Textbook of Penile Cancer

Textbook of Penile Cancer Asif Muneer • Manit Arya • Simon Horenblas Editors Textbook of Penile Cancer Editors Asi...

Author: Asif Muneer | Manit Arya | Simon Horenblas

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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

v

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.

vii

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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x

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

xi

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

1

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

13

3

Diagnosis and Pathology of Penile Cancer . . . . . . . . . . . . . . . . . . . . Alcides Chaux and Antonio L. Cubilla

27

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

103

6

Management of Penile Cancer Using Penile-Preserving Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Paul Hadway, Peter R. Malone, Suks Minhas, and Asif Muneer

125

Management of Locally Advanced and Metastatic Penile Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Asif Muneer, Afshin Mosahebi, Vijay Sangar, and Suks Minhas

143

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8

Cancer of the Male Urethra . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Raj Nigam, Usama Ahmed, Alex Freeman, Suks Minhas, and Asif Muneer

167

9

Management of Lymph Nodes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Niels M. Graafland and Simon Horenblas

183

10

Prognostic Indicators in Penile Cancer . . . . . . . . . . . . . . . . . . . . . . . . Vincenzo Ficarra, Giacomo Novara, Guido Martignoni, and Filiberto Zattoni

215

xiii

xiv

11

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

237

259

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

16

291

Future Directions in Penile Cancer . . . . . . . . . . . . . . . . . . . . . . . . . . . Paul K. Hegarty and Curtis A. Pettaway

301

Appendix . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

319

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

325

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

xvi

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


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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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


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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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.

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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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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

13

14

D.A.M. Heideman et al.

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

2 Molecular Biology of Penile Cancer

15

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

16


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%


17

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.

18

2.4.1


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


2.4.3

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

20


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


2.4.8

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

22


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

27

28

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

30


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

32


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


33

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.

34

a


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


35

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

36


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


37

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

38

a


b

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


39

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.

40

a


b

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


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

42


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

(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


53

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

54


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


55

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

56


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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111. Zargari O. Exclusive penile Kaposi’s sarcoma: report of an HIV-negative man successfully treated with radiotherapy. J Eur Acad Dermatol Venereol. 2006;20:318-320. 112. Demir A, Temiz Y, Bozkurt SU, et al. An HIV-negative penil Kaposi’s sarcoma. Int Urol Nephrol. 2004;36:559-561. 113. Chitale SV, Peat D, Meaden JD, et al. Kaposi’s sarcoma of the glans penis in an HIV negative patient. Int Urol Nephrol. 2002;34:251-253. 114. Schwartz RA, Cohen JB, Watson RA, et al. Penile Kaposi’s sarcoma preceded by chronic penile lymphoedema. Br J Dermatol. 2000;142:153-156. 115. Micali G, Nasca MR, De Pasquale R, et al. Primary classic Kaposi’s sarcoma of the penis: report of a case and review. J Eur Acad Dermatol Venereol. 2003;17:320-323. 116. Lowe FC, Lattimer DG, Metroka CE. Kaposi’s sarcoma of the penis in patients with acquired immunodeficiency syndrome. J Urol. 1989;142:1475-1477. 117. Katsikas VS, Kalyvas KD, Ioannidis SS, et al. Leiomyosarcoma of the penis. Sarcoma. 2002;6:75-77. 118. Liu S, Shun C, Chang S, et al. Leiomyoma of the corpus cavernosum of the penis. Int J Urol. 2007;14:257-258. 119. Fetsch JF, Brinsko RW, Davis CJ Jr, et al. A distinctive myointimal proliferation (‘myointimoma’) involving the corpus spongiosum of the glans penis: a clinicopathologic and immunohistochemical analysis of 10 cases. Am J Surg Pathol. 2000;24:1524-1530. 120. McKenney J, Collins M, Carretero A, et al. Penile myointimoma in children and adolescents: a clinicopathologic study of 5 cases supporting a distinct entity. Am J Surg Pathol. 2007;31:1622-1626. 121. Vardar E, Gunlusoy B, Arslan M, et al. Myointimoma of the glans penis. Pathol Int. 2007;57:158-161. 122. Arena F, di Stefano C, Peracchia G, et al. Primary lymphoma of the penis: diagnosis and treatment. Eur Urol. 2001;39:232-235. 123. Cherian J, Rajan S, Thwaini A, et al. Secondary penile tumours revisited. Int Semin Surg Oncol. 2006;3:33. 124. Saltzman B, Srinivas V, Morse MJ, et al. Sacrococcygeal chordoma metastatic to penis. Urology. 1985;25:541-543. 125. Mondaini N, Mondaini A, Mondaini L, et al. Priapism due to sacrococcygeal chordoma metastasis treated with radiation therapy. Int J Impot Res. 2005;17:300-301. 126. Jimenez-Verdejo J, Fernandez PL, Haddad A, et al. Extraskeletal Ewing’s sarcoma metastatic to penis. Br J Urol. 1992;70:206-207. 127. Ballesterios JJ, Serrano S, Rosell R, et al. Penis metastasis of a monophasic tenosynovial sarcoma. Urologia. 1982;49:898-902. 128. Cardoso Guimaraes G, Rodrigues De Souza R, Paiva Gadelha Guimaraes A, et al. Penile metastasis of chondrosarcoma of the jaw. Urology. 2003;61:837. 129. Grimm MO, Spiegelhalder P, Heep H, et al. Penile metastasis secondary to follicular thyroid carcinoma. Scand J Urol Nephrol. 2004;38:253-255. 130. Okinami T, Ishitoya S, Imamura M, et al. A case of penile metastasis of malignant melanoma with priapism. Hinyokika Kiyo. 2009;55:149-152. 131. Cubilla AL. The role of pathologic prognostic factors in squamous cell carcinoma of the penis. World J Urol. 2009;27:169-177. 132. Novara G, Galfano A, De Marco V, et al. Prognostic factors in squamous cell carcinoma of the penis. Nat Clin Pract Urol. 2007;4:140-146. 133. Emerson R, Ulbright T, Eble J, et al. Predicting cancer progression in patients with penile squamous cell carcinoma: the importance of depth of invasion and vascular invasion. Mod Pathol. 2001;14:963-968. 134. Ficarra V, Martignoni G, Maffei N, et al. Predictive pathological factors of lymph nodes involvement in the squamous cell carcinoma of the penis. Int Urol Nephrol. 2002;34:245-250. 135. Ficarra V, Zattoni F, Cunico S, 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;103:2507-2516.

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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-

4

Radiological Imaging in Penile Cancer

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

b

c

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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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a

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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

a

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

4


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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a

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

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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

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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 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

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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 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

10

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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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5 mm Tumor thickness

5 mm Tumor thickness

−45

AGE

< 45

Total points 0

50

Probability of positive lymph node

100

0.1

150

200

250

0.2 0.3 0.4 0.5 0.6 0.7 0.8

300

350

0.9

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

10


231

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)

232

V. Ficarra et al.

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

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Textbook of Lung Cancer,

Textbook of Uncommon Cancer

Textbook of Lung Cancer, Second Edition

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IASLC Textbook of Prevention and Early Detection of Lung Cancer

The MASCC Textbook of Cancer Supportive Care and Survivorship

Prevention of Cancer (The Biology of Cancer)

Prevention of Cancer (The Biology of Cancer)

Causes of Cancer (The Biology of Cancer)

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Textbook of neurology

A Textbook of Theosophy

Williams Textbook of Endocrinology

Textbook of Neonatal Resuscitation

Textbook of Natural Medicine

Textbook of Polymer Science

Textbook of Rabbit Medicine

Textbook of Malignant Hematology

Shimizu's textbook of dermatology

Textbook of Cognitive Psychology

Textbook of Natural Medicine

Textbook of Arthroscopy

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