in human penile cancer. J Urol. 2008;179(5):2030-2034. Epub 2008 Mar 19. 47. Peter M, Rosty C, Couturier J, et al. MYC activation associated with the integration of HPV DNA at the MYC locus in genital tumors. Oncogene. 2006;25:5985-5993. 48. Couturier J, Sastre-Garau X, Schneider-Maunoury S, Labib A, Orth G. Integration of papillomavirus DNA near myc genes in genital carcinomas and its consequences for proto-oncogene expression. J Virol. 1991;65(8):4534-4538.
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49. Sastre-Garau X, Favre M, Couturier J, Orth G. Distinct patterns of alteration of myc genes associated with integration of human papillomavirus type 16 or type 45 DNA in two genital tumours. J Gen Virol. 2000;81(Pt 8):1983-1993. 50. Alves G, Fiedler W, Guenther E, Nascimento P, Campos MM, Ornellas AA. Determination of telomerase activity in squamous cell carcinoma of the penis. Int J Oncol. 2001;18(1):67-70. 51. Ikeda R, Kobayashi Y, Shiroma K, Suzuki K, Ueda Y. Telomerase activity in giant condyloma acuminatum. Urol Int. 2000;65(4):220-223. 52. Yanagawa N, Osakabe M, Hayashi M, Tamura G, Motoyama T. Frequent epigenetic silencing of the FHIT gene in penile squamous cell carcinomas. Virchows Arch. 2008;452(4):377-382. 53. Martins AC, Faria SM, Velludo AJ, et al. Carcinoma of the penis: the value of proliferating cell nuclear antigen (PCNA). Int Braz J Urol. 2000;26:38-42. 54. Guimarães GC, Leal ML, Campos RS, et al. Do proliferating cell nuclear antigen and MIB-1/ Ki-67 have prognostic value in penile squamous cell carcinoma? Urology. 2007;70(1):137-142. 55. Berney DM, Stankiewicz E, Adlan AM, et al. DNA topoisomerase I and IIalpha expression in penile carcinomas: assessing potential tumour chemosensitivity. BJU Int. 2008;102(8): 1040-1044. 56. Gentile V, Sciarra A, Parente U, Cardillo MR, Pierangeli A, Degener AM. Human papilloma virus DNA detection, p53 and Ki67 expression in penile verrucous and squamous cell carcinomas in the same patient. Sex Transm Dis. 2009;36(7):417-418. 57. Gentile V, Vicini P, Giacomelli L, Cardillo MR, Pierangeli A, Degener AM. Detection of human papillomavirus DNA, p53 and ki67 expression in penile carcinomas. Int J Immunopathol Pharmacol. 2006;19(1):209-215. 58. Stankiewicz E, Kudahetti SC, Prowse DM, et al. HPV infection and immunochemical detection of cell-cycle markers in verrucous carcinoma of the penis. Mod Pathol. 2009;22(9): 1160-1168. 59. Faria SM, Martins AC, Velludo, et al. Imunoespressão do Ki-67 no carcinoma do pênis. Acta Cir Bras. 2000;15(suppl 2):31-33. 60. Zhu Y, Zhou XY, Yao XD, Dai B, Ye DW. The prognostic significance of p53, Ki-67, epithelial cadherin and matrix metalloproteinase-9 in penile squamous cell carcinoma treated with surgery. BJU Int. 2007;100(1):204-208. 61. Papadopoulos O, Betsi E, Tsakistou G, et al. Expression of cyclin D1 and Ki-67 in squamous cell carcinoma of the penis. Anticancer Res. 2007;27(4B):2167-2174. 62. Protzel C, Knoedel J, Zimmermann U, Woenckhaus C, Poetsch M, Giebel J. Expression of proliferation marker Ki67 correlates to occurrence of metastasis and prognosis, histological subtypes and HPV DNA detection in penile carcinomas. Histol Histopathol. 2007;22(11):1197-1204. 63. Berdjis N, Meye A, Nippgen J, et al. Expression of Ki-67 in squamous cell carcinoma of the penis. BJU Int. 2005;96(1):146-148. 64. Campos RS, Lopes A, Guimaraes GC, Carvalho AL, Soares FA. E-cadherin, MMP-2, and MMP-9 as Prognostic markers in penile cancer: analysis of 125 patients. Urology. 2006;67(4):797-802. 65. Golijanin D, Tan JY, Kazior A, et al. Cyclooxygenase-2 and microsomal prostaglandin E synthase-1 are overexpressed in squamous cell carcinoma of the penis. Clin Cancer Res. 2004;10(3):1024-1031. 66. Wishnow KI, Johnson DE, Fritsche H. Squamous cell carcinoma antigen (TA-4) in penile carcinoma. Urology. 1990;36(4):315-317. 67. Laniado ME, Lowdell C, Mitchell H, Christmas TJ. Squamous cell carcinoma antigen: a role in the early identification of nodal metastases in men with squamous cell carcinoma of the penis. BJU Int. 2003;92(3):248-250. 68. Touloupidis S, Zisimopoulos A, Giannakopoulos S, Papatsoris AG, Kalaitzis C, Thanos A. Clinical usage of the squamous cell carcinoma antigen in patients with penile cancer. Int J Urol. 2007;14(2):174-176. 69. Hungerhuber E, Schlenker B, Schneede P, Stief CG, Karl A. Squamous cell carcinoma antigen correlates with tumor burden but lacks prognostic potential for occult lymph node metastases in penile cancer. Urology. 2007;70(5):975-979.
Chapter 3
Diagnosis and Pathology of Penile Cancer Alcides Chaux and Antonio L. Cubilla
3.1
Penile Anatomy for the Surgical Pathologist
The penis can be divided into three segments: the root, the shaft, and a distal portion encompassing the glans, coronal (balanopreputial) sulcus, and foreskin1 (Fig. 3.1). The penile root anchors the erectile tissues of the shaft to the pubic arc and perineal membrane. The shaft is composed mainly of three columns of erectile tissue, two dorsally located corpora cavernosa and one ventrally located corpus spongiosum. The distal penis is the most important part from the point of view of surgical pathology because it is the site of origin of the majority of penile tumors.2,3
3.1.1
Gross Features
The glans is the most distal cone-shaped portion of the penis and is covered by a soft rubbery mucosal membrane devoid of adnexal structures extending through the coronal sulcus and inner foreskin. It contains the glans corona, frenulum, and meatus urethralis. The corona corresponds to the most proximal and widest portion of the glans. The frenulum is an infolding of the inner foreskin inserted at the level of the meatus urethralis. The meatus urethralis is a ventrally located slit-like orifice near the tip of the glans which receives the distal (penile) urethra. From a cut surface through the glans the following anatomical levels are discernable from surface to deep tissues: (1) a squamous mucosa; (2) corpus spongiosum, forming most of the glans volume; and (3) corpus cavernosum, surrounded by the tunica albuginea. The foreskin is a mucocutaneous infolding which covers the glans and presents an inner
A. Chaux (*) Department of Pathology, Instituto de Patologia e Investigacion, Asuncion, Paraguay A. Muneer et al. (eds.), Textbook of Penile Cancer, DOI 10.1007/978-1-84882-879-7_3, © Springer-Verlag London Limited 2012
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A. Chaux and A.L. Cubilla
Scarpa’s fascia
Suspensory ligament
Corpus cavemosum
Superficial fascia of penis
Buck’s fascia (deep fascia of penis) Bulbospongiosus muscle
Corpus spongiosum
Fig. 3.1 Anatomy of penis
mucosal surface that reflects over itself to continue in the outer surface as the preputial skin. The zone of reflection forms the preputial orifice. At cut surface the foreskin presents the following anatomical levels from surface to deep tissues: 1. A squamous mucosa 2. Bundles of the dartos muscle extending from the homologous layer in the shaft 3. Preputial skin The coronal sulcus is a cul-de-sac located between the glans corona and the inner foreskin. From surface to deep tissues the following anatomical layers are recognized: 1. A squamous mucosa 2. Bundles of dartos muscle, reflecting from fibers passing from the shaft to the foreskin 3. Buck’s fascia The penile shaft is covered by skin, similar to that found elsewhere. A transverse section through the middle of the shaft will disclose the following anatomical levels (Fig. 3.2): 1. Skin of the shaft 2. Bundles of dartos muscle 3. Buck’s fascia
3 Diagnosis and Pathology of Penile Cancer Dorsal nerve of penis
29 Deep dorsal vein Dorsal artery
Tunica albuginea
Corpus cavernosum
Buck’s fascia Dartos muscle
Corpus spongiosum Penile skin
Fig. 3.2 Transverse section of the penile shaft
4. Two dorsally located corpora cavernosa enclosed in a tunica albuginea and separated by a median septum 5. A ventrally located corpus spongiosum with the penile urethra. The penile urethra enters the corpus spongiosum in the penile root and runs throughout its entire length. Proximal to the meatus urethralis it expands to form the fossa navicularis. Surrounding the penile urethra there is a connective tissue merging imperceptibly to the corpus spongiosum.
3.1.2
Microscopic Features
In uncircumcised men the mucosa covering the glans, coronal sulcus, and inner foreskin is formed by a nonkeratinizing stratified squamous epithelium of about 5–7 cells thick (Fig. 3.3a). No sweat glands or other adnexal structures are observed. Underlying it there is a lamina propria composed of connective tissue, about 2–3 mm thick. The glans is composed mainly of corpus spongiosum but the rounded endings of corpora cavernosa frequently protrudes into its deepest region. Both corpus spongiosum and cavernosum are specialized types of erectile tissues formed by anastomosizing venous-like vascular channels immersed in a fibroelastic stroma. However, vascular spaces in the corpus spongiosum are more ample, irregular and spaced
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a
b
c
d
Fig. 3.3 Penile histology. (a) A nonkeratinized squamous epithelium and underlying lamina propria. (b) Corpus spongiosum with ample vascular spaces immersed in a fibroelastic stroma. (c) Corpus cavernosum with densely packed vascular spaces, irregular lumina, and denser stroma. (d) Most of the distal urethra is covered by a stratified columnar epithelium with intermingled mucin-producing cells. Note openings of Littré glands in the lower half field
from each other while in the corpora cavernosa they are more compacted, vascular lumina are more compressed, and stroma is denser (Fig. 3.3b, c). In the foreskin, beneath the lamina propria, bundles of the dartos muscle, extending from the homologous layer in the shaft, are easily discernable (Fig. 3.4a). The outer surface of the foreskin is formed by a prolongation of the skin of the shaft and shows similar histological features. The preputial dermis and the mucosal lamina propria are very similar in its microscopic aspect and differences between them are best noted examining the covering epithelium. Rete ridges of the epidermis are more irregular, keratinocytes are more or less pigmented, a thin stratum corneum is observed and adnexal structures are usually found (Fig. 3.4b). In the squamous epithelium of the inner foreskin the basement is almost flat and no pigmentation, stratum corneum, or adnexal structures are normally detected (see Fig. 3.3a). The penile shaft is covered by the same type of skin found elsewhere, a keratinizing stratified squamous epithelium with sweat glands and pilosebaceous units. The dartos layer underneath is composed of interlacing bundles of smooth muscle separated by loose connective tissue. The Buck’s fascia, extending from the root
3 Diagnosis and Pathology of Penile Cancer
a
31
b
Fig. 3.4 Penile histology. (a) Bundles of smooth muscle fibers typical of the dartos layer in foreskin, coronal sulcus, and shaft. (b) The foreskin outer surface is a keratinizing squamous epithelium with irregular rete ridges, pigmented keratinocytes, and pilosebaceous units
to the coronal sulcus and located beneath the dartos layer, is composed of loose connective tissue with abundant vessels and nerves. Deeper lies the tunica albuginea surrounding both corpora cavernosa. It is composed of dense hypocellular connective tissue that encases them throughout their entire length. The median septum separating the corpora cavernosa depicts similar features. Ventrally located in the angle formed by both corpora cavernosa is the column of corpus spongiosum which contains the distal (penile) urethra running throughout its entire length from the root to the meatus urethralis. The epithelium of the distal urethra is urothelial only in its most proximal section and from here it changes to a stratified columnar epithelium with interspersed goblet-like cells (Fig. 3.3d). It maintains this morphology up to the fossa navicularis where it changes to the typical epithelium that covers the glans. Underneath the epithelium of the distal urethra there is a lamina propria of loose connective tissue which imperceptibly merges with the surrounding erectile tissue of the corpus spongiosum. Mucin-secreting glands, named Littré glands, are found in the periurethral area and empty their secretion into the urethral lumen (see Fig. 3.3d).
3.1.3
Vascularization, Lymphatic Drainage, and Nerve Supply of the Penis
The vascular supply of penile erectile tissues is provided by paired branches of the internal pudendal artery, either by the perineal artery (which supplies corpus spongiosum) or the cavernosal artery (which supplies corpora cavernosa). The dorsal artery of the penis, another terminal branch of the internal pudendal artery, supplies the skin, Buck’s fascia, tunica albuginea and corpus spongiosum and is located deep to Buck’s fascia. The arteries give off circumflex branches to the corpus spongiosum
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and corpora cavernosa. Branches of the external pudendal arteries which are branches of the proximal femoral arteries also supply the penile skin. The venous drainage is provided by the dorsal veins of the penis. The superficial dorsal vein, which runs across the dermis of the penile shaft, drains the skin and foreskin. It empties into one of the external pudendal veins. The deep dorsal vein, which may be single or multiple, is located in Buck’s fascia and drains the corpora cavernosa, glans, and corpus spongiosum via circumflex veins, before entering the internal pudendal veins and ultimately the prostatic and pelvic venous plexus. The cavernous veins travel along the dorsum of the urethral bulb under the crus of the penis to drain into the internal pudendal system. The crural veins arise from the dorsolateral surface of the penis and drain into the internal pudendal veins. This pattern of venous vascularization is important since it explains why the majority of penile secondary tumors originate in the prostate, bladder, and rectum and the preferential involvement of corpora cavernosa by metastatic disease.4 Lymphatics from the penis drain directly into the inguinal lymph nodes. A superficial system drains the skin and a deeper lymphatic system drains the corpora and the glans penis. The sentinel node (or nodes) is expected to be found at the inner superior quadrant of the inguinal region. This sentinel node is the purported first lymph node affected by metastatic disease.5 Inguinal lymph nodes then drain into pelvic nodes. Drainage of penile lymphatics directly into pelvic nodes is an exceedingly rare phenomenon. Very infrequently there is a prepubic lymph node.6 Pelvic (iliac) nodes drain into paraaortic lymph nodes and from thereon into other systemic lymph nodes. The pattern of lymphatic drainage explains the sequence of sentinel node – inguinal nodes – pelvic nodes that is followed during regional and systemic spread.7 Identification and evaluation of sentinel lymph nodes status in penile cancer patients with clinically nonpalpable lymph nodes (cN0), a procedure which nowadays is performed using radioisotopes, permits the more rational implementation of radical groin dissections.8 The pudendal nerve (S2-4) is the major somatic and sensory nerve supply to the penis. After emerging through Alcock’s canal, the pudendal nerve gives off a dorsal branch which runs along as the dorsal nerve of the penis. The nerve is deep to Buck’s fascia and lateral to the dorsal arteries. The pudendal nerve then divides into the inferior rectal and perineal branches. The perineal nerve supplies motor function to the bulbospongiosus muscle and innervates the corpus spongiosum. The cavernous nerves course along with the cavernous artery and vein along the prostatic capsule as part of the prostatic neurovascular bundle.
3.2
Histological Classification of Penile Malignant Tumors
Most tumors affecting the penis are primary carcinomas arising in the epithelium lining glans, coronal sulcus, and inner foreskin.2 Glans tumors represent about 80% of all cases, followed by those exclusive to the foreskin (15%) and coronal sulcus (5%).1,2 Tumors originating in the skin of the shaft are exceedingly uncommon. In almost one-half of all cases, especially in geographical areas of high incidence, tumors extend through multiple anatomical compartments and determination of the
3 Diagnosis and Pathology of Penile Cancer
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Table 3.1 Pathological classification of penile malignant tumors Squamous cell carcinoma Squamous cell carcinoma, usual type Warty (condylomatous) carcinoma Verrucous carcinoma Papillary, not otherwise specified (NOS) carcinoma Basaloid carcinoma Sarcomatoid carcinoma Adenosquamous carcinoma Pseudoglandular (acantholytic, adenoid) carcinoma Carcinoma cuniculatum Pseudohyperplastic carcinoma Mixed carcinoma Other malignant epithelial tumors Clear cell carcinoma Extramammary Paget’s disease Malignant melanoma Nonepithelial malignant tumors Soft-tissue sarcomas (Kaposi’s sarcoma, leiomyosarcoma, others) Malignant lymphoma Secondary tumors
primary site of origin is not possible.2,9 The vast majority of tumors are squamous cell carcinomas (SCC) although a variegated spectrum of histological subtypes, each one with distinctive clinicopathological features, is observed.2,9,10 Other rare subtypes of penile primary tumors include clear cell carcinoma, basal cell carcinoma, and Paget’s disease. Malignant melanocytic lesions and sarcomas can also be observed in the penis and affect the glans or shaft. Finally, the penis can also be involved by metastatic disease, mainly from tumors originating in the genitourinary and lower digestive tract. A selected list of penile malignant tumors is provided in Table 3.1. About 50–65% of all penile SCC correspond to the usual (classic, typical) subtype.2,9-11 This variant is characterized by infiltrative tumor nests of polygonal neoplastic cells with distinctive cell borders, ample and eosinophilic cytoplasm, and tendency to squamous maturation and keratin pearl formation (Fig. 3.5a). Nuclear atypia can range from subtle to clearly anaplastic, but most tumors are composed of neoplastic cells with moderate pleomorphism (Fig. 3.5b). Usual SCCs composed entirely of well-differentiated or poorly differentiated neoplasic cells are very uncommon and their presence should raise suspicion about the correct classification. Verruciform carcinomas, representing 19–28% of all penile tumors,9-11 form a distinctive group of penile cancers characterized by an exophytic papillomatous pattern of growth. They are low-grade neoplasms which can sometimes invade deep anatomical levels but are associated with a low metastatic rate and a better prognosis when compared with usual SCC. This group encompasses warty, verrucous, and papillary carcinomas. A recently described SCC variant, the carcinoma cuniculatum, and a rare HPV-related tumor, the giant condyloma or Buschke-Löwenstein tumor, also belong to this category.12 Morphological features and clues to differential diagnosis will be covered in more detail in the following sections.
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b
Fig. 3.5 Squamous cell carcinoma, usual type. (a) Well-differentiated (grade 1) usual SCC. Tumor nests exhibit minimal cytological atypia, mostly limited to basal/parabasal layers, with ample eosinophilic cytoplasm, distinctive cellular borders, and keratin pearl formation. (b) Moderately differentiated (grade 2) usual SCC with more evident nuclear atypias. Neoplastic cells retain the morphological features of squamous differentiation, although to a lesser degree
Basaloid and sarcomatoid carcinomas correspond to the most aggressive variants of all penile SCC. Basaloid carcinoma, which represents 4–10% of all penile carcinomas, is characterized by highly infiltrative neoplastic nests.9-11,13 Sarcomatoid carcinoma, which accounts for 1–3% of all penile SCC, is also a deeply infiltrative neoplasm which is often associated with necrosis and hemorrhage.9-11,14,15 Most of the tumor is composed of anaplastic spindle cells resembling those of different sarcoma variants. Tumors composed of an admixture of different subtypes of SCC represent up to one-quarter of all penile carcinomas.9,11 The most frequent combination corresponds to tumors in which warty and basaloid components are intermingled, followed by usual carcinomas mixed with other keratinizing SCC variants, especially a combination of verrucous and usual SCCs. Combinations of usual with either warty or basaloid carcinomas are less frequent. In rare occasions adenobasaloid, mucoepidermoid, or some other polymorphic carcinomas are observed. Some rare variants of penile SCC include adenosquamous, pseudohyperplastic, and pseudoglandular carcinomas.16-18 Several other types of epithelial malignant tumors, such as clear cell carcinomas, basal cell carcinomas, extramammary Paget’s disease, and malignant melanomas have been reported but they are uncommon.2,19-23 Penile sarcomas correspond mainly to tumors of vascular and muscular origin.24-28 Malignant lymphomas can also involve the penis, either primary or secondarily.29 Other malignant tumors have been reported affecting primarily the penis but are extremely unusual to warrant detailed descriptions.30-34
3.3
Precancerous and Associated Lesions
Penile precancerous lesions encompass a morphological spectrum of epithelial lesions ranging from extremely well-differentiated precursors, almost indistinguishable from reactive processes, to lesions with the typical aspect of a carcinoma in
3 Diagnosis and Pathology of Penile Cancer
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situ. Nomenclature for these precancerous lesions has been inconsistent and nonstandardized and terms such as Bowen’s disease, erythroplasia of Queyrat, penile squamous intraepithelial lesion (low and high grade), dysplasia (mild, moderate, and severe), and carcinoma in situ, have been in use for several years.35,36 Recently, we had proposed a novel classification system, based on cell morphology, squamous differentiation, and pathogenesis.37 Penile intraepithelial neoplasia (PeIN), according to this view, is classified into differentiated (squamous, simplex) and warty, basaloid, and mixed warty-basaloid subtypes. Differentiated PeIN is the most common subtype, frequently associated with lichen sclerosus and usually not associated with HPV. On the contrary, warty and/or basaloid PeIN, less common lesions, are usually p16INK4a positive and most likely related to HPV.37
3.3.1
Penile Intraepithelial Neoplasia
Penile intraepithelial neoplasia is classified into four categories depending on the degree and type of cell differentiation: differentiated (“simplex”), basaloid, warty, and warty-basaloid. Regardless of its histological aspect PeIN clinically presents as whitish irregular areas, sometimes with a pearly aspect, either as an isolated lesion or in continuity or adjacent to an invasive tumor. Occasionally, foci of PeIN are found as multicentric lesions, separated from the main invasive component. Differentiated PeIN is characterized by acanthosis, parakeratosis, and atypical epithelial cells with retained tendency to squamous maturation. In its classical form nuclear atypia, consisting of nuclear pleomorphism, hyperchromasia, irregular nuclear membrane, coarse chromatin, and evident nucleolus, is more prominent at the bottom layers (Fig. 3.6a). At both ends of the spectrum there are minimally atypical differentiated PeIN, which can be difficult to differentiate from squamous hyperplasia, and pleomorphic differentiated PeIN, which can be confused with basaloid or warty PeIN. In minimally atypical differentiated PeIN there are p53/ Ki-67 positive cells above the basal layer. In pleomorphic PeIN the most distinguishing feature is the presence of ample and eosinophilic (keratinized) cytoplasm and a greater degree of nuclear pleomorphism, features contrasting to those found in basaloid PeIN (see below). In addition, koilocytes are absent in differentiated PeIN and are conspicuous in warty PeIN. In basaloid PeIN the entire epithelium is replaced by a monotonous population of small to intermediate-sized cells with scant basophilic cytoplasm, indistinctive cell borders, abundant apoptosis, and high mitotic rates (Fig. 3.6b). Occasionally there are larger basophilic and/or spindle cells. The surface and base are usually flat and a parakeratotic layer may be present. In warty PeIN, epithelial cells are more pleomorphic, cytoplasm is ampler, and koilocytes are easily found, mainly in the superficial layers (Fig. 3.6c). Caution should be taken to not confuse epithelial clear cells with koilocytic changes. Neoplastic cells with clear and ample cytoplasm can be observed in differentiated PeIN, especially in the uppermost layers. Koilocytes should exhibit wrinkled and hyperchromatic nuclei with a well-defined perinuclear halo. Binucleation and even multinucleation are common findings and pleomorphic
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a
b
c
d
Fig. 3.6 Precancerous lesions. (a) Differentiated PeIN showing atypical cells distributed throughout the entire epithelium (although more prominent at bottom layers), suprabasal acantholysis, retained squamous maturation, and parakeratosis. (b) In basaloid PeIN the epithelium is replaced by a monotonous proliferation of small to intermediate-sized cells with scant cytoplasm, indistinctive cellular borders, and high mitotic/apoptotic rate. (c) Warty PeIN is characterized by a spiky parakeratotic surface and conspicuous koilocytosis, more evident at upper layers. (d) Lichen sclerosus, recognized by the dense subepithelial collagenization in the lower left field, associated with differentiated PeIN (“atypical lichen sclerosus”)
koilocytes, in which the nuclear pleomorphism is greater, can also be observed. In warty PeIN the surface is spiky and parakeratosis is invariably found. The presence of a more pleomorphic cell population, koilocytes, and a spiky surface allows the distinction from basaloid PeIN. Finally, in warty-basaloid PeIN both aforementioned patterns coexist, usually with the basaloid component at the bottom layers and the warty areas at the surface. In rare occasions a mixed differentiated and warty/basaloid pattern is observed in the same specimen but usually separated one from another as multicentric lesions. Over expression of p16INK4a can help in distinguishing differentiated PeIN from in situ lesions depicting warty and/or basaloid features.37 The former is usually negative while the latter tends to be positive, especially with basaloid and wartybasaloid PeIN. There is a striking correspondence between the type of PeIN and the subtype of associated SCC.37 Differentiated PeIN tends to be found in association with keratinizing variants of penile SCC such as usual, papillary, and verrucous
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carcinomas while warty and/or basaloid PeIN are commonly found in tumors with similar invasive morphology. Mixed tumors also tend to present PeIN with mixed features.
3.3.2
Lichen Sclerosus
Histologically, lichen sclerosus is characterized by a dense subepithelial collagenization with an underlying band-like chronic inflammatory infiltrate.38 The epithelium above these changes can be atrophic, hyperplastic, or even show atypical changes (Fig. 3.6d). When atypical changes are observed in the upper lying epithelium the in situ lesion usually shows a differentiated PeIN morphology.37 The association of lichen sclerosus with warty and/or basaloid PeIN is exceedingly rare. Although there is controversy about the true preneoplastic nature of lichen sclerosus, a wealth of data suggests a precancerous role.38-45 In addition, given its association with specific subtypes of penile SCC in which the HPV detection rate is very low or even nil46,47 and the rarity of its presence in HPV-related tumors, such as warty and/or basaloid carcinomas,46-48 it is likely that lichen sclerosus, as well as differentiated PeIN, participates in a non-HPV pathogenic pathway.
3.4
3.4.1
Problematic Diagnostic Areas in the Surgical Pathology of Penile Carcinomas Determination of Malignancy in Hyperplasias and Extremely Low-Grade Neoplasms
Squamous hyperplasias are very common penile lesions that often accompany diverse benign and malignant conditions, sometimes simulating neoplastic processes.35,36 Their morphological aspect is variegated and the surgical pathologist should be aware of their proteiform presentation and learn to separate them from significant neoplastic conditions. Squamous hyperplasias commonly are flat on the surface and on the interface between lesion and stroma, but other variants such as verrucous, papillary, and pseudoepitheliomatous may be found. In general, flat hyperplasia should be distinguished from differentiated PeIN, verrucous hyperplasia from verrucous carcinoma, papillary hyperplasia from papillary NOS carcinoma and pseudoepitheliomatous hyperplasia from pseudohyperplastic carcinomas. In flat hyperplasia there is hyperkeratosis and hypergranulosis, orderly maturation, and absence of cell atypia (Fig. 3.7a). In differentiated PeIN, a closely related lesion, the surface is frequently parakeratotic, there is subtle alteration of the cell maturation process and presence of basal cell atypia, which may be minimal (see Fig. 3.6a). In cases, especially those associated with lichen sclerosus, it may not be possible to
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Fig. 3.7 (a) Squamous hyperplasia. There is an acanthotic epithelium, hyperkeratosis, and hypergranulosis but without cytological atypia. (b) Pseudohyperplastic carcinoma can be confused with pseudoepitheliomatous hyperplasia but nests are more irregular and surrounded by an evident stromal reaction, invasion beyond lamina propria is commonly observed, and there is cytological atypia, although minimal
distinguish squamous hyperplasias from differentiated PeIN and immunohistochemistry for p53 and Ki-67 may be helpful, as mentioned above. There are no isolated morphological features to separate verrucous hyperplasia from verrucous carcinoma other than the focality, small size, and often subclinical presentation of verrucous hyperplasias. Morphologically both lesions may be identical and verrucous hyperplasia may indeed represent an early stage of verrucous carcinomas at smaller size. The extreme degree of differentiation characterizes all verrucous hyperplasias and most verrucous carcinomas and atypias can be very subtle in the latter. Clinical background can be helpful in these cases. In papillary hyperplasia the low-power view of the lesion may simulate a papillary carcinoma. However, in the former the papillae lack the complex architecture usually found in the latter. Also, atypical changes are absent in papillary hyperplasia while in papillary carcinomas neoplastic cells show mild to moderate atypia. Finally, papillary hyperplasias tend to remain confined to the lamina propria while most papillary carcinomas invade penile erectile tissues and are associated with a prominent stromal reaction. Among the most challenging diagnostic problems in the surgical pathology of penile cancer is the distinction of pseudoepitheliomatous hyperplasia from pseudohyperplastic carcinomas. On limited biopsy materials these lesions mimic each other and often a wide resection or even circumcision or penectomy specimens are required for correct pathological diagnosis. Deep invaginations of hyperplastic tongues or finger-like prolongations of benign tissues resemble cancer on tangential cuts. Extreme differentiation of invasive pseudohyperplastic carcinomas simulates benign non-neoplastic invaginations.17 Epithelial nests are regular and peripheral palisading is a constant feature in pseudoepitheliomatous hyperplasia while in pseudohyperplastic carcinomas epithelial nests are more irregular and peripheral palisading is inconspicuous (Fig. 3.7b). A diagnostic clue in the foreskin, where most of pseudohyperplastic carcinomas occur, is depth of invasion. Hyperplasias
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Table 3.2 Differential diagnosis in penile verruciform tumors Warty carcinoma Papillae
Long and spiky, prominent parakeratosis
Fibrovascular Conspicuous cores Tumor base Irregular and jagged Histological Low-grade grade heterogeneousa Koilocytosis Conspicuous, at surface and deep nests Metastatic Low rate
Papillary carcinoma, Verrucous NOS carcinoma Variegated morphology, slight to moderate hyperkeratosis Irregular and variable Irregular and jagged Low-grade heterogeneousa
Carcinoma cuniculatum
Straight, Straight, prominent prominent hyperkeratosis hyperkeratosis
Absent
Very rare or Very rare or absent absent Broad and Broad and pushing pushing Low-grade Low-grade homogeneous homogeneous Absent Absent
Low
Nil
Nil
Giant condylomas Arborizing, rounded, slight hyperkeratosis Conspicuous Broad and pushing Not applicable
Conspicuous, mostly at surface Not applicable
a
Areas of high-grade in a minority of cases
are more superficial than cancers and do not affect preputial dartos which is usually invaded by pseudohyperplastic carcinomas. Unlike hyperplasias, invasive carcinoma nests are surrounded by reactive stroma. Intraepithelial squamous pearl formation is more typical of carcinoma and rarely found in hyperplasias. Perineural invasion does not occur in hyperplasia and is occasionally found, although in rare cases, in well-differentiated carcinomas. Several biopsies are sometimes required for a correct classification of hyperplasias or extremely differentiated non-invasive or invasive carcinomas.
3.4.2
Differential Diagnosis of Verruciform Tumors
The term “verruciform tumors” refers to all penile tumors presenting a predominantly exophytic pattern of growth. As a group, verruciform tumors are characterized by a well-differentiated morphology, low metastatic rate, and better survival compared with the usual SCC variant. Verruciform tumors include warty, papillary, and verrucous carcinoma. Rare tumors, such as carcinoma cuniculatum and giant condyloma (Bushke-Löwenstein tumor) also belong to this category. The hallmark of all these is the presence of papillomatosis. Differences among subtypes are established evaluating the architecture of papillae, extension of fibrovascular cores, morphology of tumor base, degree of differentiation, and presence of koilocytic changes (Table 3.2). Additional immunohistochemical and molecular techniques may help in difficult cases.
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Fig. 3.8 Warty (condylomatous) carcinoma. (a) Papillae harboring conspicuous fibrovascular cores. There are nuclear atypias, koilocytosis, and parakeratosis. (b) Tumor front is jagged and irregular and stromal reaction is evident. Note koilocytotic changes in superficial papillae as well as in deeper tumor nests
Warty carcinomas represent 7–10% of all penile cancers and 34–35% of all verruciform tumors and are characterized by papillae with prominent fibrovascular cores, a spiky surface with evident parakeratosis, and conspicuous koilocytosis (Fig. 3.8a).9,10,49 Tumor base is irregular and jagged and stromal reaction is common (Fig. 3.8b). The presence of koilocytes is not limited to papillae and they are also easily found in infiltrative tumor nests. Warty carcinoma frequently invades penile erectile tissues, either corpus spongiosum or cavernosum. Tumors limited to the lamina propria are uncommon. Most tumors are moderately differentiated (grade 2) although areas of highgrade can be found in up to one-quarter of the cases. Inguinal nodal metastases are present in about one-third of all patients but the mortality rate is low, ranging from 0% to 9%. Papillary, not otherwise specified (NOS) carcinomas account for 5–15% of all penile carcinomas and 27–53% of all verruciform tumors and are similar to warty carcinomas except that papillae are architecturally more complex with round, spiky, or blunt tips (Fig. 3.9a).9,10,50 Parakeratosis is a common finding but is not as prominent as in warty carcinomas. Acanthosis ranges from mild to moderate and koilocytes are absent. Fibrovascular cores are irregular and their presence is not constant in most of the papillae. Tumors are usually low-grade but in rare occasions areas of poorly differentiated cells can be found. As in warty carcinomas, these foci of anaplastic cells do not predominate, representing only about 5% of the tumor mass. Tumor base is jagged and irregular, stromal reaction ranges from moderate to intense, and invasive tumor nests usually retain the same degree of differentiation of papillae (Fig. 3.9b). Verrucous carcinoma, which represents 3–8% of all penile SCC and 12–38% of all verruciform tumors, is quite different compared to the aforementioned tumors. Papillae are characterized by marked acanthosis, fibrovascular cores are very inconspicuous or absent, and intraepithelial keratin plugs are frequently found (Fig. 3.10a).9,10 Koilocytes are absent and parakeratosis ranges from mild to prominent. Tumor base is broad and pushing and stromal reaction is moderate to severe (Fig. 3.10b). Occasionally finger-like invaginations from the main mass are observed
3 Diagnosis and Pathology of Penile Cancer
a
41
b
Fig. 3.9 Papillary, NOS carcinoma. (a) Papillae show irregular fibrovascular cores, with moderate acanthosis and parakeratosis. Koilocytotic changes are absent. (b) Tumor base is irregular and jagged and stromal reaction is intense. Neoplastic cells retain the morphological features of those located in papillae
a
b
Fig. 3.10 Verrucous carcinoma. (a) Broadly based highly differentiated acanthotic tumor with a sharp delimitation of tumor and stroma. There is minimal basal atypia. (b) Tumor base is broad and pushing with well-defined boundaries. Stromal reaction is readily evident
but the interface between the tumor base and stroma is regular and remains welldefined. In verrucous carcinoma neoplastic cells are extremely well-differentiated whilst warty and papillary carcinomas range from well to moderately differentiated, with a minority of the cases in the poorly differentiated category. Verrucous carcinomas usually invade up to the lamina propria or corpus spongiosum and extension beyond these areas is infrequent while warty and papillary tend to infiltrate deeper into penile tissues and with an irregular tumor front. Verrucous carcinoma should be distinguished not only from other verruciform tumors but also from other variants with verrucous features such as mixed usual-verrucous (hybrid) carcinoma.9 In hybrid verrucous carcinoma typical areas of verrucous carcinoma coexist with foci of an otherwise usual low or high-grade SCC (Fig. 3.11).9,11 Distinction is clinically important since pure verrucous carcinomas and verrucous carcinomas with minimal
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Fig. 3.11 Mixed usual-verrucous (hybrid) SCC. Tumor nests of well-differentiated neoplastic cells corresponding to a verrucous carcinoma are observed in the right field intermingled with a high-grade usual SCC in the left and lower field. Stromal reaction is intense
a
b
Fig. 3.12 Rare verruciform tumors. (a) Carcinoma cuniculatum. Well-differentiated tumor nests forming cysts (left field) and sinus-like (right field) structures. (b) Giant condyloma with fibrovascular cores and conspicuous koilocytosis but no evident cytological atypias. Tumor growth shows a broad and pushing front
(<2 mm) stromal invasion (microinvasive verrucous carcinomas) are not associated with nodal metastasis and prognosis is excellent, despite the large size these tumors can reach.9 However, in hybrid verrucous carcinoma metastatic and recurrence rates are higher and prognosis approaches that of a usual SCC.51-53 Generous sampling is advised in order to rule out the presence of usual SCC foci. Although rare, carcinoma cuniculatum and giant condyloma should also be considered in the differential diagnosis of verruciform tumors. Carcinoma cuniculatum is similar to a verrucous carcinoma at the surface but is characterized by extensive infiltration of deep erectile tissues, usually up to the corpora cavernosa, with the formation of sinusand cyst-like tracts (Fig. 3.12a).12 Fistulization to foreskin or the penile shaft is not unusual. Neoplastic cells are extremely well differentiated and retain this morphology throughout the tumor, even in the deepest infiltrative nests. Despite the deep erectile tissue invasion the prognosis is excellent and similar to a pure verrucous carcinoma. Giant condyloma is characterized by papillomatosis, acanthosis, prominent fibrovascular cores and a broad and pushing tumor base (Fig. 3.12b). Koilocytes are
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easily found but nuclear atypia is minimal and limited to the basal layers. Deep penetration can be observed but morphology remains bland. The presence of a regular tumor front of invasion and lack of nuclear atypia permits the distinction between giant condyloma and warty carcinoma. Prominent fibrovascular cores and conspicuous koilocytosis aid in the differential diagnosis with verrucous carcinoma. Finally, as stated above, in papillary carcinomas the tumor base is jagged and irregular and koilocytes are absent. Malignant change in a giant condyloma is not a rare event and should be ruled out. In most cases malignant foci correspond to usual SCC and should be evaluated using the same approach for conventional penile carcinomas. Generous sampling is imperative for proper evaluation of this and other verruciform tumors. Some verruciform tumors are complex, showing more than one histological pattern and are difficult to classify. In this context, identification and genotyping of HPV can be helpful.46-48,54 Verrucous and papillary carcinomas are usually negative for HPV while in warty carcinomas and giant condylomas HPV is found in the majority of cases. High-risk HPV, mainly genotypes 16 and 18, are found in the former while in the latter low-risk genotypes, mainly HPV-6 and HPV-11, predominate. Patterns of p16INK4a expression can also be useful. Warty carcinomas tend to be p16INK4a positive while giant condylomas and papillary and verrucous carcinomas are consistently negative. Notwithstanding this, there will be some rare cases in which the distinction between a papillary, warty, or verrucous carcinoma will not be possible on morphological or molecular grounds, especially in limited biopsies and small lesions. In these cases the diagnosis of “verruciform tumor, not otherwise specified” would be appropriate. Histological grading is particularly useful in these situations since it seems that it has a greater impact on prognosis than tumor depth or thickness.55,56
3.4.3
Subtyping in Poorly Differentiated Tumors
High-grade penile tumors include basaloid, sarcomatoid, and high-grade usual SCC, each of them presenting distinctive morphological features. Clinically, these tumors are characterized by an aggressive course, with high recurrence and metastatic rates and dismal prognosis.9,10,53 Grossly, basaloid carcinomas tend to present a vertical pattern of growth with an ulcerated surface and have a glans predilection.10,13 Invasion of deep erectile tissues is the rule although some rare superficial cases have been reported.56 Histologically, basaloid carcinoma is characterized by the presence of deeply infiltrative tumor nests composed of a monotonous population of smallto-intermediate-sized cells with basophilic cytoplasm, high nuclear/cytoplasmic ratio, inconspicuous nucleoli, indistinctive boundaries, lack of intercellular bridges, high mitotic rate, and abundant apoptosis, all hallmarks of basaloid differentiation (Fig. 3.13). Nests are usually regular and a surrounding clear space artifact is frequently seen. The presence of abrupt parakeratosis and necrotic debris located in the center of tumor nests is a constant feature. In some occasions a more variegated
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Fig. 3.13 Basaloid carcinoma. Deeply infiltrative tumor nests composed of neoplastic cells with scant and basophilic cytoplasm, indistinctive cellular borders, and high mitotic rate. Areas of central necrosis (left field) and abrupt parakeratosis (right field) in tumor nests are characteristic
a
b
Fig. 3.14 Sarcomatoid carcinoma. (a) Malignant proliferation of spindle cells, with morphological features resembling leiomyosarcoma or fibrosarcoma. (b) Prominent pseudovascular pattern of growth simulating an angiosarcoma
morphology is observed with pleomorphic and fusiform cells, hyperchromatic nuclei, coarser chromatin, and evident nucleoli within more irregular tumor nests. These pleomorphic variants can be confused with high-grade usual SCC (see below). In other occasions an adenoid-like aspect is noted with tumor nests showing a cribriform pattern or the presence of pseudolumina. Differentiating this variant from pseudoglandular SCC can be difficult and it is discussed in the following sections. Grossly, most sarcomatoid carcinomas may be polypoid and exhibit a vertical pattern of growth with extensive areas of necrosis and hemorrhage. Histologically, the predominant neoplastic population depicts a spindle cell morphology resembling fibrosarcoma, leiomyosarcoma, or even malignant fibrous histiocytoma (Fig. 3.14a).9,10,14,15 Myxosarcoma- and angiosarcoma-like areas may occasionally predominate (Fig. 3.14b).57 Nuclear atypia is overt and mitoses are abundant and often atypical. Evidence of squamous differentiation, with neoplastic nests of an otherwise usual SCC, is found in the majority of cases although it can be very inconspicuous. Conversely, caution should be taken to identify sarcomatoid areas in an otherwise usual SCC. The presence of sarcomatoid differentiation, even if focal, suggests an aggressive biological behavior and should be enough to classify a tumor
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Fig. 3.15 High-grade usual SCC. Marked nuclear pleomorphism is evident and tumor presents a predominant solid pattern of growth. Signs of squamous differentiation are usually found (lower left field), although may be focal. Neoplastic cells retain their squamous features with eosinophilic cytoplasm and distinctive cellular borders
as a sarcomatoid carcinoma. The main differential diagnosis is with true penile sarcomas. However, penile sarcomas usually originate in the penile shaft, manifesting as a tumor mass or with priapism or Peyronie’s-like signs and symptoms, while sarcomatoid carcinomas preferentially affects the glans. Immunohistochemical stains are helpful in problematic cases and are usually indicated to confirm the diagnosis.14,15,27,57 Neoplastic cells are positive for p53 and 34bE12 and negative for muscle-specific actin, smooth muscle actin, desmin, and S-100. High-grade usual SCC can grossly simulate a basaloid or a sarcomatoid carcinoma. Histologically, it is composed of anaplastic cells with nuclear pleomorphism, irregular nuclear membrane, coarse chromatin, prominent nucleolus, and abundant and atypical mitoses (Fig. 3.15). Cytoplasm ranges from scant to ample but usually retains squamous features with an eosinophilic hue, distinctive boundaries, and intercellular bridges. These anaplastic squamous cells can predominate or be very inconspicuous. However, their mere presence is associated with an increased risk for nodal metastasis regardless of the proportion found.58 The vast majority of highgrade usual SCC also harbors areas of low-grade, mainly grade 2 but also grade 1 in some occasions. This heterogeneity is a typical feature of usual SCC in general. Distinction from basaloid and sarcomatoid carcinoma should be straightforward. Nevertheless, as previously stated, the pleomorphic variant of basaloid carcinoma can be confused with a high-grade usual SCC. Clues for differential diagnosis are found in the morphological features of the cytoplasm of neoplastic cells.
3.4.4
Heterogeneous Tumors of Mixed Histology
About 10–24% of all penile carcinomas show mixed features9,11 and are composed of two (or very rarely three) morphologically distinctive SCC subtypes. One of the components should represent at least 20% of the tumor mass. The gross aspect is variegated but mixtures of growth pattern are common. When the tumor is composed of low- and highgrade areas it is not unusual that the former presents a verruciform or superficial spreading pattern while the latter depicts a vertical growth pattern. The most frequent mixed tumor is warty-basaloid carcinoma, representing about one-half of all mixed SCC.59
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Fig. 3.16 Warty-basaloid carcinoma. Infiltrative tumor nests composed of a mixed population of neoplastic cells with koilocytes located at the center and basaloid cells at the periphery
This variant can show three different patterns of growth: (1) exophytic superficial verruciform areas corresponding to warty carcinoma and deeply infiltrative tumor nests corresponding to basaloid carcinoma; (2) deeply infiltrative non-verruciform tumor with mixed morphology: warty areas in the periphery and basaloid areas in the center of tumor nests (Fig. 3.16); and (3) exophytic tumor composed of mixed papillae with basaloid areas at the bottom and warty areas at the superficial layers. In all cases, neoplastic cells morphologically correspond to those previously described in the corresponding sections. Caution should be taken especially for not confusing warty-basaloid carcinomas with pure warty carcinomas since the metastatic rate of the former is expected to be higher than the latter. Considering the potential impact on prognosis any proportion of basaloid areas observed in an otherwise warty carcinoma should be recorded and the tumor classified as warty-basaloid carcinoma. In addition, typical condylomas can be found in association with warty-basaloid carcinomas in about one-half of all cases.11 Another mixed tumor, which represents about one-quarter of all mixed tumors, is hybrid verrucous carcinoma, which has been discussed previously (see Fig. 3.11). The association of usual SCC with other subtypes is rare although mixtures of the former with papillary, warty, and basaloid carcinomas have been reported.11 Another subtype that can present with a mixed morphology is sarcomatoid SCC in which areas of other subtypes are frequently found, usually as a minor component. These tumors should always be classified as sarcomatoid carcinomas, even if the other subtype represents more than 20% of the tumor mass, as treatment and outcome will depend only on the presence of sarcomatoid areas. Finally, therapeutic planning and prognosis should consider the highest histological grade, maximum level of anatomical infiltration, and presence of perineural/vascular invasion, regardless of tumor subtypes and the proportions found.
3.4.5
Penile Carcinomas with Glandular Features
Adenosquamous carcinoma is a rare SCC variant characterized by the presence of solid squamous tumor nests intermingled with areas of glandular differentiation. About a dozen cases have been reported.9,16,60-64 The tumor originates in the glans
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b
Fig. 3.17 Carcinomas with glandular features. (a) In adenosquamous carcinoma areas of glandular differentiation are intermingled with squamous features. Tumor is highly infiltrative and squamous areas are of high grade. (b) The pseudogland, a structure formed by a solid tumor nest with extensive central acantholysis, is the hallmark of pseudoglandular carcinoma. Pseudolumina are filled with necrotic debris, desquamated cells, neutrophils, and an amorphous eosinophilic material. Stromal reaction is intense
central/perimeatal region and has a tendency for deep infiltration. Most tumors are of high-grade, with frequent vascular and perineural invasion. Metastatic rate is high but cancer-specific mortality remains low. Histologically, areas with squamous differentiation predominate and both components tend to stay segregated with only minimal intermingling (Fig. 3.17a). The glandular component is positive for mucin stains and CEA. The main differential diagnosis is with penile tumors with glandular features, including mucoepidermoid, pseudoglandular, urothelial carcinomas of the distal urethra with glandular differentiation and true adenocarcinomas of Littré glands. Mucoepidermoid carcinoma of the penis is an exceedingly rare tumor which is histologically similar to its cervical counterpart.65,66 The neoplastic population is composed of cells with squamous differentiation and cells showing evidence of glandular differentiation (pale, granular, and ample cytoplasm with positivity for mucin stains and CEA) without well-defined glandular or ductal structures. Although more data are needed, it appears that mucoepidermoid carcinoma is more aggressive than conventional adenosquamous carcinoma.66 In pseudoglandular carcinoma the extensive acantholysis can simulate glands lumina but there is no true epithelial lining (see below). Urothelial carcinomas originating in the distal penile urethra or extending from the prostate, bladder, or even ureter/renal pelvis, can depict glandular features.16 However, a previous history of urothelial carcinoma elsewhere and the frequent finding of in situ urothelial carcinoma (which is absent in adenosquamous carcinoma) aid in the differential diagnosis. In problematic cases immunohistochemical markers for urothelial differentiation, such as uroplakin III and thrombomodulin, may be useful.67,68 In adenocarcinomas originating in Littré glands there is no true squamous differentiation and tumors tend to be ventrally located with only secondary extension to the perimeatal glans area. Finally, entrapment of Littré’s glands by an otherwise usual SCC can simulate the aspect of an adenosquamous
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carcinoma. However, the morphology of the glandular component remains bland and admixtures are limited to the periurethral area. About ten cases of pseudoglandular penile carcinoma have been reported.18,69 The hallmark of this variant is the pseudogland, a solid tumor nest with extensive central acantholysis simulating a glandular lumen (Fig. 3.17b). However, the morphological picture is variegated and solid nests with intracellular edema and prominent bridges are mixed with others showing extensive acantholysis. Lumina are filled with keratin, necrotic debris, or micro abscesses. The presence of intracytoplasmic empty vacuoles, either in single cells or adopting a collaret configuration, is a constant feature. Pseudoglandular carcinoma is a high-grade deeply infiltrative neoplasm associated with an aggressive biological behavior. It should be distinguished from other tumors showing glandular features and from the angiosarcomatoid variant of sarcomatoid carcinoma. In the latter the presence of epitheloid and fusiform neoplastic cells surrounding pseudovascular spaces in an alveolar fashion may simulate an acantholytic pattern of growth.15,18,57 Careful examination of the tumor will reveal features of sarcomatoid carcinoma elsewhere.
3.4.6
Malignant Epithelial Tumors with Clear Cell Features
3.4.6.1
Clear Cell Carcinoma
Clear cell carcinomas of the penis are rare tumors of probably sweat gland origin characterized by the presence of neoplastic cells with intracytoplasmic prominent PAS-positive material.19 Tumors preferentially affect the foreskin inner mucosa and are consistently HPV positive, mainly genotype 16. Clear cell carcinomas are composed of solid proliferations of clear cells, sometimes with geographical areas of necrosis. Histology is of a high-grade tumor with evident nuclear atypias. Extensive vascular invasion and a high metastatic rate are common findings. This unusual variant of penile cancer should be distinguished from penile SCC showing clear-cell features, urothelial clear cell carcinomas, and sebaceous carcinomas. Caution should be taken for not confusing glycogenated clear cells with koilocytes and with true neoplastic clear cells. Glycogenated clear cells can be found in usual and other welldifferentiated keratinizing SCC variants but changes are focal and usually not prominent. These cells exhibit squamous differentiation with uniform and pyknotic nuclei and tend to predominate in the superficial areas and central regions of tumor nests. Koilocytes are readily found in warty carcinomas and also show clear cell changes and squamous maturation but nuclei are characteristically wrinkled and hyperchromatic and bi- and multinucleation are common.49 In keratinizing and warty carcinomas neoplastic cells exhibit a broad spectrum of squamous differentiation ranging from cubic basal cells to polygonal more mature cells while in clear cell carcinoma they tend to proliferate in solid sheets and uniformly show a high-grade histology. However, in problematic cases immunohistochemistry may help in the differential diagnosis since clear cell carcinomas are consistently positive for MUC-1 while this
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b
Fig. 3.18 Extramammary Paget’s disease. (a) Rounded and large atypical cells with clear cytoplasm, named “Paget cells” are found throughout the entire epithelium, although they are more prominent at bottom layers (Courtesy of Elsa Velazquez, M.D., Brigham and Women’s Hospital, Harvard Medical School, Boston, MA). (b) Immunohistochemistry for carcinoembryonic antigen (CEA) showing intense positivity in Paget cells (Courtesy of Elsa Velazquez, M.D., Brigham and Women’s Hospital, Harvard Medical School, Boston, MA)
marker is usually negative in penile SCC. Other markers of sweat gland tumors, such as CEA and EMA, can also be useful. Extension from a clear cell urothelial carcinoma can simulate a clear cell carcinoma. However, urothelial carcinomas usually present with a previous history of urothelial malignancy elsewhere, are centered on the urethra and perimeatal area and only secondarily affect the foreskin, and show areas of urothelial carcinoma in situ in most cases. Urothelial markers (uroplakin III, thrombomodulin) may serve in problematic cases. Sebaceous carcinomas show neoplastic cells with clear cytoplasms but the nuclei are small, indented, and irregular and the clear aspect correspond to lipid vacuoles.70-72
3.4.6.2
Extramammary Paget’s Disease
Extramammary Paget’s disease (EMPD) shares many clinicopathological features with its mammary homologue but also presents remarkable differences regarding pathogenesis and association with underlying malignancies.73-75 EMPD has a predilection for the perianal region, perineum, groin, pubic area, scrotum, and penis, although it has been observed in other apocrine gland-rich areas (such as axilla and ear) in isolated cases.73,76 An exclusively penile location is very rare as the penis is usually affected as part of a more disseminated disease extending throughout the scrotum, perineum, and penis. In most cases the lesion is limited to the epidermis (primary EMPD) but in 11% of patients an underlying malignancy is found (secondary EMPD), usually from the prostate or bladder but also from the testicles, ureter, or kidney.77 Primary EMPD is a form of intraepithelial adenocarcinoma in which large round neoplastic cells with ample and clear cytoplasm (Paget cells) are found throughout the epithelium, although they are more abundant in the bottom layers (Fig. 3.18a).76 Paget cells frequently compress surrounding
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keratinocytes and in occasions form gland-like structures with a central lumen. Nuclei are large and vesicular and nucleoli are prominent. Mitoses may be numerous and it is not unusual to find melanin within the cytoplasm of these cells. The epithelium may be atrophic or, more frequently, hyperplastic, with orto- or parakeratosis. Paget cells can also be found within the epithelial sheets of hair follicles, sweat gland excretory ducts, or secretory coils. It has been postulated that these cells originate in the intraepidermal portion of sweat glands, from pluripotent keratinocyte stem cells or from yet-uncharacterized Toker-like cells present in the genital area.73,76,78-80 In some occasions invasion of the underlying dermis is seen and this can progress to vascular invasion, regional and distant metastasis, and death.73,76,80,81 In secondary EMPD an underlying tumor is found, mainly from the genitourinary or lower gastrointestinal tract. Morphologically it is similar to primary EMPD and efforts should be aimed to identify, if present, the associated internal malignancy. Immunohistochemistry is crucial in achieving this. Paget cells in primary EMPD are usually positive for CK7, MUC-1, and MUC-5AC and negative for MUC-2, MUC-6, and CK20.73,78,81 They are also positive for glandular markers such as CAM 5.2, EMA, CEA and GCDFP-15 (Fig. 3.18b).73 Conversely, Paget cells in secondary EMPD, which probably originates from the epidermotropic dissemination of the underlying tumor,73,78 are usually positive for specific tissue markers such as PSA (prostate), uroplakin-III (urothelium), and CDX-2 (colon-rectum). They are also positive for MUC-2 and negative for GCDFP-15.73,78 The differential diagnoses of EMPD include conditions in which clear cells are present within the epidermis (clear cell papulosis, pagetoid diskeratosis, and benign mucinous metaplasia) and neoplasm with an intraepithelial pattern of growth (malignant melanoma, mycosis fungoides, and pagetoid Bowen’s disease). Clear cell papulosis is a rare clinicopathological entity which preferentially affects the pubic area of young Asian individuals.82-84 Clinically, multiple small white papules are seen along the milky line and lower abdomen. Histologically it is characterized by the presence of round cells with ample clear cytoplasm and bland cytology preferentially located in the bottom layers of the epithelium. The immunophenotype of these cells is similar to that presented by Paget cells but morphology is distinctive.82,84,85 Pagetoid dyskeratosis is frequently found in the inner foreskin of patients with phimosis.86-88 Histologically it is characterized by round pale cells interspersed between normal keratinocytes, predominantly located in the upper layers of the epithelium.88 Cytology remains bland and intercellular bridges are observed between the clear cells and the surrounding keratinocytes. Nuclei are centrally located and are small and pyknotic, occasionally pale, with a perinuclear halo. Clusters of cells can be found but no glandular structures are discernible. Mitotic activity is very low. Cells are negative for PAS, mucicarmine, Alcian-Blue, EMA, CK7, and CEA and positive for 34bE12 and CK22.86,87 Finally, in benign mucinous metaplasia, a condition preferentially found in the inner foreskin mucosa of elder patients,89-92 gobletlike cells are found in the upper portions of the stratified epithelium, replacing
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more than infiltrating it, with abundant clear cytoplasm and basally located nuclei. These cells are positive for PAS, Alcian Blue, CAM 5.2, CEA, and EMA. Association with chronic inflammatory conditions (nonspecific chronic posthitis, Zoon’s balanitis) is common supporting the view that mucinous metaplasia is rather a reaction process than a distinctive entity. Malignant melanomas and mycosis fungoides can be very difficult to distinguish from EMPD based solely on the morphology.74,76,93 Immunohistochemistry is frequently needed in such cases. In some cases a penile carcinoma in situ can present with cells extending throughout the epithelium in a pagetoid and nested fashion (Pagetoid Bowen’s disease) but immunohistochemistry for mucin and glandular markers will allow the distinction with EMPD.94,95
3.5 3.5.1
Malignant Melanoma and Non-epithelial Tumors Malignant Melanoma
Primary malignant melanoma of the penis is a rare disease accounting for less than 1% of all penile cancers.23,96 Preferential location is in the glans (60–80% of all cases), followed by the penile shaft and foreskin.97 Melanomas of the distal penile urethra are even rarer but have been reported and tend to affect the fossa navicularis and infrequently the pendulous urethra or meatus urethralis.23,98,99 Grossly, they present as small, brown or black, often ulcerating, lesions and the clinical aspect is similar to that presented for cutaneous melanomas elsewhere. When affecting the distal urethra, tumors are typically polypoid. Histologically, malignant melanomas show a variegated picture with solid, nested, fusiform or mixed patterns of growth. Tumor cells are polygonal with ample and eosinophilic cytoplasm and marked nuclear atypia in most cases (Fig. 3.19a). Coarse brown intracytoplasmic pigment is usually seen but it may be inconspicuous or even absent (amelanotic melanoma). Presence of clear, vacuolated, rhabdoid or pleomorphic giant cells is not uncommon. Mitoses are abundant and often atypical. As with melanomas in other anatomical sites radial and vertical phases of growth are described. Adverse prognostic factors include presence of ulceration, tumor depth of 3.5 mm or more, and tumor diameter greater than 15 mm.100 Guidelines for the management of penile melanomas have been proposed.23 Distinction between malignant melanoma and other pigmented benign lesions is made following the criteria reported for conventional cutaneous melanocytic lesions. The presence of nuclear pleomorphism, intraepithelial pagetoid spread, and lack of maturation strongly suggest a malignant tumor. Malignant melanoma can also be confused with Paget’s disease, especially in its radial phase. When the fusiform pattern of growth predominates, the differential diagnosis should include a sarcomatoid carcinoma and a primary penile sarcoma. Immunohistochemistry for melanocytic markers (S-100, HMB-45 and melan-A) are useful for the differential diagnosis.
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a
b
c
d
Fig. 3.19 Malignant melanoma and nonepithelial malignant tumors. (a) Malignant melanoma showing pleomorphic neoplastic cells with a solid-fusiform pattern of growth. Melanin pigment is observed in some tumor cells. (b) Kaposi’s sarcoma, characterized by a spindle cell neoplastic proliferation with interspersed slit-like vascular spaces. (c) Penile leiomyosarcomas. A pleomorphic spindle cell neoplastic growth is readily observed (Courtesy of Liang Cheng, M.D., Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN). (d) In malignant lymphomas atypical lymphocytes are observed infiltrating penile tissues with a diffuse pattern of growth
3.5.2
Sarcomas
Primary sarcomas of the penis are rare, representing less than 5% of all penile cancers and about 2% of all genitourinary sarcomas.27,101-104 They can be classified into superficial and deep-seated tumors depending on whether they are located above or below the tunica albuginea (in the penile shaft) or invade the corpus spongiosum of the glans.105 The superficial tumors are usually of low grade with a small tendency for nodal metastasis and systemic dissemination while deep-seated sarcomas are biologically more aggressive and associated with a dismal prognosis.27 Ominous prognostic factors include larger size (>5 cm), deep location (corpus cavernosum and spongiosum), high-grade histology, incomplete surgical resection, positive surgical margins, presence of metastatic disease, and pRB expression.27,101,106,107 The most common penile sarcoma is Kaposi’s sarcoma, followed by leiomyosarcomas.27,108
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Other malignant soft-tissue tumors of the penis have been reported and their morphological and immunohistochemical features are similar to those found elsewhere in the body.27,108,109 Kaposi’s sarcoma preferentially affects patients with human immunodeficiency virus (HIV) infection although it has been reported in HIV-negative individuals.105,108,110-115 In patients with acquired immunodeficiency syndrome (AIDS), a population commonly associated with this malignancy, up to 20% of all Kaposi’s sarcomas affect the genital area.28,116 The glans penis is the most common location but it may also affect the coronal sulcus, foreskin, or skin of the shaft.115 Clinically, it presents as erythematous maculae to lilaceous plaques and nodules. Histological features are similar to those described elsewhere and include a patch, plaque, and nodular stage (Fig. 3.19b). In the patch stage a subtle proliferation of slit-like and/or angulated jagged vessels is seen between collagen bundles. Extravasated erythrocytes, hemosiderin-laden macrophages and an inflammatory infiltrate of lymphocytes and plasma cells are also observed. An important morphological clue of Kaposi’s sarcoma is the “promontory sign” in which newly formed vessels protrude into the lumen of pre-existing ones. In the plaque stage the vascular proliferation is more diffuse and prominent spindle cells begin to appear between the vessels. Intracytoplasmic and extracellular PAS-positive hyaline globules may also be seen. The nodular stage is characterized by confluence of neoplastic spindle cells to form well-defined nodules with a storiform pattern of growth. Slit-like spaces containing erythrocytes are readily found. Dilated blood vessels, hemosiderin-laden macrophages, and an evident inflammatory infiltrate are commonly observed at the periphery. The main differential diagnoses include benign and malignant vascular tumors and tumors with a fusiform pattern of growth.27 Neoplastic cells in Kaposi’s sarcoma are positive for CD31 and CD34 and negative for desmin, allowing its distinction from other nonvascular fusiform tumors. In problematic cases, identification of human herpes virus 8 (HHV-8) is helpful for confirming the diagnosis. Leiomyosarcomas preferentially involve the shaft or penile base and are more likely to be superficial than deep-seated.102,105,108,117 The typical gross aspect is of a white-to-tan firm tumor with irregular borders. Microscopically, tumors are composed of spindle cells with abundant eosinophilic cytoplasm, focal juxtanuclear vacuoles, and blunt-ended nuclei with evident atypias (Fig. 3.19c). Atypical changes range from moderate to severe and anaplastic giant cells are not unusual. Mitoses are easily found and can be numerous. Myxoid changes can also be noted in some cases. Neoplastic cells are positive for muscle-specific actin, a-smooth muscle actin, and desmin. Differential diagnosis of penile leiomyosarcoma includes leiomyoma, myointimoma, nodular Kaposi’s sarcoma, malignant fibrous histiocytoma, and sarcomatoid carcinoma. Penile leiomyoma is an exceedingly rare tumor which is histologically similar to other leiomyomas in other anatomical locations.104,108,118 Myointimoma can simulate a leiomyosarcoma for its fusiform/plexiform pattern of growth but neoplastic cells are devoid of significant cytological atypias and exhibit positivity for muscle-specific actin (HHF-35), a-smooth muscle actin, and calponin but minimal reactivity for desmin.119-121 Nodular Kaposi’s sarcoma can be confused with superficial leiomyosarcoma, especially by its atypical spindle cell pattern of
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growth, but the H&E morphology and immunophenotype of neoplastic cells allow a proper diagnosis. Sometimes a malignant melanoma can exhibit a predominant storiform pattern of growth and be similar to a leiomyosarcoma. The presence of more typical melanoma areas elsewhere and positivity for melanocytic markers helps in the distinction. Malignant fibrous histiocytoma is an exclusion diagnosis and should be established only when other tumors have been ruled out.109 Finally, considering that sarcomatoid carcinoma is a far more prevalent tumor than true penile leiomyosarcoma differential diagnosis should include this SCC variant as well. The presence of epithelial nests within the tumor mass, associated areas of PeIN, and pattern of immunoexpression are helpful clues for distinguishing these two tumors.14,15
3.5.3
Malignant Lymphoma
Genitourinary malignant lymphomas are uncommon, representing less than 7% of all extranodal lymphomas.29 The majority of cases are secondary to systemic dissemination and the most frequently affected anatomical site is the testicle. Primary penile lymphomas are exceedingly rare.122 Non-Hodgkin lymphomas, either of B or T cell types, predominate over Hodgkin lymphomas. Histologically, a dense infiltrate of atypical lymphocytes is seen (Fig. 3.19d). Despite the rarity of the lesion, establishing a suspicion of a penile lymphoma should be straightforward. Confirmation and phenotyping is done by immunohistochemistry following the criteria established for lymphomas elsewhere. In the very rare cases of mycosis fungoides of the penis, neoplastic cells can be confused with extramammary Paget’s disease.93
3.6
Metastatic Tumors to the Penis
Despite its rich vascularity metastatic tumors to the penis are rare with about 400 worldwide cases reported, mostly as single cases.4,123 The majority of these tumors originate in the genitourinary and gastrointestinal tract. Prostatic adenocarcinomas and bladder urothelial carcinomas represent together almost two-thirds of all secondary penile tumors with an equal distribution between them. Metastases from clear cell renal carcinomas and testicular germ cell tumors have also been reported, as well as urothelial carcinomas originating in the renal pelvis, ureter, or proximal urethra but to a much lesser frequency. Tumors originating in the gastrointestinal tract represent about one-fifth of all cases of secondary penile tumors. Adenocarcinomas from the lower tract (rectum and distal colon) account for twothirds of all GI metastatic carcinomas but tumors arising in the stomach or esophagus are occasionally reported. About 5% of penile metastasis originates in the lungs or, more rarely, the upper airways. Other anecdotal primary sites include
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tongue, seminal vesicles, bone, thyroid gland, cutaneous melanomas, chordomas, Ewing’s sarcomas, synovial sarcomas, and jaw chondrosarcomas.4,124-130 The preferred anatomical location is the penile shaft, mainly the corpora cavernosa, but secondary foci can also be found in the glans, corpus spongiosum, or even foreskin or outer skin. Microscopically, tumor cells are predominantly found permeating the vascular spaces of erectile tissues. The histological aspect is similar to the primary tumor and diagnosis is straightforward in most cases given that the majority of patients present a previous or concurrent history of malignancy elsewhere. A penile secondary tumor as the primary manifestation of a disseminated malignant disease is a very rare event. In the presence of penile secondary involvement prognosis is dismal and the majority of patients die within 6 months from diagnosis.4
3.7
Methods of Identification and the Value of Pathological Prognostic Factors
Several pathologic features have been proposed as prognostic factors in an attempt to estimate the likelihood of inguinal nodal metastasis and systemic dissemination.131,132 Among all of them histological grade, vascular/perineural invasion, and anatomical level of tumor infiltration seem to be the most important.55,58,133-141 In addition, several risk-group stratification systems and nomograms using some of these pathologic factors have been designed and tested.55,138,140,142-146 Pathologic features should be evaluated using surgical specimens since biopsies are unreliable for establishing all pertinent data excepting the confirmation of malignancy.147 Special care should be taken for specimen processing, gross description, and sample sections. Data obtained from pathological examination of the specimen should be used for therapeutic planning (adjuvant therapy, groin dissection) and surveillance strategies.
3.7.1
Histological Grade
Histological grade has been repeatedly reported as an important prognostic factor. 53,55,58,136,139,140,143,144,148-150 High-grade tumors tend to metastasize and disseminate much more frequently than low-grade tumors, even if superficially located.56 For consistency we propose the use of a simple 3-tier system which emphasizes both ends of the spectrum55: grade 1, tumors composed of neoplastic cells almost indistinguishable from normal squamous cells, except for a minimal basal/parasabal atypia (see Fig. 3.5a); grade 3, tumors composed by any proportion of anaplastic cells (nuclear pleomorphism, coarse chromatin, prominent nucleolus, irregular and thickened nuclear membrane, abundant and atypical mitoses, see Fig. 3.15); and grade 2, the remainder of cases not ffitting the criteria for grades 1 or 3, with neoplastic cells showing evident but not extreme nuclear atypia and ample eosinophilic cytoplasm
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with a clear tendency toward squamous maturation (see Fig. 3.5b). Up to one-half of all cases of SCC are heterogeneous, meaning that they harbor more than one histological grade.58 These heterogeneous cases should be graded according to the highest grade found in the tumor, regardless of its proportion.
3.7.2
Anatomical Level of Infiltration
The maximum anatomical level infiltrated by tumor should be grossly determined and histologically confirmed. Special attention should be given to distinguish corpus spongiosum from corpus cavernosum invasion. When it is carefully determined, there is a strong association between anatomical level of infiltration and the risk of nodal metastasis.140,151 In addition, tumor staging is performed by determining the deepest anatomical structure invaded by tumor using the system proposed by the American Joint Committee on Cancer/International Union Against Cancer (AJCC/UICC)152 (Table 3.3). There are some shortcomings with this system.153,154 It considers one single stage (T2) for tumors invading either corpus spongiosum or cavernosum. However, tumors invading the latter show a higher metastatic rate when compared with those limited to the former.140 A second limitation is that it utilizes histological grade for substratification of T1 tumors only and not for all stages. Nonetheless, deeply invading low-grade tumors exhibit a lesser tendency for nodal metastates compared with superficial high-grade tumors.56 Finally, it considers infiltration of the penile urethra as an indication of a high-stage tumor (T3). However, urethral invasion has proven neither to be an independent prognostic factor nor to have any impact in the metastatic rate or systemic dissemination of a penile cancer.9 The deepest anatomical level infiltrated by tumor should always be used in conjunction with other pathological factors such as histological subtype/grade and vascular/perineural invasion.
3.7.3
Perineural Invasion
Perineural invasion has proven to be an important prognostic factor for predicting nodal metastasis and mortality55,138,140 and should always be reported. Identification of perineural invasion should be straightforward for the pathologist (Fig. 3.20a) but caution should be taken for not confusing it with tumor nests surrounding nerve bundles (nerve entrapment).
3.7.4
Vascular Invasion
Several reports have established the value of vascular (either lymphatic or venous) invasion as a prognostic factor for penile cancer metastasis.133,135-138,155 Lymphatic invasion is observed more frequently (Fig. 3.20b) although venous invasion can
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Table 3.3 2009 TNM classification of penile cancer T – primary tumor TX T0 Tis Ta T1
Primary tumor cannot be assessed No evidence of primary tumor Carcinoma in situ Non-invasive verrucous carcinoma, not associated with destructive invasion Tumor invades subepithelial connective tissue T1a Tumor invades subepithelial connective tissue without lymphovascular invasion and is not poorly differentiated or undifferentiated (T1G1-2)
T2 T3 T4 N – regional lymph nodes NX N0 N1 N2 N3
T1b Tumor invades subepithelial connective tissue without with lymphovascular invasion or is poorly differentiated or undifferentiated (T1G3-4) Tumor invades corpus spongiosum/corpora cavernosa Tumor invades urethra Tumor invades other adjacent structures Regional lymph nodes cannot be accessed No palpable or visibly enlarged inguinal lymph node Palpable mobile unilateral inguinal lymph node Palpable mobile multiple or bilateral inguinal lymph nodes Fixed inguinal nodal mass or pelvic lymphadenopathy, unilateral or bilateral
M – distant metastases M0 No distant metastasis M1 Distant metastasis 2009 TNM pathological classification of penile cancer The pT categories correspond to the T categories. The pN categories are based upon biopsy, or surgical excision pN – regional lymph nodes pNX Regional lymph nodes cannot be assessed pN0 No regional lymph node metastasis pN1 Intranodal metastasis in a single inguinal lymph node pN2 Metastasis in multiple or bilateral inguinal lymph nodes pN3 Metastasis in pelvic lymph node(s), unilateral or bilateral or extranodal extension of regional lymph node metastasis pM – distant metastases pM0 No distant metastasis pM1 Distant metastasis G – histopathological grading GX Grade of differentiation cannot be assessed G1 Well differentiated G2 Moderately differentiated G3–4 Poorly differentiated/undifferentiated
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a
b
Fig. 3.20 Pathological prognostic factors. (a) Perineural invasion is characterized by invasion of neoplastic cells into the perineural spaces of peripheral nerves. (b) A tumor embolus found within a lymphatic vascular space. Note the high-grade carcinoma in the lower right field
be present, especially in advanced stages. Neoplastic emboli can also be found in vascular erectile tissues. Attention should be paid for not confusing clear space artifacts surrounding tumor nests with true vascular spaces. The use of endothelial-specific markers could help in this matter but in practice they are rarely needed.
3.7.5
Depth of Invasion/Tumor Thickness
Depth of invasion refers to the maximum distance between the basement membrane of adjacent non-invasive epithelium to the deepest point of tumor invasion. It is the preferred method for smaller non-exophytic tumors. Tumor thickness is measured from the non-necrotic non-keratinized tumor surface to its deepest point of infiltration. Depth and thickness are measured in millimeters and are of equal equivalence, except for verruciform tumors. Given their exophytic pattern of growth, thickness should be preferred for these tumors. Notwithstanding this, their utility as a prognostic factor has been demonstrated.55,133,141,149 Tumors measuring less than 5 mm thick are at low risk for metastasis while in tumors of more than 10 mm thick this risk increases considerably.55 In tumors measuring 5–10 mm histological grade and perineural invasion should be considered.55
3.7.6
Histological Subtype
The value of histological subtypes as a prognostic factor has been established in several studies.9,10,141 Some SCC subtypes, such as verrucous and pseudohyperplastic carcinomas and carcinoma cuniculatum, are associated with an extremely low,
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even null, metastatic rate.9,10,12 Other subtypes, including sarcomatoid, basaloid, pseudoglandular, and high-grade usual carcinomas, are intrinsically more aggressive and present with nodal involvement and systemic dissemination.9,10,13,15,18,53 A third group is composed of tumors with intermediate aggressiveness and includes low-grade usual, warty, and papillary SCC.9,10,49,50 Histological subtyping should always be accompanied with histological grade, anatomical level of infiltration, and presence of vascular/perineural invasion.
3.7.7
Resection Margins
Since the presence of local recurrence is associated with an increased risk for regional metastasis and systemic dissemination156 it is crucial to obtain negative resection margins to avoid this event in patients treated by surgery.157 The sites of margin involvement include Buck’s fascia and urethral/periurethral tissues with surrounding corpus spongiosum while corpora cavernosa and the penile shaft skin are less frequently compromised.158 Evaluation of surgical margins in a penectomy specimen should include submission of both corpora cavernosa as well as distal urethra, shaft skin, and Buck’s fascia. In circumcision and wide excision, the specimen margins should be inked and completely submitted.
3.7.8
Molecular Prognostic Factors
Several molecular biomarkers have been evaluated as prognostic factors for penile cancer159,160 including cell cycle-related proteins, such as p53, p16INK4a, p21, Ki-67, and PCNA62,137,161-167 and proteins associated with tumor progression, such as E-cadherin, telomerase activity, matrix metalloproteinases, COX-2, and PGE synthase-1.137,168-170 Genetic imbalances, ploidy status, and specific proto-oncogenes mutations were addressed as well.171-176 However, none of the aforementioned biomarkers has a clear and defined utility in the management of patients with penile cancer.
3.7.9
The Prognostic Index
The Prognostic Index is a stratification system which combines the predictive power of histological grade, anatomical level of infiltration, and perineural invasion to define three distinctive groups of patients with different risks for nodal metastasis. The Index is constructed by adding up numerical values assigned to histological grade (1 point for grade 1, 2 points for grade 2, and 3 points for grade 3 tumors), anatomical level of infiltration (1 point for tumors invading up lo lamina propria,
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2 points for invasion of corpus spongiosum/preputial dartos, and 3 points for invasion of corpus cavernosum/preputial skin), and perineural invasion (0 points if absent and 1 point if present). A score, ranging from 2 to 7, is obtained. Patients with scores 2 and 3 are at low risk for nodal metastasis and, in the absence of clinical evidence of nodal involvement, a surveillance program should suffice for them. Patients with scores 5, 6, and 7 are at high risk for nodal metastasis and should receive a prophylactic groin dissection, regardless of the clinical status of the inguinal nodes. Patients with score 4 are problematic to handle and other procedures, such as imaging studies and dynamic sentinel lymph node biopsy, should be used to better define the likelihood of inguinal metastasis.
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136. Slaton J, Morgenstern N, Levy D, et al. Tumor stage, vascular invasion and the percentage of poorly differentiated cancer: independent prognosticators for inguinal lymph node metastasis in penile squamous cancer. J Urol. 2001;165:1138-1142. 137. Zhu Y, Zhou X, Yao X, et al. The prognostic significance of p53, Ki-67, epithelial cadherin and matrix metalloproteinase-9 in penile squamous cell carcinoma treated with surgery. BJU Int. 2007;100:204-208. 138. Ornellas A, Nóbrega B, Wei Kin Chin E, et al. Prognostic factors in invasive squamous cell carcinoma of the penis: analysis of 196 patients treated at the Brazilian National Cancer Institute. J Urol. 2008;180:1354-1359. 139. Leewansangtong S, Srinualnad S, Chaiyaprasithi B, et al. The risks of lymph node metastasis and the prognostic factors in carcinoma of the penis: analysis of 50 patients treated with bilateral ilioinguinal lymphadenectomy. J Med Assoc Thai. 2001;84:204-211. 140. Chaux A, Caballero C, Soares F, et al. The prognostic index: a useful pathologic guide for prediction of nodal metastases and survival in penile squamous cell carcinoma. Am J Surg Pathol. 2009;33:1049-1057. 141. Dai B, Ye D, Kong Y, et al. Predicting regional lymph node metastasis in Chinese patients with penile squamous cell carcinoma: the role of histopathological classification, tumor stage and depth of invasion. J Urol. 2006;176:1431-1435. 142. Solsona E, Algaba F, Horenblas S, et al. EAU guidelines on penile cancer. Eur Urol. 2004;46:1-8. 143. Solsona E, Iborra I, Rubio J, et al. Prospective validation of the association of local tumor stage and grade as a predictive factor for occult lymph node micrometastasis in patients with penile carcinoma and clinically negative inguinal lymph nodes. J Urol. 2001;165:1506-1509. 144. Hungerhuber E, Schlenker B, Karl A, et al. Risk stratification in penile carcinoma: 25-year experience with surgical inguinal lymph node staging. Urology. 2006;68:621-625. 145. Ficarra V, Zattoni F, Artibani W, et al. Nomogram predictive of pathological inguinal lymph node involvement in patients with squamous cell carcinoma of the penis. J Urol. 2006;175:1700-1704. 146. Kattan M, Ficarra V, Artibani W, et al. Nomogram predictive of cancer specific survival in patients undergoing partial or total amputation for squamous cell carcinoma of the penis. J Urol. 2006;175:2103-2108. 147. Velazquez EF, Barreto JE, Rodriguez I, et al. Limitations in the interpretation of biopsies in patients with penile squamous cell carcinoma. Int J Surg Pathol. 2004;12:139-146. 148. Hegarty P, Kayes O, Freeman A, et al. A prospective study of 100 cases of penile cancer managed according to European Association of Urology guidelines. BJU Int. 2006;98:526-531. 149. McDougal WS. Carcinoma of the penis: improved survival by early regional lymphadenectomy based on the histological grade and depth of invasion of the primary lesion. J Urol. 1995;154:1364-1366. 150. Villavicencio H, Rubio-Briones J, Regalado R, et al. Grade, local stage and growth pattern as prognostic factors in carcinoma of the penis. Eur Urol. 1997;32:442-447. 151. Rubio-Briones J, Villavicencio H, Regalado R, et al. Squamous cell carcinoma of the penis: treatment protocol according to our 14 years of experience. Arch Esp Urol. 1997;50: 473-480. 152. Edge SB, Byrd DR, Compton C, et al., eds. AJCC Cancer Staging Manual. 7th ed. New York: Springer; 2009:447-456. 153. Leijte J, Gallee M, Antonini N, et al. Evaluation of current TNM classification of penile carcinoma. J Urol. 2008;180:933-938. 154. Leijte JA, Horenblas S. Shortcomings of the current TNM classification for penile carcinoma: Time for a change? World J Urol. 2009;27:151-154. 155. Guimarães G, Lopes A, Campos R, et al. Front pattern of invasion in squamous cell carcinoma of the penis: new prognostic factor for predicting risk of lymph node metastases. Urology. 2006;68:148-153. 156. Lont AG MP, Meinhardt W, van Tinteren H, et al. Penis conserving treatment for T1 and T2 penile carcinoma: clinical implications of a local recurrence. J Urol. 2006;176:575-580. 157. Velazquez EF, Cubilla AL. Penile squamous cell carcinoma: anatomic, pathologic and viral studies in Paraguay (1993–2007). Anal Quant Cytol Histol. 2007;29:185-198.
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158. Velazquez EF, Soskin A, Bock A, et al. Positive resection margins in partial penectomies: sites of involvement and proposal of local routes of spread of penile squamous cell carcinoma. Am J Surg Pathol. 2004;28:384-389. 159. Muneer A, Kayes O, Ahmed HU, et al. Molecular prognostic factors in penile cancer. World J Urol. 2009;27:161-167. 160. Kayes O, Ahmed H, Arya M, et al. Molecular and genetic pathways in penile cancer. Lancet Oncol. 2007;8:420-429. 161. Lopes A, Bezerra AL, Pinto CA, et al. p53 as a new prognostic factor for lymph node metastasis in penile carcinoma: analysis of 82 patients treated with amputation and bilateral lymphadenectomy. J Urol. 2002;168:81-86. 162. Martins A, Faria S, Cologna A, et al. Immunoexpression of p53 protein and proliferating cell nuclear antigen in penile carcinoma. J Urol. 2002;167:89-92. 163. Prowse D, Ktori E, Chandrasekaran D, et al. Human papillomavirus-associated increase in p16INK4A expression in penile lichen sclerosus and squamous cell carcinoma. Br J Dermatol. 2008;158:261-265. 164. Ferreux E, Lont A, Horenblas S, et al. Evidence for at least three alternative mechanisms targeting the p16INK4A/cyclin D/Rb pathway in penile carcinoma, one of which is mediated by high-risk human papillomavirus. J Pathol. 2003;201:109-118. 165. Gentile V, Vicini P, Giacomelli L, et al. Detection of human papillomavirus DNA, p53 and ki67 expression in penile carcinomas. Int J Immunopathol Pharmacol. 2006;19:209-215. 166. Berdjis N, Meye A, Nippgen J, et al. Expression of Ki-67 in squamous cell carcinoma of the penis. BJU Int. 2005;96:146-148. 167. Guimarães G, Leal M, Campos R, et al. Do proliferating cell nuclear antigen and MIB1/Ki-67 have prognostic value in penile squamous cell carcinoma? Urology. 2007;70:137-142. 168. Alves G, Fiedler W, Guenther E, et al. Determination of telomerase activity in squamous cell carcinoma of the penis. Int J Oncol. 2001;18:67-70. 169. Campos R, Lopes A, Guimarães G, et al. E-cadherin, MMP-2, and MMP-9 as prognostic markers in penile cancer: analysis of 125 patients. Urology. 2006;67(4):797-802. 170. Golijanin D, Tan JY, Kazior A, et al. Cyclooxygenase-2 and microsomal prostaglandin E synthase-1 are overexpressed in squamous cell carcinoma of the penis. Clin Cancer Res. 2004;10:1024-1031. 171. Sastre-Garau X, Favre M, Couturier J, et al. Distinct patterns of alteration of myc genes associated with integration of human papillomavirus type 16 or type 45 DNA in two genital tumours. J Gen Virol. 2000;81:1983-1993. 172. Leis PF, Stevens KR, Baer SC, et al. A c-rasHa mutation in the metastasis of a human papillomavirus (HPV)-18 positive penile squamous cell carcinoma suggests a cooperative effect between HPV-18 and c-rasHa activation in malignant progression. Cancer. 1998;83:122-129. 173. Ornellas AA, Ornellas MH, Otero L, et al. Karyotypic findings in two cases of moderately differentiated squamous cell carcinomas of the penis. Cancer Genet Cytogenet. 1999;115:77-79. 174. Ornellas AA, Ornellas MH, Simoes F, et al. Cytogenetic analysis of an invasive, poorly differentiated squamous cell carcinoma of the penis. Cancer Genet Cytogenet. 1998;101:78-79. 175. Ornellas AA, Mendes Campos M, Ornellas MH, et al. Penile cancer: flow cytometry study of ploidies in 90 patients. Prog Urol. 2000;10:72-77. 176. Alves G, Heller A, Fiedler W, et al. Genetic imbalances in 26 cases of penile squamous cell carcinoma. Genes Chromosom Cancer. 2001;31:48-53.
Chapter 4
Radiological Imaging in Penile Cancer Alex P. S. Kirkham
4.1
Introduction
Although the EAU guidelines for penile cancer suggest that the only mandatory imaging modality required is an ultrasound of the inguinal nodes,1 a variety of other radiological techniques can provide further information with regards to the extent of the primary tumor as well as metastatic disease. These techniques have an important role in both the oncological and surgical planning for the primary tumor as well as the inguinal and pelvic lymph nodes. We will initially describe the radiological anatomy of the penis and its draining nodes, as well as some techniques for scanning with ultrasound and MRI. Next, we will address local staging. We finish with the assessment of nodal and metastatic spread, and an outline of the use of imaging in penile cancer.
4.2
Anatomy and Techniques
The penis is a superficial organ and most cancers can be seen and palpated, so that local staging by physical examination may not necessarily be less accurate than by imaging.2 However, ultrasound can produce very high resolution images, and the soft tissue definition with MRI is excellent. We will focus on the anatomy visible with these two techniques; CT has limited contrast and spatial resolution and therefore is disappointing when used for imaging the penis.
A.P.S. Kirkham Department of Radiology, University College London Hospital, London, UK A. Muneer et al. (eds.), Textbook of Penile Cancer, DOI 10.1007/978-1-84882-879-7_4, © Springer-Verlag London Limited 2012
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A.P.S. Kirkham Cavernosal vein Dorsal artery, Nerve and accompanying veins
Superficial dorsal vein Deep dorsal vein Tunica albuginea
Corpus cavernosum
Buck’s fascia
Skin Dartos fibres
Cavernosal artery Urethral vein
Urethra
Superficial fascia
Corpus spongiosum
Fig. 4.1 A diagram of the fascial layers of the penis: axial section. The relatively loose layer of Colles fascia can be difficult to see on imaging and contains superficial vessels
4.2.1
MR Anatomy
Both the corpora cavernosa and the corpus spongiosum are of intermediate to high signal on T1-weighted sequences, and high signal on T2 (Figs. 4.1–4.5). The corpus spongiosum is of similar signal to the glans, and may be higher or lower than the corpora cavernosa on T2-weighted sequences.3 Variable layering effects are a normal appearance in the tumescent corpus cavernosum (Fig. 4.2b). Contrast between high signal in the corpora and the fascial layers of the penis is higher on T2 than T1-weighted sequences.4 Both the corpus spongiosum and the corpora cavernosa are surrounded by a fibrous sheath: the tunica albuginea, with inner (circular) and outer (longitudinal) layers,5 but is a single smooth low signal structure on both T1and T2-weighted sequences. Outside the tunica albuginea is a tough, enveloping layer of deep fascia, often termed Buck’s fascia, which fuses proximally with the deep fascia of the urogenital region. Like the tunica albuginea, it is of low signal on T1 and T2-weighted sequences, and most authors assert that the two layers appear fused on MR and cannot be readily distinguished.6,7 However, connective tissue and fat between the tunica albuginea and Buck’s fascia in the midline posteriorly contains the low signal deep dorsal vessels (with the vein and sometimes the arteries seen on axial scans) and often allows the two structures to be differentiated for the dorsal part of their circumference5; laterally they are usually apposed but can sometimes be differentiated on both T1 and T2-weighted sequences, where Buck’s fascia is of slightly higher signal than the tunica albuginea8 (Fig. 4.2 a, c). The tunica albuginea is thin-
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Fig. 4.2 Axial T2-weighted (a, b) and T1-weighted (c) images through the penis in different patients after intracavernosal alprostadil. Note the differing conspicuity of the Buck’s fascia and the dorsal vessels: clearly visible in patients (a, c) but not (b). Black arrowheads mark the tunica albuginea, and white arrowheads Buck’s fascia. The thick white arrow shows the superficial dorsal vein in (a), and the thinner white arrows the deep dorsal vessels. The cavernosal arteries are marked by black arrows. The urethra, lying in the middle of the corpus spongiosum, is marked by an asterisk. Note the layering of signal within the corpora cavernosa in (b), a normal finding
a
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72 Fig. 4.3 T2-weighted sagittal section close to the midline (a) after intracavernosal alprostadil and (b) without tumescence. Black arrows mark the tunica albuginea, large white arrows the corpus spongiosum, small white arrows the urethra within it, and black arrows the bulbocavernosus muscle. The white arrow head marks the entry of the urethra into the roof of the bulb. An asterisk marks the glans. The ‘corrugated’ appearance of the corpus cavernosum in (a) is because of the midline intercavernosal septum. Note the considerably thicker tunica albuginea in the detumescent state, and the lower signal in the corpus cavernosum; the glans is not in the midline sagittal plane
A.P.S. Kirkham
a
b
ner over the corpus spongiosum than cavernosum, and in the glans it is hard to distinguish, fusing completely with the subepithelial connective tissue toward the tip.9 The superficial dorsal vein may be seen outside Buck’s fascia in the midline. After intravenous contrast, enhancement in the corpora cavernosa radiates axially from the cavernosal arteries, and from proximal to distal.10 Outside Buck’s fascia lie the superficial vessels in a loose, superficial fascial layer (also called Dartos fascia),
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b
Fig. 4.4 T2-weighted coronal section through the base (a) and shaft (b) of the penis after intracavernosal alprostadil. In (a) a white arrowhead marks the ischiocavernosus muscle, and a black arrowhead the bulbocavernosus. A white arrow shows the urethra entering the bulb. Inferior pubic rami are marked by asterisks. In (b), a black arrowhead marks the tunica albuginea and a white arrowhead Buck’s fascia. The glans is well seen (thick white arrows)
continuous with Colles’ fascia of the perineum and containing a few thin dartos muscle fibers. Hematoma or urine arising deep to an intact Buck’s fascia is confined to the penis. In contrast, blood or hematoma lying in the superficial fascia may extend to the scrotum and anterior abdominal wall.11 The most proximal part of the corpus spongiosum is the bulb, surrounded by the low signal bulbospongiosus muscle (Fig. 4.4). Its roof is pierced by the urethra, which then runs centrally within the corpus spongiosum and is of intermediate to low signal on T1 and T2-weighted sequences. The most proximal part of the corpora cavernosa are the crura, attached to the ischium and with their medial parts covered by the low signal ischiocavernosus.3 The superficial and deep inguinal nodes are well seen on MRI (Fig. 4.5), as are the pelvic nodes. The fascia lata separates the superficial from deep nodes, with the deep lying medial to the femoral vein, and Cloquet’s node often the most conspicuous.12 Superficial nodes may be divided into five subgroups, defined according to their relations to a central group at the confluence of greater saphenous and femoral veins13 (Fig. 4.5a). The conspicuity and accuracy of measurement of lymph nodes depends very much on the techniques used for both CT and MRI,14 but MR with a slice thickness of 3 or 4 mm has the potential to accurately delineate nodes well under 8 mm in short axis diameter,14 with a very low coefficient of variability between observers (0.05 in one series15). Ultrasound using a high resolution linear probe will be at least as accurate. Discriminating features of benign and malignant nodes will be discussed later in the chapter.
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Fig. 4.5 (a) Thick-slab T1 spin echo coronal image of the superficial inguinal nodes. The horizontal group is shown by the white arrows: the most medial (asterisk) is defined as the ‘sentinel’ node by Senthil Kumar et al.85 and would also fit the definition by Cabanas.90 Black arrowheads mark the superficial epigastric vein; note that on the left the sentinel node lies medial to the superficial epigastric vein, but on the right is anterior to it. White arrowheads mark the long saphenous vein and the black arrow the junction between the superficial epigastric and long saphenous veins. (b) Axial T2-weighted image of the groin in a patient scanned because of a penile prosthesis. Note the horizontal chain of the superficial nodes (small white arrows, each with a fatty hilum). They lie superficial to the fascia lata (white arrowheads). The saphenous vein (black arrow) passes through the cribriform fascia (lying in the oval defect of the fascia lata) to join the femoral vein (v). The femoral artery is marked a, the femoral nerve n, and the spermatic cord s. The larger white arrow shows a deep inguinal node medial to the femoral vein
4.2.2
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b
Ultrasound Anatomy
Most of the structures seen on MRI are visible on ultrasound using a high-frequency (10 MHz or more) linear probe. The tunica albuginea and Buck’s fascia are not readily distinguished, but appear as a smooth, echogenic structure surrounding the less echogenic corpora16 (Figs. 4.6 and 4.7). In the tumescent state, the corpus cavernosum is slightly less echogenic than the spongiosum, but the two are not markedly different and the radiologist must be careful to identify each correctly. The tunica around the corpus spongiosum is thinner than around the corpora cavernosa, and
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Fig. 4.6 Two axial images of the shaft of the tumescent penis: the first (a) taken at an angle of 45° to avoid diffraction artifact, and the second (b), in the standard transverse plane with the probe ventral. The urethra (white arrow) is sometimes seen well within the corpus spongiosum. Tunica albuginea and Buck’s fascia (black arrows) appear as one echogenic layer, thickest around the corpora cavernosa. White arrowheads show superficial vessels, and black arrowheads the cavernosal vessels
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b
importantly, subepithelial connective tissue and the thin tunica albuginea are impossible to distinguish from each other in the glans, which has implications for the staging of small tumors located in this area.9 The urethra is visible within the corpus spongiosum and can be traced through the glans to the external urethral meatus (Fig. 4.7). Cavernosal vessels are easily seen in the erect state, but with the correct Doppler settings should also be seen without erection.17 The dartos fascia layer is difficult to reliably distinguish but ultrasound does show well the difference between skin and corpus cavernosum, spongiosum, or glans. The penis should be scanned both from the dorsal and the ventral aspect. For very superficial tumors it can be difficult to move the focal zone superficially enough
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Fig. 4.7 Longitudinal image of the glans. White arrowheads mark the end of the tumescent corpus cavernosum, and black arrows show the urethra. The glans (marked with an asterisk) is not shown optimally on this image; for a better view of its outlines see Fig. 4.9, which also shows a tumor
for sharp images and a spacer may be useful; an alternative is to scan from the opposite aspect. Lymph nodes are well seen in the groin, but much less reliably identified in the pelvis. In normal nodes a fatty hilum is often visible, with smooth nodal parenchyma of uniform thickness and a radiating vascular pattern; normal and pathological appearances will be described in detail later in this chapter.
4.2.3
MRI Technique
Our mainstay for MR imaging of the penis is high resolution (matrix at least 256 × 192), small field of view, thin-slice (4 mm or less) T2-weighted spin echo sequences, without fat suppression, in orthogonal planes, using a surface coil. In addition, we usually perform T1 spin echo sequences in the axial plane. One of the strengths of MR imaging is the anatomical information it provides, and it helps if the imaging planes correspond accurately to those of the scanner. Taping the penis to the anterior abdominal wall in the midline, with padding if necessary, helps to achieve this, although others tape the penis in a dependent position because of breathing artifact.7 There is little evidence that contrast enhancement improves the performance of MRI for local staging,18 but in certain cases enhancement of the corpora cavernosa may be useful to differentiate intracavernosal tumor invasion. In practice we have found it difficult to define the vascular anatomy with contrast-enhanced scans as the vessels are fairly small: ultimately they are better seen as flow voids on T2-weighted sequences or areas of high signal on STIR. If contrast is given, we use intracavernosal prostaglandin and perform T1-weighted fat saturated sequences before and at least 10 min after contrast. It can take some time for full opacification of the tumescent corpora cavernosa, a point that is particularly relevant for the imaging of priapism patients.8
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Images of the pelvic nodes can be obtained by extending the axial scans into the pelvis, or performing a separate T1 or T2-weighted spin echo pelvic scan at slightly higher slice thickness (4–5 mm). The groin nodes are also well seen on the coronal images of the penis, and scanning in orthogonal planes is useful for estimating short axis diameter.
4.2.4
Artificial Erection Technique
We routinely use intracavernosal prostaglandin E1 (alprostadil) at a dose of 10 mg when scanning tumors with both ultrasound and MRI. This stretches the tunica albuginea, making defects or invasion easier to see, and it increases contrast between intermediate signal tumor and high signal corpus spongiosum or cavernosum. For patients with erectile dysfunction, the dose may be increased to 20 mg (especially if it has been used before), and in young patients with normal erections it can be reduced to 5 mg. Sildenafil and manual stimulation have a good result in most patients but the time to onset is longer and they are not as reliable as intracavernosal agents.19 The contraindications to intracavernosal alprostadil are penile implants and conditions predisposing to priapism: sickle cell disease, myeloma, and polycythemia. Tumors invading the corpora, anatomical abnormalities, and clotting derangement are only relative contraindications.20 The risk of priapism is small (around 1% in a large group of patients with erectile dysfunction of mixed cause,21 and in 1 out of 9 patients in a small study of penile cancer18), and it can usually be treated by aspiration of blood from the corpora or by the intracavernosal administration of a adrenergic agents such as phenylephrine.22
4.3
Performance of Ultrasound and MRI in Primary Tumor Staging
The majority of penile lesions are primary squamous cell tumors, although melanoma,23 basal cell carcinoma,24 sarcoma,25 and lymphoma26 have also been reported, and metastases are common enough to account for several case series,27,28 with bladder the commonest site of origin – either by hematogenous or urethral spread of transitional cell carcinoma.29,30 On MRI primary tumors are of intermediate signal: lower than the contents of the corpora (particularly when tumescent) but higher than the low signal layers of tunica albuginea and Buck’s fascia (Figs. 4.8–4.11). On ultrasound squamous carcinomas are often heterogenous, but hypoechoic compared to the relatively echogenic tunica albuginea (Figs. 4.9–4.11). Although metastases have a variable appearance, they can usually be distinguished, like primary tumors, from the important normal structures.
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Fig. 4.8 T2-weighted axial MR of the glans showing a pT1G2 squamous cell carcinoma (white arrowheads). The underlying high signal spongiosus is a little compressed but not clearly invaded by the superficial tumor. This was correctly staged T1 on MRI
a
Fig. 4.9 Ulcerating lesion on the glans (white arrowheads, with a white arrow showing the ulcerated part), pT2 on histology and correctly called T2 on MRI (a) and ultrasound (b). CC marks corpus cavernosum, and S the spongiosal part of the glans. In contrast to Fig. 4.8, note that on MR the underlying high signal of the spongiosal tissue of the glans is altered by the tumor, although the tips of the cavernosa are well seen and not involved. The ultrasound confirms involvement of the spongiosal tissue of the glans but not the corpora cavernosa
b
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Radiological Imaging in Penile Cancer
Fig. 4.10 (a) T3 tumor (white arrowheads) with invasion of the corpus spongiosum (CS), corpora cavernosum (L CC), and urethra. Note the fluid in the obstructed urethra (white arrow), a useful sign of involvement, seen on both MRI and ultrasound (b). For an image of more subtle invasion of the corpus cavernosum, see Fig. 4.12
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Fig. 4.11 While most T3 tumors may be adequately assessed clinically, and excision margins confirmed by frozen section, imaging helps to show these rare cases of a skip lesion in the corpus cavernosum. In (a), two discrete tumor foci are seen in the corpora cavernosa on T2-weighted MRI (confirmed as discontinuous on histology). In a Doppler ultrasound image from another patient (b), a hypervascular nodule (white arrows) is seen discrete from the main tumor mass (arrowheads). A black arrow marks the normal cavernosal artery
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Local staging has important implications for surgical planning and prognosis. The distinction between Ta and T1 disease is usually difficult because of the small size of the tumor, with Ta lesions often difficult to see at all on MRI. Imaging becomes important in the distinction between T1 and T2 disease: in other words, is one of the corpora invaded? As to which corpus is involved is also a relevant question, both for surgical planning and because disease-specific survival is considerably better with invasion of the spongiosum compared to cavernosum.31,32 The T3 classification (defined as involvement of prostate or urethra, TNM 2002) is also problematic. First, invasion of the prostate is uncommon without invasion of adjacent structures (i.e, T4) disease.32 Second, if the urethra is invaded, it is often near the meatus and may be treatable with penile-preserving surgery and has a good prognosis.32 This is reflected in the current survival rates for T2 and T3 disease, which are very similar.32 Several studies have examined the performance of ultrasound and MRI in the local staging of penile cancer. The first to assess staging accuracy was in 1994, when ultrasound without intracavernosal agents was compared to histopathology.9 It was difficult to distinguish between involvement of subepithelial connective tissue (T1) and corpus spongiosum (T2), because the tunica albuginea appeared much thinner over the spongiosum compared to the cavernosum, and blended completely with subepithelial connective tissue in the glans. One case of invasion of the corpus cavernosum was correctly identified. The correlation between tumor ‘thickness’ on ultrasound and histology was excellent (R = 0.94). No correlation was seen between grade and acoustic impedance. A second study using ultrasound mainly of clinically T2 lesions found that it measured the size of tumor better than clinical examination and found that tumor was hyperechoic or hypoechoic in roughly equal numbers (Fig. 4.8), and that several cases of urethral invasion not suspected clinically were predicted by ultrasound.33 However, the main focus of this study was the estimation of tumor size, not stage. MR imaging of tumors was first described in detail by Hricak et al. in 1988,3 but the first study to assess local staging accuracy was published in 1995.34 Nine patients were scanned without intracavernosal agents using a 0.5 T magnet and spin echo sequences around 5 mm in thickness, with T1 sequences pre and post contrast: considerably inferior to modern parameters. One tumor in the prepuce was not identified on MRI, and one focus of fibrosis was called tumor (this was also the clinical impression), but otherwise staging was correct. In one case urethral invasion was detected on MR when it was not suspected clinically. T2 sequences gave the best results in 5; in two contrast agents gave ‘better delineation’. Clinical findings, ultrasound, and MRI were compared in a study using a 1.5 T machine with T2 and T1 pre and post iv contrast, but not using intracavernosal agents to produce tumescence for the scan.2 This group found that tumor size was best determined by clinical examination, and that the positive clinical impression of T2 disease was correct in 6/6 patients. However, MRI predicted all cases of corpus cavernosum infiltration, while one was missed clinically and three missed on ultrasound. Urethral infiltration was seen in four patients and detected in three on MRI, two on ultrasound, and one clinically. Ultrasound and MRI had similar precision in predicting infiltration depth. The authors concluded that imaging (in particular with MRI) was useful when
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infiltration of the corpora ‘could not be determined properly by clinical examination’, and that MRI is useful for showing the proximal extent of disease and planning the extent of surgery.2 MR is likely better than ultrasound for very proximal lesions, which can be hard to see on ultrasound because the more proximal structures are deeper.16 The first study to describe the use of MRI with intracavernosal agents for staging was published in 2004,18 again using a 1.5 T magnet and T2 and T1 pre and post contrast sequences, with 3–4 mm slice thickness. 10 mg of alprostadil intracavernosally produced adequate tumescence in nine patients, but priapism in one. MRI correctly identified all cases of cavernosal invasion (five patients) but overestimated disease in three, with two T1 lesions called T2, and one T2 lesion called T3 due to apparent urethral involvement. A larger study published in 2007 assessed MR after 10–20 mg alprostadil in 55 patients, with T2 and T1 pre and post contrast sequences.35 Although MR was described as ‘excellent’ and correctly predicted involvement of the corpus cavernosum in two patients, it did overstage the disease, with six cases of T1 tumors called T2. This was ascribed to technical factors – poor response to prostaglandin, previous radiotherapy, motion artifact and infection – but it is likely that some of the error was also due to fundamental limits to the resolution of MRI and the difficulty in distinguishing abutment and bulge from true invasion. No cases of priapism were seen. It is worth discussing the T staging in the glans in some detail, especially as it is the site of the majority of penile carcinomas.36 It was noted in an early ultrasound study that the tunica albuginea in the glans becomes difficult to see and blends with subepithelial connective tissue.9 Not only is staging therefore more difficult, but the finding of T2 disease has different implications, with glansectomy (partial or complete) the treatment of choice37,38 as opposed to partial or total penectomy when T2 disease involves the distal corpora cavernosa.39 While imaging may be relatively poor in early T2 disease in the glans, this may matter little if surgical margins are confirmed with frozen section analysis39; on the other hand prediction of cavernosal involvement seems excellent on modern MRI35 and is important for counseling the patient and surgical planning. We have discussed the use of contrast in the section on MRI techniques, and reiterate here that although there are no publications formally comparing accuracy with and without contrast, we have not generally found it useful if intracavernosal agents are used to produce erection. While an early series without intracavernosal prostaglandin found that contrast ‘provided a better delineation of tumor’ in two patients,34 a more recent series using artificial erection, showed consistently better delineation of tumor and corpora cavernosa on T2-weighted images than T1 (including with contrast).18
4.4
Other Primary Penile Tumors
Anterior urethral tumors are rare, and usually of the squamous type rather than TCC,40,41 with survival highly dependent on local stage.42 Penile tumors tend to present early and have a good prognosis; those of the bulbomembranous urethra
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Fig. 4.12 T2-weighted sagittal image showing a recurrent transitional cell tumor of the urethra (white arrowheads). Subtle low signal in the corpus cavernosum (white arrows) indicates early invasion (confirmed on histology). Compare with Fig. 4.3 to see how easily this might be missed on a scan without alprostadil. The fluid in the proximal urethra (black arrows) is a sign of urethral obstruction
are commoner but usually present later,40,43 although penis-preserving surgery is still feasible in some.44 Appearances on MRI and ultrasound are similar to other squamous tumors of the penis, although urethral obstruction (and visible fluid in the urethra proximal to the tumor) is expected earlier (Fig. 4.12). Next, although over 95% of penile tumors are squamous, many other types occur.7 Hemangioma, lymphangioma, neurofibroma, and leiomyoma are benign tumors which have been described in the penis45 and are likely to have similar appearances to elsewhere. Epithelioid sarcomas are very rare, but important because they can mimic Peyronie’s disease or chronic inflammation and have a propensity for local spread and recurrence and lymphatic involvement; T2 appearances are variable: sometimes the lesion is low signal (like fibrosis),46 others isointense to corpora on T2 images.47 Kaposi’s sarcoma is very rare; there are no specific features to make the diagnosis but there are usually lesions elsewhere and MR is useful for delineating spread. Melanoma often presents late in the penis, with lymphatic spread48,49 and recurrence is common; a specific MR feature of melanoma metastases is hyperintensity on unenhanced T1-weighted sequences, and loss of signal on T2* images due to high protein content.50 Penile lymphoma most often occurs in the shaft (often outside the corpora), but is also seen in the glans, and may occur as a result of hematogenous spread or local extension. The signal intensity, as elsewhere in the body, is usually homogenous and intermediate on T1 and T2-weighted sequences, with reports of enhancement after iv contrast varying from ‘minimal’26 to ‘obvious’.27
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Fig. 4.13 (a) Involvement of the penis with metastasis from renal cell carcinoma. Malignant priapism is one area where both Doppler ultrasound and contrastenhanced scans may be useful. The presentation was with high-flow priapism (systolic velocity >50 cm/s). The velocity 1 week later fell to <20 cm/s and at this point an MR was performed. The T2-weighted image (b) shows subtle patchy signal in the corpora cavernosa but the subtracted postcontrast image shows peripheral enhancement most prominent at the corporal tips (white arrows), an atypical appearance for low flowpriapism, where persisting enhancement is usually seen at the base, and around the cavernosal vessels. Histology confirmed renal cell carcinoma
4.5
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Penile Metastases
Metastasis to the penis are rare, with genitourinary and gastrointestinal tumors comprising 80%: mainly bladder, prostate, rectum, kidney, and testis (in that order).51,52 Other reported sites of origin are lung, nasopharynx, pancreas, liver, and melanoma, as well as lymphoma.52 The route of spread is debated: seeding from instrumentation in prostate and bladder tumors is possible, but arterial, venous, and even extension along nerves has been postulated, and in around three quarters there is spread to other organs, resulting in a poor prognosis.52 The commonest site of involvement is the corpora cavernosa, with tumor in corpus spongiosum and glans less common, and a common presentation is of difficulty in voiding.28 Here we might mention the use of cavernosometry to delineate intracavernosal filling defects53 – an invasive and sometimes painful technique that has been almost entirely superseded in this context by the use of MR or ultrasound, especially with intracavernosal agents. The imaging appearances of metastases vary from discrete nodules to extensive, often peripheral infiltration3,28 (Fig. 4.13). Both ultrasound and MRI can be used to delineate tumor and in spite of one case report describing a false-positive infiltration of the tunica albuginea on ultrasound but not MRI,54 there are little data to suggest which modality is most sensitive or specific in this context.
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Penile metastases may result in priapism, and this was the presenting symptom in 27% of a case review of 51 patients with penile metsatasis.52 The mechanism is likely to be interruption to venous drainage leading to stasis and thrombosis,52 although at least in some cases there may be malignant irritation of the nerves55 or intracavernosal shunting, with the last two likely to show increased, rather than reduced, flow on Doppler ultrasound.56 MRI and ultrasound may have complimentary roles in this context, and may be used to distinguish true priapism from extensive infiltration. MRI likely provides the best anatomical detail – including the distinction of thrombus from tumor if contrast is used,8 with ultrasound providing additional information on the flow in the cavernosal arteries.
4.6
Assessing Lymph Nodes and Distant Metastases
There are several approaches to determining whether there is nodal involvement due to penile cancer. At the simplest level the nodes may be palpated. Next, we may use imaging to assess not only size, but morphology of the nodal chain. Functional techniques such as PET or MR lymphography may add further information, and finally we may use histology: either by fine needle aspiration, biopsy, sentinel lymph node biopsy, or lymphadenectomy. We will discuss the performance of each of these investigations, and at the end of this section address the appropriate nodal staging investigations for different grades of disease.
4.6.1
Ultrasound and MR Appearance of Lymph Nodes
Normal lymph nodes are usually ovoid in shape, with a fatty hilum and an organized vascular pattern radiating from the hilum57 (Fig. 4.14). Some features, such as focal areas of necrosis, are highly specific for malignancy, and in general malignant nodes tend toward roundness and may lose their fatty hilum58 (Fig. 4.15). One recent study of the use of ultrasound in 44 patients, the majority of whom had penile cancer, showed that in 42/44 patients with metastasis at least one of the following features suggestive of malignancy was present: long/short axis ratio < 2, absent hilum, wide cortex, or eccentric cortical widening. The problem with this study is that although the individual criteria had acceptable specificity, and each had a positive predictive value >78%, many reactive nodes also showed at least one malignant feature.59 Others emphasize that the presence of a normal fatty hilum cannot be used to exclude malignancy.60 A further set of criteria based on Resistive index and Pulsatility index have been proposed, with one author finding that cutoffs of RI > 0.8 and PI > 1.6 had a sensitivity (specificity) of 80% (94%) and 94% (97)%, respectively, in the four fifths of neck nodes that had detectable flow.61 Whether such results could be replicated in penile squamous carcinoma is, however, uncertain, and Doppler studies can be challenging: morphology and size are the mainstay of diagnosis.
86 Fig. 4.14 (a–c) Features of a benign lymph node (arrowheads) on ultrasound, doppler ultrasound, and MRI respectively. Note the fatty hila in each case (white arrow). The ultrasound shows ovoid nodes with a regular cortex of uniform thickness; on doppler (b), small vessels radiate symmetrically from the hilum (small white arrows). MRI (c) shows nodes in short axis: approximately round, but with fatty hila and regular cortex
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What of size criteria? As benign nodes enlarge, they preserve their ovoid shape, if the ratio of long to short axis diameters remained >2, the negative predictive value in two series was 81–87%.59,62 Because malignant nodes tend to be more circular, enlargement of the short axis is often used for detecting them: one study of vulval
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c Fig. 4.15 Several features of malignant nodes. (a) Ultrasound shows an enlarged node with eccentric, lobulated enlargement of the cortex (arrowheads show the hilum, and the arrows the eccentric widening), and (b) a doppler trace of the same node showing a resistive index of 1.2. (c–f) Malignant nodes (arrowheads) with necrosis on ultrasound, CT, T2-weighted MRI, and postcontrast MRI (in different patients). The necrotic focus (white arrow, (c)) is nearly anechoic on ultrasound. On CT (d) it is of low density (close to water). (e) A node consisting of an eccentric nodule (black arrow) and fluid necrosis (white arrow) on a T2-weighted axial MR sequence. (f) A postcontrast gradient echo fat-saturated coronal sequence of the same node showing the nonenhancing necrotic component
88 Fig. 4.15 (continued)
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nodes (studies purely of penile cancer are sparse) found that a short axis of 8 mm diameter or more had a sensitivity of 83% for the detection of malignancy.63 However, this was a small group of patients and overall there is great overlap in short axis size between malignant and benign nodes in the groin.64,65 Sohaib et al. achieved a sensitivity and specificity of 40% and 97% using 10 mm for superficial nodes, and 50% and 100% using 8 mm for deep inguinal nodes,66 while others have achieved better results (sensitivity of 87%, specificity 81%) for a morphological criterion of short/ long axis ratio >0.75. The fundamental limits to the technique are that (1) a small degree of infiltration will not significantly affect the size of a node and (2) reactive nodal enlargement from local inflammation is particularly common in cancer of the penis, and the cause of nodal enlargement in 25–50% of palpable groin nodes at presentation,1,67 though palpable nodes at follow-up are almost always malignant.68 In the pelvis studies of genitourinary cancers which have primarily used size criteria (usually conducted with CT and MRI) have shown sensitivity ranging from 6% to 78% for malignancy, with specificity 65% to 98%, depending on the cancer studied and the size criterion used.69,70 The commonest size criterion for pelvic nodes (usually based on studies of commoner cancers such as prostate and cervix) is 10 mm in short axis,14,70 though others advocate 8 mm if the node is round71; there are no large studies specifically of penile cancer in the pelvis. Although signal intensity is a poor discriminator in inguinal72 and pelvic nodes (including with contrast enhancement),14 necrosis (Fig. 4.15) in a pelvic node (indicated by a component showing signal characteristics of fluid) is a highly suggestive
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Fig. 4.16 Positive lymph nodes on PET. (a) Two nodes (large arrows) in the right groin are suspicious by morphology and size criteria (though they could also be reactive). (b) On PET they show markedly increased uptake and were positive at histology. Several smaller nodes in the left groin were negative on PET (small arrows) and at histology. Pelvic nodes were negative at PET and histology after pelvic nodal dissection
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finding,7 and in head and neck squamous cancers at least is a reliable indicator of malignancy.73 Although often occurring in larger nodes, it can also be seen in those <1.5 cm; on MRI as a focus of fluid signal, on CT as a low density focus and on ultrasound as a hypo or hyperechoic focus, or one that shows fluid movement with pressure from the probe.73 For this assessment MRI and CT are likely comparable, with ultrasound inferior (especially in the pelvis, where views are poor).73
4.6.2
Improving the Performance of Lymph Node Staging
4.6.2.1
Positron Emission Tomography (PET)
Squamous cancers usually have a high glycolytic rate and show increased uptake of glucose and an analogue, fluorodeoxyglucose,74 which can be labeled with 18F. Modern PET scanners usually also have a CT capability, to enable accurate coregistration of functional and anatomical information (vital when assessing nodes), which has been shown to increase the performance compared to the two tests alone75,76 (Fig. 4.16). The first study of PET in penile cancer included ten patients with primary disease and three with recurrence, the majority of whom were not suspected to have
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lymphadenopathy clinically. Analyzed by patient, 4/5 of those with positive nodes were correctly identified, and there were no false positives. Because uptake of squamous carcinoma is often intense, malignant nodes measuring 0.7–1.1 cm were correctly identified as positive, but one 5 mm node was missed. Most of the primary lesions in the penis also showed uptake.77 This early study was encouraging but PET cannot overcome the fundamental problem of resolution: a recent study examining 42 clinically negative groins in 24 patients found that only one of five patients with clinically occult metastases was correctly identified, with the missed foci of nodal tumor <1 cm in each case.78 PET may have more of a role in the detection of pelvic metastases in patients with histologically or cytologically proven involved groin nodes, either at presentation or during follow-up. In a recent series of 18 patients, with analysis and surgical correlation possible in 28 hemi-pelvises, PET identified 10/11 tumor-positive cases and correctly identified all 17 negative cases.79 In five patients, there were distant sites of uptake thought to represent metastasis, confirmed histologically in four. At the level of individual nodes, there was one false negative, containing a 5 mm deposit, but it is important to note that the true positive deposits were 9 mm or more in diameter,79 and that most would be expected to be detected by size criteria, although the short axis size of the lymph nodes was not specifically stated in this study.
4.6.2.2
MR Lymphography
Although MRI usually has good soft tissue contrast, tumor does not usually have a markedly different signal to lymph nodes.72 We have already mentioned that size criteria are ineffective, with in some studies well over half of involved nodes having a size smaller than the 1 cm size criterion that results in acceptable specificity.70 Morphologic criteria such as irregular border or mixed signal intensity may have a high specificity but the problem remains that these properties are easier to see in large nodes and may miss small deposits of tumor.64,80,81 The use of superparamagnetic iron oxide nanoparticles such as ferumoxtran-10 (Sinerem – Guerbet, Aulnay-sous-Bois, France) can markedly increase the contrast between tumor and normal lymph node. If injected intravenously the particles are taken up throughout the body by macrophages that accumulate in benign lymph nodes. The iron oxide results in reduced signal on T2 and T2* images, so that tumor involvement in nodes is seen as an area of relatively high signal that has failed to darken (Fig. 4.17). With this technique we have the ability to detect deposits down to a diameter of around 2 mm,82 and the results are a clear improvement on using size criteria alone. In the study published in the New England Journal of Medicine, sensitivity (specificity) for the detection of nodal involvement in prostate cancer improved from 35% (90%) to 91% (98%) with Sinerem,82 and in one study in a smaller number of patients with penile cancer, involving seven patients, sensitivity by node increased from 13% (76%) to 100% (97%).72
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Fig. 4.17 Image (a) shows two deep inguinal nodes of similar size on a standard T2-weighted axial sequence. Both are of high signal. After Sinerem – image (b), the left node (arrow) becomes uniformly dark, indicating functioning (benign) lymphatic tissue. The right-sided node (arrowhead) remains partly high signal, indicating infiltration by tumor. By kind permission of Drs. S. McDougall and M. Harisinghani
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Sinerem is well-tolerated, with one case of fatal anaphylactic shock with administration of the undiluted product,83 but although it remains under active study in Europe and the USA, it has not been fully licensed in either, and whether it ever will be is uncertain.
4.6.2.3
FNA Biopsy
A study of 118 patients with penile cancer published in 1991 found that ‘the classification of regional nodes by clinical examination is hardly improved by additional imaging studies’, with fine needle aspiration detecting no additional cancers.84 However, later studies are more encouraging. In a series of 28 patients, those with clinically suspicious groin nodes were subjected to FNA and then block dissection; 17 were histologically positive and FNA had sensitivity and specificity of 100%. However, the authors cautioned that all but one patient had stage II or III disease, and that the technique was much more difficult in impalpable nodes.85 A later study in 16 men with palpable nodes showed a sensitivity of 93% and specificity of 91% in 25 FNA samples (14 nodes were positive) performed by urologists without ultrasound guidance, giving an accuracy of 92%. In contrast, clinical assessment had an accuracy of only 66%.86
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More recently a series of 43 patients with 83 clinically node-negative inguinal regions underwent ultrasound-guided FNA before either sentinel node biopsy or inguinal block dissection. Thirty four groins had suspicious nodes (length/width < 2, wide cortex or narrow/absent hilum) and underwent FNA. The sensitivity was only 39%, with a specificity of 100%, and the authors propose it as a useful technique to lessen the need for sentinel node biopsy: if positive on FNA, they proceeded straight to inguinal node dissection.87 It is clear from this study, however, that FNA, even guided by ultrasound, cannot be used to exclude tumor in groins with impalpable disease. Recent work by another group in 61 clinically node-negative patients proceeding to sentinel node biopsy on the same day showed positive cytology at ultrasound-guided FNA in eight inguinal ‘basins’, but false-negative results in six groins. The sensitivity of the technique is given at 74%, but it is hard to draw this conclusion from the data.88
4.6.2.4
Sentinel Node Biopsy
A modified inguinal lymph node dissection is likely to sample the first draining node of a penile cancer, but although it has less morbidity than a radical groin dissection, significant complications remain, with lymphoedema, wound necrosis and seroma often seen.89 Might it be possible to sample the first draining node and further minimize morbidity? In a study in 1977, initially using lymphangiography, Cabanas identified a sentinel lymph node at the anterior or medial aspect of the superficial epigastric vein, medial to and above the epigastric–saphenous junction.90 In 15 patients positive for metastatic disease, this node was always involved, and sometimes the only positive node. Others describe ‘the most medial inguinal node of the horizontal chain’, just lateral to the pubic tubercle, as frequently enlarged,85 but there are several reports of patients with negative sentinel nodes (according to the Cabanas definition) who went on to develop pelvic nodal tumor,91,92 and it is clear that an anatomical approach alone is insufficiently sensitive to locate the ‘sentinel’ (or first draining) node. Subsequent work from the MD Anderson Cancer center suggested that even an ‘extended’ sentinel node dissection might miss a quarter of involved groins and could not be recommended.93 Lymphoscintigraphy, with injection of a radiolabeled tracer into the primary tumor and imaging of draining nodes with a gamma probe was described 30 years ago94 and node mapping with injection of blue dye was described for melanoma in 1992.95 In the penis it was first described in 2000 by Steinbecker96 and Han,97 who used both 99mtecnetium-labeled sulphur colloid and blue dye, locating the sentinel node with a g probe. The first study to use sentinel node biopsy in penile cancer examined 90 patients with clinically node-negative disease.98 Lymphoscintigraphy with 99mTecnetiumlabeled nanocolloid showed 217 sentinel nodes on imaging with a gamma camera; the following day 1 mL of patent blue dye was injected intradermally around the tumor, and the combination of blue staining and positivity with a g probe identified
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Fig. 4.18 Sentinel node identification. Static image taken 2 h after injection of labeled colloid radiotracer into the skin around a penile lesion (black arrow). Uptake has only occurred in right-sided nodes, and a reinjection should be considered. The first draining node (asterisk, arrow head) is the sentinel node; the more superior node (arrow head) lies along the distal external iliac chain
208 sentinel nodes in 149 inguinal regions, with lymphatic drainage to both groins occurring in 81% of patients and an overall surgical node identification rate of 98%. Around one quarter of nodes were only positive with the gamma probe; three quarters also stained with blue dye. Sentinel nodes were positive in 19 inguinal regions, but a confirmatory regional lymph node dissection was performed only if the sentinel node was positive. At median follow-up of 36 months, there were five regional recurrences, giving a sensitivity (which given the follow-up, may be an overestimate) of around 80% (Fig. 4.18). A similar technique was used in a further study of 140 patients with clinically nodenegative groins. At least one sentinel node was seen in all but two patients, and was positive in 37 inguinal regions of 31 patients, in which case a ‘standard’ groin node dissection was performed.99 It was the only involved node in 78% of patients. The median follow-up was 52 months and the sensitivity 84%. A follow-up study by the same group showed improved results (sensitivity 95%) with some modifications to the technique: preoperative ultrasound with FNA of suspicious nodes, serial sectioning of the sentinel node, and surgical exploration of groins with nonvisualized sentinel nodes.100 A recent study of 60 patients from Denmark with clinically negative groins (or negative FNA with palpable nodes) showed a comparable sensitivity of 91%.101 Series with confirmatory lymph node dissections rather than clinical follow-up are smaller. One, using a similar technique to that described above, found metastases in 5 of 16 patients, bilateral in 3.102 Again, three quarters of nodes also showed dye uptake, and all groins negative at sentinel node biopsy were negative at subsequent inguinal dissection. However, in one groin a sentinel node was not seen and tumor was subsequently found in two nodes at inguinal dissection: the sensitivity was 88%. A further series of 31 patients again had one patient with a positive node at inguinal dissection without an identifiable sentinel node, and one false-negative sentinel node, out of a total of seven positive groins, giving a sensitivity of 71%. The findings with palpable nodes were less encouraging in a study of 15 patients, nine with clinically palpable nodes, with sentinel node biopsy (without dye) followed by groin dissection. 3/18 groins without clinically suspicious nodes were positive and
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correctly identified using sentinel node biopsy but of the clinically suspicious groins, 7/12 of which had tumor, six were not identified by the sentinel node technique.103 Importantly, many nodes at the dissection which were highly suspicious for tumor (and proved positive) did not take up tracer: the poor performance in palpable nodes is likely due to partial necrosis and lymphatic blockage.103 A similar effect has been seen in breast cancer.104 In summary, sentinel node biopsy may have a high sensitivity when no groin nodes are palpable, but there are several compelling reasons for first performing ultrasound +/− FNA. First, ultrasound may detect over half (8/14 in one study88) of involved groins, indicating the need for a formal inguinal node dissection. Second, FNA may sometimes detect disease where sentinel node biopsy does not: first, a sentinel node is not always identified,100 or may be misidentified as a ‘neo’ sentinel node because of rerouting of lymph drainage around a positive node obstructed by tumor.100 Second, histological analysis is inevitably prone to a small degree of error: in the study by Crawshaw et al. 2/17 positive nodes were called negative at initial histological analysis, with micrometastases found on pathological re-examination.88 Others have also described missed micrometastases at initial analysis, and because of the exacting demands on the pathologist do not routinely use frozen section analysis.100
4.7
Imaging the Complications of Surgery
Radical inguinal node dissection in particular has a high incidence of complications, including wound infection, skin necrosis, wound dehiscence, lymphoedema, and lymphocele.13 Imaging can sometimes be used to distinguish an abscess from hematoma, seroma, or lymphocele; on CT or MRI, infection often results in a thicker, enhancing wall and heterogenous contents (sometimes with air).105 However, aspiration is often diagnostic in groin collections, with ultrasound guidance if necessary.
4.8
Distant Metastases
At presentation, distant metastases are present in only 3% of patients and are associated with a very poor prognosis, with the commonest sites lung, liver, and retroperitoneum, as well as bone.106 In likely node-positive cases an abdominal CT will image para-aortic nodes or liver, although MR is a sensitive method for the detection of abdominal nodes,107 retroperitoneal disease, and liver108 if the correct sequences are performed. The EAU recommends a pelvic CT for positive inguinal nodes and an abdominal CT for positive pelvic nodes, though we perform a CT of abdomen and pelvis in all cases of node-positive disease. In either case, unless there is a high clinical suspicion, a plain chest radiograph is adequate, rather than CT.1 If there is symptomatic bone pain or pathological fracture, a bone scan may be used to delineate metastases,1 although CT can provide more anatomical information, and there is emerging evidence that MRI (using STIR sequences) may be as effective as bone scan in the detection of bony metastases.109
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If performed for pelvic staging, a combined PET/CT scan is likely to be a sensitive test for abdominal, chest, and bone metastases given the high uptake of the primary tumor.77
4.9
An Approach to Staging the Disease: EAU Guidelines
The most recent EAU guidelines give an approach for staging the disease, and to summarize them1 we might divide up the staging according to the TNM classification. T: local staging. Ultrasound and MRI are ‘optional’. MRI is likely slightly more accurate for larger tumors with deep invasion; in smaller tumors ultrasound may be of higher resolution, though if the tumor is small and superficial imaging may not add usefully to clinical and operative findings. Some authors now advocate MRI for all suspected penile cancers,7 though this is not part of the guidelines. N: nodal staging. The appropriate investigations depend on clinical and pathological findings. For high-risk (pT2 or G3) disease, there is a strong case for bilateral lymphadenectomy regardless of clinical findings (although some centers still perform sentinel node biopsy100). For low and intermediate-risk disease with impalpable nodes, ultrasound +/− fine needle aspiration can be performed first; if positive, the need for inguinal lymphadenectomy is clear. If negative, then in low-grade tumors surveillance is reasonable. For intermediate-(pT1 G2), defined in the 2004 guidelines110) risk tumors, sentinel node biopsy, if available, may be used, and some would advocate its use in some cases of low-risk disease with significant potential for metastasis (particularly pT1 G167), or according to nomograms of risk including depth and perineural invasion.111 However, the learning curve is steep and this necessitates the centralization of surgery for penile cancer. One other possible application of sentinel node biopsy is in the contralateral groin, with impalpable nodes, when tumor has already been found on the opposite side. For palpable nodes, sentinel node biopsy is not reliable, and an attempt at diagnosis should be made by FNA, core or excision, ideally when a possible inflammatory swelling has been allowed to subside, with the option of repeating the FNA/core biopsy in negative cases. PET and lymphotropic nanoparticles are described as ‘under investigation’. M: CT of the pelvis +/− abdomen is recommended in all cases of node-positive disease, with bone scan in symptomatic patients.
4.10
Follow-up
The type and frequency of follow-up varies with the stage and grade of disease at initial presentation, but most patients with penile cancer will require surveillance, primarily to detect local recurrence and nodal disease which have the potential for cure, as opposed to metastatic disease which has an almost universally poor
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Table 4.1 Follow-up intervals for pelvic nodes in the most recent (2009) EAU guidelines Follow-up interval – Follow-up interval – Maximum length Groin findings years 1 and 2 years 3,4, and 5 of follow-up Clinically negative, “wait 3 months 6 months 5 years and see” Negative groin nodes at 6 months 1 year 5 years dissection Positive groin nodes at 3 months 6 months 5 years dissection
outcome.112 The rate of such local recurrence and nodal metastasis varies greatly with disease grade, but is around 30% for patients with T1G2 tumors.113 Current EAU guidelines from 2009 recommend primarily clinical follow-up after partial penectomy, but intensive imaging follow-up for nodal recurrence, according to the schedule in Table 4.1. The previous guidelines, published in 2004, recommended CT follow-up, together with chest radiographs, for lymph node-positive patients,110 but the most recent guidelines modify the schedule and replace CT with ultrasound +/− fine needle aspiration, both for node positive and node-negative patients.1 Bone scans and abdominal CT are reserved for symptomatic patients. This reliance on ultrasound +/− FNA depends on radiological and cytological expertise, and is also inadequate for the early detection of pelvic nodal disease, as all but the most superficial pelvic nodes are difficult to see on ultrasound unless clearly enlarged. It may be, therefore, that in some patients CT is more practical than ultrasound, or that a combination of the two techniques most suitable. For a clinically suspected local recurrence, a follow-up MRI may be used to stage the disease and plan surgery, although the presence of fibrosis may complicate assessment. There is some evidence for pelvic cancers that on dynamically enhanced scans fibrosis enhances later than tumor,114 but little evidence that the resolution of gradient echo sequences used is sufficient to detect small foci of recurrence in the penis.7
4.11
Future Directions
The data on sentinel node biopsy is accumulating, though this is a rare disease and large studies take time. While it is established as a useful technique, larger studies will help to determine whether, together with ultrasound, it is sufficiently sensitive to exclude tumor in patients with relatively high-risk disease. MRI is likely to become increasingly used: not only as the best modality for local staging, but also in the characterization of nodes. One small study of lymphotrophic nanoparticles has given impressive results,72 but it is very hard to say whether the technique might be comparable in efficacy to sentinel node biopsy. There is no reason why the two techniques could not be assessed in the same group of patients to answer the question.
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PET seems fundamentally compromised in resolution, but the studies in pelvic nodes are encouraging, although it is not yet clear whether early detection of involved pelvic nodes can have a significant impact on prognosis. This question is even more relevant to the detection of distant metastasis: while whole body MRI is emerging as a rival to CT and bone scan,108 and PET could potentially play the same role, the clinical impact may be limited. A focus on outcome is important: while MRI and sentinel node biopsy are impressive techniques, they are expensive and not available in all centers. They will have to prove their worth, in terms of better survival and reduced morbidity, against simpler techniques such as ultrasound and superficial node dissection.
References 1. Pizzocaro G, Algaba F, Horenblas S, et al. EAU Guidelines on penile cancer 2009. Eur Urol. 2010;57(6):1002-1012. 2. Lont AP, Besnard APE, Gallee MPW, et al. A comparison of physical examination and imaging in determining the extent of primary penile carcinoma. BJU Int. 2003;91:493-495. 3. Hricak H, Marotti M, Gilbert TJ, et al. Normal penile anatomy and abnormal penile conditions: evaluation with MR imaging. Radiology. 1988;169:683-690. 4. Pretorius ES, Siegelman ES, Ramchandani P, et al. MR imaging of the penis. Radiographics. 2001;21:S283-S298. discussion S298-S299. 5. Hsu GL, Hsieh CH, Wen HS, et al. Penile venous anatomy: an additional description and its clinical implication. J Androl. 2003;24:921-927. 6. Singh AK, Gonzalez-Torrez P, Kaewlai R, et al. Imaging of penile neoplasm. Semin Ultrasound CT MR. 2007;28:287-296. 7. Kochhar R, Taylor B, Sangar V. Imaging in primary penile cancer: current status and future directions. Eur Radiol. 2010;20(1):36-47. 8. Kirkham APS, Illing RO, Minhas S, et al. MR imaging of nonmalignant penile lesions. Radiographics. 2008;28(3):837-853. a review publication of the Radiological Society of North America, Inc. 9. Horenblas S, Kroger R, Gallee MP, et al. Ultrasound in squamous cell carcinoma of the penis: A useful addition to clinical staging? A comparison of ultrasound with histopathology. Urology. 1994;43:702-707. 10. Kaneko K, De Mouy EH, Lee BE. Sequential contrast-enhanced MR imaging of the penis. Radiology. 1994;191:75-77. 11. Bertolotto M, Mucelli RP. Nonpenetrating penile traumas: sonographic and Doppler features. AJR Am J Roentgenol. 2004;183:1085-1089. 12. Jacobellis U. Modified radical inguinal lymphadenectomy for carcinoma of the penis: technique and results. J Urol. 2003;169:1349-1352. 13. Protzel C, Alcaraz A, Horenblas S, et al. Lymphadenectomy in the surgical management of penile cancer. Eur Urol. 2009;55:1075-1088. 14. Yang WT, Lam WW, Yu MY, et al. Comparison of dynamic helical CT and dynamic MR imaging in the evaluation of pelvic lymph nodes in cervical carcinoma. AJR Am J Roentgenol. 2000;175:759-766. 15. Rockall AG, Sohaib SA, Harisinghani MG, et al. Diagnostic performance of nanoparticleenhanced magnetic resonance imaging in the diagnosis of lymph node metastases in patients with endometrial and cervical cancer. J Clin Oncol. 2005;23:2813-2821. 16. Bertolotto M, Serafini G, Dogliotti L, et al. Primary and secondary malignancies of the penis: ultrasound features. Abdom Imaging. 2005;30:108-112.
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17. Wilkins CJ, Sriprasad S, Sidhu PS. Colour Doppler ultrasound of the penis. Clin Radiol. 2003;58:514-523. 18. Scardino E, Villa G, Bonomo G, et al. Magnetic resonance imaging combined with artificial erection for local staging of penile cancer. Urology. 2004;63:1158-1162. 19. Bacar MM, Batislam E, Altinok D, et al. Sildenafil citrate for penile hemodynamic determination: an alternative to intracavernosal agents in Doppler ultrasound evaluation of erectile dysfunction. Urology. 2001;57:623-626. discussion 626-627. 20. Hatzimouratidis K, Hatzichristou DG. A comparative review of the options for treatment of erectile dysfunction: Which treatment for which patient? Drugs. 2005;65:1621-1650. 21. Linet OI, Ogrinc FG. Efficacy and safety of intracavernosal alprostadil in men with erectile dysfunction. The Alprostadil Study Group. N Engl J Med. 1996;334:873-877. 22. Muruve N, Hosking DH. Intracorporeal phenylephrine in the treatment of priapism. J Urol. 1996;155:141-143. 23. Te CC, Vemulapalli S, Confer SD, et al. Recurrent malignant melanoma of the penis. Urology. 2008;72(5):e15-e16. 1185. 24. Ribuffo D, Alfano C, Ferrazzoli PS, et al. Basal cell carcinoma of the penis and scrotum with cutaneous metastases. Scand J Plast Reconstr Surg Hand Surg. 2002;36:180-182. 25. Sasso F, Delicato G, Gentile G, et al. Primary synovial sarcoma of the penis. J Urol. 2002;168:633. 26. Chiang K-H, Chang P-Y, Lee S-K, et al. MR findings of penile lymphoma. Br J Radiol. 2006;79:526-528. 27. Kendi T, Batislam E, Basar MM, et al. Magnetic resonance imaging (MRI) in penile metastases of extragenitourinary cancers. Int Urol Nephrol. 2006;38:105-109. 28. Lau TN, Wakeley CJ, Goddard P. Magnetic resonance imaging of penile metastases: a report on five cases. Australas Radiol. 1999;43:378-381. 29. Sherwood JB, Sagalowsky AI. The diagnosis and treatment of urethral recurrence after radical cystectomy. Urol Oncol. 2006;24:356-361. 30. Bordeau KP, Lynch DF. Transitional cell carcinoma of the bladder metastatic to the penis. Urology. 2004;63:981-983. 31. Villavicencio H, Rubio-Briones J, Regalado R, et al. Grade, local stage and growth pattern as prognostic factors in carcinoma of the penis. Eur Urol. 1997;32:442-447. 32. Leijte JA, Gallee M, Antonini N, et al. Evaluation of current TNM classification of penile carcinoma. J Urol. 2008;180:933-938. discussion 938. 33. Agrawal A, Pai D, Ananthakrishnan N, et al. Clinical and sonographic findings in carcinoma of the penis. J Clin Ultrasound. 2000;28:399-406. 34. de Kerviler E, Ollier P, Desgrandchamps F, et al. Magnetic resonance imaging in patients with penile carcinoma. Br J Radiol. 1995;68:704-711. 35. Kayes O, Minhas S, Allen C, et al. The role of magnetic resonance imaging in the local staging of penile cancer. Eur Urol. 2007;51:1313-1318. discussion 1318-1319. 36. Pow-Sang MR, Benavente V, Pow-Sang JE, et al. Cancer of the penis. Cancer Control. 2002;9:305-314. 37. Smith Y, Hadway P, Biedrzycki O, et al. Reconstructive surgery for invasive squamous carcinoma of the glans penis. Eur Urol. 2007;52:1179-1185. 38. Brown CT, Minhas S, Ralph DJ. Conservative surgery for penile cancer: subtotal glans excision without grafting. BJU Int. 2005;96:911-912. 39. Minhas S, Kayes O, Hegarty P, et al. What surgical resection margins are required to achieve oncological control in men with primary penile cancer? BJU Int. 2005;96:1040-1043. 40. Gillitzer R, Hampel C, Wiesner C, et al. Single-institution experience with primary tumours of the male urethra. BJU Int. 2008;101:964-968. 41. Dinney CP, Johnson DE, Swanson DA, et al. Therapy and prognosis for male anterior urethral carcinoma: an update. Urology. 1994;43:506-514. 42. Farrer JH, Lupu AN. Carcinoma of deep male urethra. Urology. 1984;24:527-531. 43. Gheiler EL, Tefilli MV, Tiguert R, et al. Management of primary urethral cancer. Urology. 1998;52:487-493.
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44. Christopher N, Arya M, Brown RS, et al. Penile preservation in squamous cell carcinoma of the bulbomembranous urethra. BJU Int. 2002;89:464-465. 45. Dehner LP, Smith BH. Soft tissue tumors of the penis: a clinicopathological study of 46 cases. Cancer. 1970;25:1431-1447. 46. Oto A. MR findings of penile epithelioid sarcoma. Eur Radiol. 2000;10:1836. 47. Sirikci A, Bayram M, Demirci M, et al. Penile epithelioid sarcoma: MR imaging findings. Eur Radiol. 1999;9:1593-1595. 48. de Bree E, Sanidas E, Tzardi M, et al. Malignant melanoma of the penis. Eur J Surg Oncol. 1997;23:277-279. 49. Rashid AM, Williams RM, Horton LW. Malignant melanoma of penis and male urethra. Is it a difficult tumor to diagnose? Urology. 1993;41:470-471. 50. Gaviani P, Mullins ME, Braga TA, et al. Improved detection of metastatic melanoma by T2*weighted imaging. AJNR Am J Neuroradiol. 2006;27:605-608. 51. Perez LM, Shumway RA, Carson CC 3rd, et al. Penile metastasis secondary to supraglottic squamous cell carcinoma: review of the literature. J Urol. 1992;147:157-160. 52. Chan PT, Begin LR, Arnold D, et al. Priapism secondary to penile metastasis: a report of two cases and a review of the literature. J Surg Oncol. 1998;68:51-59. 53. Escribano G, Allona A, Burgos FJ, et al. Cavernosography in diagnosis of metastatic tumors of the penis: 5 new cases and a review of the literature. J Urol. 1987;138:1174-1177. 54. Andresen R, Wegner HE, Dieberg S. Penile metastasis of sigmoid carcinoma: comparative analysis of different imaging modalities. Br J Urol. 1997;79:477-478. 55. Wilson F, Staff WG. Malignant priapism: an unexpected response to local anaesthetic infiltration of the dorsal nerves of the penis. Br J Surg. 1982;69:469. 56. Golijanin D, Singer E, Davis R, et al. Doppler evaluation of erectile dysfunction – Part 2. Int J Impot Res. 2007;19:43-48. 57. Restrepo R, Oneto J, Lopez K, et al. Head and neck lymph nodes in children: the spectrum from normal to abnormal. Pediatr Radiol. 2009;39:836-846. 58. Ahuja AT, Ying M. Sonographic evaluation of cervical lymph nodes. AJR Am J Roentgenol. 2005;184:1691-1699. 59. Krishna RP, Sistla SC, Smile R, et al. Sonography: an underutilized diagnostic tool in the assessment of metastatic groin nodes. J Clin Ultrasound JCU. 2008;36:212-217. 60. Evans RM, Ahuja A, Metreweli C. The linear echogenic hilus in cervical lymphadenopathy – A sign of benignity or malignancy? Clin Radiol. 1993;47:262-264. 61. Steinkamp HJ, Maurer J, Cornehl M, et al. Recurrent cervical lymphadenopathy: differential diagnosis with color-duplex sonography. Eur Arch Otorhinolaryngol. 1994;251:404-409. 62. Vassallo P, Wernecke K, Roos N, et al. Differentiation of benign from malignant superficial lymphadenopathy: the role of high-resolution US. Radiology. 1992;183:215-220. 63. Abang Mohammed DK, Uberoi R, de BL A, et al. Inguinal node status by ultrasound in vulva cancer. Gynecol Oncol. 2000;77:93-96. 64. Kataoka MY, Sala E, Baldwin P, et al. The accuracy of magnetic resonance imaging in staging of vulvar cancer: a retrospective multi-centre study. Gynecol Oncol. 2001;117(1):82-87. 65. Bipat S, Fransen GA, Spijkerboer AM, et al. Is there a role for magnetic resonance imaging in the evaluation of inguinal lymph node metastases in patients with vulva carcinoma? Gynecol Oncol. 2006;103:1001-1006. 66. Sohaib SA, Richards PS, Ind T, et al. MR imaging of carcinoma of the vulva. AJR Am J Roentgenol. 2002;178:373-377. 67. Hughes B, Leijte J, Shabbir M, et al. Non-invasive and minimally invasive staging of regional lymph nodes in penile cancer. World J Urol. 2009;27:197-203. 68. Ornellas AA, Seixas AL, Marota A, et al. Surgical treatment of invasive squamous cell carcinoma of the penis: retrospective analysis of 350 cases. J Urol. 1994;151:1244-1249. 69. Eisner BH, Feldman AS. Nanoparticle imaging for genitourinary cancers. Cancer Biomark. 2009;5:75-79. 70. Hovels AM, Heesakkers RA, Adang EM, et al. The diagnostic accuracy of CT and MRI in the staging of pelvic lymph nodes in patients with prostate cancer: a meta-analysis. Clin Radiol. 2008;63:387-395.
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71. Jager GJ, Barentsz JO, Oosterhof GO, et al. Pelvic adenopathy in prostatic and urinary bladder carcinoma: MR imaging with a three-dimensional TI-weighted magnetization-prepared-rapid gradient-echo sequence. AJR Am J Roentgenol. 1996;167:1503-1507. 72. Tabatabaei S, Harisinghani M, McDougal WS. Regional lymph node staging using lymphotropic nanoparticle enhanced magnetic resonance imaging with ferumoxtran-10 in patients with penile cancer. J Urol. 2005;174:923-927. discussion 927. 73. King AD, Tse GM, Ahuja AT, et al. Necrosis in metastatic neck nodes: diagnostic accuracy of CT, MR imaging, and US. Radiology. 2004;230:720-726. 74. Laubenbacher C, Saumweber D, Wagner-Manslau C, et al. Comparison of fluorine-18-fluorodeoxyglucose PET, MRI and endoscopy for staging head and neck squamous-cell carcinomas. J Nucl Med. 1995;36:1747-1757. 75. Antoch G, Saoudi N, Kuehl H, et al. Accuracy of whole-body dual-modality fluorine-18-2fluoro-2-deoxy-D-glucose positron emission tomography and computed tomography (FDGPET/CT) for tumor staging in solid tumors: comparison with CT and PET. J Clin Oncol. 2004;22:4357-4368. 76. Schoder H, Larson SM, Yeung HW. PET/CT in oncology: integration into clinical management of lymphoma, melanoma, and gastrointestinal malignancies. J Nucl Med. 2004;45(Suppl 1): 72S-81S. 77. Scher B, Seitz M, Reiser M, et al. 18 F-FDG PET/CT for staging of penile cancer. J Nucl Med. 2005;46:1460-1465. 78. Leijte JAP, Graafland NM, Valdés Olmos RA, et al. Prospective evaluation of hybrid18F-fluorodeoxyglucose positron emission tomography/computed tomography in staging clinically node-negative patients with penile carcinoma. BJU Int. 2009;104:640-644. 79. Graafland NM, Leijte JAP, Valdés Olmos RA, et al. Scanning with 18 F-FDG-PET/CT for detection of pelvic nodal involvement in inguinal node-positive penile carcinoma. Eur Urol. 2009;56:339-345. 80. Kim JH, Beets GL, Kim MJ, et al. High-resolution MR imaging for nodal staging in rectal cancer: Are there any criteria in addition to the size? Eur J Radiol. 2004;52:78-83. 81. Brown G, Richards CJ, Bourne MW, et al. Morphologic predictors of lymph node status in rectal cancer with use of high-spatial-resolution MR imaging with histopathologic comparison. Radiology. 2003;227:371-377. 82. Harisinghani MG, Barentsz J, Hahn PF, et al. Noninvasive detection of clinically occult lymphnode metastases in prostate cancer. N Engl J Med. 2003;348:2491-2499. 83. Bernd H, De Kerviler E, Gaillard S, et al. Safety and tolerability of ultrasmall superparamagnetic iron oxide contrast agent: comprehensive analysis of a clinical development program. Invest Radiol. 2009;44:336-342. 84. Horenblas S, Van Tinteren H, Delemarre JF, et al. Squamous cell carcinoma of the penis: accuracy of tumor, nodes and metastasis classification system, and role of lymphangiography, computerized tomography scan and fine needle aspiration cytology. J Urol. 1991;146:1279-1283. 85. Senthil Kumar MP, Ananthakrishnan N, Prema V. Predicting regional lymph node metastasis in carcinoma of the penis: a comparison between fine-needle aspiration cytology, sentinel lymph node biopsy and medial inguinal lymph node biopsy. Br J Urol. 1998;81:453-457. 86. Saisorn I, Lawrentschuk N, Leewansangtong S, et al. Fine-needle aspiration cytology predicts inguinal lymph node metastasis without antibiotic pretreatment in penile carcinoma. BJU Int. 2006;97:1225-1228. 87. Kroon BK, Horenblas S, Deurloo EE, et al. Ultrasonography-guided fine-needle aspiration cytology before sentinel node biopsy in patients with penile carcinoma. BJU Int. 2005;95:517-521. 88. Crawshaw JW, Hadway P, Hoffland D, et al. Sentinel lymph node biopsy using dynamic lymphoscintigraphy combined with ultrasound-guided fine needle aspiration in penile carcinoma. Br J Radiol. 2009;82:41-48. 89. Bouchot O, Rigaud J, Maillet F, et al. Morbidity of inguinal lymphadenectomy for invasive penile carcinoma. Eur Urol. 2004;45:761-765. discussion 765-766. 90. Cabanas RM. An approach for the treatment of penile carcinoma. Cancer. 1977;39:456-466. 91. Wespes E, Simon J, Schulman CC. Cabanas approach: Is sentinel node biopsy reliable for staging penile carcinoma? Urology. 1986;28:278-279.
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92. Perinetti E, Crane DB, Catalona WJ. Unreliability of sentinel lymph node biopsy for staging penile carcinoma. J Urol. 1980;124:734-735. 93. Pettaway CA, Pisters LL, Dinney CP, et al. Sentinel lymph node dissection for penile carcinoma: the M. D. Anderson Cancer Center experience. J Urol. 1995;154:1999-2003. 94. Sullivan DC, Croker BP Jr, Harris CC, et al. Lymphoscintigraphy in malignant melanoma: 99mTc antimony sulfur colloid. AJR Am J Roentgenol. 1981;137:847-851. 95. Morton DL, Wen DR, Wong JH, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg. 1992;127:392-399. 96. Steinbecker KM, Muruve NA. Lymphoscintigraphy for penile cancer. J Urol. 2000;163: 1251-1252. 97. Han KR, Brogle BN, Goydos J, et al. Lymphatic mapping and intraoperative lymphoscintigraphy for identifying the sentinel node in penile tumors. Urology. 2000;55:582-585. 98. Tanis PJ, Lont AP, Meinhardt W, et al. Dynamic sentinel node biopsy for penile cancer: reliability of a staging technique. J Urol. 2002;168:76-80. 99. Kroon BK, Horenblas S, Meinhardt W, et al. Dynamic sentinel node biopsy in penile carcinoma: evaluation of 10 years experience. Eur Urol. 2005;47:601-606. discussion 606. 100. Leijte JAP, Kroon BK, Valdés Olmos RA, et al. Reliability and safety of current dynamic sentinel node biopsy for penile carcinoma. Eur Urol. 2007;52:170-177. 101. Jensen JB, Jensen KM, Ulhoi BP, et al. Sentinel lymph-node biopsy in patients with squamous cell carcinoma of the penis. BJU Int. 2009;103:1199-1203. 102. Perdonà S, Autorino R, Gallo L, et al. Role of dynamic sentinel node biopsy in penile cancer: our experience. J Surg Oncol. 2006;93:181-185. 103. Hungerhuber E, Schlenker B, Frimberger D, et al. Lymphoscintigraphy in penile cancer: limited value of sentinel node biopsy in patients with clinically suspicious lymph nodes. World J Urol. 2006;24:319-324. 104. de Kanter AY, Menke-Pluijmers MB, Henzen-Logmans SC, et al. Reasons for failure to identify positive sentinel nodes in breast cancer patients with significant nodal involvement. Eur J Surg Oncol. 2006;32:498-501. 105. Fayad LM, Carrino JA, Fishman EK. Musculoskeletal infection: role of CT in the emergency department. Radiographics. 2007;27:1723-1736. 106. Rippentrop JM, Joslyn SA, Konety BR. Squamous cell carcinoma of the penis: evaluation of data from the surveillance, epidemiology, and end results program. Cancer. 2004;101: 1357-1363. 107. Sohaib SA, Koh D-M, Husband JE. The role of imaging in the diagnosis, staging, and management of testicular cancer. AJR Am J Roentgenol. 2008;191:387-395. 108. Schmidt GP, Baur-Melnyk A, Haug A, et al. Whole-body MRI at 1.5 T and 3 T compared with FDG-PET-CT for the detection of tumour recurrence in patients with colorectal cancer. Eur Radiol. 2009;19:1366-1378. 109. Hovels AM, Heesakkers RA, Adang EM, et al. Cost-effectiveness of MR lymphography for the detection of lymph node metastases in patients with prostate cancer. Radiology. 2009;252:729-736. 110. Solsona E, Algaba F, Horenblas S, et al. EAU guidelines on penile cancer. Eur Urol. 2004;46:1-8. 111. Ficarra V, Zattoni F, Artibani W, et al. Nomogram predictive of pathological inguinal lymph node involvement in patients with squamous cell carcinoma of the penis. J Urol. 2006;175:1700-1704. discussion 1704–5. 112. Horenblas S, van Tinteren H, Delemarre JF, et al. Squamous cell carcinoma of the penis. III. Treatment of regional lymph nodes. J Urol. 1993;149:492-497. 113. Schlenker B, Tilki D, Gratzke C et al: Intermediate-differentiated invasive (pT1 G2) penile cancer-oncological outcome and follow-up. Urol Oncol. Epub Nov, 2006. 114. Hawnaur JM, Zhu XP, Hutchinson CE. Quantitative dynamic contrast enhanced MRI of recurrent pelvic masses in patients treated for cancer. Br J Radiol. 1998;71:1136-1142.
Chapter 5
Premalignant Lesions of the Penis Majid Shabbir, Nicholas A. Watkin, and Asif Muneer
5.1
Introduction
Premalignant lesions present a particularly unique challenge in penile cancer. They can be difficult to distinguish from other benign dermatoses and have an uncertain natural history. A tendency for delayed presentation, with an all too common history of long-term self management, or unsuccessful treatment, often results in a relatively treatable premalignant lesion progressing to an invasive carcinoma, requiring more aggressive surgery, with poorer outcomes. A better understanding of the risk factors involved in the development and progression of premalignant lesions is essential. Effective early recognition and treatment before invasion would provide the best approach to the management of these lesions. The current understanding of penile cancer is based on small, nonrandomized, retrospective studies due to the rarity of this malignancy. However, with the introduction of specialist penile cancer centers, our knowledge of the biological behavior and management of this rare neoplasm has progressed. Several risk factors have been associated with penile cancer. These include the presence of a foreskin, phimosis, poor hygiene, smoking, chronic inflammation, and having multiple sexual partners. One of the most important and widely studied risk factors in genital tumors is the role of human papilloma virus (HPV) infection. Progress in our understanding of its association with penile cancer has shed light onto its pathogenesis and progression from in situ disease to invasive malignancy.
M. Shabbir (*) Department of Urology, Institute of Urology, University College London Hospital, London, UK
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HPV Infection and Penile Cancer
Much of our understanding of how HPV infection may lead to premalignant lesions and invasive tumors is based on studies of carcinogenesis in cervical cancer. However, while almost 100% of cervical SCCs are related to sexually transmitted HPV infection, rates of HPV in penile cancer are reported between 30% to 100%.1-6 The reasons for this wide range include geographical variations and different cultural attitudes towards sex between the reporting centers, as well as technical differences in the methodology used for HPV detection. A recent systematic review of established PCR techniques has found HPV DNA in approximately 50% of all penile SCCs.7 In this respect, penile tumors are more similar to vulval carcinomas, which also share a similar pathogenesis and histology.5,8 The human papilloma virus exerts its tumorigenic effect via expression of the viral oncogenes E6 and E7.9 E6 interacts with p53, while E7 interacts with retinoblastoma (RB) to block the activity of these tumor suppressor genes.10,11 The resultant deregulation of cell cycle control and apoptotic cellular mechanisms results in malignant transformation to carcinoma in situ or invasive malignancy if left untreated.12 The marked difference in the prevalence, age of peak incidence, and rate of progression of both cervical and penile tumors may underlie either differing pathogenic mechanisms or differing tissue susceptibility and pathogenic response to the same HPV infection in these two malignancies. While the cervical model of carcinogenesis gives a good basis for tumor development and progression in penile cancer, it does not fully explain the complete pathogenesis. Premalignant penile lesions can be broadly divided into those related to HPV infection and those which are not HPV related, but due to chronic inflammation. HPV-related lesions include: • • • •
Giant condyloma Bowenoid papulosis Bowen’s disease Erythroplasia of Queyrat Those due to chronic inflammation include:
• • • •
BXO Cutaneous horn Leukoplakia PKMB
Much of the terminology used to describe the different premalignant lesions are eponymous and nonstandardized, and a recent reclassification system based on cell morphology, squamous differentiation, and pathogenesis has been suggested and discussed in greater detail in Chap. 3.13 In the new proposed classification system the term Penile Intraepithelial Neoplasia (PeIN) is used to describe premalignant lesions, and is further subclassified into differentiated, warty, basaloid, and mixed warty-basaloid subtypes. Differentiated PeIN is the subtype most frequently associated with chronic inflammation and not HPV, while the remaining three warty/
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basaloid PeIN subtypes represent those related to HPV infection. In the remainder of this chapter however, we will use the more common and widely established terminology.
5.3
HPV-Related Premailgnant Conditions
Several types of HPV have been identified in malignant penile lesions. ‘High risk’ HPV types 16 and 18 are the most common, being found in 60–75% of in situ and invasive tumors.6,14 Premalignant lesions associated with high-risk HPV include Bowen’s disease, erythroplasia of Queyrat (EQ), and Bowenoid papulosis. Low-risk HPV types 6 and 11 are associated with other premalignant lesions such as giant condylomata acuminate (GCA), or Buschke–Löwenstein tumors.
5.3.1
Penile Intraepithelial Neoplasia (PIN)
The term penile intraepithelial neoplasia (PIN) is used to describe different premalignant penile lesions, and is often used interchangeably in the text with the term carcinoma in situ (CIS). It is not to be confused with the newer term PeIN in the more recently proposed classification systems.13 PIN presents in different clinicopathological forms, and with differing degrees of dysplasia ranging from mild (PIN I) and moderate (PIN II), to severe (PIN III). PIN III is more synonymous with carcinoma in situ CIS, and is eponymously known as Erythroplasia of Queyrat and Bowen’s disease. Both are essentially the same histological premalignant condition, differing primarily only in location.15 Lesions arising from the mucosal surfaces of the genitalia, such as the inner prepuce and glans, are called Erythroplasia of Queyrat (EQ), while Bowen’s disease is essentially considered the same pathological process affecting the skin of the penile shaft. Lesions which occur in Bowen’s disease are usually solitary, well defined, scaly, dullred plaques, often with areas of crusting (Fig. 5.1). Occasionally lesions may be heavily pigmented, resembling melanoma. While they primarily occur on the shaft, associated lesions are sometimes encountered in the inguinal and suprapubic region. Lesions may also occasionally have associated leukoplakic, nodular, or ulcerated changes. Lesions in EQ are usually sharply defined plaques, which have a smooth, velvety, bright red appearance (Fig. 5.2). They are usually painless, but can have areas of erosion. The vast majority occur in uncircumcised men with phimotic foreskins. HPV has a high prevalence in CIS, with reported rates of high-risk HPV-16 in approximately 80% of Bowen’s disease cases16 and 88% of EQ cases in small series.17 However, these two entities have differing rates of progression to invasive disease. Invasive SCC has been reported in 5% of cases of Bowen’s disease,18 while EQ has reported transformation rates of up to 30%.17,19 The exact cause for this difference is unclear; one theory is that the mucosal location of EQ is more susceptible to invasive transformation. Other theories surround possible different pathogenic
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Fig. 5.1 Bowen’s disease of the penis
Fig. 5.2 Erythroplasia of Queyrat presenting in a 45-year-old uncircumcised male who noticed a progressive red area on the glans penis
processes related to co-infection with other HPV subtypes. A small series looking at HPV subtypes in eight patients with EQ found co-infection with HPV-8 in all cases, while no co-infection was detected in control patients with Bowen’s disease.17 The effect of this co-infection on the invasiveness of EQ remains unclear. At present, there is no clear evidence linking aggressiveness of PIN based on the HPV types involved. In fact no study has clearly identified any difference in the transformation rate of PIN lesions based on the presence or absence of HPV infection, and more research into this field is required.
5.3.2
Bowenoid Papulosis
Unlike EQ and Bowen’s Disease, Bowenoid Papulosis (BP) occurs primarily in young sexually active men in their 30s, and is more synonymous with moderate
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Fig. 5.3 Bowenoid papulosis in a 40-year-old man. Multifocal lesions are seen on the infrapubic area and penile shaft
dysplasia (PIN II).15 It is highly contagious, and the sexual partners of patients affected often have evidence of cervical intraepithelial neoplasia.20 Lesions occur primarily on the penile shaft, although they can also occasionally arise on the glans and prepuce. They usually appear as multiple, red, velvety, maculopapular areas, which can coalesce to form larger plaques (Fig. 5.3). Associated pigmentation leads to a brownish appearance, and they often cause pruritis or discomfort. Like EQ and Bowen’s Disease, BP is commonly associated with HPV-16. HPV-16 had a reported prevalence of approximately 70% in one small series of 16 patients.21 However, unlike the more dysplastic PIN III lesions, it usually runs a benign course, with malignant transformation in less than 1% of cases, usually in immunocompromised patients.21
5.3.3
Giant Condyloma Accuminatum (Bushke–Löwenstein Tumor)
Condyloma acuminata are warty, exophytic growths which can affect any part of the anogenital region and are generally considered benign. On the penis, lesions typically occur around the coronal sulcus and frenulum, but can also be found as flat lesions on the penile shaft. They can occasionally extend into the anterior urethra, but extension into the posterior urethra and bladder is usually only seen in immunocompromised patients.22 They are due to infection with low-risk HPV types 6 and 11.23,24 In keeping with BP, these lesions typically occur in sexually active men in their third decade. Small lesions can be treated with topical podophyllin or trichloroacetic acid. Alternative topical treatment options include imiquimod cream. Laser therapy and cryotherapy can also be used for lesions on the glans. Occasionally the lesions are intraurethral and small lesions can be managed using 5-FU inserted into the urethra. Larger lesions may require resection using a pediatric resectoscope.
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Fig. 5.4 Giant condylomata acuminata in a 51-year-old patient from Eastern Europe. Presentation only occurred following voiding difficulties. Despite the extensive lesion which destroyed the glans penis and distal urethra, the corpus cavernosum was spared
Confluence of lesions can lead to the development of large, exophytic, cauliflower- like growths known as giant condyloma acuminate (GCA) or BushkeLöwenstein tumors, after the original description of the condition by the authors in 1925.25 (Fig. 5.4). Risk factors for the development of GCA include immunosuppression, chronic irritation, and poor hygiene,26 and consequently they are more common in uncircumcised men. Although histologically their appearance is benign, these lesions can behave in a malignant fashion, invading adjacent structures.1 Due to their behavior, they are often considered to be an intermediary lesion somewhere between benign condylomas and invasive SCC.27 GCA is at risk of malignant transformation into invasive SCC, with reported rates between 30% and 56%.26,28,29 These tumors were previously classified as verrucous carcinomas, but recently there has been a move away from this based on the pathogenic HPV elements involved with GCA which are not seen with verrucous tumors.
5.4
HPV Infection and Malignant Transformation
Not all invasive SCC subtypes have the same association with HPV infection. In a recent review of 200 cases, Cubilla et al. reported a preferential association of basaloid and warty-basaloid SCC subtypes with HPV infection in approximately 80% of cases, while no HPV was detected in verrucous, mixed verrucous-papillary, pseudohyperplastic, and pseudoglandular SCCs.30 Lower rates of HPV DNA were detected in usual type (24%), sarcomatoid (17%), mixed (19%), and papillary NOS (15%) carcinomas. Most of the time only one HPV subtype was identified (77%). HPV-16 was the most commonly found genotype (72%) followed by HPV-6 (9%) and HPV-18 (6%), either alone or as co-infection. There was no specific correlation between the HPV subtype involved and the histological type of SCC, although usual type SCC had the greatest variety of HPV subtypes detected. In 6% of tumors, only low-risk HPV-6 and 11 were found. Half of these were usual type, and the remainder were warty-basaloid type, underlining the malignant potential of even ‘low risk’ HPV lesions.
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A significant association between HPV status and histological grade was also reported in this study, with 6%, 21%, and 53% of grade 1–3 tumors, being HPV positive, respectively (P < 0.0001).30 This is in keeping with previous studies showing HPV DNA associated with higher grade and more aggressive penile tumors,1 and would suggest a detrimental prognostic effect of HPV-positive status. This would seem logical given its increased association with a basaloid subtype. However, no other study has been able to show any such correlation. In a retrospective study of 29 patients, Weiner et al. (1992) found no statistical differences in tumor grade, incidence of nodal involvement, or survival based on HPV status.31 Likewise, in their review of 82 penile cancer cases, Bezerra et al. found no difference in lymph node metastases or 10-year survival rate based on HPV status alone.2 Other studies have even suggested a possible survival advantage, with a 5 year disease-specific survival of 92% in HPV-positive groups compared to 78% in the HPV-negative groups.32 Further analysis of larger databases with multivariate analysis, after correction for confounding factors such as histological grade and subtype, would give a more accurate assessment of the true prognostic effect of HPV infection.
5.5
Non-HPV-Related Premalignant Conditions
There are a number of premalignant penile lesions which are not related to HPV infection. These are primarily due to chronic inflammation, and include genital lichen sclerosus et atrophicus (LS), penile cutaneous horn, leukoplakia, and pseudoepitheliomatous, keratotic and micaceous balanitis (PKMB). Unlike HPV-related tumors, progression of these premalignant lesions is largely into keratinizing/verrucous SCC (Fig. 5.5).
5.5.1
Genital Lichen Sclerosus Et Atrophicus (LS)
Balanitis Xerotica Obliterans (BXO) is now better defined as the male genital variant of lichen sclerosus et atrophicus (LS). It was initially described as a chronic, progressive, scleroatrophic inflammatory process of unknown etiology affecting the glans penis, prepuce, and in advanced cases, the anterior urethra and meatus, either individually or in any combination. It occurs almost exclusively in uncircumcised men. Lesions classically appear as pale, atrophic plaques, which may coalesce and sclerose, causing phimosis and meatal stenosis (Fig. 5.6). It presents most commonly in men in their third and fourth decades. Its exact etiology remains unclear; theories have hypothesized a possible autoimmune element,34 or even a genetic basis based on HLA antigens,35 although the true pathogenesis is likely to be multifactorial. LS was initially considered to be a benign condition. However, in the late 1970s, case reports first suggested a possible association between LS and penile cancer.36,37 Studies in the last decade have looked at this association in more detail. Barbagli et al. retrospectively reviewed the histology of 130 patients with LS and reported premalignant or malignant features in 11 (8.4%), with 6 (55%) of this group showing
Fig. 5.5 Relationship between histology, HPV presence, clinical manifestation, and putative transformation of penile precursor lesions into penile cancer (With kind permission from Springer Science + Business Media: Bleeker et al.,33 Fig. 1)
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Fig. 5.6 Extensive lichen sclerosus in a 45-year-old man affecting the foreskin and the glans penis. There were also areas of CIS on the glans penis
evidence of some epithelial dysplasia.38 Nasca et al. reported on a series of 86 patients with LS. SCC was subsequently found in 5.8%, with a mean interval from onset of LS to invasive tumor of 17 years (range 10–24 years). In all cases epithelial dysplasia and LS were found adjacent to tumor foci, indicating possible histological progression from chronic inflammation to dysplasia and eventually to malignant transformation.39 The mechanism by which invasive malignancy may develop in LS remains elusive. In the largest series to date, SCC was found in 2.3% of 522 patients diagnosed with LS.40 As well as this metachronous relationship, other series reviewing patients referred for treatment of penile cancer found LS to be a much more common synchronous finding in this group. Rates between 28% and 50% have been reported.41-43 The concept of LS as a premalignant lesion remains contentious. For many, the discrepancy between the high rates of synchronous LS compared to the low rates of metachronous tumors points to this being an associated risk factor as opposed to a causal factor. Indeed, many urologists do not routinely follow up patients with LS particularly once they have been circumcised. With vulval carcinoma, where lichen sclerosus has been shown more definitively to progress to invasive cancer in 4–5% of cases,44 patients with vulval LS are closely reviewed with frequent repeat biopsy.45 Although European guidelines consider LS to be a premalignant condition,46 no consensus has been agreed on how best to follow up these patients.21 The low rate of metachronous transformation and long latency period makes routine follow-up of all patients with LS unfeasible. One solution is to limit specialist follow-up to patients with chronic active disease, teaching the remaining patients, in whom LS regresses after treatment, self examination.41 The development of persistent skin lesions or chronic inflammation in patients with LS should be monitored closely and biopsied to ensure no concurrent cancer exists.
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Fig. 5.7 Cutaneous penile horn on the penis. Courtesy of Bhushan Kumar, Chandigarh, India (Reproduced by permission of Prof CB Bunker and Elsevier Saunders47)
5.5.2
Cutaneous Penile Horn
This is a rare exophytic, conical, keratotic mass, which arises in areas of chronic inflammation (Fig. 5.7). Little is known about its pathogenesis, but longstanding preputial inflammation and phimosis are known to play an important role.48,49 Histological examination can reveal areas of keratoacanthoma, and even intraepithelial carcinoma. They have a risk of malignant transformation into lowgrade verrucous or keratinizing SCC, reported in approximately 30% of cases.50,51
5.5.3
Leukoplakia
These are rare white, verrucous plaques that can arise on mucosal surfaces. Oral lesions have a strong association with chronic tobacco use and carry a clear risk of transformation into invasive SCC. Genital lesions are less well understood. They occur primarily on the glans or prepuce. Clinically they can resemble areas of LS. They occur more commonly in patients with diabetes, probably related to recurrent and chronic infection.52,53 Evidence of fissuring, ulceration, or erosion increases the risk of malignant transformation in these lesions. Although the precise incidence of malignant transformation is unknown, 10–20% of penile leukoplakia can show dysplastic changes microscopically.52,54
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Fig. 5.8 PKMB. Courtesy of Bhushan Kumar, Chandigarh, India (Reproduced by permission of Prof CB Bunker and Elsevier Saunders47)
5.5.4
Pseudoepitheliomatous, Keratotic, and Micaceous Balanitis (PKMB)
This is a rare condition, primarily affecting elderly, uncircumcised men. Its precise etiology is still unknown.55 Clinically, the foreskin loses its elasticity, and can become phimotic. Retraction usually reveals a solitary, well-circumscribed, hyperkeratotic lesion on the glans with a laminated (micaceous) appearance (Fig. 5.8). Occasionally the lesion may form into a keratotic mass and can behave more like a verrucous carcinoma.51,56-58 The presence of a nodular component raises the possibility of malignant transformation into invasive SCC,57-59 although given the rarity of the condition, this risk is difficult to quantify.
5.6
Treatment of Premalignant Penile Lesions
The non-invasive nature of premalignant lesions makes them amenable to curative penile preserving therapies. Before starting any treatment a biopsy should be performed in order to confirm the diagnosis and ensure that the lesion does not have any invasive elements. A number of different approaches can be utilized for premalignant lesions, depending on the size, site, and type of lesion. These approaches include the use of topical chemotherapy or immunotherapy, laser treatment, photodynamic therapy, and surgical excision. Due to the low number of patients treated in small studies, most of the recommendations for treatment are based on level III evidence. Circumcision is an essential part of the management of premalignant conditions. As well as removing the lesion if confined solely to the prepuce, it also prevents persistence of an environment suited to HPV infection, chronic inflammation, and progression to invasive disease. It also facilitates follow-up and clinical examination, which is essential with minimally invasive approaches. When performing the
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circumcision, an adequate clearance margin must be achieved. In difficult cases, a swab soaked in 5% acetic acid applied to the penis for 2–3 min allows a more accurate detection of occult CIS. The abnormal areas are stained white (‘acetowhite’ reaction), and this can be used to guide the margins of excision.60
5.6.1
Topical Therapies
Topical therapies for premalignant penile lesions can take the form of chemotherapy or immunotherapy. They are best suited to immunocompetent patients with well-defined solitary lesions although there is a poor response rate in the immunosuppressed or those with widespread ‘field changes’.61 Lesions amenable to treatment with topical therapy include PIN, BP, and PKMB. They are not suitable for LS, GCA, or cutaneous horn.
5.6.1.1
5-Fluorouracil
The most common first-line treatment is topical 5% 5-Fluorouracil (5-FU or 5-fluoro-2,4(1H, 3H)-pyrimidinedione; chemical formula C4H3FN2O2). This antimetabolite chemotherapeutic agent is a pyrimidine analogue. It is metabolized both inside cells and by the liver and excreted by the kidneys. It non-competitively inhibits thymidylate synthase, reducing the production of thymidine. When inside the cell it is transformed into several cytotoxic metabolites that become incorporated into RNA and DNA, triggering cell cycle arrest and apoptosis. Its actions are S phase specific. Protocols vary among clinicians on how frequently the 5-FU is applied. When applied topically between 4 and 6 weeks on alternate days, it is safe, with low morbidity and minimal systemic absorption. Patients are advised to apply the topical cream with or without gloves provided that thorough hand washing is performed following application. The treated area often becomes encrusted and inflamed during the treatment period and patients should be advised to expect this and continue treatment (Figs. 5.9 and 5.10). Additional application of topical steroid can be used if the areas become uncomfortable during the treatment period. It can take between 4 and 8 weeks for the areas to heal. Early studies reported sustained response rates approaching 100% at 5 years, although the numbers of patients treated in these studies are small (<10).62
5.6.1.2
Imiquimod
Non or partial responders to topical 5-FU can be treated with immunotherapy using topical 5% Imiquimod cream for a similar length of time as second-line treatment.63 The exact mechanism of action of this novel immunomodulatory therapy is unclear. It is known to utilize the toll-like receptor 7 to activate immune cells, to secrete cytokines such as interferon-a, tumor necrosis factor and various interleukins (IFNa, IL-1,6,12, TNFa). Langerhan’s cells in the skin are also activated and
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Fig. 5.9 CIS of the glans penis before starting treatment with topical 5-FU
Fig. 5.10 Same area of CIS following topical treatment with 5-FU
migrate to local lymph nodes and trigger the adaptive immune system. Other cells believed to be activated are natural killer cells, macrophages, and B lymphocytes. Imiquimod can be applied for 5 days a week for a period of 4–6 weeks. The frequency of application can be reduced provided that the inflammatory response is maintained.64,65 While success has been reported in a number of case reports,63 and small case series,61 no large-scale long-term efficacy data are currently available.
5.6.1.3
Other Topical Agents
Other topical therapies include the use of 2–3% testosterone propionate or 0.05% clobetasol propionate for LS. Small case series from the late 1970s and 1980s reported favorable outcomes with topical testosterone.66,67 A study comparing these two treatments for vulval LS reported 6 month response rates of 77.5% and 91.7%, respectively, with recurrence rates of 20% and 6.7% in the 2 groups.68 However, the
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use of these treatments has never become established for penile LS. Given the long latency to invasive SCC in patients with LS, any possible beneficial effect in preventing malignant transformation would be difficult to prove.
5.6.2
Laser Treatment, Cryotherapy, and Photodynamic Therapy
Carbon dioxide (CO2) and Neodymium: yttrium aluminium garnet (Nd:YAG) lasers have been used as first-line therapy with reasonable response rates and good cosmetic and functional results. The CO2 laser is typically used at a power setting between 15 and 20 W, and has a penetration of 2–2.5 mm. Direct focusing of the beam allows it to be used as a scalpel to excise tissue for histological analysis. Ablation sites generally heal in 3–4 weeks. The Nd:YAG laser is typically used with the power set between 24 and 60 W. It has a tissue penetration of 4–6 mm, but causes tissue coagulation and therefore prevents histological diagnosis and a risk of understaging the disease. Larger lesions can be treated using this laser, but ablation sites can take up to 2–3 months to heal (Fig. 5.11). Treatment with either of these lasers is usually well tolerated, with minor complications ranging from minor pain and bleeding at treatment sites, to preputial lymphoedema in those patients who have retained their foreskin.69 In one study, van Bezooijen et al. reported their experience of 19 Tis patients treated with laser therapy. After a mean follow-up of 32 months, 26% required successful retreatment for histologically confirmed Tis recurrence, while one patient (5%) progressed to invasive disease, highlighting the importance of close follow-up after such minimally invasive surgery.70 In a more recent study assessing the combined use of both lasers, 13/67 (19%) patients had disease recurrence, with upgrading from the original tumor in 3/13 (23%) cases.71 Higher recurrence rates after laser treatment may reflect a tendency to tackle larger tumors with this minimally invasive approach compared to those treated by other topical therapies. Lasers have been used to treat lesions up to stage T2, but this approach has been shown to be associated with higher overall recurrence (48%), and evidence of nodal progression in 23%,72 highlighting the need for careful case selection. Laser therapy is primarily used to treat PIN and BP, and is not suitable for LS, large GCA, or cutaneous horn. Cryotherapy has been used for a multitude of skin lesions by dermatologists for some time. The technique of using either liquid nitrogen or nitrous oxide to generate rapid freeze/ slow thaw cycles, can achieve tissue damage at temperatures below −20°C, although temperatures of −50°C are required to effectively kill malignant cells. Tissue damage occurs by formation of intracellular and extracellular ice crystals, leading to disruption of cell membranes and cell death. While there is little comparative data on the use of this modality for penile lesions, a large study of 299 patients comparing cryotherapy to topical chemotherapy with 5-FU and surgical excision for Bowen’s disease affecting both men and women, primarily in extragenital locations, showed cryotherapy to have a greater risk of recurrence (13.4%) when compared to 5-FU (9%) and surgical excision (5.5%) after 5 years follow-up.73 Photodynamic therapy (PDT) for penile PIN is still in its infancy. This technique involves covering the affected region with a topical photosensitizing cream
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Fig. 5.11 Appearance of the penis in a 49-year-old smoker who had undergone circumcision for grade 3 SCC Stage T1 of the foreskin 3 years previously and CO2 laser treatment of SCC Stage Tis of the glans penis 9 months previously at another institution. Frontal views of the penis (a) before and (b) after 5% acetic acid preparation show enhancement of the lesions: SCC Stage Tis and PENIN involving left side (arrows) and SCC Stage T1 involving ventral glans (arrows). Same views (c) immediately after KTP/532 laser treatment and (d) 2 months postoperatively (Reprinted from Tietjen and Malek,69 Copyright 1998, with permission from Elsevier)
containing chemicals such as delta-5-aminolaevulinic acid (ALA) for approximately 3 hours. Such chemicals are preferentially taken up and retained by malignant cells. The area is then treated by illumination of an incoherent light from a specialist PDT lamp leading to photoselective cell death of sensitized cells. One study looking at ten patients treated with PDT found an initial response in 7/10 patients.74 4/10 had a complete response after a mean follow-up of 35 months, but required between 2 and 8 treatments (mean of 4 treatments). 3/10 patients had persistent recurrence refractory to PDT, although none of these patients progressed to invasive disease. Further trials on this technology are awaited.
5.6.3
Surgical Excision
Patients developing an extensive field change or recurrent disease are best managed by surgical excision. Repeated topical therapy can result in unsightly scarring and a denuded glans that can make clinical monitoring difficult. Intractable in situ disease or non-invasive verrucous disease can be effectively treated by excising the diseased area with an adequate margin combined with split thickness skin grafting, or by
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Fig. 5.12 Glans resurfacing procedure showing the glans epithelium and subepithelium sharply dissected off the underlying corpus spongiosum in quadrants
total glans resurfacing. This technique was first described by Bracka for the management of severe BXO, but has been adapted for Tis/Ta disease.40
5.6.3.1
Technique of Glans Resurfacing
This procedure is performed under a general or regional anesthetic with preoperative antibiotic cover and with the use of a tourniquet at the base of the penis. The glans and distal penis is sometimes soaked in 5% acetic acid to help highlight any dysplastic or warty changes • The glans epithelium is marked in quadrants from the meatus to the coronal sulcus. A perimeatal and circumcoronal incision is performed, and the glans epithelium and subepithelial tissue is then completely removed off the underlying spongiosum, starting from the meatus to the coronal sulcus for each quadrant (Fig. 5.12).75 • Deep biopsies from the corpus spongiosum are taken from each quadrant for separate frozen section analysis to ensure that there is no invasive element to the lesion. Care is taken when dissecting over the coronal sulcus as the epithelium is particularly adherent at this point due to the condensation of penile fascia. A split thickness skin graft is harvested from the thigh (Fig. 5.13) using a dermatome and is placed over the denuded glans (Fig. 5.14). Graft thickness can range from 0.008 to 0.016 inch. The graft is sutured and quilted using multiple 5-0 or 6-0 interrupted absorbable sutures (Figs. 5.15–5.17). • The patient is catheterized (14F silicone catheter) either urethrally or a suprapubic catheter can be inserted and the glans penis is dressed with a soft siliconecoated dressing (e.g. Mepitel®) and a gauze dressing followed by a foam dressing in order to help immobilize the graft. The dressing is left in place for 5 days with the patient remaining on strict bed rest for the first 48 h. On the 5th day the dressing and catheter are removed, and the patient is discharged with wound care advice for review in clinic the following week.
5 Premalignant Lesions of the Penis Fig. 5.13 A split thickness skin graft is harvested from the thigh using an air or electric dermatome. The exposed corpus spongiosum is then covered with the split thickness skin graft
Fig. 5.14 Appearance following dissection of the glans epithelium and subepithelium
Fig. 5.15 The split skin graft is trimmed to the correct size and either button holed or cut in order to accommodate the urethral meatus
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Fig. 5.16 The graft is sutured to the subcoronal skin and also quilted to the glans penis. Some surgeons do not quilt the graft but ensure that the dressings applied immobilize the graft
Fig. 5.17 Post operative appearance of the glans after 6 months
This approach allows preservation of maximal penile length, form, and function and combines a good cosmetic appearance with good oncological control. Graft take is excellent, and the cosmetic appearance 6 weeks after surgery is excellent. In a report of ten patients treated with total glans resurfacing for recurrent, refractory, or extensive disease, no patient had evidence of disease recurrence after a mean follow-up of 30 months,76 and over 80% were sexually active within 3 months of surgery.
5.6.3.2
Moh’s Micrographic Surgery
An alternative surgical approach is excision using Mohs’ micrographic surgery, which involves removing the entire lesion in thin sections, with concurrent histological examination to ensure clear margins microscopically.77 This technique allows maximal preservation of normal penile tissue, but is difficult and time consuming, requiring both a surgeon and pathologist trained in the technique to ensure adequate oncological clearance. A recent review of outcome from this technique
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Table 5.1 Treatment options available for premalignant lesions of the penis Penile lesion Treatment options Erythroplasia of Queyrat and Bowen’s Topical – 5-FU, Imiquimod disease Ablative – Laser, PDT, cryotherapy Surgery – Local excision with or without grafting Bowenoid papulosis
Topical – 5-FU, Imiquimod Ablative – Laser, cryotherapy Surgery – Local excision
Giant condylomata acuminata Penile horn Leukoplakia Pseudoepitheliomatous, keratotic, and micaceous balanitis
Large lesions – Surgical excision Surgical excision Circumcision combined with local excision Ablative – Laser, cryotherapy Surgery – Local excision
reported a high (32%) recurrence rate,78 and the uptake and use of the technique worldwide has been very limited. All premalignant lesions are suitable for treatment by surgical excision. In all cases careful histological examination of the lesion and margins is essential, and close follow-up is mandatory. A summary of the treatment options is shown in Table 5.1.
5.7
Follow-Up
As with all minimally invasive approaches, life-long follow-up is essential to ensure early detection of recurrence. Local recurrence rates for SCC using penile-preserving techniques can be as high as 30%, with the majority occurring in the first 2 years.79 While the recurrence rate for premalignant disease will be lower, a similar clinical follow-up schedule should probably be employed given its uncertain natural history and risk of malignant transformation in up to 30% of cases. Patients should be followed up 3 monthly for the first 2 years, reducing to 6 monthly to complete at least 5 years followup. Cases with proven HPV should also be referred for contact screening.
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28. Chu QD, Vereridis MP, Libbey NP, Wanebo HJ. Giant condyloma acuminatum (Buschke Lowenstein tumor) of the anorectal and perianal regions. Dis Colon Rectum. 1994;37:950-957. 29. Bertram P, Treutner KH, Rubben A, et al. Invasive squamous cell carcinoma in giant anorectal condyloma (Buschke Lowenstein tumor). Langenbecks Arch Chir. 1995;380:115-118. 30. Cubilla AL, Lloveras B, Alejo M, et al. The basaloid cell is the best tissue marker for human papillomavirus in invasive penile squamous cell carcinoma: a study of 202 cases from Paraguay. Am J Surg Pathol. 2010;34(1):104-114. 31. Wiener JS, Effert PJ, Humphrey PA, Yu L, Liu ET, Walther PJ. Prevalence of human papillomavirus types 16 and 18 in squamous-cell carcinoma of the penis: a retrospective analysis of primary and metastatic lesions by differential polymerase chain reaction. Int J Cancer. 1992;50(5):694-701. 32. Lont AP, Kroon BK, Horenblas S, et al. Presence of high-risk human papillomavirus DNA in penile carcinoma predicts favorable outcome in survival. Int J Cancer. 2006;119(5):1078-1081. 33. Bleeker MCG, Heideman DAM, Snijders PJF, et al. Penile cancer: epidemiology, pathogenesis and prevention. World J Urol. 2009;27:141-150. 34. Meyrick Thomas RH, Ridley CM, Black MM. The association of lichen sclerosus et atrophicus and autoimmune related disease in males. Br J Dermatol. 1983;109:661-664. 35. Purcell KG, Spencer LV, Simpson PM, et al. HLA antigens in Lichen sclerosus et atrophicus. Arch Dermatol. 1990;126:1043-1045. 36. Bingham JS. Carcinoma of the penis developed in lichen sclerosus et atrophicus. Br J Vener Dis. 1978;54:350-351. 37. Weigand DA. Lichen sclerosus et atrophicus, multiple dysplastic keratoses and squamous-cell carcinoma of the glans penis. J Dermatol Surg Oncol. 1980;6:45-50. 38. Barbagli G, Palminteri E, Mirri F, Guazzoni G, Turini D, Lazzeri M. Penile carcinoma in patients with genital lichen sclerosus: a multicenter survey. J Urol. 2006;175(4):1359-1363. 39. Nasca MR, Innocenzi D, Micali G. Penile cancer among patients with genital lichen sclerosus. J Am Acad Dermatol. 1999;41:911-914. 40. Depasquale I, Park AJ, Bracka A. The treatment of balanitis xerotica obliterans. BJU Int. 2000;86:459-465. 41. Pietrzak P, Hadway P, Corbishley CM, Watkin NA. Is the association between balanitis xerotica obliterans and penile carcinoma underestimated? BJU Int. 2006;98(1):74-76. 42. Powell J, Wojnarowska F. Lichen sclerosus. Lancet. 1999;353:1777-1783. 43. Perceau G, Derancourt C, Clavel C, et al. Lichen sclerosus is frequently present in penile squamous cell carcinomas but is not always associated with oncogenic human papillomavirus. Br J Dermatol. 2003;148(5):934-938. 44. Carli P, Cattaneo A, De Magnis A, Biggeri A, Taddei G, Giannotti B. Squamous cell carcinoma arising in vulval lichen sclerosus: a longitudinal cohort study. Eur J Cancer Prev. 1995;4(6):491-495. 45. Scurry J. Does lichen sclerosus play a central role in the pathogenesis of human papillomavirus negative vulvar squamous cell carcinoma? The itch-scratch-lichen sclerosus hypothesis. Int J Gynecol Cancer. 1999;9:89-97. 46. Algaba F, Horenblas S, Pizzocaro G, Solsona E, Windahl T. European Association of Urology. EAU guidelines on penile cancer. Eur Urol. 2002;42:199-203. 47. Bunker CB. Male Genital Skin Disease. London: Elsevier Saunders; 2004. 48. Lowe FC, McCullough AR. Cutaneous horns of the penis: an approach to management. J Am Acad Dermatol. 1985;13:369-373. 49. Hemandez-Graulau JM, Fiore A, Cea P, et al. Multiple penile horns: case report and review. J Urol. 1988;139:1055-1056. 50. Solivan GA, Smith KJ, James WD. Cutaneous horn of the penis: its association with squamous cell carcinoma and HPV-16 infection. J Am Acad Dermatol. 1990;23:969-972. 51. Yeager JK, Findlay RF, Mcaleer IM. Penile verrucous carcinoma. Arch Dermatol. 1990;126(9): 1208-1210. 52. Mikhail GR. Cancers, precancers, and pseudocancers in the male genitalia. a review of clinical appearances, histopathology, and management. J Dermatol Surg Oncol. 1980;6:1027-1035.
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53. Schellhammer PF, Jordan GH, Robey EL, et al. Premalignant lesions and nonsquamous malignancy of the penis and carcinoma of the scrotum. Urol Clin North Am. 1992;19:131-142. 54. Lever WF, Schaumburg-Lever G. Histopathology of the Skin. 5th ed. Philadelphia: JB Lippincott; 1990. 55. Bargman H. Pseudoepitheliomatous, keratotic, and micaceous balanitis. Cutis. 1985;35:77-79. 56. Bashir SJ, Grant JW, Burrows NP. Pseudoepitheliomatous, keratotic and micaceous balanitis after penile squamous cell carcinoma. Clin Exp Dermatol. 2010;35(7):749-751. 57. Gray MR, Ansell ID. Pseudo-epitheliomatous hyperkeratotic and micaceous balanitis: evidence for regarding it as pre-malignant. Br J Urol. 1990;66(1):103-104. 58. Beljaards RC, van Dijk E, Hausman R. Is pseudoepitheliomatous micaceous and keratotic balanitis synonymous with verrucous carcinoma? Br J Dermatol. 1987;117:641-646. 59. Bart RS, Kopf AW. On a dilemma of penile horns: pseudoepitheliomatous, hyperkeratotic and micaceous balanitis? J Dermatol Surg Oncol. 1977;3(6):580-582. 60. Pietrzak P, Corbishley C, Watkin N. Organ-sparing surgery for invasive penile cancer: early follow-up data. BJU Int. 2004;94(9):1253-1257. 61. Porter WM, Francis N, Hawkins D, et al. Penile intraepithelial neoplasia: clinical spectrum and treatment of 35 cases. Br J Dermatol. 2002;147(6):1159-1165. 62. Goette DK, Elgart M, DeVillez RL. Erythroplasia of Queyrat treatment with topically applied 5-Fluorouracil. JAMA. 1975;232(9):934-937. 63. Micali G, Nasca MR, Tedeschi A. Topical treatment of intraepithelial penile carcinoma with imiquimod. Clin Exp Dermatol. 2003;28(Suppl 1):4-6. 64. Slade HB, Owens ML, Tomai MA, Miller RL. Imiquimod 5% cream (Aldara). Expert Opin Investig Drugs. 1998;7:437-449. 65. Suzuki H, Wang B, Shivji GM, et al. Imiquimod, a topical immune response modifier, induces migration of Langerhans cells. J Invest Dermatol. 2000;114:135-141. 66. Pasieczny TA. The treatment of balanitis xerotica obliterans with testosterone propionate ointment. Acta Derm Venereol. 1977;57(3):275-277. 67. Skierlo P, Heise H. Testosterone propionate ointment—a therapeutic trial in lichen sclerosus et atrophicus [Article in German]. Hautarzt. 1987;38(5):295-297. 68. Ayhan A, Guven S, Guvendag Guven ES, Sakinci M, Gultekin M, Kucukali T. Topical testosterone versus clobetasol for vulvar lichen sclerosus. Int J Gynaecol Obstet. 2007;96(2):117-121. 69. Tietjen DN, Malek RS. Laser therapy of squamous cell dysplasia and carcinoma of the penis. Urology. 1998;52:559-565. 70. van Bezooijen BP, Horenblas S, Meinhardt W, Newling DW. Laser therapy for carcinoma in situ of the penis. J Urol. 2001;166(5):1670-1671. 71. Windahl T, Andersson SO. Combined laser treatment for penile carcinoma: results after longterm follow up. J Urol. 2003;169(6):2118-2121. 72. Meijer RP, Boon TA, van Venrooij GE, Wijburg CJ. Longterm follow-up after laser therapy for penile carcinoma. Urology. 2007;69(4):759-762. 73. Hansen JP, Drake AL, Walling HW. Bowen’s Disease: a four-year retrospective review of epidemiology and treatment at a university center. Dermatol Surg. 2008;34(7):878-883. 74. Paoli J, Ternesten Bratel A, Löwhagen GB, Stenquist B, Forslund O, Wennberg AM. Penile intraepithelial neoplasia: results of photodynamic therapy. Acta Derm Venereol. 2006;86(5):418-421. 75. Hegarty PK, Shabbir M, Hughes B, et al. Penile preserving surgery and surgical strategies to maximize penile form and function in penile cancer: recommendations from the United Kingdom experience. World J Urol. 2009;27:179-187. 76. Hadway P, Corbishley CM, Watkin NA. Total glans resurfacing for premalignant lesions of the penis: initial outcome data. BJU Int. 2006;98(3):532-536. 77. Mohs FE, Snow SN, Larson PO. Mohs micrographic surgery for penile tumors. Urol Clin North Am. 1992;19(2):291-304. 78. Shindel AW, Mann MW, Lev RY, et al. Mohs micrographic surgery for penile cancer: management and long-term followup. J Urol. 2007;178(5):1980-1985. 79. Leijte JA, Kirrander P, Antonini N, Windahl T, Horenblas S. Recurrence patterns of squamous cell carcinoma of the penis: recommendations for follow-up based on a two-centre analysis of 700 patients. Eur Urol. 2008;54(1):161-168.
Chapter 6
Management of Penile Cancer Using Penile-Preserving Techniques Paul Hadway, Peter R. Malone, Suks Minhas, and Asif Muneer
6.1
Introduction
Penile cancer is a rare disease, in the UK it accounts for <1% of all male malignancies. The incidence of penile cancer in England and Wales is 1.2–1.5 per 100,000 per year.1 This figure is very similar to other Western European and North American countries. However, in parts of Africa, Asia, and South America penile cancer has been reported to account for up to 20% of all male malignancies.2 The presentation of penile SCC can manifest as several different subtypes with varying growth patterns. The penile lesion can be nodular, ulcerative, an erythematous area, or it may present with phimosis which obscures the tumor. Invasive disease is generally straightforward to diagnose, unlike premalignant penile lesions which can be difficult to differentiate from benign genital dermatoses. Previous penile radiotherapy may also make the diagnosis less clear. More importantly, carcinoma in situ (CIS) may coexist with invasive disease and therefore histological diagnosis is mandatory in order to determine the grade and pathological characteristics. The TNM staging system for penile cancer has recently been revised and the grading is by Broder’s system, dividing tumors into well, moderate, and poorly differentiated lesions.3 Many guidelines relating to the management of this disease, although controversial are based on small, single institute series which are often retrospective. Consequently, the National Institute for Clinical Excellence (NICE) recommends that patients with penile cancer in the UK should be managed in supraregional centers which treat at least 25 new cases per annum, or cover a population of at least four million.4 The development of such centers has allowed for the implementation of new surgical techniques together with research resources which continues to further our understanding of this uncommon but potentially fatal disease.
P. Hadway (*) Department of Urology, Churchill Hospital, Oxford, Oxfordshire, UK A. Muneer et al. (eds.), Textbook of Penile Cancer, DOI 10.1007/978-1-84882-879-7_6, © Springer-Verlag London Limited 2012
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Table 6.1 Local recurrences after radical surgery
Author(s) Rempelakos et al.6 Leijte et al.7 Ornellas et al.8
Local recurrence Operation Patients no no (%) Partial penectomy 227 0 Total penectomy 75 0 Partial penectomy 214 15 (5.1) Total penectomy 71 0 Partial penectomy 522 25 (4) Total penectomy 98 0
Mean Salvage surgery follow-up procedures (no) (months) >120 6.6 21 (TP) 4 (PP)
11
TP total penectomy, PP partial penectomy
Traditionally, radical surgery or radiotherapy have been the mainstay of treatment for penile cancer. Radical surgery undoubtedly provides excellent locoregional control. It is, however, associated with urinary and sexual dysfunction as well as significant psychological morbidity.5 Radical radiotherapy preserves the penis, but often leaves the patient with a disfigured and dysfunctional organ. In addition, recurrence rates following radiotherapy of up to 40% have been reported, and recurrent disease can be difficult to both clinically detect and subsequently manage. Penile-preserving techniques have been developed with the aim of providing both oncological control with minimal anatomical and functional disruption. Early diagnosis and accurate staging is essential when such techniques are utilized. In the UK, where only 15–20% of tumors invade the corpus cavernosum at presentation, the vast majority will be able to benefit from penile-preserving therapies. This probably holds true for other Western countries, although in less developed countries patients often present late with advanced disease and therefore penile-preserving techniques are unsuitable. In this chapter we discuss the penile-preserving therapeutic options available for the management of patients with penile cancer based on the grade, stage, and location of the primary lesion. The management of stage T4, high-grade stage T3, or advanced stage T2 disease using radical surgery is not in question (Table 6.1). However, the requirement for such surgery in less advanced, lower grade disease has been challenged. Several authors have published data disputing the need for continuing to use the conventional 2 cm resection margin. Agrawal and colleagues examined 64 partial and total penectomy specimens, looking for disease extension into healthy tissue. They found that of 52 grade 1 and grade 2 tumors, only seven had positive margins 5 mm from the visible tumor; 25% of grade 3 tumors had microscopic extension up to 10 mm.9 In a further study, Hoffman and coworkers looked at surgical specimens from 14 patients with penile SCC undergoing conventional surgery. At 33 months of followup none of these patients had developed local recurrence, including seven patients with resection margins of £10 mm.10 In a larger series, Minhas and colleagues reviewed the resection margins in patients undergoing penile-preserving surgery and reported the local recurrence rates. In this study, 48% had a surgical clearance of £10 mm, while 90% had clearance of £20 mm. Local recurrence rates were
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skin
Ta
subcutaneous tissue corpus cavernosum
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T1 T2
T2 T3 T3
corpus spongiosum urethra CIS
Fig. 6.1 T staging of penile tumors
reported in only 4%, with a mean follow-up time of 26 months. Furthermore, longterm survival does not appear to be compromised by local recurrence, as most cases are still surgically salvageable.11
6.2
Management of Carcinoma In Situ and Superficial Verrucous Carcinoma (Tis and Ta)
Curative penile-preserving therapies can be readily utilized due to the non-invasive nature of Tis and Ta tumors (Fig. 6.1).
6.2.1
Topical Therapy
Carcinoma in situ accounts for approximately 10% of penile malignancies at diagnosis.12 CIS can arise on the shaft of the penis, where it is called Bowen’s disease, or as one or more red, moist patches on the mucosal surfaces of the glans penis or inner prepuce, where it is known as erythroplasia of Queyrat (EQ). CIS can easily be misdiagnosed as a benign skin condition or other penile dermatoses such as candidal balanitis, Zoon’s balanitis, or erosive lichen planus. It can also coexist with balanitis xerotica obliterans (BXO). Thus it is important that an early biopsy is taken in order to make the diagnosis and plan treatment. If left untreated, the observed risk of progression to invasive SCC is 5–33%.13 When invasive disease is absent, first-line therapy with topical 5% 5-Fluorouracil (5-FU) cream can be used and has already been discussed in Chap. 5. Although several regimes exist, the most popular is application on alternate days for a 4 week period although this is adjusted according to the response. Small studies (<10 patients) have shown excellent response rates approaching 100% at 5 years.14 The use of topical chemotherapy is safe and generally well tolerated. Patients who do
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not respond or who develop recurrence can be offered further topical therapy with 5% Imiquimod given in a similar regime. The success of this immune modulating cream has only been described in case reports.15
6.2.2
Cryotherapy and Photodynamic Therapy (PDT)
Cryotherapy offers another treatment option, but has been associated with meatal stenosis, severe inflammation, spontaneous bleeding, pain, and infection.16 EQ has also been managed with topical aminolevulinic acid (ALA) and PDT, but concern exists regarding the carcinogenic potential of this treatment.17 Stables and coworkers reported the use of topical ALA and PDT in four patients with EQ. Of two patients with localized disease, one had a complete response with no relapse at 36 months, but the second had a recurrence at 18 months despite an initial complete response. The two patients with extensive disease both had a reduction in disease burden, but required laser vaporization to complete the treatment.18 Axcrona and colleagues evaluated ALA and PDT in ten patients with CIS. Of these, five had CIS in isolation and five had previously undergone penile-preserving surgery for invasive disease but had residual concomitant CIS. Three of the ten were found to have residual disease confirmed on biopsy after a median follow-up of 20 months (range 15–36). They reported no loss of substance or fibrosis in the treated area, and the long-term cosmetic results were excellent. However, patients did report pain in the first week following treatment. The authors concluded that the therapy appeared promising in selected cases in combination with close follow-up.19
6.2.3
Laser Therapy
Laser treatment has been utilized in the treatment of penile carcinoma. It may be carried out in the outpatient setting, and has the additional advantage of producing excellent cosmetic and functional results. Carbon dioxide (CO2) and Neodymium:YAG (Nd:YAG) are the most commonly used lasers. The main difference between these is their penetration potential: CO2 laser has a longer wavelength (10,600 nm vs. 1,064 nm) and does not penetrate human tissues compared to Nd:YAG. A depth of 4–6 mm can be achieved with the Nd:YAG laser, but any tumor invading to greater than 6 mm is unsuitable for laser surgery. Assessment of tumor depth before starting laser treatment is therefore essential. This can be either accomplished with a biopsy or with ultrasound or magnetic resonance imaging (MRI). All of these modalities have limitations and run the risk of understaging the primary lesion.
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Table 6.2 Local recurrence post laser therapy
Author(s) Bandieramonte et al.23 Tietjen and Malek24 Windahl and Andersson25
Local recurrence Laser type Patient no no (%) CO2 224 32 (14.2) 118 (T1-2) 12 (11.3) CO2/Nd:YAG 44 (T1-2) 5 (11.4) CO2/Nd:YAG 67 13 (19) 46 (T1-3) 10 (21.7)
Salvage surgery procedures 23PPS/8PP/1TP
Mean follow-up (months) 66
3PPS/2PP 11PPS/2PP
58 42
PPS penile-preserving surgery, PP partial penectomy, TP total penectomy
Several studies support the use of laser in penile carcinoma. In 1995 Windhal reported the treatment of 19 patients, eight managed with CO2 laser alone and 11 with both CO2 and Nd:YAG. They reported two recurrences (11%) which were salvageable with further laser therapy. Both patients were disease free at 12 and 52 months.20 Shirahana and colleagues demonstrated the importance of case selection.21 They selected patients with carcinomas less than 6 mm thick, based on MRI and ultrasound scan assessments. Ten cases of CIS or stage T1 penile carcinoma were free of disease at 6 years. Two cases of stage T2 penile carcinoma were also included in this series. These were treated aggressively with a combination of chemoradiation and adjuvant laser therapy. Both were free of disease at 7 and 8 years of follow-up, respectively. More recently, Meijer and colleagues applied laser therapy to 44 tumors ranging from Tis to T2 disease and reported a local recurrence rate of 48% overall. Twenty three percent progressed during follow-up to develop nodal disease, 80% of these having originally presented with T2 disease. This study confirmed the benefit of laser therapy in low-stage disease and highlighted the danger of disease progression in higher stage cases where laser therapy is unsuitable.22 Overall, as with any organ-preserving therapy, local recurrences are higher than with conventional surgery and close follow-up is essential to allow early detection and intervention without compromising the patients’ survival (Table 6.2). Patient selection is also very important with late stage disease tending to be resistant to laser monotherapy. Complications of this treatment modality occur in 1–7% and include bleeding, moderate pain, and preputial lymphoedema.23-25 The long healing period is a further disadvantage of laser therapy.
6.2.4
Immunotherapy
The reported use of immuno-monotherapy in penile carcinoma is limited to noninvasive stage Ta verrucous carcinomas (VC). Maiche and colleagues described the
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successful use of subcutaneous interferon-a in three cases of VC in young patients26 one patient had recurrent tumor but refused further surgery. He was given 5 months of interferon treatment and was found to be tumor free at 10 years follow-up. In another case, interferon was used as a primary therapy in a patient again refusing surgery. He was treated for 3 months and was tumor free at 7 years. Risse and coworkers reported the treatment of VC in several anatomical locations including the penis. They concluded that interferon monotherapy may slow tumor growth and thus be used as an adjuvant therapy to surgical excision, but that this treatment modality would not prevent surgery or death.27
6.2.5
Total Glans Resurfacing (TGR)
Although the topical therapies described may be successful, they all have limitations and side effects. They require high levels of patient compliance and can be awkward to apply, often causing discomfort to the patients. Furthermore, the diffuse nature of EQ poses the risk of insufficient treatment and recurrence. Patients therefore need careful long-term surveillance and frequent re-treatment. The technique of TGR offers a surgical alternative. This procedure, first described by Bracka for the treatment of severe BXO28 and has been adapted for the management of CIS and stage Ta penile cancer patients with relapsing or extensive disease.29 It involves removal of the glans epithelium and subepithelial tissues in quadrants. Frozen-section biopsies are then taken from the underlying corpus spongiosum in order to confirm complete excision. The corpus spongiosum of the glans is then covered with a split thickness skin graft. The detailed surgical technique is described in Chap. 5. Watkin’s group have reported the initial outcome data on ten patients undergoing TGR. The men were followed 3-monthly for 2 years, 6-monthly for a further 2 years, and yearly thereafter. They found no evidence of disease recurrence at a median follow-up of 30 months (range 7–45). The graft take was successful in all cases and excellent cosmetic results were described. All patients who were previously sexually active were again sexually active within 3–5 months of surgery.29 There are several advantages of using the technique of TGR. Unlike any other treatment, an undamaged histological specimen is obtained to confirm complete excision of the disease. This is important when dealing with a premalignant condition. Given that the glans and sub-coronal epithelial and subepithelial tissues are completely excised, the chance of local recurrence is minimal, although long-term follow-up is still required. Moreover, TGR restores normal anatomy with minimal scar tissue formation. It appears particularly suitable for younger men in whom there is minimal operative risk, and in whom cure is paramount.
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6.3 6.3.1
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T1 Lesions Confined to the Prepuce Circumcision/Wide Local Excision
Circumcision is by far the commonest operation in the surgical management of penile carcinoma, and is indicated for primary curative therapy in low-stage preputial disease.30 However, adequate clearance margins must be achieved. If the lesion is more extensive the excision may be extended onto the shaft skin or coronal sulcus as necessary.31,32 Circumcision is always recommended prior to radiotherapy, allowing for accurate targeting and tumor definition. It also aids surveillance for local recurrence. Recurrence rates of up to 30% have been reported following circumcision,33,34 the majority of these occurring in the first 2 years following surgery.35 Close postoperative surveillance is therefore essential. However, salvage surgery has a high success rate and does not appear to affect the disease-specific survival.31,36 If CIS is present at the resection margin then this can be treated with topical 5% 5-FU or Imiquimod cream and then closely observed.
6.4
T1 Lesions on the Glans Penis
The management of these lesions remains controversial as several options are available. Careful case selection is important in order to ensure that low-risk tumors (i.e., T1 G1-2 in the absence of CIS) are differentiated from high-risk ones. Wide local excision (WLE) and primary closure may be possible if the lesion is discrete and not too close to the external meatus. For larger tumors, following WLE, a split thickness skin graft can be utilized to minimize distortion of the glans and reduce functional impairment. Complete excision is essential at the initial operation. However in some series, recurrence rates of up to 50% have been reported, most occurring in the first two postoperative years.37 Recurrent disease can be managed successfully with further surgery in most cases without compromising disease-specific survival.36,38 Close surveillance and patient education is vital for the early detection of relapse. Where there is coexisting CIS, topical chemotherapy with 5% 5-FU cream can be used. Again close follow-up is imperative.
6.4.1
Mohs Microsurgery
This technique involves the excision of the penile tumor in thin layers combined with microscopic assessment of the underside of each layer and systematic use
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of frozen sections.39 Two variations exist. The first is a chemical fixation method whereby tissues are fixed in situ with zinc chloride paste prior to excision. In the second, local anesthetic is used prior to excision of fresh tissue which is then analyzed using frozen sections. The latter is recommended for small tumors. Complication rates of 1.2–3.6% have been reported, including residual urethral disease, wound dehiscence, and meatal stenosis.40 Although Moh’s microsurgery is generally well tolerated and preserves the maximum amount of healthy underlying penile tissue, it is time consuming, requires highly skilled personnel, and importantly can leave the glans penis mis-shapen and requiring reconstructive surgery.
6.5
T2 Lesions Confined to the Glans Penis
Distal penile tumors (Fig. 6.2) involving the glans penis or distal corporal heads are traditionally successfully managed by performing a partial penectomy. Patients with such lesions can now benefit from penile-preserving surgery which maintains penile length and has a better cosmetic result. Austoni and coworkers highlighted the anatomical distinction between the corpora cavernosa and the corpus spongiosum and proposed glansectomy as a surgical option for patients with penile cancer confined to the glans.41 Approximately 80% of all cases of invasive penile carcinoma are potentially amenable to this operation. The extent of tumor invasion is confirmed with preoperative MRI imaging, with intracavernosal prostaglandin induced erection (Chap 4).42,43
6.5.1
Total Glansectomy and Split Skin Grafting
This technique involves the isolation and excision of tumors located on the glans penis (Fig. 6.2). A circumferential incision is made in the distal shaft skin down to Buck’s fascia (Fig. 6.3). At this level a plane is developed distally to separate the glans from the underlying corporal heads. The urethra is transected and frozen-section analysis of the tunica albuginea and distal urethral margin is performed in order to ensure complete excision44 (Figs. 6.4 and 6.5). The urethra is mobilized to allow formation of an urethrostomy at the tip of the penis. The shaft skin is sutured 2 cm from the tip leaving the corporal heads exposed. A split thickness skin graft is quilted to the exposed corpora to create a neoglans. A urethral catheter is placed and the patient remains on strict bed rest for 4 days35 (Fig. 6.6). A novel dressing technique that allows immediate postoperative mobilization has recently been described by Malone. Rather than ‘quilting’ the skin graft to the
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Management of Penile Cancer Using Penile-Preserving Techniques
Fig. 6.2 Penile tumor located on the glans and involving the inner prepuce which can be excised by performing a glansectomy
Fig. 6.3 Circumferential incision of the penile skin and penile fascia has been extended down to the level of Buck’s fascia
Fig. 6.4 A plane can be developed between the glans and the corporal tips which allows the glans and the tumor to be dissected off
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Fig. 6.5 Glans and tumor dissected off with the urethra just about to be transected
Fig. 6.6 The penile shaft skin is sutured to the corporal tips and a split skin graft is used to reconstruct a neoglans
neoglans, a proflavine soaked gauze tie over dressing is sutured to the newly formed meatus distally and corona proximally, using interrupted 4–0 monofilament sutures. Twenty-four of twenty-nine patients were discharged from hospital 1 or 2 days postoperatively with a urethral catheter in situ. The patients had their catheters and dressings removed 10 days after surgery. Graft take and cosmetic outcomes were reported as excellent.45 One study has reviewed three cases of penile verrucous carcinoma, angiosarcoma, and melanoma limited to the glans.46 All patients underwent glansectomy with clear resection margins. No local recurrences were reported at 12–48 months. Erections, sexual and urinary function had normalized shortly after the operation in all cases. Hatzichristou and colleagues reported seven cases of verrucous carcinoma treated with glansectomy.47 In this series, one patient required further surgery at 3 months for a local recurrence but all patients were alive and tumor free at 18–65 months.
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Management of Penile Cancer Using Penile-Preserving Techniques
Table 6.3 Local recurrence following penile-preserving surgery Local Patients recurrence no Author Procedure no (%) 49 Bissada et al. Local excision 30 3 (10) Shindel et al.40 Mohs procedure 33 8/25 (32) Brown et al.50 P/T glansectomy no grafting 5 0 Pietrzak et al.35 P/T glansectomy + grafting 39 1 (2.5) Smith et al.51 P/T glansectomy + resurfacing 72 3 (4)
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Salvage Mean surgery follow up procedures (months) 3 PPS 67.3 7MP/1PP – – 12 1 PPS 16 3 PPS 27
MP Mohs procedure, PP partial penectomy, PPS penile-preserving surgery, P/T partial/total
Pietrzak and coworkers documented one local recurrence in a patient who had undergone partial glansectomy and reconstruction, but all 39 patients who underwent total glansectomy and skin graft reconstruction were disease free at 2 years.35 In the largest series reported, the same group presented their medium-term outcome data. Of 72 patients (65 new tumors, 7 recurrent tumors post radiotherapy; 49% T1, 51% T2) undergoing glansectomy and reconstruction, there were three late recurrences (6%) with a mean follow-up of 27 months (range 4–68). Excellent functional and cosmetic results were described and there was no disease-specific mortality among those with local recurrence48 (Table 6.3). In an attempt to avoid the morbidity associated with skin grafts, novel techniques of glans excision and primary closure with shaft skin advancement and eversion of the urethral mucosa have been described. Brown and colleagues described subtotal glans excision without grafting. In this study of five patients with tumor stages T1G2 (2 men), T1G3 (2 men), and T2G2, all in the absence of CIS, they were able to preserve the urethral meatus while excising the glans penis (clearance margins ³5 mm on frozen sections). The urethral meatus was sutured down to the distal corpora and the penile skin advanced and approximated to it. At a mean follow-up of a year they reported no disease recurrence. The key advantage over total glansectomy was felt to be a reduction in spraying during micturition due to the preserved urethra.50 A disadvantage, however, is that this technique is inappropriate for patients with urethral invasion. Another novel modification described by Gulino and coworkers involves mobilization of the whole urethra off the corpora, and then opening the ventral aspect of the urethra longitudinally for approximately 3 cm. This is fashioned to cover the corporal heads, thus avoiding the need for a skin graft.52 However, the final cosmetic result is inferior compared to using a split skin graft.
6.6 6.6.1
T2 Tumors Invading the Corpora Cavernosa Distal Corporectomy and Split Thickness Skin Grafting
This more extensive technique is required if there is evidence of corporal involvement, or if frozen sections of the corpora, urethra, or tunica albuginea are positive.
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The operation is similar to a total glansectomy described above but includes the resection of the distal corporal heads and adjacent urethra. A rounded neoglans is then reconstructed from the corpora. The shaft skin is fully mobilized to prevent later retraction and shortening, and the denuded corporal heads are then covered by a split thickness skin graft. Penile lengthening manoeuvres can be performed at the same time or at a later date.51 An extra 2–3 cm can be gained by dividing the penile suspensory ligaments beneath the pubic arch. A dorsal V-Y skin advancement and a ventral V-Y phalloplasty to lower the insertion of the scrotal skin may also help relieve tethering and traction.53 The cosmetic outcome is better than for conventional surgery. However, following excision of larger tumors not all patients will have an adequate penile length to allow voiding while standing or be able to have penetrative sexual intercourse. Therefore, patients need to be well informed prior to surgery and expectations managed accordingly. Case selection is very important, as is close follow-up. The technique can also be used to salvage recurrent disease.54
6.7
Radiotherapy
This is a well established although now infrequently used therapy for penile carcinoma, which is most appropriate for small T1 or T2 lesions in patients unfit or unwilling for surgery. External beam radiotherapy (EBRT) or brachytherapy can be used either in the form of interstitial brachytherapy (IBRT), where the radiation source is implanted into the cancer, or plesiotherapy where the radiation source surrounds the tumor. EBRT has been shown to offer local control rates of 60–70%. Using the Toronto technique, the whole of the penis is irradiated with the use of a rectangular wax mould to ensure even distribution of radiation around the shaft of the penis.55 A total dose of 50–70 Gy is required, given in 15–30 daily sessions over 3–8 weeks on an outpatient basis. Acute radiation reactions (mucositis, skin irritation, and tissue edema) are common and often necessitate termination of treatment. The lengthy regime is a further disadvantage. In contrast, brachytherapy regimes are shorter but require in-patient isolation. IRBT involves the temporary implantation of radioactive wires or needles, usually iridium-192, into the penis. The wires are held in place by two external templates such as the Gerbaulet’s glans applicator,56 the distribution of holes along them ensuring an even administration of radiation. A dose of 50–70 Gy is the aim, administered over 5–7 days (see Chap. 12 for a more detailed explanation of the technique). Plesiotherapy can be utilized in patients with discrete, superficial lesions (£5 mm).57,58 There are two types of device. The first (high dose) uses a personalized mould containing catheters appropriately located according to the tumor position. The catheters are after-loaded with iridium-192 wires. The second (low dose) is more popular and involves the placement of two moulds around the penis. The inner
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Fig. 6.7 Fibrosis of the penile skin and glans penis following treatment with radiotherapy
one straightens the penis and the outer is loaded with radioactive wires. Patient cooperation and dexterity are essential for success. The mould is applied for 12 h a day for a week, giving a total dose of 60 Gy. Despite the more targeted dose of radiation with brachytherapy side effects remain common. The risks of infection, radioepidermitis, and mucositis necessitate antibiotic, anti-inflammatory and analgesic prescription. With all modes of radiotherapy, late complications occur at rates proportional to the dose delivered, with up to 40% affected.56,59 Urethral strictures occur in 15–40% of patients33,60 and skin changes such as telangiectasia, hypochromasia, and superficial necrosis are frequently observed. To date there are no prospective randomized trials assessing the effectiveness of radiotherapy compared with other treatments for penile cancer but information from retrospective studies has been consistent.61,62 Recurrence rates range from 15% to 40%, higher than for both conventional and penile-preserving surgery although the vast majority of recurrences are surgically salvageable. The overall organ-preservation rates are in the region of 60–80%, with no compromise in 5 and 10-year survival. These data may appear acceptable to some, but when compared to surgical outcomes with preservation rates of 90–95%, they are less so. Functional and cosmetic impairment due to radiofibrosis of the corpora and penile skin is frequently encountered (Fig. 6.7).
6.8
Salvage Post-Radiotherapy
McClean and colleagues reported that up to 40% of patients undergoing radical radiotherapy require salvage surgery for local recurrence.61 The chronic skin changes associated with radiotherapy make clinical detection of disease recurrence difficult. Watkin’s group published their data on 17 patients with this problem. Patients were treated over a 7 year period, presenting at a mean of 9 years (range
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1–29) post radiotherapy. All 17 patients underwent salvage surgery, 14/17 with total glansectomy and skin graft reconstruction. Despite some technical challenges with brittle non-compliant tissues, all the grafts took well. Fifteen of 17 (88%) were found to have tumors ranging from G1T1-G3T2a. At a mean follow-up of 3 years (range 1–6) 16/17 men were recurrence free and none had metastatic nodal disease. The authors concluded that all chronic ulceration and non-healing tissue should be treated as malignancy until proven otherwise.54
6.9
6.9.1
More Advanced Disease: Metastatic and Advanced Loco-Regional Tumors Chemotherapy
Penile carcinomas are chemosensitive to a certain degree. Systemic chemotherapy has been used mainly in the palliative setting, for metastatic and advanced locoregional disease.63-68 It also has a role in down-staging locally advanced tumors prior to surgery.33,69,70 Bleomycin, cisplatin, methotrexate, and vinblastine are the most frequently used agents, usually in combination with one another or with radiotherapy/immunotherapy.70,71 Their response rate is often partial and short lasting.68 With regard to the use of systemic chemotherapy as a curative primary organpreserving therapy for penile carcinoma, Cotsadze and coworkers reported their experience in 33 patients.71 Four different chemotherapy regimes were utilized: bleomycin monotherapy (11 cases), vinblastine and bleomycin (11 cases), cisplatin and bleomycin (6 cases), and cisplatin, vinblastine and bleomycin (6 cases). They reported an overall 49% complete response rate after only one cycle of treatment. Organ preservation was increased to 61% by adjuvant cryodestruction in partial responders. However, none of the stage T3 patients responded completely. The local recurrence rate was 19% and all of these patients were salvaged surgically. The 5 and 10-year survival rates were 78% and 73%, respectively. There was no advantage in using multidrug chemotherapy compared to bleomycin monotherapy. Mitropoulos and colleagues treated 12 cases (stage-T2/T3) with immunochemotherapy (cisplatin and interferon-a).69 They reported a 75% response rate. Four (33%) cases responded completely and 5 (42%) responded partially (defined as reduction in the size of tumor by more than 50%). They found a 50% local recurrence rate in the complete response group. All recurrences were surgically salvaged by undergoing penile amputation.
6.10
Conclusion
Definitive management of penile carcinomas is stage dependent. Due to the rarity of the disease there are no randomized prospective trials comparing the available treatment options. Since the development of larger supraregional treatment centres in the
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UK, the utilization of penile-preserving techniques has improved. Such surgical techniques have been shown in this chapter to provide good oncological control while minimizing the functional and psychological morbidity often associated with conventional surgery and radiotherapy. The vast majority of experts agree that stage Ta, T1, T2, and distal T3 tumors of all grades can be successfully treated with penile-preserving therapies. Careful case selection, based on both tumor and patient characteristics is required. Close followup is essential following penile preserving treatment as the local recurrence rate is higher compared to partial or total penectomy.
References 1. Cancer trends in England and Wales. Available at: www.statistics.gov.uk. 1950–1999. 2. Pow Sang MR, Benavente V, Pow Sang JE, et al. Cancer of the penis. Cancer Control. 2002;9:305-314. 3. Broders AC. Squamous cell epithelioma of the skin. Ann Surg. 1921;73:141. 4. National Institute for Clinical Excellence. Guidance on Cancer Services. Improving Outcomes in Urological Cancers-the Manual. London: NICE; 2002:83-85. http://www.nice.org.uk/pdf/ Urological_Manual.pdf. 5. Opjordsmoen S, Fossa SD. Quality of life in patients treated for penile cancer. A follow-up study. Br J Urol. 1994;74(5):652-657. 6. Rempelakos A, Bastas E, Lymperakis CH, et al. Carcinoma of the penis: experience from 360 cases. J BUON. 2004;9(1):51-55. 7. Leijte JA, Kirrander P, Antonini N, et al. Recurrence patterns of squamous cell carcinoma of the penis: recommendations for follow up based on a two centre analysis of 700 patients. Eur Urol. 2008;54(1):161-168. 8. Ornellas AA, Kinchin EW, Nobrega BL, et al. Surgical treatment of invasive squamous cell carcinoma of the penis: Brazilian National Cancer Institute long-term experience. J Surg Oncol. 2008;97(6):487-495. 9. Agrawal A, Pai D, et al. The histological extent of the local spread of carcinoma of the penis and its therapeutic implications. BJU Int. 2000;85(2):299-301. 10. Hoffman M, Renshaw A, Loughlin KR. Squamous cell carcinoma of the penis and microscopic pathologic margins. How much margin is needed for local cure? Cancer. 1999;85(7): 1565-1568. 11. Minhas S, Kayes O, Hegarty P, et al. What surgical resection margins are required to achieve oncological control in men with primary penile cancer? BJU Int. 2005;96(7):1040-1043. 12. Tercedor J, Lopez Hernandez B. Papilomavirus humanos y carcinoma epidermoide cutaneomucoso. Piel. 1991;6:470-471. 13. Malek RS. Laser treatment of premalignant and squamous cell lesions of the penis. Lasers Surg Med. 1992;12:246-253. 14. Goette DK, Elgart M, DeVillez RL. Erythroplasia of Queyrat. Treatment with topically applied fluorouracil. JAMA. 1975;232(9):934-937. 15. Micali G, Nasca MR, Tedeschi A. Topical treatment of intraepithelial penile carcinoma with imiquimod. Clin Exp Dermatol. 2003;28(suppl 1):4-6. 16. Dawber R, Colver G, Jackson A. Premalignant lesions. In: Dawber R, Colver G, Jackson A, eds. Cutaneous Cryosurgery. London: Martin Dunitz; 1992:77-93. 17. Varma S, Holt PJA, Anstey AV. Erythroplasia of Queyrat treated with topical aminolaevulinic acid photodynamic therapy: a cautionary tale. Br J Dermatol. 2000;142:825-828.
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18. Stables GI, Stringer MR, Robinson DJ, Ash DV. Erythroplasia of Queyrat treated by topical aminolaevulinic acid photodynamic therapy. Br J Dermatol. 1999;140(3):514-517. 19. Axcrona K, Brennhovd B, Alfsen GC, Giercksky KE, Warloe T. Photodynamic therapy with methyl aminolevulinate for atypical carcinoma in situ of the penis. Scand J Urol Nephrol. 2007;41(6):507-510. 20. Windhal T, Hellsten S. Laser treatment of localised squamous cell carcinoma of the penis. J Urol. 1995;154:1020-1023. 21. Shirahama T, Takemoto M, Nishiyama K, et al. A new treatment for penile conservation in penile carcinoma: a preliminary study of combined laser hyperthermia, radiation and chemotherapy. Br J Urol. 1998;82:687-693. 22. Meijer RP, Boon TA, van Venrooij GE, Wijburg CJ. Longterm follow-up after laser therapy for penile carcinoma. Urology. 2007;69(4):759-762. 23. Bandieramonte G, Colecchia M, Mariani L, et al. Peniscopically controlled CO2 laser excision for conservative treatment of in situ and T1 penile carcinoma: report of 224 patients. Eur Urol. 2008;54(4):875-882. 24. Tietjen DN, Malek RS. Laser therapy of squamous cell dysplasia and carcinoma of the penis. Urology. 1998;52(4):559-565. 25. Windahl T, Anderson SO. Combined laser treatment for penile carcinoma: results after longterm follow up. J Urol. 2003;169(6):2118-2121. 26. Maiche AG, Pyrhonen S. Verrucous carcinoma of the penis: three cases treated with interferon-alpha. Br J Urol. 1997;79:481-483. 27. Risse L, Negrier P, Dang PM, et al. Treatment of verrucous carcinoma with recombinant alphainterferon. Dermatology. 1995;190(2):142-144. 28. Depasquale I, Park AJ, Bracka A. The treatment of balanitis xerotica obliterans. BJU Int. 2000;86(4):459-465. 29. Hadway P, Corbishley CM, Watkin NA. Total glans resurfacing for premalignant lesions of the penis: initial outcome data. BJU Int. 2006;98(3):532-536. 30. Bissada NK. Conservative extirpative treatment of cancer of the penis. Urol Clin North Am. 1992;19(2):283-292. 31. McDougall WS, Kirchner FK, Edward RH, Killian LT. Treatment of carcinoma of the penis: the case of primary lymphadenectomy. J Urol. 1986;136:38-41. 32. Das S. Penile amputation for the management of primary carcinoma of the penis. Urol Clin North Am. 1992;19(2):277-282. 33. Pizzocaro G, Piva L, Tana S. Up-to-date management of carcinoma of the penis. Eur Urol. 1997;32:5-15. 34. Colberg JW, Andriloe GL, et al. Surgical management of penile cancer. In: Vogelzang NJ, Scardino PT, Shipley WU, et al., eds. Comprehensive Textbook of Genitourinary Oncology. Baltimore: Williams and Wilkins; 1999:1103-1109. 35. Pietrzak P, Corbishley C, Watkin NA. Organ sparing surgery for invasive penile cancer. Early follow up data. BJU Int. 2004;94:1253-1257. 36. Lindegaard JC, Nielsen OS, et al. A retrospective analysis of 82 cases of cancer of the penis. Br J Urol. 1996;77(6):883-890. 37. Horenblas S, Van Tintern H. Squamous cell carcinoma of the penis. IV. Prognostic factors of survival: analysis of tumour, nodes, and metastatic classification system. J Urol. 1994;151(5):1239-1243. 38. Lont AP, Gallee MPW, Meinhardt W, van Tintern H, Horenblas S. Penis conserving treatment for T1 and T2 penile carcinoma: clinical implications of a local recurrence. J Urol. 2006;176:575-580. 39. Mohs FE, Snow SN, Larson PO. Mohs micrographic surgery for penile tumours. Urol Clin North Am. 1992;19(2):291-304. 40. Shindel AW, Mann MW, Lev RY, et al. Mohs micrographic surgery for penile cancer: management and long-term follow up. J Urol. 2007;178(5):1980-1985. 41. Austoni E, Fenice O, Kartalas Goumas Y, et al. New trends in the surgical treatment of penile carcinoma. Arch Ital Urol Androl. 1996;68(3):163-168.
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42. Scardino E, Villa G, Bonomo G, et al. Magnetic resonance imaging combined with artificial erection for local staging of penile cancer. Urology. 2004;63:1158-1162. 43. Kochhar R, Taylor B, Sangar V. Imaging in primary penile cancer: current status and future directions. Eur Radiol. 2010;20:36-47. doi:10.1007/s00330-009-1521-4. 44. Algaba F, Arce Y, Lopez-Beltran A, et al. Intraoperative frozen section diagnosis in urological oncology. Eur Urol. 2005;47(2):129-136. 45. Malone PR, Thomas JS, Blick C. A tie over dressing for graft application in distal penectomy and glans resurfacing: the TODGA technique. BJU Int. 2011;107(5):836-840. 46. Davis JW, Schellhammer PF, Schlossberg SM. Conservative surgical therapy for penile and urethral carcinoma. Urology. 1999;53:386-392. 47. Hatzichristou DG, Apostolidis A, Tzortzis V, et al. Glansectomy: an alternative surgical treatment for Buschke-Lowenstein tumours of the penis. Urology. 2001;57:966-969. 48. Smith Y, Hadway P, Biedrzcki O, Perry MJA, Corbishley C, Watkin NA. Reconstructive surgery for invasive squamous carcinoma of the glans penis. Eur Urol. 2007;52(4):1179-1185. 49. Bissada NK, Yakout HH, Fahmy WE, et al. Multi-institutional long-term experience with conservative surgery for invasive penile carcinoma. J Urol. 2003;169(2):500-502. 50. Brown CT, Minhas S, Ralph DJ. Conservative surgery for penile cancer: subtotal glans excision without grafting. BJU Int. 2005;96:911-912. 51. Smith Y, Hadway P, Ahmed S, et al. Penile preserving surgery for male distal urethral carcinoma. BJU Int. 2007;100(1):82-87. 52. Gulino G, Sasso F, Falabella R, et al. Distal urethral reconstruction of the glans for penile carcinoma: results of a novel technique at 1-year follow up. J Urol. 2007;178(3):941-944. 53. Miranda-Sousa A, Keating M, Moreira S, Baker M, Carrion R. Concomitant ventral phalloplasty during penile implant surgery: a novel procedure that optimizes patient satisfaction and their perception of phallic length after penile implant surgery. J Sex Med. 2007;4:1494-1499. 54. Shabbir M, Hughes BE, Swallow T, Corbishley C, Perry MJA, Watkin N. Management of chronic ulceration after radiotherapy for penile cancer. J Urol. 2008;179(4):785. 55. Ozsahin M, Jichlinski P, Weber DC, et al. Treatment of penile carcinoma: To cut or not to cut? Int J Radiat Oncol Biol Phys. 2006;66(3):674-679. 56. Gerbaulet A, Lambin P. Radiation therapy of cancer of the penis. Indications, advantages and pitfalls. Urol Clin North Am. 1992;19(2):325-332. 57. Akimoto T, Mitsuhashi N, Takahashi I, et al. Brachytherapy for penile cancer using silicon mold. Oncology. 1997;54(1):23-27. 58. Neave F, Neal AJ, Hoskin PJ, et al. Carcinoma of the penis: a retrospective review of treatment with iridium mould and external beam irradiation. Clin Oncol R Coll Radiol. 1993;5(4):207-210. 59. Koch MO, Smith JA Jr. Local recurrence of squamous cell carcinoma of the penis. Urol Clin North Am. 1994;21(4):739-743. 60. Ravi R, Chaturvedi HK, Sastry DVLN. Role of radiation therapy in the treatment of carcinoma of the penis. Br J Urol. 1994;74:646-651. 61. McLean M, Ahmed M, Warde P, et al. The results of primary radiation therapy in the management of squamous cell carcinoma of the penis. Int J Radiat Oncol Biol Phys. 1993;25(4):623-628. 62. Horenblas S, van Tinteren H, et al. Squamous cell carcinomas of the penis. II. Treatment of the primary tumour. J Urol. 1992;147:1533-1538. 63. Shammas FV, Ous S, Fossa SD. Cisplatin and 5-fluorouracil in advanced cancer of the penis. J Urol. 1992;147(3):630-632. 64. Corral DA, Sella A, Pettaway CA, et al. Combination chemotherapy for metastatic or locally advanced genitourinary squamous cell carcinoma: a phase II study of methotraxate, cisplatin and bleomycin. J Urol. 1998;160(5):1770-1774. 65. Haas GP, Blumenstein BA, Gangliano RG, et al. Cisplatin, methotraxate and bleomycin for the treatment of carcinoma of the penis: a Southwest Oncology Group study. J Urol. 1999;161(6):1823-1825. 66. Roth AD, Berney CR, Rohner AS, et al. Intra-arterial chemotherapy in locally advanced or recurrent carcinomas of the penis and anal canal: an active treatment modality with curative potential. Br J Cancer. 2000;83(12):1637-1642.
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67. Kattan J, Culine S, Droz JP, et al. Penile cancer chemotherapy: twelve years’ experience at Institut Gustave-Roussy. Urology. 1993;42(5):559-562. 68. Ahmed T, Sklaroff R, Yagoda A. Sequential trials of methotrexate, cisplatin and bleomycin for penile cancer. J Urol. 1984;132(3):465-468. 69. Bandieramonte G, Lepera P, Mogha D, Faustini M, Pizzocaro G. Neoadjuvant chemotherapy and conservative surgery for exophytic T1N0 carcinoma of the penis. Fourth International Congress on Anticancer Chemotherapy; 1993; Paris. Abstract 178. 70. Mitropoulos D, Dimopoulos MA, Kiroudi-Voulgari A, et al. Neoadjuvant cisplatin and interferon-alpha 2B in the treatment and organ preservation of penile carcinomas. J Urol. 1994;152(4):1124-1126. 71. Cotsadze D, Matveev B, Zak B, Mamaladze V. Is conservative organ-sparing treatment of penile carcinoma justified? Eur Urol. 2000;38:306-312.
Chapter 7
Management of Locally Advanced and Metastatic Penile Cancer Asif Muneer, Afshin Mosahebi, Vijay Sangar, and Suks Minhas
7.1
Introduction
Neoplastic lesions of the penis are rare and the majority of patients will present with lesions affecting the glans and prepuce. Penile-preserving surgical techniques are now well established and result in excellent functional and cosmetic results.1-3 However, up to 14% of patients may present with locally advanced primary disease in association with extensive inguinal metastases due to an aggressive histological subtype or a delayed presentation. There may also be extension of tumor into adjacent organs such as the prostate, rectum, and bladder as well as osseous structures. Extensive metastatic disease within the inguinal regions also presents a therapeutic challenge as the presence of extranodal disease with involvement of skin, subcutaneous tissue, muscle, and femoral vessels renders it unresectable. With such advanced disease, there may be little option but to commence palliative treatment as the prognosis is generally very poor.
7.2
Presentation and Evaluation of Patients with Advanced Penile Cancer
Patients with advanced disease present with a host of constitutional symptoms. They may be cachectic, lethargic, and anemic particularly if an ulcerating inguinal mass has been bleeding intermittently. The performance status of these patients will determine the extent to which they will tolerate a multimodality approach to the management of their disease. Another feature of advanced disease is the development of hypercalcemia in the absence of osseous metastases. This has been reported in previous studies and is thought to arise as a result of the secretion of a parathyroid hormone protein analogue resulting in a paraneoplastic hypercalcemia due to osteoclastic bone resorption.4,5 The A. Muneer (*) Department of Urology, University College London Hospital, London, UK A. Muneer et al. (eds.), Textbook of Penile Cancer, DOI 10.1007/978-1-84882-879-7_7, © Springer-Verlag London Limited 2012
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development of hypercalcemia can result in patients becoming dehydrated, lethargic, confused, and very weak. Often the hypercalcemia is overlooked particularly when there is no evidence of bone metastases. The patients are then deemed to have a poor performance status making them unsuitable for any palliative surgery. Therefore monitoring the serum calcium and treating hypercalcemia with a combination of intravenous fluids and bisphosphonates may improve the patient’s performance status prior to undergoing palliative chemotherapy/radiotherapy. The presence of infection and malnutrition is also associated with a leucocytosis and hypoalbuminemia. The nature of penile cancer combined with the pattern of disease dissemination means that patients with a delayed presentation often have unsightly fungating inguinal disease together with impaired urinary and anorectal function. The majority of these patients will have some functional impairment in voiding as the primary tumor obstructs the penile urethra. These patients may present with urinary retention but commonly dribbling incontinence is the main feature. More proximal involvement of the membranous urethra and prostate will cause urinary incontinence. Cross-sectional imaging using CT or MRI allows an accurate assessment of the extent of the disease as distant lymph node involvement or lung metastases are common. For patients with suspected recurrent lymph node involvement, a PET scan is also helpful.
7.3
Locally Advanced Penile Cancer
Traditionally patients with penile cancer have been surgically managed using one of three procedures, circumcision for preputial tumors, partial penectomy for distal tumors involving the glans penis or distal penile shaft, total penectomy combined with a perineal urethrostomy for more extensive tumors infiltrating into the proximal penile shaft. These techniques have been utilized in order to ensure clear tumor margins which traditionally have been defined as being 2 cm. However, studies have challenged this and demonstrated that smaller resection margins do not appear to compromise oncological control.1,6,7 More recently penile-preserving surgery such as glansectomy or wide local excisions with grafting have been employed in order to maintain penile length resulting in a more acceptable functional and cosmetic outcome. Partial penectomy and total penectomy procedures are now reserved for cases where penile-preserving surgical options are not suitable due to the extent of the disease.
7.4 7.4.1
Partial Penectomy Preoperative Staging
Patients presenting with penile lesions located on the glans penis with a palpable invasion into the distal tunica albuginea and corpus cavernosum are amenable to partial penectomy procedures. The preoperative evaluation using MRI to assess the extent of the tumor can aid in the management of these patients as it can demon-
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Fig. 7.1 MRI showing a tumor of the glans penis infiltrating into the distal corporal tips. This patient was managed by performing a glansectomy and distal corporectomy
strate tumor involvement of the glans penis extending into the distal corporal tips (Fig. 7.1) in which case a glansectomy and distal corporectomy will still preserve penile length.8 However, if the tumor shows a more proximal extension then a conventional partial penectomy is performed.
7.4.2
Operative Procedure
Various techniques have been described in order to perform a partial penectomy. The aim is to ensure that the tumor is removed with adequate tumor-free margins while preserving enough length for the patient to void standing up and also have enough length to resume sexual activity. If this is not possible some groups would proceed directly to a total penectomy and perineal urethrostomy. However, in the majority of cases by incorporating some additional penile lengthening procedures, converting to a total penectomy is usually not required.
7.4.3
Patient Preparation
The procedure is performed with the patient supine. If inguinal lymphadenectomy is to be performed at the same time, the patient is draped with the inguinal regions exposed. Antibiotics are administered preoperatively and continued postoperatively as these lesions are often associated with concomitant infection. Figure 7.2 shows a penile SCC in a 65 year-old man. In order to prevent tumor spillage into the operative field the tumor is covered with either a condom, gauze swab, or a surgical glove. The resection limit is marked with a pen ensuring that an adequate tumor-free margin is maintained (Fig. 7.3).
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Fig. 7.2 Penile tumor involving the glans penis and distal corpus cavernosum
Fig. 7.3 The tumor is covered in order to avoid spillage of malignant cells and the skin limits are marked
The common surgical techniques use a circumcoronal incision of the penile shaft skin with partial degloving of the penis. This is useful if a neoglans is to be reconstructed using a split skin graft. Alternatively, if a graft is not going to be used for reconstruction, the penile skin is brought forward and used to cover the corporal tips. Once the skin and superficial fascial layers are dissected, Bucks fascia is identified (Fig. 7.4). This distinct tough shiny layer is then marked at the area where the corpus cavernosum is going to be transected. The neurovascular bundle is mobilized, ligated, and divided prior to transection of the penis (Fig. 7.5). A tourniquet placed at the penile base will minimize the bleeding prior to transection of the corpus cavernosum. In cases where penile lengthening is required, the suspensory ligament can also be divided (Fig. 7.6). Once transected, the corpora are mobilized off the non-involved urethra and the urethra is then divided ensuring that it is approximately 1.5–2 cm longer than the corporal margins in order to enable adequate spatulation of
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Fig. 7.4 The skin and penile fascia are dissected to the level of Buck’s fascia
Fig. 7.5 The neurovascular bundle is ligated and the penis transected leaving the urethra protruding by 1.5 cm. Further biopsies of the proximal margin can be taken in order to ensure that the margins are clear of tumor
the urethra. Further biopsies from the proximal corporal margin and urethra are sent for frozen-section analysis in order to ensure that the margins are clear of tumor. The corpora are oversewn with 2/0 absorbable sutures and the tourniquet can then be released (Figs. 7.7 and 7.8). The urethra is spatulated dorsally and sutured to the corporal margin (Figs. 7.9 and 7.10). The alternative options available in order to construct a neoglans are: 1. Suture the skin longitudinally and then circumferentially to the urethra. 2. Suture the skin just proximal to the corporal margin and construct a neoglans using a split thickness skin graft.9 3. Button hole the skin flap and bring the urethra through the button hole followed by primary closure of the skin. A 14Ch or 16Ch Foley catheter is left in situ and removed after 1 week. If a split skin graft is used, we prefer to harvest the graft from the anterior or anteromedial thigh with a graft thickness between 0.012 and 0.016 in. harvested using an air or
148 Fig. 7.6 Division of the suspensory ligament allows penile mobilization in order to gain additional length
Fig. 7.7 The corpus cavernosum is oversewn
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Fig. 7.8 The urethra is spatulated and a neourethra is formed
Fig. 7.9 The penile shaft skin is drawn forward and sutured to the urethra
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Fig. 7.10 Final appearance of the penis
electric dermatome. This is sutured to the neoglans using a combination of 4/0 and 5/0 absorbable sutures. The dressings are applied in order to immobilize the graft and then subsequently removed on day 5.
7.4.4
Surgical Procedures to Gain Additional Penile Length
A number of techniques can be utilized in order to gain additional penile length. 1. The penis can be completely degloved and this allows division of the suspensory ligament. Reattachment to the inferior pubic bone with 2/0 ethibond sutures ensures that the penis does not retract back (Fig. 7.6). 2. Where there is a prominent peno-scrotal web, a scrotoplasty can be performed which again allows the patient to hold on to the penile shaft and direct voiding while standing.10 3. In patients with a prominent suprapubic fat pad either liposuction or a suprapubic fat pad excision can be performed. 4. If the penile stump continues to retract, a malleable penile prosthesis can maintain penile length sufficient to allow the patient to void.
7.4.5
Postoperative Complications
Although the procedure is relatively straightforward, the main complication relates to meatal stenosis. A 6% incidence of urethral meatal stenosis has been reported.11 This can be avoided by ensuring that the urethra is adequately mobilized and spatulated dorsally. Patients in whom a split skin graft is used inevitably have an area of graft failure along the suture line resulting from oversewing of the corporal tips. This is a relatively small area of graft failure and generally granulates and heals after a period of time.
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7.5 7.5.1
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Total or Radical Penectomy Preoperative Staging
Radical penectomy is reserved for cases where extensive tumor involvement of the penile shaft necessitates complete excision of the penis and crura. Again preoperative MRI is useful in order to demonstrate the proximal extension of the tumor as there may be skip lesions extending proximally. Figure 7.11 shows an extensive tumor which has been imaged using MRI confirming that the tumor involves the pendulous penile shaft as well as multiple skip lesions more proximally. Therefore adequate tumor margins can only be obtained by performing a total penectomy. The level of dissection does not have to extend to include the crural attachment with the pubic bone unless there is tumor involvement of the proximal crura. It is useful to preserve the crura in patients who are to be considered for reconstruction using phalloplasty procedures at a later date as they provide a support for the proximal ends of the penile prostheses used during reconstructive surgery (see Chap. 11). However, in some advanced cases of penile cancer the tumor extends proximally to involve the crura and pubic bones. In these patients a conventional radical penectomy is required which involves detaching the crura from the pubic bone. Patients with extensive sarcomas of the penis or recurrent disease in the penile stump may also require a radical penectomy. Rarely metastatic disease from the genitourinary system presents with nodular lumps within the corpus cavernosum and again MR imaging is useful for diagnostic evaluation (see Chap. 4 for examples of metastatic disease infiltrating the penis).
Fig. 7.11 Penile MRI demonstrating an extensive penile tumor
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7.5.2
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Operative Procedure
For a radical penectomy the patient is positioned in the lithotomy position.
7.5.3
Patient Preparation
Preoperative antibiotics and thromboprophylaxis is given. An elliptical incision is marked around the penis which can be modified to incorporate a larger part of the scrotal skin which has the advantage of pulling up the scrotal contents once the incision is closed thereby reducing any obstruction to the perineal urethrostomy when voiding in the sitting position. Preoperative staging using MRI is useful in order to determine the extent of the tumor as illustrated in Fig. 7.11 which shows extensive tumor within the corpus cavernosum to the level of the crural attachments.
7.5.4
Operative Procedure
The skin and superficial fascia is divided. The penis is mobilized and the deep dorsal vein and neurovascular bundle ligated and divided. The suspensory ligament is divided and the dissection continues proximally. A separate inverted U incision is made in the perineum for the creation of a perineal urethrostomy (Fig. 7.12). Following the division of the superficial fascial layers and splitting of the bulbospongiosus muscles, the urethra is identified and mobilized. Ensuring that there is an adequate urethral length, the urethra is transected and spatulated ventrally (6 o’clock position) in order to allow the tip of the U to be incorporated ventrally. The crura are followed down to the level of the pubic bone and a periosteal elevator is used to completely divide the crura off the pubic bone. The dorsal artery is present at this point and requires identification and ligation.
Fig. 7.12 Incision utilized to form a perineal urethrostomy
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For the subtotal procedure, the crura are transected after gaining proximal control using vascular clamps. The crura are then oversewn using 2/0 NAS. The skin is then sutured to the urethra using 3/0 and 4/0 sutures. A 14Ch Foley catheter is left in situ and removed after 1 week to 10 days. Antibiotics are continued for 1 week. A drain is left in the perineum and also the pubic area. A pressure dressing is applied to reduce hematoma formation.
7.5.5
Postoperative Complications
Stenosis of the perineal urethrostomy is a common complication and often requires revision surgery as opposed to repeated dilatations. The stenosis can be avoided by ensuring that the inverted U has a fairly obtuse angle at the apex and that the urethral spatulation is of an adequate length.
7.6
Oncological Control Following Surgery for Locally Advanced Penile Tumors
The technique of partial penectomy and radical penectomy has been employed since the first century as it was found that excision of the penile tumor using these techniques results in adequate disease control. Patients undergoing these procedures have a low recurrence rate. The local recurrence rate following a partial penectomy is 0–8%.11,12 However, in terms of functional outcomes, the procedures are deemed drastic with a significant psychological impact related to demasculinization.
7.7
Advanced Penile Tumors with Bulky Disease
Some patients with penile cancer will always continue to present late. Aggressive penile SCC subtypes particularly sarcomatoid lesions can progressively cause widespread necrosis of the adjacent skin. In such cases, autoamputation of the penis results followed by widespread malignant infiltration of the subcutaneous tissue.13 If left untreated concomitant sepsis may ensue which is often fatal. Figure 7.13 illustrates a sarcomatoid SCC of the penis in a 51-year-old patient presenting after first noticing a small penile lesion 12 months previously. Extensive lesions such as these are not amenable to radiotherapy and require prompt surgical resection for palliation (Fig. 7.14). In this particular patient the presence of a large abdominal pannus allowed complete resection followed by primary closure of the defect using an abdominoplasty (Fig. 7.15). Despite postoperative chemoradiation this particular patient died after 7 months.
154 Fig. 7.13 Advanced sarcomatoid SCC of the penis
Fig. 7.14 Surgical resection of the lesion with preservation of the testicles and spermatic cord
Fig. 7.15 Primary closure of the wound by performing an abdominoplasty
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7.8
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Advanced Metastatic Inguinal Lymph Node Disease (N1–N3 Large or Fixed Nodes)
The step wise metastatic involvement of lymph nodes in patients with penile cancer begins at the level of the inguinal lymph nodes. In contrast to early stage disease where lymph nodes are either impalpable or small and palpable, in advanced disease the lymph nodes may form large palpable lesions which are adherent to the overlying skin or fixed to the underlying fascia or muscle. Inevitably these large masses are associated with extracapsular extension of tumor and therefore in order to gain local control the overlying skin and subcutaneous tissue must be excised. With metastatic lymph nodes deep to the skin primary closure of the defect is possible aided by mobilization of the superior and inferior skin flaps. However, larger defects following resection of inguinal metastatic disease associated with skin ulceration often requires the use of pedicled skin flaps in order to cover the resulting defect. Bulky ulcerating inguinal N3 disease can undergo palliative resection of the tumor and overlying skin followed by coverage of the defect using a pedicled skin flap. This allows palliation with regard to symptoms such as pain and sepsis and also reduces the risk of femoral vessel hemorrhage due to malignant infiltration. When circumstances demand a large area of inguinal soft tissue sacrifice, primary closure may be obtained by scrotal skin rotation flaps,14 an abdominal wall advancement flap,15 or a myocutaneous flap based on the rectus abdominis or tensor fascia lata16,17 for more extensive defects. These techniques will be described later in the chapter.
7.9
The Role of Preoperative Chemoradiation in Advanced Disease
There is a paucity of data related to preoperative chemoradiation regimens in penile cancer prior to surgery in cases of advanced disease. Until the data available is more meaningful, clear guidelines are not available and a case by case approach is used to manage these challenging cases. The benefits of preoperative radiotherapy do not appear to improve overall survival and in the majority of cases the surgery has to be performed promptly in order to avoid vascular infiltration or sepsis. Metastatic lymph nodes which have progressed to such an extent that they have penetrated through the skin and present as ulcerating lesions can be managed using external beam radiotherapy to the inguinal regions. A series published by Ravi et al.18 included 41 patients (66 groins) who were treated with palliative radiotherapy to the inguinal regions for fixed inguinal nodes. Within this group 56% of patients obtained a relief in symptoms. However, the 5 year disease-free survival was only 1%. In addition to this 33 patients were treated with preoperative radiotherapy (40 Gy) over
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Fig. 7.16 Ulcerating groin lesion treated with palliative radiotherapy
Fig. 7.17 CT imaging shows the extent of the groin lesion and also a pathological hip fracture
a 4 week period prior to undergoing an inguinal lymphadenectomy. The incidence of extranodal disease was only 8% with a further 3% groin recurrence. This suggests that local control is improved with preoperative radiotherapy. Radiotherapy was ineffective for pelvic node metastases although it did relieve painful bony metastases. An ulcerating inguinal lesion is shown in Fig. 7.16. The CT image shows the extent of the disease and also shows a pathological hip fracture (Fig. 7.17) which was fixed before commencing radiotherapy (Fig. 7.18). Following palliative radiotherapy the tumor showed an incomplete response (Fig. 7.19) although the skin lesion regressed (Fig. 7.20). There may be some advantage in preoperative chemotherapy prior to undergoing the surgery. The studies published thus far have generally been small retrospective case series. Early reports include Shammas et al.19 who reported a 28% response using a combination of cisplatin and 5-FU. Studies by Ahmed et al.20 investigated singleagent use of methotrexate, cisplatin, or bleomycin. This group evaluated 39 patients with overall response rates of 1.5%, 25%, and 21% for methotrexate, cisplatin, and
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Fig. 7.18 Internal fixation of the hip prior to radiotherapy
Fig. 7.19 CT imaging shows an incomplete response to radiotherapy
bleomycin, respectively. Bleomycin and methotrexate showed treatment-related deaths of 7% and 12%, respectively.21 Subsequently, Gagliano et al. undertook a SWOG study of 26 patients who were administered single-agent cisplatin at a dose of 50 mg/m² (days 1 and 8 of 28 day cycle).22 This was a lower dose used than that used by Ahmed et al., who utilized a once-weekly regimen over 3 weeks at doses between 70 and 120 mg/m². The overall response rate obtained in the SWOG study was 15%, with no treatment-related deaths.
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Fig. 7.20 The ulcerating skin lesion has regressed allowing better symptom control with regard to bleeding and pain
The above two studies led to the evaluation of combined chemotherapy in advanced penile cancer. A Phase II study utilizing bleomycin, methotrexate, and cisplatin was undertaken and reported in 1999.23 In this prospective study, 45 patients were studied, of which, 40 were evaluable. The overall response rate was 32.5%, with 5 treatment-related deaths (12.5%). The median overall survival in this group was 28 weeks. The toxicity was obviously too high in order to continue the study. There have been other combined chemotherapy regimens such as 5-FU and cisplatin,19 irinotecan and cisplatin,24 interferon-alpha and 13-CRA, and paclitaxel, ifosfamide, and cisplatin (TIP).25 In the latter TIP study, 20 patients were evaluated, with an overall response rate of 55% and median overall survivals of 11 months. Irinotecan and cisplatin treatment showed overall response rates of 31%, with median overall survivals of 4.7%. Bleomycin and methotrexate have shown toxicity which is too high for modern therapy. On the other hand, cisplatin or taxol-based combinations seem to provide good overall response rates with much less toxicity. The success rates of Taxol-containing chemotherapy regimens have led to the initiation of one of the first national, multicentre, Phase II chemotherapy studies in the UK. The TPF study uses taxol, cisplatin and 5-FU. The primary endpoint in this study is response rate in all patients recruited with metastatic or locally advanced disease. This study is ongoing and is expected to be reported in 2011/2012. The Netherlands Cancer Institute have reported a series of 19 retrospective cases of unresectable penile cancer which were treated with varying regimens, including single-agent bleomycin and cisplatin, and 5-FU, but no Taxol-based regimen.26 Of the 19 patients evaluable, 12 patients responded (63%) with 2 complete and 10 partial responses. Of the 12 responders, 9 underwent further surgery and 8 of these showed no evidence of disease at a median follow-up of 20.4 months. Unfortunately, all 3 who did not respond to chemotherapy died within 8 months. There were some deaths related to chemotherapy, and these were mainly in those patients receiving bleomycin. Bermejo et al. presented a smaller retrospective case series of ten
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patients, who again received multiple combined chemotherapy regimens.27 There were four complete responses, all of whom went on to have surgery, and two of these patients were still alive at 48 months. In those patients who had stable disease, of which there were five, the majority were dead within 7 months. Pizzocaro et al. undertook a prospective study using Taxol, cisplatin, and 5-FU. Of the six patients treated, four patients had a complete response of which three underwent consolidative surgery with a good outcome. Those patients who progressed or had stable disease faired poorly.28 A phase II study has been published by Pagliaro et al. from MD Anderson.29 A total of 30 patients with stage N2 or N3 disease underwent neoadjuvant treatment using paclitaxel, ifosfamide, and cisplatin. Fifty percent had an objective response with a total of 22 patients (73%) undergoing surgery following chemotherapy. After a median follow-up of 34 months, 9 (30%) patients remained free of recurrence. Therefore on the basis of the published series, cisplatin-based chemotherapy may have a role as there are patient responses and it may allow the extensive lesions to become resectable. However, the optimum regimens have yet to be defined.
7.10
The Surgical Management of Advanced Metastatic Inguinal Disease
Following the resection of bulky disease from the inguinal regions, various techniques can be utilized to facilitate the coverage of the resulting groin defects. Primary closure of the groin defects can be achieved by undermining the upper and lower skin flaps to ensure that a tension-free closure is achieved if there is a large pannus available to allow mobilization. Alternatively an advancement flap can be used.15 Primary closure has also been achieved using a skin stretch device.30 Wound closure can be combined with a sartorius muscle transposition in order to cover the exposed femoral vessels. However, it is debatable as to whether the sartorius transposition reduces the lymph drainage postoperatively.31 Other techniques which have been described include the use of an omental flap in order to reduce the risk of lymphoedema.32 However, for more extensive defects, a pedicled flap provides good coverage while also reducing subsequent complications.
7.11
Pedicled Flaps for Reconstruction
A number of pedicled flaps have been described for reconstruction following extensive groin dissections. These include the rectus femoris pedicled flap, vertical rectus abdominis myocutaneous (VRAM), anterolateral thigh (ALT), and tensor fascia late (TFL) flaps. Of these, the VRAM, TFL, and ALT flap have been used most extensively.
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Tensor Fascia Lata Pedicled Flap
The TFL flap is based on the ascending branch of the lateral circumflex femoral artery which is located approximately 8–10 cm below the anterior superior iliac spine. The motor nerve supply is via the superior gluteal nerve which enters posteriorly. The sensory supply is via the lateral cutaneous branch of T12 and the lateral femoral cutaneous nerve of the thigh. An island of skin can be harvested up to 15 cm in width. The flap can be elevated up to 8 cm above the knee. The lateral circumflex femoral artery passes between the rectus femoris and the vastus lateralis where it gives off the transverse branch which pierces the TFL muscle. The flap can then be mobilized and rotated. For groin defects extensive mobilization is not required due to the close proximity of the defect to the flap. The donor area is covered with a split skin graft. The TFL flap is well vascularized and complications are limited to either wound dehiscence or necrosis of the distal tip of the flap.
7.11.2
The ALT
The ALT flap can be used as a pedicled or free flap for large groin defects. It is a fascio-cutaneous flap (consisting of skin & fascia only). As such it makes it a potentially large donor site of supple and sometimes sensate tissue. The skin paddle can be as large as 8 by 25 cm with primary closure attainable. Wider flaps can be harvested but the donor site would have to be skin grafted. The flap has a large caliber pedicle, but the anatomy can be variable. In the majority of cases perforators travel through the vastus lateralis making dissection of this flap difficult and tedious. The anterolateral thigh flap lies on the axis of the septum dividing the vastus lateralis and the rectus femoris muscles. Arterial inflow is supplied by the descending branch of the lateral circumflex femoral artery (LCFA), which travels deep within the space between the rectus femoris muscle and the vastus lateralis muscle usually in the septal plane, which could be used to identify the pedicle. The pedicle can be as long as 7 or 8 cm and the flap can be innervated by a major branch of the lateral cutaneous nerve of the thigh, which enters the flap at the superior aspect, and can be traced proximally to provide length. The junction of the proximal and middle third is often the site of a perforator that pierces the tensor fascia lata. This point can be incorporated in the flap to keep the TFL perforator as a “lifeboat” in the rare situation when the distal perforators are of poor quality or injured during dissection. The junction of the middle and distal third is marked and is also incorporated into the flap. This area defined by the middle third of the axis line generally encompasses all perforating vessels, with a pencil Doppler exam helping to reassure the surgeon that perforators are present. The flap design can be adjusted depending on findings of the Doppler exam. The anterior flap is elevated first, noting any vessels perforating the substance of the rectus femoris. Vessels approaching or near the septum are preserved until the
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posterior flap is elevated and the nourishing vessels to the flap have been identified with certainty. Below, two perforators are found. The superior perforator clearly arises out of the rectus femoris muscle. The inferior perforator appears to arise either via the septum or through the vastus lateralis muscle. Both are preserved for the time being. The posterior flap is elevated toward the septum, again checking for major perforating vessels, this time through the vastus lateralis. Here the lower perforator can be seen to travel through the vastus. It should be dissected toward the descending branch of the LCFA. The septum is identified and any septal perforators are noted. If there are, and they are large, they can be used to perfuse the flap. If one or two good-quality perforators are visualized in the septum, then the anterior elevation can continue until the septum is isolated both medially and laterally. If the blood supply is entirely septal, the descending branch of the lateral femoral circumflex artery is found at the base of the septum between the rectus femoris and vastus lateralis and traced proximally. When a flap perfuses from a transmusclular perforator, then this perforator is traced through the muscle to the descending branch. The size of the perforator will determine whether an additional vessel is needed. Vessels can be temporarily clamped with micro clamps to determine inflow dominance. The entire flap can then be isolated on the dominant perforator(s) and the descending branch of the lateral circumflex femoral vessels.
7.11.3
Vertical Rectus Abdominis Myocutaneous Flap (VRAM)
The VRAM flap allows coverage of large defects and utilizes tissue which is well away from any previously irradiated area. The fact that it is a pedicled vascularized flap reduces the probability of flap failure provided that the inferior epigastric complex has been preserved and not involved in the disease. The technique has been extensively utilized in our own series of patients to cover groin defects following extensive resections.17 A template of the groin defect is made which is then used to mark out the size of the VRAM flap. Once marked out the skin and underlying rectus abdominis is mobilized and detached superiorly (Fig. 7.21). An incision is then made along the medial border of the rectus fascia and the skin island is deepened toward the superior portion of the flap until the linea alba is seen. The left rectus abdominis muscle can be visualized under the rectus fascia. The lateral incision parallels the incision in the rectus fascia keeping intact a 5-cm width of rectus fascia to be taken with the flap. This ensures that the perforators coming off the anterior surface of the muscle through the rectus fascia are not damaged and the underlying rectus abdominis is mobilized and detached superiorly. The inferior epigastric vessels can be seen emerging from the lateral portion of the rectus muscle. The flap is mobilized on the inferior epigastric vascular pedicle and tunneled in order to cover the groin defect. A synthetic mesh is then used to reconstruct the abdominal wall and the skin is closed primarily (Figs. 7.22–7.23).
162 Fig. 7.21 Preoperative marking of a recurrent lesion in the right groin which is to be removed and the defect covered with a VRAM flap
Fig. 7.22 Mobilization of the VRAM flap in order to cover the skin defect
Fig. 7.23 Closure of the abdominal and groin wound has been performed
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Visceral and Bone Metastases
Advanced cancers can present with visceral metastases particularly to the lungs and liver. The overall prognosis in these patients is very poor and surgery is limited to palliative relief of urinary symptoms or ureteric obstruction due to extensive pelvic disease. Proximal extension of penile tumors can involve the inferior pubic rami due to local infiltration. If this is the solitary area of osseous involvement, an inferior pubectomy can be performed at the same time as the radical penectomy. Extensive recurrent disease has been treated in a small series by performing a hemipelvectomy which is only a realistic option for younger patients with unilateral disease.33 In this particular series seven patients underwent a hemipelvectomy of which four died within 12 months. Symptomatic osseous metastases to long bones can result in pathological fractures and therefore early fixation of these areas is indicated. Anorectal involvement: Advanced cancers infiltrating into the anorectal areas can result in a series of debilitating symptoms including rectal bleeding, tenesmus, irretractable pain, and bowel obstruction. Once these symptoms have manifested, the tumor is generally irresectable from the anorectal area and palliative diversion using a colostomy is indicated. A colostomy allows palliative radiotherapy to be given to the anorectal region for pain relief and provide local control. Where the tumor has infiltrated the prostate or bladder with early local extension into the rectum, a complete pelvic exenteration can be planned in order to remove the entire mass and combine this with a urinary diversion and colostomy.
7.13
The Benefits of Surgical Intervention in Advanced Cases
There is no doubt that the majority of patients presenting with advanced disease will die within 12 months if treated conservatively. The lack of an efficacious chemotherapeutic agent which has been shown to consistently result in a response means that these patients have limited options available to them. In those patients with a reasonable performance status palliative surgery provides a means to reduce pain, remove unsightly fungating lymph node disease, and allow the patient to regain some aspects of their bladder and bowel function. More importantly, it gives the patients a more dignified period to at least go home and be near their relatives. As the disease already has a tremendous psychological burden on the patient, it is always a positive step to be able to walk around at home with better pain control and social support of the family.
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Palliative Options in Patients with a Poor Performance Status
A combination of neoadjuvant chemotherapy and extensive surgical resection may not be suitable for all patients due to the poor performance status of patients presenting with advanced metastatic disease. Radiotherapy can palliate symptoms such as pain and local bleeding from ulcerative lesions. Local tumor infiltration into the urethra results in obstructive voiding symptoms and therefore some form of urinary diversion is required either via a suprapubic catheter or perineal urethrostomy prior to undertaking further palliative treatment. Patients presenting with bulky recurrent disease in the inguinal region often have disease encasing the femoral vessels. The femoral vein is often thrombosed and therefore a combination of anticoagulation together with an inferior vena cava filter will reduce the risk of thromboembolism particularly if the tumor responds to chemoradiation. Endoluminal vascular stents can be inserted into the femoral artery in order to keep it patent as well as reduce the risk of hemorrhage due to tumor infiltration.
7.15
Conclusion
The options for patients with advanced penile cancers or cancers arising from the distal urethra with bulky nodal disease are limited as there are currently no effective chemotherapeutic regimens available. These patients often present with a poor performance status and are unlikely to tolerate the side effects of chemotherapy. Surgical resection of these lesions with reconstruction offers both symptom control and in those patients without M1 disease, a chance for cure. With the advent of novel taxane based combination therapy, neoadjuvant chemotherapy may allow previous non-responders to reduce the tumor burden and therefore allow surgical resection. However, further trials are required before this can become standardized and therefore at present the patients continue to be managed on a case by case approach.
References 1. Minhas S, Kayes O, Hegarty P, et al. What surgical resection margins are required to achieve oncological control in men with primary penile cancer? BJU Int. 2005;96:1040. 2. Pietrzak P, Corbishley C, Watkin N. Organ-sparing surgery for invasive penile cancer: early follow-up data. BJU Int. 2004;94:1253. 3. Smith Y, Hadway P, Biedrzycki O, et al. Reconstructive surgery for invasive squamous carcinoma of the glans penis. Eur Urol. 2007;52:1179. 4. Dorfinger K, Maier U, Base W. Parathyroid hormone related protein and carcinoma of the penis: paraneoplastic hypercalcemia. J Urol. 1999;161:1570.
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5. Akashi T, Fuse H, Muraishi Y, et al. Parathyroid hormone related protein producing penile cancer. J Urol. 2002;167:249. 6. Hoffman MA, Renshaw AA, Loughlin KR. Squamous cell carcinoma of the penis and microscopic pathologic margins: How much margin is needed for local cure? Cancer. 1999;85:1565. 7. Agrawal A, Pai D, Ananthakrishnan N, et al. The histological extent of the local spread of carcinoma of the penis and its therapeutic implications. BJU Int. 2000;85:299. 8. Kayes O, Minhas S, Allen C, et al. The role of magnetic resonance imaging in the local staging of penile cancer. Eur Urol. 2007;51:1313. 9. de Souza LJ. Subtotal amputation for carcinoma of the penis with reconstruction of penile stump. Ann R Coll Surg Engl. 1976;58:398. 10. Parkash S, Ananthakrishnan N, Roy P. Refashioning of phallus stumps and phalloplasty in the treatment of carcinoma of the penis. Br J Surg. 1986;73:902. 11. Horenblas S, van Tinteren H, Delemarre JF, et al. Squamous cell carcinoma of the penis. II. Treatment of the primary tumor. J Urol. 1992;147:1533. 12. McDougal WS, Kirchner FK Jr, Edwards RH, et al. Treatment of carcinoma of the penis: the case for primary lymphadenectomy. J Urol. 1986;136:38. 13. Rajaian S, Gopalakrishnan G, Kekre NS. Auto amputation of penis due to advanced penile carcinoma. Urology. 2010;75:253. 14. Skinner DG. Management of extensive, localized neoplasms of lower abdominal wall. Pubectomy and scrotal skin transfer technique. Urology. 1974;3:34. 15. Tabatabaei S, McDougal WS. Primary skin closure of large groin defects after inguinal lymphadenectomy for penile cancer using an abdominal cutaneous advancement flap. J Urol. 2003;169:118. 16. Airhart RA, de Kernion JB, Guillermo EO. Tensor fascia lata myocutaneous flap for coverage of skin defect after radical groin dissection for metastatic penile carcinoma. J Urol. 1982;128:599. 17. Kayes OJ, Durrant CA, Ralph D, et al. Vertical rectus abdominis flap reconstruction in patients with advanced penile squamous cell carcinoma. BJU Int. 2007;99:37. 18. Ravi R, Chaturvedi HK, Sastry DV. Role of radiation therapy in the treatment of carcinoma of the penis. Br J Urol. 1994;74:646. 19. Shammas FV, Ous S, Fossa SD. Cisplatin and 5-fluorouracil in advanced cancer of the penis. J Urol. 1992;147:630. 20. Ahmed T, Sklaroff R, Yagoda A. Sequential trials of methotrexate, cisplatin and bleomycin for penile cancer. J Urol. 1984;132:465. 21. Ahmed HU, Arya M, Minhas S. Dynamic sentinel lymph node biopsy in penile cancer. Expert Rev Anticancer Ther. 2006;6:963. 22. Gagliano RG, Blumenstein BA, Crawford ED, et al. cis-Diamminedichloroplatinum in the treatment of advanced epidermoid carcinoma of the penis: a Southwest Oncology Group Study. J Urol. 1989;141:66. 23. Haas GP, Blumenstein BA, Gagliano RG, et al. Cisplatin, methotrexate and bleomycin for the treatment of carcinoma of the penis: a Southwest Oncology Group Study. J Urol. 1999;161:1823. 24. Theodore C, Skoneczna I, Bodrogi I, et al. A phase II multicentre study of irinotecan (CPT 11) in combination with cisplatin (CDDP) in metastatic or locally advanced penile carcinoma (EORTC PROTOCOL 30992). Ann Oncol. 2008;19:1304. 25. Pagliaro LC, Williams DL, Daliani D. Neoadjuvant paclitaxel (P), ifosfamide (I) and cisplatin (C) chemotherapy prior to inguinal/pelvic lymphadenectomy for stage T any, N”-3 M0 squamous carcinoma (SCC) of the penis. J Urol. 2006; 175(4). 26. Leijte JA, Kerst JM, Bais E, et al. Neoadjuvant chemotherapy in advanced penile carcinoma. Eur Urol. 2007;52:488. 27. Bermejo C, Busby JE, Spiess PE, et al. Neoadjuvant chemotherapy followed by aggressive surgical consolidation for metastatic penile squamous cell carcinoma. J Urol. 2007;177:1335.
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28. Pizzocaro G, Nicolai N, Milani A. Taxanes in combination with cisplatin and fluorouracil for advanced penile cancer: preliminary results. Eur Urol. 2009;55:546. 29. Pagliaro LC, Williams DL, Daliani D, et al. Neoadjuvant paclitaxel, ifosfamide, and cisplatin chemotherapy for metastatic penile cancer: a phase II study. J Clin Oncol. 2010;28:3851. 30. Melis P, Bos KE, Horenblas S. Primary skin closure of a large groin defect after inguinal lymphadenectomy for penile cancer using a skin stretching device. J Urol. 1998;159:185. 31. Erba P, Wettstein R, Rieger UM, et al. A study of the effect of sartorius transposition on lymph flow after ilioinguinal node dissection. Ann Plast Surg. 2008;61:310. 32. Benoit L, Boichot C, Cheynel N, et al. Preventing lymphedema and morbidity with an omentum flap after ilioinguinal lymph node dissection. Ann Surg Oncol. 2005;12:793. 33. Block NL, Rosen P, Whitmore WF Jr. Hemipelvectomy for advanced penile cancer. J Urol. 1973;110:703.
Chapter 8
Cancer of the Male Urethra Raj Nigam, Usama Ahmed, Alex Freeman, Suks Minhas and Asif Muneer
8.1
Introduction
Although tumors of the penile urethra are very rare, they frequently present to surgeons who routinely manage primary penile tumors. Urethral tumors have a similar histological subtype to those tumors arising from the glans penis; however, the management of these tumors depends on the location of the lesion in the urethra.
8.2
Epidemiology
Primary cancers of the male urethra are very rare and represent <1% of genitourinary malignancies and 0.02% of all malignancies.1 The prevalence is higher in Afro-Caribbean men and also increases with age.2 The low incidence of urethral cancer has meant that a very limited amount of evidence-based literature is available regarding the management of these lesions.
8.3
Anatomical and Histological Classifications
The urethra can be subdivided into an anterior and a posterior component. The posterior urethra comprises the prostatic and membranous parts and the urethral epithelial lining is of transitional cell origin. The anterior urethra consists of the bulbar and
R. Nigam (*) Department of Urology, Royal Surrey County Hospital, Guildford, Surrey, UK A. Muneer et al. (eds.), Textbook of Penile Cancer, DOI 10.1007/978-1-84882-879-7_8, © Springer-Verlag London Limited 2012
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Fig. 8.1 Anatomical subdivision of the male urethra
Prostatic Urethra
Penile Urethra
Bulbo-membranous Urethra
Table 8.1 The distribution of the tumor subtypes is dependent on the urethral segment that they arise from Urethral location Epithelium Tumor subtype Prostatic Urothelium TCC Bulbo- membranous Pseudostratified columnar Adenocarcinoma, SCC, TCC cells Penile Stratified squamous SCC Table 8.2 Reported frequency of histological subtypes Literature reports n 212 TCC (%) 25 SCC (%) 59 Adenocarcinoma (%) 8 Other (%) 8
Epidemiological data 1615 55 22 16 5
penile urethra and there is a transition from pseudostratified columnar to stratified squamous epithelium in the anterior urethra (Fig. 8.1). The three main tumor subtypes which occur in the male urethra are transitional cell carcinomas (TCC), squamous cell carcinomas (SCC), and adenocarcinomas. Melanoma and lymphomas have also been reported but are rare. Squamous cell carcinomas are the commonest histological subtype followed by transitional cell carcinomas and then adenocarcinomas. Anterior urethral tumors are also more common than posterior urethral tumors. In the fossa navicularis and the anterior urethra SCC predominates. However, in the posterior urethra TCC accounts for approximately 90% of the tumors. In the bulbar and membranous regions, adenocarcinomas or SCC account for 80–90% of the tumors. (Table 8.1).3 A comparison of the relative frequency of urethral tumors from literature reports 4-12 and epidemiological data2 reflects the inaccuracy of the true incidence of this tumor (Table 8.2).
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Table 8.3 TNM staging for male urethral cancer Primary tumor (T) Tx T0 Ta Tis T1 T2 T3 T4 Regional lymph nodes (N) Nx N0 N1 N2 Distant metastasis (M) M0 M1
Primary tumor cannot be assessed No evidence of primary tumor Noninvasive papillary, polypoid, or verrucous carcinoma Carcinoma in situ Tumor invades subepithelial connective tissue Tumor invades any of the following: corpus spongiosum, periurethral muscle, prostate Tumor invades any of the following: corpus cavernosum, beyond prostatic capsule, bladder neck Tumor invades other adjacent organs Regional lymph nodes cannot be assessed No regional lymph nodes Metastasis in single lymph node (<2 cm) Metastasis in single lymph node (>2 cm) or multiple nodes No distant metastasis Distant metastasis
Adapted from Edge13
8.4
Risk Factors for the Development of Urethral Cancer
The risk factors associated with the development of urethral cancer include advancing age, chronic inflammation of the urethra, and urethral stricture disease. Previous urethral surgery and radiotherapy are also risk factors as are immunosuppression and smoking. Infection of the distal urethra with HPV-16 has also been implicated.2,14 A study by Cupp et al. reported that all six of their patients diagnosed with distal urethral carcinomas and one at the penoscrotal junction was HPV-16 positive whereas no HPV-16 DNA was detected in the remaining nine proximal urethral carcinomas.14 This suggests that the pathogenesis in the development of distal and proximal urethral carcinomas may differ.
8.5
Staging of Urethral Cancer
The most commonly used staging system utilizes the TNM classification as indicated in the 2010 AJCC cancer staging handbook (Table 8.3).13 The alternative staging system known as the Whitmore classification is shown in Table 8.4.15
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Table 8.4 The Whitmore classification of urethral tumors Stage 0 Stage A Stage B Stage C
Stage D
Confined to mucosa only (in situ carcinoma) Into but not beyond lamina propria Into but not beyond the substance of the corpus spongiosum, or into but not beyond the prostate Direct extension into tissue beyond the corpus spongiosum (corpus cavernosum, muscle, fat, fascia, skin, direct skeletal involvement), or beyond the prostatic capsule 1. Inguinal lymph nodes 2. Pelvic lymph nodes below the bifurcation of the aorta 3. Lymph nodes above the bifurcation of the aorta 4. Distant
Table 8.5 Reported frequency of the presenting symptoms for patients with urethral cancer Hopkins Srinivas and Dinney Dalbagni Thyavihally et al.36 Khan37 et al.5 et al.7 et al.11 n 26 200 21 46 36 Urinary obstruction (%) 38 47 29 43 42 Palpable mass (%) 56 79 25 28 28 Hematuria (%) 60 22 25 17 19 Urethral discharge (%) 60 22 25 11 –
8.6
The Clinical Presentation of Male Urethral Cancer
The diagnosis of early urethral cancer is difficult and the presentation is often delayed by which time the tumor is obvious. Urethral bleeding, urethral discharge, and hematuria are common presenting symptoms as are urinary frequency and obstructive voiding symptoms (Table 8.5). Recurrent urethral strictures, penile pain, and even a palpable mass in the penile urethra may also be a presenting feature. In the later stages periurethral abscesses, urethrocutaneous fistulae, and incontinence may also occur.
8.7
The Diagnosis and Investigation of Urethral Cancer
The management of urethral cancer depends on the anatomical location of the tumor and the staging of the primary lesion and the status of the inguinal lymph nodes. Examination of the penis may reveal a discrete nodular lump in the anterior urethra. More distal tumours progressively infiltrate the glans spongiosum and eventually extend out of the urethral meatus (Fig. 8.2). The physical examination should also include a bilateral inguinal examination in order to detect the presence of palpable lymphadenopathy. Cytological examination of the urine may detect the presence of malignant cells, although it is noted that voided urine cytology has a high sensitivity
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Fig. 8.2 Distal urethral SCC presenting in a 62-year-old man who presented with urethral bleeding and a firm mass in the glans penis
in detecting high-grade (poorly differentiated) bladder TCC, there is a reduced sensitivity in detecting urethral SCC.16 Imaging of the primary tumor can be performed using a range of imaging techniques including ultrasound, penile MRI (see Chap. 4), and cross-sectional imaging in order to detect the presence of abnormal lymphadenopathy. Although ascending and descending urethrography has been used previously, these techniques have now been superseded by the use of penile MRI. Cystourethroscopy and a biopsy of the lesion should be attempted before undertaking definitive treatment. In some patients with recurrent stricture disease, a biopsy may have been performed incidentally. It is important to ensure that the biopsy is of a sufficient size in order to allow a reliable histological analysis (Fig. 8.3). One study comparing the penile SCC biopsy specimens to the final postpenectomy specimens found a 30% discordance between the two sample types both in the grade and histological subtype of the tumor.17 In most cases, the biopsy was unable to determine the deepest point of invasion or the presence of lymphovascular invasion, both of which are important prognostic indicators.18,1917
8.8
The Surgical Management of Penile Urethral Carcinoma
The first description of male urethral cancer was by Thiaudierre in 1834.18 Subsequently McCrea and Furlong reported a survival rate of <10 months for patients who did not undergo any definitive treatment for the disease.19 Even as late as 1967 a published cohort of 46 men treated with palliation or no treatment resulted in a survival of only 3–15 months. In 1954, Hotchkiss and Amelar described radical surgical treatment in the form of penile amputation for five patients and radical cystectomy for two patients with posterior urethral tumors.20 Despite this report the surgical management only came to the fore when Farrer and
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Squamous cell carcinoma
Benign urethra Urethral Squamous Cell Carcinoma, H&E stain, x 40 magnification b
Invasive squamous cell carcinoma
Squamous carcinoma-insitu Urethral Squamous Cell Carcinoma, H&E stain, x 400 magnification
Fig. 8.3 (a, b) Histological specimens from the same 62-year-old man as in Fig. 8.2, presenting with an anterior urethral tumor. Comparison is made with normal urethral histology
Lupu reported an improved 5 year cancer specific survival rate of 30% compared to 3% in those who had undergone radical surgery compared to those who had not.21
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Since then the literature has defined the radical nature of the exenteration required to treat these tumors, particularly posterior urethral tumors.22 This invariably has involved urinary diversion combined with anterior pelvic exenteration with inferior pubectomy. Although excellent local control has been reported, contemporary series have sought to identify the limits of such a resection which are compatible with good local control.23 This has been coupled with the role of neoadjuvant and adjuvant therapies without diminishing the pivotal role played by surgery in the successful management of urethral cancer. In 1994 Dinney et al. reported on a series of 23 men from the MD Anderson Cancer Centre.5 This showed that the prognosis was dependent on the anatomical location of the tumor. For anterior urethral cancers the survival rate was better with a 60% cancer-specific survival at 4 years compared to below 30% at 31 months for posterior urethral tumors. The study proposed that tumors of the fossa navicularis and anterior urethra should be treated by performing a distal urethrectomy and penile amputation and that posterior urethral tumors required an en bloc resection of the penis, scrotum, prostate, bladder, and inferior pubic rami. Similar results were published in 1999 from the Memorial Sloan-Kettering Hospital which reported a 69% 5 year survival rate for anterior urethral tumors and 26% for posterior urethral tumors. Low-stage disease and an anterior location were significant prognostic factors. Of the 46 cases reported in this study 40 had surgery alone and 6 had preoperative radiotherapy. The latter presented with advanced disease and therefore had a worse prognosis.7 The observed and overall survival rates for patients with urethral cancer using data from the National Cancer Data Base shows that the survival rate for men is dependent on the stage of the disease (Fig. 8.4).
8.8.1
Penile-Preserving Techniques and Reconstruction
Organ preservation for function and cosmesis has been the mantra which has recently guided the development of penile-preserving surgical techniques for conventional SCC of the penis. The management of superficial low-stage TCC of the urethra by transurethral resection (TUR) is well established. This applies to anterior as well as posterior urethral tumors. However, apart from using TUR for TCC, the role of TUR, fulguration, and local excision is more controversial for SCC.24 Table 8.6 illustrates the variation in the management of patients with urethral tumors in studies which have used penile-preserving techniques. Smith et al. reported on 18 patients who underwent penile-preserving surgery for urethral carcinoma. The median follow-up was 21 months and no local recurrences were reported.12 The margin of resection was <5 mm in eight men which is compatible with similar reports defining the safe margins of resection for conventional SCC penis.23 Distal fossa navicularis tumors with invasion into the glans can be treated by performing a glansectomy and utilizing a split-skin graft in order to reconstruct a
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Observed survival rate
90 80 70 60 50 40 30 20 10 0 I II III IV V VI
0
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100.0 100.0 100.0 100.0 100.0 100.0
96.8 93.2 90.2 82.4 78.6 58.9
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87.9 75.6 68.8 59.4 43.8 31.0
86.0 67.2 64.8 54.2 31.8 25.9
79.3 61.6 59.0 50.6 28.4 21.8
Years from diagnosis
Fig. 8.4 Observed and overall survival rates for 1,278 patients diagnosed with urethral cancer (Data from the National Cancer Data Base. Used with permission of the American Joint Committee on Cancer (AJCC). Chicago, Illinois. The original source for this material is the AJCC Cancer Staging Handbook, Seventh Edition (2010) published by Springer Science and Business Media LLC, www.springerlink.com)
Table 8.6 Comparison of the surgical management of urethral tumors Author Number of cases Surgical management 12 Smith 18 SCC Algorithm based on anatomical location Mandler and Pool25 3 (1 SCC; 2 TCC) Baskin26 1 SCC Neoadjuvant chemoradiation and distal urethrectomy Bird27 3 SCC Subcutaneous penectomy/urethrectomy Davis28 1 SCC Urethrectomy alone Kent29 1 TCC TUR + chemotherapy Christopher30 1 SCC Urethrectomy, nerve-sparing radical prostatectomy and Mitrofanoff diversion + adjuvant chemoradiation
neoglans (Chap 6). Depending on the distal urethral involvement, this can be combined with an anterior urethrectomy with the proximal urethra brought out as a hypospadiac opening. Excision of the adjacent ventral tunica albuginea with reconstruction using autologous or synthetic graft material in order to ensure tumor-free margins can be carried out at the time of the anterior urethrectomy (Fig. 8.5). An algorithmic approach for the management of distal lesions has been proposed (Fig. 8.6).12 Again, there is an emphasis on achieving satisfactory cosmetic outcomes without compromising oncologic control. Surgical margins of 5 mm from the visible
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Fig. 8.5 Distal urethrectomy has been performed together with excision of a segment of the adjacent tunica albuginea. The resulting defect is closed using a Pelvicol® graft
Management of anterior urethral cancer Clinical examination, urethroscopy +/– biospy
Lesion just visible at urethral meatus
Formation of hypospadias, biospy +/– topical 5fluoruracil cream
Proven superficial T1 tumour
Tumour extends into glans spongiosus but not corpora cavemosa
Tumour extends into distal corpora cavemosa
Two stage distal urethroplasty with buccal mucosa graft
Glansectomy with hypospadias and partialthickness skin graft reconstruction
Glansectomy and distal corporectomy with partial thickness graft and penile lengthening
Large pendulous urethral tumour or multifocal disease
Anterior urethrectomy, excision of adjacent tunica, corporeal reconstruction and perineal urethrostomy
Fig. 8.6 Management of male anterior urethral cancers (Reprinted from Smith et al.12)
edge of the tumor were used. Of the 18 patients treated using this approach, no patient experienced a local recurrence, 14 had no evidence of disease at 26 months follow-up and two of the six patients with positive nodal disease succumbed to metastatic complications. The published outcomes following surgical treatment for patients diagnosed with urethral cancer are shown in Table 8.7.
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Table 8.7 Results following surgery for male urethral cancer Number of Mean follow-up Overall Author patients (months) survival (%) Eng9 10 189 70 Dalbagni7 10 125 83 Gheiler6 9 42 Farrer21 2 102 100 Dinney5 6 55 83 Smith12 18 21 88
Disease-free survival (%) 70
Local control(%) 100
89 100 83 67
100 83 100
Adapted from Koontz and Lee31 with permission from Elsevier
8.8.2
The Surgical Management of Inguinal Lymph Nodes
The biological behavior of anterior urethral SCC is similar to that of conventional SCC of the penis as the pattern of lymphatic drainage is similar. Tumors from the glans and penile urethra metastasize initially to the superficial inguinal lymph nodes and then subsequently to the deep inguinal lymph nodes. Although prophylactic dissection was originally considered controversial for urethral cancers it is now accepted that urethral tumors should be managed along similar guidelines to those proposed for SCC penis.12 Therefore, superficial and radical inguinal node dissections are carried out according to the grade and stage of the primary tumor in accordance with the EAU guidelines 2009.32 Posterior urethral cancers are very likely to metastasize to the pelvic nodes and often a pelvic lymphadenectomy is also included in the surgical management.
8.8.3
The Role of Radiotherapy in the Management of Urethral Cancer
External beam radiotherapy (EBRT) and brachytherapy implants or a combination of both have been used in the management of urethral tumors. Historically EBRT has been used in the adjuvant setting following surgery for male urethral cancer but is often a primary treatment for urethral cancers in females. A number of studies have shown that the outcomes following radiotherapy alone are poor.33 However, these studies involve selected patients who may have presented with poor prognostic features or a poor performance status, hence prevented radical surgery being undertaken. The EBRT technique follows a traditional 2-field pelvis treatment which also incorporates the common, internal and external iliac vessels and also the inguinal nodes if the anterior urethra is involved with tumour. Initial doses of 45 Gy are delivered in 25 fractions. Recently intensity-modulated radiation therapy (IMRT) has been used in treating other genitourinary malignancies and undoubtedly reduces the toxicity. A survival rate of 67% has been reported for 140 patients with low-stage disease treated with radiotherapy alone from an analysis of a number of publications.
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However, the nonuniformity of the patients and the treatments given in these studies does not lend itself to providing recommendations. Advanced urethral cancers fared worse with the survival rate declining to 34%.1,27 In locally advanced tumors the use of radiotherapy alone again shows poor results. There is some evidence to suggest that a combination of brachytherapy with EBRT with the aim of increasing the overall radiation dose may improve the overall outcome by decreasing the failure rates when compared to EBRT alone. However, the majority of these studies are related to female urethral cancers.28,29 The complication rates following radiotherapy range between 16% and 20%. Currently dose reduction without compromising tumor control appears to be the best way of reducing the morbidity associated with this treatment.9,14 The complications following radiotherapy include penile lymphoedema and urethral stricture disease for anterior lesions. For posterior urethral tumors there is a risk of fistula formation with the bladder or rectum.
8.8.4
The Role of Brachytherapy in the Management of Urethral Cancer
Brachytherapy utilizes interstitial iridium implants placed along the length of the anterior urethra (Fig. 8.7). The implant can be delivered intraluminally as well as using a urethral catheter closed at the proximal end and loaded with a radioactive source. Suprapubic urinary diversion is also required. The target volume is determined by dividing the tumor into intraluminal and infiltrating components. Brachytherapy may be preceded by a transurethral resection of the intraluminal component of the tumor with the aim of reducing the overall target volume dose. A safety margin of 10 mm from the tumor edge and 5 mm for the infiltrating component is used. A dose of 60–65 Gy is delivered over 3–5 days when brachytherapy alone is used although 20–25 Gy is required when brachytherapy is used in combination with EBRT.1 The 5 year survival rates range between 30% and 50%. The outcome appears to be dependent on tumor size with a 5 year survival rate of 60% being reported for tumors <20 mm. However, this falls to <20% for tumors which are over 50 mm. As with surgery the anterior urethral tumors fare better than the posterior urethral tumors. Complications are reported in 25–30% of patients. Acute side effects relate to the severe inflammation caused by the implant which results in penile and urethral pain. Local infection and abscess formation may also occur and urethral stricture disease is common.
8.8.5
The Use of Chemotherapy and Chemoradiation
Combination therapy in the form of chemotherapy and radiotherapy is utilized in an attempt to improve the long-term outcomes for patients diagnosed with urethral
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Fig. 8.7 Interstitial brachytherapy of the penile urethra using hypodermic needle and plastic template. The penis is kept away from the testicles using a sponge (From Gerbaulet et al.34. Reprinted with permission)
cancer. Multimodality therapy offers the advantage of local and systemic control and facilitates future surgery either in the neoadjuvant setting or as salvage therapy. Radiosensitization of tumors by chemotherapeutic agents appears to enhance the efficacy of EBRT. Studies have used regimens based on the treatment of anal SCC which uses a combination of Mitomycin C and 5-FU whereas others have used cisplatin and 5-FU based on the common SCC penis regimens. For primary urethral TCC, bladder- based regimens are often used. Nigro et al. first utilized a neoadjuvant chemoradiation approach in the treatment of SCC of the anus.35 Combined chemoradiation is now the first-line treatment for SCC of the anus. A number of institutions have since chosen to treat primary urethral SCC with the same regimen used for anal SCC due to the similar tumor histology, embryological development, an association with HPV-16, and a high rate of local recurrence.6 This has been investigated in a series of 18 patients treated with a uniform chemoradiation protocol. All 18 patients presented with invasive carcinoma of the
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DAY 1 Chemotherapy:
Radiotherapy:
Day 1: 5-FU (IV infusion over 24 hours @ 1000mg/m2) Mitomycin C (IV Bolus @ 10mg/m2)
Total radiation dose: 45−55Gy Primary lesion: additional 12−15Gy Given over 25 fractions
Day 2-4: 5-FU (IV infusion over 24 hours @ 1000mg/m2)
Irradiation sites: - Primary lesions (genitalia) - Perineum - Inguinal lymph nodes - External iliac lymph nodes
Day 29: 5-FU (IV infusion over 24 hours @ 1000mg/m2) Mitomycin C (IV Bolus @ 10mg/m2)
Day 30−32: 5-FU (IV infusion over 24 hours @ 1000mg/m2)
DAY 32 Fig. 8.8 Modified Nigro chemoradiation protocol used by Cohen et al. in the treatment of male primary urethral carcinoma
male urethra and were treated with chemotherapy consisting of 5-FU and Mitomycin C with concurrent external beam radiotherapy to the genitalia, perineum, and inguinal and external iliac lymph nodes.6 The treatment schedule is summarized below (Fig. 8.8). The follow-up was performed at 6 weeks and then every 3–6 months for the first 2 years and biannually thereafter. Salvage surgery was only undertaken in nonresponders to initial treatment and those with recurrent disease. Of the 18 patients, three were nonresponders and died of the disease despite extensive salvage surgery. The remaining 15 patients (83%) experienced a complete response following chemoradiation. Four of the 15 patients experienced local recurrences and underwent further surgery. A total of 10 patients (56%) experienced no recurrences from the primary tumor (5 proximal urethra/5 distal urethra). All 10 patients with no disease recurrence did however develop urethral strictures which required surgical intervention including complex urethral reconstruction in three patients. The 5-year overall and disease-specific survival rate was found to be 60% and 83%, respectively. These results are extremely promising considering that 84% of patients had T3 or T4 disease and that 34% had node-positive disease.6 Cohen and colleagues’ approach represents a promising treatment option for male primary urethral carcinomas with effective organ preservation and local disease control.
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A further study by Gheiler and coworkers showed that disease control could be achieved in 70% of patients with a mean follow-up of 43 months.6 In the 21 patients reported, the best results were found in tumors staged as T3 or above (42%), multimodality therapy yielded the optimal outcomes with disease-free survival reaching 60%. Surgery alone was found to be the best modality in stage Ta-2N0M0 patients in the same study.
8.9
Conclusion
Male urethral cancer is a rare tumor where the survival is dependent upon the anatomical location as much as it is on the traditional parameters of staging and grading of histological and cytological architecture. Due to the rarity of this malignancy, large scale clinical trials have yet to be established and the management is based on a case by case approach. For early stage disease, surgery alone, offers both local control and a better disease-free survival. In the modern era, armed with the knowledge of adequate surgical margins, organ- preserving and reconstructive techniques, surgery need not be the extensive and disfiguring option it once was. For advanced disease a multimodality approach using neoadjuvant chemotherapy and radiotherapy in combination with a surgical resection appears to offer the best treatment option.
References 1. Gerbaulet A, Haie-Meder C, Marsiglia H, et al. Brachytherapy in cancer of the urethra. Ann Urol (Paris). 1994;28(6-7):312-317. 2. Swartz MA, Porter MP, Lin DW, Weiss NS. Incidence of primary urethral carcinoma in the United States. Urology. 2006;68(6):1164-1168. 3. Bakkali H, Benjaafar N, Mansouri A, et al. Primary adenocarcinoma of the male urethra. A case report. Cancer Radiothér. 2002;6(6):358-362. 4. Hopkins SC, Nag SK, Soloway MS. Primary carcinoma of male urethra. Urology. 1984;23(2):128-133. 5. Dinney CP, Johnson DE, Swanson DA, Babaian RJ, von Eschenbach AC. Therapy and prognosis for male anterior urethral carcinoma: an update. Urology. 1994;43(4):506-514. 6. Gheiler EL, Tefilli MV, Tiguert R, de Oliveira JG, Pontes JE, Wood DP Jr. Management of primary urethral cancer. Urology. 1998;52(3):487-493. 7. Dalbagni G, Zhang ZF, Lacombe L, Herr HW. Male urethral carcinoma: analysis of treatment outcome. Urology. 1999;53(6):1126-1132. 8. Hakenberg OW, Franke HJ, Froehner M, Wirth MP. The treatment of primary urethral carcinoma–the dilemmas of a rare condition: experience with partial urethrectomy and adjuvant chemotherapy. Onkologie. 2001;24(1):48-52. 9. Eng TY, Naguib M, Galang T, Fuller CD. Retrospective study of the treatment of urethral cancer. Am J Clin Oncol. 2003;26(6):558-562. 10. Thyavihally YB, Wuntkal R, Bakshi G, Uppin S, Tongaonkar HB. Primary carcinoma of the female urethra: single center experience of 18 cases. Jpn J Clin Oncol. 2005;35(2):84-87.
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11. Thyavihally YB, Tongaonkar HB, Srivastava SK, Mahantshetty U, Kumar P, Raibhattanavar SG. Clinical outcome of 36 male patients with primary urethral carcinoma: a single center experience. Int J Urol. 2006;13(6):716-720. 12. Smith Y, Hadway P, Ahmed S, Perry MJ, Corbishley CM, Watkin NA. Penile-preserving surgery for male distal urethral carcinoma. BJU Int. 2007;100(1):82-87. 13. Urethra. In: Edge SB, Byrd DR, Compton CC, Fritz AG, Greene FL, Trotti A, eds. AJCC Cancer Staging Manual. 7th ed. New York: Springer; 2010. 14. Cupp MR, Malek RS, Goellner JR, Espy MJ, Smith TF. Detection of human papillomavirus DNA in primary squamous cell carcinoma of the male urethra. Urology. 1996;48(4):551-555. 15. Ray B, Canto AR, Whitmore WF Jr. Experience with primary carcinoma of the male urethra. J Urol. 1977;117(5):591-594. 16. Touijer AK, Dalbagni G. Role of voided urine cytology in diagnosing primary urethral carcinoma. Urology. 2004;63(1):33-35. 17. Velazquez EF, Barreto JE, Rodriguez I, Piris A, Cubilla AL. Limitations in the interpretation of biopsies in patients with penile squamous cell carcinoma. Int J Surg Pathol. 2004;12(2):139-146. 18. Thiaudierre PD. Bull Gen de Therap. 1834:240. 19. McCrea LE, Furlong JH Jr. Primary carcinoma of the male urethra. Urol Surv. 1951;1(1):1-30. 20. Hotchkiss RS, Amelar RD. Primary carcinoma of the male urethra. J Urol. 1954;72(6): 1181-1191. 21. Farrer JH, Lupu AN. Carcinoma of deep male urethra. Urology. 1984;24(6):527-531. 22. Bracken RB. Exenterative surgery for posterior urethral cancer. Urology. 1982;19(3): 248-251. 23. Minhas S, Kayes O, Hegarty P, Kumar P, Freeman A, Ralph D. What surgical resection margins are required to achieve oncological control in men with primary penile cancer? BJU Int. 2005;96(7):1040-1043. 24. Zeidman EJ, Desmond P, Thompson IM. Surgical treatment of carcinoma of the male urethra. Urol Clin North Am. 1992;19(2):359-372. 25. Mandler JI, Pool TL. Primary carcinoma of the male urethra. J Urol. 1966;96(1):67-72. 26. Baskin LS, Turzan C. Carcinoma of male urethra: management of locally advanced disease with combined chemotherapy, radiotherapy, and penile-preserving surgery. Urology. 1992;39(1):21-25. 27. Bird E, Coburn M. Phallus preservation for urethral cancer: subcutaneous penectomy. J Urol. 1997;158(6):2146-2148. 28. Davis JW, Schellhammer PF, Schlossberg SM. Conservative surgical therapy for penile and urethral carcinoma. Urology. 1999;53(2):386-392. 29. Kent D, Gee JR, Amato RJ, Pisters LL. Successful management of metastatic urethral cancer with organ preservation. J Urol. 2001;166(6):2308. 30. Christopher N, Arya M, Brown RS, Payne HA, Woodhouse CR, Ralph DJ. Penile preservation in squamous cell carcinoma of the bulbomembranous urethra. BJU Int. 2002;89(4):464-465. 31. Koontz BF, Lee WR. Carcinoma of the urethra: radiation oncology. Urol Clin North Am. 2010;37(3):459-466. 32. Pizzocaro G, Algaba F, Horenblas S, et al. EAU penile cancer guidelines 2009. Eur Urol. 2010;57(6):1002-1012. 33. Dalbagni G, Zhang ZF, Lacombe L, Herr HW. Female urethral carcinoma: an analysis of treatment outcome and a plea for a standardized management strategy. Br J Urol. 1998;82(6):835-841. 34. Gerbaulet A, Lambin P, Haie-Meder C, et al. Brachytherapy in penile cancer. Ann Urol. 1994;28:306-311. 35. Nigro ND, Vaitkevicius VK, Considine B Jr. Dynamic management of squamous cell cancer of the anal canal. Invest New Drugs. 1989;7(1):83-89. 36. Hopkins SC, Nag SK, Soloway MS. Primary carcinoma of male urethra. Urology. 1984 Feb;23(2):128-133 37. Srinivas V, Khan SA. Male urethral cancer. A review. Int Urol Nephrol. 1988;20(1):61-65
Chapter 9
Management of Lymph Nodes Niels M. Graafland and Simon Horenblas
9.1
Introduction
The majority of penile cancers are squamous cell carcinomas (~95%) which typically show a step-wise lymphogenic spread prior to hematogenic dissemination. The primary draining lymph nodes are invariably located within the inguinal lymphatic region. Thereafter, dissemination usually continues to the pelvic nodes and/ or distant sites. At initial presentation, distant metastases are present in only 1–2% of the patients and are virtually always associated with clinically evident lymph node metastases. The presence of nodal involvement is the single most important prognostic factor.1-7 As the currently available noninvasive staging modalities have a low sensitivity in detecting the regional lymph node status (i.e. missing micrometastatic disease), the optimal management of clinically node-negative (cN0) patients has been the subject of debate.8 Approximately 20–25% of these cN0 patients have occult metastasis. Some clinicians manage these patients with close surveillance, while others will perform an inguinal lymphadenectomy. Other approaches are dynamic sentinel node biopsy, modified lymphadenectomy and radical inguinal lymphadenectomy in those patients considered to be at risk for occult metastases, so called “risk-adapted approach”.9 While close surveillance may lead to unintentional delay because of outgrowth of occult metastases in 20–25% of cN0 patients, elective as well as risk-adapted inguinal lymphadenectomy is considered unnecessary in 75–80% of such cases, because of the absence of metastases.10 Furthermore, lymphadenectomy is associated with a high morbidity rate. Up to 35–70% of patients have short- or long-term complications.11-14
N.M. Graafland (*) Department of Urology, The Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands A. Muneer et al. (eds.), Textbook of Penile Cancer, DOI 10.1007/978-1-84882-879-7_9, © Springer-Verlag London Limited 2012
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The management of patients with metastatic inguinal nodal disease is clear. If deemed operable, these patients require an inguinal lymphadenectomy. In these patients, the therapeutic value of regional lymphadenectomy justifies the complications associated with this procedure. Surgery remains the cornerstone of therapy in patients with metastatic disease, with curative outcomes in approximately 80% of patients with one or two involved inguinal nodes without extranodal extension.1-7 However, controversy remains on the extent of surgery. There are a number of issues which include: 1. How extensive does the inguinal lymph node dissection have to be? 2. Should all patients with unilateral nodal involvement undergo bilateral lymphadenectomy? 3. Should all of these patients also undergo a pelvic lymphadenectomy? All these aspects will be discussed, together with the pattern of lymphatic dissemination and the role of staging.
9.2
Patterns of Lymphatic Dissemination
Bilateral lymphatic drainage to the inguinal region is considered the normal lymphatic anatomy of the penis. Lymphoscintigraphic studies in penile carcinoma have shown bilateral drainage in most patients (>90%) (Fig. 9.1).15,16
9.2.1
Anatomy of the Inguinal Lymph Nodes
The lymph nodes in the inguinal lymphatic region are the first draining nodes for the penis, and the anatomy has been described by various authors.17,18 Historically, the inguinal lymphatic region was divided into two groups, the superficial and deep lymph nodes. The superficial inguinal lymph nodes are located beneath Camper’s fascia and above the fascia lata covering the muscles of the thigh. The deep inguinal nodes are located deep to the fascia lata and medial to the femoral vein. These nodes intercommunicate with each other and then drain into the pelvic nodes. From a clinical perspective, this anatomic distinction is not very useful as the superficial nodes cannot be distinguished from the deep nodes by physical examination or imaging. Daseler et al. divided the inguinal region into five sections by drawing a horizontal and vertical line through the point where the saphenous vein drains into the femoral vein with one central zone directly overlying the junction (Fig. 9.2).17 A recent lymphoscintigraphic study by Leijte et al. has shown that the majority of the first draining lymph nodes is located in Daseler’s superomedial segment, although there is individual variation.19 In the same study, skip metastases (circumventing the inguinal lymphatic region) to the pelvic lymph nodes was not identified.19 Further confirming the rarity of direct pelvic drainage is a large series of 100 lymphangiographic examinations of the drainage of the penis by Cabañas in which no direct drainage to the pelvic region was found.20
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Fig. 9.1 Lymphoscintigram showing bilateral drainage with bilateral nodal uptake of tracer (anterior view, left lateral view, right lateral view after 10 min and anterior view after 2 h)
Fig. 9.2 Division of inguinal region, originally described by Daseler
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Following lymphatic dissemination to the groin, metastatic cells spread in a step wise pattern, with tumor cells embolizing to the pelvic lymph nodes and/or distant sites such as the lungs, bone, and para-aortic lymph nodes. Primary hematogenic spread has only been documented in squamous cell carcinoma of the sarcomatoid subtype.21 The first draining pelvic lymph nodes after inguinal dissemination are most commonly located in the external iliac chain.19,22 The inguinal region is anatomically connected to the pelvic region, whereby the first node medial to the femoral vein in the inguinal canal is considered the first pelvic node, also called the node of Cloquet or node of Rosenmüller. The risk of metastatic disease beyond the groins is correlated with the number of involved inguinal lymph nodes and/or presence of extranodal extension.4,22 The positive and negative predictive value of pelvic lymph node involvement in penile cancer, based on a tumor-positive node of Cloquet is 80% and 86%, respectively.22 In rare cases lymph nodes can be found in the suprapubic area (prepubic lymph nodes).23 It is unknown whether true crossing vessels run from one inguinal region to the other through these suprapubic nodes. Cross-over from one pelvic region to the other or cross-over from the inguinal lymphatic region to the contralateral pelvic region has not been observed clinically or by lymphoscintigraphy. Although there is individual variation, on average the number of lymph nodes in the inguinal region is 10–20. The majority are located in the superficial region with only a minority (on average 3–5) in the deep inguinal region. The same amount of lymph nodes is found in the pelvic region.17
9.3
Assessment of Inguinal Lymph Nodes
The key issue in lymph node staging is the unreliability of the currently available modalities which detect occult nodal involvement. However, given that early resection of the inguinal lymph nodes is associated with a therapeutic benefit,24-26 it is imperative that those patients with metastatic disease in the inguinal lymph nodes undergo an inguinal lymphadenectomy at the earliest possible time. Unfortunately the high morbidity rate associated with performing an elective inguinal lymphadenectomy makes the operation unsuitable for every penile cancer patient who does not have inguinal nodal involvement. Hence there is uncertainty about the timing of lymphadenectomy as well as identifying those patients who would benefit. However, three clinical groups can be identified: those with clinically node-negative (cN0) groins, those with palpable inguinal lymph nodes (cN+), and those with immobile (fixed) inguinal lymph nodes.
9.3.1
Clinical Examination
The majority of patients diagnosed with penile cancer in Western countries present without any palpable abnormalities in the groins and only 20% present with palpable nodes.27 Inguinal lymph nodes that become palpable during follow-up are due to
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metastasis in nearly 100% of cases.28 Physical examination of the inguinal region is of limited value in accurate detection, especially of small metastases. One study has shown a sensitivity and specificity of physical examination of 21% and 90%, respectively.29 Approximately 20–25% of cN0-patients will harbor occult metastases. These occult metastases are, by definition, not detected by physical examination. In the cN+ patients approximately 70% will actually have metastatic inguinal nodal involvement.7 The remainder will have enlarged inguinal nodes secondary to infection associated with the primary tumour. Traditionally antibiotic treatment was advised for 6 weeks to treat the inflammation followed by a further re-assessment of the inguinal lymph nodes. However, in order to avoid a delay in diagnosis, this is no longer recommended. Patients with lymph node involvement should undergo inguinal lymphadenectomy.30 Patients with fixed inguinal lymph nodes will invariably have advanced nodal disease which has been discussed in Chap. 7. The currently available noninvasive staging techniques which can be used to stage the groin besides physical examination include ultrasonography combined with fine-needle aspiration cytology (FNAC) of morphologically suspicious looking nodes, CT scan, MR imaging, and PET/CT-scanning. These modalities are especially useful in the obese patient or those who are difficult to examine as additional imaging may identify metastases not detected by physical examination.
9.3.1.1
Ultrasound with Fine-Needle Aspiration Cytology (FNAC)
Ultrasound is noninvasive, quick, and inexpensive and can easily be combined with fine-needle aspiration cytology (FNAC) of morphologically suspicious-looking lymph nodes. In a series of 43 patients with 83 cN0-groins, ultrasound-guided FNAC had a sensitivity and specificity of 39% and 100%, respectively.31 Ultrasoundguided FNAC has been utilized preoperatively to screen the cN0-groin and to further analyze the groins of the patients with palpable inguinal lymph nodes (cN+). In a series of 16 patients staged cN+ and not having antibiotic treatment, FNAC alone (without ultrasonography) showed a sensitivity and specificity of 93% and 91%, respectively.32 False-negative rates for FNAC have been reported in up to 15%. If the clinician remains suspicious, repeat fine needle aspiration cytology is indicated and if it is still inconclusive, then excisional biopsy can be performed. Care must be taken when performing an open biopsy such that in the event of a malignant node the site of the biopsy can be excised during the subsequent lymphadenectomy.
9.3.1.2
CT Imaging
The role of CT in staging the inguinal lymph nodes is poorly understood due to a paucity of studies. One report published in 1991 described a small series of 14 patients that underwent preoperative CT-scanning. A sensitivity and specificity of 36% and 100% were found, respectively. None of the occult metastases in cN0-groins were identified. However, these results are a reflection of the CT
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technology available at the time of the study. Currently with the use of multislice CT-scanners and increased spatial resolution, results are probably better. Nevertheless, the problem of missing a small metastasis still remains. The diagnostic accuracy regarding the pelvic lymph nodes is poor, in accordance with the experience recently reported by other centers.33 Therefore, CT imaging is not recommended as the initial staging tool for cN0-patients, although it is suitable in those who are difficult to examine (e.g. obese patients). By contrast, CT-scanning can be useful in cN+ patients to determine the extent of disease and this will be discussed later.
9.3.1.3
MR Imaging
MR imaging with lymphotrophic nanoparticles (LN-MRI, coated ultrasmall particles of iron oxide, USPIOs, ferrumoxtran-10) has shown promising results in identifying occult metastases in a study of seven patients with penile cancer.34 MR imaging was performed before and also 24 hours after intravenous ferumoxtran-10 administration. In this small series, LN-MRI has shown a sensitivity of 100% and a specificity of 97%. This imaging technique has also revealed high diagnostic accuracies in staging lymph nodes in prostate cancer and bladder cancer.35 However, ferrumoxtran-10 is not FDA-approved; hence it is not yet commercially available. Furthermore, the manufacturer has withdrawn the application for marketing authorization for lymphotrophic nanoparticles in Europe. In addition, conventional MR imaging is also limited by its spatial resolution. Thus, its use is also limited for staging the cN0-groin.
9.3.1.4
PET/CT Scan
Positron emission tomography (PET) instrumentation detects subnanomolar concentrations of radioactive tracer in vivo. Following malignant transformation, a range of tumors can be characterized by elevated glucose metabolism and subsequent increased uptake of the intravenously injected radiolabelled glucose analogue [18F]-fluorodeoxyglucose (FDG). PET combined with low-dose CT imaging (PET/ CT) in a single scanner fuses the acquired data into one image containing both functional and anatomical information (Fig. 9.3). The accuracy of the combined images is reported to be higher than separate PET and CT images.36-38 In 2005, Scher et al. published the first results of PET/CT scanning in penile cancer.39 They found promising results with a sensitivity of 80% and specificity of 100% on a per-patient basis, respectively. However, these results may be a little optimistic. The limitations of MR-imaging with respect to spatial resolution are also true for PET/CT. In a recent prospective study of 42 cN0-groins that underwent preoperative PET/CT scanning without pretreatment antibiotics, PET/CT missed one out of five occult metastases. In addition, three false-positive results were found
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Fig. 9.3 (a) Example of fused PET/CT-scan in two planes. (b) Cross-sectional plane
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among the 37 remaining groins leading to a specificity of 92%.40 The false-positive findings were associated with inflammatory responses within the lymph nodes. In summary, each of the above-mentioned techniques is not reliable enough in assessing the cN0-patient because of a limited spatial resolution of at least 2–5 mm. Consequently, false-negative findings (i.e. missing small metastases) are inevitable with the currently available noninvasive staging techniques. Furthermore, it is important to emphasize that reported diagnostic accuracies are partly a reflection of patient selection with lower sensitivities reported when only cN0 patients are studied. Furthermore, CT and MR imaging have other additional disadvantages including the nonspecific morphological characteristics (i.e. size and shape of the node), which make a nonmetastatic node indistinguishable from one harboring
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metastatic disease. Apart from ultrasound when combined with FNAC, lymph nodes can be falsely labeled as a metastasis as opposed to being abnormal secondary to infection and none of these imaging modalities provide histopathological evidence again apart from ultrasound-guided FNAC.
9.4
Assessment of the Pelvic Lymph Nodes
Metastases to the pelvic lymph nodes are found only in conjunction with the presence of inguinal metastases. Imaging in patients at high risk for pelvic metastasis may show pelvic lymphadenopathy, while assessment of the pelvic lymph nodes in the absence of inguinal nodal involvement is not indicated. Currently CT-scanning is not very accurate in predicting pelvic nodal involvement and has a sensitivity of only 20%.41 However, morphologically suspicious pelvic lymph nodes (defined as short-axis diameter more than 10 mm and/or central necrosis) in the presence of inguinal nodal involvement are malignant unless proven otherwise.41 The likelihood of pelvic involvement is also related to the number of positive inguinal lymph nodes and also the presence of extranodal extension in the inguinal specimen.4,22 Patients at high risk for pelvic metastasis may benefit from preoperative PET/CT-scanning.42 Although no direct comparison has been made between PET/CT-scanning and CT-imaging, PET/CT-scanning is likely to be more accurate in the preoperative staging of the pelvic lymph nodes. This is primarily based upon the experience in other malignancies.36-38 Additionally, distant metastasis can be identified with PET/ CT-scanning due to whole-body scanning. The use of other imaging modalities (e.g. MRI) to stage the pelvic lymph nodes in patients with penile carcinoma has not been fully evaluated.
9.5
Management of the Inguinal Lymph Nodes in Clinically Node-Negative (cN0) Patients
The timing of lymphadenectomy is of major interest in cN0-patients. There often appears to be a choice between “too late” or “too early” and an evidence-based approach is difficult as the available published studies have a small number of patients, selection biases, and the lack of randomized trials. As mentioned above, current imaging techniques are unreliable in cN0-patients. Several risk-adapted management approaches have been used and advocated during the last decades (Table 9.1). Basically, these management policies can be divided into noninvasive management (surveillance), minimally invasive staging (dynamic sentinel node biopsy / modified inguinal lymphadenectomy), or invasive staging techniques (radical lymphadenectomy). The fact that approximately 20% of the cN0-patients have occult metastases, inguinal lymphadenectomy is an unnecessary procedure in approximately 80% of patients. Furthermore, lymphadenectomy is associated with
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Table 9.1 Available management approaches for cN0-patients Advantages Disadvantages Close surveillance No unnecessary morbidity Survival disadvantage compared in patients without with early dissection in those occult metastasis with initial occult metastasis Nomogram Some patients develop inoperable inguinal recurrences Minimally invasive staging Patients are pathologically In some patients metastases are staged with minor missed (i.e. false-negative) and Modified inguinal lymphmorbidity develop inguinal recurrences adenectomy (MIL) Dynamic sentinel node Only pN+ patients suffer Some patients cannot be salvaged biopsy (DSNB) from (completion) hereafter LND morbidity Risk-adapted No occult metastases are Unnecessary in 80% of patients lymphadenectomy missed and severe short and long-term morbidity Elective lymphadenectomy
risks and prone to a number of complications which will be discussed later. In general, a lymphadenectomy in all cN0 patients (sometimes described as early, prophylactic, or pre-emptive) is not recommended.
9.5.1
Noninvasive Staging Techniques
9.5.1.1
Close Surveillance
The basis of close surveillance involves a regular clinical examination of the patient proceeding to lymphadenectomy when lymph node metastases become clinically evident. This avoids the morbidity associated with lymphadenectomy and therefore patients with cN0 disease who subsequently are unlikely to develop inguinal lymph node metastases are not overtreated. While this has been advocated in the past, with seemingly good results, recent non-randomized retrospective studies indicate that this approach is associated with a negative effect on survival rates.24,26 McDougal argued a shift in philosophy toward prophylactic lymphadenectomy.24 In his report which included 27 cN0 patients, a survival advantage was described in patients undergoing prophylactic inguinal lymphadenectomy (11/12 survivors) versus therapeutic inguinal lymphadenectomy (1/3 survivors). Furthermore, 10/12 patients who had no regional treatment at diagnosis presented with metastatic inoperable disease during follow-up.24 Lont et al. have shown that the 3-years disease-specific survival of 68 patients treated with surgical staging (by dynamic sentinel node biopsy) and completion ipsilateral inguinal lymphadenectomy (only if the sentinel node was tumor-positive) was 91% compared with 79% of a historical cohort of 85 patients managed with active surveillance whereby lymphadenectomy was performed when the inguinal nodes became clinically evident.25 Thus, immediate resection of clinically occult metastases in comparison with lymphadenectomy only
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when metastases are clinically apparent has shown to substantially improve survival rates.24-26 Another disadvantage of close surveillance is that, despite a rigid followup, patients may still develop inoperable inguinal nodal disease. As there are currently no curative chemotherapeutic regimens available for the treatment of disseminated disease, early surgical staging and/or lymphadenectomy is the preferred option. Therefore, surveillance has gradually lost its role in managing all cN0-patients. Such management remains an option only in those patients at low risk for occult metastases, e.g. patients with pTis, pTa, and pT1G1 tumors. Patients with pTis and pTa tumors have a very low risk of metastatic disease, while the chance of occult metastases in pT1G1 tumors is estimated to be 0–5%.43 A recently published series by Hughes et al. has shown that the chance of regional nodal involvement of 105 cN0 patients with T1G2 tumors is 9%. This figure is probably more reliable than previously published risk estimates of 0–50%,10,44 given the large cohort in Hughes’ study. The incidences of regional nodal involvement of patients with T1G3 or T2-4 tumors are reported to range between 68% and 73%.9,43,45 However, two recent studies have shown that the risk of regional involvement are considerably lower ranging from 18% to 23%.10 Given the aforementioned risk estimates of the different tumors, the 2009 EAU guidelines advise minimally invasive staging in cN0 patients with at least a T1G2 tumor and surveillance in Tis, Ta, and T1G1 tumors.30
9.5.1.2
Predictive Nomogram for Occult Metastasis
Another non-invasive approach is the use of a preoperative nomogram predictive of inguinal metastases.46 In one nomogram the following parameters were used for risk assessment: tumor thickness (£5 mm vs. >5 mm), growth pattern (vertical vs. horizontal), grade (well vs. intermediate vs. poor), lymphovascular invasion (absent vs. present), corpora cavernosa infiltration (absent vs. present), corpora spongiosum infiltration (absent vs. present), urethral infiltration (absent vs. present), cN-status (cN0 vs. cN+). In clinical practice this particular nomogram may be a useful tool but still requires validation. It remains to the discretion of the doctor in collaboration with the patient to determine at which cut-off point to embark on a lymphadenectomy.
9.5.1.3
Risk-Adapted Lymphadenectomy
The basis of risk-adapted approaches is risk assessment for harboring lymph node metastases based on histopathological features in the primary tumor, such as tumor stage (T-stage),43,47 tumor grade (i.e. grade (G) 1, 2, or 3),47-49 presence of lymphovascular invasion (LVI),50,51 perineural invasion (PNI)48,49 and depth of infiltration.48 The EAU guidelines have included tumor stage, grade, and absence or presence of LVI into a risk-adapted approach for the management of the inguinal regions. Three risk-groups have been identified: low-risk tumors (pTis, pTa, pT1G1), intermediate-risk tumors (pT1G2, no LVI), and high-risk tumors (pT1G3, pT2-3 G1-3, or presence of
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LVI).9,43 If patients are considered suitable for surveillance, the 2009 EAU guidelines advise follow-up in patients with low-risk tumors only, and surgical staging in intermediate and high-risk cN0-patients. In a prospective study of 100 patients managed according to these EAU guidelines, none of the patients considered “low-risk” developed lymph node metastases during a mean follow-up of 29 months. On the other hand, elective lymphadenectomy was unnecessary in 82% of the patients with high-risk features, because no evidence of metastatic spread was found with histopathology.10 In another series of 118 patients it was estimated that 63% of high-risk patients will be subjected to unnecessary lymphadenectomy.52 Both studies indicate that the current EAU high-risk stratification is not accurate enough in order to stratify these patients. It appears that the risk of occult nodal involvement in cN0 patients with low-risk (T1G1) is low and these patients can still be subjected to close surveillance with subsequent inguinal lymphadenectomy when metastases become clinically evident.
9.5.2
Minimally Invasive Staging Techniques
To circumvent the above-mentioned dilemmas regarding lymphadenectomy, minimally invasive staging techniques have been developed. The basis of these techniques is to limit the morbidity in patients with pathological node-negative (pN0) groins, and to identify occult metastases at the earliest opportunity. Only patients with proven lymphatic spread undergo a completion therapeutic radical lymphadenectomy. In the last two decades, two approaches have been introduced worldwide: modified inguinal lymphadenectomy (MIL) and dynamic sentinel node biopsy (DSNB).
9.5.2.1
Modified Inguinal Lymphadenectomy (MIL)
The MIL was proposed by Catalona in 1988 after being performed in six patients with invasive carcinoma of the penis or distal urethra.53 The aim of this approach is to remove all the lymph nodes that are the most probable location of first-line lymphatic invasion, and exclude the regions lateral to the femoral artery and caudal to the fossa ovalis. The lymph node packet can be analyzed by frozen section and if it confirms metastatic disease then a radical inguinal lymphadenectomy can be performed. The anatomic location of these lymph nodes was based on earlier lymphatic drainage studies. The medial margin of MIL was the adductor longus muscle, the lateral margin was the lateral border of the femoral artery, the superior margin was the external oblique muscle above the spermatic cord, and the inferior margin was the fascia lata just distal to the fossa ovalis. The advantage of this MIL is a smaller skin incision and a smaller node dissection resulting in reduced morbidity compared with standard lymphadenectomy. However, limiting the dissection field led to a high number of false-negative findings as reported by several other authors. Several case studies have attested to this unreliability with nodal recurrences after negative MIL varying from
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0% to 15%.54-57 For example, Lopes et al. have described a prospective study of 13 cN0-patients staged with MIL in whom none had tumor-bearing lymph nodes in the dissected fields while two false-negative procedures came to light during follow-up.55 However, one of the problems associated with the MIL technique are the various boundaries used for the dissection. Two recent studies have suggested that for an optimal modified lymphadenectomy procedure, the traditional boundaries should be extended.19,22 Unfortunately, both studies used different anatomical fields. Hence direct comparison for the optimal boundaries of MIL remains to be defined. Zhu and associates advise the following boundaries for an optimal MIL: The medial margin is the medial surface of the adductor longus muscle, the lateral margin is the lateral surface of the saphenous vein and femoral artery, and the superior margin is the spermatic cord. All “superficial” and “deep” inguinal lymph nodes in the limits should be removed. Their assumption needs confirmation in prospective clinical studies.
9.5.2.2
Dynamic Sentinel Node Biopsy (DSNB)
Sentinel node biopsy for penile cancer was first reported by Cabañas in 1977.58 This was based on lymphangiograms of the penis and the lymph node medial to the superficial epigastric vein was identified as being the first echelon lymph node or so called “sentinel node”. It was assumed that a negative sentinel node was indicative for absence of further lymphatic spread and therefore no lymphadenectomy was indicated. Sentinel node surgery consisted of identification and removal of this lymph node with completion lymphadenectomy only in those with a tumor-positive lymph node. However, this initial “static” procedure, based on anatomic landmarks only, did not take into account individual drainage patterns. Several false-negative results were reported, and the technique was largely abandoned. The sentinel node procedure was revived by Morton et al. in 1992, by using patent blue-V or isosulfan blue dye as a tracer enabling individual lymphatic mapping.59 This technique with the addition of a preoperative radioactive tracer (technetium-99m-labeled nanocolloid 99mTc) forms the basis of the modern sentinel node biopsy era and is also used in, for example, breast cancer and melanoma. Since 1994, dynamic sentinel node biopsy (DSNB) has been performed at the authors’ institution to stage cN0-patients.52
9.5.2.3
Technique of DSNB
Conventional lymphoscintigraphy is performed following the injection of 99mTc nanocolloid intradermally just proximal to the tumor or coronal sulcus. Commonly between 30 and 70 MBq are injected into 3–4 sites (Fig. 9.4a). Once localized the sentinel nodes are marked. Intraoperatively the penis is injected with patent blue dye (Blue Patenté V, Laboratoire Guerbet, Aulnay-Sous-Bois, France) in the same position as the nanocolloid. A gamma-ray detection probe is then used to identify and remove the radioactive lymph nodes which directly drain the penis as identified
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Fig. 9.4 (a) Patent blue injection at time of surgery. (b) Hand held gamma detector during surgery to identify spot with highest radiation. (c) Blue and radioactive sentinel node with blue efferent lymphatic channel
by the lymphoscintigraphy (Fig. 9.4b, c).15,52,60 Patients who are found to have tumor within the sentinel lymph nodes undergo a completion lymphadenectomy. Compared with the above-mentioned “static” procedure first described by Cabañas,58 the “dynamic” approach investigates the individual drainage patterns for each individual patient. The DSNB procedure was first described by Horenblas et al. in 2001 in a report of 55 patients with T2 or greater tumors.61 With this dynamic approach a sensitivity of 80% was reported. However, the false-negative rates have raised concerns about its diagnostic accuracy. Furthermore, patients with negative sentinel nodes remained on rigid follow-up. During the years, the DSNB protocol has been modified after detailed analysis of the false-negative cases.62 The initial procedure was extended by pathological examination of the sentinel node by serial sectioning and immunohistochemical staining instead of routine paraffin sections, and addition of preoperative ultrasonography with fine-needle aspiration cytology to detect pathologically enlarged nodes, that fail to pick up radioactivity. Furthermore, exploration of groins with nonvisualization on preoperative lymphoscintigram (occurring in approximately 4–6% of cN0-groins)15,19,33 and intraoperative palpation of the wound have been introduced. The current modified procedure has evolved into a reliable minimally invasive staging technique with an associated sensitivity of 93–95% together with a low morbidity,52,63 and is comparable with the results in breast cancer and melanoma. Recently,
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in a large prospective series of 323 patients from two tertiary referral hospitals who use essentially the same protocol, DSNB was shown to be a reliable method with a low complication rate.60 The combined sensitivity of this procedure was 93% with a specificity of 100%. Complications occurred in less than 5% of explored groins and almost all were transient and could be managed conservatively. Some critics of the technique have pointed out that there is an associated learning curve as the falsenegative rate diminished during the years from 20–22% initially to a recent 5–7%. However, in the above-mentioned recently published series from two hospitals, no learning curve could be demonstrated in the initial 30 procedures done at one of the two hospitals.60 DSNB is a versatile tool that can also be used in the following clinical settings: Unilateral cN0-patients, while the other node-positive side is managed by a formal lymphadenectomy; a second DSNB after initial tumor-negative DSNB in patients who developed a recurrence of a primary tumor. Recently Graafland et al. describe 12 patients, in whom a second DSNB was performed due to penile cancer recurrence. A new sentinel node was identified in 80%. Also in patients in whom the primary tumor has already been removed DSNB is still possible. In a series with 40 patients with clinically node-negative penile carcinoma after previous therapeutic primary tumor resection the results were similar to the favorable experience with the DSNB in patients with their tumor still present.
9.5.2.4
Staging Recommendations
Currently, DSNB is recommended in cN0-groins of patients with penile tumors ³T1G2 (Fig. 9.5). Only patients with a tumor-positive sentinel lymph node should undergo a therapeutic ipsilateral inguinal lymphadenectomy. Compliant patients with lower-risk tumors (pTis, pTa, and pT1G1) can be managed with close surveillance followed by lymphadenectomy if metastases become clinically apparent. All patients should undergo inguinal ultrasound with fine needle aspiration cytology (FNAC) of the lymph nodes if they are morphologically suspicious.
9.6
Management of the Groin in Clinically Node-Positive (cN+) Patients
Surgery remains the cornerstone of treatment in patients with metastatic disease in the groins. Cure can be attained in approximately 80% of patients who have one or two involved inguinal nodes without extranodal extension.1-7 Preoperatively, inguinal nodal involvement can be found with FNAC or excision biopsy. We prefer FNAC as it is easily performed in an out-patient setting, it is relatively noninvasive, and it does not interfere with the subsequent lymphadenectomy. Although the reported sensitivity of FNAC is higher in cN+ patients compared to cN0 patients, it is recommended to repeat the ultrasound with FNAC when clinical suspicion remains despite tumor-negative cytological results. If doubt remains an excision biopsy is advised. In removing the
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Fig. 9.5 (a) Preferred incision, parallel to the inguinal ligament and a few centimeters under the inguinal crease. (b) Preferred incision for right inguinal lymphadenectomy, appearance after lymphadenectomy
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suspicious enlarged node the surgeon should pay attention to the anatomical localization of the inguinal incision, as the inguinal scar should be removed at the time of completion inguinal lymphadenectomy. Patients presenting with fixed inguinal nodes are candidates for neoadjuvant chemotherapy prior to undergoing surgery.64
9.7 9.7.1
Indications for Therapeutic Lymphadenectomy Indication for Inguinal Lymphadenectomy
Ipsilateral inguinal lymphadenectomy is indicated when tumor-bearing lymph nodes are found with sentinel node biopsy, FNAC, or excision biopsy. Should a bilateral inguinal dissection be undertaken in all patients with unilateral inguinal involvement? At the authors’ institute the timing of detection, the number of palpable
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nodes and the number of positive nodes found in the resection specimen were considered initially indicative for a contralateral lymphadenectomy.65 Patients who developed a unilateral inguinal recurrence during follow-up were managed by unilateral dissection assuming that bilateral nodal metastases develop at the same rate and that the absence of clinical nodal involvement of the contralateral side after observation suggested a tumor-free groin. Previous studies have suggested that the likelihood of bilateral involvement is related to the number of involved nodes in the unilateral resected inguinal specimen.1,65 With two or more metastases the probability of occult contralateral involvement is 30% and this may warrant an early contralateral inguinal lymphadenectomy. Currently, ultrasound-guided FNAC and DSNB are used to solve the problem at the authors’ institute in those patients presenting initially with unilateral positive nodes. Contralateral groins with tumor-negative sentinel nodes are under close surveillance. Hence, nodal staging and management has emerged from treatment per patient to management per groin.
9.7.2
Indication for Pelvic Lymphadenectomy
In general, 20–30% of patients with positive inguinal nodes have positive pelvic nodes.1,4,22 Although patients with pelvic lymphadenopathy are considered to have a bleak outcome, pelvic lymphadenectomy can be curative in some patients. In particular, those patients with occult pelvic metastases may benefit. Several authors have shown that the likelihood of pelvic nodal involvement is related to the number of positive nodes in the inguinal specimen and presence of extranodal extension.1-7,22 Patients with one intranodal inguinal metastasis have a very low probability of pelvic node involvement (<5%, unpublished data).4,22 At the authors’ institute a pelvic dissection is considered unnecessary in these patients. In all other patients with two or more inguinal nodes involved or extranodal extension an ipsilateral pelvic lymphadenectomy of the affected side is performed. There is ample clinical and published evidence that cross-over from the groin to the contralateral pelvic area does not occur.4,22,65 Therefore, contralateral pelvic lymphadenectomy is not recommended in patients with unilateral nodal involvement. Patients with preoperative evidence of pelvic metastases are unlikely to be cured by surgery alone and are candidates for neoadjuvant chemotherapy before undergoing surgery (Fig. 9.5).
9.8 9.8.1
Surgical Techniques of Lymphadenectomy Inguinal Lymphadenectomy
Several surgical approaches have been described in order to minimize the complications associated with the procedure. The patient is placed supine with the legs abducted and externally rotated. A variety of incisions can be used. For inguinal
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Fig. 9.6 (a) Skin incision. (b) Incision through the subcutaneous fat. (c, d) Identification of the subcutaneous fascia
node dissection the incisions can be divided into horizontal and vertical. The vascular supply to the skin of the inguinal area is such that horizontal incisions are preferred over vertical ones. The key to minimizing the morbidity following lymphadenectomy is correct tissue handling and ensuring that the skin flaps are developed in the correct plane.66 No lymph nodes are found in the layer between the skin and subcutaneous fascia. At the authors’ institute a parainguinal incision, a few centimeters below the groin crease, is the preferred type of incision (Fig. 9.6). The skin should be incised until the subcutaneous fascia is identified. Then the proximal and distal skin flaps are developed. The boundaries of the dissection are as follows: proximally, the inguinal ligament; distally, the crossing of the sartorius muscle and the adductor longus muscle (also referred to as the entrance of Hunter’s canal, where the femoral vessels go under the muscles of the leg); the medial boundary is the adductor longus muscle; the lateral margin is the sartorius muscle. The floor of the dissection consists of the fascia lata, the femoral vessels and the pectineus muscle (Fig. 9.7). As the femoral nerve is located beneath the fascia lata, it is not seen during standard lymphadenectomy. The surgeon who seldom performs this operation has a tendency to carry the operation too far laterally and medially, unnecessarily removing too much tissue. Since inguinal lymphadenectomy can be a curative procedure, it is important to meticulously remove all of the lymphatic tissue. There have been a series of modifications to the technique of inguinal lymphadenectomy in order to reduce the morbidity. Transposition of the sartorius muscle according to Baronofsky can be undertaken if the patient is deemed at high risk for wound complications.67 The origin of the sartorius muscle at the anterior superior iliac spine is
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Fig. 9.7 Boundaries of inguinal node dissection, cranial: inguinal ligament, distal: crossing of sartorius muscle and adductor longus, medial: adductor longus muscle, lateral: sartorius muscle. The floor consists of the femoral vessels. The saphenous vein is spared in this patient
transected and the muscle together with its overlying fascia is sutured to the inferior margin of the inguinal ligament. Excellent coverage of the femoral vessels is achieved with no long-term sequelae. The saphenous vein can also be spared, if possible, in order to minimize postoperative lymphedema. After performing the dissection, the skin edges are carefully inspected; any area with doubtful viability should be excised. There are no comparative studies on the use of antibiotics but it seems reasonable to give prophylactic antibiotics at the time of surgery, as this type of surgery should be considered a contaminated procedure, because of coexisting inflammatory reactions within the lymph nodes. Along with the general recommendations for prophylactic antibiotics, the authors’ group gives one dose at the start of anesthesia. Prior to closing the wound, suction drains are inserted in order to prevent lymphocele formation and also increase the chance of primary wound healing. Postoperative antibiotic use is variable among surgeons performing the procedure. Some centers continue antibiotics until the drain is removed. After 1 week the vacuum is removed and spontaneous drainage observed. Drains are removed if the drainage is <50 mL/day although some centers wait until it is <30 mL/day. Recently, some studies have investigated the use of fibrin sealant in melanoma and vulval carcinoma in order to reduce the complication rate including lymphedema. Preliminary results show that complications are not significantly reduced by applying the fibrin sealant.68,69 Immediately after surgery ambulation is strongly advised and supported with individually fitted elastic stockings. Patients are advised to use the elastic stockings for at least 6 months following surgery. After that period the need for elastic stockings depends on the individual tendency to develop lymphedema. At the authors’ institution it is routine to give low molecular weight heparin as prophylaxis for thrombosis, starting the evening before surgery. Is it necessary to perform an en-bloc dissection, to remove the primary tumor with the regional lymph nodes as one continuous specimen? This type of surgery was first introduced by Young in 1926. While oncologically sound, clinical experience shows this to be unnecessary in most patients. The rationale is that lymphatic spread occurs through a process of embolism, not through continuous growth. On practical and
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Fig. 9.8 (a and b) En bloc resection of inguinal node specimen and primary tumor
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theoretical grounds it is advisable to stage the treatment of the primary tumor and the regional nodes. One reason is the elimination of the primary tumor as a focus of infection and the other is the deposition of ‘in-transit’ metastases in the regional nodes, thus eliminating the potential risk of metastatic outgrowth in the tract between the primary tumor and the groin. En-bloc dissection is only indicated in patients with extensive primary or recurrent disease with bilateral nodal involvement (Fig. 9.8). Skin closure following lymphadenectomy can be difficult in patients with extensive metastatic disease with overlying skin involvement. The skin involved should be excised, although inevitably, this leaves a large defect. Various methods can be used to manage this surgical problem. After a sartorius transposition the wound can heal by secondary intention. Healing can be improved and hastened by applying a split-skin graft on the granulation tissue. Another method is the so-called ‘skin-stretch’ method70; by gradually increasing the pressure on the skin edges in a cyclic fashion, large skin defects are closed with no tension (Fig. 9.9). Island flaps that can be useful for closure are the rectus abdominis pedicle, gracilis pedicle, and the tensor fascia lata pedicle (Fig. 9.10).71,72 In cases of en-bloc removal, using scrotal skin and mobilizing the abdominal wall can also be used to assist in the closure of the defect. The femoral vessels can be protected by transposition of the scrotal contents and suturing the scrotal contents to the inguinal ligament.
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Fig. 9.9 (a) Skin closure by skin stretching, wound after extensive node dissection. (b) Two long needles are passed parallel to the wound (in this patient a sartorius transposition was performed). (c) A stretching apparatus is attached behind the needles and the wound edges are gradually approximated. (d) Wound edges are almost completely approximated. (e) Wound closure
9.8.2
Pelvic Lymphadenectomy
Pelvic lymphadenectomy can be undertaken simultaneously at the time of inguinal node dissection or as a separate procedure. In the first case, removal of the lymph nodes using one or two incisions has been described; most authors prefer two separate incisions (Fig. 9.11). A comparison of the various types of incisions has shown that the lowest complication rate occurs when two separate incisions are used.12,13 The pelvic node dissection is undertaken either through a lower abdominal midline incision or a unilateral muscle splitting incision. The boundaries of the pelvic node dissection are proximally, the common iliac vessels; distally, the passage of
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Fig. 9.10 (a) Large primary tumor with outlined horizontal rectus abdominal flap. (b) After excision and closure of the wound. (c) Anterior view. (d) Ulcerating lymph node metastases, with outlines of two horizontal rectus abdominal flaps and a right tensor fascia lata flap. (e) View from the right side (f) Defect after resection. (g) Wound after closure
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Fig. 9.11 Appearance after bilateral lymphadenectomy and bilateral pelvic lymphadenectomy using separate incisions
a
b Fig. 9.12 (a) Boundaries of a pelvic node dissection. Cranial: common iliac artery, caudal: inguinal canal, medial: bladder, prostate, and the medial branches of the internal iliac artery, lateral: ilioinguinal nerve, bottom: obturator fossa. (b) Medial retraction shows clearance of all tissue up the promontorium
lymphatic vessels to the groin; laterally, the ilio-inguinal nerve; medially, the bladder and prostate; and the base is the deepest part of the obturator fossa (Fig. 9.12). Care must be taken to completely remove the obturator fossa, especially the space behind the external iliac vessels, all the way to the sacrum. A large node can usually
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Fig. 9.13 (a) Skin necrosis. (b) Wound infection and dehiscence
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be found there and if left is prone to recurrence with intractable pain, because of neural ingrowth. After the dissection suction drains are left in place and removed if the spontaneous drainage is <50 mL. Laparoscopic pelvic node dissection has not had a major role in pelvic node dissection for penile cancer at our institute thus far although it is used in other centers. In view of the therapeutic potential of node dissection (with or without chemotherapy and/or radiotherapy), a complete dissection should be attempted.
9.9
Complications of Lymph Node Dissection
Even in the most experienced hands lymphadenectomy is not without complications. This accounts for the reluctance in offering lymphadenectomy to every patient presenting with penile cancer. The reported complication rate varies from 35% to 88%, and appears to be lower when inguinal lymphadenectomy is performed in a prophylactic or therapeutic setting compared with a palliative dissection.14 Furthermore, pelvic node dissection and radiotherapy have shown to increase the complication rates.4,12 The most commonly cited complications are wound infection (15 ± 10%), skin necrosis (Fig. 9.13a) with or without wound
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b
c
Fig. 9.14 (a) Lymphocele. (b) Lymphedema. (c) Serous lymphedema of the right leg
dehiscence (Fig. 9.13b) (14 ± 50%), lymphocele/seroma (10 ± 10%) (Fig. 9.14a) lymphedema (Fig. 9.14b) (27 ± 30%), and other complications including hemorrhage, thrombosis, and even death. A summary of the most frequent complications is listed in Table 9.2. Techniques in order to prevent complications have already been mentioned but will again be reviewed. Understanding the course of the vasculature of the inguinal skin is important in planning the incision. In a series from Brazil, three types of incision were compared, i.e. a large bi-iliac incision, a transverse S-shaped incision, and a skin-bridge technique with two separate incisions. The latter had the lowest incidence of skin necrosis and lymphedema.13 Utmost care must be taken when handling the skin in order to preserve its viability. Antibiotic prophylaxis and preventing venous thrombosis with low molecular weight heparin is strongly recommended.66 Individually fitted
9
Management of Lymph Nodes
Table 9.2 Complications of lymphadenectomy (%) Number of Wound Skin edge dissections infection necrosis 10111 14 50 40512 17 62 20013 15 45 10614 10 8 102a4 22 8
207
Seroma formation 16 7 10 10 18
Lymph edema 50 27 23 23 56
Death 0 1 – 2 0
a
Per-patient
stockings should be available immediately after surgery. Extensive experience in nodal dissection is an important factor in the optimal removal of all lymphatic tissue and preventing complications13; this is also shown in results from the authors’ institute. Thus it is reasonable to centralize this type of surgery and to refer patients to institutes with a large experience. Although a recent series has shown that the complication rate of lymphadenectomy has decreased, the incidence and magnitude of complications appears to remain significant with a complication-rate of 58% per-patient.14
9.9.1
Minimizing the Morbidity of Lymphadenectomy
Standard lymphadenectomy consists of the removal of all lymph nodes in the inguinal region. Recent lymphoscintigraphical and anatomical data indicate that limiting the dissection field to the central and craniomedial part may provide oncological control.19,22 Further mapping studies are in order to test the safety of this modified lymphadenectomy. Moreover, to be of real clinical value, there should be evidence of a reduction in the complication rate. An alternative option which could minimize the morbidity associated with the procedure involves using the technique of video endoscopic inguinal lymphadenectomy (VEIL). Some small series have now shown promising results with lower complication rates compared with an open procedure. Tobias-Machado et al. have reported their initial results of ten patients without palpable lymph nodes who underwent VEIL on one side and the standard open approach on the contralateral side. Although operative times were longer with the endoscopic approach compared with the open method, the mean number of retrieved and tumor-positive lymph nodes were similar. Moreover, there was a trend toward decreased postoperative morbidity.73 In another study reporting on their expanding experience, the VEIL approach led also to a significant decreased hospital stay (mean of 1 day vs. 6.4 days in patients who had undergone standard lymphadenectomy on one limb).74 The robot-assisted procedures have also recently been published in a case report.75 Until long-term oncological results are available, the laparoscopic lymphadenectomy technique is still considered investigational.
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9.9.2
N.M. Graafland and S. Horenblas
Management of Complications
After removing the suction drains a lymphocele can develop in 10–20% of patients (Fig. 9.14a). This can usually be managed by outpatient aspiration with a large needle and a large syringe. After natural resolution of the space in which the lymphocele develops the accumulation of lymphatic fluid stops. Large wound defects can be closed using a so-called Vacuum Assisted Closure (VAC) system. A sponge is inserted in the wound and sealed with plastic and a draining tube is attached to a low pressure vacuum pump (Fig. 9.15). Excellent results have been obtained, reducing, the time to secondary healing. If the defect remains large a split skin graft can be laid on top of the granulation tissue. Despite the use of elastic stockings, lymphedema can still develop in approximately 10% of patients, especially those in whom extensive surgery together with radiation therapy was necessary because of the burden of disease. Supporting therapy includes lymph massage and compression therapy. Surgical therapy using lymphatic-venous anastomosis have not been entirely successful. Legs with lymphedema are infection prone, especially with streptococcus A bacteria, leading to erisypelas. At the author’s institution antibiotic prophylaxis with monthly penicillin depots is strongly advised after two bouts of erisypelas-like infections.
9.10
Prognosis and Adjuvant Treatment
The single most important prognostic factor in penile cancer is the presence of nodal involvement. The extent of nodal involvement also has a predictive value for cancer-specific outcome. As mentioned previously, patients with one or two inguinal lymph node metastases have a 5-year survival rate of approximately 80%.1-7 Several studies have indicated that the number of inguinal nodes involved, extranodal extension and pelvic nodal involvement are unfavorable parameters for disease-specific survival (Table 9.3).1-7 Hence, the indication for adjuvant treatment is based upon the presence of these adverse prognostic indicators. At the authors’ institution, no adjuvant treatment is indicated when histopathological analysis of the removed inguinal dissected specimen shows one intranodal metastasis as cure alone by surgery can be obtained in these patients. Adjuvant ipsilateral radiotherapy to the inguinal lymphatic region is given when histopathological analysis shows two or more inguinal nodes involved or extranodal extension. The rationale for this arises from studies in head and neck squamous cell carcinomas showing an improvement in regional control following adjuvant radiotherapy.76 Adjuvant radiotherapy to the pelvic region is administered additionally when pelvic nodes are involved. Prophylactic radiation to the groins in all patients with penile cancer is not advised for the following reasons. Firstly, some patients with nonpalpable nodes will not benefit because they have no occult metastasis as is the case for elective lymphadenectomy. Secondly, all patients will be exposed to the complications of radiation
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Management of Lymph Nodes
Fig. 9.15 (a) Skin closure with the VAC system. A sponge is introduced into the wound. (b) After introduction of the sponge, the wound is covered with a plastic adhesive layer. (c) A small hole is made in the plastic sheath to accommodate a suction device for low pressure suction
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a
b
c
therapy, e.g. short-term complications like epidermolysis, and long-term effects such as lymphedema and fibrosis. Finally, the follow-up is more complicated because of the fibrotic changes, making physical examination less reliable. Although, Ravi et al. have indicated that patients with large (>4 cm) and/or fixed regional nodes may benefit from preoperative radiotherapy, the above-mentioned disadvantages outweigh the preoperative use. There are no studies available that have
210 Table 9.3 Cancer-specific survival by pathological nodal factors after inguinal lymphadenectomy
N.M. Graafland and S. Horenblas
Number of patients Factors with factor Pathological node-negative nodes 1032 1407 Pathological node-positive 1182 1117 1026 15677 No of positive nodes 1 51 1–3 582 696 £2 11177 ³3 4177 >3 102 4–5 256 >5 86 Unilateral 432 746 9377 Bilateral 241 252 286 6377 Extranodal extension 221 172 546 7977 Pelvic nodal involvement 221 302 216 1378 3477
5-year cancer-specific survival estimates (%) 95 96 53 35 51 61 82 81 76 74 33 50 8 0 86 63 69 12 60 21 49 5 0 9 42 0 0 0 30 21
investigated the efficacy of radiotherapy versus standard lymphadenectomy in terms of local control, (cancer-specific) outcome, or complications. Despite adjuvant radiotherapy, a previous study at the authors’ institution of 102 patients with metastatic penile carcinoma treated between 1956 and 2001 has shown that extranodal extension and pelvic nodal involvement are independent predictors for survival.4 These results have recently been confirmed in an updated series which has included 156 patients with metastatic penile cancer treated between 1988 and 2008.77 These data suggest that more effective treatment is needed in this subgroup of patients with high-risk metastatic penile cancer. Whether induction chemotherapy before surgery is of any benefit in this high-risk subgroup warrants further clinical studies.
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211
References 1. Srinivas V, Morse MJ, Herr HW, Sogani PC, Whitmore WF Jr. Penile cancer: relation of extent of nodal metastasis to survival. J Urol. 1987;137:880. 2. Ravi R. Correlation between the extent of nodal involvement and survival following groin dissection for carcinoma of the penis. Br J Urol. 1993;72:817. 3. Horenblas S, van Tinteren H. Squamous cell carcinoma of the penis. IV. Prognostic factors of survival: analysis of tumor, nodes and metastasis classification system. J Urol. 1994;151:1239. 4. Lont AP, Kroon BK, Gallee MP, van Tinteren H, Moonen LM, Horenblas S. Pelvic lymph node dissection for penile carcinoma: extent of inguinal lymph node involvement as an indicator for pelvic lymph node involvement and survival. J Urol. 2007;177:947. 5. Sanchez-Ortiz RF, Pettaway CA. The role of lymphadenectomy in penile cancer. Urol Oncol. 2004;22:236. 6. Pandey D, Mahajan V, Kannan RR. Prognostic factors in node-positive carcinoma of the penis. J Surg Oncol. 2006;93:133. 7. Ornellas AA, Kinchin EW, Nobrega BL, Wisnescky A, Koifman N, Quirino R. Surgical treatment of invasive squamous cell carcinoma of the penis: Brazilian National Cancer Institute long-term experience. J Surg Oncol. 2008;97:487. 8. Wespes E. The management of regional lymph nodes in patients with penile carcinoma and reliability of sentinel node biopsy. Eur Urol. 2007;52:15. 9. Solsona E, Algaba F, Horenblas S, Pizzocaro G, Windahl T. EAU guidelines on penile cancer. Eur Urol. 2004;46:1. 10. Hegarty PK, Kayes O, Freeman A, Christopher N, Ralph DJ, Minhas S. A prospective study of 100 cases of penile cancer managed according to European Association of Urology guidelines. BJU Int. 2006;98:526. 11. Johnson DE, Lo RK. Complications of groin dissection in penile cancer. Experience with 101 lymphadenectomies. Urology. 1984;24:312. 12. Ravi R. Morbidity following groin dissection for penile carcinoma. Br J Urol. 1993;72:941. 13. Ornellas AA, Seixas AL, de Moraes JR. Analyses of 200 lymphadenectomies in patients with penile carcinoma. J Urol. 1991;146:330. 14. Bevan-Thomas R, Slaton JW, Pettaway CA. Contemporary morbidity from lymphadenectomy for penile squamous cell carcinoma: the M.D. Anderson Cancer Center Experience. J Urol. 2002;167:1638. 15. Hadway P, Smith Y, Corbishley C, Heenan S, Watkin NA. Evaluation of dynamic lymphoscintigraphy and sentinel lymph-node biopsy for detecting occult metastases in patients with penile squamous cell carcinoma. BJU Int. 2007;100:561. 16. Kroon BK, Valdés Olmos R, Nieweg OE, Horenblas S. Non-visualization of sentinel lymph nodes in penile carcinoma. Eur J Nucl Med Mol Imaging. 2005;32:1096. 17. Daseler EH, Anson BJ, Reimann AF. Radical excision of the inguinal and iliac lymph glands; a study based upon 450 anatomical dissections and upon supportive clinical observations. Surg Gynecol Obstet. 1948;87:679. 18. Dewire D, Lepor H. Anatomic considerations of the penis and its lymphatic drainage. Urol Clin North Am. 1992;19:211. 19. Leijte JA, Valdes Olmos RA, Nieweg OE, Horenblas S. Anatomical mapping of lymphatic drainage in penile carcinoma with SPECT-CT: implications for the extent of inguinal lymph node dissection. Eur Urol. 2008;54:885. 20. Cabanas RM. Anatomy and biopsy of sentinel lymph nodes. Urol Clin North Am. 1992;19:267. 21. Lont AP, Gallee MP, Snijders P, Horenblas S. Sarcomatoid squamous cell carcinoma of the penis: a clinical and pathological study of 5 cases. J Urol. 2004;172:932. 22. Zhu Y, Zhang SL, Ye DW, et al. Prospectively packaged ilioinguinal lymphadenectomy for penile cancer: the disseminative pattern of lymph node metastasis. J Urol. 2009;181:2103.
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23. Kroon BK, Valdes Olmos RA, van der Poel HG, Nieweg OE, Horenblas S. Prepubic sentinel node location in penile carcinoma. Clin Nucl Med. 2005;30:649. 24. McDougal WS. Carcinoma of the penis: improved survival by early regional lymphadenectomy based on the histological grade and depth of invasion of the primary lesion. J Urol. 1995;154:1364. 25. Lont AP, Horenblas S, Tanis PJ, Gallee MP, van Tinteren H, Nieweg OE. Management of clinically node negative penile carcinoma: improved survival after the introduction of dynamic sentinel node biopsy. J Urol. 2003;170:783. 26. Kroon BK, Horenblas S, Lont AP, Tanis PJ, Gallee MP, Nieweg OE. Patients with penile carcinoma benefit from immediate resection of clinically occult lymph node metastases. J Urol. 2005;173:816. 27. Persson B, Sjodin JG, Holmberg L, Windahl T. The National Penile Cancer Register in Sweden 2000-2003. Scand J Urol Nephrol. 2007;41:278. 28. Ornellas AA, Seixas AL, Marota A, Wisnescky A, Campos F, de Moraes JR. Surgical treatment of invasive squamous cell carcinoma of the penis: retrospective analysis of 350 cases. J Urol. 1994;151:1244. 29. Horenblas S, van Tinteren H, Delemarre JF, Moonen LM, Lustig V, Kroger R. Squamous cell carcinoma of the penis: accuracy of tumor, nodes and metastasis classification system, and role of lymphangiography, computerized tomography scan and fine needle aspiration cytology. J Urol. 1991;146:1279. 30. Pizzocaro G, Algaba F, Horenblas S, et al. EAU penile cancer guidelines 2009. Eur Urol. 2010;57:1002. 31. Kroon BK, Horenblas S, Deurloo EE, Nieweg OE, Teertstra HJ. Ultrasonography-guided fineneedle aspiration cytology before sentinel node biopsy in patients with penile carcinoma. BJU Int. 2005;95:517. 32. Saisorn I, Lawrentschuk N, Leewansangtong S, Bolton DM. Fine-needle aspiration cytology predicts inguinal lymph node metastasis without antibiotic pretreatment in penile carcinoma. BJU Int. 2006;97:1225. 33. Jensen JB, Jensen KM, Ulhoi BP, Nielsen SS, Lundbeck F. Sentinel lymph-node biopsy in patients with squamous cell carcinoma of the penis. BJU Int. 2009;103:1199. 34. Tabatabaei S, Harisinghani M, McDougal WS. Regional lymph node staging using lymphotropic nanoparticle enhanced magnetic resonance imaging with ferumoxtran-10 in patients with penile cancer. J Urol. 2005;174:923. 35. Thoeny HC, Triantafyllou M, Birkhaeuser FD, et al. Combined ultrasmall superparamagnetic particles of iron oxide-enhanced and diffusion-weighted magnetic resonance imaging reliably detect pelvic lymph node metastases in normal-sized nodes of bladder and prostate cancer patients. Eur Urol. 2009;55:761. 36. Lardinois D, Weder W, Hany TF, et al. Staging of non-small-cell lung cancer with integrated positron-emission tomography and computed tomography. N Engl J Med. 2003;348:2500. 37. Antoch G, Saoudi N, Kuehl H, et al. Accuracy of whole-body dual-modality fluorine-18-2fluoro-2-deoxy-D-glucose positron emission tomography and computed tomography (FDGPET/CT) for tumor staging in solid tumors: comparison with CT and PET. J Clin Oncol. 2004;22:4357. 38. Ng SH, Yen TC, Chang JT, et al. Prospective study of [18F]fluorodeoxyglucose positron emission tomography and computed tomography and magnetic resonance imaging in oral cavity squamous cell carcinoma with palpably negative neck. J Clin Oncol. 2006;24:4371. 39. Scher B, Seitz M, Reiser M, et al. 18F-FDG PET/CT for staging of penile cancer. J Nucl Med. 2005;46:1460. 40. Leijte JA, Graafland NM, Valdes Olmos RA, van Boven HH, Hoefnagel CA, Horenblas S. Prospective evaluation of hybrid (18)F-fluorodeoxyglucose positron emission tomography/ computed tomography in staging clinically node-negative patients with penile carcinoma. BJU Int. 2009;104:640.
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41. Zhu Y, Zhang SL, Ye DW, Yao XD, Jiang ZX, Zhou XY. Predicting pelvic lymph node metastases in penile cancer patients: a comparison of computed tomography, Cloquet’s node, and disease burden of inguinal lymph nodes. Onkologie. 2008;31:37. 42. Graafland NM, Leijte JA, Valdes Olmos RA, Hoefnagel CA, Teertstra HJ, Horenblas S. Scanning with 18F-FDG-PET/CT for detection of pelvic nodal involvement in inguinal nodepositive penile carcinoma. Eur Urol. 2009;56:339. 43. Solsona E, Iborra I, Rubio J, Casanova JL, Ricos JV, Calabuig C. Prospective validation of the association of local tumor stage and grade as a predictive factor for occult lymph node micrometastasis in patients with penile carcinoma and clinically negative inguinal lymph nodes. J Urol. 2001;165:1506. 44. Naumann CM, Alkatout I, Al Najar A, et al. Lymph-node metastases in intermediate-risk squamous cell carcinoma of the penis. BJU Int. 2008;102:1102. 45. Theodorescu D, Russo P, Zhang ZF, Morash C, Fair WR. Outcomes of initial surveillance of invasive squamous cell carcinoma of the penis and negative nodes. J Urol. 1996;155:1626. 46. Ficarra V, Zattoni F, Artibani W, et al. Nomogram predictive of pathological inguinal lymph node involvement in patients with squamous cell carcinoma of the penis. J Urol. 2006;175:1700. 47. Slaton JW, Morgenstern N, Levy DA, et al. Tumor stage, vascular invasion and the percentage of poorly differentiated cancer: independent prognosticators for inguinal lymph node metastasis in penile squamous cancer. J Urol. 2001;165:1138. 48. Ornellas AA, Nobrega BL, Wei Kin Chin E, Wisnescky A, da Silva PC, Santos Schwindt AB. Prognostic factors in invasive squamous cell carcinoma of the penis: analysis of 196 patients treated at the Brazilian National Cancer Institute. J Urol. 2008;180:1354. 49. Velazquez EF, Ayala G, Liu H, et al. Histologic grade and perineural invasion are more important than tumor thickness as predictor of nodal metastasis in penile squamous cell carcinoma invading 5 to 10 mm. Am J Surg Pathol. 2008;32:974. 50. Lopes A, Hidalgo GS, Kowalski LP, Torloni H, Rossi BM, Fonseca FP. Prognostic factors in carcinoma of the penis: multivariate analysis of 145 patients treated with amputation and lymphadenectomy. J Urol. 1996;156:1637. 51. Ficarra V, Zattoni F, Cunico SC, et al. Lymphatic and vascular embolizations are independent predictive variables of inguinal lymph node involvement in patients with squamous cell carcinoma of the penis: Gruppo Uro-Oncologico del Nord Est (Northeast Uro-Oncological Group) Penile Cancer data base data. Cancer. 2005;103:2507. 52. Leijte JA, Kroon BK, Valdés Olmos RA, Nieweg OE, Horenblas S. Reliability and safety of current dynamic sentinel node biopsy for penile carcinoma. Eur Urol. 2007;52:170. 53. Catalona WJ. Modified inguinal lymphadenectomy for carcinoma of the penis with preservation of saphenous veins: technique and preliminary results. J Urol. 1988;140:306. 54. Parra RO. Accurate staging of carcinoma of the penis in men with nonpalpable inguinal lymph nodes by modified inguinal lymphadenectomy. J Urol. 1996;155:560. 55. Lopes A, Rossi BM, Fonseca FP, Morini S. Unreliability of modified inguinal lymphadenectomy for clinical staging of penile carcinoma. Cancer. 1996;77:2099. 56. D’Ancona CA, de Lucena RG, Querne FA, Martins MH, Denardi F, Netto NR Jr. Long-term followup of penile carcinoma treated with penectomy and bilateral modified inguinal lymphadenectomy. J Urol. 2004;172:498. 57. Colberg JW, Andriole GL, Catalona WJ. Long-term follow-up of men undergoing modified inguinal lymphadenectomy for carcinoma of the penis. Br J Urol. 1997;79:54. 58. Cabanas RM. An approach for the treatment of penile carcinoma. Cancer. 1977;39:456. 59. Morton DL, Wen DR, Wong JH, et al. Technical details of intraoperative lymphatic mapping for early stage melanoma. Arch Surg. 1992;127:392. 60. Leijte JA, Hughes B, Graafland NM, et al. Two-center evaluation of dynamic sentinel node biopsy for squamous cell carcinoma of the penis. J Clin Oncol. 2009;27:3325.
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61. Horenblas S, Jansen L, Meinhardt W, Hoefnagel CA, de Jong D, Nieweg OE. Detection of occult metastasis in squamous cell carcinoma of the penis using a dynamic sentinel node procedure. J Urol. 2000;163:100. 62. Kroon BK, Horenblas S, Estourgie SH, Lont AP, Valdes Olmos RA, Nieweg OE. How to avoid false-negative dynamic sentinel node procedures in penile carcinoma. J Urol. 2004;171:2191. 63. Kroon BK, Lont AP, Valdés Olmos RA, Nieweg OE, Horenblas S. Morbidity of dynamic sentinel node biopsy in penile carcinoma. J Urol. 2005;173:813. 64. Leijte JA, Kerst JM, Bais E, Antonini N, Horenblas S. Neoadjuvant chemotherapy in advanced penile carcinoma. Eur Urol. 2007;52:488. 65. Horenblas S, van Tinteren H, Delemarre JF, Moonen LM, Lustig V, van Waardenburg EW. Squamous cell carcinoma of the penis. III. Treatment of regional lymph nodes. J Urol. 1993;149:492. 66. Horenblas S. Lymphadenectomy for squamous cell carcinoma of the penis. Part 2: the role and technique of lymph node dissection. BJU Int. 2001;88:473. 67. Baronofsky ID. Technique of inguinal node dissection. Surgery. 1948;24:555. 68. Mortenson MM, Xing Y, Weaver S, et al. Fibrin sealant does not decrease seroma output or time to drain removal following inguino-femoral lymph node dissection in melanoma patients: a randomized controlled trial (NCT00506311). World J Surg Oncol. 2008;6:63. 69. Carlson JW, Kauderer J, Walker JL, et al. A randomized phase III trial of VH fibrin sealant to reduce lymphedema after inguinal lymph node dissection: a Gynecologic Oncology Group study. Gynecol Oncol. 2008;110:76. 70. Melis P, Bos KE, Horenblas S. Primary skin closure of a large groin defect after inguinal lymphadenectomy for penile cancer using a skin stretching device. J Urol. 1998;159:185. 71. Kayes OJ, Durrant CA, Ralph D, Floyd D, Withey S, Minhas S. Vertical rectus abdominis flap reconstruction in patients with advanced penile squamous cell carcinoma. BJU Int. 2007;99:37. 72. Airhart RA, deKernion JB, Guillermo EO. Tensor fascia lata myocutaneous flap for coverage of skin defect after radical groin dissection for metastatic penile carcinoma. J Urol. 1982;128:599. 73. Tobias-Machado M, Tavares A, Ornellas AA, Molina WR Jr, Juliano RV, Wroclawski ER. Video endoscopic inguinal lymphadenectomy: a new minimally invasive procedure for radical management of inguinal nodes in patients with penile squamous cell carcinoma. J Urol. 2007;177:953. 74. Tobias-Machado M, Tavares A, Silva MN, et al. Can video endoscopic inguinal lymphadenectomy achieve a lower morbidity than open lymph node dissection in penile cancer patients? J Endourol. 2008;22:1687. 75. Sotelo R, Sanchez-Salas R, Clavijo R. Endoscopic inguinal lymph node dissection for penile carcinoma: the developing of a novel technique. World J Urol. 2009;27:213. 76. Bartelink H, Breur K, Hart G, Annyas B, van Slooten E, Snow G. The value of postoperative radiotherapy as an adjuvant to radical neck dissection. Cancer. 1983;52:1008. 77. Graafland NM, van Boven HH, Van Werkhoven E, Moonen LM, Horenblas S. Prognostic significance of extranodal extension in pathological node-positive patients with penile carcinoma. J Urol. 2010;184:1347. 78. Lopes A, Bezerra AL, Serrano SV, Hidalgo GS. Iliac nodal metastases from carcinoma of the penis treated surgically. BJU Int. 2000;86:690.
Chapter 10
Prognostic Indicators in Penile Cancer Vincenzo Ficarra, Giacomo Novara, Guido Martignoni, and Filiberto Zattoni
10.1
Introduction
Penile cancer prognosis is closely related to the natural history of the neoplasm. The primary cancer progressively infiltrates penile structures, initially in a horizontal and superficial pattern of spread, followed by a stepwise vertical invasion through the penile fascia and tunica albuginea1. However, the main characteristic of this uncommon malignancy is the high tendency to metastasize through the lymphatic vasculature to superficial inguinal, deep inguinal, and pelvic lymph nodes. The majority of patients eventually die as a result of complications related to regional lymph nodes before developing distant metastases (Fig. 10.1 a, b). Distant metastases to lung, liver, bone, or brain are present in only 1–10% of patients with advanced lymph node involvement and these unfortunate individuals have an unfavorable prognosis with a mean survival of approximately 7–10 months.2,3
10.2
Metastasis to Regional Lymph Nodes
Metastatic regional lymph node involvement is the main predictive factor of an unfavorable prognosis in men with penile carcinoma. At initial diagnosis, about 28–64% of patients will have clinically palpable lymph nodes.4 However, it should be noted that in only 47–85% of cases are the enlarged inguinal lymph nodes the result of metastases5-7, while in the remaining cases, this finding is due to an infective inflammatory process in the primary tumor. Twenty-two to fifty-six percent of
V. Ficarra (*) Department of Surgical and Oncological Sciences, Urologic Unit, University of Padua, Padua, Italy A. Muneer et al. (eds.), Textbook of Penile Cancer, DOI 10.1007/978-1-84882-879-7_10, © Springer-Verlag London Limited 2012
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216 Fig. 10.1 Severe locoregional complications in patients who did not undergo lymphadenectomy (a) and in patient with a local recurrence after inguinal lymphadenectomy (b)
V. Ficarra et al.
a
b
patients with metastases to inguinal lymph nodes have concomitant pelvic lymph node metastases. As regards the clinical stage of regional lymph nodes, the 5-year cause-specific survival probabilities in the noteworthy published series ranges from 75% to 93% in patients with cN0 disease; from 40% to 70% in cN1; from 33% to 50% in cN2; and from 20% to 34% in cN3 cancers, respectively.8 However, in relation to prognosis, pathological nodal stage is significantly more important than clinical lymph node status. While patients staged as pN0 following inguinal lymph node dissection have a 5-year cancer-specific survival as high as
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217
Table 10.1 Five-year cancer-specific survival of penile cancer patients according to pathological lymph node involvement Author pN0 pN+ PN1 pN2 pN3 Srinivas et al.23 85 32 NR NR 0 Ornellas et al.31 87 29 NR NR NR Horenblas et al.10 100 NR 79 17 NR Ravi25 95 NR 86 60 0 Kulkarni and Kamat16 91 NR NR NR NR Brkovic et al.32 90 NR 80 NR 17 Pow-Sang et al.24 92 NR 80 NR 17 Pandey et al.29 95 51 NR 21 0 Novara et al.14 94 29 89 7 0
85–100%, men with any lymph node involvement (pN+) have 5-year cancer-specific survival rates of only 16–45%.9,10 Specifically, in accordance with the most recent version of the TNM staging system, 5-year cancer-specific survival estimations are 79–89% in pN1 patients; 7–60% in pN2, and 0–7% in pN3 patients, respectively (Table 10.1).11,12 Moreover, the prognosis of patients with lymph node metastases may vary according to different variables, such as number of positive lymph nodes, uni- or bilateral inguinal extension, pelvic node involvement, and the presence of extranodal extension.5,12-14 The 1997 TNM classification does not take into account the prognostic impact of the number of involved metastatic regional nodes. This parameter has been widely studied and there is an inverse correlation between the number of metastatic lymph nodes and 5-year cancer-specific survival. Recently, Pandey et al. showed 5-year cancer-specific survival rates of 75% in patients with 1–3 metastatic lymph nodes, 8.4% in patients with 4–5 metastatic nodes, and 0% in those with more than 5 nodes involved. In this last category of patients, the estimated 3-year survival rate was only 12.5%. The number of metastatic nodes was an independent prognostic factor in patients with lymph node-positive disease. The presence of metastasis in 4–5 nodes causes a 4.5-fold increase in the death risk (hazard ratio (HR) 4.598–95% confidence interval (CI) 1.256–16.830) compared to those patients harboring metastases in a lower number of lymph nodes. Moreover, the involvement of more than 5 nodes caused a 12-fold increase in the death risk (HR 12.06–95% CI 2.525–57.59), compared to the patients with less than 4 positive lymph nodes.12 Furthermore, the same study showed that patients with bilateral pathological lymph node involvement had a 2.6-fold higher risk of cancer-specific mortality compared to those with unilateral lymph node involvement.12 Leijte et al. proposed a modification to the current TNM classification distinguishing patients with mobile, unilateral lymph node involvement (N1) from those with bilateral involvement (N2). In their experience, this new classification allowed a more accurate stratification of patients with penile cancer in terms of cancer-specific survival.15 Another prognostic parameter which has not been correctly considered by the TNM classification is pelvic lymph node involvement. Currently, the N3 category
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includes both patients with deep inguinal and pelvic node extension. Patients with pelvic node metastases have a significantly lower survival rate compared to those with metastatic inguinal nodes only. Pandey et al. reported a 5-year survival of 64% in patients with inguinal metastases only and 0% in those with disease extending into the pelvic nodes. In this latter group, only 28% of patients were alive 2 years postsurgery and all of the patients died within 3 years of follow-up. In multivariate analysis, the presence of pelvic node metastases increased the risk of death by approximately 31 times (HR 31.68–95% CI 6.773–32.62) and predicted very poor survival rates. In common with other urological tumors, extranodal extension has a negative prognostic significance in penile cancer. The possible negative prognostic impact of this variable was originally reported in 1987 by Srinivas et al.13 and subsequently confirmed by Ravi in 1993.14 In the 98 patients with lymph node metastases studied by Ravi, extranodal extension was described in 17% of the cases. Specifically, all patients had >4 cm metastases and only one patient (5.8%) was alive after 5 years.14 More recent data have demonstrated that patients with extranodal extension had 2-, 3- and 5-year survival rates as low as 58%, 17.8%, and 8.9%, respectively, compared to 98%, 95%, and 90% in those patients without extranodal extension, respectively. The finding of extranodal extension was associated with a 9-fold higher risk of death (HR 9.206 –95% CI 2.598–32.62).12
10.3
Primary Tumor-Related Prognostic Factors
Approximately 12–24% of patients with penile cancer and nonpalpable lymph nodes will have occult micrometastases.16 This has been confirmed by the finding of lymph node disease progression in 9–21% of men undergoing surveillance for clinically nonpalpable inguinal nodes (cN0).17,18 Among the individuals who progressed during surveillance, 50% did so within 6 months, 77% within 1 year, and 100% within 2 years following treatment of the primary tumor.17 Early bilateral inguinal lymph node dissections have been shown to significantly improve prognosis in patients with inguinal micrometastases. However, this surgery is associated with major complications in 24–87% of cases and can result in death in 3%.19 For this reason, inguinal lymphadenectomy might be considered as an overtreatment in 75–90% of cases, where micrometastases are not present. In order to minimize overtreatment and the resultant morbidity investigators have sought to study the pathological and molecular features of the primary tumor with a view to predicting regional lymph node involvement. Histological subtype, local extension, grading, lymphatic and/or venous embolization, and perineural invasion within the primary tumor are the most important predictors of lymph node involvement in patients with penile cancer9,11. More controversial is the role of growth pattern, tumor thickness, and presence of HPV infection.
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10.4 10.4.1
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Clinical Factors Age
There is controversy regarding the influence of the patient’s age at diagnosis and the risk of disease progression to regional lymph nodes. In patients £50 years old, the percentage of lymph node metastases is 39–58%, which is similar to the rate of 48–52% in patients >50 years old.20-22 In 1996 Lopes et al. reported significantly different 5-year survival rates among patients £40, 41–60, and >60 years old of 64.5%, 59.6%, and 38.4%, respectively (p = 0.05).23 More recently, the same group have observed significant differences in univariate analysis between patients £50 and >50 years old, namely 61% and 41%, respectively (p = 0.002).20 In contrast, Lont et al. have reported 5-year survival rates of 78% in patients £60 and 85% in those >60 years old (p = 0.28).24 Recent data have demonstrated that age is an independent predictor of overall survival (HR 2.3–95% CI 1.0–5.1), as well as the presence of lymph node metastases (HR 3.2–95% CI 1.8–5.6) and pathological stage of the primary tumor (HR 1.9 – 95% CI 1.0–3.6).25
10.4.2
Clinical Stage of Primary Tumor
The latest version of the TNM staging system is more easily applicable in defining the pathological extension of the malignancy rather than elucidating the clinical stage of the tumor.7 In fact, the 1978 TNM version may be more adequate to define the clinical stage of the disease. According to this older classification, penile cancer might be classified into exophytic lesions £2 cm (T1); superficial lesions of 2–5 cm or with minimal depth invasion (T2); lesions >5 cm or with deep invasion (T3); neoplasms infiltrating adjacent structures (T4).26 Even though the major series have reported that the percentage of lymph node metastases increased with the local clinical stage, only Ficarra et al. have demonstrated that this clinical parameter was related to the risk of groin lymph node involvement in univariate analysis. Specifically, they found a percentage of inguinal metastases of 25% in cT1, 34% in cT2, and 66% in cT3-4. However, multivariate analysis has shown that this parameter had no independent prognostic role, because the only clinical prognostic factor able to independently predict inguinal metastases was the finding of palpable or fixed inguinal lymph nodes.3 More recently others have reported lymph node metastasis rates of 34–42% in cT2 and 48–52% in cT3-4.21,22 In terms of 5-year survival, the seminal study reporting statistically significant differences between the different clinical stages of the primary tumor was published in 1994 by Horenblas et al. These authors demonstrated a 5-year survival of 94% in cT1, 59% in cT2, and 52% in cT3-4 cancers.27 Generally, there is an increase in the proportion of lymph node involvement in patients with higher clinical stage, especially comparing cT1 and cT2-T3 cancers.
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Pathological Factors Primary Tumor Histological Subtypes
The WHO classification distinguishes the following histological subtypes: usual, basaloid, verrucous, warty, papillary, sarcomatoid, adenosquamous, and mixed squamous cell carcinoma (SCC).28 Some authors have reported a significant correlation between the WHO histological classification and the percentages of lymph nodes involved in addition to cancer-related mortality. Warty, verrucous, and papillary SCC of the penis are characterized by a relatively low tendency to metastasize to inguinal lymph nodes, ranging between 0–11% of cases. In contrast, sarcomatoid, basaloid, and adenosquamous SCC have an exceptionally high tendency to metastasize to regional lymph nodes with percentages ranging from 50% to 75%. The typical SCC has an intermediate behavior with a 25% risk of lymph node involvement. Mixed forms are similar to typical SCC. In typical SCC, regional lymph node involvement is mainly related to gross pathological features, such as pathological stage (>pT1), and depth of invasion (>6 mm).29 It should be noted that most published data refer to typical SCC, which represents the most frequent subtype of penile cancer. Hence, there is always a need to obtain adequate histological characterization of the primary tumor.
10.5.2
Primary Tumor Pathological Extension (pT)
In individuals with nonmetastatic disease, the prognostic importance of the pathological stage of the primary tumor is related to its association with the presence of occult metastases in nonpalpable inguinal lymph nodes. There is an unequivocally direct correlation between the local extension of the primary tumor and the risk of involvement of regional nodes. The presence of pathological lymph node involvement is 0–58% in pT1 tumors, 43–82% in pT2, and 50–100 in pT3 tumors.8 Recently, Lont et al. reported a 5-year survival of 95% in patients with pT1 penile cancer, which is significantly higher than the 74% observed for patients with pT2-3 disease (p = 0.003). In this particular investigation evaluating 176 patients, pathological stage of the primary tumor turned out to be an independent prognostic factor for survival (HR 4.0–95% CI 1.1–14.0), together with vascular embolization (HR 4.5–95% CI 1.4–14.6) and regional lymph node metastases (HR 7.0–95% CI 2.8–17.6).24 However, conflicting data had previously been reported. Bezerra et al. analyzed data from 82 patients, reporting 5-year cancerspecific survival rates of 80% in pT1, 62% in pT2, 64% in pT3, without any statistically significant difference amongst stages.10 Similarly, in 2002 Lopes et al. reported 5-year cancer-specific survival rates of 57% in pT1, 52% in pT2, and 49% in pT3 neoplasms.20 In 2008, Leijte et al. demonstrated that the current TNM classification required updating in order to better stratify the patients according to the local extension of
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Fig. 10.2 Well (a) and poorly (b) differentiated usual squamous cell carcinoma
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the primary tumor. They demonstrated that patients classified as pT2 did not have a different cancer-specific survival in comparison with those classified as pT3. For this reason, they proposed to reclassify patients with penile cancer distinguishing the cases with invasion of the corpus spongiosum (new pT2) from those with invasion of the corpora cavernosa (new pT3). Also, a new pT4 category was suggested, which would include tumors invading adjacent structures (including prostate). This proposed update of the pT stage allowed the authors to stratify patients with penile cancer into subgroups with significantly different prognoses.15
10.5.3
Histological Grade (G)
Penile cancer histological grading is usually assigned according to the classification published by Broders in 1921, defining grade 1 or well differentiated, grade 2 or moderately differentiated, and grade 3 or poorly differentiated tumors (Fig. 10.2 a, b).30
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The histological tumor grade was shown to be a powerful predictor of metastatic involvement of the regional lymph nodes. The proportion of patients with pathological lymph node involvement ranged from 0% to 48% in grade 1, from 30% to 79% in grade 2, and from 47% to 100% in grade 3 tumors.8 In 2001 Slaton et al. used the Broders classification in association with two further parameters: the percentage of poorly differentiated tumor and nuclear grades.31 As regards nuclear grade, it was possible to classify penile cancer into three different categories based on nuclear size, nucleolar polymorphism, and nucleus/cytoplasm ratio. The study showed that only a cut-off percentage £ or >50% of poorly differentiated tumor was related to significantly different percentages in inguinal metastases. No significant differences were observed between Broders or nuclear grading systems, but the study included only 48 patients.31 Most of the studies failed to identify statistically significant differences in 5-year cancer-specific survival across the different histological grades. Only Horenblas et al. showed significantly different 5-year survival rates among patients with grade 1 and grade 3 tumors (79% vs. 47%), respectively.27 More recent studies reported 5-year cancer-specific survival rates of 53–83% in welldifferentiated tumors and 47–74% in moderately and poorly differentiated ones.10,20,24
10.5.4
Lymphatic and Venous Embolization
Lymphatic embolization is defined as the presence of nests of carcinomatous cells in a lumen with thin walls, without smooth muscle fibers or red blood cells. The same condition with red blood cells or smooth muscle fibers is considered as venous embolization (Fig. 10.3a, b).10,23,32 Venous and lymphatic embolization are two important factors which are able to independently predict the presence of inguinal lymph node metastases.17,20 Patients without lymphatic embolization in the primary tumor demonstrate lymph node metastases in 17–30.6% of cases,20 whereas 62–83.3% of patients with lymphatic embolization have lymph node metastases. In all the published series such differences in the risk of lymph node metastases were statistically significant. Similarly, patients with venous embolization have lymph node metastases in 69–89%, significantly more than the 24–43.8% reported in patients without venous embolization. The presence of malignant emboli in peritumoral lymphatic vessels has a negative impact on the 5-year survival of penile cancer patients. In 2001, Bezerra et al. reported 5-year survival rates as high as 88% in patients without lymphatic embolization and 55% in those with this feature (p = 0.004).10 Similar results were reported by Lopes et al. in 2002 when these authors reported 5-year cancer-specific survival in 65% of patients without and 41.5% in those with lymphatic embolization (p = 0.004).20 However, this parameter failed to be an independent predictor of cancer-specific survival in multivariate analysis.
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Fig. 10.3 Penile cancer with lymphatic embolization (a) or vascular embolization (b)
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As regards the impact of venous embolization on survival, Bezerra et al. reported 5-year survival of 73.7% in patients without and 52% in those with venous embolization10 while Lopes et al. in 2002 reported 5-year survival of 56% and 38%, respectively, in those without and with venous embolization.20 Lont et al. reported 5-year cancer-specific survival rates of 83% in patients without and 69% in those with venous embolization.24 Such differences were not significant even in univariate analysis.
10.5.5
Perineural Invasion
Perineural invasion is defined by the presence of tumoral nests composed of poorly differentiated neoplastic cells in the perineural space. Recently, Chaux et al. highlighted that perineural invasion was an independent predictor of pathological lymph node involvement together with histological grades. As a result of this observation,
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the presence/absence of perineural invasion was included in a prognostic index designed to predict the presence of nodal metastases in patients with penile cancer. Perineural invasion was not shown to be an independent predictor of cancer-specific survival.33 Although this parameter should be taken into consideration by pathologists and reported in the final histopathological evaluation, its prognostic role needs to be elucidated in further studies.
10.5.6
Tumor Thickness
Tumor thickness is usually measured from the top of the tumor to the deepest tumor cell and reported in mm.31 Its ability to predict node involvement is controversial. The percentage of metastatic nodes reported ranged from 22% to 44%, in patients with tumor thickness £5 mm and from 38% to 57% in those with tumor thickness >5 mm. Velazquez et al. studied 134 patients with a tumor thickness of 5–10 mm and in this group of patients they reported that the high-grade tumors with perineural involvement were those with the highest risk of node involvement.33 Five-year cancer-specific survival rates were reported to be 56–78% in patients with tumor thickness £5 mm and 48–64% in those >5 mm.
10.5.7
Growth Pattern
The growth pattern in penile cancer can be classified into verrucous, superficial, and vertical patterns (Fig. 10.4a, b).34 In 1997 Villavicencio et al. reported inguinal metastases in no patients with verrucous tumors, in 35% of those with superficial, and in 100% of those with vertical growth patterns (p = 0.0009). Similarly, they reported significantly better survival in patients with superficial compared to those with vertical growth tumors (p = 0.0004). In contrast, survival was similar in patients with verrucous and superficial growth pattern tumors.9 An interesting study was peformed in 2006 by Guimaraes et al. 21 These authors classified their patients according to the classification proposed by Anneroth et al.35 and Bryne et al.36 for oral cavity squamous cell cancers. This classification describes the pattern of invasion at the tumor–host interface and therefore demonstrates the infiltrative characteristics of the neoplasm. This pattern was defined as either infiltrating (invasion in blocks of small solid strands of cells broadly infiltrating the organ’s stroma) or pushing (tumor cells invading large cell blocks with well-defined tumor–host interfaces). Patients with an infiltrating pattern of invasion had node metastases in 64.6%, significantly higher than the 23% reported in patients with a pushing pattern of invasion (p < 0.001). This pathological parameter was an independent predictor of node involvement (HR 4.18–95% CI 1.5–11.3), as well as lymphatic embolization (HR 3.95–95% CI 1.5–10.4) and clinical lymph node stage (HR 3.85–95% CI 1.4–10).21
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Fig. 10.4 Vertical (a) and superficial (b) growth pattern according to Cubilla classification
10.5.8
Human Papilloma Virus (HPV) Infection
HPV infection occurs in 15–85% of cases of SCC penis. HPV-16 and 18 are the most frequently detected types. Specifically, HPV-16 is present in 25–95% of cases and HPV-18 in the remaining 5–75% of the cases. Rarely, other HPV types are detected in penile cancer.37 In contrast to the established role of HPV as a risk factor, little is known about its prognostic significance in penile SCC. In 1992 Wiener et al. documented no significant difference in survival between patients with HPV-positive and those with HPVnegative tumors.38 Bezerra et al. in 2001 hypothesized that the presence of HPV DNA in the primary tumor could have a prognostic impact. Their study showed node metastases in 73.8% of HPV-negative and 26.2% of HPV-positive tumors, but such a difference was not statistically significant (p = 0.38). They also failed to observe significant survival differences between the two groups of patients.10 Similar results were reported by Lopes et al. in a series of 82 patients who had undergone penectomy and inguinal lymph node dissection. In this series HPV-positive tumors had inguinal metastases in 44% of cases, compared to 54.4% in HPV-negative tumors. Moreover, 5-year cancer-specific survival rates were 44.7% and 53.1%, respectively (p = 0.271).20 A more recent study was conducted in the Netherlands on 171 patients treated for penile cancer between 1963 and 2001. Positive lymph nodes were found in 71% of HPV-negative patients and 29% of HPV-positive ones (p = 0.90).24 Also, Protzel et al. did not find any correlation between the presence of HPV DNA and node involvement.39
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Table 10.2 Stratification of patients with penile cancer combining pathological extension (pT) and grading (G) of primary tumor Risk group Solsona et al. classification49 EAU classification2 Ornellas et al.30 Low Tis/Ta/T1G1 Tis - TaG1-2 - T1G1 T1G1, T1G2 Intermediate T1G2-3 or T2-3G1 T1G2 T2-3G1, T2-3G2 High T2-T3G2-3 T2-T3 or G3 T1-2G3, T4G1-3
Concerning cancer-specific survival, Lont et al. reported 5-year cancer-specific survival rates of 92% for HPV-positive and 78% for HPV-negative patients (p = 0.03). In this study, HPV was able to predict survival regardless of primary tumor pathological stage, venous embolization, and regional lymph node involvement.24 Currently, there is no scientific explanation concerning why HPV-negative patients should have lower cancer-specific survivals.
10.6 10.6.1
Integrated Prognostic Models Solsona et al. and European Association of Urology (EAU) Risk Groups
The risk of regional lymph node involvement can be estimated in a more accurate fashion combining the information provided by the pathological stage and the histological grading of the primary tumor (Table 10.2). In 1992 Solsona et al. proposed a stratification of penile cancer patients into 3 groups, each with a different risk for inguinal node involvement, combining the pathological stage and histological grade of the primary tumor. Patients with pT1/grade 1 disease were classified as low risk of node involvement; those with pT1/grade 2–3 and pT2/grade 1 as intermediate risk; those with pT2/grade 2–3 or ³pT3 as high risk. The percentage of node metastases in the 3 groups was 0%, 36.4%, and 80%, respectively.40 This classification was validated in 2001 by the same group in a prospective series of 37 patients where the percentage of inguinal metastases was 0% in low-risk, 33% in intermediate-risk, and 83% in high-risk groups.41 The ability of the Solsona et al. classification to stratify patients with penile cancer according to the different risk of inguinal lymph node metastases was recently confirmed in an Italian multicentre study analyzing 175 patients observed between 1980 and 2002. In this study, lymph node metastases were observed in 4% of low-risk, 29.1% in intermediate-risk, and 53.5% in high-risk patients (p < 0.001).17 The expert panel drafting the EAU guidelines proposed a similar but slightly different classification to that by Solsona et al. in 1992. Specifically, patients were classified as low risk in cases of pTis, pTaG1-2, pT1G1 disease; as intermediate risk in case of pT1G2 tumors; as high risk in case of ³pT2 or G3 cancer.42 The risk of inguinal metastases according to the EAU classification was 4% in low-risk, 34.8% in intermediate-risk, 45.8% in high-risk patients.17
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Nevertheless, a recently published study by Novara et al. showed that both the Solsona et al. and the EAU risk groups have a low prognostic accuracy. In this study the receiver operating characteristic (ROC) curves showed values of 0.697 (95% CI 0.618–0.777) for the Solsona et al. classification and 0.632 (95% CI 0.548–0.715) for the EAU one.43 Ornellas et al. recently proposed a new classification of penile cancer patients into 3 different risk groups according to primary tumor pathological stage and histological grade. Patients were defined as low risk in cases of T1G1-2 tumor; as intermediate risk in T2G1-2 or T3G1-2 disease; as high risk in case of T1-3G3 or T4G1-3 cancer. The authors observed a significant difference in terms of 10-year cancer-specific survival between low and intermediate-risk patients (p = 0.01) and between intermediate- and high-risk patients (p < 0.001).31
10.6.2
Nomograms
Nomograms are mathematical predictive models integrating prognostic information arising from the main clinical and/or pathological variables, thus improving their prognostic accuracy. The first nomograms concerning penile cancer were published by Ficarra and Kattan in 2006. Three nomograms were published with the aim of predicting inguinal lymph node involvement44 and 5-year cancer-specific survival of penile cancer patients.45 More recently, Baghat et al. proposed a similar nomogram again with a view to predicting the probability of positive lymph nodes.46 The Ficarra nomogram44 was generated to predict lymph node involvement in penile cancer patients, integrating data from eight different clinical and pathological variables (clinical inguinal lymph node stage, pathological tumor thickness, growth pattern, histological grade, lymphatic and/or venous embolization, corpora cavernosa infiltration, corpus spongiosum, and/or urethral infiltration) (Fig. 10.5). This integrated staging system demonstrated excellent prognostic accuracy, with an AUC of the ROC curves of 0.876 and good calibration.44 Although, the use of this nomogram in clinical practice is potentially limited by the lack of external validation, the panel of international consultation on penile cancer proposed to use it to stratify patients with penile cancer in three different risk groups. The low-risk category includes patients who have a probability of positive nodes of 0–-10%; the intermediate-risk category includes cases with a probability of involved nodes ranging between 11% and 50% and the high-risk group includes cases with a probability greater than 50%. The international consultation on penile cancer recommended a different management of inguinal lymph nodes according to this risk-group stratification.47 In 2006, Kattan et al. proposed two nomograms which were able to estimate 5-year cancer-specific survival in penile cancer patients.45 In the first model, the 5-year cancer-specific survival probabilities were estimated according to clinical stage of the inguinal lymph nodes and the pathological findings of the primary tumor after partial or total penectomy (tumor thickness, growth pattern, grade, venous and/or lymphatic embolization, corpora cavernosa infiltration, corpus spongiosum
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Fig. 10.5 Ficarra nomogram predicting the probability of inguinal lymph node metastases
infiltration, and urethra infiltration). The concordance index of this first model was 0.728. This model, which also showed good calibration, may be used to estimate survival probabilities after surgery for the primary tumor, regardless of locoregional lymph node management (Fig. 10.6). In the second model, the 5-year cancer-specific survival probabilities were estimated according to the pathological findings of the primary tumor after partial or total penectomy and the pathological stage of inguinal lymph nodes after lymphadenectomy. This model may be useful for patients undergoing either inguinal lymphadenectomy (pN0/pN+) or watchful waiting (NX) to plan the most appropriate follow-up schedule and to identify patients who need adjuvant therapy to improve their outcome (Fig. 10.7).45 In 2009, Baghat et al. proposed a new nomogram to predict the probability of positive lymph nodes using only four parameters: age of patients at diagnosis, clinical inguinal lymph node status, histologic grade, and absence or presence of lymphovascular invasion (Fig. 10.8).46 This nomogram could be considered both as a simplified version and as the first external validation of the Ficarra nomogram. The authors reported a concordance index of 0.74 significantly inferior to those reported by Ficarra et al. in the first nomogram predicting lymph node involvement in penile cancer.
10.6.3
Penile Cancer Prognostic Index
In 2009 Chaux et al. proposed a new integrated pathological tool to predict lymph node involvement and survival in patients with penile SCC. This system included
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Fig. 10.6 Kattan Nomogram predicting 5-year cancer-specific survival according to pathological findings of primary tumor and clinical stage of lymph nodes
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Fig. 10.7 Kattan Nomogram predicting 5-year cancer-specific survival according to pathological findings of primary tumor and pathological stage of lymph nodes
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Fig. 10.8 Bhagat nomogram predicting the probability of positive lymph node according to clinical lymph nodes status, presence of lymphatic or venous embolization, grading and age of the patients (With kind permission from Springer Science + Business Media57)
histological grade (grade 1: 1 point; grade 2: 2 points; grade 3: 3 points), perineural invasion (absent: 0 points; present: 1 point), and anatomical level of infiltration. This last parameter considered the infiltration of lamina propria (level 1: 1 point), corpus spongiosum/dartos (level 2: 2 points), and corpus cavernosum/preputial skin (level 3: 3 points). The index significantly correlated to tumor thickness, perineural invasion, and vascular invasion but not to the presence of urethral invasion. Interestingly, the prognostic index score significantly correlated with the percentage of inguinal nodal metastases. Specifically, patients with score 2–4 had a 0–20% risk of lymph node involvement, while patients with score 5–7 showed a 50–79% risk of nodal metastases. Similarly, using survival analysis data, the Prognostic Index allows one to distinguish between three different groups with good (index 2–4), intermediate (index 5–6), and poor (index 7) prognoses.33 The concordance index of this index was not reported by the authors and therefore it is not possible to compare the prognostic accuracy of this tool with those calculated for previous nomograms. Table 10.3 shows the included variables and the prognostic accuracy of different available integrated systems.
10.7
Molecular Factors
p53 is a tumor-suppressor gene located on the short arm of chromosome 17. Alterations in this gene have been implicated in the pathogenesis of many tumors. However, it was not until 2002 that Lopes et al. evaluated, for the first time, the
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Table 10.3 Variables and prognostic accuracy of different integrated systems to predict pathological lymph node involvement (NA - not available) Variables pT Grading Vascular embolization Perineural invasion Tumor thickness Growth pattern Anatomical infiltration Age Clinical N stage Concordance index
Solsona EAU Ornellas risk-groups risk-groups risk-groups
Ficarra nomogram
Bhagat Prognostic nomogram index
Y Y N
Y Y N
Y Y N
Y Y N
N Y Y
N Y N
N N N N
N N N N
N N N N
Y Y Y N
N N N N
Y N N Y
Y N 0.697
Y N 0.632
Y N NA
Y Y 0.876
Y Y 0.740
Y N NA
prognostic significance of p53 in patients with penile SCC. The group demonstrated positive inguinal lymph nodes in 39.6% of p53-negative and 67.6% of p53-positive patients (p = 0.01). In multivariate analysis p53 was an independent predictor of inguinal lymph node metastases.20 In a more recent article,, Zhu et al. observed metastatic node disease in 29% of patients with low p53 expression and in 67% of those with high p53 expression. Additionally, in this study, p53 was an independent predictor of node metastases, together with the presence of lymphatic and venous emboli.47 The same investigators noted 3-year cancer-specific survival rates of 87% in men with low p53 levels and 41% in those with high p53 (p < 0.001) and p53 was subsequently reported to be an independent predictor of cancerspecific survival (p = 0.01). E-cadherins are a type of intercellular cell adhesion molecule. Decrease in expression of E-cadherins promotes invasion and the development of metastatic disease.49 Low E-cadherin expression has been correlated with the risk of metastases in several malignancies. In 2007 Zhu et al. reported 28% of patients with node metastases among those with high E-cadherin expression and 58% of patients among those with low E-cadherin levels (p = 0.0009), but this variable was not associated with lymph node involvement.48 Additionally, Campos et al. showed that low E-cadherin levels were not independent predictors of survival at multivariable analysis.22 MMP-2 and MMP-9 are part of a group of enzymes that degrade type IV collagen in the basement membrane and are involved in the invasion mechanism.50 In relation to disease-free survival, Campos et al. identified high MMP-9 expression as an independent predictor of disease recurrence (HR 3.2–95% CI 1.2–8.3), as well as distant metastases (HR 57.9– 95%CI 7.4–453.9), and urethral infiltration (HR 3.5– 95%CI 1.3–9.2).22 Conversely, Zhu et al. observed a significant 3-year cancer-specific survival difference between patients with low and high MMP-9 expression (p = 0.006), but this result was not confirmed in multivariate analysis.48 Ki-67 is a nonhistone nuclear matrix protein expressed in all cell-cycle phases except G0 and thus Ki-67 protein expression (assessed, for example, by immunohistochemistry)
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is a reliable tool to evaluate tumor cell proliferation. Most authors have not demonstrated any significant correlation between Ki67 expression and pathological lymph node involvement or patient survival.48,51 In contrast, Guimaraes et al. observed a positive correlation between MIB-1/Ki-67 overexpression (>10%) and the presence of inguinal metastases.25 Similar conclusions were drawn by Protzel et al., who reported lymph node metastases in 0% of patients with Ki-67 <15%, whereas lymph nodes were positive in 53% of those with Ki-67 between 15% and 60%, and in 100% of those with Ki-67 over 60% (p = 0.005).39 Proliferating cell nuclear antigen (PCNA) has been rarely evaluated in penile cancer. Guimaraes et al. showed that node metastases were present in 31.7% of PCNA-negative and 50% of PCNA positive patients. In multivariate analysis, PCNA was an independent predictive factor for node involvement together with lymphatic and/or vascular embolization, lymph node clinical stage, and MIB-1/Ki-67 absence. However, PCNA was not an independent predictor of overall or diseasefree survival.25 The cell membrane protein KAI11 (“Kang ai” = Chinese for “anti-cancer”) was originally demonstrated as a metastasis suppressor gene in prostate cancer.52 Downregulation of KAI11/CD82 is associated with the development of metastases and poor prognosis in several carcinomas.53-55 Protzel et al. found that all patients with reduced or absent KAI11/CD82 expression had inguinal lymph node metastases (p = 0.0002). Moreover, they reported a significant overall survival advantage in patients expressing more than 50% of these suppressor proteins.56 In conclusion, the tumor suppressor gene p53, E-cadherin and matrix metalloproteinases (MMP) 2 and 9, Ki-67, proliferating cell nuclear antigen (PCNA) and cell membrane protein KAI11 are the most extensively studied and promising molecular prognostic factors used in predicting the risk of lymph node involvement in patients with penile cancer. As a result of the conflicting results available in the literature and, above all, the limited number of cases included in the studies, the panel of the international consultation on penile cancer have recommended their use as only investigational tools for the moment.
References 1. Velazquez EF, Soskin A, Bock A, Codas R, Barreto JE, Cubilla AL. Positive resection margins in partial penectomies: sites of involvement and proposal of local routes of spread of penile squamous cell carcinoma. Am J Surg Pathol. 2004;28:384-389. 2. Rippentrop JM, Joslyn SA, Konety BR. Squamous cell carcinoma of the penis: evaluation of data from the surveillance, epidemiology, and end results program. Cancer. 2004;101(6): 1357-1363. 3. Hakenberg OW, Wirth MP. Issues in the treatment of penile carcinoma. A short review. Urol Int. 1999;62(4):229-233. 4. Ornellas AA, Seixas AL, Marota A, et al. Surgical treatment of invasive squamous cell carcinoma of the penis: retrospective analysis of 350 cases. J Urol. 1994;151(5):1244-1249. 5. Horenblas S, van Tinteren H, Delemarre JF, et al. Squamous cell carcinoma of the penis. III. Treatment of regional lymph nodes. J Urol. 1993;149(3):492-497.
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6. Bouchot O, Auvigne J, Peuvrel P, et al. Management of regional lymph nodes in carcinoma of the penis. Eur Urol. 1989;16(6):410-415. 7. Pizzocaro G, Piva L, Bandieramonte G, et al. Up-to-date management of carcinoma of the penis. Eur Urol. 1997;32(1):5-15. 8. Ficarra V, Akduman B., Bouchot O., Palou J., Tobias-Machado M. Prognostic factors in penile cancer. In: Pompeo AC, Heyns CF, Abrams P, eds. Penile Cancer. International Consultation on Penile Cancer, Edition 2009. 9. Villavicencio H, Rubio-Briones J, Regalado R, et al. Grade, local stage and growth pattern as prognostic factors in carcinoma of the penis. Eur Urol. 1997;32(4):442-447. 10. Bezerra AL, Lopes A, Santiago GH, et al. Human papillomavirus as a prognostic factor in carcinoma of the penis: analysis of 82 patients treated with amputation and bilateral lymphadenectomy. Cancer. 2001;91(12):2315-2321. 11. Novara G, Galfano A, De Marco V, et al. Prognostic factors in squamous cell carcinoma of the penis. Nat Clin Pract Urol. 2007;4(3):140-146. 12. Pandey D, Mahajan V, Kannan RR. Prognostic factors in node-positive carcinoma of the penis. J Surg Oncol. 2006;93(2):133-138. 13. Srinivas V, Morse MJ, Herr HW, et al. Penile cancer: relation of extent of nodal metastasis to survival. J Urol. 1987;137(5):880-882. 14. Ravi R. Correlation between the extent of nodal involvement and survival following groin dissection for carcinoma of the penis. Br J Urol. 1993;72(5 Pt 2):817-819. 15. Leijte JA, Gallee M, Antonini N, Horenblas S. Evaluation of current TNM classification of penile carcinoma. J Urol. 2008;180:933-938. 16. Misra S, Chaturvedi A, Misra NC. Penile carcinoma: a challenge for the developing world. Lancet Oncol. 2004;5(4):240-247. 17. Ficarra V, Zattoni F, Cunico SC, et al. Gruppo Uro-Oncologico del Nord Est (Northeast Uro-Oncological Group) Penile Cancer Project. Lymphatic and vascular embolizations are independent predictive variables of inguinal lymph node involvement in patients with squamous cell carcinoma of the penis: Gruppo Uro-Oncologico del Nord Est (Northeast Uro-Oncological Group) Penile Cancer data base data. Cancer. 2005;103(12):2507-2516. 18. Leijte JA, Kirrander P, Antonini N, et al. Recurrence patterns of squamous cell carcinoma of the penis: recommendations for follow-up based on a two-centre analysis of 700 patients. Eur Urol. 2008;54(1):161-168. 19. Horenblas S. Lymphadenectomy for squamous cell carcinoma of the penis. Part 2: the role and technique of lymph node dissection. BJU Int. 2001;88(5):473-483. 20. Lopes A, Bezerra AL, Pinto CA, et al. p53 as a new prognostic factor for lymph node metastasis in penile carcinoma: analysis of 82 patients treated with amputation and bilateral lymphadenectomy. J Urol. 2002;168(1):81-86. 21. Guimarães GC, Lopes A, Campos RS, et al. Front pattern of invasion in squamous cell carcinoma of the penis: new prognostic factor for predicting risk of lymph node metastases. Urology. 2006;68(1):148-153. 22. Campos RS, Lopes A, Guimarães GC, et al. E-cadherin, MMP-2, and MMP-9 as prognostic markers in penile cancer: analysis of 125 patients. Urology. 2006;67(4):797-802. 23. Lopes A, Hidalgo GS, Kowalski LP, et al. Prognostic factors in carcinoma of the penis: multivariate analysis of 145 patients treated with amputation and lymphadenectomy. J Urol. 1996;156(5): 1637-1642. 24. Lont AP, Kroon BK, Horenblas S, et al. Presence of high-risk human papillomavirus DNA in penile carcinoma predicts favorable outcome in survival. Int J Cancer. 2006;119(5):1078-1081. 25. Guimarães GC, Leal ML, Campos RS, et al. Do proliferating cell nuclear antigen and MIB-1/ Ki-67 have prognostic value in penile squamous cell carcinoma? Urology. 2007;70(1):137-142. 26. Harmer MH. Penis (ICD-0187). In: TNM Classification of Malignant Tumours, 3rd ed. Geneva: International Union Against Cancer, pp. 126, 1978. 27. Horenblas S, van Tinteren H. Squamous cell carcinoma of the penis. IV. Prognostic factors of survival: analysis of tumor, nodes and metastasis classification system. J Urol. 1994;151(5): 1239-1243.
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28. Guimaraes GC, Cunha IW, Soares FA, et al. Penile squamous cell carcinoma clinicopathological features, nodal metastasis and outcome in 333 cases. J Urol. 2009;182:528-534. 29. Dai B, Ye DW, Kong YY, et al. Predicting regional lymph node metastasis in Chinese patients with penile squamous cell carcinoma: the role of histopathological classification, tumor stage and depth of invasion. J Urol. 2006;176(4 Pt 1):1431-1435. 30. Broders AC. Squamous-cell epithelioma of the skin: a study of 256 cases. Ann Surg. 1921;73(2): 141-160. 31. Slaton JW, Morgenstern N, Levy DA, et al. Tumor stage, vascular invasion and the percentage of poorly differentiated cancer: independent prognosticators for inguinal lymph node metastasis in penile squamous cancer. J Urol. 2001;165(4):1138-1142. 32. Ficarra V, Maffei N, Piacentini I, et al. Local treatment of penile squamous cell carcinoma. Urol Int. 2002;69(3):169-173. 33. Chaux A, Caballero C, Soares F, Guimaraes GC, Cunha IW, Reuter V, Barreto J, Rodriguez I, Cubilla AL. The prognostic index: a useful pathologic guide for prediction of nodal metastases and survival in penile squamous cell carcinoma. Am J Surg Pathol. 2009 Apr 18. 34. Cubilla AL, Barreto J, Caballero C, et al. Pathologic features of epidermoid carcinoma of the penis. A prospective study of 66 cases. Am J Surg Pathol. 1993;17(8):753-763. 35. Anneroth G, Batsakis J, Luna M. Review of the literature and a recommended system of malignancy grading in oral squamous cell carcinomas. Scand J Dent Res. 1987;95(3):229-249. 36. Bryne M, Koppang HS, Lilleng R, et al. New malignancy grading is a better prognostic indicator than Broders’ grading in oral squamous cell carcinomas. J Oral Pathol Med. 1989;18(8): 432-437. 37. Wiener JS, Effert PJ, Humphrey PA, et al. Prevalence of human papillomavirus types 16 and 18 in squamous-cell carcinoma of the penis: a retrospective analysis of primary and metastatic lesions by differential polymerase chain reaction. Int J Cancer. 1992;50(5):694-701. 38. Minhas S, Manseck A., Hegarty P., Watya S. Prevention and premalignant conditions. In: Pompeo AC, Heyns CF, Abrams P, Eds. Penile Cancer. International Consultation on Penile Cancer, Edition 2009. 39. Protzel C, Knoedel J, Zimmermann U, et al. Expression of proliferation marker Ki67 correlates to occurrence of metastasis and prognosis, histological subtypes and HPV DNA detection in penile carcinomas. Histol Histopathol. 2007;22(11):1197-1204. 40. Solsona E, Iborra I, Ricós JV, et al. Corpus cavernosum invasion and tumor grade in the prediction of lymph node condition in penile carcinoma. Eur Urol. 1992;22(2):115-118. 41. Solsona E, Iborra I, Rubio J, et al. Prospective validation of the association of local tumor stage and grade as a predictive factor for occult lymph node micrometastasis in patients with penile carcinoma and clinically negative inguinal lymph nodes. J Urol. 2001;165(5):1506-1509. 42. Solsona E, Algaba F, Horenblas S, et al. European Association of Urology. EAU Guidelines on Penile Cancer. Eur Urol. 2004;46(1):1-8. 43. Novara G, Artibani W, Cunico SC, et al. GUONE Penile Cancer Project. How accurately do Solsona and European Association of Urology risk groups predict for risk of lymph node metastases in patients with squamous cell carcinoma of the penis? Urology. 2008;71(2): 328-333. 44. Ficarra V, Zattoni F, Artibani W, G.U.O.N.E. Penile Cancer Project Members, et al. Nomogram predictive of pathological inguinal lymph node involvement in patients with squamous cell carcinoma of the penis. J Urol. 2006;175(5):1700-1704. 45. Kattan MW, Ficarra V, Artibani W, et al. GUONE Penile Cancer Project Members. Nomogram predictive of cancer specific survival in patients undergoing partial or total amputation for squamous cell carcinoma of the penis. J Urol. 2006;175(6):2103-2108. 46. Bhagat SK, Gopolakrishnan G, Kekre NS, Chacko NK, Manipadam MT, Samuel P. Factors predicting inguinal node metastasis in squamous cell cancer of penis. World J Urol. 2009 Jun 2. 47. Heyns C, Fleshner N, Sangar V, Schlenker B, Thyavihally Y, van Poppel H. Management of the lymph nodes in penile cancer. In: Pompeo AC, Heyns CF, Abrams P, eds. Penile Cancer. International Consultation on Penile Cancer, Edition 2009.
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48. Zhu Y, Zhou XY, Yao XD, et al. The prognostic significance of p53, Ki-67, epithelial cadherin and matrix metalloproteinase-9 in penile squamous cell carcinoma treated with surgery. BJU Int. 2007;100(1):204-208. 49. Behrens J, Mareel MM, Van Roy FM, et al. Dissecting tumor cell invasion: epithelial cells acquire invasive properties after the loss of uvomorulin-mediated cell-cell adhesion. J Cell Biol. 1989;108(6):2435-2447. 50. Egeblad M, Werb Z. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer. 2002;2(3):161-174. 51. Berdjis N, Meye A, Nippgen J, et al. Expression of Ki-67 in squamous cell carcinoma of the penis. BJU Int. 2005;96(1):146-148. 52. Dong JT, Lamb PW, Rinker-Schaeffer CW, et al. KAI1, a metastasis suppressor gene for prostate cancer on human chromosome 11p11.2. Science. 1995;268(5212):884-886. 53. Son BH, Choi JS, Lee JH. Prognostic values of KAI1 and survivin expression in an infiltrating ductal carcinoma of the breast. Pathology. 2005;37(2):131-136. 54. Yang X, Wei L, Tang C, et al. KAI1 protein is down-regulated during the progression of human breast cancer. Clin Cancer Res. 2000;6(9):3424-3429. 55. Zheng H, Tsuneyama K, Cheng C, et al. Expression of KAI1 and tenascin, and microvessel density are closely correlated with liver metastasis of gastrointestinal adenocarcinoma. J Clin Pathol. 2007;60(1):50-56. 56. Protzel C, Kakies C, Kleist B, et al. 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. Virchows Arch. 2008;452(4):369-375. 57. Bhagat SK, Gopolakrishnan G, Kekre NS, Chacko NK, Manipadam MT, Samuel P. Factors predicting inguinal node metastasis in squamous cell cancer of penis. World J Urol. 2010;28(1):93-98.
Chapter 11
Phallic Reconstruction Following Surgery for Penile Cancer David J. Ralph
11.1
Introduction
Penile amputation for penile cancer, whether partial, subtotal or total, is a necessary step for local control of primary tumors in cases whereby penile preserving surgery is deemed inappropriate. This often has a significant functional and psychological impact on the patient and his partner with an inevitable impact on the quality of life. Whereas the majority of patients presenting with penile cancer are elderly, sexually inactive and happy to sit down in order to void, there are others who would like to regain some normality of urinary and sexual function. These patients may be candidates for a total phallic reconstruction and a discussion of this option should be undertaken with the patient at an early stage. Patients are often devastated at the thought of penile amputation and if some comfort can be given to them by showing them examples of the long-term surgical results, or better still to see and meet other patients who have had the operation performed, then this will give them hope for the future and make the overall management less stressful. It is also important surgically, to identify early, those patients who wish to potentially have a phallic reconstruction as the decision may influence the surgical technique of the primary amputation or inguinal lymphadenectomy in order to aid the phallic reconstruction. It is much preferred to use the patient’s own healthy tissues where possible than to refashion with alternative techniques. Examples of this forward thinking approach are: • In subtotal amputation maintain as much healthy urethra by suturing it flush to the lower abdomen rather than performing a perineal urethrostomy (Fig. 11.1). • In total amputation leave as much proximal corpora to house the rear tips of the penile prosthesis
D.J. Ralph Department of Urology, Institute of Urology, University College Hospital, London, UK A. Muneer et al. (eds.), Textbook of Penile Cancer, DOI 10.1007/978-1-84882-879-7_11, © Springer-Verlag London Limited 2012
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Fig. 11.1 Subtotal penectomy with sparing of urethra ready for phalloplasty
• During inguinal lymphadenectomy, spare the long saphenous vein so that it can be used for the venous anastomosis of a subsequent free flap • If an abdominal phalloplasty is preferred, then it may be better to do this prior to any radical lymphadenectomy in order to preserve the blood supply to the flap.
11.2
Historical Considerations
Phallic reconstruction poses a difficult challenge for the penile cancer surgeon. The main goals of surgery are the creation of a cosmetically acceptable sensate neophallus with the incorporation of a neourethra to allow voiding standing up and with enough bulk to allow the insertion of a penile prosthesis in order to allow sexual intercourse.1 The classic method of penis reconstruction involved the use of abdominal flaps. The first total phallic reconstruction was attempted in 1936 by Bogoras who used a random pedicled oblique abdominal singular tube without incorporating a neourethra. Phallic rigidity was obtained by the insertion of a rib cartilage inside the flap.2 Matz and Gillies subsequently improved Bogoras’s technique by creating a phallus which incorporated a urethra using the “tube within a tube” concept. These procedures were multistaged, resulted in extensive scarring and disfigurement of the donor area, and produced a phallus with no sensation.3,4 These types of phalloplasty are currently used for salvage cases only. Further advances involved the use of infraumbilical skin and groin flaps.5-10 However, the main limitation of these techniques were the formation of a nonsensate and wedge-shaped phallus. Musculocutaneous thigh flaps, used when there is extensive abdominal scarring from previous surgery or radiotherapy, also have been abandoned due to poor results.11-16 With the advent of microsurgical techniques, a new era has started for total phallic reconstruction. Originally described by Song in 1982,17 the use of the radial arteryfree flap phalloplasty was first published in 1984 by Chang who successfully used this technique for total penile reconstruction in seven patients who had previously
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undergone a penile amputation.16 The reconstructive procedure involved the creation of ‘a tube within a tube’ using forearm skin with the urethra fashioned from the nonhair-bearing area and the whole flap based on the radial artery. Following the success of this series many teams have adopted this technique and applied some modifications in flap design in order to improve the cosmesis of the neophallus and to minimize the overall complication rate and donor site morbidity that may occur in 45% of cases.18 In particular the shape of the forearm flap has been modified in order to improve the blood supply to the flap and to reduce the risk of meatal stenosis.19-24 Ulnar artery-based flaps which reduce the amount of hair-bearing skin incorporated have also been used.25 Partial or subtotal penectomy for carcinoma of the penis or urethra results in a significant loss in sexual function. Patient satisfaction with their overall sexual life is less than 34% and therefore they represent the ideal candidates for total phallic reconstruction.26-28 The current types of phalloplasty that are used are: 1. The forearm free flap based on the radial artery (RAP) 2. The pedicled abdominal phalloplasty 3. The anterolateral thigh flap (ALT) All have their advantages and disadvantages and will be discussed in turn below.
11.3
The Radial Artery Forearm Flap Phalloplasty
This is often considered the gold standard phalloplasty as it allows the formation of a cylindrical and sensate phallus with a urethra that reaches the tip and which is less prone to complications. The disadvantage is that it leaves a considerable donor site defect on the arm which some patients find unacceptable. The nondominant forearm is used in all patients having checked the vascular competency of the superficial and deep palmar arteries with an Allen test followed by a duplex ultrasound study when there is doubt. Patients can have preoperative laser hair removal from the forearm in order to improve the cosmesis if they wish. The total phallic reconstruction is achieved with a modified Chang flap16 utilizing the following stages: 1. Creation of the phallus with competent neourethra and its microvascular transfer to the recipient site with a primary urethral anastamosis 2. Sculpture of the glans according to the Norfolk technique.15 The reservoir of a 3 piece inflatable penile implant can be inserted at this stage. 3. Insertion of a penile implant into the phallus. Each stage is performed at a minimum of 3 monthly intervals with complications of one stage being additionally dealt with to reduce the overall number of operations.
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Fig. 11.2 Flap dimensions: 4 × 16 cm for the urethra (U) and 15 × 14 cm for the phallus (P)
The forearm free flap is raised from the non-dominant arm; to minimize blood loss the procedure is performed under tourniquet compression of a maximum of 2 h of inflation time. The size of the flap varies according to the dimensions of the forearm, the length of the urethral stump, and to the patient’s expectations. The flap is separated longitudinally in two portions by a 1 cm wide strip of de-epithelialized skin to reduce fistula formation. The medial portion, obtained from the relatively hairless medial aspect of the forearm, is typically 4 × 16 cm and forms the neourethra while the lateral portion, which is usually 15 cm long and has a width of 14 cm at the base and 11 cm at the tip, will form the phallus. The flap is based on the radial artery, which is dissected to its origin with the brachial artery. The venous drainage is usually based on the cephalic vein, the venae comitantes of the radial artery, and flap veins. Sensation of the flap is provided by the cutaneous nerves of the forearm (Figs. 11.2 and 11.3a, b). The phallus is then created in a “tube within a tube” fashion. The urethral strip is tubularized around a 16 Ch catheter using 4-0 Monocryl® sutures and its proximal portion is left spatulated for 2 cm in order to allow a primary anastomosis with the stump of the penile urethra. Once the neourethra has been completely fashioned, the lateral aspect of the flap is wrapped around the neourethra to form the bulk of the phallus. The closure of the phallus is performed with 4-0 Nylon® sutures (Figs. 11.4 and 11.5). Once the phallus is completed, its vascular pedicle is divided and the free flap is transferred to the recipient site. Preparation of the recipient site varies according to the length of the penile and urethral stump; in general the urethral stump is excised and spatulated to allow the primary anastomosis to the phallic urethra. The neurovascular bundle is dissected off the corporal stumps and dorsal nerves and deep dorsal veins are identified and prepared for eventual anastomosis (Fig. 11.6). The inferior epigastric artery, long saphenous veins, and iliohypogastric and ilioinguinal nerves are also identified and dissected. The phallus is then transposed to the recipient area and vascular, neural, and urethral microsurgical anastomoses are performed as follows (Fig. 11.7): Arterial: Radial to inferior epigastric artery
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Fig. 11.3 (a) The flap raised under tourniquet control, (b) flap raised on the radial artery, cephalic vein, and venae comitantes and cutaneous nerves
a
b
Fig. 11.4 Urethra tubularized over a 16Ch catheter
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242 Fig. 11.5 Phallus portion wrapped around urethra using the tube within a tube concept
Fig. 11.6 Isolation of the dorsal vein and nerves
Venous: Cephalic to long saphenous Lateral flap to saphenous Radial venae comitantes to inferior epigastric comitantes Nerves: Medial cutaneous to ilioinguinal Lateral cutaneous to ilioinguinal, iliohypogastric, or dorsal penile
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Fig. 11.7 The vascular anastomoses in the recipient site
Fig. 11.8 When the long saphenous vein has been sacrificed following inguinal lymphadenectomy, it is still possible to directly anastamose to the femoral vein
If the long saphenous vein has been previously excised during inguinal lymph node dissection, the flap veins are anastomosed directly to the femoral vein and/or to the deep dorsal vein of the penis (Fig. 11.8). The proximal end of the spatulated neourethra is primarily joined to the mobilized urethral stump and a suprapubic and urethral catheter are left in situ (Figs. 11.9 and 11.10). After adequate preparation, the forearm donor site is covered with a fullthickness skin graft harvested from the buttock. A compression dressing is then applied to the graft and the arm elevated for 1 week, and inspected weekly thereafter (Figs. 11.11–11.14). At a minimum of 3 months post phallus reconstruction a glans is fashioned using the Norfolk technique. The phallus is incised circumferentially, mobilized distally, and then a full-thickness skin graft inserted into the defect (Figs. 11.15–11.17). As there is an appropriate skin incision to harvest the graft, it is often convenient to insert the reservoir component of the penile implant at this stage. The final stage involves the insertion of an AMS 700CX inflatable penile prosthesis which is performed through a transverse penoscrotal incision (Fig. 11.18).
244 Fig. 11.9 Separation of the penile urethra from the corporal stump
Fig. 11.10 Primary end to end spatulated urethral anastamosis
Fig. 11.11 Full-thickness skin graft harvested from the buttocks
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Fig. 11.12 Final result from primary closure of buttocks
Fig. 11.13 Full thickness graft applied to the donor arm
Fig. 11.14 Final result of arm graft at 6 weeks
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246 Fig. 11.15 A pseudoglans is made by rolling the distal skin up to form a corona and the defect grafted
Fig. 11.16 Appearance of phallus following glans sculpting
Fig. 11.17 Long term result following radial artery phalloplasty and glans sculpting
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Fig. 11.18 The corporal stump is isolated through a transverse scrotal incision
Fig. 11.19 The crura are dilated prior to phallus dilatation
The penile stump is located and the crura dilated sequentially (Fig. 11.19). The phallus is then dilated to house the cylinders which are placed within a pseudocorpus cavernosum constructed from coated Dacron® (Fig. 11.20). The penile prosthesis is left semi-inflated for 10 days and the urethral catheter removed prior to discharge. Antibiotics are continued for a further 1 week period. The patient is then taught how to cycle the device at 4 weeks (Figs. 11.21 and 11.22). At our center this technique has been used in 19 patients with a published series of 15 patients.29 The initial cancer management consisted of subtotal penectomy for pT2 and pT3 tumors in all patients, one of which had a primary urethral carcinoma. Inguinal lymphadenectomy had been performed in 16 patients with positive nodal disease present in three patients and in one a pelvic lymph node dissection was also carried out with no evidence of metastatic lymph nodes. All of the patients were disease free at the time of surgery. Following surgery, all of the patients were able to void while standing; one developed a recurrent bulbar urethral tumor, 2 years after undergoing the phalloplasty, and
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Fig. 11.20 The inflatable prosthesis used with a Dacron cap to form a pseudo-cavernosum within the phallus
Fig. 11.21 Final result with the phallus deflated
has therefore had a urethrectomy and prostatectomy, and is now voiding through a Mitrofanoff diversion. Complete phallus sensation was reported in 15 patients; of the remainder, one reported sensation only within the neourethra, one has an insensate phallus, and one is only 3 months postsurgery and is therefore too early to assess. All of the patients were very satisfied with the outcome and 9 have had a penile implant inserted. The complications from this series are shown in Table 11.1. Since its original description by Song and Chang,16,17 penile reconstruction with the use of the forearm flap has proven superior to the other techniques as it:
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Fig. 11.22 Final result with the phallus erect and sensate
Table 11.1 Complications of the phallus and donor arm
Complication Phallus Partial skin necrosis Contracture Meatal stricture Anastomotic stricture Urethral fistula Prosthesis infection Arm Incomplete graft take Contracture Loss of sensation Hand edema
No. of patients 3 2 3 1 6 1 4 2 2 1
1. Guarantees a superior cosmetic result by forming a cylindrical phallus rather than the wedge-shaped infraumbilical and groin flap phalloplasty5-10 and is less prone to postoperative contracture when compared to the musculocutaneous flaps.11-16 2. Allows the creation of a neourethra that reaches the tip of the phallus which is less prone to complications. Urethral complications with other types of phallopasty occur in up to 65% of cases and often require multiple revisions.29 3. Allows the creation of a sensate phallus whereas in other phalloplasties the sensation is minimal.29 As in all major phalloplasty surgery, complication rates are high. Loss of skin on the phallus can be a problem, particularly if the phalloplasty is large and therefore there may be impaired vascular perfusion to the edges. Urethral complications can be overcome, and are less common than in some other types of phalloplasty.29,30
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One major disadvantage of this technique is the donor site morbidity. This can be dramatically reduced by adequate preparation of the donor site for grafting.31 This involves adequate hemostasis, the advancement of the edges of the intact forearm skin to reduce the area that requires grafting and to minimize the step between normal skin and the grafted muscle for creation of a flat surface on which to place the skin graft. With regard to the cover of the defect, full-thickness grafts have proven to be superior to split skin due to a lower rate of scarring and contracture and superior cosmesis. However, despite the eventual donor site morbidity, the necessity of multiple surgical stages and the high complication rate, all patients are highly satisfied with the outcome of a functionally and cosmetically acceptable phallus. The microsurgical forearm flap phalloplasty technique has been shown to give these excellent results.32 Once the phallus has been created, obtaining rigidity adequate enough for sexual intercourse still remains a problem. Since postoperative edema, scarring, and congestion will confer adequate rigidity only in few patients,29 a ‘stiffener’ will be required in the vast majority of patients. Among the various different solutions available in the literature including transplants of autologous bone or cartilage, implants and external devices, the best results are achieved with the insertion of an inflatable penile prosthesis.32 In our series, the insertion of an inflatable penile prosthesis has yielded excellent functional results in 8 patients with only one implant requiring removal due to infection.This is perfectly in line with other series that report an infection rate of the device of 10–20%, 10 times higher than in a male patient having an implant inserted for de novo erectile dysfunction.32
11.4
Abdominal Pubic Phalloplasty
This technique is commonly used for phallus reconstruction in transsexuals but can be modified for use in penile cancer patients although no published data are available for this group.29 The advantages of this technique are that there is no donor site defect on the arm and that the operating time is shorter. The phallus however is relatively insensate, hairy, and prone to urethral complications.29 The phallus is fashioned from a flap of anterior abdominal wall skin, 12 cm wide and 12–14 cm long, measured from the base of the penile stump (Fig. 11.23). When possible, the superficial external pudendal vessels are incorporated into the base of the flap pedicle. The urethra is fashioned from a midline strip of scrotum, incorporating the original meatus, tubed over a 16Ch catheter, and brought forward to be incorporated into the abdominal flap. After mobilizing the flap, any excess subcutaneous tissue is excised in order to give a better cosmetic appearance and facilitate tubing of the phallus (Figs. 11.24 and 11.25). The anterior abdominal wall skin is then mobilized and lateral rotation flaps utilized in order to enable primary closure of the abdominal wall skin and thereby avoid the need to skin graft the donor site (Fig. 11.26). An example of the final result following a pubic phalloplasty is shown (see Figs. 11.18 and 11.19). The subsequent steps of glans sculpture and insertion of a penile prosthesis are similar to the forearm flap phalloplasty described above.
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Fig. 11.23 The dimensions of the abdominal flap are 12 × 14 cm, and the scrotal urethra marked as shown
Fig. 11.24 The abdominal flap is raised and the scrotal flap tubed to form the neourethra
The main complications with this technique relate to the urethra which is at risk of sacculation and stricturing.29 An alternative technique is to fashion a neourethra as a free flap from the forearm and insert it tubularized inside the abdominal phalloplasty as described by Dabernig which yields excellent functional results with low complication rates but at the expense of an additional surgical procedure22 (Figs. 11.27–11.29).
252 Fig. 11.25 Flap mobilized, defatted, and urethra incorporated before tubing
Fig. 11.26 Abdominal closure with rotation flaps demonstrated in a transsexual patient
Fig. 11.27 Dimensions of the forearm flap urethra
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Fig. 11.28 Urethra mobilized on the radial artery, cephalic vein, and cutaneous nerve
Fig. 11.29 End result of forearm flap urethra after microsurgical transfer
11.5
Antero-Lateral Thigh Flap Phalloplasty
The anterolateral thigh flap is another good option for phallic reconstruction.33 This is a musculocutaneous (perforator) rather than a fasciocutaneous based-flap and is based on the perforator vessels through vastus lateralis and rectus femoris from the descending branch of the lateral circumflex femoral artery (Chap. 7). The ALT flap is very reliable from a vascular point of view and is commonly used in reconstructive surgery. Rubino et al. described the ALT flap in order to create a neophallus for a female to male transsexual patient which incorporated a strip of vascularized fascia lata wrapped around the prosthesis.34 For phalloplasty, a 16 × 16 cm (14 × 20 cm if incorporating neourethra) flap needs to be raised (Fig. 11.30). The dissection is a little more difficult than for the radial forearm flap because of the perforators but
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Fig. 11.30 The anterolateral thigh flap with a line drawn between the anterior superior iliac spine and lateral condyle at knee. Midway between these two lie the main perforators. Use hand-held doppler to find the perforators and then base flap on them
Fig. 11.31 A split-skin graft is used to cover the defect
does not require the use of a tourniquet. Another advantage is that the vascular pedicle is sometimes long enough to reach the pubic area after tunneling under the rectus femoris tendon, obviating the need for microsurgical vascular anastomoses. A disadvantage is that the ALT flap has a thick subcutaneous layer and is much hairier which makes simultaneous neourethral construction using the “tube within tube” technique difficult. Often the phalloplasty is made from the ALT flap and the neourethra is then formed from a narrow (4 cm wide) radial forearm flap.22 If a neourethra is being constructed at the same time then the long axis of the flap is in line with the thigh (Figs. 11.31 and 11.32). There is only one cutaneous nerve with the ALT flap so the potential sensation is suboptimal. Careful patient selection is therefore particularly important in order to
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Fig. 11.32 Result of ALT phalloplasty in a patient presenting with congenital micropenis
gain a good cosmetic result from the ALT flap phalloplasty especially if the urethra is being fashioned primarily. Due to the large skin paddle, a split-skin graft is used to cover the donor site which is generally a large defect although it can be concealed by long undergarments.
11.6
Alternative Flaps for Phallic Reconstruction
A number of alternative flaps have been described but not used extensively. These include the deltoid flap,35 the lateral arm flap,36 the dorsalis pedis flap, the fibular flap,37 and the TFL flap.38 The advantage of the fibular osteocutaneous flap is that it allows the formation of a rigid phallus without the need for a penile prosthesis; however, there is a reduced sensation and it is associated with more urethral complications.
11.7
Conclusion
The impact of penile amputation can be devastating particularly for the younger sexually active patient. The results of phalloplasty are ever improving with the restoration of sexual and urinary function and more importantly it gives the patient confidence to lead a normal life after undergoing treatment for penile cancer. Surgeons managing penile cancer should be aware of the currently available techniques and be able to offer it to any penile cancer patient who would be considered a suitable candidate.
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References 1. Hage JJ, Bloem JJAM, Suliman HM. Review of the literature on techniques for the phalloplasty with emphasis on the applicability in female-to-male transsexuals. J Urol. 1993;150: 1093-1098. 2. Bogoras N. Uber die volle plastische wiederherstellung eines zum Koitus fahigen Penis (peniplastica totalis). Zentralbl Chir. 1936;63:1271. 3. Maltz M. Maltz Technic. In: Evolution of Plastic Surgery. New York: Froben Press; 1946: 278-279. 4. Gillies HD, Harrison RJ. Congenital absence of the penis with embryological consideration. Br J Plast Urol. 1948;1:12-28. 5. Laub DR, Laub DR II, Hentz VR. Penis construction in female to male transsexuals. In: Eicher W, Kubli F, Herms V, eds. Plastic Surgery in the Sexually Handicapped. New York: Springer Verlag; 1989:113-128. 6. Snyder CC, Browne EZ Jr. Intersex problems and hermaphroditism. In: Converse M, ed. Reconstructive Plastic Surgery: Principles and Procedures for Correction, Reconstruction and Transplantation. 2nd ed. Philadelphia: WB Saunders Co; 1977:3941-3949. chapter 100. 7. Bouman FG. The first step in phalloplasty in female transsexuals. Plast Reconstr Surg. 1987;79:662-664. 8. Mc Gregor IA, Jackson IT. The groin flap. Br J Plast Surg. 1972;25:3-16. 9. Puckett CL, Montie JE. Construction of male genitalia in the transsexual, using a tubed groin flap for the penis and a hydraulic inflation device. Plast Reconstr Surg. 1978;61:523-530. 10. Perovic S. Phalloplasty in children and adolescents using the extended pedicle island groin flap. J Urol. 1995;154:848-853. 11. Morales PA, O’Connor JJ Jr, Hotchkiss RS. Plastic reconstructive surgery after total loss of the penis. Am J Surg. 1956;92:403-408. 12. Julian R, Klein MH, Hubbard H. Management of thermal burn with amputation with amputation and reconstruction of the penis. J Urol. 1969;101:580-586. 13. Kaplan I. A rapid method for constructing a functional sensitive penis. Br J Plast Surg. 1971;24:342-344. 14. Orticochea M. A new method of total reconstruction of the penis. Br J Plast Surg. 1972;25: 347-366. 15. Persky L, Resnick M, Desprez J. Penile reconstruction with gracilis pedicled grafts. J Urol. 1983;129:603-605. 16. Chang TS, Hwang WY. Forearm flap in one-stage reconstruction of the penis. Plast Reconstr Surg. 1984;74:251-258. 17. Song R, Gao Y, Song Y, Yu Y, Song Y. The forearm flap. Clin Plast Surg. 1982;9:21-26. 18. Fang RH, Kao YS, Ma S, Lin JT. Phalloplasty in female-to-male transsexuals using free radial osteocutaneous flap: a series of 22 cases. Br J Plast Surg. 1999;52:217-222. 19. Gilbert DA, Jordan GJ, Devine CJ, Winslow BH. Microsurgical forearm ‘cricketbat-transformer’ phalloplasty. Plast Reconstr Surg. 1992;90:711-716. 20. Semple JL, Boyd JB, Farrow GA, Robinette MA. The ‘cricket bat flap’: a one-stage free forearm flap phalloplasty. Plast Reconstr Surg. 1991;88:514-519. 21. Gilbert DA, Schlossberg SM, Jordan GH. Ulnar forearm phallic reconstruction and penile reconstruction. Microsurgery. 1995;16:314-321. 22. Dabering J, Shelley OP, Cuccia G, Schaff J. Urethral reconstruction using the forearm free flap: experience in oncologic cases and gender reassignment. Eur Urol. 2007;52:547-554. 23. Hoebeke PB, Rottey S, Van Heddeghem N, et al. One stage penectomy and phalloplasty for epithelioid sarcoma of the penis in an adolescent. Eur Urol. 2007;51:1429-1432. 24. Hoebeke PB, Rottey S, Van Heddeghem N, et al. One stage penectomy and phalloplasty for epithelioid sarcoma of the penis in an adolescent: part 2. Eur Urol. 2007;51:1744-1747. 25. Gottlieb LJ, Levine LA. A new design for the radial forearm free-flap phallic construction. Plast Reconstr Surg. 1992;92:276-283.
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26. Romero FR, Romero KR, Mattos MA, Garcia CR, Fernandez Rde C, Perez MD. Quality of life after partial penectomy for penile cancer. Urology. 2005;66(6):1292-1295. 27. D’Ancona CA, Botega BJ, De Moraes C, Lavoura NS Jr, Santos JK, Rodrigues Netto N Jr. Quality of life after partial penectomy for penile carcinoma. Urology. 1997;50(4):593-596. 28. Garaffa G, Raheem AA, Christopher NA, Ralph DJ. Total phallic reconstruction after penile amputation for carcinoma. BJU Int. 2009;104:852-856. 29. Bettocchi C, Ralph DJ, Pryor JP. Pedicled pubic phalloplasty in females with gender dysphoria. BJU Int. 2005;95(1):120-124. 30. Sohn M, Bosinski HAG. Gender identity disorders: diagnostic and surgical aspects. J Sex Med. 2007;4:1193-1208. 31. Selvaggi G, Monstrey S, Hoebeke P, et al. Donor-site morbidity of the radial forearm free flap after 125 phalloplasties in gender identity disorder. Plast Reconstr Surg. 2006;118: 1171-1177. 32. Hage JJ, Bouman FG, De Graaf FH, Bloem JJA. Construction of the neophallus in femaleto-male transsexuals: the Amsterdam experience. J Urol. 1993;149:1463-1468. 33. Felici N, Felici A. A new phalloplast technique: the free anterolateral thigh flap phalloplasty. J Plast Reconstr Aesthet Surg. 2006;59:153-157. 34. Rubino C, Figus A, Dessy LA, et al. Innervated island pedicled anterolateral thigh flap for neo-phallic reconstruction in female-to-male transsexuals. J Plast Reconstr Aesthet Surg. 2009;62(3):45-49. 35. Harashima T, Ionque T, Tanaka I, et al. Reconstruction of penis with free deltoid flap. Br J Plast Surg. 1990;43:217-222. 36. Hage JJ, de Graf FH. Addressing the ideal requirements by free flap phalloplasty: some reflections on refinements of technique. Microsurgery. 1993;14:592-598. 37. Sadove RC, Sengezer M, McRobert JW, et al. One stage total penile reconstruction with a free sensate osteocutaneous fibula flap. Plast Reconstr Surg. 1993;92(7):1314-1325. 38. Santanelli F, Scuderi N. Neophalloplasty in female-to-male transsexuals with the island tensor fascia lata flap. Plast Reconstr Surg. 2000;105(6):1990-1996.
Chapter 12
The Role of Chemotherapy and Radiotherapy in the Treatment of Penile Cancer Jan M. Kerst, Luc M.F. Moonen, Niels M. Graafland, Andries M. Bergman, Floris J. Pos, and Simon Horenblas
12.1
Introduction
Squamous cell carcinoma of the penis is a rare disease in developed countries. Based on epidemiological data from the comprehensive cancer centers in the Netherlands, the age-adjusted incidence of penile cancer is estimated to be 1.5/100,000. Despite the fact that this disease is readily visible and easily accessible for both diagnostic and surgical interventions patients still present with advanced disease. Fear and embarrassment are considered the most significant reasons for the delay in seeking treatment.1,2 Due to the rarity of penile carcinoma, the literature on the value of chemotherapeutic and radiotherapeutic treatment is fragmented and the optimal chemotherapy and radiotherapy regimen is yet to be determined as studies are generally limited to small single-institution retrospective studies. In the first part of this chapter we discuss the role of these interventions in the treatment of locally advanced disease, metastatic disease, and also in the postoperative setting. The second part is focused on the role of radiotherapy in the treatment of penile cancer, and the last part is dedicated to the role of chemoradiotherapy.
J.M. Kerst (*) Department of Medical Oncology, The Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands A. Muneer et al. (eds.), Textbook of Penile Cancer, DOI 10.1007/978-1-84882-879-7_12, © Springer-Verlag London Limited 2012
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Table 12.1 Studies showing the response rate for single agent and multiagent regimens Reference Regimen n Response rate (%) Single agent therapy Ahmed21 Bleomycin (B) 14 21 Ahmed22 Methotrexate (Mtx) 13 61 Ahmed22 Cisplatin (C) 14 21 Sklarloff23 Mtx 8 38 Sheen24 Mtx 4 75 Multiagent therapy Haas2 C/B/Mtx 40 32.5 Theodore12 C/Irinotecan 28 29 Corral25 Mtx/C/B 21 57 Dexeus26 Mtx/C/B 14 72 Pizzocaro27 Vincristine/B/Mtx 13 54 Shammas8 C/5-FU 8 25 Hussein5 C/5-FU 6 100 Roth28 C/5-FU/Mtx/B 7 86 Pizzocaro14 Paclitaxel/C/FU 6 83
12.2 12.2.1
Chemotherapy Chemotherapy for Metastatic Disease
The data on the use of single-agent chemotherapy are limited due to the studies involving small numbers and mixed populations whereby chemotherapy has been administered in different settings and stages of the disease. Small studies have demonstrated modest efficacy of bleomycin, methotrexate, cisplatin, and 5-FU, either as single agents or as combination therapy, as illustrated in Table 12.1. The use of bleomycin was first reported in 1969 whereby twice weekly intravenous/intramuscular bleomycin produced an objective response in six out of eight patients.3 However, the use of bleomycin has been limited due to the associated pulmonary toxicity. The Memorial Sloan Kettering Cancer Center (MSKCC) reported the outcomes of single-agent cisplatin at both low (1.6–2.0 mg/kg) and high doses (3 mg/kg or 120 mg/m2). The overall response rate in this study was 33%. A later Southwest Oncology Group (SWOG) study of 26 patients treated with cisplatin 50 mg/m2 showed partial response in four patients.4 Multiagent therapies seem to be more active than single-agent therapy but induce considerable toxicity. Again no randomized controlled trials are currently available. In one of the early studies, Hussein et al. reported their experience using a combination of cisplatin and 5-FU in six patients (five with SCC penis and one with SCC urethra). There was one complete response (in the patient with urethral SCC) and five partial responses in this group.5 Of the five patients with penile SCC, one underwent inguinal lymphadenectomy followed by adjuvant radiotherapy but died 18 months later due to a local recurrence. The remaining patients underwent local radiotherapy with a median overall survival of 15 months.
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The most commonly used regimen is the combination of cisplatin, bleomycin, and methotrexate as studied by the Southwest Oncology Group (SWOG). Although this regimen induced response rates of 32%, the toxicity was high (five toxic deaths in 40 patients).2 Side effects included infection, gastrointestinal and pulmonary toxicity, as well as renal impairment. The reported toxic character of this regimen is in accordance with more recent literature, including the experience at our own institution (see below).6,7 Cisplatin in combination with 5-FU seems to be as active as the SWOG regimen with less toxicity.8
12.2.2
Neoadjuvant Chemotherapy
Interestingly, durable complete remissions can be obtained in patients with primary resectable and nonresectable locally advanced nodal and soft tissue disease by neoadjuvant chemotherapy followed by surgical removal of residual disease.9,10 In a review on advanced penile carcinoma, Culkin and Beer combined the results of all available studies on cisplatin-based induction chemotherapy.11 Clinical responses were found in 24 of 35 patients (69%) and 15 of the responding patients (43%) underwent subsequent surgery. Eight patients (23%) were alive without evidence of disease after 1–10 years of follow-up. In our own institution over a 33-year period, a total of 20 patients were treated with induction chemotherapy in an attempt to downstage primary unresectable inguinal lymphadenopathy. Five different chemotherapy regimens were used. An objective tumor response was achieved in 12 of 19 evaluable patients. The overall 5 year survival was 32%, while there was a significant difference (p = 0.012) in survival between responders (5-year survival 56%) and nonresponders (all nonresponders died within 9 months). Nine responders underwent subsequent surgery with curative intent, eight of them were long-term survivors without evidence of recurrent disease. The toxicity of the induction therapy was relatively high with three toxic deaths and discontinuation of treatment in one patient. All four patients were treated with bleomycin/methotrexate, combined with cisplatin in 3 and with vincristine in 1. Therefore, we do not consider combined treatment with bleomycin and methotrexate as the preferred treatment for penile cancer, either as induction therapy or as palliative therapy.7 Our group participated in the EORTC 30992 study in which cisplatin in combination with irinotecan was studied in metastatic or locally advanced penile carcinoma.12 In this series three patients treated in the neoadjuvant setting had a pathological complete remission. In our clinic we carefully select patients for induction chemotherapy in a multidisciplinary setting. Addition of the taxane docetaxel to cisplatin and 5-FU showed improved progression-free and overall survival in patients with unresectable squamous cell carcinoma of the head and neck compared with the standard regimen of cisplatin and 5-FU.13 Also penile cancer taxane-based chemotherapy seems to be both active and safe and has recently shown promising results.10,14 We are currently studying the cisplatin-5FU-docetaxel regimen as induction therapy in a phase II study.
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Treatment of head and neck squamous cell carcinoma with the epidermal growth factor receptor (EGFR) targeting antibody cetuximab has shown prolonged survival in this patient population.15 Interestingly, since EGFR is overexpressed in penile cancer, implementation of cetuximab in combination with cisplatin-based chemotherapy for the treatment of this disease might be of interest. Studies evaluating the effect of cetuximab-containing regimens in the treatment of penile cancer have been initiated. Evaluating the tumor response to induction therapy by CT scanning alone was insufficient to identify good prognosis responders and separate these patients from poor prognosis nonresponders, prior to surgical resection of residual disease. An interesting new approach is to add 18FDG-PET to CT scanning for monitoring tumor response.16,17 In our clinic preliminary results show that molecular-based imaging may be potentially more reliable compared to response assessment using CT scanning alone. In this way, early response to chemotherapy (after two cycles) can be reliably assessed.
12.2.3
Adjuvant Chemotherapy
The role of adjuvant chemotherapy is uncertain. Studies published in the 1980s suggested a potential benefit of adjuvant chemotherapy in patients with documented inguinal metastases who were treated with inguinal lymphadenectomy combined with adjuvant chemotherapy using VBM (vincristine, bleomycin, methotrexate).9,18 However, these small uncontrolled studies do not justify the implementation of adjuvant chemotherapy as standard care. Patients with pelvic nodal involvement and extranodal extension can be identified as being at high risk for disease recurrence and disease-specific death.19,20 In this subgroup of patients with high-risk penile cancer, surgery with postoperative radiotherapy seems ineffective to prevent recurrence. In these patients with unfavorable prognostic features the efficacy of adjuvant systemic treatment to prevent both disease recurrence and overall survival should form part of subsequent clinical trials in the future. Based on our present knowledge, induction treatment before surgery is a more attractive approach. Patients generally have a better performance status in order to undergo multimodality treatment. Any delay due to postoperative complications is therefore avoided and patients can be monitored for response during treatment. Unfortunately, the diagnostic tools available to identify these patients with high-risk penile cancer before surgery still have limitations.
12.3 12.3.1
Radiotherapy Introduction
With respect to the treatment of the primary tumor, surgical procedures aimed at removing the lesion with clear margins are generally considered the treatment of
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choice. Depending on the size, the location, and the extent of the tumor, the surgical intervention can range from local excision to partial or total penectomy. Although surgical approaches have achieved cancer control rates exceeding 90%, the resulting functional loss and associated psychological and sexual morbidity justifies the investigation of organ-sparing or reconstructive treatment options. Radiotherapy, whether given as external beam radiation (EBRT) or by brachytherapy, has proven to be an effective treatment modality in many tumors including squamous cell carcinoma. Radiotherapy is therefore an appealing alternative to surgical treatment in early-stage penile cancer, as it preserves penile function and maintains penile anatomy. Due to the rarity of penile cancer, randomized trials comparing the results of different treatment modalities have never been conducted. The evidence for the treatment is therefore entirely based on retrospective observational studies. Apart from its role in the treatment of the primary tumor, radiotherapy may also have a role in the treatment of the inguinal and/or pelvic lymph node areas. It can be used as an adjuvant to surgical lymphadenectomy or as a primary treatment. Also in these areas, the role of radiotherapy is not well established and is a subject of much controversy.
12.3.2
Radiotherapy as a Treatment of the Primary Tumor
12.3.2.1
EBRT
In order to deliver the radiation dose to the tumor there are two options: external beam radiotherapy (EBRT) or brachytherapy. By using external megavoltage radiation beams a relatively homogeneous dose is delivered to the target region. Tissue equivalent bolus is often required to provide sufficient dose build-up to the surface of the lesion. Normal tissues can be spared by using fractionated treatment schedules. Although superficial radiotherapy for CIS has been described using a fractionation scheme similar to that for skin cancer (35– 40 Gy/10 fractions over 2 weeks), EBRT is more appropriate in locally advanced cases. In order to avoid radiation damage to the adjacent skin, the penis is housed in a wax or Perspex cylindrical block (approximately 10 × 10 cm) which maintains the penis in a suitable upright position. The most commonly utilized fractionation scheme consists of 2-Gy daily fractions for a total dose of 60–66 Gy using two opposed beams over a 6 week period. During the treatment period, penile edema may develop and therefore the cylindrical blocks have to be upsized. External beam treatment as a single treatment modality has been used in only a small number of studies, most of these reporting on limited numbers of patients.29,30 One exception is a study by Gotsadze et al. analyzing results in 155 patients.31 This study reported local control rates for stages I and II ranging from 65% to 90%. Sarin et al. analyzed the impact of various radiation parameters such as total dose, dose per fraction, total treatment time and “Biological Equivalent Dose” (BED) with or without time, factor on local failure in 44 patients with T1 tumors. A higher incidence of local failure was observed with a total dose less than 60 Gy, dose per fraction less than
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2 Gy, and treatment time exceeding 45 days.32 The difference approached prognostic significance (p = 0.052). The incidence of complications such as urethral stricture or stenosis has been reported to be 16%–49%. A further two studies have reported on erectile function which is preserved in up to 90% of the patients.33,34
12.3.2.2
Brachytherapy
Brachytherapy (brachy is Greek for short distance) consists of placing sealed radioactive sources very close to or in contact with the tumor. Because the absorbed dose falls off very rapidly with an increasing distance from the sources, high doses can be delivered safely to a localized target region over a short time. Compared to external beam radiation, the volume of the area treated to a high dose is smaller, but the dose in homogeneity within this volume is more pronounced. By carefully selecting cases, lesions are treated using 2–3 parallel planes of needles which are held in place with predrilled Lucite templates. The geometry and dosimetry follow the Paris system (Fig. 12.1). The intersource and interplane spacing ranges from 12 to 18 mm. The planes are orientated so that the needles pass from the dorsal surface to the ventral surface of the glans. The needle placement can be performed under regional or general anesthesia and takes up to 45 min. The prescribed dose is 60 Gy, which is delivered at a rate of 50–65 cGy per hour over 4–5 days. A low dose rate implant (LDR) can be performed using Iridium-192 wires. Alternatively an automated pulse dose rate (PDR) machine (Nucletron micro Selectron PDR) using a high intensity Iridium-192 source (0.3–1 Ci) can be used. The brachytherapy needles are well tolerated and patients are catheterized and remain on bed rest with thromboprophylaxis measures (antiembolic stockings and
60 Gy isodose catheter Styrofoam collar Lucite template
Fig. 12.1 Interstitial brachytherapy according to the Paris system (With kind permission from Springer Science+Business Media: Crook et al.36 Fig. 1. Courtesy of Professor Juanita Crook, University of British Columbia)
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1.0
Proportion Failure Free
0.8
0.6
0.4
0.2 # At Risk 49 31
0.0 0
22
4
5 10 Local Failure Free Survival (Years)
15
Fig. 12.2 Local failure-free survival following interstitial brachytherapy (With kind permission from Springer Science+Business Media: Crook et.al.36 Fig. 2)
subcutaneous heparin). Moist desquamation of the treated area normally peaks at 2–3 weeks after the needles have been removed. Healing occurs after 2–3 months. Results of brachytherapy have been reported in about 20 studies. All except two of these studies report on fewer than 80 patients (Table 12.1). The largest study by Rozan et al.35 reported on 259 patients of whom 184 had been treated by brachytherapy only and 75 had a combination of external beam radiation and brachytherapy. Crook et al. reported a local failure-free survival of 87.3% at 5 years and 72.3% at 10 years36 (Fig. 12.2). Approximately two-thirds of local failures occur within 2 years with the remainder occurring after 5 years. De Crevoisier et al. reported a local recurrence rate of 20% at 8 years and a cause-specific survival of 90% at 10 years.37 In the vast majority of the studies, the patients have been treated in a period exceeding several decades. Treatment parameters such as tumor dose, dose rate, fractionation schedule, etc. have varied considerably among the patients reported within the individual studies. Also patient selection criteria have not been uniformly applied in most of the reports. Despite this wide variety in treatment parameters and patient characteristics, the outcome of the studies is remarkably concordant.33,37,38 Long-term (5–10 years) local control rates vary between 60 and 90% and seem more related to tumor characteristics than treatment parameters. Adequate surgical salvage is still possible with a success rate between 70 and 100% and reported penis preservation rate is between 52 and 86%. The most important predictors for successful brachytherapy seem to be the tumor size (less than 4 cm) and tumor location limited to the glans or the prepuce without corpus cavernosum involvement. For patients meeting these criteria, the different studies report local recurrence rates of about 20% after 5–10 years with a secondary control of about 85% of the recurrences by salvage surgery.
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Complications Associated with Radiotherapy
Radiotherapy can induce side effects and complications such as telangiectasia, atrofia, depigmentation of the skin, fibrosis, meatal stenosis, and (painful) ulcerations and necrosis. The most serious complications are meatal stenosis and persisting ulceration or necrosis. The reported incidence ranges from 8% to 45% and 0–23%, respectively. Brachytherapy which requires central planes close to the urethra is associated with a higher incidence of meatal stenosis. However, utilizing PDR after loading which allows dose optimization can reduce the urethral dose when central planes are required. Meatal stenosis is managed by meatal dilatation by the patient himself or by the urologist. Problematic meatal stenosis can be corrected by performing a meatoplasty. Management of painful penile ulceration includes the use of regular analgesia although hyperbaric oxygen may also promote wound healing. Soft tissue necrosis is more of a problem and is reported in 23% of cases and often requires surgical amputation. The reported incidence of penectomy for complications secondary to radiotherapy varies from 0% to 5%.32,33 Limited data are available concerning functional and psychosexual outcomes of organ-preservation by radiotherapy. Opsjordsmoen et al. reported on post-therapy sexuality in 30 men.34 Patients underwent a semistructured interview and completed three self-administered questionnaires (psychosocial adjustment to severe illness (PAIS), mental symptoms (GHQ), and quality of life (EORTC QLQ C-30)). A global score of overall sexual functioning was constructed consisting of sexual interest, sexual ability, sexual satisfaction, sexual identity, partner relationship, and frequency of coitus. In 10 of 12 patients treated with radiotherapy the sexual global score was not or only slightly reduced. Eleven out of fourteen patients treated with local surgery, laser beam treatment, or partial penectomy had moderate to severe reduction of global sexual score. All four patients who had undergone total penectomy recorded a severely reduced sexual global score. It was remarkable that in the patients treated by irradiation physicians evaluated the patients’ post-treatment sexuality, especially with regard to the ability to perform coitus, to be more impaired than was evaluated by the patients themselves.
12.3.4
Radiotherapy for the Management of Regional Lymph Node Metastases
Inguinal and pelvic lymph node metastases are a frequent problem in the management of penile cancer. At the time of diagnosis, 20–50% of patients have palpable lymph nodes with about 50% of these representing inflammatory adenopathy and another 50% representing metastases. Approximately 20% of the patients without palpable inguinal nodes have occult metastases.
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Elective irradiation of clinically uninvolved lymph node regions has proven to be an effective policy in many tumors, especially in squamous cell carcinoma. The concept is successfully applied in head and neck tumors, cervical cancer, anal cancer, vulvar cancer, etc. In vulvar cancer with positive groin nodes, radiation of pelvic nodes proved superior to pelvic node dissection in a randomized trial.39 However, a randomized trial performed by the Gynaecological Oncology Group in patients with squamous carcinoma of the vulva with nonsuspicious inguinal nodes comparing groin dissection and groin irradiation in conjunction with radical vulvectomy was closed prematurely because of an excessive number (18%) of groin relapses in the groin radiation arm.40 Detailed analyses of the results revealed that the radiation protocol as employed in the study was inappropriate and possibly responsible for the poor results.41 In penile cancer, elective radiotherapy has never widely been used or gained acceptance. In the EAU Guidelines a surveillance programme is strongly advised in lowrisk patients. In intermediate-risk patients a modified inguinal lymphadenectomy or alternatively a dynamic sentinel lymph node procedure is recommended. In patients at high risk of nodal involvement a modified or radical lymphadenectomy is always advised. Elective radiotherapy is not recommended based upon disappointing results in two nonrandomized studies. However, one of these studies does not at all address the question of whether elective radiation is effective.42 The study reports upon 120 patients with lymph node involvement in the groin irradiated preoperatively. It is concluded that radiation is highly effective in patients with mobile lymph nodes larger than 4 cm with only 8% of lymphadenectomy specimens showing perinodal infiltration and only 3% of such patients having postoperative groin recurrences. In a previous publication by the same authors they reported in the same patient category an incidence of 33% perinodal infiltration and 19% groin recurrences in the absence of preoperative radiation.19 Furthermore the authors report that none of the patients with positive pelvic lymph nodes survived for 5 years, despite lymphadenectomy followed by pelvic and/or para-aortic irradiation. In a further publication cited in the EAU guidelines a group of 27 patients with N0 and N1-2 carcinoma treated with bilateral groin dissection is compared with a group of 18 patients with N0 and N1-2 treated with radiotherapy to the groin.43 During follow-up two relapses occurred after radiation compared to only one after surgery. Survival rates in the N0 group was superior in the surgical group compared with the irradiated group. It can be concluded that this nonrandomized study is far from being a proof against the effectiveness of elective radiation. In penile cancer, the role of elective radiation remains unclear but based upon well-established effectiveness in other squamous carcinoma sites deserves to be explored. The place of adjuvant postoperative radiation is also surrounded by controversy. The incidence of inguinal recurrence in patients with inguinal lymph node metastasis treated with lymphadenectomy varies between 25% and 77%.11,44,45 Adjuvant radiation to the inguinal lymphatic area has been advocated by some, if histopathological examination of the inguinal specimen revealed more than one metastatic lymph node and/or extranodal extension. Chen reported that postoperative groin irradiation reduced the inguinal recurrence rate from 60% (three recurrences in five patients) to 11% (one recurrence in nine patients).46 However, larger series confirming this benefit are still lacking.
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Chemoradiotherapy
In locoregionally advanced disease (large/inoperable primary tumor, N2/N3 or extra nodal extension), survival rates are poor despite extensive surgical treatment so new treatment strategies are required. As described in the previous sections surgery, radiotherapy and chemotherapy are all effective modalities in the treatment of penile cancers. Therefore, a multimodality approach with combinations of these modalities seems a logical step. Radiotherapy (RT) in combination with concurrent chemotherapy is an established approach to improve RT efficacy. Concurrent chemo-radiotherapy (CRT) has been proven to be effective in the treatment of squamous cell carcinomas such as lung, cervical and head and neck cancer. Currently there are no studies investigating the value of CRT for locally advanced penile cancers. The situation is different for the other squamous cell carcinomas such as cancer of the vulva and the anal canal. For (locally advanced) anal squamous cell carcinoma the current standard is CRT with 5-fluorouracil (5-FU) and mitomycin (MMC), surgery is reserved for poor and non-responders to CRT. This standard is set by several controlled randomized phase III trials. In 1996 the United Kingdom Coordinating Committee on Cancer Research (UKCCCR) Anal Cancer Trial Working Party reported on a randomized phase III trial of RT alone versus CRT with 5-FU + MMC. In this trial the clinical response was assessed 6 weeks after initial treatment: good responders were recommended for boost radiotherapy and poor responders for salvage surgery. The CRT arm showed a 46% reduction in local failure compared to the RT arm (p < 0.0001). The risk of CRT patients to develop local failure was 36% at 3 years. Early morbidity was significantly more frequent in the CRT arm (p = 0.03), but late morbidity occurred at similar rates. Similar outcome was reported in 1997 by the EORTC in a phase III randomized trial between RT versus CRT with 5-FU + MMC.47 Also in this trial clinical response was assessed 6 weeks after initial treatment: good responders were recommended for boost radiotherapy. Surgical resection was performed in patients who had not responded 6 weeks after RT or patients with residual palpable disease after the completion of treatment. The addition of chemotherapy to radiotherapy resulted in a significant increase in the complete remission rate from 54% for RT alone to 80% for CRT. This led to a significant improvement of loco regional control and colostomy-free interval (p = 0.02 and p = 0.002, respectively), both in favor of CRT. The locoregional control rate improved by 18% at 5 years, while the colostomy-free rate at that time increased by 32% by the addition of chemotherapy to radiotherapy. In the CRT group approximately 70% of the patients remained free from colostomy at 5 years. No significant difference was found when severe side effects were considered, although anal ulcers were more frequently observed in the combined-treatment arm. The added value of MMC to 5-FU was examined in a RTOG/ECOG randomized phase III trial.48 Patients were randomized to receive either CRT + 5-FU versus CRT + 5-FU + MMC. At 4 years, colostomy rates were lower (9% vs. 22%;
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Good responders
RT boost
Poor responders
Surgery
Response evaluation
Locally advanced penile cancer
CRT 5-FU + MMC/ 5-FU + cisplatin
Surgery
Fig. 12.3 The possible role of CRT for penile cancer
p = 0.002), colostomy-free survival higher (71% vs. 59%; p = 0.014), and diseasefree survival higher (73% vs. 51%; p = 0.0003) in the MMC arm. RTOG 98-11, a multicenter, phase 3, randomized controlled trial compared treatment with CRT + 5-FU + MMC versus CRT + 5-FU + cisplatin in patients with anal canal carcinoma.49 Cisplatin-based therapy failed to improve disease-free survival compared with MMC-based therapy, but cisplatin-based therapy resulted in a significantly worse colostomy rate. In locally advanced cancer of the vulva, treatment seems to focus on preoperative CRT with 5-FU + MMC or 5-FU + cisplatin followed by surgery. Prospective randomized trials to assess the benefit of adding chemotherapy to radiation therapy have not been done. Although there are no prospective randomized controlled trials, there are many reports addressing the feasibility and safety of preoperative CRT for advanced vulvar carcinoma.50 Most studies use CRT with 5-FU + MMC or CRT with 5-FU + cisplatin. Bleomycin appears to be less effective and may result in severe toxicity.50,51 Preoperative CRT reduces tumor size and improves operability. With CRT using 5-FU + CDDP or 5-FU and MMC operability is achieved in 63–92% of cases.51 More than half of the patients (50–95%) become free of disease following surgery and remain free of recurrence during follow-up.50 Essentially different from CRT in anal cancer is the toxicity profile. Many patients experience severe intestinal, vaginal, or urologic complications. Even among selected patients who were fit for surgery treatment related deaths are reported.50,51 In a recent critical review by the Cochrane Gynaecological Cancer Group the current status of neoadjuvant CRT for advanced vulvar cancer is summarized.51 It was concluded that patients with a large or inoperable primary tumor or lymph nodes may benefit from chemoradiation. Given the excellent outcome of CRT in the other squamous cell carcinomas of perineal origin, CRT for locally advanced penile cancer seems a valid option. There are two options, CRT in a preoperative setting, as used in vulvar cancer, or CRT as primary treatment and surgery reserved for poor and nonresponders (Fig. 12.3).
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Conclusion
Penile cancer is a rare disease and treatment approaches have been predominantly surgical. In early-stage disease high tumor control rates can be achieved but often at the price of considerable morbidity, mutilation, and functional impairment. In highstage disease the results, even after aggressive surgical approaches, are disappointing with high recurrence rates and poor survival. Organ-sparing approaches and multimodality approaches (combinations of surgery and/or radiation and/or chemotherapy) have never been explored in a large and prospective fashion. This is in contrast with the situation in squamous cell cancer of other primary sites, such as head and neck cancer, cervical cancer, anal cancer, etc., where organ preservation and multimodality strategies have become the standard strategy. The particular role of radiation in penile cancer remains unclear but the available literature, although limited and many times of rather poor quality, suggests that radiation response is comparable with radiation responses observed in other squamous cell carcinomas.
References 1. Burgers JK, Badalament RA, Drago JR. Penile cancer. Clinical presentation, diagnosis, and staging. Urol Clin North Am. 1992;19:247. 2. Haas GP, Blumenstein BA, Gagliano RG, et al. Cisplatin, methotrexate and bleomycin for the treatment of carcinoma of the penis: a Southwest Oncology Group study. J Urol. 1999;161:1823. 3. Ichikawa T, Nakano I, Hirokawa I. Bleomycin treatment of the tumors of penis and scrotum. J Urol. 1969;102:699. 4. Gagliano RG, Blumenstein BA, Crawford ED, et al. cis-Diamminedichloroplatinum in the treatment of advanced epidermoid carcinoma of the penis: a Southwest Oncology Group Study. J Urol. 1989;141:66. 5. Hussein AM, Benedetto P, Sridhar KS. Chemotherapy with cisplatin and 5-fluorouracil for penile and urethral squamous cell carcinomas. Cancer. 1990;65:433. 6. Hakenberg OW, Nippgen JB, Froehner M, et al. Cisplatin, methotrexate and bleomycin for treating advanced penile carcinoma. BJU Int. 2006;98:1225. 7. Leijte JA, Kerst JM, Bais E, et al. Neoadjuvant chemotherapy in advanced penile carcinoma. Eur Urol. 2007;52:488. 8. Shammas FV, Ous S, Fossa SD. Cisplatin and 5-fluorouracil in advanced cancer of the penis. J Urol. 1992;147:630. 9. Pizzocaro G, Piva L. Adjuvant and neoadjuvant vincristine, bleomycin, and methotrexate for inguinal metastases from squamous cell carcinoma of the penis. Acta Oncol. 1988;27:823. 10. Bermejo C, Busby JE, Spiess PE, et al. Neoadjuvant chemotherapy followed by aggressive surgical consolidation for metastatic penile squamous cell carcinoma. J Urol. 2007; 177:1335. 11. Culkin DJ, Beer TM. Advanced penile carcinoma. J Urol. 2003;170:359. 12. Theodore C, Skoneczna I, Bodrogi I, et al. A phase II multicentre study of irinotecan (CPT 11) in combination with cisplatin (CDDP) in metastatic or locally advanced penile carcinoma (EORTC PROTOCOL 30992). Ann Oncol. 2008;19:1304.
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13. Vermorken JB, Remenar E, van Herpen C, et al. Cisplatin, fluorouracil, and docetaxel in unresectable head and neck cancer. N Engl J Med. 2007;357:1695. 14. Pizzocaro G, Nicolai N, Milani A. Taxanes in combination with cisplatin and fluorouracil for advanced penile cancer: preliminary results. Eur Urol. 2009;55:546. 15. Vermorken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus cetuximab in head and neck cancer. N Engl J Med. 2008;359:1116. 16. Scher B, Seitz M, Reiser M, et al. 18F-FDG PET/CT for staging of penile cancer. J Nucl Med. 2005;46:1460. 17. Graafland NM, Leijte JA, Valdes Olmos RA, et al. Scanning with 18F-FDG-PET/CT for detection of pelvic nodal involvement in inguinal node-positive penile carcinoma. Eur Urol. 2009;56:339. 18. Maiche AG. Adjuvant treatment using bleomycin in squamous cell carcinoma of penis: study of 19 cases. Br J Urol. 1983;55:542. 19. Ravi R. Correlation between the extent of nodal involvement and survival following groin dissection for carcinoma of the penis. Br J Urol. 1993;72:817. 20. Sanchez-Ortiz RF, Pettaway CA. The role of lymphadenectomy in penile cancer. Urol Oncol. 2004;22:236. 21. Ahmed T, Sklaroff R, Yagoda A. An appraisal of the efficacy of bleomycin in epidermoid carcinoma of the penis. Anticancer Res. 1984;4:289. 22. Ahmed T, Sklaroff R, Yagoda A. Sequential trials of methotrexate, cisplatin and bleomycin for penile cancer. J Urol. 1984;132:465. 23. Sklaroff RB, Yagoda A. Methotrexate in the treatment of penile carcinoma. Cancer. 1980; 45:214. 24. Sheen MC, Sheu HM, Huang CH, et al. Penile verrucous carcinoma successfully treated by intra-aortic infusion with methotrexate. Urology. 2003;61:1216. 25. Corral DA, Sella A, Pettaway CA, et al. Combination chemotherapy for metastatic or locally advanced genitourinary squamous cell carcinoma: a phase II study of methotrexate, cisplatin and bleomycin. J Urol. 1998;160:1770. 26. Dexeus FH, Logothetis CJ, Sella A, et al. Combination chemotherapy with methotrexate, bleomycin and cisplatin for advanced squamous cell carcinoma of the male genital tract. J Urol. 1991;146:1284. 27. Pizzocaro G, Piva L, Bandieramonte G, et al. Up-to-date management of carcinoma of the penis. Eur Urol. 1997;32:5. 28. Roth AD, Berney CR, Rohner S, et al. Intra-arterial chemotherapy in locally advanced or recurrent carcinomas of the penis and anal canal: an active treatment modality with curative potential. Br J Cancer. 2000;83:1637. 29. Zouhair A, Coucke PA, Jeanneret W, et al. Radiation therapy alone or combined surgery and radiation therapy in squamous–Cell carcinoma of the penis? Eur J Cancer. 2001;37:198. 30. Azrif M, Logue JP, Swindell R, et al. External-beam radiotherapy in T1-2N0 penile carcinoma. Clin Oncol (R Coll Radiol). 2006;18:320. 31. Gotsadze D, Matveev B, Zak B, et al. Is conservative organ-sparing treatment of penile carcinoma justified? Eur Urol. 2000;38:306. 32. Sarin R, Norman AR, Steel GG, et al. Treatment results and prognostic factors in 101 men treated for squamous carcinoma of the penis. Int J Radiat Oncol Biol Phys. 1997;38:713. 33. Crook J, Grimard L, Tsihlias J, et al. Interstitial brachytherapy for penile cancer: an alternative to amputation. J Urol. 2002;167:506. 34. Opjordsmoen S, Waehre H, Aass N, et al. Sexuality in patients treated for penile cancer: patients’ experience and doctors’ judgement. Br J Urol. 1994;73:554. 35. Rozan R, Albuisson E, Giraud B, et al. Interstitial brachytherapy for penile carcinoma: a multicentric survey (259 patients). Radiother Oncol. 1995;36:83. 36. Crook J, Ma C, Grimard L. Radiation therapy in the management of the primary penile tumor: an update. World J Urol. 2009;27:189. 37. de Crevoisier R, Slimane K, Sanfilippo N, et al. Long-term results of brachytherapy for carcinoma of the penis confined to the glans (N- or NX). Int J Radiat Oncol Biol Phys. 2009;74:1150.
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38. Kiltie AE, Elwell C, Close HJ, et al. Iridium-192 implantation for node-negative carcinoma of the penis: the Cookridge Hospital experience. Clin Oncol (R Coll Radiol). 2000;12:25. 39. Homesley HD, Bundy BN, Sedlis A, et al. Radiation therapy versus pelvic node resection for carcinoma of the vulva with positive groin nodes. Obstet Gynecol. 1986;68:733. 40. Stehman FB, Bundy BN, Thomas G, et al. Groin dissection versus groin radiation in carcinoma of the vulva: a Gynecologic Oncology Group study. Int J Radiat Oncol Biol Phys. 1992; 24:389. 41. van der Velden K, Ansink A. Primary groin irradiation vs primary groin surgery for early vulvar cancer. Cochrane Database Syst Rev. 2001;4:CD002224. 42. Ravi R, Chaturvedi HK, Sastry DV. Role of radiation therapy in the treatment of carcinoma of the penis. Br J Urol. 1994;74:646. 43. Kulkarni JN, Kamat MR. Prophylactic bilateral groin node dissection versus prophylactic radiotherapy and surveillance in patients with N0 and N1-2A carcinoma of the penis. Eur Urol. 1994;26:123. 44. Horenblas S, van Tinteren H, Delemarre JF, et al. Squamous cell carcinoma of the penis. III. Treatment of regional lymph nodes. J Urol. 1993;149:492. 45. Ozsahin M, Jichlinski P, Weber DC, et al. Treatment of penile carcinoma: To cut or not to cut? Int J Radiat Oncol Biol Phys. 2006;66:674. 46. Chen MF, Chen WC, Wu CT, et al. Contemporary management of penile cancer including surgery and adjuvant radiotherapy: an experience in Taiwan. World J Urol. 2004;22:60. 47. Bartelink H, Roelofsen F, Eschwege F, et al. Concomitant radiotherapy and chemotherapy is superior to radiotherapy alone in the treatment of locally advanced anal cancer: results of a phase III randomized trial of the European Organization for Research and Treatment of Cancer Radiotherapy and Gastrointestinal Cooperative Groups. J Clin Oncol. 1997;15:2040. 48. Flam M, John M, Pajak TF, et al. Role of mitomycin in combination with fluorouracil and radiotherapy, and of salvage chemoradiation in the definitive nonsurgical treatment of epidermoid carcinoma of the anal canal: results of a phase III randomized intergroup study. J Clin Oncol. 1996;14:2527. 49. Ajani JA, Winter KA, Gunderson LL, et al. Fluorouracil, mitomycin, and radiotherapy vs fluorouracil, cisplatin, and radiotherapy for carcinoma of the anal canal: a randomized controlled trial. JAMA. 2008;299:1914. 50. Moore DH. Chemotherapy and radiation therapy in the treatment of squamous cell carcinoma of the vulva: Are two therapies better than one? Gynecol Oncol. 2009;113:379. 51. van Doorn HC, Ansink A, Verhaar-Langereis M, et al. Neoadjuvant chemoradiation for advanced primary vulvar cancer. Cochrane Database Syst Rev. 2006;3:CD003752.
Chapter 13
Nanotechnology and the Implications for Penile Cancer Ammar Hameed, Iqbal S. Shergill, and Manit Arya
13.1
Introduction
Nanotechnology refers to the creation of functional material devices and systems through the control of matter on an atomic or molecular scale – the nanometer scale (1 nm = 1 × 10−9 m). It is at this size that the majority of biologic molecules inside living cells operate. The prefix “nano” actually originates from the Greek word nanos, meaning “little old man” or “dwarf” and the strict definition of nanotechnology is the study, design, creation, synthesis, manipulation, and application of functional materials, devices, and systems through control of matter at the nanometer scale. Nanomedicine, an offshoot of nanotechnology, refers to the highly specific monitoring, repair, construction, and control of human biological systems at the molecular level, using engineered nanodevices and nanostructures.1,2 Over the next decade, it is widely expected that nanotechnology and nanomedicine will have important and innovative applications in clinical research and medicine, as well as contributing $1 trillion to the global economy.3 Preliminary designs of nanoparticles, such as artificial red blood cells, white cells, and killer cells that can identify a particular bacteria, or cancer cells, have already been developed, and it is anticipated that nanotechnology will allow clinicians to intervene at the cellular and molecular level of any disease process in the future.
I.S. Shergill (*) Department of Urology, Wrexham Maelor Hospital, Wrexham, Clwyd, Wales, UK A. Muneer et al. (eds.), Textbook of Penile Cancer, DOI 10.1007/978-1-84882-879-7_13, © Springer-Verlag London Limited 2012
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Brief Overview of Nanotechnology
Nanotechnology involves utilization of man-made products no larger than 1–1000 nm (i.e. a few atoms to smaller than a single cell). A dictionary definition elucidates the scale of this field and allows us to define that nanoscale particles are in the 10−9 m dimension range, consistent with the magnitude of most synthetic nanoparticles to date. For a real perspective, the width of a DNA molecule is 2.5 nm; cell membranes are 6–10 nm thick; and most proteins are between 5 and 20 nm in diameter. Therefore, most conventional molecular research is already proceeding in nanoscale dimensions. Nanoscience has developed its own language unique to the discipline. Nanomedicine relates to medical research and intervention on the nanoscale. It involves the monitoring, repair, construction, and control of human biological systems at the molecular level, using engineered nanodevices and nanostructures. The National Institutes of Health Bioengineering Consortium, or BECON, held a symposium in 2000 titled “Nanoscience and Technology: Shaping Biomedical Research”.4 At the conference, eight areas of nanoscience and nanotechnology were addressed that were believed to be most pertinent to research in biomedicine. These areas included synthesis and use of nanostructures, applications of nanotechnology to therapy, biomimetic nanostructures, biological nanostructures, the electronic– biology interface, devices for early detection of disease, tools for the study of single molecules, and tissue engineering.5 Such a wide ranging portfolio of research improvement must have multidisciplinary collaboration to maximize the potential benefits in clinical medicine. Urology as a specialty is in a key position to benefit from nanotechnology. The combination of functional abnormalities (e.g. overactive bladder), reconstruction (e.g. hypospadias repair, bladder reconstruction), and oncology (e.g., staging of prostate or penile cancer) all lend themselves to the development of these novel technologies. Currently, the three main areas of integration of synthetic nanotechnology with potential availability to urologists are either for the delivery of pharmaceuticals, for tissue engineering, or as an adjunct to conventional imaging. A summary of the current nanotechnology development in urology is included in Table 13.1.
13.3
Delivery Systems for Drug and Gene Therapy
Delivery systems for drug and gene therapy are particularly attractive targets in urological practice. Novel drug delivery for prostate cancer using ceramic nanoparticles, carbon magnetic nanoparticles, protospheres, and nanogold particles has been investigated in prostate cancer. Paclitaxel-loaded biodegradable nanoparticles have been shown to be effective inhibitors of human prostate cancer cell lines in a murine model.6 In addition, enhanced cellular uptake of a triplex-forming oligonucleotide by
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Table 13.1 Nomenclature in nanotechnology Term Definition Nanoscale 1–1000 nm Nanoscience Research at a nanoscale Nanomedicine Medical intervention on a nanoscale Nanowires Devices containing a collection of wires in a microfluidic system that is connected to a computer’s signal transduction device Nanotubes C-60 allotrope of carbon arranged to form a tube Nanoshells Metal-based nanovector; for example, silica with gold shell; gold covering can be tuned to allow selective activation. Nanocantilevers Antibodies are arranged on multiple beams; protein binding results in a deflection in a particular beam, which can be read by a laser.
nanoparticle formation in the presence of polypropylenimine dendrimers has also been found in metastatic prostate cancer cell lines, indicating their potential use for delivering therapeutic oligonucleotides in cancer cells in vivo.7 Furthermore, Thomas et al.8 have shown in vitro targeting of synthesized antibody against prostate-specific membrane antigen with conjugated dendrimer nanoparticles as a suitable platform for targeted molecule delivery into appropriate antigen-expressing cells. Studies investigating gene therapy in prostate cancer have also shown enhanced in vitro DNA transfection efficiency by novel folate-linked nanoparticles,9 and similarly a human transferrin-targeted cationic liposome-DNA complex, Transferrin-lipoplex, has shown enhanced stability, improved in vivo gene transfer efficiency, and long-term efficacy for systemic p53 gene therapy when used in combination with conventional radiotherapy.10 Anderson et al.11 have recently demonstrated that a polymer, termed C32, is capable of delivering genes to cancer cells more efficiently and with less toxicity than other polymers that have been tested in the field to date. Therapeutic genes delivered to cells in this manner are able to drive cellular production of a gene-encoded protein through normal processes. By genetically engineering the normal diphtheria toxin gene, a toxin was created that would be produced only in prostate cells. When injected into prostate tumors in animals with C32 nanoparticles, tumor growth was suppressed or reversed, relative to untreated tumors. Research is also being carried out to explore whether nanoparticles can be delivered intravenously to attack metastatic tumor cells, which are found throughout the body in advanced stages of cancer.12 With the obvious financial potential of a drug delivery system, this particular aspect of nanotechnology is receiving considerable attraction from the commercial sector, specifically the pharmaceutical industry.
13.4
Nanotechnology and Imaging
Nanotechnology has the opportunity to enhance the detection of pathology in a specific and sensitive manner. The ability to overcome barriers such as the blood– brain barrier could allow more accurate imaging of the central nervous system.13
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With enhanced specificity, markers of early-stage disease in malignancy could localize tumors before they progress and become incurable by conventional methods. This targeted approach could then utilize the same systems to deliver therapeutic agents at high concentrations to the tumor thus limiting the side effects and damage to the individual. The current mainstays of medical diagnosis with traditional circulating contrast media utilize broadly untargeted approaches. These techniques are well established and use contrast media to enhance the differentiation of structures. New diagnostic pharmaceuticals used in medical imaging are now being developed, which can be considered as nanotechnologies. Magnetic resonance imaging (MRI) has been used clinically for targeted imaging with gadolinium-based14 and iron oxide–based15 nanoparticles for the enhancement of conventional diagnostic modalities. This latter modality has allowed the development of techniques to accurately stage nodal disease in prostate cancer.15 In addition, low-density lipid nanoparticles have been used to enhance ultrasound imaging.16 For each current imaging discipline it could be possible to develop nanoparticles that can provide enhanced detection and subsequently targeted therapeutic capabilities.17 Second-generation super paramagnetic compounds of cross-linked iron oxide have also been developed.18,19 Such dendritic nanoparticles have multiple arms that can complex with targeting moieties, such as antibodies or enzyme substrates, permitting both magnetic and optical properties. In Switzerland, Mattei et al.20 have taken another approach using nanocolloid for the descriptive mapping of sentinel lymph node (SLN) anatomy using fusion imaging between single-photon emission computed tomography (SPECT) and CT following intraprostatic injection of technetium-99m (99m Tc) nanocolloid.20 Scintigraphy was performed 1 hour later, and fusion images with CT were scored blindly by an experienced radiologist and nuclear medicine physician. An average of ten lymph nodes were detected per patient (range: 2–19). The location of lymph nodes was highly variable and they concluded that the lymphatic drainage of the prostate appears to be more extensive than previously described in the literature. Presacral and common iliac regions seem to be primary rather than secondary drainage sites. Para-aortic and inguinal lymph nodes previously have not been considered primary drainage sites, which suggests that significant portions of SLN are not resected with routine extended or radical pelvic lymphadenectomy. A similar approach has been used in patients diagnosed with penile cancer21 and in bladder cancer by Liedberg et al. with 70 MBq 99mTc nanocolloid.22 These research-based techniques could produce highly relevant imaging for the treatment of patients with urological malignancies, especially in the context of determining localized prostate cancer. However, more research is required to validate these techniques. As well as utilizing conventional imaging modalities, nanotechnology has the potential to revolutionize molecular diagnostics to elucidate the key molecular defects for a particular disease. This process will require high-throughput detection devices that require nanogram quantities of analytics and reagents. With the current cost of molecular diagnostics escalating, it may be that increased use will inevitably
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expose these sophisticated tests to the economies of scale and decrease costs, making such testing available at the bedside.
13.5
Nanotechnology and Cancer Treatment
Nanotechnology allows the opportunity to deliver powerful cytotoxic agents to specific cancer cells without deleterious effects to other organ systems. However, lack of progress in avoiding degradation in vivo before achievement of therapeutic benefit has impeded major advances to date. Nonetheless, some examples exemplify the exception to this. Liposomal delivery systems have now overcome take-up by the reticuloendothelial system, which has historically compromised effectiveness.23 Nanotechnologies have utilized key differences in physiological parameters of the malignant environment. Liposomal delivery of chemotherapy has been utilized in the overexpression of fenestrations in cancer neovasculature to increase drug concentrations at the site of the tumor.24 This strategy has been used in the treatment of Kaposi’s sarcoma for over a decade24 and more recently in breast cancer.25 Liposomal drug delivery can be enhanced in a number of ways including local hyperthermia with thermostable liposome,26 photosensitizers,27 and ultrasound activation.28 Derycke et al.29 investigated the use of aluminium phthalocyanine tetrasulfonate, a known photosensitizer, encapsulated in transferrin-conjugated liposomes. Transferrin is overexpressed in bladder cancer cells because of the increased requirement for iron.29 They reported that photodynamic therapy for conjugated liposomes was more effective compared with the unconjugated controls.27 Liposomes have also been used for gene therapy targeting of renal cell carcinoma. Nakanishi et al.30 have targeted renal cell carcinoma cell lines and fresh ex vivo renal cell carcinoma tissue with cationic multilamellar liposomes containing the human interferon ß gene (IAB-1). They report significant cytotoxic effects with the addition of the IAB-1 gene in this setting. Prostate-specific membrane antigen (PSMA) represents a unique, specific targeting molecule for the directed treatment of prostate cancer in vivo with nanoparticles. Thomas et al.31 have shown that the in vitro targeting of synthesized antibody against PSMA with conjugated dendrimer nanoparticles is a suitable platform for targeted molecule delivery into appropriate antigen-expressing cells.
13.6
Nanotechnology, Uro-oncology, and Penile Cancer
Advances are constantly made in the development of a diverse range of surgical instruments. Robotic and robot-assisted surgery is also propagating throughout the globe. Specific to urology, the Enseal® device (SurgRx, Palo Alto, CA, USA) has been used to seal the dorsal venous complex during laparoscopic radical retropubic prostatectomy. This device utilizes millions of nanoparticles embedded into the
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instrument to regulate the temperature of the bipolar diathermy, which, in theory, minimizes collateral thermal spread and tissue damage with effective sealing of vessels up to 7 mm in size. Units have also reported its safe use in sealing the dorsal venous complex during robot-assisted radical prostatectomy.32 This report suggests that the Enseal device is effective, but they concede that the device takes longer to use.
13.6.1
Penile Cancer Imaging
As regards neoplasms of the penis, it has been demonstrated that lymphotropic nanoparticle-enhanced magnetic resonance imaging (LNMRI) with ferumoxtran-10 can accurately predict the pathological status of regional lymph nodes.33,34 Ferumoxtran-10 is made up of superparamagnetic iron oxide nanoparticles, which are phagocytosed by macrophages in normal lymph nodes and these show homogeneous uptake of ferumoxtran-10 and appear dark on T2-weighted MR images. However, lymph nodes containing metastases lack these macrophages and subsequently do not accumulate the nanoparticles and appear bright on T2 imaging. Using this technique it is possible to detect subcentimeter metastases in morphologically normal lymph nodes and also to accurately differentiate malignancy from enlarged reactive lymph nodes. In seven patients with penile cancer, MRI with lymphotrophic nanoparticles was 100% sensitive and 97% specific for lymph node metastasis.33
13.6.2
Management of Clinically Node-Negative (cN0) Patients
Additionally, in penile cancer, dynamic sentinel node biopsy with peritumour injection of 99mTc nanocolloid has already been investigated in clinically node-negative (cN0) patients with penile cancer. The technique has progressed from the original lymphangiographic studies performed by Cabanas in 197735 to the modern day use, incorporating several modifications, to reduce the false-negative rates and therefore allowing it to mature into a reliable and safe method for assessing lymph node status in cN0 penile carcinoma patients.36 When compared with a historical series from the same institute, this nonrandomized group was reported to have less morbidity than with conventional radical inguinal lymphadenectomy.21 Kroon et al. evaluated the results of 10 years dynamic sentinel node biopsy experience in penile carcinoma, in 140 patients with clinically node-negative groins. Lymphoscintigraphy was performed after injection of 99mTc -nanocolloid around the primary tumor. The sentinel node was intraoperatively identified with the aid of patent blue dye and a gamma ray detection probe. Subsequent lymph node dissection was performed only if metastatic disease was identified in the sentinel lymph node. With a median follow-up of 52 months, they found that lymphoscintigraphy visualized at least one sentinel node in 138 patients. Sentinel node metastasis were found in 37 inguinal regions of 31 patients. The sentinel node was the only tumor-positive node in 78% (29/37) of the dissection speci-
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mens. Complications occurred in only 8% of the operated groins. False-negative results were encountered in six patients resulting in a false-negative rate of 16%. Importantly, the 5-year disease-specific survival was 96% and 66% for patients with a tumor-negative sentinel node and tumor-positive sentinel node, respectively (p = 0.001). They concluded that dynamic sentinel lymph node biopsy in penile carcinoma offered important diagnostic, prognostic, and therapeutic information at the cost of only minor morbidity. Subsequently, the same group explored the role of repeat dynamic sentinelnode biopsy in clinically node-negative patients with locally recurrent penile carcinoma after previous penile surgery and sentinel-node biopsy in 12 patients.37 They found that no sentinel nodes were seen on preoperative lymphoscintigraphy in the five groins that had previously been dissected. A sentinel node was visualized on lymphoscintigraphy in the remaining 19 undissected groins. In 15 of these groins (79%) the sentinel node was identified during surgery. Histopathological analysis showed involved sentinel nodes in four groins of three patients. Additional metastatic nodes were found in one completion inguinal lymph node dissection specimen. During a median follow-up of 32 months after the repeat sentinel node biopsy, one patient developed a groin recurrence 14 months after a tumor-negative sentinel node procedure. The conclusion from this study was that repeat dynamic sentinel node biopsy was feasible in clinically node-negative patients with locally recurrent penile carcinoma despite previous sentinel node biopsy.21 Patients undergoing inguinal lymph node dissections can suffer from troublesome lower limb lymphedema which is refractory to conservative treatment. However, the development of nanoparticles which encourage tissue regeneration will be invaluable in the management of lymphedema.
13.7
Risks of Nanotechnology
Fundamental to the success of nanotechnology is its perceived safety by the public. Many concerns have been aired concerning the use of manufactured nanoparticles. A highly intensive, media-driven debate could be expected with the introduction of nanodevices, similar to the genetically modified food debate. The impact on human health has been assessed in the United Kingdom as part of a document published by the Office of Science and Technology. This independent article produced by the Royal Society and Royal Academy of Engineering represents an exhaustive discussion on the potential exposure to nanoparticles. It raises concerns that nanoparticles, because of their size and ability to pass across cellular membranes, represent a potential biohazard. They recommend that more research is directed at the toxicology of nanoparticles. The report compares nanotechnology development with asbestos fibers, which caused widespread health and safety concerns. With stringent attention to safety, nanotechnology could have a widespread beneficial impact on many aspects of the delivery of urological care. Regulation to prevent misuse will be paramount to enable maximum benefit with minimal risk for these powerful cutting edge technologies.
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Conclusion
It is widely expected that nanotechnology and nanomedicine will have a significant impact on penile cancer research and clinical practice, allowing intervention at the cellular and molecular level. With structured and safe implementation, nanotechnologies have the potential to revolutionize urological management of penile cancer.
References 1. Shergill IS, Rao A, Arya M, Patel H, Gill IS. Nanotechnology and potential applications in urology. BJU Int. 2006;97:219-220. 2. http://nihroadmap.nih.gov/nanomedicine 3. http://nsf.gov/eng/engadvise/PastMeelings/documents/nanoupdate_000.ppt 4. BECON Nanoscience and Nanotechnology Symposium Report. 2006. National Institutes of Health Bioengineering Consortium. 1-6-2000. 5. National Institutes of Health Bioengineering Consortium. BECON Nanoscience and Nanotechnology Symposium Report. 1-6-2000. Available at URL: www.becon.nih.gov/ becon_symposia.htm. 6. Sahoo SK, Ma W, Labhasetwar V. Efficacy of transferrin-conjugated paclitaxel-loaded nanoparticles in a murine model of prostate cancer. Int J Cancer. 2004;112:335-340. 7. Santhakumaran LM, Thomas T, Thomas TJ. Enhanced cellular uptake of a triplex-forming oligonucleotide by nanoparticle formation in the presence of polypropylenimine dendrimers. Nucleic Acids Res. 2004;32:2102-2112. 8. Thomas TP, Patri AK, Myc A, et al. In vitro targeting of synthesized antibody-conjugated dendrimer nanoparticles. Biomacromolecules. 2004;5:2269-2274. 9. Hattori Y, Maitani Y. Enhanced in vitro DNA transfection efficiency by novel folate linked nano particles in human prostate cancer and oral cancer. J Control Release. 2004;97: 173-183. 10. Xu L, Frederik P, Pirollo KF, et al. Self-assembly of a virus-mimicking nanostructure system for efficient tumor-targeted gene delivery. Hum Gene Ther. 2002;13:469-481. 11. Anderson DG, Peng W, Akinc A, et al. A polymer library approach to suicide gene therapy for cancer. Proc Natl Acad Sci USA. 2004;101:16028-16033. 12. http://nanotechwire.com/news.asp?nid_1523. 13. Lockman PR, Mumper RJ, Khan MA, Allen DD. Nanoparticle technology for drug delivery across the blood-brain barrier. Drug Dev Ind Pharm. 2002;28:1-13. 14. Oyewumi MO, Yokel RA, Jay M, Coakley T, Mumper RJ. Comparison of cell uptake, biodistribution and tumor retention of folate-coated and PEG-coated gadolinium nanoparticles in tumor-bearing mice. J Control Release. 2004;95:613-626. 15. Harisinghani MG, Barentsz J, Hahn PF, et al. Noninvasive detection of clinically occult lymphnode metastases in prostate cancer. N Engl J Med. 2003;348:2491-2499. 16. May DJ, Allen JS, Ferrara KW. Dynamics and fragmentation of thick-shelled microbubbles. IEEE Trans Ultrason Ferroelectr Freq Control. 2002;49:1400-1410. 17. Sullivan DC, Ferrari M. Nanotechnology and tumor imaging: seizing an opportunity. Mol Imaging. 2004;3:364-369. 18. Schellenberger EA, Hogemann D, Josephson L, Weissleder R. Annexin V-CLIO: a nanoparticle for detecting apoptosis by MRI. Acad Radiol. 2002;9(Suppl 2):S310-S311. 19. Wunderbaldinger P, Josephson L, Weissleder R. Crosslinked iron oxides (CLIO): a new platform for the development of targeted MR contrast agents. Acad Radiol. 2002;9(Suppl 2): S304-S306.
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20. Mattei A, Fuechsel FG, Z’Brun S, Baermann C, Krause TM, Studer UE. Precise description of prostatic sentinel-lymphnodes-anatomy (Sln) using fusion imaging between Spect and Ct-scanner after intraprostatic injection of technetium-99m-nanocolloid. Poster presentation (no. 1598) at AUA 2005. 21. Kroon BK, Horenblas S, Meinhardt W, et al. Dynamic sentinel node biopsy in penile carcinoma: evaluation of 10 years experience. Eur Urol. 2005;47:601-606. 22. Liedberg F, Chebil G, Davidsson T, Gudjonsson S, Mansson W. Intraoperative sentinel node detection improves nodal staging in invasive bladder cancer. J Urol. 2006;175:84-88. 23. Gabizon A, Papahadjopoulos D. The role of surface charge and hydrophilic groups on liposome clearance in vivo. Biochim Biophys Acta. 1992;1103:94-100. 24. Langer R. Drug delivery and targeting. Nature. 1998;392(6679 Suppl):5-10. 25. Park JW. Liposome-based drug delivery in breast cancer treatment. Breast Cancer Res. 2002;4:95-99. 26. Maruyama K, Unezaki S, Takahashi N, Iwatsuru M. Enhanced delivery of doxorubicin to tumor by long-circulating thermosensitive liposomes and local hyperthermia. Biochim Biophys Acta. 1993;1149:209-216. 27. Derycke AS, Kamuhabwa A, Gijsens A, et al. Transferrin conjugated liposome targeting of photosensitizer AlPcS4 to rat bladder carcinoma cells. J Natl Cancer Inst. 2004;96: 1620-1630. 28. May DJ, Allen JS, Ferrara KW. Dynamics and fragmentation of thick-shelled microbubbles. IEEE Trans Ultrason Ferroelectr Freq Control. 2002;49:1400-1410. 29. Derycke AS, de Witte PA. Transferrin-mediated targeting of hypericin embedded in sterically stabilized PEG-liposomes. Int J Oncol. 2002;20:181-187. 30. Nakanishi H, Mizutani Y, Kawauchi A, et al. Significant antitumoral activity of cationic multilamellar liposomes containing human IFN-beta gene against human renal cell carcinoma. Clin Cancer Res. 2003;9:1129-1135. 31. Thomas TP, Patri AK, Myc A, et al. In vitro targeting of synthesized antibody-conjugated dendrimer nanoparticles. Biomacromolecules. 2004;5:2269-2274. 32. Lee D, Lee JT, Sheperd D, Abrahams H. Preliminary use of the EnsealTM system for sealing of the dorsal venous complex during robotic assisted laparoscopic prostatectomy. 1186. 2005. AUA poster 2005. 33. Tabatabaei S, Harisinghani M, McDougal WS. Regional lymph node staging using lymphotropic nanoparticle enhanced magnetic resonance imaging with ferumoxtran-10 in patients with penile cancer. J Urol. 2005;174:923-927. 34. Cabanas RM. An approach for the treatment of penile carcinoma. Cancer. 1977;39:456-466. 35. Leijte JA, Kroon BK, Valdes Olmos RA, et al. Reliability and safety of current dynamic sentinel node biopsy for penile carcinoma. Eur Urol. 2007;52(1):170-177. 36. Mueller-Lisse UG, Scher B, Scherr MK, Seitz M. Functional imaging in penile cancer: PET/ computed tomography, MRI, and sentinel lymph node biopsy. Curr Opin Urol. 2008;18: 105-110. 37. Graafland NM, Leitje JA, Valdes Olmos Ra, et al. Repeat dynamic sentinel node biopsy in locally recurrent penile carcinoma. BJU Int. 2009;105:1121-1124.
Chapter 14
Follow-Up of Patients with Penile Cancer Niels M. Graafland and Simon Horenblas
14.1
Introduction
The primary aim of oncological treatment is to eradicate the underlying cancer with minimal morbidity to the patient. Besides adequate treatment of the disease, accurate follow-up is essential. Ideally, a follow-up schedule should reflect the pattern of recurrence and should be able to detect a tumor recurrence at the earliest stage, while causing the least possible burden to the patient and the healthcare system. The other important subgoals of oncological follow-up are to facilitate audit, support the psychological well-being of the patient and his relatives in coping with the disease and the education of healthcare professionals. Those against follow-up point to the fact that standard follow-up is often unable to pick up curable recurrences. An insight into the patterns of recurrence is essential in order to provide the most optimal follow-up schedule. In this chapter, we discuss follow-up schedules according to the different treatment settings used in penile carcinoma.
14.2
Patterns of Recurrence
The majority of recurrences in penile carcinoma develop within 5 years after the primary treatment. Within this the largest proportion will occur within 2 years after the initial treatment. The interval between treatment and recurrence seems to be dependent on the type of relapse. Recent data from a large two-institutional retrospective study involving 700 patients has shown that 66% of local recurrences, 86%
N.M. Graafland (*) Department of Urology, The Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands A. Muneer et al. (eds.), Textbook of Penile Cancer, DOI 10.1007/978-1-84882-879-7_14, © Springer-Verlag London Limited 2012
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Fig. 14.1 Cumulative risk of recurrence (in patients with a simultaneous local and regional or distant recurrence, the local recurrence was taken into account). (Adapted from Leijte et al.1)
Local recurrences
25 20 15
Regional recurrences
10 5 Distance recurrences 0 700 0
523
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168
132
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6 12 18 24 30 36 42 48 54 60 66 72 78 84 Time from diagnosis
of regional recurrence, and all distant recurrences were detected within the first 2 years, respectively (see Fig. 14.1 and Table 14.1).1 Consequently, follow-up should be intense during the first 2 years after surgery. A maximal follow-up of 5 years seems reasonable to detect the majority of recurrences. Similar to other types of solid tumors, a second primary tumor could develop because the remaining epithelium of the glans of the penis remains “at risk” for developing a malignancy or because of prolonged exposure to an etiological factor (i.e. HPV infection) when penile-preserving surgery has been performed.
14.2.1
Local Recurrence
The traditional belief that a 2 cm margin was required for adequate oncological control has been challenged in recent studies.2-4 Conservative techniques, involving excision margins of only a few millimetres, appear to offer excellent oncological control. For example, in a series of 51 patients with 102 surgical margins (skin and deep), 48% measured within 10 mm of the tumor edge and 90% within <20 mm resection margin. Only two patients developed local tumor recurrence during a median follow-up of 26 months which were successfully salvaged with partial penectomy.4 This study and others have encouraged the development of penile-preserving therapies assuming such techniques give the least burden for the patient. If recurrence does occur, the majority can be successfully salvaged without jeopardizing long-term survival.4,5 A microscopically incompletely resected primary tumor using penile-preserving surgery is an independent prognosticator for local tumor recurrence.5 Therefore, re-excision is indicated if histopathological analysis reveals tumor-positive surgical margins. The reader is cautioned that different time-intervals to recurrence have been described for different treatment managements. In patients undergoing brachytherapy for tumors confined to the glans, the median time to local recurrence in patients
Adapted from Leijte et al.1
Table 14.1 Overview of recurrence per year and cumulative Local recurrence (n = 130) Years after primary treatment Absolute% Cumulative % (95% CI) Year 1 40.0% 40.0% (31–47.9%) Year 2 26.2% 66.2% (57–73.4%) Year 3 10.7% 76.9% (68.4–83.1%) Year 4 7.7% 84.6% (77–89.7%) Year 5 3.1% 87.7% (80.5–92.2%) Regional recurrence (n = 65) Absolute % Cumulative % (95% CI) 63.1% 63.1% (49.3–73.1%) 23% 86.1% (74.6–92.4%) 6.2% 92.3% (82.1–96.7%) 6.2% 98.5% (89.2–99.8%) 1.5% 100%
Distant recurrence (n = 10) Absolute % Cumulative % (95% CI) 70% 70% (22.7–88.4%) 30% 100% – – – – – –
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was 22 months, with an upper range of even 23 years.6 Twenty percent of the recurrences occurred after 5 years. Thus the primary penile tumor management should be considered when determining the maximal follow-up period. The local recurrence rate in patients treated with penile-preserving techniques ranges between 20% and 50% in some series,1,5,7-9 and in those who had undergone partial or total penectomy 7%.1 Consequently, it seems oncologically sound to advise stricter follow-up in those patients undergoing penile-preserving surgery. Although local disease recurrence alone after penile-preserving surgery appears not to have a negative impact on disease-specific survival, every local tumor can be a potential source of new metastatic spread.10 Renewed nodal staging and optimal salvage treatment is recommended when patients present with recurrence. Prevention of local recurrence is the best treatment. The selection of the specific surgical techniques depends on tumor stage and localization.11
14.2.2
Regional Recurrence
The regional recurrence rate is dependent on several factors: (1) development of a local recurrence with new lymphatic spread and concurrent regional recurrence, (2) initial nodal treatment (e.g., close surveillance, dynamic sentinel node biopsy, or elective lymphadenectomy), and (3) pathological nodal status. For example, patients who underwent penile-preserving surgery have a higher probability of local recurrence and are therefore at a higher risk for subsequent lymphatic spread. Currently, the majority of patients are staged with minimally invasive staging techniques. Recurrence rates of patients with pathological node-negative (pN0) lymph nodes ranges from 0 to 3%, while recurrence rates of those with tumor-positive lymph nodes (pN+) are approximately 20%. Clinically node-negative patients who are managed with watchful waiting (pNX) generally have a 20% chance of regional recurrence. These rates depend on tumor stage,12,13 degree of differentiation,12-15 and the presence of lymphovascular invasion.13,16,17 Historical data indicate that the majority of inguinal recurrences in patients managed with surveillance typically develop within 2 years.18 Follow-up schedules regarding regional recurrences should therefore be strict during the initial 2 years of follow-up and becoming less frequent thereafter. Although the literature indicates that regional recurrence has a major impact on survival,1 successful salvage treatment is still possible. It is important to emphasize that data regarding recurrences are often variable depending on the treatment modalities that are employed for the patients e.g. close clinical surveillance, dynamic sentinel lymph node biopsy, or lymphadenectomy. Consequently, regional tumor recurrence in a patient may present a different management approach. For example, a patient managed with close clinical surveillance who subsequently develops a regional recurrence may be cured following an inguinal lymphadenectomy. On the other hand, a patient who develops an inguinal recurrence having already undergone an inguinal lymphadenectomy has a poor prognosis. Thus, the success of salvage treatment is clearly related to the initial treatment strategy.
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Notwithstanding these differences, early detection (which may result in early salvage treatment) is oncologically sound. No data are available on the use of additional imaging techniques in facilitating the detection of recurrences. However, regular ultrasound investigation of the lymph nodes with fine-needle aspiration cytology (FNAC) of suspicious nodes may aid earlier detection of metastatic nodes that are not detected on physical examination.
14.2.3
Distant Recurrence
The majority of distant recurrences are incurable because they are often accompanied by advanced disease. It seems reasonable to focus follow-up in patients with penile carcinoma on the locoregional situation with additional imaging when indicated. It is important to emphasize that the risk of lymphatic dissemination beyond the groin is correlated with the extent of nodal involvement.19-23 In general, 20–30% of patients with positive inguinal nodes have positive pelvic nodes.19-23 The likelihood of pelvic nodal involvement is related to the number of positive nodes in the inguinal specimen and/or presence of extranodal extension.22,23 Such features and also pelvic lymphadenopathy are consequently predictors of further metastatic spread, i.e. distant metastasis. Hence, patients without or only minimal metastatic disease (e.g. one intranodal metastasis) are at low risk for development of distant recurrence. If patients have recurrences beyond the groins they are candidates for palliative treatment only or for inclusion in clinical trials as the disease-specific survival is poor. The group of patients at high risk for pelvic metastasis could potentially benefit from preoperative imaging techniques. Unfortunately, the use of CT imaging is limited. Recently, Zhu et al. showed that CT imaging detected pelvic lymphadenopathy with a 37.5% sensitivity and 100% specificity.24 These figures are in accordance with data from CT imaging in detecting lymph node metastasis in prostate cancer.25 In recent years, fluorine-18-fluorodeoxyglucose (18F-FDG) positron emission tomography with CT (PET/CT) for staging lymph nodes have shown its superiority compared with CT imaging or PET alone.26,27 For example, in 260 patients with solid tumors, the nodal status identified by PET/CT was significantly more accurate compared to CT alone (92% vs. 76%).27 In patients with clinically nodepositive penile carcinoma PET/CT imaging has also shown potential in depicting pelvic lymphadenopathy with a sensitivity of 91% (95% confidence interval [CI]: 58–100) and specificity of 100% (95% CI: 80–100).28 An extra advantage of screening patients at risk for pelvic nodal involvement with whole-body PET/CT imaging is identification of distant metastasis. Although in the previous study, no direct comparison was made with CT alone, no differences are to be expected in favor of contrast-enhanced CT imaging in depicting pelvic metastasis.26,27 Considering the poor survival in patients with pelvic metastasis, patients with preoperative evidence of pelvic lymphadenopathy are in need for more treatment than surgery alone. Neoadjuvant chemotherapy has successfully been used in small series,29,30 and is probably required to improve survival.
Adapted from Leijte et al.1
3 months
pN+
6 months
1 year
6 months
3 months 6 months
6 months 1 years
Years 3, 4, and 5
3 months 6 months
Interval of follow-up Years 1 and 2
pN0
Recommendations for follow-up of primary tumor Penile-preserving treatment Amputation Recommendations for follow-up of the inguinal lymph nodes Wait and see
Table 14.2 Recommendations for follow-up
Regular self-examination Ultrasound with FNAC Regular self-examination Ultrasound with FNAC Regular self-examination Ultrasound with FNAC
Regular self-examination Regular self-examination
Examinations
5 years
5 years
5 years
5 years 5 years
Maximum length of follow-up
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14.3
289
Follow-Up Recommendations
Based on the patterns of recurrence the following scheme is suggested. A maximum follow-up of 5 years is recommended. The majority of recurrences will develop within the first 2 years, hence there is more intense follow-up in these years. During the first 2 years, a 3-month follow-up is recommended in the patients who have undergone penile-preserving techniques and 6-month interval for patients undergoing a penile amputation. The role of self-examination by the patient should also be emphasized. Regarding the follow-up of the regional lymph nodes during the first 2 years, a more intense follow-up is advised in the patients who underwent close surveillance (pNX), are staged with minimally invasive staging techniques (such as dynamic sentinel node biopsy), or staged pN+. Patients staged pN0 after prophylactic lymphadenectomy have a lower risk of recurrence and can be managed less strictly with 6-month intervals in the first 2 years. Ultrasound with FNAC of suspicious-looking nodes is recommended when indicated in addition to a physical examination in order to detect metastases that are difficult to palpate. For all these groups mentioned above, the follow-up can be less intense in years 3, 4, and 5 (Table 14.2). Additional imaging should be performed on indication.
References 1. Leijte JA, Kirrander P, Antonini N, Windahl T, Horenblas S. Recurrence patterns of squamous cell carcinoma of the penis: recommendations for follow-up based on a two-centre analysis of 700 patients. Eur Urol. 2008;54:161. 2. Hoffman MA, Renshaw AA, Loughlin KR. Squamous cell carcinoma of the penis and microscopic pathologic margins: How much margin is needed for local cure? Cancer. 1999;85:1565. 3. Agrawal A, Pai D, Ananthakrishnan N, Smile SR, Ratnakar C. The histological extent of the local spread of carcinoma of the penis and its therapeutic implications. BJU Int. 2000;85:299. 4. Minhas S, Kayes O, Hegarty P, Kumar P, Freeman A, Ralph D. What surgical resection margins are required to achieve oncological control in men with primary penile cancer? BJU Int. 2005;96:1040. 5. Lont AP, Gallee MP, Meinhardt W, van Tinteren H, Horenblas S. Penis conserving treatment for T1 and T2 penile carcinoma: clinical implications of a local recurrence. J Urol. 2006; 176:575. 6. de Crevoisier R, Slimane K, Sanfilippo N, et al. Long-term results of brachytherapy for carcinoma of the penis confined to the glans (N- or NX). Int J Radiat Oncol Biol Phys. 2009;74:1150. 7. Bandieramonte G, Colecchia M, Mariani L, et al. Peniscopically controlled CO2 laser excision for conservative treatment of in situ and T1 penile carcinoma: report on 224 patients. Eur Urol. 2008;54:875. 8. Windahl T, Andersson SO. Combined laser treatment for penile carcinoma: results after long-term followup. J Urol. 2003;169:2118. 9. Meijer RP, Boon TA, van Venrooij GE, Wijburg CJ. Long-term follow-up after laser therapy for penile carcinoma. Urology. 2007;69:759. 10. Graafland NM, Leijte JA, Valdes Olmos RA, van Boven HH, Nieweg OE, Horenblas S. Repeat dynamic sentinel node biopsy in locally recurrent penile carcinoma. BJU Int 2009 [Epub ahead of print].
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11. Hegarty PK, Shabbir M, Hughes B, et al. Penile preserving surgery and surgical strategies to maximize penile form and function in penile cancer: recommendations from the United Kingdom experience. World J Urol. 2009;27:179. 12. Solsona E, Iborra I, Rubio J, Casanova JL, Ricos JV, Calabuig C. Prospective validation of the association of local tumor stage and grade as a predictive factor for occult lymph node micrometastasis in patients with penile carcinoma and clinically negative inguinal lymph nodes. J Urol. 2001;165:1506. 13. Slaton JW, Morgenstern N, Levy DA, et al. Tumor stage, vascular invasion and the percentage of poorly differentiated cancer: independent prognosticators for inguinal lymph node metastasis in penile squamous cancer. J Urol. 2001;165:1138. 14. Ornellas AA, Nobrega BL, Wei Kin Chin E, Wisnescky A, da Silva PC, Santos Schwindt AB. Prognostic factors in invasive squamous cell carcinoma of the penis: analysis of 196 patients treated at the Brazilian National Cancer Institute. J Urol. 2008;180(4):1354-1359. 15. Velazquez EF, Ayala G, Liu H, et al. Histologic grade and perineural invasion are more important than tumor thickness as predictor of nodal metastasis in penile squamous cell carcinoma invading 5 to 10 mm. Am J Surg Pathol. 2008;32:974. 16. Lopes A, Hidalgo GS, Kowalski LP, Torloni H, Rossi BM, Fonseca FP. Prognostic factors in carcinoma of the penis: multivariate analysis of 145 patients treated with amputation and lymphadenectomy. J Urol. 1996;156:1637. 17. Ficarra V, Zattoni F, Cunico SC, et al. Lymphatic and vascular embolizations are independent predictive variables of inguinal lymph node involvement in patients with squamous cell carcinoma of the penis: Gruppo Uro-Oncologico del Nord Est (Northeast Uro-Oncological Group) Penile Cancer data base data. Cancer. 2005;103:2507. 18. Lubke WL, Thompson IM. The case for inguinal lymph node dissection in the treatment of T2-T4, N0 penile cancer. Semin Urol. 1993;11:80. 19. Srinivas V, Morse MJ, Herr HW, Sogani PC, Whitmore WF Jr. Penile cancer: relation of extent of nodal metastasis to survival. J Urol. 1987;137:880. 20. Ravi R. Correlation between the extent of nodal involvement and survival following groin dissection for carcinoma of the penis. Br J Urol. 1993;72:817. 21. Horenblas S, van Tinteren H, Delemarre JF, Moonen LM, Lustig V, van Waardenburg EW. Squamous cell carcinoma of the penis. III. Treatment of regional lymph nodes. J Urol. 1993;149:492. 22. Lont AP, Kroon BK, Gallee MP, van Tinteren H, Moonen LM, Horenblas S. Pelvic lymph node dissection for penile carcinoma: extent of inguinal lymph node involvement as an indicator for pelvic lymph node involvement and survival. J Urol. 2007;177:947. 23. Zhu Y, Zhang SL, Ye DW, et al. Prospectively packaged ilioinguinal lymphadenectomy for penile cancer: the disseminative pattern of lymph node metastasis. J Urol. 2009;181:2103. 24. Zhu Y, Zhang SL, Ye DW, Yao XD, Jiang ZX, Zhou XY. Predicting pelvic lymph node metastases in penile cancer patients: a comparison of computed tomography, Cloquet’s node, and disease burden of inguinal lymph nodes. Onkologie. 2008;31:37. 25. Hovels AM, Heesakkers RA, Adang EM, et al. The diagnostic accuracy of CT and MRI in the staging of pelvic lymph nodes in patients with prostate cancer: a meta-analysis. Clin Radiol. 2008;63:387. 26. Lardinois D, Weder W, Hany TF, et al. Staging of non-small-cell lung cancer with integrated positron-emission tomography and computed tomography. N Engl J Med. 2003;348:2500. 27. Antoch G, Saoudi N, Kuehl H, et al. Accuracy of whole-body dual-modality fluorine-18-2fluoro-2-deoxy-D-glucose positron emission tomography and computed tomography (FDGPET/CT) for tumor staging in solid tumors: comparison with CT and PET. J Clin Oncol. 2004;22:4357. 28. Graafland NM, Leijte JA, Valdes Olmos RA, Hoefnagel CA, Teertstra HJ, Horenblas S. Scanning with 18 F-FDG-PET/CT for detection of pelvic nodal involvement in inguinal node-positive penile carcinoma. Eur Urol. 2009;56:339. 29. Culkin DJ, Beer TM. Advanced penile carcinoma. J Urol. 2003;170:359. 30. Leijte JA, Kerst JM, Bais E, Antonini N, Horenblas S. Neoadjuvant chemotherapy in advanced penile carcinoma. Eur Urol. 2007;52:488.
Chapter 15
Living with Penile Cancer: Effects on Psychology and Quality of Life Ian Eardley and Victor Palit
15.1
Introduction
The male penis is first the organ through which a man passes urine and voids in the standing position. Second, the penis is an organ that is used for sexual purposes, either when masturbating or when penetrating a woman for procreation or for sexual pleasure. However, and perhaps no less importantly, the penis is also of enormous psychological importance to men. In many cultures the penis symbolizes masculinity with attributes such as strength, endurance, ability, courage, intelligence, knowledge, dominance over other men, and possession of women. Some of these concepts date back over many thousands of years; for instance, there is evidence that prehistoric cave dwellers equated the values of strength and power (as well as virility and fertility) to penile size. Given this historical context it is perhaps no surprise that even today many men place great importance on the size and appearance of their penis. Diseases that affect the penis not only potentially interfere with the physiological functions outlined above but will also result in psychological consequences on “masculinity” that can be devastating. This is particularly true for penile cancers. Not only will the presence of a neoplastic lesion affect voiding function, sexual function, and the psyche, but the subsequent treatment, which almost invariably involves some form of partial or total amputation of the penis, will have long-term consequences for the man. There will be an alteration in the way that the patient voids combined with a change in his ability to have satisfactory sexual intercourse, and there will inevitably be an effect upon his psyche. It is largely for these reasons that there have been attempts in recent years to undertake a more conservative
I. Eardley (*) Pyrah Department of Urology, St. James University Hospital, Leeds, West Yorkshire, UK
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approach in managing penile cancer, in the hope that surgery will more likely preserve normal genitourinary function and minimize the psychological distress of therapy. The degree to which these functional and psychological effects have been assessed in men with penile cancer, and in men who have undergone surgical treatment for penile cancer, is limited. There are very few studies that assess sexual function and almost no studies that assess voiding function in these men while the psychological effects have been assessed infrequently and inconsistently. Given the trend toward more conservative surgery, it is perhaps surprising that at this time there is very little good-quality evidence to support the presumption that penilepreserving techniques have less functional and psychological morbidity than the more traditional radical therapies.
15.2
Patients’ Experiences Prior to and at the Time of Diagnosis of Penile Cancer
Psychology undoubtedly plays a role in the delay in diagnosis that is commonly seen in this disease as evidenced by the frequency with which patients present with advanced cancer, and the significant delay that commonly occurs between the development of symptoms and the presentation to a physician. For instance, in one series of 700 men, over 50% had at least T2 disease at the time of diagnosis and treatment1 while in a second series of men with a localized tumor of the penis, treated by laser therapy, over a third of patients experienced a delay of more than 6 months between the appearance of symptoms and the definitive diagnosis being made.2 While some of the delays undoubtedly reflect medical misdiagnosis, it has been suggested that between 15% and 50% of men delay seeking treatment for penile cancer for psychological reasons.3 These reasons include fear, embarrassment, and symptom denial despite the abnormality being clearly visible and palpable. While there is a suggestion that this delay is more commonly seen in single men as opposed to married men,2 there is no evidence that it is associated with the age of the patient. Where misdiagnosis has occurred, the patient will often experience concomitant frustration at the delay in seeing a doctor who is able to recognize and treat the underlying tumor. The diagnosis itself is typically accompanied by shock, fear, and disbelief.4 The initial concerns usually relate to the diagnosis of cancer and the fear of dying as a result of the disease. At this time, there is typically a dependence upon others which helps many men to cope with the initial shock of the diagnosis. The main support comes from the patient’s partner,4 although healthcare professionals and other patients can provide valuable insight into the practicalities of treatment, and perhaps more importantly the relatively good prognosis of patients with penile cancer following treatment. After the initial shock comes the fear of the practical effects of treatment, which for most patients will involve some form of excisional surgery of the tumor. There is a growing realization for the patient that there may be some impact upon voiding,
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upon sexual function, and upon masculinity. Although in many patients the stereotypical masculine response to illness is to “get on with it” there will inevitably be underlying concerns and fears. For example there will be anxiety regarding the risk of tumor recurrence and the potential effects upon sexual function and relationships. Within existing relationships, there may be a concern that surgery will significantly affect their sexual life, while men who are not in a relationship will be concerned about starting and maintaining future relationships. Even within close relationships there may be a tendency for the patient to attempt to hide the full extent of the surgery from their partner for fear of ridicule or for fear of sexual incompetence.4 Outside the relationship, it is common for the man to wish to hide the true diagnosis, and to simply be seen as a “cancer sufferer” rather than have to admit to a disease affecting the penis, with the accompanying perception of some reduction in his masculinity. Although any cancer diagnosis results in an inevitable decline in sexuality and a general state of health, this decline is likely to be more significant in men with penile cancer and often does not recover with time.
15.3
Sexual Experiences Following Treatment for Penile Cancer
Once surgery has taken place, the fears that initially dominated, namely the fears for recurrence and survival are gradually replaced by concerns regarding rehabilitation, particularly regarding urinary and sexual function. A number of studies have investigated sexual function following surgery for penile cancer, but the literature regarding voiding function is extremely limited. Studies investigating patients who have undergone a partial or total penectomy for penile cancer have been limited to small retrospective studies. A Norwegian study of 30 men who had been treated for penile cancer assessed sexual function by using a semistructured interview together with a number of self-administered questionnaires.5 The median age of the patients was 57 years and all had undergone treatment at least 11 months previously (median delay 80 months). Unsurprisingly, those patients (n = 4) who had undergone the most radical surgery (namely, total penectomy) had the worst sexual function, as evidenced by a reduced sexual interest, severely limited sexual ability, markedly reduced sexual enjoyment, and markedly reduced sexual frequency. Those who had undergone radiotherapy (n = 12) or local excision or laser therapy (n = 5) had the best sexual function, while those patients who had undergone partial penectomy (n = 9) were in an intermediate position. There was a suggestion that the younger men had better sexual function than the older men, although comorbidities that might affect sexual function (such as diabetes) were not recorded. A subsequent Brazilian study explored sexual function in 18 men who had undergone partial penectomy by means of a structured interview and completion of the International Index of Erectile Function (IIEF).6,7 The partial penectomy procedure followed the principle that a minimum 2 cm margin of tumorfree tissue was required to achieve oncological control. The median age of the men
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was 52 years, and all had been sexually active prior to surgical treatment. All had a minimum residual penile stump length of at least 2.5 cm following surgery and the median time from surgery was 23.5 months. Patients were asked to retrospectively assess their sexual function before surgery and to then assess their function at the time of interview. Significant reductions in erectile function, orgasmic function, sexual desire, and intercourse satisfaction were identified. These two studies, taken together have led to a view that the more radical the penile surgery, the greater the effect on sexual function, with even partial penectomy having significant adverse effects. The traditional view that surgery for penile cancer requires a 2-cm tumor-free margin in all cases has been challenged.8,9 Recently a more conservative approach using treatment modalities such as laser therapy, brachytherapy, or by conservative surgery such as glans resurfacing or glansectomy has been advocated.9 While the potential benefits of using a more conservative surgical approach has not been fully evaluated the effects of laser therapy for Tis, T1, and T2 tumors has been investigated in some detail.2 A cohort of 67 Swedish men were treated using a combined carbon dioxide and neodymium:YAG laser for tumor excision in a single centre between 1986 and 2000. Forty six with a median age of 63.5 years were available for follow-up and were assessed by formal interview at a median of 3 years following treatment. Of the 46 men, six had not been sexually active prior to treatment and a further 10 never resumed sexual activity following treatment. In the rest, there was maintenance of normal sexual activities, with some partners performing manual genital stimulation (17/46) and fellatio (7/46). An assessment of life satisfaction suggested that domains relating to sexual life and partner relation were comparable to Swedish men of approximately the same age. Set against this, somatic and psychological health in the patients with penile cancer was lower than might have been expected, perhaps reflecting ongoing anxiety regarding their long-term prognosis. A second smaller study explored sexual function in 14 men who had undergone glansectomy, or partial penectomy followed by glans reconstruction using urethra.10 This was a prospective study, which used the IIEF to assess sexual function up to 1 year following surgery, and appeared to show no significant loss in erectile function, orgasmic function, or sexual desire. In summary then, there is evidence that partial and total penectomy adversely affects sexual function, with the greatest degree of dysfunction occurring in men who undergo more radical surgery and therefore lose more penile length. A general rule is that a residual postoperative penile length of 4 cm or more can still allow patients to achieve an adequate erection as well as ejaculate. Attempts at conservative therapy appear to be oncologically safe, but the evidence that they provide better sexual outcomes is at this time limited. Indeed, the quality of the evidence is relatively poor, with most publications being small and retrospective in nature. Although radiotherapy for localized disease is rarely used nowadays, there is some evidence of maintenance of sexual interest following treatment with a minimal impact on sexual activity or coital frequency. However, the studies reporting this5,11 reported the use of radiotherapy in a younger cohort of men than those undergoing surgery which might be expected to affect the outcome. Sexual enjoyment and satisfaction remains high following radiotherapy or laser treatment indicating
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that therapeutic options which maintain length and appearance have the lowest impact on sexual function.5,11,12
15.4
Experiences with Micturition Following Treatment for Penile Cancer
The literature regarding the effects of penile surgery on voiding function is limited. Men who undergo a total penectomy will inevitably need to sit down to void. In addition those who undergo more “radical” partial penectomies will also need to sit down to void, and will need to attend to hygiene issues when urine dribbles down over the scrotum. What is perhaps less obvious, is that even those with a penile stump often have difficulty in finding “something to hold on to”4 while those who have undergone conservative penile surgery may have problems with spraying of the urinary stream. Some men use a funnel in order to minimize spraying of urine at the time of micturition but the extent of the urinary problems, the need for treatment, and the effect upon the psyche of the patient are poorly documented in the literature and need further research.
15.5
Psychological Effects in Men Who Have Undergone Treatment for Penile Cancer
The psychological effects of penile cancer surgery have been poorly researched, although it is relatively easy to speculate on the relevant issues. Mental illness has been observed in 20% of men who have undergone treatment for penile cancer, most commonly related to anxiety disorders.13 The central theme relates to the patient’s perception that masculinity has somehow been lost or diminished.4 There will be a notable change in the appearance of the penis, and a probable loss of length for those who have undergone penile surgery. As described earlier, penile size has historically been associated with attributes such as strength, virility, endurance, ability, courage, intelligence, and knowledge, and the psychological effects of any form of excisional surgery should not be underestimated. Qualitative research suggests that one area of concern is the appearance.4 Even within a stable relationship, there may be reticence or embarrassment in showing the postoperative penis to their partner and particularly for single men this concern may result in a barrier to further relationships. The underlying concerns include fear of rejection or some form of sexual humiliation and therefore any surgical technique that produces a cosmetically acceptable appearance should theoretically alleviate this concern to some degree. There is some evidence that conservative surgery, including laser surgery has a lesser effect upon this problem. In one study 78% of men undergoing treatment with laser reported a satisfactory cosmetic result,12 while
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there are several studies suggesting that men undergoing penile-preserving surgery have a high satisfaction rate following surgery.14-16 Men who undergo surgery for penile cancer also have concerns in relation to the appearance of their penis in front of other men, as might be experienced in a urinal or in the communal showers of a sports club. Accordingly they often avoid the urinal and pass urine in private, while there is a tendency to avoid communal showers and changing rooms. Again the achievement of cosmetically acceptable outcomes by the use of more conservative surgical approaches should alleviate this, although data to support these techniques are limited. It is in these areas of fear and anxiety regarding masculinity, sexual function, and voiding function that patient support is most important. It is important for the healthcare professional team to anticipate these concerns and to provide support, either verbal or written. Online resources for patients might be expected to help, but given the rarity of penile cancer, particularly in the Western world, the availability of good-quality patient information, written or electronic is currently limited. Healthcare professionals should provide support and information from the moment the patient first seeks medical attention. In the United Kingdom a dedicated penile cancer nurse specialist provides this support and acts as a point of contact for the patients as they make their journey through the treatment pathway (Fig. 15.1). They are able to explain the steps of investigation and treatment, while providing support for the practical problems and wound management issues (Figs. 15.2 and 15.3) outlined in this chapter. For those patients undergoing more radical surgery, patients can be introduced to the concept of phalloplasty reconstruction which can ultimately allow patients to improve their selfesteem and body image as well as allowing them to void standing (see Chap. 11).
15.5.1 Effects of Treatment for Penile Cancer on Quality of Life Data regarding quality of life following surgery for penile cancer has been reviewed.17 The authors in this review identified 128 men from 6 separate studies in whom quality-of-life data had been collected, of which 5 were retrospective studies. Control groups were rarely assessed. They found that any conclusions from the data were limited by the many and varied instruments used to assess quality of life, by the methodology used to collect the data, and the small numbers of patients studied and it is perhaps not surprising that contradictory results were often obtained. For instance the General Health Questionnaire (GHQ) was used in 3 studies, with two suggesting impaired well-being5,18 and the third19 suggesting no such impairment. The Hospital and Depression Scale (HADS) was used in two studies, and while one suggested significant impairment18 the other suggested no change.19 Although we might assume that conservative treatments for penile cancer will be associated with a less marked effect upon quality of life further work in this area is still required. We need prospective studies with a larger sample size, using appropriately validated instruments that assess both general aspects of quality of life as well as disease specific.
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Fig. 15.1 A penile cancer nurse specialist provides preoperative information and support to a newly diagnosed patient
Fig. 15.2 Dressings and close monitoring of grafts is essential to achieve an excellent postoperative result
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Fig. 15.3 Postoperative appearance of a penilepreserving procedure using a split-skin graft
15.6
Conclusion
The penis has enormous symbolic importance to all men, as well as being important for sexual function and micturition. Surgical treatment of penile cancer is often mutilating and will inevitably affect both of these functions, and will have additional psychological impact. Currently the data describing these changes, together with the accompanying effects upon quality of life are poorly documented, and the data that exist are generally of poor quality, in that it is usually retrospective, uncontrolled, and performed in small numbers of patients. We still need to know more about the functional and psychological effects of conservative treatments and also the effects of radical and conservative surgery for penile cancer in order to counsel our patients. The impact of penile cancer on sexual function and quality of life should be addressed soon after diagnosis and information resources made available to the patients in order to prepare them psychologically.
References 1. Leijte JAP, Kirrander P, Antonini N, Windahl T, Horenblas S. Recurrence patterns of squamous cell carcinoma of the penis: recommendations for follow-up based on a two-centre analysis of 700 patients. Eur Urol. 2008;54:161-169. 2. Skeppner E, Windahl T, Andersson SO, Fugl-Meyer K. Treatment-seeking, aspects of sexual activity and life satisfaction in men with laser-treated penile carcinoma. Eur Urol. 2008;54: 631-639. 3. Misra S, Chaturvurdi A, Misra NC. Penile carcinoma: a challenge for the developing world. Lancet Oncol. 2004;5:240-247.
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4. Bullen K, Matthews S, Edwards S, Marke V. Exploring men’s experiences of penile cancer surgery to improve rehabilitation. Nurs Times. 2009;102:12. 5. Opjordsmoen S, Waehre H, Aass N, Fossa SD. Sexuality in patients treated for penile cancer: patients experience and doctor’s judgement. Br J Urol. 1994;73:554-560. 6. Romero FR, Romero KRP, Mattos MAE, Garcia CRC, Fernandes RC, Perez MDC. Sexual function after partial penectomy for penile cancer. Urology. 2005;66:1292-1295. 7. Rosen RC, Riley A, Wagner G, Osterloh H, Kirkpatrick J, Mishra A. The international index of erectile function (IIEF): a multidimensional scale for the assessment of erectile dysfunction. Urology. 1997;49:822-829. 8. Smith Y, Hadway P, Biedrzycki O, Perry MJ, Corbishley C, Watkin NA. Reconstructive surgery for invasive squamous carcinoma of the glans penis. Eur Urol. 2007;52:1179-1185. 9. Minhas S, Kayes O, Hegarty P, Kumar P, Freeman A, Ralph D. What surgical resection margins are required to achieve oncological control in men with primary penile cancer. BJU Int. 2005;96:1040-1043. 10. Gulino G, Sasso F, Falabella R, Bassi PF. Distal urethral reconstruction of the glans for penile carcinoma: results of a novel technique at 1-year follow-up. J Urol. 2007;178:941-944. 11. Ficarra V, Mofferdin A, D’Amico A, et al. Comparison of the quality of life of patients treated by surgery or radiotherapy in epidermoid cancer of the penis. Prog Urol. 1999;9(4):715-720. 12. Windahl T, Skeppner E, Andersson SO, et al. Sexual function and satisfaction in men after laser treatment for penile carcinoma. J Urol. 2004;172(2):648-651. 13. Opjordsmoen S, Fossa SD. Quality of life in patients treated for penile cancer. A follow-up study. Br J Urol. 1994;74(5):652-657. 14. Palminteri E, Berdondini E, Lazzeri M, et al. Resurfacing and reconstruction of the glans penis. Eur Urol. 2007;52(3):893-899. 15. Shindel AW, Mann MW, Lev RY, et al. Mohs micrographic surgery for penile cancer management and long term follow up. J Urol. 2007;178(5):1980-1985. 16. Brown CT, Minhas S, Ralph DJ. Conservative surgery for penile cancer: subtotal glans excision without grafting. BJU Int. 2005;96(6):911-912. 17. Maddineni SB, Lau MM, Sangar VK. Identifying the needs of penile cancer sufferers: a systematic review of the quality of life, psychosexual and psychosocial literature in penile cancer. BMC Urol. 2009;9:8. 18. Ficarra V, Righetti R, D’Amico A, et al. General state of health and psychological well being in patients after surgery for urological malignancy. Urol Int. 2000;65:130-134. 19. D’Ancona CA, Botega NJ, De Moraes C, Lavoura NS, Santos JK, Rodrigues Netto N. Quality of life after partial penectomy for penile carcinoma. Urology. 1997;50:593-596.
Chapter 16
Future Directions in Penile Cancer Paul K. Hegarty and Curtis A. Pettaway
16.1
Introduction
It is apparent that for penile cancer patients as a whole, surgery as a single therapy can cure 80–90% of patients according to large or unselected series.1,2 This does not mean that surgery has reached its limit in the management of penile cancer. For example, recent data indicating that lymph node density (LND) is the strongest predictor of disease specific survival (DSS)3 imply that perhaps the quality of lymph node dissection is important in altering the natural history among patients with metastatic disease. With the limitations of surgery, novel strategies for treating both the primary tumor and the use of multimodal strategies in advanced disease are important areas requiring development. Therefore, it is important that patients are treated within a system that applies surgery (as well as other therapies) appropriately and effectively in order to maximize the cure while minimizing the morbidity. Cancer control or cure is not the sole objective, as both the quality of life and survivorship issues frequently supervene following treatment. The patient’s priorities may change as the prognosis changes with each stage of treatment. These factors should be routinely addressed in units managing penile cancer. This chapter addresses some of the gaps in our understanding of the disease, and its management. It will discuss several controversial areas and future clinical trials in order to address these gaps. We will also look at the likely impact of primary prevention on the incidence and demographics of penile cancer. Finally, we examine the rationale for changes in the delivery of penile cancer care and how this could not only impact clinical care but also potentially improve both clinical and basic science research. P.K. Hegarty (*) Department of Urology, Guys Hospital, London, UK
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Penile Cancer Staging: Modifications to the 6th Edition TNM Staging System
The TNM staging system is a widely accepted staging tool. However, deficiencies in the 6th edition of the American Joint Committee on Cancer (AJCC) were highlighted in a report of 513 cases treated over a 50-year period at a single center.1 They described no difference in survival between stages T2 and T3 and nodal stages N1 and N2. Importantly based upon their own data they recommended changes in the staging system (i.e., the existing sixth edition TNM) with more meaningful prognostic stratification. This modified TNM system was relevant in that the variables examined were a part of routine clinical staging in distinction to the 6th edition TMN which is in essence a pathologic system. On January 1, 2010, the 7th edition of the unified TNM staging for penile cancer became standard.4 This represents a consensus between representatives of the American Joint Committee on Cancer (AJCC) and Union Internationale Contre le Cancer (UICC). This is the first change in the official TNM penile cancer staging since 1987 and includes a number of significant changes: • T1 is subdivided into T1a and T1b, based on lymphovascular invasion (LVI) and grade. This has the practical division of T1 into high and low risk for selecting patients for ILND, when inguinal nodes are clinically impalpable. • Invasion of the prostate has moved from T3 to T4, with T3 denoting urethral invasion only. • There is provision for clinical and pathologic lymph node assessment. The distinction between superficial and deep inguinal lymph nodes has been eliminated. • In the absence of nodal or metastatic disease, the new subdivision T1b becomes Stage II, while T1a remains Stage I. • Any lymph node positive disease is now at least Stage III. Clinical and pathologic staging not only determines prognosis but forms the basis of integrating multimodal therapy in the management of advanced disease. These changes aim to clarify the management of cancer, facilitate meaningful comparison between cohorts, and support multi-institutional research. Future studies should compare the prognostic value of both the 7th edition TNM4 and that proposed by Leitje et al.1 using large data sets to determine the optimal variables that best stratify patient prognosis.
16.3
Management of the Primary Lesion
Significant progress in surgical techniques, laser therapy, and patient selection has resulted in preservation of function and (or) form in the majority of cases of penile cancer. Centers in the UK have described the results of more conservative/
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reconstructive surgical strategies.5,6 Laser therapy has become an excellent treatment strategy for low-stage lesions (i.e. Tis, T1) and has been shown to maintain quality of life.5 Brachytherapy is also an alternative strategy for organ preservation with encouraging results from a few centers of excellence. A recent report from Toronto and Ottawa describes the delivery of 60 Gy over 4–5 days7 using either continuous low-dose rate or pulse dose rate intratumoral radiotherapy. Cause-specific survival at 10 years was 83.6%. Ten of the sixty-seven cases required penectomy for local recurrence (8 cases) or tissue necrosis (2 cases). Urethral stenosis occurred in 9%. These data raise the need for a randomized trial of brachytherapy versus surgery in the management of the primary lesion in terms of efficacy and quality of life outcomes. Such a study would require collaboration between clinicians and a willingness for patients to undergo randomization to the two different modalities.
16.4 16.4.1
Management of Regional Lymph Nodes Clinically Negative Inguinal Lymph Nodes (cN0 Disease)
This has been the main area of controversy in the management of penile cancer. It is clear that early inguinal lymph node dissection (ILND) is superior to delayed ILND.8 Although the evidence for this is retrospective, a prospective randomized trial is currently neither feasible nor ethical given that surgical cure of patients with metastatic disease is limited to those patients with low volume metastases.3,9 However, traditional ILND is associated with significant morbidity, from both the incision and the disruption of lymphatic channels.10 This has fueled very different strategies. The first is improving patient selection for ILND by performing dynamic sentinel node biopsy (DSNB). This approach is associated with a significantly reduced morbidity. After a decade of evolution in penile cancer, the false negative rate is down to about 7% in a report on 323 patients from the two pioneering centers.11 Of note the authors of the study did not see significant evidence for a learning curve at the second center where recurrence rates were similarly low. This suggested that the modified procedure developed by the Netherland’s group was transferable to another center.11 Despite this low rate, the consequences of a false negative study are of a concern as development of nodal disease proved fatal in 4 of the 6 patients who had an initial negative DSNB.12 The technique of DSNB is likely to be refined further with the development of alternative dyes or markers, which will hopefully reduce the false negative rate further. A superficial inguinal lymph node dissection with frozen section analysis of the lymph nodes remains an excellent option for the initial management of high-risk patients presenting with clinically negative groins.13 The other strategy of reducing the morbidity of ILND has been addressed by two pioneering groups. These have been termed video endoscopic inguinal lymphadenectomy (VEIL)14 or the endoscopic lymphadenectomy for penile cancer
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(ELPC).15 Both use laparoscopic access approaches and principles to perform an ILND. This reduces the skin incision related morbidity substantially. The lymphatic complications such as prolonged lymph drainage or lymphocoele are similar to open ILND. Further innovations in this field may involve use of fibrin glue or other tissue sealants. There have been no reports on this technique since first described in 1990.16 These biological products are frequently used in other minimal access procedures such as laparoscopic partial nephrectomy as hemostatic agents but their efficacy is unproven for sealing lymph vessels. This is an area for a future penile cancer study whereby novel sealants for lymphatic channels may be investigated. One could certainly also envisage a future randomized trial between DSNB and VEIL/ELPC in determining efficacy as a staging procedure, complications, and quality of life among clinically node negative high-risk patients.
16.5
16.5.1
Integrating Therapy to Improve Survival in Advanced Disease Chemotherapy
While overall cancer-specific survival rates of 80–90% in early stage penile cancer have been reported with surgery alone. Higher stage disease (i.e., bilateral inguinal metastases, extranodal extension, pelvic nodal metastases) requires additional treatment in order to achieve a cure. The neoadjuvant paradigm aims to treat systemic disease prior to surgery as in other conditions, such as bladder cancer.17 Three contemporary series have shown that selected patients can benefit from induction chemotherapy. Corral et al.18 reported on the long-term follow-up of a prospective group of patients treated with bleomycin, methotrexate, and cisplatin. Objective responses were noted in 12 (57%) including 2/5 with distant metastases. Six patients in the group (28.5%) achieved disease-free status with either chemotherapy alone (n = 2) or surgery (n = 3) or radiotherapy (n = 1) with a median survival of 27.8 months. This was significantly longer than that of those not achieving disease-free status (6.7 months, p = 0.004). Thus, this prospective study showed that a multidisciplinary approach to achieve a disease-free status could prolong survival. Subsequently, Leijte et al.19 from the Netherlands Cancer Institute reviewed their experience with neoadjuvant chemotherapy in patients with unresectable disease on presentation. The series included 20 patients treated with five different regimens including (1) single agent bleomycin; (2) bleomycin, vincristine, methotrexate; (3) cisplatin, 5-fluorouracil; (4) bleomycin, cisplatin, methotrexate; and (5) cisplatin, irinotecan. The objective responses were evaluable in 19 (one patient died due to bleomycin toxicity after 2 weeks) with 12 responses (63%, 2 complete, 10 partial). Among 12 responders only 9 subsequently underwent surgery, as two died of bleomycin-related complications while the third was deemed too unfit for surgery. Eight of nine responding patients undergoing
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surgery (two were pT0) were free of disease at their last assessment with a median follow-up of 20 months. This is in contrast to three nonresponders who underwent surgery for palliative intent. All three died within 4–8 months due to loco-regional recurrence. The findings from this study indicate that response to chemotherapy together with an aggressive surgical approach provides the optimal scenario for significant palliation or potential cure. In a separate study, Bermejo et al.20 described the surgical considerations and complications among ten patients who had either a response or stable disease after combination chemotherapy followed by surgery. The regimens utilized included (1) bleomycin, methotrexate, cisplatin; (2) paclitaxel, ifosfamide, cisplatin (TIP), or paclitaxel, carboplatin. This cohort of patients exhibited bulky inguinal or pelvic metastases with the only exclusions being patients with fixed pelvic masses or complete encasement of the femoral vessels. Among five patients exhibiting an objective response, three were alive and disease-free at 48, 50, and 73 months. Two further patients died (one of disease at 30 months, another of unknown causes at 21 months). Among the five remaining patients with stable disease, three died from the disease within 7 months one patient treated with bleomycin died of “failure to thrive” at 8 months. However, another patient treated with paclitaxel and carboplatin achieving only stable disease was alive and disease-free at 84 months. These data appear to reinforce the concept that response to systemic chemotherapy prior to surgery enhances the chance for long-term survival among those undergoing surgical resection. Related to systemic therapy the authors reported that the TIP regimen was well tolerated and all three pT0 responses at surgery were among patients treated with TIP. This provided the rationale for the prospective phase II study of 30 patients (registered on the National Institute of Health clincaltrials.gov website as NCT00512096). This cohort has completed therapy with the final results pending. Preliminary analysis of data of the first 20 patients describes an objective response rate of 55% and a pathologic complete response in 10% (two patients).21 In the United Kingdom, a multicenter nonrandomized trial has been opened examining the role of neoadjuvant docetaxel, cisplatin, and 5-fluorouracil (TPF) chemotherapy in patients with locally advanced or metastatic penile cancer. Primary outcome is to assess the efficacy of the regimen. The secondary outcomes are to assess the number of cases rendered operable following chemotherapy, to evaluate safety and tolerability of the regime and to report outcomes in terms of disease-free and overall survival. The inclusion criteria are histologically proven squamous cell carcinoma of the penis, and the following stages: M1 disease, T any and N any M0 with N3 disease M0 with inoperable N2 disease Any T4 disease. Optional inclusion of N1 disease, depending on discussion by the multidisciplinary team. All cases are to receive three courses of chemotherapy, without a nontreatment arm. A total of 26 cases are to be recruited. Based on the activity of this regime, this phase II study may lead to larger studies.
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Radiotherapy
The literature is particularly sparse in the area of radiotherapy as a treatment modality for advanced penile cancer. One of the largest series demonstrating a benefit of radiotherapy for lymph node metastases and/or distant metastases from penile cancer was published by Ravi and associates in 1994.22 Pertinent to the advanced disease presentation setting, 33 patients were treated with preoperative radiotherapy at 40 Gy over 4 weeks and subsequently underwent inguinal lymphadenectomy. Of note, after radiotherapy and surgery only 8% had evidence of extranodal extension (ENE) and 3% recurred within the groin. This is relevant as in a prior report within a contemporary time frame the incidence of ENE was 33% among patients treated with surgery alone and groin recurrence was noted in 19%. The difference for both ENE and local recurrence were both statistically lower (p = <0.01 and 0.03, respectively). The data are strongly suggestive but not definitive that preoperative radiotherapy for nodes ³4 cm without skin fixation improved local control. The 5-year survival among the latter group was 70%. In women with cancer of the vulva, a disease site that has a natural history and lymphatic drainage similar to that of the penis, Hyde et al.23 reported that debulking plus adjuvant radiotherapy was as effective as radical inguinal node dissection. Parthasarthy et al.24 noted that after primary inguinal node dissection, there was improved disease-free survival when they received adjuvant postoperative radiotherapy. Specific to bulky inguinal nodes at presentation the Gynecologic Oncology Study Group performed a phase II study to assess the efficacy of preoperative chemoradiation prior to inguinal lymphadenectomy among patients with bulky N2/ N3 inguinal nodes from vulvar squamous cancer.25 Forty-two patients received split course chemoradiation consisting of cisplatin (50 mg/m2) and 5-fluorouracil [5-FU] (1000 mg/m2) combined with 4760 cGy to the primary tumor and inguinal nodes. In a total of 38 patients, 37 were taken to surgery and had an inguinal node dissection and in 15 (40.5%) no tumor was found. Thirty-six of thirty-seven patients (97%) had no inguinal recurrence. However, only 12 patients (31%) remained alive without evidence of disease at 78 months follow-up as death due to other causes7 and distant metastases9 occurred. Thus preoperative chemoradiation in this prospective study improved resectability and local control among this cohort of patients with bulky inguinal metastases. Thus there is some evidence in advanced stage penile cancer that preoperative radiotherapy for bulky nonfixed nodes may improve resectability and decrease local recurrence. However, the morbidity of this approach requires further study. Based on the available data from other squamous malignancies, the use of chemoradiation should be further explored in multi-institutional trials.
16.6
Molecular Biology of Penile Cancer
Much of the research into penile cancer has been based upon clinicopathologic factors as predictors of metastasis or survival. Focus is now shifting toward genetic and epigenetic events in penile cancer. Recently, an excellent review on this topic was
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published by Muneer et al.26 They discuss the complexity of interaction of HPV within the cell, much of which is derived from cervical cancer research in women. In a systematic review of 31 papers published between 1986 and 2008, constituting data from 1,466 cases, the majority HPV subtypes were HPV-16 and HPV-18.27 The incidence of HPV depends on the histological subtype, ranging from 76% being detected in basaloid SCC to as low as 25% in verrucous SCC. Overall 52% of invasive penile cancers out of 145 cases from Denmark are associated with HPV.28 HPV appears to inhibit the action of p53 on cell regulation. Interestingly, HPV-negative penile cancer is usually associated with mutation of p53. This may explain why cases of penile cancer that are HPV negative have a poorer prognosis.29 Thus virtually all penile cancer cases are associated with either a mutated p53 or inhibition of the wild-type (normal) p53. Thus the central role of p53 in the pathogenesis of penile cancer should be the focus of future research with restoration of normal function a specific goal. Future gene therapy may well be focused on this, and is likely to benefit from studies performed in more common squamous malignancies.
16.7
Growth Factor Receptors and Tyrosine Kinases
Growth factor receptors mitigate their intracellular signal transduction pathway via intracellular tyrosine kinases that modulate cellular functions such as protein synthesis, cell turnover, cell adhesion and migration, among other processes. Several growth factor receptor inhibitors and tyrosine kinase inhibitors (TKIs) have been developed in the last decade. They have entered clinical use, notably in renal cell cancer where agents such as sunitinib, sorafenib, and bevacizumab are showing clinical utility as single agent therapies. In non-small cell lung cancer epidermal growth factor receptor (EGFR) mutation or over-expression predicted for response to Erlotinib, however, screening for mutations appeared to have most benefit among women with non-squamous malignancy.30 Clinical trials of EGFR antibodies or TKIs had only modest survival benefits in lung cancer. This may well be due to redundancy in the signaling pathways, with several different receptor tyrosine kinase being simultaneously activated such that inhibition of only one may not have a large impact on downstream effects. This has been demonstrated in glioblastoma cell lines and tumor tissue where the activation of multiple receptor tyrosine kinases was shown. In fact, downstream signaling was only affected with the use of combined strategies (i.e., erlotinib, imatinib, and a C-met inhibitor together).31 Another factor in the impact of targeted therapy may be the magnitude of inhibition. While many epithelial malignancies over-express EGFR, the degree of up-regulation may vary. A recent paper correlated lung cancer histopathology with the expression of EGFR.32 Over-expression was more prevalent in squamous cell carcinomas (SCC) than adenocarcinomas (ADC) (71% vs. 48%). Until recently, no trial or case report had explored the application of such agents in penile cancer.33 Pagliaro et al. recently described a preliminary experience with EGFR expression and therapy among patients with metastatic penile cancer.34 Thirteen cases were assayed
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for EGFR expression with tissue from lymph node metastasis in five patients, inguinal or scrotal skin metastasis in two patients, and the primary tumor in six patients. Tumor cells in all cases were positive for EGFR, and 9 were scored as 3+ or strongly positive. All of the patients received one or more EGFR-targeted therapies including erlotinib (one patient), cetuximab (three patients), or cetuximab combined with one or more cytotoxic agents (nine patients). Six patients received a second or third EGFR-targeted therapy. Grade 3 or 4 adverse events were limited to cellulitis, thrombocytopenia, and tumor hemorrhage (one patient each). Two patients had disease progression during initial treatment with paclitaxel, ifosfamide, and cisplatin (TIP), then had partial responses to TIP plus cetuximab. Two patients had partial responses to cetuximab and cisplatin, also after having disease progression while receiving TIP. A patient with visceral metastases who had extensive prior chemotherapy received cetuximab and cisplatin as salvage treatment and experienced objective tumor regression lasting 3 months. These results indicate that EGFR plays a clinically important role in metastatic penile carcinoma and is a promising target for therapy.
16.8
Personalized Medicine
As our knowledge of the underlying pathogenesis of cancer increases, clinicians will be able to select patients for more targeted therapeutic options. A number of units are developing tumor and serum biobanks with the aim of characterizing the DNA signature as well as the epigenetic phenomena to correlate with clinical outcomes and response to therapy. A group from Maastricht plans to use a tissue bank to study the genomics and proteomics of patients with penile cancer (National Institute of Health, ClinicalTrials.gov Identifier NCT00157352). There is a need for consensus between tissue banks on methods of DNA and protein extraction as well as standardization of assay protocols and clinical parameters, so that meaningful comparisons can be made and facilitate collaboration. We look forward to the publication of DNA heat maps, demonstrating the genes that are up-regulated and down regulated in penile cancer. It would be particularly interesting to compare the genetic fingerprint of primary tumors with those from lymph node metastases. With the evolution of DNA finger-printing and the characterization of cellular processes, it is likely that therapies will be tailored according to a patient’s tumor profile. The concept of personalized medicine is currently available in breast cancer, with therapies selected according to estrogen, progesterone, and HER2/neu status. However, this will continually evolve with array-based technologies to develop gene signatures.35 The primary tumor in penile cancer can be easily biopsied for characterization of the cancer prior to choosing the therapy. Furthermore, inguinal nodes are more accessible than intraabdominal lymph nodes in order to perform fine needle aspiration for cytological examination. Therefore, penile cancer is suitable for neoadjuvant targeted therapy of primary and/ or nodal disease. Future urologic oncologists may well work with oncologists who treat other squamous sites (e.g., lung, vulva, or head/neck cancer) in treating cancer based on its DNA and receptor signature rather than the location of the primary tumor.
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16 14
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Fig. 16.1 Age at diagnosis for a total of 100 consecutive patients in the UK2
16.9
Impact of Specific Prevention Strategies on Disease Incidence
The age at presentation in a prospective study from the UK demonstrates the number of cases presenting in each 5-year group, from age 30 (Fig. 16.1). The average age at presentation was 62 with a quarter of cases occurring in men under 50 years of age. The Organisation for Economic Co-operation and Development (OECD) publishes the estimated and projected demographics, broken down by country.36 Their data are based on birth rates, mortality, and immigration. From these they derive the projected data comparing population distribution according to age for the years 2000 and 2050 (Fig. 16.2). Scenario planning is a means of linking multiple factors to generate a number of potential futures that can be used for strategic planning. It does not represent a forecast, as it provides a range of possible outcomes, or as defined by Porter37 “an internally consistent view of what the future might turn out to be - not a forecast, but one possible future outcome”. Scenario planning involves examining relevant parameters, either singly or in combination. This can lead to the formation of clusters of possible futures to assist in strategic planning. From Fig. 16.2, the magnitude of change for each 5-year group is estimated and predicts how this will influence prevalence of penile cancer in 2050. From this it is possible to formulate a model that assesses the potential interaction of risk factor management and demographics for a whole population. In the first scenario, no action is taken to prevent penile cancer and the model presumes stable incidence of disease. Due to the increasing numbers of men in the older age groups, this projects that the number of men presenting with penile cancer will increase by 47%, with the greater proportion being in older men (Fig. 16.3). The median age at presentation shifts from the 60–64 age group to the 65–69 age group.
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in 2000 1
in 2050 UNITED KINGDOM
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85+ 80 − 84 75 − 79 70 − 74 65 − 69 60 − 64 55 − 59 50 − 54 45 − 49 40 − 44 35 − 39 30 − 34 25 − 29 20 − 24 15 − 19 10 − 14 5−9 0−4 .10
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Fig. 16.2 Population distribution among males in the UK. Blue bar represents 2000 data, whereas the other line in the bar represents projected demographics for 2050, as published by the OECD36
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Fig. 16.3 Projected increase in incidence of penile cancer in the UK by the year 2050. This model can then be applied in the following two interventional scenarios, circumcision and HPV vaccination
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Circumcision
The incidence of penile cancer is far lower in countries where neonatal circumcision is routine. Furthermore, a renewed interest in circumcision in health promotion has been fuelled due to the observed 50–60% risk reduction of contracting HIV demonstrated in some studies38,39 (Fig. 16.4). In the UK, circumcision is performed for medical reasons in only 0.3% of boys under the age of five.40 Circumcision reduces the risk of developing HPV by two-thirds.41 This model is applied to estimate the potential benefit of circumcising all males up to the age of 12 commencing in 2012. It assumes the maximal benefit of reducing the risk of penile cancer by two-thirds. By 2050 only men under age 50 will have been exposed to the programme. This translates into an overall increase of 5% in incidence by 2050 relative to the projected rate (Fig. 16.5) in 2050 which would increase by 47%. More patients would be in the older part of the range, the median age at presentation being between 65 and 69 years. Thus the initial benefit in a programme of routine neonatal circumcision would be seen in the prevention of penile cancer in younger men, at an age when they are more sexually active.
16.9.2
HPV Vaccination
The second scenario focuses on what effect a vaccine against HPV could have. There is a clear rationale in vaccinating young females to prevent cervical cancer. Vaccinating males has been suggested to reduce the total HPV burden in the population as a whole,42 often described as the “herd effect”. It is attractive to consider vaccinating both males and females to prevent HPV-related malignancies. In particular, cost-effectiveness analysis favors male vaccination in the circumstance of poor uptake by females. It is estimated that the cost of investigating and treating HPV in males between age 15 and 24 is $2.9 billion per annum.43 This is the same direct medical costs as for HIV, whereas genital herpes costs one-tenth of this and hepatitis B only $5.8 million. HPV is implicated in up to 90% of early penile cancer. This scenario goes to the extreme position of how much a national program of vaccinating all males aged up to 22 years, from the year 2012, would impact on the incidence of penile cancer in 2050. This model makes a number of assumptions, namely that the programme is well organized with full compliance due to a strong health promotion campaign, that the vaccinated males are naive to HPV exposure, and that there is a 90% risk reduction for the cohort that receives the vaccine. These assumptions are used to see the potential maximal impact such a programme could have on the primary prevention of penile cancer. The age of the men in 2050 will include those over age 22 in 2007, who would have missed out on vaccination. This model predicts a 27% reduction compared to current rates as demonstrated in Fig. 16.6. Again there would be a greater proportion of patients in the older (unvaccinated) age groups, where the median age at presentation would lie between 70 and 74 years.
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a
b
Fig. 16.4 Circumcision clinics based on the Orange Farm model in rural areas may benefit populations with a high incidence of HPV-related penile cancer. (a) Orange Farm circumcision clinic, which was developed in order to provide a comprehensive adult male circumcision service in African low-income settings with a high incidence of HIV. (b) The interior of the clinic, where trained medical staff perform male circumcisions (Photos courtesy of Bertran Auvert, University of Versailles)
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25
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Fig. 16.5 Projected incidence of penile cancer with program of circumcising boys under age 12
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Fig. 16.6 Incidence of penile cancer if vaccination program is successful
Thus it is clear that even with a major programme of primary prevention that presumes a successful 90% risk reduction for all participants translates to a 27% reduction in overall disease incidence can be anticipated within four decades. Again the most dramatic risk reduction is among young men. Furthermore, eradication of high-risk HPV is surely going to have a significant impact in the long-run for both males and females. Such an analysis is currently wanting. Regardless of whether such programmes occur, there will be an ongoing requirement for service provision
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in the long term. These two approaches provide our best chance of preventing penile cancer. Countries with a higher prevalence of penile cancer may see greater benefits in the long term.
16.10
The Future of Penile Cancer Research and Clinical Care
Much of the research in penile cancer has been driven by interested clinicians, usually with smaller patient data sets from a wide referral base with little or no designated research funding. Progress in our knowledge of this condition has been hampered by a combination of factors including: • • • • •
Rarity of penile cancer in the developed nations, particularly in the United States Paucity of prospective studies Absence of penile cancer lobby in matters of health policy Lack of multicenter collaboration Scarcity of funding
16.10.1
Super-regional Referral Units
The concept of Super-regional referral units could serve as the “engine” of change for some of the above dilemmas as few surgeons see sufficient cases to develop expertise. Small surgical volumes probably impact on outcomes for individual patients. Currently there is a paucity of prospective studies and little by way of multi-disciplinary care available. Unfortunately to date there has been only one prospective study addressing quality of life, psychosexual well being, and social issues relating to penile cancer and its treatment.44 This deficit needs to be addressed by referral centers treating a high volume of cases. To address these dilemmas, a number of countries have developed compulsory referral networks, whereby all new cases of penile cancer are referred to specialized units. In the UK, it is recommended that such a unit covers a population of at least four million people.45 Other countries may require different stipulations according to the national incidence. There are several advantages to this healthcare network. • It concentrates skill-sets into one disease-based unit. The care is patient centered with a full range of service that should include dedicated nursing, psychosexual counseling, radiology, pathology, urology, plastic surgery and administrative support, as well as access to social and spiritual support teams. Such units should have academic links, working with biostatisticians, tumor registries, tissue banks, and laboratory scientists. • The network can collect all cases from a prescribed geographical area. This means that research will represent a larger cohort, including a whole spectrum of the endemic disease rather than highly selected cases that may be found with other referral systems.
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• These networks are better placed to design and recruit for clinical trials. Due to the holistic approach of such a unit, they have the potential for multimodal therapy for advanced disease and may perform quality of life studies. Being at the frontline of delivery of care, they can advise on the development of preventative strategies. • They may reduce morbidity of inguinal lymph node dissection (ILND), by evolving techniques such as DSNB or VEIL. They may work with surgical oncologists who manage inguinal nodes for other pathologic entities (e.g., melanoma, vulval cancer, head and neck) to draw on the experience gained in more common malignancies where appropriate. • Due to enhanced patient flow, networks should provide higher level evidence by virtue of prospective studies, with better follow-up addressing not just direct oncological parameters but also survivorship issues. • Using agreed upon international staging, management, and reporting systems, there is potential (and need) for multinational studies as well as specific clinical trials. There are also some theoretical and practical disadvantages to this approach. • Research and development is limited to fewer clinicians/scientists, although it is doubtful that the other extreme of dilution of case volumes is preferable. • Patients may dislike having to travel for management of their cancer and subsequent follow-up. This may affect compliance. Hopefully the prospect of holistic management with potentially improved cancer outcomes would outweigh this disadvantage for the individual. • There may be resistance of clinicians to refer cases to the unit, but national guidelines should overcome such obstacles. • Adequate funding for the unit to achieve optimal clinical, research, and administrative goals may be difficult in the setting of a rare disease; however, collectively the units could generate more of a political lobby.
16.11
Conclusion
There are indications that many of the obstacles to progress are being overcome with higher quality research being carried out. There are a number of international collaborations, for example the International Consultation in Urologic Disease on Penile Cancer held in Santiago, Chile, brought together leaders in the field from throughout the world and resulted in guidelines published covering penile cancer in detail (November 2008 – full report available at
[email protected]). A nonprofit foundation would be of particular benefit in the coordination of research with respect to soliciting and managing philanthropic contributions and the coordination distribution of funds through peer reviewed research grants. Countries with a low incidence of disease should develop super-regional referral systems similar to the UK model described above. Countries with a higher incidence of penile cancer can provide resources in terms of clinical data and tissue. Collaboration
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across the developed and developing worlds, along with better funding, is a key to the success in the expanding our understanding and improving the management of penile cancer.
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19. Leijte JA, Kerst JM, Bais E, et al. Neoadjuvant chemotherapy in advanced penile carcinoma. Eur Urol. 2007;52(2):488-494. 20. Bermejo C, Busby JE, Spiess PE, Heller L, Pagliaro LC, Pettaway CA. Neoadjuvant chemotherapy followed by aggressive surgical consolidation for metastatic penile squamous cell carcinoma. J Urol. 2007;177:1335-1338. 21. Pagliaro L, Williams D, Daliani D, et al. Neoadjuvant paclitaxel, ifosfamide, and cisplatin chemotherapy prior to inguinal/pelvic lymphadenectomy for stage Tany, N2-3, M0 squamous carcinoma of the penis (abstract #602). J Urol. 2006;175:195. 22. Ravi R, Chaturvedi HK, Sastry DV. Role of radiation therapy in the treatment of carcinoma of the penis. Br J Urol. 1994;74(5):646-651. 23. Hyde SE, Valmadre S, Hacker NF, et al. Squamous cell carcinoma of the vulva with bulky positive groin nodes – nodal debulking versus full groin dissection prior to radiation therapy. Int J Gynecol Cancer. 2007;17(1):154-158. 24. Parthasarathy A, Cheung MK, Osann K, et al. The benefit of adjuvant radiation therapy in single-node-positive squamous cell vulvar carcinoma. Gynecol Oncol. 2006;103(3): 1095-1099. 25. Montana GS, Thomas GM, Moore DH, et al. Preoperative chemo-radiation for carcinoma of the vulva with N2/N3 nodes: a gynecologic oncology group study. Int J Radiat Oncol Biol Phys. 2000;48(4):1007-1013. 26. Muneer A, Kayes O, Ahmed HU, Arya M, Minhas S. Molecular prognostic factors in penile cancer. World J Urol. 2009;27:161-167. 27. Miralles-Guri C, Bruni L, Cubilla AL, Castellsagué X, Bosch FX, de Sanjosé S. Human papillomavirus prevalence and type distribution in penile carcinoma. J Clin Pathol. 2009;62: 870-878. 28. Krustrup D, Jensen HL, van der Brule AJ, Frisch M. Histological characteristics of human papilloma-virus-positive and -negative invasive and in situ squamous cell tumours of the penis. Int J Exp Pathol. 2009;90:182-189. 29. Lont AP, Kroon BK, Horenblas S, et al. Presence of high-risk human papillomavirus DNA in penile carcinoma predicts favorable outcome in survival. Int J Cancer. 2006;119:1078-1081. 30. Rosell R, Moran T, Queralt C, et al. Screening for epidermal growth factor mutations in lung cancer. N Engl J Med. 2009;361:958-967. 31. Stommel JM, Kimmelman AC, Ying H, et al. Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. Science. 2007;318:287-290. 32. Lee HJ, Xu X, Choe G, et al. Protein overexpression and gene amplification of epidermal growth factor receptor in nonsmall cell lung carcinomas: comparison of four commercially available antibodies by immunohistochemistry and fluorescence in situ hybridization study. Lung Cancer. 2010;68(3):375-382. 33. Heidenreich A, Thüer D, Pfister D. Value of targeted therapy for penile cancer. Urologe A. 2008;47:1320-1327. in German. 34. Pagliaro LC, Osai W, Tamboli P, Vakar-Lopez F, Pettaway CA. Epidermal growth factor receptor expression in and targeted therapy for metastatic squamous cell carcinoma of the penis. J Clin Oncol (Meet Abstr). 2007;25:14045. 35. Soitirou C, Pusztai L. Molecular origins of cancer: gene-expression signatures in breast cancer. N Engl J Med. 2009;360:790-800. 36. OECD Statistic Portal. Available at: http://www.oecd.org/statsportal/ 37. Porter ME. Competitive Advantage. New York: Free Press; 1985. 38. Bailey RC, Moses S, Parker CB, et al. Male circumcision for HIV prevention in young men in Kisumu, Kenya: a randomised controlled trial. Lancet. 2007;369:643-656. 39. Gray RH. Male circumcision for HIV prevention in men in Rakai, Uganda: a randomised trial. Lancet. 2007;369:657-666. 40. Cathcart P. Trends in paediatric circumcision and its complications in England between 1997 and 2003. Br J Surg. 2006;93:885-890. 41. Castellsagué X, Bosch FX, Muñoz N, et al. Male circumcision, penile human papillomavirus infection, and cervical cancer in female partners. N Engl J Med. 2002;45:1105-1112.
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42. Giuliano AR. Human papillomavirus vaccination in males. Gynecol Oncol. 2007;107: S24-S26. 43. Chesson HW, Blandford JM, Gift TL, Tao G, Irwin KL. The estimated direct medical cost of sexually transmitted diseases among American youth, 2000. Perspect Sex Reprod Health. 2004;36:11-19. 44. Maddineni SB, Lau MM, Sangar VK. Identifying the needs of penile cancer sufferers: a systematic review of the quality of life, psychosexual and psychosocial literature in penile cancer. BMC Urol. 2009;9:8. 45. National Institute for Clinical Excellence. Guidance on Cancer Services. Improving Outcomes in Urological Cancers – The Manual. London: NICE; 2002:83-85. http://www.nice.org.uk/ pdf/Urological_Manual.pdf.
Appendix
Appendix 1: Penile Cancer Staging Systems The Jackson staging system was initially introduced in 1966 and divided patients into four groups based on the operability and nodal metastases.
Table A.1 Jackson classification 1966 • Stage I Confined to glans or prepuce • Stage II Invasion into shaft or corpora • Stage III Operable inguinal lymph node metastasis • Stage IV Tumor invades adjacent structures; inoperable inguinal lymph node metastasis
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The first TNM classification was introduced in 1968 and following two subsequent revisions the 1987 TNM staging system remained unchanged until recently. Table A.2 TNM 2002 classification of penile cancer Primary tumor TX Primary tumor cannot be assessed T0 No evidence of primary tumor Tis Carcinoma in situ Ta Noninvasive verrucous carcinoma T1 Tumor invades subepithelial connective tissue T2 Tumor invades corpus spongiosum or cavernosum T3 Tumor invades urethra or prostate T4 Tumor invades other adjacent structures Regional lymph nodes NX Regional lymph nodes cannot be assessed N0 No regional lymph node metastasis N1 Metastasis in a single superficial inguinal lymph node N2 Metastasis in multiple or bilateral superficial inguinal lymph nodes N3 Metastasis in deep inguinal or pelvic lymph node(s), unilateral or bilateral Distant metastasis (M) MX: Distant metastasis cannot be assessed M0: No distant metastasis M1: Distant metastasis
An additional prognostic grouping has also been developed and recently modified. Table A.3 Original AJCC/UICC stage groupings Stage 0 • Tis, N0, M0 • Ta, N0, M0 Stage I • T1, N0, M0 Stage II • T1, N1, M0 • T2, N0, M0 • T2, N1, M0 Stage III • T1, N2, M0 • T2, N2, M0 • T3, N0, M0 • T3, N1, M0 • T3, N2, M0 Stage IV • T4, any T, M0 • Any T, N3, M0 • Any T, any N, M1 More recently this has been modified by the AJCC which has subdivided Stage III into IIIa and IIIb as shown below Stage IIIa T1-3, N1, M0 Stage IIIb T1-3, N2, M0
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The most recent TNM classification was introduced in 2009 which has introduced a subdivision for T1 tumors and redefined the nodal staging. Table A.4 2009 TNM clinical classification of penile cancer T
Primary tumor TX T0 Tis Ta T1
Primary tumor cannot be assessed No evidence of primary tumor Carcinoma in situ Non-invasive verrucous carcinoma, not associated with destructive invasion Tumor invades subepithelial connective tissue T1a Tumor invades subepithelial connective tissue without lymphovascular invasion and is not poorly differentiated or undifferentiated (T1G1-2) T1b Tumor invades subepithelial connective tissue without/with lymphovascular invasion or is poorly differentiated or undifferentiated (T1G3-4)
T2 T3 T4
Tumor invades corpus spongiosum or corpus cavernosum Tumor invades urethra Tumor invades other adjacent structures
N
Regional lymph nodes NX Regional lymph nodes cannot be assessed N0 No palpable or visibly enlarged inguinal lymph node N1 Palpable mobile unilateral inguinal lymph node N2 Palpable mobile multiple or bilateral inguinal lymph nodes N3 Fixed inguinal nodal mass or pelvic lymphadenopathy, unilateral or bilateral
M
Distant metastases M0 No distant metastasis M1 Distant metastasis
2009 TNM pathological classification of penile cancer The pT categories correspond to the T categories. The pN categories are based upon biopsy, or surgical excision pN
Regional lymph nodes: pNX Regional lymph nodes cannot be assessed pN0 No regional lymph node metastasis pN1 Intranodal metastasis in a single inguinal lymph node pN2 Metastasis in multiple or bilateral inguinal lymph nodes pN3 Metastasis in pelvic lymph node(s), unilateral or bilateral or extranodal extension of regional lymph node metastasis
pM
Distant metastases pM0 No distant metastasis pM1
Distant metastasis (continued)
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Table A.4 (continued) G
Histopathological grading GX Grade of differentiation cannot be assessed G1 Well differentiated G2 Moderately differentiated G3–4 Poorly differentiated/undifferentiated
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Appendix 2: Penile Cancer Useful Organisations and Links University College London Hospitals NHS Trust 250 Euston Road London NW1 2PG www.uclh.org University College London Hospital is one of the largest penile cancer centres in Europe with a well-established clinical and research programme. All aspects of penile cancer management are undertaken including minimally invasive surgery for inguinal and pelvic lymph nodes and penile reconstruction following amputation. NKI Dept. of Urology, Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital Plesmanlaan 121, 1066 CX Amsterdam The Netherlands www.nki.nl The NKI has centralised the management of penile cancer in The Netherlands and has been at the forefront of developing the technique of sentinel lymph node biopsy for penile cancer. Orchid St Bartholomew’s Hospital London EC1A 7BE www.orchid-cancer.org.uk Orchid is the UK’s only registered charity specialising in all three male specific cancers – testicular, prostate, and penile tumours. Orchid works to improve the lives of people affected by male cancers through educational campaigns and raising awareness, a range of support services and a pioneering, world class research programme. European Association of Urology (EAU) The EAU has continually published a comprehensive set of guidelines for the management of penile cancer. www.uroweb.org
Index
A Abdominal pubic phalloplasty, 250–252 Advanced metastatic inguinal disease, 159 Advanced metastatic inguinal lymph node disease, 155 Advanced penile cancer, 143–144 with bulky disease, 153–154 AJCC. See American Joint Committee on Cancer (AJCC) ALT. See Anterolateral thigh (ALT) American Joint Committee on Cancer (AJCC), 169, 174, 302 Anterolateral thigh (ALT), 159, 160 Antero-lateral thigh flap phalloplasty, 252–255
B Balanitis Xerotica Obliterans (BXO), 109, 118, 127 Biological equivalent dose (BED), 263 Bone metastases, 163 Bowenoid papulosis, 106–107 Brachytherapy, 177, 264–265 Bulky disease, advanced penile tumors, 153–154 Bushke–Löwenstein tumor, 107–108 BXO. See Balanitis Xerotica Obliterans (BXO)
C Cell proliferation markers, 20 Cervical intraepithelial neoplasia (CIN), 6, 7 Chemoradiotherapy (CRT), 268–269 Chemotherapy, 304–305 and chemoradiation, 177–180
treatment adjuvant, 262 metastatic disease, 260–261 neoadjuvant, 261–262 Chromosomal aberrations, 18 CIN. See Cervical intraepithelial neoplasia (CIN) Circumcision, 311 Clear cell carcinoma, 48–49 Clinically negative inguinal lymph nodes (cN0 disease), 191, 216, 303–304 Clinically node-negative (cN0) patients, 278–279 C32 nanoparticle polymers, 275 cN0 disease. See Clinically negative inguinal lymph nodes (cN0 disease) CRT. See Chemoradiotherapy (CRT) Cryotherapy, 128 Cutaneous penile horn, 112 Cyclo-oxygenase-2 (COX), 21
D Deltoid flap, 255 Diagnosis and pathology anatomy of penis gross features, 27–29 lymphatic drainage, 31–32 microscopic features, 29–31 nerve supply, 31–32 vascularization, 31–32 clear cell carcinoma, 48–49 extramammary Paget’s disease (EMPD), 49–51 extremely low-grade neoplasms, malignancy, 37–39
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326 Diagnosis and pathology (cont.) glandular differentiation, 46–48 heterogeneous tumors, 45–46 histological classification, 32–34 hyperplasias, malignancy, 37–39 malignant lymphoma, 54 malignant melanoma, 51–52 metastatic tumors, 54–55 pathological prognostic factors histological grade, 55–56 histological subtype, 58–59 infiltration, anatomical level of, 56, 57 invasion, depth of, 58 molecular prognostic factors, 59 perineural invasion, 56, 58 prognostic index, 59–60 resection margins, 59 tumor thickness, 58 vascular invasion, 56, 58 precancerous and lesions (PeIN) lichen sclerosus, 37 penile intraepithelial neoplasia, 35–37 sarcomas, 52–54 verruciform tumors, differential diagnosis, 39–43 Disease specific survival (DSS), 301 Distant metastases, 95–96 Dorsalis pedis flap, 255 Drug and gene therapy, 274–275 Dynamic sentinel node biopsy (DSNB), 194–196, 303, 304, 315
E EAU. See European association of urology (EAU) EAU guidelines, 96–97 EBRT. See External beam radiotherapy (EBRT) E-cadherins, 20 EGFR. See Epidermal growth factor receptor (EGFR) ELPC. See Endoscopic lymphadenectomy for penile cancer (ELPC) EMPD. See Extramammary Paget’s disease (EMPD) Endoscopic lymphadenectomy for penile cancer (ELPC), 303, 304 Enseal® device, 277 Epidemiology and etiology and adjacent lesions, 4–5 HPV-related precursor lesions, 5–7 non-HPV-related precursor lesions, 7–8 risk factors
Index genital warts and HIV infection, 4 human papillomavirus, 3 noncircumcision, 2 penile injury, 4 psoralen-UV-A photochemotherapy, 4 smoking, 3 Epidermal growth factor receptor (EGFR), 262, 307–308 Erythroplasia of Queyrat (EQ), 5, 105–106, 127 European Association of Urology (EAU), 323 guidelines, 96, 97 risk groups, 226–227 External beam radiotherapy (EBRT), 176–177, 263–264 Extramammary Paget’s disease (EMPD), 49–51 F Fascial layers, 70 Ferumoxtran-10, 278 Fibular flap, 255 Flat penile lesions (FPL), 6 5-Fluorouracil (5-FU), 114, 115, 268 FNA biopsy, 92–93 FPL. See Flat penile lesions (FPL) G Giant condyloma accuminatum, 107–108 Glans, anatomical levels, 27 Growth factor receptors, 307–308
H Historical considerations, 238–239 HIV infection and genital warts, 4 Human papillomavirus (HPV), 3, 13, 225–226 vaccination, 311, 313–314
I IAB-1. See Interferon b gene (IAB-1) ILND. See Inguinal lymph node dissection (ILND) Imiquimod, 114, 115 Immunotherapy, 129–130 Inguinal lymph node dissection (ILND), 303–304, 315 Inguinal lymph nodes, 176 anatomy, 184–186 clinical examination CT imaging, 187–188 MR imaging, 188
Index PET/CT scan, 188–190 ultrasound with fine-needle aspiration cytology (FNAC), 187 indication for, 197–198 minimally invasive staging techniques dynamic sentinel node biopsy (DSNB), 194–196 modified inguinal lymphadenectomy (MIL), 193–194 noninvasive staging techniques close surveillance, 191–192 occult metastasis, 192 risk-adapted lymphadenectomy, 192–193 surgical techniques, 198–202 Interferon b gene (IAB-1), 277 J Jackson classification, 319 L Laser therapy, 128–129 Lateral arm flap, 255 Leukoplakia, 127 Lichen sclerosus (LS), 7, 8, 37 Lichen sclerosus et atrophicus, 109–111 Liposomal drug delivery, 277 LNMRI. See Lymphotropic nanoparticleenhanced magnetic resonance imaging (LNMRI) Locally advanced penile cancer, 144 oncological control, 153 LS. See Lichen sclerosus (LS) Lymphatic drainage, 31–32 Lymph nodes clinical examination CT imaging, 187–188 MR imaging, 188 PET/CT scan, 188–190 ultrasound with fine-needle aspiration cytology (FNAC), 187 dissection, complications of lymphocele/seroma, 206 management of complications, 208 morbidity of lymphadenectomy, 207 prognosis and adjuvant treatment, 208–210 skin necrosis, 205 FNA biopsy, 92–93 inguinal lymphadenectomy, 198–202 lymphatic dissemination
327 anatomy of inguinal lymph nodes, 184–186 bilateral lymphatic drainage, 184–185 MR lymphography, 91–92 pelvic lymphadenectomy, 202–205 pelvic lymph nodes, 190 positron emission tomography (PET), 90–91 sentinel node biopsy, 93–95 therapeutic lymphadenectomy inguinal lymphadenectomy, 197–198 pelvic lymphadenectomy, 198 ultrasound and MR appearance, 85–90 Lymphoscintigraphy, 278 Lymphotropic nanoparticle-enhanced magnetic resonance imaging (LNMRI), 278
M Magnetic resonance imaging (MRI), 76–77, 276 lymph nodes, 85–90 primary tumor staging, 77–82 Male urethra cancer anatomical and histological classifications, 167–169 clinical presentation, 170 diagnosis and investigation, 170–171 epidemiology, 167 risk factors, 169 staging of, 169–170 surgical management brachytherapy, 177 chemotherapy and chemoradiation, 177–180 external beam radiotherapy (EBRT), 176–177 inguinal lymph nodes, 176 penile-preserving techniques and reconstruction, 174–176 symptoms, 174 Malignant lymphoma, 54 Malignant melanoma, 51–52 Matrix metallo-proteinases (MMP-2, MMP-9), 21 Memorial Sloan Kettering Cancer Center (MSKCC), 260 Metastatic inguinal disease, 159 Metastatic inguinal lymph node disease, 155 Metastatic tumors, 54–55
328 Minimally invasive staging techniques modified inguinal lymphadenectomy (MIL), 193–194 recurrence rates, 286–287 Mitomycin (MMC), 268 Moh’s micrographic surgery, 120–121, 131–132 Molecular biology, 306–307 HPV-independent penile carcinogenesis, 16–17 HPV-mediated penile carcinogenesis, 14–16 molecular concept, 13–14 p14ARF/MDM2/p53 and/or p16INK4a/cyclin D/Rb pathways cell proliferation markers, 20 chromosomal aberrations, 18 cyclo-oxygenase-2 (COX), 21 E-cadherins, 20 epigenetic events, 19–20 matrix metallo-proteinases (MMP-2, MMP-9), 21 Myc activation, 19 prostaglandin E2 (PGE2) synthase, 21 RAS, 18 squamous cell carcinoma antigen (SCC antigen), 21–22 telomerase, 19 Molecular prognostic factors, 59 MR anatomy, 70–74 MRI. See Magnetic resonance imaging (MRI) MR lymphography, 91–92 MSKCC. See Memorial Sloan Kettering Cancer Center (MSKCC) 99m Tc-nanocolloid, 278 Myc activation, 19
N Nanoscience, 274 Nanotechnology and cancer treatment, 275 clinically node-negative (cN0) patients, 278–279 definition, 273, 274 drug and gene therapy delivery systems, 274–275 and imaging, 275–277 nanoparticle preliminary designs, 273 nanoscale particle dimension, 274 nomenclature, 275
Index penile cancer imaging, 278 risks of, 279 uro-oncology, 277–278 Nigro chemoradiation protocol, 179 NKI, 323
O Orchid, 323
P Paclitaxel-loaded biodegradable nanoparticles, 274 Partial penectomy operative procedure, 145 patient preparation, 145–150 postoperative complications, 150 preoperative staging, 144–145 surgical procedures, 150 Pathological prognostic factors. See also Diagnosis and pathology histological grade, 55–56 histological subtype, 58–59 infiltration, anatomical level of, 56, 57 invasion, depth of, 58 molecular prognostic factors, 59 perineural invasion, 56, 58 prognostic index, 59–60 resection margins, 59 tumor thickness, 58 vascular invasion, 56, 58 Pedicled flap ALT flap, 160–161 tensor fascia lata pedicled flap, 160 vertical rectus abdominis myocutaneous flap (VRAM), 161–162 PeIN. See Penile intraepithelial neoplasia (PeIN) Pelvic lymphadenectomy indication for, 198 surgical techniques of, 202–205 Penile cancer prognostic index, 228–230 Penile cancer staging systems, 319–322 Penile intraepithelial neoplasia (PeIN), 35–37, 105–106 Penile metastases, 84–85 Penile-preserving techniques in situ and superficial verrucous carcinoma cryotherapy and photodynamic therapy (PDT), 128 immunotherapy, 128–129 laser therapy, 128–129
Index topical therapy, 127–128 total glans resurfacing (TGR), 130 T staging, 127 and reconstruction, 173–176 T1 lesions glans penis, 130–131 prepuce, 131 Perineal urethrostomy, 237–238 Perineural invasion, 56 PET. See Positron emission tomography (PET) Phallic reconstruction abdominal pubic phalloplasty, 250–252 antero-lateral thigh flap phalloplasty, 252–255 deltoid flap, 255 dorsalis pedis flap, 255 fibular flap, 255 historical considerations, 238–239 lateral arm flap, 255 perineal urethrostomy, 237–238 radial artery forearm flap phalloplasty, 239–250 TFL flap, 255 Phallus and donor arm, complications, 249 Photodynamic therapy (PDT), 128 Positron emission tomography (PET), 90–91 Premalignant lesions HPV infection, 104–105, 108–109 HPV-related premailgnant conditions bowenoid papulosis, 106–107 giant condyloma accuminatum, 107–108 penile intraepithelial neoplasia (PIN), 105–106 malignant transformation, 107–108 non-HPV-related premalignant conditions cutaneous penile horn, 112 leukoplakia, 127 lichen sclerosus et atrophicus (LS), 109–111 PKMB, 113 penile cancer, 104–105 treatment laser treatment, cryotherapy, and photodynamic therapy, 116–117 topical therapies, 114–116 Preoperative chemoradiation role, 155–159 Primary lesion, 302–303 Primary tumor pathological extension (Pt), 220–221 Prognostic index, 59–60 Prognostic indicators clinical factors
329 age, 219 clinical stage, primary tumor, 219 integrated prognostic models European association of urology (EAU) risk groups, 226–227 nomograms, 227–228 pathological stage and histological grading, 226 penile cancer prognostic index, 228–230 molecular factors, 230–232 pathological factors growth pattern, 224–225 histological grade (G), 221–222 human papilloma virus (HPV) infection, 225–226 lymphatic and venous embolization, 222–223 perineural invasion, 223–224 primary tumor histological subtypes, 220 primary tumor pathological extension (Pt), 220–221 tumor thickness, 224 primary tumor-related prognostic factors, 218 Prostaglandin E2 (PGE2) synthase, 21 Prostate-specific membrane antigen (PSMA), 277 Psoralen-UV-A (PUVA) photochemotherapy, 4 Psychology and quality of life micturition experiences, 295 psychological effects, 295–298 sexual experiences, 293–295 time of diagnosis, 292–293 Pudendal nerve (S2-4), 32 PUVA. See Psoralen-UV-A (PUVA) photochemotherapy
R Radial artery forearm flap phalloplasty, 239–250 Radical penectomy operative procedure, 152–153 patient preparation, 152 postoperative complications, 153 preoperative staging, 151 Radiological imaging anatomy and techniques erection, 77 MR anatomy, 70–74
330 Radiological imaging (cont.) MRI technique, 76–77 ultrasound anatomy, 74–76 complications of, 95 distant metastases, 95–96 EAU guidelines, 96 follow-up intervals, 96–97 lymph nodes and distant metastases FNA biopsy, 92–93 MR lymphography, 91–92 positron emission tomography (PET), 90–91 sentinel node biopsy, 93–95 ultrasound and MR appearance, 85–90 penile metastases, 84–85 primary tumor staging, 77–82 Radiotherapy, 136–137, 306 chemoradiotherapy, 268–269 primary tumor brachytherapy, 264–265 complications, 266 EBRT, 263–264 regional lymph node metastases, 266–267 RAS protein, 18 Recurrence patterns cumulative risk, 283–285 distant recurrence, 287 local recurrence, 284, 286 recommendations, 288–289 regional recurrence, 286–287 Regional lymph nodes, 303–304
S Sarcomas, 52–54 SCC. See Squamous cell carcinoma (SCC) Sentinel lymph node (SLN) anatomy, 276 Sentinel node biopsy, 93–95 Single-photon emission computed tomography (SPECT), 276 Southwest oncology group (SWOG), 260 SPECT. See Single-photon emission computed tomography (SPECT) Split-skin graft, 254, 298 Squamous cell carcinoma (SCC), 33–34, 220, 259 Squamous cell carcinoma antigen (SCC antigen), 21–22 Superregional referral units, 314–315 Surgical pathology. See also Diagnosis and pathology basaloid carcinoma, 44 heterogeneous tumors, 45–46
Index high-grade usual SCC, 45 malignancy, 38–39 malignant epithelial tumors, clear cell features, 48–51 penile carcinomas, glandular features, 46–48 sarcomatoid carcinoma, 44 verruciform tumors, 39–43 SWOG. See Southwest oncology group (SWOG)
T Telomerase, 19 Tensor fascia late (TFL), 159–161 TFL flap, 255 TGR. See Total glans resurfacing (TGR) TNM classification, 57, 320 clinical classification, 321–322 staging system, 302 Total glans resurfacing (TGR), 130 Transferrin-lipoplex, 275 T staging, penile tumors, 127 Tyrosine kinases, 307–308
U UICC. See Union Internationale Contre le Cancer (UICC) Ultrasound anatomy, 74–76 lymph nodes, 85–90 primary tumor staging, 77–82 Union Internationale Contre le Cancer (UICC), 302 University College London Hospitals NHS Trust, 323 Urology, 274
V Vascular invasion, 56–58 VEIL. See Video endoscopic inguinal lymphadenectomy (VEIL) Verruciform tumors, 39–42 Vertical rectus abdominis myocutaneous (VRAM), 159, 161–162 Video endoscopic inguinal lymphadenectomy (VEIL), 303, 304, 315 Visceral metastases, 163 VRAM. See Vertical rectus abdominis myocutaneous (VRAM)