Adrenocortical Carcinoma Basic Science and Clinical Concepts ppt

Mille Schembechler Professor of Adrenal Cancer Director – Endocrine Oncology Program Director – Center for Organogenesis University of Michigan Health System University of Michigan Tobia

Adrenocortical Carcinoma

Gary D Hammer · Tobias Else

Editors

Adrenocortical Carcinoma Basic Science and Clinical Concepts

1 3

Gary D Hammer, MD, Ph.D

Mille Schembechler Professor of Adrenal

Cancer

Director – Endocrine Oncology Program

Director – Center for Organogenesis

University of Michigan Health System

University of Michigan

Tobias Else, MDDepartment of Internal MedicineDivision of Metabolism, Endocrinology

& DiabetesUniversity of Michigan Health SystemUniversity of Michigan

ISBN 978-0-387-77235-6 e-ISBN 978-0-387-77236-3

DOI 10.1007/978-0-387-77236-3

Springer New York Dordrecht Heidelberg London

Library of Congress Control Number: 2010934103

© Springer Science+Business Media, LLC 2011

All rights reserved This work may not be translated or copied in whole or in part without the written permission of the publisher (Springer Science+Business Media, LLC, 233 Spring Street, New York,

NY 10013, USA), except for brief excerpts in connection with reviews or scholarly analysis Use in connection with any form of information storage and retrieval, electronic adaptation, computer software,

or by similar or dissimilar methodology now known or hereafter developed is forbidden.

The use in this publication of trade names, trademarks, service marks, and similar terms, even if they are not identified as such, is not to be taken as an expression of opinion as to whether or not they are subject

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While the advice and information in this book are believed to be true and accurate at the date of going

to press, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made The publisher makes no warranty, express or implied, with respect

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Printed on acid-free paper

Springer is part of Springer Science+Business Media ( www.springer.com )

While a number of international meetings over the past two decades have indeedfocused on adrenal tumors in the context of hormone excess (Cushing’s syndrome,hyperaldosteronism, and pheochromocytoma), few have exclusively catered to thescience and clinical care of ACC and those afflicted with the disease With only

a single FDA-approved drug for ACC (mitotane – a derivative of the pesticideDDT), institutional experiences varied widely until recently when historic biaseshave slowly yielded to data-driven treatment strategies A large part of the impetusfor this push has come from Europe, where the availability of country-wide inte-grated networks for treatment has allowed a small number of centers in Italy, France,and Germany (among others) to develop specific expertise and specific treatmentprotocols for this rare disease

In an attempt to facilitate coordination of global efforts, a consensus conferencewas organized and held at the University of Michigan in September 2003 At thatmeeting, an international group of physicians and scientists with research interestand clinical expertise in ACC set up initial guidelines for the diagnosis and treat-ment of ACC Three principles emerged Successful treatment of ACC demandscoordinated care in the context of a multidisciplinary team dedicated to the dis-ease Future therapies for ACC need to be predicated on hypothesis-driven researchbased on a thorough analysis of tumor biology Lastly, major advancement in thefield demands national and international collaborative networks to facilitate anal-ysis of large datasets and coordinate future clinical trials The FIRM-ACT (FirstInternational Randomized Trial in locally advanced and Metastatic AdrenocorticalCancer Treatment) that coordinated over 35 ACC centers in a single multina-tional trial set precedence for the actualization of these principles The Second

v

vi Preface

International Adrenal Cancer Symposium: Clinical and Basic Science held at theUniversity of Michigan in March 2008 built upon the momentum of the 2003consensus meeting and the successful development of a large international ACCnetwork through the FIRM-ACT trial

Over the past decade, the ACC research community has grown to a critical masswith new data emerging in the laboratory and clinic In times of electronic pub-lications we routinely rely on journal articles and expert reviews on both clinicaland research topics While such publications are informative, when approached bySpringer about the possibility of editing such a textbook, we became convinced thatthe time had come to compile the accumulated clinical and basic science knowledge

of 50 years of active research on this rare cancer into a concise medical textbook.The overall goal of this book is therefore to provide definitive reference material forscientists and clinicians, to introduce trainees to concepts of ACC management, and

to stimulate further research, future collaborations, and networking

As opposed to a solitary review article, a textbook with multiple chaptersdedicated to discrete topics in the field provides contributors the opportunity toobjectively review historic data and detail the current state of clinical care andresearch accomplishments While this is a major advantage of a textbook, it is also amajor challenge for a book that focuses solely on a rare cancer where data are scant

In editing this book, we tried to ensure that each individual chapter covers established knowledge in the area, but also allows room for expert opinion Lastly,because ACC has been linked to several genetic disorders that usually escape discus-sion in a focused review of adrenal tumors, the various syndromes will be discussed

well-in their entirety well-in separate chapters The 32 Chapters of the 9 Sections are authored

by the scientific and clinical leaders in the field

With publication of this first edition, the editors want to extend special thanks

to our colleagues within the ACC community, the contributors, Rachel, Todd andLesley of the editorial staff at Springer Publishing House, and Lisa K Byrd of theUniversity of Michigan

We are hopeful that this first edition of the textbook provides an intellectual form for the continued coalescence and dissemination of knowledge on ACC infuture editions Both the authors and editors welcome comments and recommenda-tions for improvement in writing or via electronic mail The editors’ and authors’institutional and e-mail addresses are given in the contributor’s section

Part I History of Adrenocortical Carcinoma Research

and Clinical Care

1 The History of Adrenocortical Carcinoma Treatment – A

Part II Epidemiology, Presentation and Diagnosis

3 Epidemiology of Adrenocortical Carcinoma 23

Martin Fassnacht and Bruno Allolio

4 Clinical Presentation and Initial Diagnosis 31

Bruno Allolio and Martin Fassnacht

5 Diagnostic Approach to Incidentaloma 49

Holger S Willenberg and Stefan R Bornstein

6 Computed Tomography/Magnetic Resonance Imaging

of Adrenocortical Carcinoma 67

Melvyn Korobkin, Anca M Avram, and Hero K Hussain

7 Functional Imaging of Adrenocortical Carcinoma 85

Anca M Avram and Stephanie Hahner

8 Classical Histopathology and Immunohistochemistry 107

Wolfgang Saeger

vii

viii Contents

9 Cellular and Molecular Pathology of Adrenocortical

Carcinoma 127

Tobias Else

Part V Genetic and Molecular Aspects

10 Overview of Genetic Syndromes Associated

with Adrenocortical Cancer 153

Tobias Else

11 Li–Fraumeni Syndrome 173

David Malkin

12 TP53 Molecular Genetics 193

Gerard P Zambetti and Raul C Ribeiro

13 Telomeres and Telomerase in Adrenocortical Carcinoma 207

Tobias Else and Peter J Hornsby

14 Beckwith–Wiedemann Syndrome 227

Michael DeBaun and Jennifer Horst

15 The Insulin-Like Growth Factor System in Adrenocortical

Growth Control and Carcinogenesis 235

Christian Fottner, Ina M Niederle, and Matthias M Weber

16 WNT/ β-Catenin Signaling in Adrenocortical Carcinoma 263

Sébastien Gaujoux, Frédérique Tissier, and Jérôme Bertherat

Part VI Models of Adrenocortical Cancer

17 Adrenocortical Stem and Progenitor Cells:

Implications for Cancer 285

Joanne H Heaton and Gary D Hammer

18 Adrenocortical Cell Lines 305

Jeniel Parmar, Anita Kulharya, and William Rainey

19 Mouse Models of Adrenal Tumorigenesis 325

Felix Beuschlein

Part VII Therapies

20 Overview of Treatment Options for Adrenocortical Carcinoma 343

Gary D Hammer

21 Chemotherapy 351

Alfredo Berruti, Paola Sperone, Paola Perotti, Anna Ferrero,

Luigi Dogliotti, and Massimo Terzolo

22 Mitotane 369

Massimo Terzolo, Arianna Ardito, Barbara Zaggia, Silvia De

Francia, and Fulvia Daffara

Contents ix

23 Pharmacotherapy for Hormone Excess in Adrenocortical

Carcinoma 383

Richard J Auchus

24 Surgery for Adrenocortical Carcinoma 403

James T Broome, Barbra S Miller, Paul G Gauger,

and Gerard M Doherty

25 Radiation Therapy for Adrenocortical Carcinoma 427

Aaron Sabolch and Edgar Ben-Josef

26 Follow-Up and Monitoring of Adrenocortical Carcinoma 443

Britt Skogseid and Gerard M Doherty

Part VIII Unique Cohorts and Future Perspectives

27 Aldosterone-Producing Adrenocortical Carcinoma 457

Anna Patalano, Maria V Cicala, and Franco Mantero

28 Adrenocortical Cancer in Children 467

Carlos Rodriguez-Galindo, Gerard P Zambetti,

and Raul C Ribeiro

29 Genome-Wide Studies in Adrenocortical Neoplasia 483

Thomas J Giordano

30 New Strategies for the Treatment of Adrenocortical

Carcinoma 493

Lawrence S Kirschner

Part IX Adrenal Cancer Networks and Registries

31 The Dutch Adrenal Network 517

Ilse G.C Hermsen, Yvonne E Groenen, and Harm R Haak

32 The ENS@T Initiative 521

Xavier Bertagna

Index 533

Bruno Allolio Department of Internal Medicine I, Endocrine and Diabetes Unit,

University of Würzburg, Josef-Schneider-Str 2, 97080 Würzburg, Germany,allolio_b@medizin.uni-wuerzburg.de

Arianna Ardito Department of Clinical and Biological Sciences, Medicina

Interna 1, AOU San Luigi Gonzaga, University of Turin, Regione Gonzole, 10,

10043 Orbassano, Italy, arianna.ardito@gmail.com

Richard J Auchus Division of Endocrinology and Metabolism, Department of

Internal Medicine, UT Southwestern Medical Center Dallas, 5323 Harry HinesBoulevard, Dallas, TX 75390, USA, richard.auchus@utsouthwestern.edu

Anca M Avram Division of Nuclear Medicine/Radiology, University of

Michigan Health System, University of Michigan, 1500 East Medical CenterDrive, Ann Arbor, MI 48105, USA, ancaa@umich.edu

Edgar Ben-Josef Department of Radiation Oncology, University of Michigan

Health System, University of Michigan, 1500 East Medical Center Drive, RoomUHB2C490, Ann Arbor, MI 48109-0010, USA, edgarb@med.umich.edu

Alfredo Berruti Oncologia Medica, Azienda Ospedaliero Universitaria San Luigi,

Regione Gonzole, 10, 10043 Orbassano, Italy, alfredo.berruti@gmail.com

Jérôme Bertherat Endocrinology, Metabolism and Cancer Department, Institut

Cochin, Descartes University, INSERM U567, CNRS UMR8104, Paris France;Reference center for rare adrenal disorders, Assistance Publique Hôpitaux de Paris,Hôpital Cochin, Paris Descartes University, 27 Rue du Faubourg Saint-Jacques,

75014 Paris, France, jerome.bertherat@cch.aphp.fr

Xavier Bertagna Endocrinology Department, Cochin Hospital, Paris, France;

National Network COMETE, INCa, Paris, France; European Network for theStudy of @drenal Tumors (ENS@T), 27 Rue du Faubourg Saint-Jacques, 75014Paris, France, xavier.bertagna@cch.aphp.fr

Felix Beuschlein Department of Medicine, Endocrine Research, University

Hospital Innenstadt, Ziemssenstr 1, 80336 Munich, Germany,

felix.beuschlein@med.uni-muenchen.de

xi

xii Contributors

Stefan R Bornstein Department of Medicine, Carl Gustav Carus Medical School,

University of Dresden, Fetscherstraße 74, 01307 Dresden, Germany,

stefan.bornstein@uniklinikum-dresden.de

James T Broome Vanderbilt Endocrine Surgery Center, Vanderbilt University,

597 Preston Research Building, 2220 Pierce Ave, Nashville, TN, USA,

james.broome@vanderbilt.edu

Maria V Cicala Division of Endocrinology, Department of Medical and Surgical

Sciences, University of Padua, Via Ospedale 105, 35128 Padova, Italy,

mariaverena.cicala@unipd.it

Fulvia Daffara Department of Clinical and Biological Sciences, Medicina

Interna 1, AOU San Luigi Gonzaga, University of Turin, Regione Gonzole, 10,

10043 Orbassano, Italy, fulviaclaudia@libero.it

Silvia De Francia Department of Clinical and Biological Sciences, Farmacologia,

AOU San Luigi Gonzaga, University of Turin, Regione Gonzole, 10, 10043Orbassano, Italy, silvia.defrancia@unito.it

Michael DeBaun Division of Pediatric Hematology-Oncology, Department of

Pediatrics, Washington University School of Medicine, 660 South Euclid Avenue,Box 8067, St Louis, MO 63110-1093, USA, debaun_m@kids.wustl.edu

Luigi Dogliotti Oncologia Medica, Azienda Ospedaliero Universitaria San Luigi,

Regione Gonzole 10, 10043 Orbassano, Italy, luigi.dogliotti@unito.it

Gerard M Doherty Department of Surgery, University of Michigan Health

System, The University of Michigan, 2920 Taubman Center, 1500 East MedicalCenter Drive, Ann Arbor, MI 48109, USA, gerardd@umich.edu

Tobias Else Department of Internal Medicine – Division of Metabolism,

Endocrinology & Diabetes, University of Michigan Health System, University ofMichigan, Domino’s Farms, Lobby C, Suite 1300, 24 Frank Lloyd Wright Drive,

PO Box 451, Ann Arbor, MI 48106, USA, telse@med.umich.edu

Martin Fassnacht Department of Internal Medicine I, Endocrine and Diabetes

Unit, University Hospital of Würzburg, Josef-Schneider-Str 2, 97080 Würzburg,Germany, fassnacht_m@medizin.uni-wuerzburg.de

Anna Ferrero Oncologia Medica, Azienda Ospedaliero Universitaria San Luigi,

Regione Gonzole 10, 10043 Orbassano, Italy, anna.ferrero80@gmail.com

Christian Fottner Schwerpunkt Endokrinologie und Stoffwechselerkrankungen,

I Medizinische Klinik und Poliklinik, Universitätsmedizin, Johannes GutenbergUniversität Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany,

fottner@endokrinologie.klinik.uni-mainz.de

Paul G Gauger Department of Surgery, University of Michigan Health System,

University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109,USA, pgauger@umich.edu

Contributors xiii

Sébastien Gaujoux Endocrinology, Metabolism and Cancer Department, Institut

Cochin, INSERM U567, CNRS UMR8104, Paris, France; Department of Digestiveand Endocrine Surgery, Assistance Publique Hôpitaux de Paris, Hôpital Cochin,Paris Descartes University, 27 Rue du Faubourg Saint-Jacques, 75014 Paris,France, sebastien.gaujoux@gmail.com

Thomas J Giordano Departments of Pathology and Internal Medicine,

University of Michigan Health System, University of Michigan, 1500 East MedicalCenter Drive, Ann Arbor, MI 48109, USA, giordano@med.umich.edu

Yvonne E Groenen Department of Internal Medicine, Máxima Medical Centre,

Ds Th Fliednerstraat 1, PO Box 90052, 5600 PD Eindhoven, Leiden UniversityMedical Centre, Leiden, The Netherlands, y.groenen@mmc.nl

Stephanie Hahner Department of Internal Medicine I, Endocrine and Diabetes

Unit, University Hospital of Würzburg, Josef-Schneider-Str 2, 97080 Würzburg,Germany, hahner_s@medizin.uni-wuerzburg.de

Gary D Hammer Endocrine Oncology Program – Comprehensive Cancer

Center, Department of Internal Medicine – Division of Metabolism, Endocrinology

& Diabetes, Department of Molecular & Integrative Physiology, Department ofCell & Developmental Biology, University of Michigan, 1528 BSRB, 109 ZinaPitcher PI., Ann Arbor, MI 48109-2200, USA, ghammer@med.umich.edu

Harm R Haak Department of Internal Medicine, Máxima Medical Centre, Ds.

Th Fliednerstraat 1, PO Box 90052, 5600 PD Eindhoven, Leiden UniversityMedical Centre, Leiden, The Netherlands, h.haak@mmc.nl

Joanne H Heaton Department of Internal Medicine, Division of Metabolism,

Endocrinology & Diabetes, University of Michigan Medical School, 109 ZinaPitcher Place, 1680 BSRB, Ann Arbor, MI 48109, USA, heatonj@med.umich.edu

Ilse G.C Hermsen Department of Internal Medicine, Máxima Medical Centre,

Ds Th Fliednerstraat 1, PO Box 90052, 5600 PD Eindhoven, Leiden UniversityMedical Centre, Leiden, The Netherlands, i.hermsen@mmc.nl

Peter J Hornsby Department of Physiology and Barshop Institute for Longevity

and Aging Studies, University of Texas Health Science Center, 15355 LambdaDrive, San Antonio, TX 78245, USA, hornsby@uthscsa.edu

Jennifer Horst Department of Pediatrics, Washington University School of

Medicine, Washington University, One Brookings Drive, St Louis, MO 63130,USA, horst_j@kids.wustl.edu

Hero K Hussain Department of Radiology, University of Michigan Health

System, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI

48105, USA, hhussain@med.umich.edu

Lawrence S Kirschner Division of Endocrinology, Diabetes and Metabolism,

Department of Internal Medicine and Department of Molecular Virology,

xiv Contributors

Immunology and Medical Genetics, The Ohio State University, Columbus EnarsonHall 154 W 12th Avenue, Columbus, OH 43210, USA,

lawrence.kirschner@osumc.edu

Melvyn Korobkin Department of Radiology, University of Michigan Health

System, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI

48105, USA, korobkin@umich.edu

Anita Kulharya Department of Pediatrics, Pathology and Cytogenetics, Medical

College of Georgia, 1120 15th Street, BG-1071, Augusta, GA 30912, USA,akulhary@mail.mcg.edu

David Malkin Division of Hematology/Oncology, Department of Pediatrics, The

Hospital for Sick Children, University of Toronto, 555 University Avenue, Toronto,

ON M5G 1X8, Canada, david.malkin@sickkids.ca

Franco Mantero Division of Endocrinology, Department of Medical and Surgical

Sciences, University of Padua, Via Ospedale 105, 35128 Padova, Italy,

franco.mantero@unipd.it

Barbra S Miller Department of Surgery, University of Michigan Health System,

University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109,USA, barbram@umich.edu

Ina M Niederle Schwerpunkt Endokrinologie und Stoffwechselerkrankungen,

I Medizinische Klinik und Poliklinik, Universitätsmedizin, Johannes GutenbergUniversität Mainz, Langenbeckstrasse 1, 55131 Mainz, Germany,

niederle@1-med.klinik.uni-mainz.de

Jeniel Parmar Department of Physiology, Medical College of Georgia, 1120 15th

Street Room CA3091, Augusta, GA 30912, USA, jparmar@students.mcg.edu

Anna Patalano Division of Endocrinology, Department of Medical and Surgical

Sciences, University of Padua, Via Ospedale 105, 35128 Padova, Italy,

anna.patalano@libero.it

Paola Perotti Oncologia Medica, Azienda Ospedaliero Universitaria San Luigi,

Regione Gonzole, 10, 10043, Orbassano, Italy, oncotrial.sanluigi@gmail.com

William Rainey Department of Physiology, Medical College of Georgia, 1120

15th Street Room CA3094, Augusta, GA 30912, USA, wrainey@mail.mcg.edu

Raul C Ribeiro Department of Oncology, St Jude Children’s Research Hospital,

262 Danny Thomas Place, Memphis, TN 38105, USA, raul.ribeiro@stjude.org

Carlos Rodriguez-Galindo Department of Pediatric Oncology, Dana-Farber

Cancer Institute and Children’s Hospital, 44 Binney Street, Boston, MA 02115,USA, carlos_rodriguez-galindo@dfci.harvard.edu

Aaron Sabolch Radiation Oncology, University of Michigan Medical School,

1500 East Medical Center Drive, Ann Arbor, MI 48109, USA, sabolch@umich.edu

Contributors xv

Wolfgang Saeger Institute of Pathology of the Marienkrankenhaus, Alfredstraße

9, 22087 Hamburg, Germany, saeger.patho@marienkrankenhaus.org

David E Schteingart Endocrine Oncology Program, Comprehensive Cancer

Center, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI

48109, USA, dschtein@umich.edu

Britt Skogseid Department of Endocrine Oncology, Uppsala University Hospital,

University of Uppsala, Akademiska sjukhuset/Uppsala, SE-751 85, Uppsala,Sweden, britt.skogseid@medsci.uu.se

Paola Sperone Oncologia Medica, Azienda Ospedaliero Universitaria San Luigi,

Regione Gonzole 10, 10043 Orbassano, Italy, paola.sperone@email.it

Massimo Terzolo Department of Clinical and Biological Sciences, Medicina

Interna 1, AOU San Luigi Gonzaga, University of Turin, Regione Gonzole, 10,

10043 Orbassano, Italy, terzolo@usa.net

Norman W Thompson Surgery Emeritus Faculty, University of Michigan, Rm

2124C Taubman Health Care Center, 1500 East Medical Center Drive, Ann Arbor,

MI 48105, USA, normant@umich.edu

Frédérique Tissier Endocrinology, Metabolism and Cancer Department, Institut

Cochin, INSERM U567, CNRS UMR8104, Paris, France; Department of

Pathology, Assistance Publique Hôpitaux de Paris, Hôpital Cochin, Paris DescartesUniversity, Rue du Faubourg Saint-Jacques, 75014 Paris, France,

frederique.tissier@cch-ap-hop-paris.fr

Matthias M Weber Schwerpunkt Endokrinologie und

Stoffwechselerkrankungen, I Medizinische Klinik und Poliklinik,

Universitätsmedizin, Johannes Gutenberg Universität Mainz, Langenbeckstrasse 1,

55131 Mainz, Germany, mmweber@uni-mainz.de

Holger S Willenberg Department of Endocrinology, Diabetes and

Rheumatology, University Hospital Duesseldorf, Moorenstr 5, D–40225

Duesseldorf, Germany, holger.willenberg@uni-duesseldorf.de

Barbara Zaggia Department of Clinical and Biological Sciences, Medicina

Interna1, AOU San Luigi Gonzaga, University of Turin Regione Gonzole, 10,

10043 Orbassano, Italy, barbara.zaggia@libero.it

Gerard P Zambetti Department of Biochemistry, St Jude Children’s Research

Hospital, 262 Danny Thomas Place, Memphis, TN 38105, USA,

gerard.zambetti@stjude.org

Part I

History of Adrenocortical Carcinoma

Research and Clinical Care

Chapter 1

The History of Adrenocortical Carcinoma

Treatment – A Medical Perspective

David E Schteingart

Knowledge of the genetic and molecular alterations in adrenocortical carcinoma(ACC) has advanced in the past two decades, as a result of newer laboratory method-ology to study mechanisms of oncogenesis and tumor pathophysiology In contrast,limited progress has been made in our ability to treat and prolong survival in patientswith advanced disease Over the past five decades, a number of reports have summa-rized the experience of individual medical institutions with ACC; and collectively,based on several thousand cases, there is relative consensus on the epidemiology

of ACC, its clinical presentation, criteria for pathological diagnosis, and tumorresponse to standard cytotoxic chemotherapy Unfortunately, survival of patientswith advanced disease remains poor (Fig.1.1), and targeted therapies based on newknowledge of the biology of these tumors are only in clinical trial phase This intro-duction will attempt to highlight the early experience with mitotane that forms thebasis of our current approach to the management of patients with ACC

Initial publications recognized that ACCs are rare, highly malignant tumors withpoor prognosis It was appreciated that the tumoral production of excessive steroidhormones and coincident metabolic syndromes allow for a more timely diagnosis

In 1961, Soffer et al [2] detailed several cases of feminizing syndrome ated with large malignant tumors These patients developed metastases and theirlife expectancy was just a few months While aldosterone-producing ACCs werenoted to be rare, Cushing’s syndrome was the most common clinical presentation

associ-in adult patients Biochemical associ-investigation revealed elevated 17-ketosteroids, but

no distinguishing pattern between adrenocortical carcinoma and benign tal adrenal hyperplasia At that time, diagnostic tests for adrenal tumors associatedwith Cushing’s syndrome relied on the lack of response to stimulation with ACTH

congeni-or metyrapone Assessment of the risk of malignancy was based on the finding

G.D Hammer, T Else (eds.), Adrenocortical Carcinoma,

DOI 10.1007/978-0-387-77236-3_1,  C Springer Science+Business Media, LLC 2011

4 D.E Schteingart

Stages I & II (N = 25) Stages III (N = 20) Stages IV (N = 24)

80 100

60 40 20

0

months

Fig 1.1 Survival of patients with adrenocortical carcinoma according to stage [1 ]

of large tumors on a variety of imaging platforms including simple nal x-rays, intravenous pyelograms, or procedures with perirenal/retrorectal gasinsufflation

abdomi-It was accepted over 60 years ago that surgery was the most effective ment for ACC As detailed in the accompanying historical section by Thompson,while a variety of surgical approaches were developed and improved upon overthe past few decades, the importance of complete resection cannot be overstated.Nonetheless, the ability to safely remove these tumors, especially those associatedwith Cushing’s syndrome, improved only with the availability of glucocorticoidsthat could be administered easily in stress doses during and following surgery Cecil

treat-in 1932 [3], as quoted by Soffer, reported that 39% of surgical patients died inadrenal insufficiency shock within hours post-operation The availability of hydro-cortisone made surgical resection of adrenal tumors safe However, as many ACCpatients presented with metastatic disease or distant recurrences, additional sys-temic therapies were necessary Of the various cytotoxic drugs used, mitotane hasbeen the oldest, with selective activity against ACC However, acceptance of itsuse as a pharmacologic agent has been controversial since its initial use Severalchemical compounds derived from DDT were initially tested as adrenalytic agents.These included amphenone, perthane, methylenedianiline, and DDD Amphenone B

(1,2-bis-(p-aminophenyl)-2-methyl propane-1) synthesized in 1950 was found to

block 11, 17, and 21-hydroxylation of corticosteroids in ACC and cause a decrease

in steroid excretion However, it was associated with severe toxicity Nelsonand Woodward first reported that commercial DDD [2,2-bis(parachlorophenyl)-1,1-dichloroethane] and its ethyl derivative, perthane, can produce adrenocorticalatrophy in the dog Subsequently, mitotane, the o,p-isomer in the mixture, wasfound to be active as an adrenolytic agent and useful in the treatment of patientswith ACC

1 The History of Adrenocortical Carcinoma Treatment – A Medical Perspective 5

Fig 1.2 Transformation of mitotane via P450 hydroxylation, dehydrochlorination, and formation

of an acyl chloride, a highly reactive species that covalently binds to bionucleophiles within the adrenal cell or converts to the acetic acid derivative, o,p -DDA or o,p-DDE

The specificity of mitotane for the adrenal cortex and ACC suggested a ment for biotransformation of the drug for activity within the adrenal cortex in waysthat differ from that which takes place in other extra-adrenal sites The mechanism

require-of the adrenolytic effects require-of mitotane involves transformation to an acyl chloridevia P450-mediated hydroxylation and covalent binding to specific bionucleophiles(Fig.1.2) The ability of mitotane to be metabolically transformed and covalentlybound determines its pharmacological activity As a result of the transformation

to bioactive mitotane, oxidative damage followed by the formation of free cals such as superoxide induces lipid peroxidation and, ultimately, cellular death(Fig.1.3) The metabolic activity of mitotane varies among species, the drug beingmost effective in dogs and modestly effective in humans Normal adrenal corticesand adrenal glands of patients with ACTH-dependent adrenocortical hyperplasiaare also susceptible to the toxic effects of mitotane (Fig 1.4), but only 33% ofpatients with ACC respond It is likely that different tumors vary in their ability toinduce metabolic transformation or initiate free radical production, and as a conse-quence may express variable sensitivity to mitotane Substituting the hydrogen on

radi-6 D.E Schteingart

100

60 80

drug alone

40

drug + 50 μM

α -tocopherol acetate

20

Cell Doublings (% of control)

drug + 500 uM

α -tocopherol acetate

0

drug ( μM) drug ( μM)

40 20

size (cm)

Fig 1.4 Appearance of the adrenal gland in a patient with ACTH-dependent Cushing’s disease,

treated with low doses of mitotane for 1 year

the beta carbon by a methyl group blocks the metabolic transformation (Fig.1.5).Methylated mitotane does not have adrenolytic activity

Hertz et al in the mid-1950s, treated 16 patients with Cushing’s syndrome due tometastatic ACC with o,p-DDD, 10 g daily for 2–4 months Seven patients had radio-logical evidence of tumor regression and 13 patients had marked decrease in urinary17-hydroxycorticoids Clinical remission of Cushing’s syndrome was noted in sixpatients, lasting 4 months to 2 years Unfortunately, patients experienced severe tox-icity [2] Measurable disease response, overall clinical improvement, and decreases

in urinary steroid levels have since been described The mean survival is short(8.4 months) when the drug is used after the appearance of metastatic disease.Isolated case reports describe impressive remissions and even cures of ACC withmitotane therapy alone In general, survival appears to depend on the size of theprimary lesion and the degree of local and distant extension of the neoplasm at thetime of initial surgery

1 The History of Adrenocortical Carcinoma Treatment – A Medical Perspective 7

Fig 1.5 Inactivation of the adrenolytic activity of mitotane by substituting the hydrogen at the

β-carbon by a methyl group (mitometh)

In 1967, Eisenstein [4] recommended that patients in whom ACC cannot be pletely removed should be treated with o,p-DDD Fifteen years later, the concept

com-of post-surgical mitotane therapy was extended to patients following a completeresection but with a high risk of recurrence In 1982, Schteingart et al first pre-dicted that the post-surgical use of mitotane would be most effective when institutedearly as adjuvant therapy following resection of the primary tumor and before localextension or distant metastases occur [5]

While it was well accepted then that surgery was the most effective treatment forACC, in 1983, Thompson [6] emphasized the possibility of better treatment outcomewith earlier diagnosis and combination of aggressive surgical treatment (includingrepeated debulking of recurrent disease) and adjuvant treatment with mitotane In

a review of 23 patients treated between 1953 and 1981, six patients had resection

of the primary tumor and local radiation therapy without mitotane; mean survivalfor this group was 10.3 months In contrast, 17 patients treated with surgery andmitotane therapy had a mean survival of 46.6 months Longest survival was in thegroup that received adjuvant treatment before and after surgery for local recurrenttumor, with a mean survival of 74 months

While mitotane remains the only drug to be selective for treating patients withmetastatic ACC, not all agree that its limited efficacy justifies the associated side-effects [7,8] Regardless, until new targeted therapies emerge as more effective andselective candidates for ACC, mitotane will remain as an important part of mostACC treatment regimens, with proven results both in the adjuvant setting and inthe treatment of advanced disease, by itself or in combination with other cytotoxicdrugs (Chapter 22)

The natural history of ACC has not changed dramatically over the past 40 years[9] In spite of the multiple treatment approaches suggested, life expectancy forpatients with ACC has remained constant However, our experience in the pastfive decades has taught us that the clinical evolution of these patients varies andsome patients can survive for several years with surgical and medical treatment.Therefore, the main tasks for the future are to define those clinical characteristicsthat are associated with a better prognosis and response to current treatment regi-mens and to find new therapeutic modalities that may lead to a cure of the majority

of ACC patients, whose tumors are unresectable and/or do not respond to availablechemotherapies

8 D.E Schteingart

Lessons from these early cases include (1) detection and treatment in Stages Iand II can be associated with good prognosis; (2) aggressive surgical resection isassociated with better outcome; (3) mitotane therapy may be beneficial in extendingsurvival either as adjuvant therapy or given for advanced disease

References

1 Brennan MF (1987) Adrenocortical carcinoma CA Cancer J Clin 37:348–365

2 Soffer LJ et al (1961) The human adrenal gland Lea & Febiger, Philadelphia, PA

3 Cecil HF (1933) Hypertension, obesity, virilism and pseudohermaphroditism as caused by suprarenal tumors J.A.M.A 100:463

4 Eisenstein AB (1967) The adrenal cortex Little, Brown and Company, Boston, MA

5 Schteingart DE et al (1982) The treatment of adrenal carcinoma Arch Surg 117:1142–1146

6 Thompson NW (1983) Adrenocortical carcinoma In: Thompson NW, Vinik AI (eds) Endocrine surgery update Grune and Stratton, New York, pp 119–128

7 Luton JP et al (1990) Clinical features of adrenocortical carcinoma, prognostic factors, and the effect of mitotane therapy N Engl J Med 322:1195–1201

8 Hogan TF et al (1978) o,p-DDD (mitotane) therapy of adrenal cortical carcinoma:

observa-tions on drug dosage, toxicity and steroid replacement Cancer 42:2177–2181

9 Bilimoria KY et al (2008) Adrenocortical carcinoma in the United States Treatment utilization and prognostic factors Cancer 113(11):3130–3136

Chapter 2

The History of Adrenocortical Carcinoma

Treatment – A Surgical Perspective

Norman W Thompson

The early history of adrenocortical carcinoma (ACC) is obscure because of the rarity

of the disease, confusing nomenclature, inability to diagnose before death, rance of its hormonal manifestations, and a vague appreciation of its clinical course.Most reported cases in the 19th century were based on autopsy findings, and thetumors were classified by a variety of terms including hypernephroma, sarcoma,fibromyxosarcoma, and carcinoma The commonly used term, hypernephroma, wasfirst proposed by Grawitz et al in 1893 and falsely assumed that tumors arose inrests of adrenocortical tissue within the kidney [1] This concept was reinforced byFelix Birch-Hirchfield who used it to define benign and malignant tumors of bothadrenals and kidneys, some with apparent hormonal disturbances [2] The designa-tion of hypernephroma for some adrenal tumors persisted in the literature until the1940s; later it became restricted to what is now referred to as renal cell cancer [3 8]

igno-In 1905, it was stated that no adrenal tumor had been diagnosed before tion or autopsy [9] None had been suspected on the basis of a hormonal syndromealthough an association of virilization and an adrenal tumor found at autopsy wasfirst observed in 1811 [10] It was not until 1890 that a decrease in virilizationwas first documented following resection of an adrenal tumor Cushing’s syndromewas not recognized until 1910 but was not associated with an adrenal malignancyuntil Walters et al in 1934 described the same syndrome in patients with adrenaltumors and emphasized that the characteristic findings were not exclusively related

opera-to pituitary disease [11]

The first tumor operations on the adrenal glands were done to remove “largeabdominal swellings” [10] Knowsly Thornton of London is credited with the firstknown successful operation to remove an adrenal cancer in 1899 [12] His patientwas a 36-year-old, very hirsute female who was found at operation to have a20-pound left adrenal tumor It required a left nephrectomy as well to remove this

G.D Hammer, T Else (eds.), Adrenocortical Carcinoma,

DOI 10.1007/978-0-387-77236-3_2,  C Springer Science+Business Media, LLC 2011

10 N.W Thompson

large tumor She slowly recovered after developing a subphrenic abscess that neously drained into a bronchus After dramatic improvement, her hirsutism remiseduntil a recurrence 2 years later caused her death [13] Thornton, interestingly, waswell prepared for this operation, having previously served as Joseph Lister’s housesurgeon (antiseptic technique) and Spencer Wells’ assistant The latter was a pioneer

sponta-in the development of hemostats and hemostatic techniques The first small serieswas presented by Otto Ramsay later in 1899 who reported three patients operatedfor large palpable malignant adrenal tumors [14] In addition, he reviewed a total of

64 other published reports of patients with either carcinomas [15] or sarcomas [13]

of the adrenals The diagnosis was difficult in all and impossible in many Thetumors were found to spread rapidly and the prognosis was considered dismal.Surgery was considered the only hope of temporary relief, but only five patients hadbeen operated and only two with success, Thornton’s and another by Howard Kelly

in Baltimore with a good result 1 year after excision of a large “fibromyxosarcoma.”From 1905 to 1929, a number of patients were described with what was termedthe adrenogenital syndrome and others with adrenal tumors with virilism [5,16].Bulloch, in 1905, reported ten girls and two boys who all died within 2 yearsfrom malignant adrenal tumors, most with metastases Most were considered hyper-nephromas associated with sexual abnormalities, usually in children [10] In 1921,Collett from Oslo described a 2-year-old with progressive virilization over 18months who had a palpable tumor of the left adrenal [10] This was excised afterwhich the hirsutism regressed for 2 years This was probably the first successfuladrenal operation in a child Other similar cases soon followed and surgical exci-sion seemed to confirm that these tumors caused virilism, perhaps by producing aninternal secretion Although patients with pure adrenal virilism had had tumors suc-cessfully removed, several with Cushing’s or closely related syndromes had died

in “shock” several hours after straightforward operations At autopsy, their ing adrenals were found to be atrophic After 1932, many patients with Cushing’sdisease (pituitary) were reported Cushing’s syndrome and adrenal virilism werenot always clearly distinguished, and the term “suprarenal cortical syndrome” wassometimes used to describe both Kepler at the Mayo Clinic stressed the frequency

remain-of the intermediate forms, especially with ACCs [17] By 1933 there was clear dence that the pituitary secreted an adrenocortical factor which was later recognized

evi-as ACTH Whatever the underlying cause, the development of Cushing’s syndromerequired the presence of the adrenal cortex Those surgeons including Waltman,Waters, and James Priestly at the Mayo Clinic recognized three main problems:(1) to determine the nature of the adrenal lesion; (2) to relieve the syndrome inpatients without adrenal tumors; (3) to prevent operative deaths from adrenal insuf-ficiency Since 1927, they had been developing an adrenocortical extract and using

it perioperatively with some success In 1934, they reported ten female patients withCushing’s syndrome who had been operated upon, with five having adrenal tumors,four of which were carcinomas One tumor was palpable, one was seen on x-ray,and three found at operation Three developed acute adrenocortical failure, and one

of them who was treated in 1923 before cortical extract was available died Theother two received cortical extracts and recovered Three of the five with tumors

2 The History of Adrenocortical Carcinoma Treatment – A Surgical Perspective 11

underwent remission [11] By 1938, the Mayo group had removed tumors cessfully from 16 consecutive patients, most of whom had Cushing’s syndrome.Elsewhere, adrenal crises were all too frequent after surgical excision of tumors,and by 1943 more than 80% of such patients were reported to have died [10,17–

suc-20] The potent preparation of “cortin” at the Mayo Clinic, apparently, was the mostimportant factor allowing their success The intensive search for the active corticalsubstance(s) was ongoing from 1927 until its eventual discovery and preparation in1949

It was imperative for the management of Cushing’s syndrome to have such apreparation whether treatment be pituitary or adrenal surgery The dismal progno-sis for patients with Cushing’s syndrome was emphasized by Charles Plotz’s paper

on the natural history of the disease in 222 patients in 1952 showing a high dence of cardiovascular disease, psychosis, and osteoporosis Therapy had beeneffective in only 5 of their own 33 patients (pituitary irradiation in three and exci-sion of adrenal adenomas in two) The overall mortality was 50% after 5 years fromonset Infections and cardiovascular disease were the most common causes of death.Another 20% died from surgical operations [10]

inci-Between 1930 and the discovery of cortisone in 1949, details of nearly 300patients with ACC were published [15, 17, 19–22] Metastases were still oftenseen initially or soon after operation The clinical features were in order of fre-quency, virilism, Cushing’s syndrome, and combined Cushing’s and virilism Theseaccounted for 75% and only 25% were apparently without a syndrome Rarely,feminization was reported This was first described in 1915, but only 30 additionalcases were seen in the next 30 years and all were associated with an adrenal malig-nancy producing estrogens in excess In 1930, Anderson described an ACC withfatal hypoglycemia but no other metabolic disturbance [23] Ten similar cases ofAnderson’s syndrome were reported in the next 30 years, a few of whom went intoremission after tumor removal Three quarters of the 300 patients reported under-went operation and one-third died postoperatively The mortality was greatest inthose with Cushing’s and least in those with nonsecreting tumors In the surviv-ing group, some had good long-term results, but only when the tumor had beencompletely excised

A milestone in the treatment of ACC was the general availability of cortisoneafter 1950 By 1948, only a few grams were available at the Mayo Clinic Thefirst patient with Cushing’s disease in whom this was used perioperatively was

on December 3, 1949 Within a year, 18 patients underwent successful tal adrenalectomies there using cortisol pre- and postoperatively [10,15] Kendall,Hench, and Reichstein received the Nobel Prize in 1950 for the development of cor-tisone and its use in adrenal surgery as well as in rheumatology Soon, syntheticanalogues of cortisone including prednisone, prednisolone, and dexamethasonebecame widely available By 1957, an intravenous preparation of cortisol, hydro-cortisone, was used intraoperatively and in urgent situations of adrenal insufficiency

subto-By 1955, Tait and Simpson in London and Reichstein in Basel had isolated and pared electrocortin, later renamed aldosterone for clinical use as fludrocortisone in

pre-1956 [24] Thus, surgeons in the 1950s for the first time could operate on patients

12 N.W Thompson

with ACC and Cushing’s syndrome without the danger of acute adrenal insufficiencycausing an immediate crisis or early postoperative death Remission of symptomsand findings followed rapidly in patients with ACCs where excisions were possible.They were usually complete within 1 year Parallel developments occurred with theintroduction of drugs which inhibited adrenocortical tumors from secreting steroids.These included amphenone, metyrapone, and aminoglutethimide in the mid-1960s.These were of some benefit in alleviating symptomatic persistence or recurrencesafter operations [25]

Many more cases of ACC were reported after 1950 The principal endocrinefeatures in nearly 90% of patients were Cushing’s, virilization, a combination ofboth, feminization and rarely aldosteronism (first case in 1955) [10,19, 21,22,

24,26–31] Although more women were diagnosed in life, the overall incidence inmales was higher Despite improved diagnostic tests such as urinary steroids, dex-amethone suppression test (1960s), and an RIA for ACTH in the mid-1960s, thelag period between the onset of symptoms and the diagnosis was about 8 months.Local invasion and distant metastases at the time of exploration were still frequent.Although there were no good statistics on survival in the 1950s, the general con-sensus was that most patients died from the disease unless fortunate enough to havebeen operated before either local invasion was extensive or metastatic disease hadoccurred One of the reasons for lack of good data was the rarity of the disease asemphasized by Steiner’s 1954 report from the Los Angeles County Hospital [21]

In his study of all autopsies there from 1918 to 1947, only 15 cases of ACC werefound, accounting for only 0.2% of all tumors In 1952, Rappaport in a collectivereview found a total of 238 hormonal and 34 nonhormonal cases of ACC duringthe 20-year period from 1930 to 1949 [19] Wood, in 1957, could find only 27cases of nonhormonal ACC in the European and American literature from 1923 to

1956 [10] MacFarlane in 1958 reviewed 55 patients from London teaching tals which included 35 with hormonal and 25 with nonhormonal findings [21] Theiraverage age was 32 years and ranged from infants to 68 years For those with hor-monal symptoms, 80% were less than 40 years of age and 65% with nonhormonalfindings were greater than 50 years The average duration of symptoms before treat-ment was 13.2 months, 17 months for those with hormonal symptoms but only 10.8months for those without hormonal symptoms One-third of all patients had localinvasion and all but two of these patients had distant metastases Overall, 34 of the

hospi-55 patients (61.8%) had metastatic disease at diagnosis The liver was involved in67%, the lungs in 47%, and local nodes in 44% For those who were untreated, sur-vival was only 2.9 months for those with nonhormonal findings and 3.8 months forthose with hormonal symptoms MacFarlane was the first to propose an operativestaging system based on tumor size, local invasion, nodal and distant metastases.Stage I tumors were 5 cm or smaller without local invasion or metastases, a rarefinding as the average tumor size was 12 cm An operation was performed in 42

of the 55 patients and considered radical and potentially curative in 20 (36.4%)

A palliative excision was performed in 12 (22%) patients The operative mortalitywas still high at 26% overall but fell from 35% before 1952 to 16.7% after 1952.This was attributed primarily to the availability of cortisone The 2-year survival

2 The History of Adrenocortical Carcinoma Treatment – A Surgical Perspective 13

was 24% and occurred only in those undergoing radical extirpation and adequatehormone replacement therapy MacFarlane considered dissection of lymph nodes oflimited value and nephrectomy unnecessary unless the kidney was directly involved.London surgeons favored a thoracoabdominal extrapleural approach, resecting the11th rib to allow maximum exposure

The next major event in the management of ACC was the introduction of o,pDDD (mitotane), an analogue of the insecticide DDT which had previously beenfound in animal studies to cause adrenocortical atrophy It was first used clinically in

-1960 to treat inoperable or recurrent ACCs In -1960, Bergenstad reported o,p-DDDsufficiently effective that the National Cancer Institute sponsored its productionand distribution for clinical investigation [3] Previously, the NCI had reported 38patients with ACC treated there [30] In only 18 was it possible to attempt a curativeoperation, whereas in the others, either a palliative procedure or biopsy was done.They noted a 50% mortality 2 years after first symptoms, and only seven were alivemore than 5 years after the onset of symptoms, with only two disease-free In those

in whom a curative operation could not be attempted, the mortality was 70% after 2years The causes of death included large pulmonary and abdominal masses causingpneumonia, caval thrombosis, sepsis, and pulmonary embolus The first major report

of the NCI evaluation of o,p-DDD was by Hutter et al in 1966 [33,34] By then,they had collected 138 previously unpublished cases in which o,p-DDD was usedand compared those with the 48 previously treated and reported cases elsewhere.The average age of their patients was 37.6 years and 92 were female and 43 weremales Cushing’s syndrome was found in 59% and virilization in 19% Local spreadwas found in 65%, whereas 53% developed pulmonary and 44% liver metastases.Survival was better in females with 52 versus 38 alive 4 years after diagnosis Themedian survival after diagnosis for all females was 56 months and only 19 monthsfor males Mitotane was considered effective in some cases but was of limited value

in prolonging survival The next major report on the use of mitotane in ble ACC cases was by Lubitz et al in 1973 [35] They reported on 115 patientswith inoperable ACC seen between 1965 and 1969 A disease response was seen

inopera-in 61% of patients treated, lastinopera-ing an average of 10.3 months Although 84% had

an adverse response to the drug involving the gastrointestinal, central nervous, anddermatological systems, these were all reversible with discontinuance or decrease

in drug dosage They found that 45% showed a favorable clinical response and thatelevated steroid levels fell in 85% Even though there were no cures, the mean dura-tion of life for the entire group was only 8.4 months with treatment Van Slooten,

in 1983, was one of the first to observe that serum level monitoring of mitotanewas important [36] He found that if the serum level was maintained at 14 μg/ml

or higher, the survival time at 26.5 months was 50% compared to only 14.5 months

if the level was less than 14 μg/ml Their recommendation was that all patients

receiving mitotane should have serum level monitoring and the drug dose adjustedaccordingly

Since then, several large series of ACC patients have been reported and althoughthere had been hope that with the widespread use of a variety of imaging techniquesthe diagnosis of ACC would be made at an earlier stage, that has not occurred

14 N.W Thompson

[26–28,37, 38] Luton et al in reporting 105 patients from France, again foundmore females than males in a clinical series (75/30) with a mean age of 46 years[38] Their duration of symptoms was 8.7 months at diagnosis and nearly 70% hadendocrine symptoms When steroid studies were done, 79% were functional At thetime of diagnosis, 30% had distant metastases Operations were performed in 80%and 59% received mitotane The median disease-free interval after operation was12.1 months during which tumor dissemination occurred in 82% The median sur-vival time was 14.5 months and the 5-year survival was only 22% They, like others,concluded that mitotane should be used as it did lower hormone levels and wastransiently beneficial, particularly when endocrine symptoms were present Again,survival benefits were not proven

Since the first patients with ACC were recognized and treated, a radical cal extirpation remains the only real chance for cure in those patients who do notalready have hematogenous spread In such cases, a number of important surgicalprinciples must be considered in order to increase the possibility of a successful out-come (Table2.1) Earlier diagnosis, allowing for that option, has not been seen inany large series Operative mortality has improved because of the recognition andtreatment of adrenal insufficiency in those patients with Cushing’s syndrome andcontralateral adrenal atrophy Steroid replacement with hydrocortisone and fludro-cortisone in patients treated with mitotane has also decreased morbidity The overalloperative mortality has dropped from the pre-1950s level of 30–40% to less than 5%

surgi-in most reports Chemotherapy and radiotherapy are traditionally of a very limitedvalue in terms of a curative approach Mitotane is the only adjunctive therapy cur-rently available, although generally considered to be of only transient benefit Itshould be noted, however, that several dozen long-term remissions in patients withdistant metastases have been reported [2,27,39] Obviously, the continued failure

to detect ACC at an early stage remains a major deterrent to successful therapy.The hope for the future is that new drugs specifically targeted to individual tumors,based on gene profiling, can be developed Until that day, ACC will remain a mostchallenging disease for physicians and surgeons to manage

Table 2.1 Basic principles learned in surgical management of ACC (Figs. 2.1 – 2.3 are case sketches provided courtesy of the author N W Thompson)

1 Adequate steroid preparation and maintenance in patients with Cushing’s syndrome or while on long-term mitotane therapy.

2 In case of a high suspicion of an ACC, needle biopsy is contraindicated pre-operatively; spillage of tumor cells will prevent cure (Fig 2.1a , b ).

3 Incisions allowing wide local exposure of the tumor and intra-abdominal metastases, making every effort to avoid rupturing the tumor capsule when it is localized and potentially curable.

4 Avoidance of laparoscopic techniques.

5 Preparation for possible aortopulmonary bypass in cases where tumor extends into the vena cava This assumes appropriate pre-operative imaging in all patients (Fig 2.2a , b ).

6 Nephrectomy is not beneficial unless kidney or renal vein is invaded (Fig 2.3 ).

7 A reoperative procedure is indicated where local recurrence can be excised without

excessive risks (see Fig 2.1 ).

8 Use of mitotane postoperatively in all patients without anaplastic histopathology providing serum monitoring can maintain serum levels above 14 μg/ml and below 20 μg/ml.

2 The History of Adrenocortical Carcinoma Treatment – A Surgical Perspective 15

a

b

Fig 2.1 (a) A 32-year-old female with large right adrenal ACC mistakenly diagnosed as a hepatic

cell adenoma with hemorrhage because of 14-year history of birth control pills, 5-day history of severe right upper quadrant pain, and a percutaneous, transhepatic FNA diagnosis She was referred

for a right hepatic lobectomy (b) Same patient 2 years later with recurrent ACC limited to right

lobe of liver along the FNA tract Following right lobectomy, there was no evidence of recurrence

2 years later

16 N.W Thompson

a

Fig 2.2 (a) A 35-year-old female with nonfunctional ACC and limited extension into the vena

cava Right adrenalectomy and nephrectomy (tumor adherence to kidney) and gortex patch of caval

excision site (b) A 40-year-old male 1 year post right adrenalectomy for 11 cm ACC with caval

extension Developed Budd Chiari syndrome and treated with cisplatinum and VP-16 Referred

2 years later for possible operative treatment No other metastatic disease With cardiopulmonary bypass and cold arrest, tumor thrombus into right atrium excised and endovenectomy of all tumors

in vena cava and both left and middle hepatic veins excised A pericardial patch was used for the vena cava and distal hepatic veins The patient had an uneventful course with complete relief of the Budd Chiari syndrome

2 The History of Adrenocortical Carcinoma Treatment – A Surgical Perspective 17

b

Fig 2.2 (continued)

18 N.W Thompson

Fig 2.3 A 47-year-old female with large left adrenal ACC with tumor thrombus into left renal

vein Adrenalectomy, nephrectomy, and excision of two liver metastases resulted in palliation of Cushing’s syndrome for 16 months

3 Curtis BF (1900) Nephrectomy for suprarenal tumor Ann Surg 31:759–760

4 Fey B (1926) L’abord du rein par voie thoraco-abdominal Arch Urol Clin Necker 5:168–178

5 Holmes G (1925) Virilism associated with a suprarenal tumor Q J Med 18:143–152

6 Kennedy CM, Lister WA (1927) Suprarenal hypernephroma Lancet 2:739–751

7 Keyser LD, Walters W (1924) Carcinoma of the suprarenal JAMA 82:87–88

8 Lisser H (1933) Successful removal of adrenal cortical tumor Trans Associa Am Physicians 48:224–235

9 Richards O (1905) Growths of the kidneys and adrenals Guy’s Hosp Rep 59:217–332

2 The History of Adrenocortical Carcinoma Treatment – A Surgical Perspective 19

10 Welbourn RB (1990) The history of endocrine surgery Praeger, New York

11 Walters W et al (1934) The suprarenal cortical syndrome Ann Surg 100:670–688

12 Thornton JK (1890) Abdominal nephrectomy for large sarcoma of the left suprarenal capsule: recovery Trans Clin Soc London 23:150–153

13 Robson AWM (1899) Removal of the suprarenal capsule Br Med J 2:1100–1101

14 Ramsay O (1899) Malignant tumors of the suprarenal gland Johns Hopkins Hosp Bull nos 94–96:20–29

15 Walters W, Sprague RG (1949) Hyperfunctioning tumors of the adrenal cortex Ann Surg 129:677–701

16 Broster LB et al (1932) Adreno-genital syndrome: unilateral adrenalectomy Brit J Surg 19:557–570

17 Kepler EJ, Keating FR (1941) Diseases of the adrenal glands Arch Int Med 68:1010–1036

18 Murray GG, Simpson G (1929) Virilism due to an adrenal hypernephroma Lancet 2:734–749

19 Rapaport E et al (1952) Mortality in surgically treated adrenocortical tumors Postgrad Med 11:325–329

20 Thompson KW, Eisenharatt L (1943) Further consideration of the Cushing’s syndrome J Clin Endocrinol Metab 3:445–452

21 MacFarlane DA (1958) Cancer of the adrenal cortex Ann R Coll Surg Engl 23:155–162

22 Priestly JT (1952) Lesions of the adrenal glands Surg Clin N Am 32:1053–1064

23 Anderson HB (1933) Successful removal of adrenal cortical tumor Trans Associa Am Physicians 48:224–235

24 Thompson NW (1983) Adrenocortical carcinoma.In: Thompson NW, Vinik AI (eds) Endocrine surgery update Grune and Straton, New York

25 Sahteingart DE et al (1982) Treatment of adrenal carcinomas Arch Surg 117:1142–1147

26 Cohn K et al (1986) Adrenocortical carcinoma Surgery 100:1170–1177

27 Icard P et al (1992) Adrenocortical carcinoma in surgically treated patients: a retrospective study on 156 cases by the French Association of Endocrine Surgery Surgery 112:972–980

28 Kelly WF et al (1979) Cushing’s syndrome due to adrenocortical carcinoma Acta Endocrinologica 91:303–318

29 Lewinsky BS et al (1974) The clinical and pathologic features of “non-hormonal” tical tumors Cancer 33:778–790

adrenocor-30 Lipsett MB et al (1963) Clinical and pathophysiologic aspects of adrenocortical carcinoma.

Am J Med 35:374–383

31 Richie JP, Gittes RE (1980) Carcinoma of the adrenal cortex Cancer 45:1957–1964

32 Bergenstall DM et al (1960) Chemotherapy of ACC with o,p-DDD Ann Int Med 53:672–680

33 Hutter AM, Kayhoe DE (1966) Adrenal cortical carcinoma: clinical features of 138 patients.

Am J Med 41:572–580

34 Hutter MM, Jr, Kayhoe DE (1966) Adrenal cortical carcinoma Results of treatment with

o,p-DDD in 138 patients Am J Med 41:581–589

35 Lubitz JA et al (1973) Mitotane use in inoperable adrenal cortical carcinoma JAMA 223:1109–1112

36 VanSlooten H et al (1984) The treatment of adrenocortical carcinoma with o,p-DDD:

prognostic simplification of serum level monitoring Eur J Cancer Oncol 20:47–53

37 Hogan TF et al (1978) o,p-DDD (mitotane) therapy of adrenal cortical carcinoma Cancer

Part II

Epidemiology, Presentation and Diagnosis

Chapter 3

Epidemiology of Adrenocortical Carcinoma

Martin Fassnacht and Bruno Allolio

3.1 Incidence of Adrenocortical Carcinoma

It is generally accepted that adrenocortical carcinoma (ACC) is a rare disease.However, valid data on the exact incidence and prevalence of ACC are lacking.Adrenal masses are among the most frequent tumors in humans The vast major-ity of these tumors are nowadays found incidentally, and the prevalence of theseadrenal incidentalomas is estimated as at least 3% in a population over the age

of 50 years and increases to as much as 10% in the elderly [1 5] However, it iswell established that about 80% of these incidentally detected adrenal masses rep-resent hormonally inactive adrenal adenomas and only a small minority are ACCs[2,4,6] Data obtained from the National Cancer Institute Survey from the early1970s estimated an incidence of 1–2 per million population per year, leading to0.2% of cancer deaths in the United States [7] A more recent analysis of the SEERdatabase, including data from 12 US states, indicated an annual age-adjusted inci-dence of 0.72 per million [8, 9] However, data from the German ACC Registrysuggest that the incidence is >1 per million (Fassnacht & Allolio, unpublished data)and may be even higher

An exceptionally high annual incidence of ACC has been reported for children

in southern Brazil, with 3.4–4.2 affected patients per 1 million children vs an mated worldwide incidence of 0.3 per 1 million children younger than 15 years[10–12] (see alsoChapter 28) Some reports indicate a bimodal age distribution with

esti-a first peesti-ak in childhood esti-and esti-a second higher peesti-ak in the fourth esti-and fifth decesti-ade [13].However, in the German ACC Registry, we do not see an absolute peak in childhood(Fig.3.1) and the median age is 46 years (range 0.3–86 years) However, based onthe low incidence of malignancies in children, in general the incidence of ACC inthe German ACC Registry in children below the age of ten may be considered arelative peak (Fig.3.1)

G.D Hammer, T Else (eds.), Adrenocortical Carcinoma,

DOI 10.1007/978-0-387-77236-3_3,  C Springer Science+Business Media, LLC 2011

24 M Fassnacht and B Allolio

Fig 3.1 Age and sex distribution at primary diagnosis of ACC in 579 patients Data from the

German ACC Registry (October 2009)

3.2 Risk Factors for Adrenocortical Carcinoma

In most series, women are more often affected than men (ratio 1.5:1; Fig.3.1)[14–20], leading to the hypothesis that sex hormones may have an influence onACC tumorigenesis Interestingly, this female predominance seems to be true onlyfor functional tumors [20,21] However, data on the association of risk factors andthe development of ACC are rather scarce The best (although still very limited) datawere derived from a case–control study based on the National Mortality FollowbackSurvey, which included a questionnaire sent to the next of kin of almost 20,000deceased adults in the United States In this study, 176 patients who died of adrenalcancer (the majority of them suffered most likely from ACC) were compared with

352 controls Among women, an increased risk for developing ACC was found forever users of oral contraceptives (hazard ratio= 1.8, 95% confidence interval (CI)

1.0–3.2), especially for those who used them before the age 25 (hazard ratio= 2.5,

95% CI 1.2–5.5) In this context, it is remarkable that in two independent Frenchseries a high percentage (9.3 and 5.1%) of female patients with ACC were diag-nosed during pregnancy [17,19] Furthermore, there is some in vitro evidence thatestrogens harbor a proliferative potential for ACC cells [22,23]

In addition, the above mentioned survey suggested an increased risk for oping ACC in male heavy smokers (hazard ratio 2.0, 95% CI 1.0–4.4), but not infemale smokers [24] The increased risk for male smokers was also seen in anotherseries in 250,000 US veterans [25] Furthermore, a small study in rats describedthree ACCs in 80 rats that were exposed to chronic tobacco inhalation in compari-son to none in 93 controls [26] Nevertheless, these epidemiological studies have to

devel-be assessed with caution, devel-because in none of the cases ACC was confirmed by tological reports and in some patients adrenal metastases of lung cancer may havebeen misdiagnosed as ACC Accordingly, a recent review on tobacco use and cancer