Controversies in Skull Base Surgery 9781626239531

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Controversies in Skull Base Surgery

Andrew S. Little, MD Assistant Professor Department of Neurosurgery Barrow Neurological Institute St. Joseph’s Hospital and Medical Center Phoenix, Arizona, USA Michael A. Mooney, MD Resident Department of Neurosurgery Barrow Neurological Institute St. Joseph’s Hospital and Medical Center Phoenix, Arizona, USA

99 illustrations On the cover The illustration depicts three different skull base surgical options: expanded, endoscopic endonasal surgery, transcranial microsurgery, and radiosurgery.

Thieme New York • Stuttgart • Delhi • Rio de Janeiro

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Executive Editor: Timothy Y. Hiscock Managing Editor: Sarah Landis Director, Editorial Services: Mary Jo Casey Production Editor: Naamah Schwartz International Production Director: Andreas Schabert Editorial Director: Sue Hodgson International Marketing Director: Fiona Henderson International Sales Director: Louisa Turrell Director of Institutional Sales: Adam Bernacki Senior Vice President and Chief Operating Officer: Sarah Vanderbilt President: Brian D. Scanlan Library of Congress Cataloging-in-Publication Data Names: Little, Andrew S., editor. | Mooney, Michael A. (Neurosurgeon), editor. Title: Controversies in skull base surgery / [edited by] Andrew S. Little, Michael A. Mooney. Description: New York : Thieme, [2019] Identifiers: LCCN 2019005266| ISBN 9781626239531 (hardcover) | ISBN 9781626239548 (e-book) Subjects: | MESH: Skull Base–surgery Classification: LCC RD529 | NLM WE 705 | DDC 617.5/14–dc23 LC record available at https:// lccn.loc.gov/2019005266 © 2019 Thieme Medical Publishers, Inc. Thieme Publishers New York 333 Seventh Avenue, New York, NY 10001 USA +1 800 782 3488, [email protected] Thieme Publishers Stuttgart Rüdigerstrasse 14, 70469 Stuttgart, Germany +49 [0]711 8931 421, [email protected]

Important note: Medicine is an ever-changing science undergoing continual development. Research and clinical experience are continually expanding our knowledge, in particular our knowledge of proper treatment and drug therapy. Insofar as this book mentions any dosage or application, readers may rest assured that the authors, editors, and publishers have made every effort to ensure that such references are in accordance with the state of knowledge at the time of production of the book. Nevertheless, this does not involve, imply, or express any guarantee or responsibility on the part of the publishers in respect to any dosage instructions and forms of applications stated in the book. Every user is requested to examine carefully the manufacturers’ leaflets accompanying each drug and to check, if necessary in consultation with a physician or specialist, whether the dosage schedules mentioned therein or the contraindications stated by the manufacturers differ from the statements made in the present book. Such examination is particularly important with drugs that are either rarely used or have been newly released on the market. Every dosage schedule or every form of application used is entirely at the user’s own risk and responsibility. The authors and publishers request every user to report to the publishers any discrepancies or inaccuracies noticed. If errors in this work are found after publication, errata will be posted at www.thieme.com on the product description page. Some of the product names, patents, and registered designs referred to in this book are in fact registered trademarks or proprietary names even though specific reference to this fact is not always made in the text. Therefore, the appearance of a name without designation as proprietary is not to be construed as a representation by the publisher that it is in the public domain.

Thieme Publishers Delhi A-12, Second Floor, Sector-2, Noida-201301 Uttar Pradesh, India +91 120 45 566 00, [email protected] Thieme Publishers Rio de Janeiro, Thieme Publicações Ltda. Edifício Rodolpho de Paoli, 25º andar Av. Nilo Peçanha, 50 – Sala 2508 Rio de Janeiro 20020-906 Brasil +55 21 3172-2297 / +55 21 3172-1896 www.thiemerevinter.com.br Barrow Neurological Institute holds copyright to all diagnostic images, photographs, intraoperative videos, animations, and art, including the cover art, used in this work and the accompanying digital content, unless otherwise stated. Used with permission from Barrow Neurological Institute, Phoenix, Arizona. Cover design: Thieme Publishing Group Cover art: Peter M. Lawrence, MS, CMI Typesetting by Thomson Digital, India Printed in The Unites States of America by King Printing Company, Inc. ISBN 978-1-62623-953-1 Also available as an e-book: eISBN 978-1-62623-954-8

54321

This book, including all parts thereof, is legally protected by copyright. Any use, exploitation, or commercialization outside the narrow limits set by copyright legislation, without the publisher’s consent, is illegal and liable to prosecution. This applies in particular to photostat reproduction, copying, mimeographing, preparation of microfilms, and electronic data processing and storage.

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This book is dedicated to my family, whose love and support has cleared the path to complete this project and has never failed to inspire me. Andrew S. Little To my wife and children for their support. To my colleagues and mentors at Barrow Neurological Institute for their inspiration. Michael A. Mooney

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Contents Video Contents . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

xi

Foreword. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

xiii

Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

xv

Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

xvii

Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

xix

Part I Vestibular Schwannoma 1

Controversies in the Natural History of Acoustic Neuromas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

2

Mark E. Whitaker

2

Controversies in Radiosurgery for Acoustic Neuromas: Single-Session Therapy versus Hypofractionated Therapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

5

David S. Xu, Colin J. Przybylowski, Andrew J. Meeusen, and Randall W. Porter

3

Management of Residual Vestibular Schwannoma After Subtotal Resection: Observation, Repeat Surgery, or Radiosurgery? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

10

Scott Brigeman and Kaith K. Almefty

4

Treatment Strategies for Small Intracanalicular Vestibular Schwannomas in Young Patients with Good Hearing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

15

Daniel A. Donoho, Ben A. Strickland, Jonathan J. Russin, Rick A. Friedman, and Steven L. Giannotta

Part II Meningioma 5

Transcranial Approaches Are Preferred for Certain Tuberculum and Olfactory Groove Meningiomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

24

Farshad Nassiri, Suganth Suppiah, and Gelareh Zadeh

6

Endoscopic Endonasal Surgery Is the Best Treatment for Certain Anterior Fossa Skull Base Meningiomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

28

Douglas A. Hardesty, Alaa S. Montaser, Alexandre B. Todeschini, Ricardo L. Carrau, and Daniel M. Prevedello

7

Controversies in the Management of Petroclival Meningiomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

37

Robert S. Heller and Carl B. Heilman

8

Does Embolization Have a Role to Play in the Treatment of Skull Base Meningiomas? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

43

Colin J. Przybylowski, Jacob F. Baranoski, Rami O. Almefty, Dale Ding, Andrew F. Ducruet, and Felipe C. Albuquerque

9

The Role of Radiotherapy for Atypical and Anaplastic Meningiomas . . . . . . . . . . . . . . . . . . . . . . .

48

Brooke K. Leachman, Stephanie E. Weiss, and Leland Rogers

10

Emerging Chemotherapy and Targeted Therapy for Aggressive Meningiomas . . . . . . . . . . . .

58

Yoko Fujita, Ben K. Hendricks, and Nader Sanai

v

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Contents

Part III Pituitary Adenoma 11

The Role of Transsphenoidal Surgery Following Nondiagnostic Inferior Petrosal Sinus Sampling in Cushing Syndrome . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

66

Pamela S. Jones and Brooke Swearingen

12

Pharmacotherapy Options After Failed Surgery for Cushing Disease . . . . . . . . . . . . . . . . . . . . . . . .

70

Kevin C. J. Yuen

13

Primary Medical Therapy for Acromegaly, Ready for Prime Time?

..........................

78

The Role of Radiosurgery for Pituitary Adenomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

87

Elana V. Varlamov, Winnie Liu, Shirley McCartney, Justin S. Cetas, and Maria Fleseriu

14

Gabriella Paisan, Ching-Jen Chen, and Jason Sheehan

15

Exploration of the Cavernous Sinus Is Effective During Transsphenoidal Surgery for Pituitary Adenoma. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

94

Engelbert J. Knosp and Alexander S.G. Micko

16

Surgery versus Medical Management: First-Line Treatment for Pituitary Apoplexy . . . . . . .

96

Garni Barkhoudarian, Sheri Palejwala, and Daniel F. Kelly

17

Alternative Treatment Strategies for Atypical and Aggressive Pituitary Adenomas . . . . . . .

102

Gregory K. Hong

Part IV Craniopharyngioma 18

Controversies in Radical Resection versus Subtotal Resection with Radiation in Craniopharyngioma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

111

Taylor J. Abel and James T. Rutka

19

The Role of Open and Endoscopic Approaches to Craniopharyngiomas

....................

116

The Molecular Pathogenesis of Craniopharyngioma and Potential Therapeutic Targets . .

125

Neil Majmundar, Jean Anderson Eloy, and James K. Liu

20

Douglas A. Hardesty

Part V Rathke Cleft Cyst and Other Sellar Lesions 21

Resection versus Cyst Fenestration: The Best Treatment for Rathke Cleft Cysts

22

Headache in Patients with Rathke Cleft Cysts

...........

131

.................................................

137

Justin L. Hoskin, Kevin C. J. Yuen, and Kerry L. Knievel

23

Rathke Cleft Cyst Surgery: Indications, Outcomes, and Complications

.....................

141

David L. Penn and Edward R. Laws Jr.

24

Controversies in the Management of Histiocytosis and Xanthogranulomas

...............

147

Surgical Approach Selection for Skull Base Chordoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

154

Christina E. Sarris and Ruth E. Bristol

Part VI Other Cranial Tumors 25

Paul A. Gardner, Ahmed Jorge, Juan C. Fernandez-Miranda, Eric W. Wang, and Carl H. Snyderman

vi

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Contents

26

Chordoma Genetics and Tumor Phenotype Profiles . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

167

William L. Harryman and Anne E. Cress

27

Surgery versus Radiation versus Observation: What Treatment Is Best for Skull Base Paraganglioma? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

173

Gregory P. Lekovic, Kevin A. Peng, Eric P. Wilkinson, William H. Slattery, and Kathryn Y. Noonan

28

Management of Chondrosarcoma of the Cranial Base

.......................................

181

Jonathan A. Forbes, Vijay K. Anand, and Theodore H. Schwartz

29

Natural History and Treatment Strategies for Posterior Fossa Epidermoids

...............

187

Indications for and Outcomes of Radiosurgery in Trigeminal and Jugular Foramen Schwannomas . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

194

Steven B. Carr, Omar Arnaout, and Charles Teo

Part VII Cranial Nerve Schwannoma 30

Andrew Faramand, Ajay Niranjan, Hideyuki Kano, and L. Dade Lunsford

31

Challenges of Applying Endoscopic Techniques for Cranial Nerve Schwannomas . . . . . . . . .

199

Rachel Blue, Tracy M. Flanders, and John Y.K. Lee

32

Management of Cranial Nerve III, IV, and VI Schwannomas

.................................

204

Treatment of Facial Pain in Patients with Trigeminal Schwannoma . . . . . . . . . . . . . . . . . . . . . . . . .

209

Jai Deep Thakur, Christopher Storey, Anil Nanda, and Hai Sun

33

John P. Sheehy and Zaman Mirzadeh

Part VIII Sinonasal Malignancies 34

Induction Therapy for Esthesioneuroblastoma . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

214

Sheri K. Palejwala, Christopher H. Le, and G. Michael Lemole Jr.

35

Surgical Approach for Esthesioneuroblastoma: Controversy in Approach Selection . . . . . .

221

Jamie J. Van Gompel and Jeffrey Janus

36

What Is the Role of Surgery for Adenoid Cystic Carcinoma?. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

225

David William Hsu, Marvin Bergsneider, and Marilene B. Wang

37

Proton versus Photon Therapy for Sinonasal Malignancies: Pros and Cons of Each Method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

229

Emad Youssef

Part IX Surgical Approaches and Techniques 38

Controversies in Skull Base Reconstruction Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

235

Chad A. Glenn, Thomas A. Ostergard, and Michael E. Sughrue

39

The Role of Lumbar Drains in Skull Base Surgery

.............................................

245

Nathan T. Zwagerman, Carl Snyderman, Eric W. Wang, Paul A. Gardner, and Juan C. Fernandez-Miranda

40

The Role of Postoperative Antibiotics in Endoscopic Endonasal Surgery . . . . . . . . . . . . . . . . . . .

249

Erin K. Reilly, Marc R. Rosen, James J. Evans, and Mindy R. Rabinowitz

vii

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Contents

41

Does Otorhinolaryngology Collaboration Improve Outcomes in Endonasal Skull Base Surgery? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

253

Kyle VanKoevering, Ricardo L. Carrau, Daniel M. Prevedello, and Bradley A. Otto

42

Controversies in Outcome Measures of Skull Base Surgery

..................................

258

Gill E. Sviri, Shuli Brammli-Greenberg, and Ziv Gil

43

To Bypass or Not? The Role of Revascularization in Skull Base Surgery

.....................

264

Transcranial versus Endoscopic Repair of Lateral Sphenoid Recess Encephaloceles . . . . . . . .

274

Justin R. Mascitelli, Sirin Gandhi, and Michael T. Lawton

44

Brian H. Song, Christopher H. Le, and G. Michael Lemole Jr.

45

Cranioplasty Techniques . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

282

Salvatore Lettieri and Christine Oh

46

The Future of Robotics in Skull Base Surgery

..................................................

288

S. Harrison Farber, James J. Zhou, Arnau Benet, Andrew S. Little, and Michael A. Mooney

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

viii

293

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Video Contents Video 15.1 Resection of a parasellar invasive pituitary macroadenoma. Video 29.1 Keyhole endoscopic-assisted removal of a posterior fossa epidermoid tumor. Video 44.1 Endoscopic trans-pterygoid approach to the lateral sphenoid recess.

xi

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Foreword In my more than 40 years of practicing skull base and vascular neurosurgery, I have found that one persistent challenge we all face is to stay current on the changing paradigms of disease management for patients with skull base disease. Obtaining the best available evidence in a field dominated by expert opinion and bias is problematic. In addition, skull base diseases are rare, which can impede the development of truly useful treatment guidelines. Furthermore, there are often myriad treatment options and scant evidence of the superiority of any one option over another. Numerous intersecting trends shape the current care of the skull base patient. These trends include the emergence of endonasal and intracranial endoscopy, the development of state-of-the-art endovascular surgery techniques, the widespread adoption of radiosurgery, the increased focus on quality-of-life issues for patients, and an improved understanding of the molecular drivers of skull base neoplasms. Our early skull base efforts were directed at gaining adequate access to deep skull base pathologies, which led to the development of extensive petrosal, transfacial, far lateral, and transoral routes. Success was defined by the dramatic resection of mass lesions, such as meningiomas, chordomas, juvenile angiofibromas, and chondrosarcomas. Complications attributed to these approaches and resections were accepted as unavoidable. Thus, a transcochlear approach that resulted in the loss of hearing and, at best, incomplete facial function was deemed to have acceptable morbidity when it allowed the clipping of a giant midbasilar artery aneurysm. However, as our specialty matured, our paramount vision shifted toward minimally invasive corridors to pathologies, with an emphasis on maintaining and improving the patient’s quality of life. This comprehensive volume beautifully documents this sea change by illuminating the

current state of skull base surgery. Drs. Andrew Little and Michael Mooney have focused on documenting morbidity, such as nasal obstruction, drainage, and crusting after successful endonasal procedures—complaints generally ignored or minimized but of great importance to the patient’s quality of life. Only when these symptoms are documented can they be appropriately addressed. Drs. Little and Mooney have not only taken on—and met —the challenge of documenting the current state of skull base surgery but also have provided the reader with guidelines for treating patients with skull base disease. They have assembled a cadre of experts in their respective fields who artfully describe the controversies with which they are confronted. In the chapters they have contributed to this volume, these authors share their experiences, biases, and institutional preferences, and they summarize the best available evidence in tabular format. Many authors also present instructional case examples and offer suggestions for future studies to help clarify areas of controversy. Over the years, I have taken great pride in the clinical and academic accomplishments of Drs. Mooney and Little. This book demonstrates their continued professional growth. Since I have had the honor of being involved in their training, I can personally attest to their discernment, the excellence of their surgical skills, and their devotion to their patients and their profession. I enthusiastically recommend this comprehensive text as a concise and evidence-based summary of current treatments for practitioners caring for patients with skull base diseases. Robert F. Spetzler, MD J.N. Harber Chairman Emeritus of Neurological Surgery Director Emeritus Barrow Neurological Institute Phoenix, Arizona, USA

xiii

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Preface We are proud to present the inaugural edition of Controversies in Skull Base Surgery. Skull base surgery is a multidisciplinary specialty that addresses generally uncommon, complex, and sometimes awe-inspiring disorders that fall at the intersection of what neurosurgeons, otolaryngologists, radiation oncologists, radiologists, plastic surgeons, and oncologists treat. Advances in endoscopic, microsurgical, radiosurgical, and pharmacotherapeutic treatment strategies have changed the way that skull base pathology is treated in modern practice. This text was conceived to address a glaring need in skull base surgery; namely, a concise source that summarizes the best available evidence to treat the broad array of skull base concerns. Contributing authors, who are experts in their respective subspecialties, have compiled compelling summaries of disease management options and offered their insights and biases. Because there are obvious knowledge gaps due to the rare nature of the diseases treated, controversy ensues. We hope this text provides a balanced reading of available literature. Some authors have also suggested ideas for future studies to help clarify important questions. The busy practitioner will utilize this concise and

comprehensive resource to guide treatment recommendations and stay current on best available medical evidence. This resource is appropriate for neurosurgery, otolaryngology, radiation oncology, and endocrinology faculty, residents, medical students and other providers of care to skull base patients. The text is arranged in sections centered on common themes. These themes include acoustic neuroma, meningioma, pituitary adenoma, craniopharyngioma, Rathke’s cleft cysts and other sellar lesions, cranial nerve schwannomas, chordoma and other cranial tumors, sinonasal malignancies, and surgical approaches and techniques. The table below describes the levels of evidence assigned to the literature reviewed in this textbook. Readers should consult it to obtain guidance on the strength of evidence behind the authors’ assertions. We hope readers will find this useful as they try to achieve an understanding of this discipline. Andrew S. Little, MD Michael A. Mooney, MD

Levels of scientific evidence used in this textbook* Level

Therapeutic Studies

Investigating the Outcome of Disease

Investigating a Diagnostic Test

I

1. Randomized, controlled trial

1. Prospective study

1. Testing of previously developed diagnostic criteria in a series of consecutive patients (with universally applied reference gold standard)

2. Systematic review of Level I randomized, controlled trials (studies were homogeneous)

2. Systematic review of Level I studies

2. Systematic review of Level I studies

1. Prospective cohort study

1. Retrospective study

1. Development of diagnostic criteria on basis of consecutive patients (with universally applied reference gold standard)

2. Poor-quality randomized, controlled trial (e.g., 45% between studies. In patients with “significant” shrinkage, overall tumor size reduction was approximately 50%. However, a review of reported data for all patients, regardless of change in tumor size, revealed a weighted average tumor volume reduction of only 19.4% patients.35 A prospective open-label study of octreotide LAR found that microadenomas and macroadenomas responded with similar tumor mass reduction (i.e., 54 and 49%, respectively). Significant (> 30%) shrinkage was observed in 64% of patients with microadenomas and in 80% of macroadenomas at 24 weeks.11 Mercado et al reported similar results on tumor shrinkage in patients treated with octreotide LAR as primary therapy. Significant (> 20%) tumor shrinkage was found in 63 and 75% of patients at weeks 24 and 48, respectively.13 In a systematic review of effects of two different lanreotide formulations, SR and Autogel, tumor shrinkage was reported in 29 to 100% of patients treated with lanreotide SR and in 66 to 77% of patients who received lanreotide Autogel treatment.36 Interestingly, tumor size reduction does not always correlate with reduction in GH and IGF-1 levels9,28,36,37; and tumor volume decrease can be seen in the absence of adequate biochemical control.36,37 This phenomenon is thought to be related to the divergence of the cytotoxic and GH-suppressive effects of SRLs at a postreceptor level.37 Some authors also suggest that GH receptor subtype may be a determinant of this differential effect.38

Biochemical Control and Tumor Shrinkage with Pasireotide Pasireotide was evaluated and compared to octreotide LAR in a randomized, double-blind, head-to-head, superiority study.12 The patient population included both previously surgically treated and treatment-naïve patients. In the overall population, more patients achieved biochemical control (normal IGF-1 and GH < 2.5 μg/L) on pasireotide than on octreotide LAR (31.3% vs. 19.2% respectively, p = 0.007). In the treatment-naïve arm, pasireotide induced biochemical control in 25.7% of patients compared with 17.3% in the octreotide LAR arm; however, the difference was not significant. Of note, this was an intention-totreat study that might explain relatively low biochemical control rates when compared to other previously published octreotide LAR data. In addition, in about a quarter of patients, pasireotide and octreotide doses were not uptitrated as recommended per protocol. The authors speculated that higher control rates might have been achieved with higher doses. It is possible that hyperglycemia was one of the limiting factors for the pasireotide group, though lack of “up titration” was also present for the octreotide group. Hyperglycemia-related adverse events were reported in 57.5 and 21.7% of pasireotide and octreotide LAR arms, respectively (35.6% difference, 95% CI, 25.5–44.9%).12 In the combined postsurgical and de novo arms, tumor shrinkage was similar with pasireotide and octreotide LAR (approximately 40%), and significant (> 20%) tumor size reduction was achieved in 80 and 77% of patients treated with pasireotide and octreotide LAR, respectively. Furthermore,

79

80

Study type

Phase 1: double-blinded placebo-controlled Phase 2: prospective, open label, randomized to two different doses Phase 3: prospective, open label

Prospective, open label

Prospective, open label

Prospective, open label

Prospective, open label

Prospective, open-label dose escalation

Prospective, open label

Prospective, open label

Prospective, open label, randomized

Prospective, open label

Prospective, open label

Prospective, randomized

Author, year

Newman 199810

Bevan 200223

Colao 200127

Cozzi 20069

Colao 2006 Clin Endo11

Colao 200729

Mercado 200713

Luque-Ramírez 201031

Amato 200220

Colao 2006 JCEM28

Colao 2009 JCEM25

Karaca 201117 12

60

12

24

12

12

24

6

Median 48

24

12

2 6 39

Study duration (mo)

Octreotide LAR vs. surgery

Octreotide LAR, lanreotide SR

Octreotide LAR, lanreotide SR

Octreotide LAR vs. lanreotide SR

Octreotide LAR

Octreotide LAR

Octreotide LAR

octreotide LAR

Octreotide LAR

Octreotide LAR

Octreotide-SC (24 weeks) then octreotide LAR in 15 of 27 patients

Octreotide-SC

Therapy described

22

45

99

20

19

68

56

34

67

15

27

26

Treatment naïve patients (n)

0

0

0

0

0

0

0

0

0

21

0

81

Patients with previous surgery or radiation (n)

NA

84

86.8

50

73.6

88.2

89

61.7

72

33

74

84

Macroadenoma (%)

46%

34%

NA

61.5% micro 35% macro (NS)

70.1%

53.3% operated 71.4% naïve (NS)

53%

97.8%

45.5%

GHc and IGF-1 27% in octreotide LAR group 64% in surgery group (NS)

100%

GH and IGF-1 42.2%

57.6%

GHb and IGF-1 41.0% in lanreotide SR 37.5% in octreotide LAR (NS)

54%

GH and IGF-1 25%

44%

GH and IGF-1 80.3%

84.6% micro 45% macro (NS)

68.7%

73.3% operated 76.2% naïve (NS)

79%b

68% naïve 62% nonnaïve (NS)

IGF-1

Biochemical controla

NA GH fell > 2 SD below baseline in 70% naïve 61% nonnaïve

GH

Table 13.1 Summary of prospective studies evaluating SRLs as primary medical therapy for acromegaly. Studies are arranged by type of intervention

64 in octreotide LAR group 100 in surgery group

NA

72.7

NA

42

75

Overall 68.1

64 in micro 80 in macro

82.1

80

73

23

Patients with tumor shrinkage (%)

> 20

Overall 74.9 in octreotide LAR 78.2 in lanreotide SR (NS)

> 25

Overall 30 in lanreotide SR 34 in octreotide LAR (NS)

> 25

> 20

II

> 30

mean 62

> 25 in naïve patients

> 30

> 25

Tumor shrinkage (%)

I

II

II

I

II

II

II

II

II

II

II

Level of evidence

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12

12

Prospective, randomized

Prospective, randomized

Prospective, open label

Prospective, open label

Prospective, open label

Prospective, open label

Prospective, open label

Prospective, open label

Prospective, randomized, double-blinded

Colao 2009 Clin Endo15

Fahlbusch 201716

Baldelli 200022

Lombardi 200930

Colao 2009 Clin Endo26

Annamalai 201321

Caron 201424

Maiza 200732

Colao 201412 12

Mean 84

12

6

24

Pasireotide vs. octreotide LAR

Octreotide-SC, octreotide LAR, lanreotide Autogel

Lanreotide Autogel

Lanreotide Autogel

Lanreotide Autogel

Lanreotide Autogel

Lanreotide SR

Octreotide LAR vs. surgery

Octreotide LAR vs. surgery

Therapy described

207

36

89

30

26

39

23

41

81

Treatment naïve patients (n)

151

0

0

0

0

12

95

0

0

Patients with previous surgery or radiation (n)

NA

50

100

70

76.9

48.7 (in naïve)

22

100

90

Macroadenoma (%) IGF-1

67%

50%

40%

57.7%

33% in naïve and 50% nonnaïve (NS)

51% operated 37% irradiated and 70% naïve (NS)

GH and IGF-1 naïve and nonnaïve: 31.3% in pasireotide 19.2% in octreotide LAR (p = 0.007) naïve only: 25.7% in pasireotide 17.3% in octreotide LAR (NS)

GH and IGF-1 58%

70%

GH and IGF-1 43.5%

77.8%

60%

GH and IGF-1 53.8%

57.7%

72% in naïve 50% in nonnaïve (NS)

GHc 64% operated 37% irradiated 78% naïve (naïve vs. operated p < 0.05; naïve vs. irradiated p < 0.0005)

GH and IGF-1 6.7% in Oct-LAR group 50% in surgery group (p = 0.006)

GH and IGF-1 24 weeks 25% in octreotide LAR group 49% in surgery group (p = 0.047) 48 weeks 28% in octreotide LAR group 39% in surgery group (NS)

GH

Biochemical controla

bGH < 5

control defined as GH level < 2.5 µg/L; normal IGF-1; Both GH level < 2.5 µg/L and normal IGF-1. mU/L (< 1.66 µg/L). cGH < 2.5 µg/L or glucose-suppressed GH < 1 µg/L. Abbreviation: SC, subcutaneous; LAR, long-acting repeatable/release; NA, not available; SD, standard deviation; NS, nonsignificant; macro, macroadenomas; micro, microadenomas.

aBiochemical

12

Study type

Author, year

3

Study duration (mo)

Table 13.1 (continued)

Naïve and nonnaïve: 80 in pasireotide 77 in octreotide LAR (NS) naïve: NA

72

62.9

79

76.9

NA

22

NA

73 in octreotide LAR group 95 in surgery group

Patients with tumor shrinkage (%)

Naïve and nonnaïve: > 20

> 20

> 20

> 20

> 25

NA

> 20 in naïve patients

NA

> 20

Tumor shrinkage (%)

I

II

II

II

II

II

II

I

I

Level of evidence

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81

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Pituitary Adenoma when analyzed separately, postsurgery and de novo groups achieved a similar degree of tumor size reduction.12 These results suggest that due to its overall superiority in lowering GH and IGF-1 levels, pasireotide may be considered as primary medical treatment in patients with higher likelihood of first-generation SRLs resistant tumors, with the caveat of higher risk of hyperglycemia.

First-Generation SRLs versus Transsphenoidal Surgery There are only three prospective randomized studies comparing efficacy of SRLs as primary therapy with TSS.15,16,17 Colao et al performed a randomized, 48-week study of octreotide LAR versus TSS. Biochemical response (normal IGF-1 and GH < 2.5 μg/L) at 24 weeks was observed in 25% medically treated and 49% operated patients (p = 0.047). However, the difference was not significant at 48 weeks (28 vs. 39%, medically treated and operated patients, respectively). Notably, patients in the octreotide LAR group had higher GH levels and larger tumors compared with surgical group, which could have influenced the results.15 As expected, there were more cases of gastrointestinal adverse events (asymptomatic gallstones, gallbladder sludge, diarrhea) in the octreotide LAR group (71%) compared with surgery group (41%). On the other hand, surgery resulted in a higher percentage of respiratory events (28 vs. 5%) and new hypopituitarism requiring treatment in 14% of subjects.15 In a randomized prospective study by Karaca et al in 22 patients, biochemical response (normal IGF-1 and random GH < 2.5 μg/L or glucose suppressed GH < 1 μg/L) was observed in 27% of octreotide LAR treated and 64% surgically treated patients. Although surgery seemed to achieve better results, the difference was not statistically significant. There was also no difference in adrenal axis hypofunction at 12 months, but greater percentage of glucose intolerance and asymptomatic biliary disease was found in the octreotide group. This study also estimated the cost of treatment and follow-up in surgical and medical groups. The authors found that medical treatment was more expensive ($10,000 per patient per year) compared with surgical treatment ($2000 per patient per year).17 A meta-analysis assessed efficacy of SRLs versus surgical approach by combining data from 35 prospective and retrospective, controlled and uncontrolled studies. Unlike most studies that reported biochemical control (GH < 2.5 μg/L and normal IGF1), this meta-analysis focused on remission rates defined by normal IGF-1 and GH < 1 μg/L. Overall remission rates with surgery were higher than those with medical treatment (67 vs. 45%, p = 0.02), however, when stratified by follow-up periods, surgical remission rates were significantly higher only at longer follow-up periods (> 24 months), but not at shorter follow-up periods (< 24 months). Interestingly, studies with a single surgeon reported higher remission rates that those with more than one surgeon.14 It has been previously shown that surgical debulking improves postoperative control by SRLs suggesting that surgery should be considered for macroadenomas even when the likelihood of cure is low.39,40 A recent randomized prospective study of 41 patients with “severe” acromegaly (macroadenoma, GH ≥ 12.5μg/L and elevated IGF-1) found a slim 6.7% normalization rate of GH and IGF-1 with primary octreotide LAR treatment compared with 50% after surgery at 3 months. Adjunctive octreotide LAR in

82

those who did not achieve surgical remission resulted in a total of 76.9% normalization of biochemical parameters at 6 months. This study confirmed that a rapid initial control can be achieved with surgery and suggested that debulking improves response rate to SRLs. However, longer-term comparison with primary medical treatment could not be performed as the primary medical therapy was administered only for 3 months.16 In addition to rapid GH decrease, surgery has also the advantage of providing information about the pathology of the tumor, specifically granulation pattern and somatostatin receptor positivity, which serve as predictors of responsiveness to SRLs and may allow for better and timely biochemical control by choosing individualized single-agent or combination treatment.41,42 On the other hand, T2 magnetic resonance imaging (MRI) appearance of GH adenoma has been shown to correlate with granulation pattern and predict responsiveness to SRLs in primary medical therapy. In particular, T2 hypointense adenomas correlate with densely granulated pattern and respond better to SRL treatment.43,44 Therefore, T2 MRI intensity can help in guiding the choice of therapy (surgery vs. medical therapy) in uncertain situations or indicating that more potent agents or combination therapy would be required early in the course of treatment if the predicted response to medical therapy is relatively low. Other parameters, such as younger age, high GH level at diagnosis, male sex, aryl hydrocarbon receptor-interacting protein (AIP) mutation, have also been implicated in a more aggressive course for GH-secreting adenoma and lower rate of response to first-generation SRLs.41,42,45

13.2.3 Growth Hormone-Receptor Antagonist as Primary Medical Therapy Pegvisomant has been mostly used as an adjunctive therapy in patients who are not cured by surgery, but also as a primary therapy in patients who are not candidates for surgery, normalizing IGF-1 levels in 67.6 to 97% of patients.19,46 The ACROSTUDY showed that pegvisomant was overall well tolerated and exhibited a favorable safety profile in acromegaly patients.47 However, data on primary treatment with pegvisomant is limited. A retrospective study examined pegvisomant as primary therapy (group 1) versus adjunctive therapy in operated patients without prior medical treatment (group 2) versus adjunctive therapy in operated patients pretreated medically before surgery (group 3). There was no difference in the rates of normalization of IGF-1 in the three groups (76.9 vs. 85.2 vs. 78.3%, p = NS). The time to normalization of IGF-1 was also similar (0.5 vs 0.7 vs 0.6 years, respectively). There were more patients with microadenomas in primary medical treatment group, and their pretreatment IGF-1 level was higher. Increase in tumor size was noted in only one patient from group 2 and was considered not clinically significant.19 This study suggests that there may be a role of pegvisomant monotherapy as effective primary medical therapy, but further prospective studies are needed.

13.2.4 Dopamine Agonists as Primary Medical Therapy Data on DAs in treatment of acromegaly are scarce and are considered of limited efficacy. Most studies were small in patient

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Primary Medical Therapy for Acromegaly, Ready for Prime Time? risk of tumor growth, however, transient liver function enzyme elevation was present in about a third of patients.53,54

number and enrolled a mixed patient population (treatmentnaïve, previously treated with another agent, and those treated with surgery and radiation) and none were placebo-controlled or randomized. Meta-analysis of prospective, nonrandomized studies of cabergoline concluded that about a third of patients achieve normalization of IGF-1 on cabergoline, with tumor shrinkage in 0 to 62% of cases.48 In a retrospective study, Sherlock et al observed normalization of IGF-1 in 32% and GH in 28% of patients treated with DAs. Percent reduction of GH and IGF-1 level was similar in treatment-naïve patients and those treated with surgery prior to DAs.49 Given the paucity of data and limited efficacy, treatment with DAs is recommended as adjunctive therapy in mild acromegaly, but not as primary therapy.

SRLs and Cabergoline Addition of cabergoline to ongoing SRL therapy can induce biochemical control in 30 to 56% of patients.55,56,57 One prospective study subdivided 52 patients, uncontrolled on SRLs, into 3 groups: (1) surgery plus octreotide LAR, (2) octreotide LAR only, and (3) combination of surgery, radiation, and octreotide LAR. Investigators found a similar IGF-1 response to the addition of cabergoline in the dose of up to 3 mg/weeks in all three groups by 6 months of therapy (40, 42.1, and 33.3%, respectively).57 Of note, all patients in the octreotide LAR group had macroadenomas.

13.2.5 Combination Therapy as Primary Medical Therapy

Pegvisomant and Cabergoline One prospective58 and one retrospective59 study evaluated combination therapy with pegvisomant and cabergoline and found normalization of IGF-1 in 68 and 28% of the patients respectively. Almost all patients had undergone previous surgery in both studies, and thus primary combination therapy effects could not be assessed separately. A suggested personalized approach to primary medical therapy is presented in ▶ Fig. 13.1.

SRLs and Pegvisomant Pegvisomant has been shown to normalize IGF-1 in up to 95% of cases when coadministered in patients uncontrolled on SRL therapy.50,51 One long-term prospective study of 4.9 years noted similar rates of normalization of IGF-1 in patients previously treated surgically and those receiving combination therapy as primary treatment (95.7 vs. 98.5%; p = 0.604).52 There was no increased

Growth hormone secreting adenoma (except a tumor with optic chiasm compression)

Fig. 13.1 Suggested approach to primary medical management of growth hormonesecreting adenomas.

Invasive adenoma (low probability of remission)

1. Poor surgical candidate 2. Patient refuses surgery 3. No experienced pituitary neurosurgeon available OR surgery significantly delayed

Consider surgical debulking

Initiate medical therapy

Are factors associated with resistance to first generation somatostatin receptor ligands present? (younger age at onset, male sex, high GH levels, or hyperintense tumor on T2 MRI)

YES

NO

Consider pasireotide or pegvisomant

Initiate octreotide LAR or lanreotide

Uncontrolled

Reconsider surgery

Controlled

Uncontrolled

Biochemical and imaging monitoring

Add pegvisomant or change to pasireotide

Uncontrolled

Reconsider surgery

Controlled

Biochemical and imaging monitoring

Controlled

Biochemical and imaging monitoring

83

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Pituitary Adenoma

Table 13.2 Summary of randomized controlled trials evaluating preoperative somatostatin receptor ligands in acromegaly. Author (year)

Total adenomas; n (macroadenomas; n)

SRL

Carlsen (2008)60

62 (51)

Shen (2010)61

Postoperative remission ratea

Level of evidence

Preoperative intervention (mo)

Postoperative assessment (mo)

Preoperative SRL (%)

No preoperative SRL (%)

p-value

OctreotideLAR

6

3

38

16

NS

I

39 (39)

OctreotideLAR

3

3 6 26–28

31.6 42.1 31.6

5 10 10

0.044 0.031 NS

I

Mao (2010)65

98 (98)

Lanreotide-SR

4

4

38.8

18.4

0.025

I

(2012)64

49 (49)

Lanreotide-SR

3

3

45.8

20

< 0.05

I

62 (51) 62 (44)

OctreotideLAR

6

12 60

38 41

24 27

NS NS

I

Li

Fougner (2014)63 aRemission

rate defined as normal IGF-1 and suppressed GH after glucose loading. Abbreviations: LAR, long-acting repeatable; NS, not significant; SRL, somatostatin receptor ligand.

13.2.6 Preoperative Use of Somatostatin Receptor Ligands A few prospective studies have examined the role of preoperative treatment with SRLs and the rate of subsequent cure. A theoretical advantage of decreasing tumor size is that it may facilitate a complete resection, while reduced preoperative GH level may decrease anesthesia complications related to laryngeal edema and impaired cardiovascular dynamics seen in acromegaly.4,60,61,62 Nevertheless, there is no robust evidence to support the use of preoperative treatment SRL in improving long-term surgical cure rates and perioperative complications. The Preoperative Octreotide Treatment of Acromegaly (POTA) study compared patients with acromegaly who were treated and not treated with SRL for 6 months prior to surgical resection.60 Investigators found higher cure rates for macroadenomas (defined by normal IGF-1) in the pretreatment group at 3 months after surgery (50 vs. 16%, p = 0.017). However, when using both normal IGF-1 and glucose-suppressed GH < 2 mU/L (< 0.66 μg/L) there was no difference in cure rates between the two groups. They also noted no difference in rates of surgical complications or length of hospital stay (3.7 days in pretreated patients vs. 3.6 days in direct surgery patients, p = 0.54). In subsequent evaluations at year 1 and year 5, the cure rates remain similar between patients pretreated with SRL and those who underwent surgical resection directly.63 On the contrary, Mao and colleagues reported higher rates of short-term (4 months) cure in patients pretreated with SRL than those who underwent surgery (38.8 vs. 18.4%, p = 0.025). Of note, among those with invasive macroadenomas, a greater number of patients were cured in the pretreated group compared with surgery-only group. Nevertheless, the number of macroadenomas with cavernous sinus invasion was too small to draw any definitive conclusions. Similarly, Li and colleagues demonstrated a superior cure rate in patients with invasive macroadenomas pretreated with SRL for 3 months prior to surgical resection compared to patients who underwent TSS without SRL pretreatment (45.8 vs. 20%, p < 0.05).64 Disappointingly, the superior cure rates described by Mao and Li were not replicated in another study that followed patients for an average of 28 months after surgery.61 Shen’s study demonstrated initial higher cure rates in patients pretreated with SRLs prior to

84

surgery (42.1 vs. 10%, p = 0.031) but the difference dissipated (31.6 vs. 10%, p = 0.13) by the study’s last evaluation (▶ Table 13.2).60,61,63,64,65 Interestingly, patients treated with SRL prior to surgery demonstrated improved cardiac ejection fraction, glucose tolerance, sleep apnea, and hypertension suggesting that anesthesia and surgery complications risk could be reduced.61 However, risk reduction has not yet been confirmed in the randomized controlled studies and current evidence shows similar rates of postoperative morbidity, difficult airway management, and length of hospitalization.60,65 In addition, no difference in rates of pituitary dysfunction and visual impairment has been observed. Nonetheless, the lack of apparent operative risk reduction may be due to small sample sizes or other unrecognized factors. Until further evidence is available, patients with highest preoperative risk, such as high-output heart failure, uncontrolled hypertension, or severe pharyngeal edema, should be considered for SRL pretreatment.

13.3 Conclusions Primary medical therapy for treatment of acromegaly is a reasonable alternative to TSS in certain clinical cases such as poor surgical candidates, lack of a skilled pituitary neurosurgeon, low likelihood of cure, and patient’s preference for medical treatment, with the caveat that there is no urgent need to decompress the optic chiasm. First-generation SRLs are the mainstay of primary medical therapy; however, there is emerging data on efficacy of pegvisomant and combination therapy. SRL pretreatment prior to surgical resection of pituitary macroadenoma cannot be routinely recommended to improve postoperative outcomes. Further research is needed to clarify the effect of SRL pretreatment on surgical morbidity and mortality in high-surgical-risk patients.

13.4 Suggestions for Future Studies Given the discrepancy in rates of biochemical control between SRLs studies, more randomized controlled trials are needed to assess primary medical and surgical treatment outcomes at

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Primary Medical Therapy for Acromegaly, Ready for Prime Time? different follow-up time points. In addition, studies evaluating cost effectiveness and quality of life are also needed. [22]

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Pituitary Adenoma [42] Fougner SL, Casar-Borota O, Heck A, Berg JP, Bollerslev J. Adenoma granulation pattern correlates with clinical variables and effect of somatostatin analogue treatment in a large series of patients with acromegaly. Clin Endocrinol (Oxf). 2012; 76(1):96–102 [43] Puig-Domingo M, Resmini E, Gomez-Anson B, et al. Magnetic resonance imaging as a predictor of response to somatostatin analogs in acromegaly after surgical failure. J Clin Endocrinol Metab. 2010; 95(11):4973–4978 [44] Heck A, Ringstad G, Fougner SL, et al. Intensity of pituitary adenoma on T2weighted magnetic resonance imaging predicts the response to octreotide treatment in newly diagnosed acromegaly. Clin Endocrinol (Oxf). 2012; 77 (1):72–78 [45] Gadelha MR, Kasuki L, Korbonits M. Novel pathway for somatostatin analogs in patients with acromegaly. Trends Endocrinol Metab. 2013; 24(5):238–246 [46] van der Lely AJ, Hutson RK, Trainer PJ, et al. Long-term treatment of acromegaly with pegvisomant, a growth hormone receptor antagonist. Lancet. 2001; 358(9295):1754–1759 [47] Freda PU, Gordon MB, Kelepouris N, Jonsson P, Koltowska-Haggstrom M, van der Lely AJ. Long-term treatment with pegvisomant as monotherapy in patients with acromegaly: experience from ACROSTUDY. Endocr Pract. 2015; 21(3):264–274 [48] Sandret L, Maison P, Chanson P. Place of cabergoline in acromegaly: a metaanalysis. J Clin Endocrinol Metab. 2011; 96(5):1327–1335 [49] Sherlock M, Fernandez-Rodriguez E, Alonso AA, et al. Medical therapy in patients with acromegaly: predictors of response and comparison of efficacy of dopamine agonists and somatostatin analogues. J Clin Endocrinol Metab. 2009; 94(4):1255–1263 [50] Feenstra J, de Herder WW, ten Have SM, et al. Combined therapy with somatostatin analogues and weekly pegvisomant in active acromegaly. Lancet. 2005; 365(9471):1644–1646 [51] van der Lely AJ, Bernabeu I, Cap J, et al. Coadministration of lanreotide Autogel and pegvisomant normalizes IGF1 levels and is well tolerated in patients with acromegaly partially controlled by somatostatin analogs alone. Eur J Endocrinol. 2011; 164(3):325–333 [52] Neggers SJCMM, Franck SE, de Rooij FWM, et al. Long-term efficacy and safety of pegvisomant in combination with long-acting somatostatin analogs in acromegaly. J Clin Endocrinol Metab. 2014; 99(10):3644–3652 [53] Neggers SJ, de Herder WW, Janssen JA, Feelders RA, van der Lely AJ. Combined treatment for acromegaly with long-acting somatostatin analogs and pegvisomant: long-term safety for up to 4.5 years (median 2.2 years) of follow-up in 86 patients. Eur J Endocrinol. 2009; 160(4):529–533

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[54] Neggers SJCMM, van Aken MO, Janssen JAMJL, Feelders RA, de Herder WW, van der Lely A-J. Long-term efficacy and safety of combined treatment of somatostatin analogs and pegvisomant in acromegaly. J Clin Endocrinol Metab. 2007; 92(12):4598–4601 [55] Jallad RS, Bronstein MD. Optimizing medical therapy of acromegaly: beneficial effects of cabergoline in patients uncontrolled with long-acting release octreotide. Neuroendocrinology. 2009; 90(1):82–92 [56] Mattar P, Alves Martins MR, Abucham J. Short- and long-term efficacy of combined cabergoline and octreotide treatment in controlling igf-I levels in acromegaly. Neuroendocrinology. 2010; 92(2):120–127 [57] Vilar L, Azevedo MF, Naves LA, et al. Role of the addition of cabergoline to the management of acromegalic patients resistant to longterm treatment with octreotide LAR. Pituitary. 2011; 14(2):148–156 [58] Higham CE, Atkinson AB, Aylwin S, et al. Effective combination treatment with cabergoline and low-dose pegvisomant in active acromegaly: a prospective clinical trial. J Clin Endocrinol Metab. 2012; 97(4):1187–1193 [59] Bernabeu I, Alvarez-Escolá C, Paniagua AE, et al. Pegvisomant and cabergoline combination therapy in acromegaly. Pituitary. 2013; 16(1):101–108 [60] Carlsen SM, Lund-Johansen M, Schreiner T, et al. Preoperative Octreotide Treatment of Acromegaly study group. Preoperative octreotide treatment in newly diagnosed acromegalic patients with macroadenomas increases cure short-term postoperative rates: a prospective, randomized trial. J Clin Endocrinol Metab. 2008; 93(8):2984–2990 [61] Shen M, Shou X, Wang Y, et al. Effect of presurgical long-acting octreotide treatment in acromegaly patients with invasive pituitary macroadenomas: a prospective randomized study. Endocr J. 2010; 57(12):1035–1044 [62] Fleseriu M, Hoffman AR, Katznelson L, AACE Neuroendocrine and Pituitary Scientific Committee. American Association of Clinical Endocrinologists and American College of Endocrinology disease state clinical review: management of acromegaly patients: what is the role of preoperative medical therapy? Endocr Pract. 2015; 21(6):668–673 [63] Fougner SL, Bollerslev J, Svartberg J, Øksnes M, Cooper J, Carlsen SM. Preoperative octreotide treatment of acromegaly: long-term results of a randomised controlled trial. Eur J Endocrinol. 2014; 171(2):229–235 [64] Li ZQ, Quan Z, Tian HL, Cheng M. Preoperative lanreotide treatment improves outcome in patients with acromegaly resulting from invasive pituitary macroadenoma. J Int Med Res. 2012; 40(2):517–524 [65] Mao ZG, Zhu YH, Tang HL, et al. Preoperative lanreotide treatment in acromegalic patients with macroadenomas increases short-term postoperative cure rates: a prospective, randomised trial. Eur J Endocrinol. 2010; 162(4):661–666

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The Role of Radiosurgery for Pituitary Adenomas

14 The Role of Radiosurgery for Pituitary Adenomas Gabriella Paisan, Ching-Jen Chen, and Jason Sheehan Abstract Pituitary adenomas are a commonly encountered intracranial tumor. The management options for pituitary adenomas are varied, and the treatment course for each patient depends largely on the tumor’s size and endocrine profile. Although tumors requiring intervention often undergo surgical resection or medical management as first-line treatment, stereotactic radiosurgery (SRS) also plays an important role in the management of pituitary adenomas. SRS is recommended for patients with substantial residual tumor or in cases of tumor recurrence after surgical resection. It is also recommended for patients with functioning adenomas who fail to achieve hormonal control after surgical resection. SRS has been shown to be a safe treatment for pituitary adenomas and, in select cases, may be used as an upfront treatment for pituitary adenoma patients. Neurological deficits following SRS are rare, and hypopituitarism, the most common complication, can be managed with hormone replacement. Therefore, with reasonable tumor control rates and acceptable adverse effect profile, SRS has become a mainstay in the treatment of pituitary adenomas. However, as SRS has increased in use and its applications have grown, a number of questions regarding its use in treating pituitary adenomas remain unanswered. In this chapter, we summarize the literature regarding SRS treatment for pituitary adenomas, including optimal treatment parameters such as margin dose, target delineation, and treatment timing. Keywords: pituitary adenoma, stereotactic Gamma Knife, outcomes, radiation

radiosurgery,

14.1 Introduction Pituitary adenomas account for about 10 to 20% of all intracranial tumors.1,2,3 Depending on tumor size and biochemical profile, the clinical presentation of these lesions may vary widely. Functioning adenomas can cause a range of symptoms related to hormone overproduction, while symptomatic nonfunctioning adenomas (NFAs), although occasionally discovered incidentally, typically present due to compression of adjacent structures. This often manifests as visual field deficits due to compression of the optic apparatus, hyperprolactinemia or hypopituitarism due to compression of the pituitary gland, or a focal neurological deficit due to compression of the cranial nerves traversing the cavernous sinus.1 Management options for pituitary adenomas vary greatly. Depending on the tumor’s clinical presentation and functional status, treatment options may include microsurgical or endoscopic resection, medical therapy, radiation, stereotactic radiosurgery (SRS), or observation alone. With the exception of prolactinomas, which are often treated medically, surgical resection remains the first-line treatment for functioning adenomas and for NFAs that are large enough to cause compressive symptoms. SRS delivers focused, high-dose radiation to a target in a limited number of sessions (typically one but occasionally up to

five fractions). The sharp dose dropoff of the focused radiation beams at the isodose line minimizes radiation exposure to adjacent structures, such as the optic apparatus, hypothalamus, cavernous sinus and its contents, normal pituitary gland, and brain parenchyma. SRS is most often used as an adjunct treatment to surgical resection for recurrent or residual pituitary adenomas. As SRS becomes more readily available at centers around the world, an increasing number of patients with pituitary adenomas are being treated using this modality. Thus, the role for SRS in pituitary adenoma treatment deserves revisiting. Despite the abundant literature regarding SRS for pituitary adenomas, optimal treatment parameters, including margin dose, target delineation, number of fractions, dose to critical structures, and treatment timing, remain disputed. In this chapter, we summarize and discuss the most recent literature regarding these areas of controversy.

14.2 Topic Review 14.2.1 SRS Outcomes for Pituitary Adenomas The evidence supporting the use of SRS in pituitary adenoma treatment derives largely from retrospective cohort studies and systematic reviews (Level III evidence). Unfortunately, more rigorous evidence, such as randomized clinical trials, does not exist. Given the evidence from large numbers of retrospective single- and multicenter studies, SRS has largely been embraced as a treatment of choice for recurrent or residual pituitary adenomas.

Outcomes for Nonfunctioning Pituitary Adenomas The major series describing radiosurgical outcomes for NFAs are listed in ▶ Table 14.1.4,5,6,7,8,9,10,11,12,13,14,15,16,17 The mean/ median follow-up period of these studies ranged from 33 to 98 months. The reported tumor control rate, defined by most series as stable tumor size or shrinkage on radiographic follow-up, ranged from 85 to 100% (mean 96%). In the largest series to date, Sheehan et al (2013) reported an overall tumor control rate of 93% with SRS after a mean follow-up period of 36 months in a multicenter retrospective analysis of 512 patients treated with SRS for NFAs.10 Tumor control was more likely to be achieved in those with small tumor volume (< 5 cm3) and in those with adenomas without suprasellar extension.10 In a more recent single-center study comprising 272 patients with NFAs treated with SRS, Losa et al (2017) reported a 90% tumor control rate after a median of 79 months.9 In addition, the authors observed a 79% 10-year progression-free survival, suggesting adequate long-term tumor control with SRS. Hypopituitarism remains the most common adverse effect following SRS for NFAs. The studies listed in ▶ Table 14.1 reported an average incidence of approximately 7% (range: 0– 27%). The incidence of hypopituitarism increases with duration

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Pituitary Adenoma

Table 14.1 Summary of the radiosurgical literature for nonfunctioning pituitary adenomas Study

Year

SRS type

Number of patients

Mean/median follow-up (mo)

Mean/median margin dose (Gy)

Tumor control (%)

Post-SRS hypopituitarism (%)

Liscák et al4

2007

GK

140

60

20

100

1

Pollock et al5

2008

GK

62

64

16

97

27

Hoybye et al17

2009

GK

23

78

20

100

0

Kobayashi et al16

2009

GK

71

50

NR

97

8

Castro et al8

2010

GK

14

42

13

100

0

Hayashi et al14

2010

GK

43

36

18

100

0

Iwata et al6

2011

CK

100

33

12 Gy/3 Fr, 25 Gy/5 Fr

98

2

El-Shehaby et al15

2012

GK

21

44

12

85

0

Runge et al13

2012

LINAC

65

83

13

98

10

Wilson et al12

2012

LINAC

51

50

14

100

NR

Sheehan et al10

2013

GK

512

36

16

93

21

Hasegawa et al11

2015

GK

16

98

15

100

0

2015

GK

57

46

15

89

20

2017

GK

272

79

15

90

NR

Bir et

al7

Losa et al9

Abbreviations: CK, CyberKnife; GK, Gamma Knife; Gy, Gray; LINAC, linear accelerator NR, not reported; mo, months; SRS, stereotactic radiosurgery.

Table 14.2 Summary of the radiosurgical literature for Cushing disease Series

Year

SRS type

Voges et al19

2006

LINAC

17

Castinetti et al20

2007

GK

40

Petit et al21

2008

PBT

33

Pollock et al22

2008

GK

Tinnel et al23

2008

GK

Kobayashi et

al16

Number of patients

Mean/median follow-up (mo)

Mean/median margin dose (Gy)

Endocrinological remission (%)

59

16

53

55

30

43

62

20

52

8

73

20

87

12

37

25

50

2009

GK

30

64

29

35

Wan et al24

2009

GK

68

67

23

28

Hayashi et al14

2010

GK

13

36

25

38

Wein et al29

2012

LINAC

17

23

18

59

Sheehan et al25

2013

GK

96

48

22

70

Grant et al28

2014

GK

15

40

35

73

Wilson et al26

2014

LINAC

36

66

20

22

al27

2015

GK

26

78

NR

81

Marek et

Abbreviations: GK, Gamma Knife; Gy, Gray; LINAC, linear accelerator; PBT, proton-beam therapy; SRS, stereotactic radiosurgery; mo, months.

of follow-up due to the latent effect of radiosurgery. Although hypopituitarism is a relatively serious adverse effect, morbidity associated with hypopituitarism can be mitigated by hormone replacement therapy. Hypopituitarism often occurs in a delayed fashion following SRS. In a single-center series with significant long-term follow-up to study the onset of hypopituitarism after SRS, Xu et al found that 80 of 262 patients (30%) developed new-onset hypopituitarism after treatment of their pituitary adenoma. Of note, the actuarial risk of developing post-SRS hypopituitarism was 31.5% at 5-year follow-up, thus underscoring the importance of long-term endocrine follow-up in patients treated with SRS.18 Serious complications, such as visual and cranial nerve deficits, are relatively uncommon, with an incidence of approximately 9% in the multicenter study by

88

Sheehan et al.10 Predictors of new or worsening cranial nerve deficits included larger tumor volume, prior history of radiation therapy, and prior history of endocrinopathy.

Outcomes for Functioning Pituitary Adenomas Tumor control in functioning adenomas comprises both radiologic tumor control and endocrine remission. The major SRS series describing outcomes for Cushing disease, acromegaly, and prolactinomas are listed in ▶ Table 14.2, ▶ Table 14.3 and ▶ Table 14.4, respectively. SRS plays an important role in the treatment of persistent Cushing disease (▶ Fig. 14.1). Endocrine remission can be

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The Role of Radiosurgery for Pituitary Adenomas

Table 14.3 Summary of the radiosurgical literature for acromegaly Series

Year

SRS type

Number of patients

Mean/median follow-up (mo)

Mean/median margin dose (Gy)

Endocrinological remission (%) 50

Jezkova et al30

2006

GK

96

54

35

Voges et al19

2006

LINAC

64

54

17

38

Pollock et al31

2007

GK

46

63

20

50

Roberts et al32

2007

CK

9

25

21

44

Vik-Mo et al33

2007

GK

61

66

27

17

Tinnel et al23

2008

GK

9

35

25

44

Castinetti et al34

2009

GK

43

102

24

42

Ronchi et al35

2009

GK

35

120

20

46

Wan et al24

2009

LINAC

103

67

21

37

Hayashi et al14

2010

GK

25

36

25

40

Iwai et al36

2010

GK

26

84

20

38

Poon et

al37

2010

GK

40

74

20–35

75

Franzin et al38

2012

GK

103

71

23

61

Liu et al39

2012

GK

40

72

21

48

Wilson et al40

2013

LINAC

86

66

20

14

Yan et al41

2013

LINAC

22

95

15

68

Lee et al42

2015

GK

176

62

25

67

Grant et al28

2014

GK

13

40

35

61

Abbreviations: CK, CyberKnife; GK, Gamma Knife; Gy, Gray; LINAC, linear accelerator; SRS, stereotactic radiosurgery; mo, months.

Table 14.4 Summary of the radiosurgical literature for prolactinomas Series

Year

SRS type

Voges et al19

2006

LINAC

13

Tinnel et al23

2008

GK

4

Castinetti et al34

2009

GK

15

Jezkova et al45

2009

GK

35

Kobayashi et

al16

Number of patients

Mean/median follow-up (mo)

Mean/median margin dose (Gy)

Endocrinological remission (%)

56

20

15

20

30

50

86

30

47

76

34

37

2009

GK

27

37

18

44

Wan et al24

2009

GK

176

67

35

23

Tanaka et al46

2010

GK

22

60

25

17

Liu et al39

2013

GK

22

36

15

27

Grant et al28

2014

GK

2

40

35

100

Wilson et al48

2015

LINAC

13

72

20

92

Cohen-Inbar et al47

2015

GK

38

42

25

50

Abbreviations: GK, Gamma Knife; Gy, Gray; LINAC, linear accelerator; SRS, stereotactic radiosurgery; mo, months.

achieved in approximately 53% (range: 22–87%) of patients using a mean margin dose of 24 Gy (range: 18–35 Gy) after a mean/median follow-up range of 23 to 78 months (▶ Table 14.2).14,16,19,20,21,22,23,24,25,26,27,28,29 Endocrine remission is typically defined as the normalization of 24-hour urinary free cortisol and a normal serum cortisol off suppressive medications. As with other functioning tumors, adrenocorticotropic hormone (ACTH)-secreting tumors often require higher margin doses to achieve endocrine remission than those required to achieve tumor control alone for NFAs. At our institution, we achieved a remission rate of 70% in 96 patients using a mean margin dose of 22 Gy after a median follow-up of 48 months.25 The mean time interval from SRS to endocrine remission was approximately 16 months (range: 1–165 months).

The SRS literature for acromegaly is summarized in ▶ Table 14.3.14,19,22,23,24,28,30,31,32,33,34,35,36,37,38,39,40,41,42 Endocrine remission is typically defined as normalization of insulin-like growth factor-1 (IGF-1) and growth hormone level normalization off suppressive medication (▶ Fig. 14.2). Among recent studies, endocrine remission was achieved in approximately 50% of patients (range 14–75%) after a mean/median follow-up range of 36 to 120 months. Due to the insidious nature of acromegaly, these tumors tend to be relatively large and often infiltrative on presentation, which may play a role in lower and delayed remission rates compared to patients with Cushing disease. Factors associated with endocrine remission include small tumor volume, cessation of somatostatin analogs in the periSRS period, and a higher margin radiation dose.43

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Pituitary Adenoma

Fig. 14.1 Case of Cushing disease treated with SRS. The patient is a 17-year-old male who underwent two transsphenoidal resections of an adrenocorticotropic hormone-secreting macroadenoma causing persistent Cushing disease. At his 3-month follow up, his 24-hour urinary free cortisol was still elevated, and he was still symptomatic of Cushing disease. He underwent Gamma Knife radiosurgery (GKRS) to the residual tumor. (a) His planning magnetic resonance imaging for GKRS. The tumor can be seen infiltrating the right cavernous sinus (arrow). A margin dose of 22 Gy at the 50% isodose line was delivered to the tumor. He went into remission in 6 months and was followed until May 2013 and never had a recurrence of Cushing disease. He did eventually develop delayed partial hypopituitarism (gonadotropin deficiency) but experienced no other adverse effects from GKRS. (b, c) His follow-up imaging showed no sign of tumor recurrence.

Fig. 14.2 Case of acromegaly treated with SRS. Patient treated with Gamma Knife radiosurgery (GKRS) for acromegaly. From left to right, the images show the pituitary adenoma at the time of GKRS, at 14-month follow-up, and at 33month follow-up, respectively. The graphs depict the patient’s growth hormone and IGF-1 levels in the post-SRS period.

The SRS literature for prolactinomas is summarized in ▶ Table 14.4.16,19,23,24,28,34,44,45,46,47,48 Endocrine remission rates for prolactinomas after SRS vary widely (range: 15–100%) across recent studies, and the literature is relatively sparse in comparison to that of Cushing disease and acromegaly. Because prolactinomas typically respond well to medical therapy, SRS is often reserved for those resistant to medical management, which may represent a more aggressive tumor subtype. In the largest series to date, Wan et al found a relatively low endocrine remission rate of 23% in 176 patients with prolactinomas using a median margin dose of 35 Gy after a median follow-up of 67 months.24 At our institution, we achieved an endocrine remission

90

rate of 50% in 38 patients with prolactinomas using a median margin dose of 25 Gy after a median follow-up of 42 months.47 Negative predictors of remission include cavernous sinus invasion of the adenoma and use of dopamine agonist at the time of SRS.47

14.2.2 Areas of Controversy Silent Corticotroph Adenomas Silent corticotroph adenomas (SCAs) comprise approximately 3–19% of NFAs.49,50 Although hormonally silent, these tumors

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The Role of Radiosurgery for Pituitary Adenomas demonstrate positive staining for corticotroph cells on histology. Tumor control rates for SCAs after SRS appear to be lower than those for non-SCAs. In a recent multicenter study from the International Gamma Knife Research Foundation consortium, Cohen-Inbar et al reported a tumor control rate of 82% (41 of 50 patients) in patients with SCAs compared to a rate of 94% (289 of 307 patients) in patients with non-SCAs (p = 0.0065).51 In the same study, the SCA group demonstrated a significantly higher risk of post-SRS visual deficits secondary to tumor progression. The authors also found that higher margin doses (≥ 17 Gy) were associated with improved tumor control in the SCA subgroup (p = 0.003). Therefore, SCAs appear to be an aggressive form of NFA with higher rates of tumor recurrence after SRS. As such, it may be prudent to administer higher doses of radiation to these tumors than generally used for NFAs. Future studies are needed to corroborate the benefits of higher radiation doses in treating these tumors.

Cessation of Antisecreting Medications The negative effects of antisecreting medications on SRS outcomes of Cushing disease, acromegaly, and prolactinomas have been reported over the past two decades.47,52 However, the cause for this relationship remains poorly understood. Landolt et al were the first to identify the negative effect of octreotide on SRS for acromegaly, which was associated with a significantly longer time to growth hormone and IGF-1 level normalization.52 Similar radioprotective effects were also observed in patients taking dopamine agonists for prolactinomas or ketoconazole for Cushing disease.25,51 Indeed, in our own study of 23 prolactinoma patients, those taking dopamine agonists at the time of SRS were more likely to fail to achieve endocrine remission (32 versus 50% overall).47 Similarly, in our series of 96 patients with Cushing disease, we found that temporary cessation of ketoconazole around the time of SRS significantly improved the time to endocrine remission (21.8 months if treated while on ketoconazole vs. 12.6 months if treated while temporarily off ketoconazole; p < 0.012).25 Therefore, whenever possible, temporary discontinuation of antisecreting medications is recommended before SRS of functioning pituitary adenomas. This recommendation is based on the available level III and IV evidence, and future trials are needed to assess the risks and benefits of temporary cessation of medical therapy prior to SRS.

Whole-sellar Radiation for MRI-Negative Cushing Disease Although endocrine remission and radiological tumor control are usually linked, hormone oversecretion may sometimes persist despite tumor stability on imaging. This is particularly common for Cushing disease. Despite recent advances in pituitary adenoma detection using 3 T or higher magnetic resonance imaging (MRI), small ACTH-secreting adenomas can be difficult to visualize, with failure-to-detect rates ranging from 46 to 64%.53 In addition, ACTH-secreting adenomas often have microscopic infiltrates that cannot be readily seen on imaging or accessed surgically. Therefore, these patients may continue to have hormonally active disease despite a negative MRI after surgical resection. For these challenging adenomas, treatment with total or partial hypophysectomy has been suggested. However, SRS in the

form of whole-sellar targeting has also been proposed. Recently, at our institution, we reported the outcomes of 64 patients who underwent whole-sellar radiation using SRS with median margin dose of 25 Gy for patients with no visible tumor on imaging or tumor infiltration of dura or venous sinuses at the time of prior resection such that tumor extirpation was not possible.54 Twenty (71%) of the 28 patients with Cushing disease achieved remission at a median time to remission of 10 months (range: 5–62 months). Twenty-two (69%) of 32 patients with acromegaly had normalization of IGF-1 at a median time to remission of 24 months (range: 5–62 months). Patients with prolactinomas had the lowest remission rate (only two of the four patients treated), with a median time to remission of 13 months (range: 8–18 months). The most common adverse effect after whole-sellar SRS was new-onset hypopituitarism (44%), and this was associated with higher margin doses. Newonset visual deterioration (n = 1) and cranial nerve deficits (n = 3) were observed in four patients. Therefore, whole-sellar SRS for invasive or MRI-negative functioning pituitary adenomas after failed surgical resection seems to offer reasonable rates of endocrine remission with an acceptable safety profile. However, whole-sellar SRS does likely convey a higher risk of hypopituitarism.

Early versus Late SRS Treatment Despite gross total resection, tumor recurrence rate for NFAs approaches 20%.55,56,57,58 Thus, patients with pituitary adenomas are generally followed with serial imaging after surgical resection to monitor for tumor recurrence, and SRS is often employed as an adjunct for residual or recurrent tumors. Although SRS is an effective and often-used treatment for pituitary adenomas, there remains a lack of consensus on whether SRS should be used early in the postoperative period or after a period of observation demonstrating adenoma growth. A recent multicenter matched cohort study conducted by the International Gamma Knife Research Foundation compared early (within 6 months, n = 111) versus late (after 6 months, n = 111) Gamma Knife radiosurgery (GKRS) following surgical resection for patients with an NFA.59 As expected, there was a significantly higher rate of tumor recurrence in the late cohort (p = 0.013). There was no difference in the rate of post-SRS hypopituitarism between the two groups (p = 0.68). However, other adverse effects, such as visual field deficits, were not included in the analysis. Therefore, although early SRS does appear to achieve higher rates of tumor control on imaging, it is still unclear whether early SRS confers any clinical benefit over observation and subsequent SRS for confirmed tumor growth.

Upfront SRS SRS is often reserved for residual or recurrent pituitary adenomas, however upfront SRS may be considered in select cases.60 In particular, upfront SRS can be considered for patients who are poor surgical candidates, and those with adenomas that reside largely in the cavernous sinus so that significant tumor volume reduction is unlikely to be achived.11,58,61 Lee et al reported the outcomes of 41 patients who underwent upfront SRS treatment among 569 patients with NFAs at three academic centers.61 Patients underwent upfront SRS in lieu of surgical resection either due to personal preference or due to the

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Pituitary Adenoma elevated risk of surgery posed by their medical comorbidities. The investigators reported an overall tumor control rate of 93% using a median margin dose of 12 Gy at a follow-up of 4 years. Thus, although surgical resection should remain the first-line treatment of most pituitary adenomas, upfront SRS in select patients appears to be safe and effective in achieving long-term tumor control.

●

●

14.3 Author and Institutional Biases The University of Virginia is a high-volume tertiary referral center for pituitary adenomas. Referral biases and patient selection could have affected our outcomes in pituitary adenoma patients. In addition, our SRS platform for pituitary adenomas is predominantly the Gamma Knife but some patients were treated with linear accelerator (LINAC) systems. These radiosurgical platforms and the techniques associated with radiosurgical delivery have become more refined over the past 30 years. Advances in these approaches could bias outcomes in pituitary adenoma patients. The nuances of the author’s own radiosurgical technique may also influence our results. At the University of Virginia, we typically limit the maximum dose to the anterior optic pathways to 8 Gy in single-fraction SRS. However, in our experience, these structures can tolerate increased doses of radiation if delivered as hypofractionated SRS.62 For example, if divided in five fractions, we are able to deliver up to of 25 Gy to the optic pathways without causing visual deficits. Regarding the gradient index (i.e., the steepest radiation falloff), we have sought to use multiisocentric planning and beam blocking to achieve a steep radiation fall off to the hypothalamus. Finally, we try to minimize the radiation delivered to the pituitary stalk and avoid “hot spots” within the cavernous sinus when possible.

14.4 Conclusions SRS plays an important and expanding role in the management of patients with pituitary adenomas. SRS is recommended for patients with substantial residual tumor or tumor recurrence after surgical resection. SRS is also recommended for those with functioning adenomas that fail to achieve hormonal control after surgical resection. Neurological deficit following SRS is uncommon, and hypopituitarism, the most common adverse event, can typically be managed with hormone replacement therapy. Although early SRS after surgical resection offers unclear benefits to pituitary adenoma patients, upfront SRS should be considered in certain patient populations. With its reasonable tumor control rates and acceptable adverse effect profile, SRS has become a mainstay in the treatment of pituitary adenomas.

14.5 Suggestions for Future Studies ●

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Some pituitary adenomas appear to require higher doses of radiation to achieve tumor control relative to other subtypes,

●

as is the case with SCAs. Future studies may wish to delineate the underlying causes of these observed differences in radiosensitivity between pituitary adenoma types and subtypes.50 What is the optimal dose and fractionation scheme for larger pituitary adenomas in which hypofractionated SRS is utilized? Our results thus far regarding the utility of early SRS after surgical resection for pituitary adenomas have not demonstrated a clear clinical benefit over late SRS. However, the question remains if there is an optimal timing of SRS for pituitary adenomas after surgical resection, and if there is a subset of patients that may benefit from earlier SRS.59 Given the apparent negative effects of pituitary suppressive medications on the rates and timing of endocrine remission for functioning adenomas, future studies should attempt to determine the optimal timing for cessation of suppressive medications around the time of SRS.25

References [1] Dekkers OM, Pereira AM, Romijn JA. Treatment and follow-up of clinically nonfunctioning pituitary macroadenomas. J Clin Endocrinol Metab. 2008; 93 (10):3717–3726 [2] Laurent J, Webb K, Jane J. Pituitary adenomas. In: Berger MS, Prados MD, eds. Textbook of Neuro-Oncology. Philadelphia: Elsevier; 2005:351–356 [3] Ostrom QT, Gittleman H, Farah P, et al. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2006–2010. Neuro-oncol. 2013; 15 Suppl 2:ii1–ii56 [4] Liscák R, Vladyka V, Marek J, Simonová G, Vymazal J. Gamma Knife radiosurgery for endocrine-inactive pituitary adenomas. Acta Neurochir (Wien). 2007; 149(10):999–1006, discussion 1006 [5] Pollock BE, Cochran J, Natt N, et al. Gamma Knife radiosurgery for patients with nonfunctioning pituitary adenomas: results from a 15-year experience. Int J Radiat Oncol Biol Phys. 2008; 70(5):1325–1329 [6] Iwata H, Sato K, Tatewaki K, et al. Hypofractionated stereotactic radiotherapy with CyberKnife for nonfunctioning pituitary adenoma: high local control with low toxicity. Neuro-oncol. 2011; 13(8):916–922 [7] Bir SC, Murray RD, Ambekar S, Bollam P, Nanda A. Clinical and radiologic outcome of Gamma Knife radiosurgery on nonfunctioning pituitary adenomas. J Neurol Surg B Skull Base. 2015; 76(5):351–357 [8] Castro DG, Cecílio SAJ, Canteras MM. Radiosurgery for pituitary adenomas: evaluation of its efficacy and safety. Radiat Oncol. 2010; 5:109 [9] Losa M, Spatola G, Albano L, et al. Frequency, pattern, and outcome of recurrences after Gamma Knife radiosurgery for pituitary adenomas. Endocrine. 2017; 56(3):595–602 [10] Sheehan JP, Starke RM, Mathieu D, et al. Gamma Knife radiosurgery for the management of nonfunctioning pituitary adenomas: a multicenter study. J Neurosurg. 2013; 119(2):446–456 [11] Hasegawa T, Shintai K, Kato T, Iizuka H. Stereotactic radiosurgery as the initial treatment for patients with nonfunctioning pituitary adenomas. World Neurosurg. 2015; 83(6):1173–1179 [12] Wilson PJ, De-Loyde KJ, Williams JR, Smee RI. A single centre’s experience of stereotactic radiosurgery and radiotherapy for non-functioning pituitary adenomas with the Linear Accelerator (LINAC). J Clin Neurosci. 2012; 19(3): 370–374 [13] Runge MJR, Maarouf M, Hunsche S, et al. LINAC-radiosurgery for nonsecreting pituitary adenomas. Long-term results. Strahlenther Onkol. 2012; 188(4): 319–325 [14] Hayashi M, Chernov M, Tamura N, et al. Gamma Knife robotic microradiosurgery of pituitary adenomas invading the cavernous sinus: treatment concept and results in 89 cases. J Neurooncol. 2010; 98(2):185–194 [15] El-Shehaby AMN, Reda WA, Tawadros SR, Abdel Karim KM. Low-dose Gamma Knife surgery for nonfunctioning pituitary adenomas. J Neurosurg. 2012; 117 Suppl:84–88 [16] Kobayashi T. Long-term results of stereotactic Gamma Knife radiosurgery for pituitary adenomas. Specific strategies for different types of adenoma. Prog Neurol Surg. 2009; 22:77–95

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The Role of Radiosurgery for Pituitary Adenomas [17] Höybye C, Rähn T. Adjuvant Gamma Knife radiosurgery in non-functioning pituitary adenomas; low risk of long-term complications in selected patients. Pituitary. 2009; 12(3):211–216 [18] Xu Z, Lee Vance M, Schlesinger D, Sheehan JP. Hypopituitarism after stereotactic radiosurgery for pituitary adenomas. Neurosurgery. 2013; 72(4): 630–637, 636–637 [19] Voges J, Kocher M, Runge M, et al. Linear accelerator radiosurgery for pituitary macroadenomas: a 7-year follow-up study. Cancer. 2006; 107(6): 1355–1364 [20] Castinetti F, Nagai M, Dufour H, et al. Gamma Knife radiosurgery is a successful adjunctive treatment in Cushing’s disease. Eur J Endocrinol. 2007; 156(1):91–98 [21] Petit JH, Biller BMK, Yock TI, et al. Proton stereotactic radiotherapy for persistent adrenocorticotropin-producing adenomas. J Clin Endocrinol Metab. 2008; 93(2):393–399 [22] Pollock BE, Brown PD, Nippoldt TB, Young WF, Jr. Pituitary tumor type affects the chance of biochemical remission after radiosurgery of hormone-secreting pituitary adenomas. Neurosurgery. 2008; 62(6):1271–1276, discussion 1276–1278 [23] Tinnel BA, Henderson MA, Witt TC, et al. Endocrine response after Gamma Knife-based stereotactic radiosurgery for secretory pituitary adenoma. Stereotact Funct Neurosurg. 2008; 86(5):292–296 [24] Wan H, Chihiro O, Yuan S. MASEP Gamma Knife radiosurgery for secretory pituitary adenomas: experience in 347 consecutive cases. J Exp Clin Cancer Res. 2009; 28:36 [25] Sheehan JP, Xu Z, Salvetti DJ, Schmitt PJ, Vance ML. Results of Gamma Knife surgery for Cushing’s disease. J Neurosurg. 2013; 119(6):1486–1492 [26] Wilson PJ, Williams JR, Smee RI. Cushing’s disease: a single centre’s experience using the linear accelerator (LINAC) for stereotactic radiosurgery and fractionated stereotactic radiotherapy. J Clin Neurosci. 2014; 21(1):100–106 [27] Marek J, Ježková J, Hána V, et al. Gamma Knife radiosurgery for Cushing’s disease and Nelson’s syndrome. Pituitary. 2015; 18(3):376–384 [28] Grant RA, Whicker M, Lleva R, Knisely JPS, Inzucchi SE, Chiang VL. Efficacy and safety of higher dose stereotactic radiosurgery for functional pituitary adenomas: a preliminary report. World Neurosurg. 2014; 82(1–2):195–201 [29] Wein L, Dally M, Bach LA. Stereotactic radiosurgery for treatment of Cushing disease: an Australian experience. Intern Med J. 2012; 42(10):1153–1156 [30] Jezková J, Marek J, Hána V, et al. Gamma Knife radiosurgery for acromegaly— long-term experience. Clin Endocrinol (Oxf). 2006; 64(5):588–595 [31] Pollock BE, Jacob JT, Brown PD, Nippoldt TB. Radiosurgery of growth hormone-producing pituitary adenomas: factors associated with biochemical remission. J Neurosurg. 2007; 106(5):833–838 [32] Roberts BK, Ouyang DL, Lad SP, et al. Efficacy and safety of CyberKnife radiosurgery for acromegaly. Pituitary. 2007; 10(1):19–25 [33] Vik-Mo EO, Oksnes M, Pedersen P-H, et al. Gamma knife stereotactic radiosurgery for acromegaly. Eur J Endocrinol. 2007; 157(3):255–263 [34] Castinetti F, Nagai M, Morange I, et al. Long-term results of stereotactic radiosurgery in secretory pituitary adenomas. J Clin Endocrinol Metab. 2009; 94 (9):3400–3407 [35] Ronchi CL, Attanasio R, Verrua E, et al. Efficacy and tolerability of gamma knife radiosurgery in acromegaly: a 10-year follow-up study. Clin Endocrinol (Oxf). 2009; 71(6):846–852 [36] Iwai Y, Yamanaka K, Yoshimura M, Kawasaki I, Yamagami K, Yoshioka K. Gamma Knife radiosurgery for growth hormone-producing adenomas. J Clin Neurosci. 2010; 17(3):299–304 [37] Poon TL, Leung SCL, Poon CYF, Yu CP. Predictors of outcome following Gamma Knife surgery for acromegaly. J Neurosurg. 2010; 113 Suppl:149–152 [38] Franzin A, Spatola G, Losa M, Picozzi P, Mortini P. Results of Gamma Knife radiosurgery in acromegaly. Int J Endocrinol. 2012; 2012:342034 [39] Liu X, Kano H, Kondziolka D, et al. Gamma Knife radiosurgery for clinically persistent acromegaly. J Neurooncol. 2012; 109(1):71–79 [40] Wilson PJ, De-Loyde KJ, Williams JR, Smee RI. Acromegaly: a single centre’s experience of stereotactic radiosurgery and radiotherapy for growth

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15 Exploration of the Cavernous Sinus Is Effective During Transsphenoidal Surgery for Pituitary Adenoma Engelbert J. Knosp and Alexander S.G. Micko Abstract Parasellar invasiveness into the cavernous sinus is the most important prognostic factor for incomplete resection and recurrence of pituitary adenomas. Pituitary adenomas extending and invading the space of the cavernous sinus represent a different entity of tumors with higher growth rates, and extension into the inferior compartment plays a particularly important role. However, surgical resection of pituitary adenoma tissue extending/invading the space of the cavernous sinus is feasible and can improve the rate of endocrine remission, with a low rate of complications. Keywords: pituitary adenoma, cavernous sinus, parasellar, endocrine remission, gross total resection, extended approach

15.1 Surgical Treatment of Pituitary Adenomas Extending into the Space of the Cavernous Sinus Pituitary adenomas are endocrine tumors that arise from parenchymal cells of the anterior pituitary gland. In surgical series, they account for 10 to 15% of all intracranial tumors.1 Although pituitary adenomas are mostly benign neoplasms amenable to surgery, some show invasive growth into surrounding structures that may lead to postoperative recurrence.2,3 Besides lactotroph adenomas (prolactin [PRL]-secreting adenomas) which are usually treated by dopamine agonists, the mainstay of treatment algorithms is surgical resection usually via the transsphenoidal approach. The goal of transsphenoidal surgery is selective pituitary adenoma resection with preservation of normal gland tissue and neural structures.4 Avoidance of intra- and postoperative complications and at the same time high rates of gross total resection and endocrine remission is mandatory. Due to the consequence of rupture of the internal carotid artery (ICA) or injury of cranial nerves III–VI, surgery of the cavernous sinus had been avoided in the past. Only after the pioneer works of Parkinson, Dolenc, and others, surgery of the cavernous sinus—intradural or transcranial—became possible. Using the transsphenoidal route, the risk of ICA injury is reported to be 0.5 to 1.6%.5 Based on a wider field of view and the possibility to get a view “around the corner,” endoscopic transsphenoidal surgery has evolved to go beyond the sellar region to resect pathologies via extended approaches. Furthermore, endoscopic transsphenoidal surgery provides an easily accessible midline corridor to the cavernous sinus with equivalent or superior results to transcranial approaches especially in pituitary adenomas (▶ Table 15.1).6 Invasion into the compartments of the cavernous sinus is responsible for failure of endocrine remission and recurrence of

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tumor mass. Cavernous sinus involvement has shown to significantly reduce the rate of biochemical remission in acromegalic patients.7 However, in our experience, these tumor remnants are often soft and can be resected to a certain extent. Even a subtotal resection of cavernous sinus tumor has shown to reduce the overall tumor burden and improve the results of postoperative radiation therapy.8 Therefore, extended transsphenoidal approaches have been established to reach and adequately expose the cavernous sinus compartments.9 The relation of the inferior intracavernous ICA to the tumor tissue is crucial for surgical planning.10,11 To reach this area, the bone overlying the cavernous sinus and the ICA has to be removed carefully under steady control of a Doppler ultrasonography probe. Venous bleeding from the cavernous sinus has to be controlled by packing with hemostatic compounds. If tumor components are present lateral to the ICA, the vessel itself has to be gently mobilized to achieve a gross total resection.12 Extended approaches to the cavernous sinus have shown to improve gross total resection rates in Knosp grade 3 and 4 tumors; however, complication rates have been reported to be higher than in standard endoscopic procedures.13 Especially the rate of ICA injuries in these surgeries is considerably high.14 The authors argue that part of this risk is due to patients undergoing reoperation and the presence of scar tissue at the time of the second operation.12 However, the risk of permanent cranial nerve deficit has been reported to be at a low rate and there is a high chance of improvement of preoperative deficits.15 In addition, intraoperative neurophysiological monitoring might be helpful to reduce possible deficits, especially in extended approaches.16 If a resection is planned to go beyond the superior, inferior, or lateral borders of the sellar region, reconstruction of a possible dural defect is mandatory and has to be planned in advance to the extended approach by preparation of a nasoseptal mucosal flap.17,18 Further pathologies of the anterior and middle fossa of the skull base, such as craniopharyngiomas and anterior skull base meningiomas, have led to the increased utilization of extended transsphenoidal endoscopic approaches in the past decade.19,20,21,22,23 Similar rates of gross total resection and visual outcomes compared to the transcranial approaches could be achieved.24,25 However, rates of postoperative cerebrospinal fluid leaks have been high, especially in comparison to pituitary adenoma cases.

15.2 Case Example We report on the case of a 44-year-old female patient, who presented with sudden headache and cranial nerve III palsy. Magnetic resonance imaging showed a suprasellar (Hardy grade: B) and parasellar (Knosp grade left side: 4, right side: 0) mass, with two cystic lesions indicating an apoplectic event. At presentation, the patient’s laboratory values showed no signs of

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Table 15.1 Exploration of the cavernous sinus Study

Year

Briceno et

al7

Koutourousiou et al6

Ajlan et

al26

Micko et al27

2017

2017

2017

2015

Level of evidence

III

IV

III

III

Study design

Materials

Outcome measure

Findings

Systematic review of level III studies

14 studies, 270 patients

Remission after TSS among patients with growth hormone-secreting pituitary adenomas with and without CS invasion

CS involvement leads to a statistically significant lower rate of biochemical remission in acromegalic patients

Case series

234 patients, 175 (75%) pituitary adenomas

EES treatment of invasive pituitary adenomas and nonadenomatous lesions

EES provides an easily accessible midline corridor to the CS with equivalent or superior results to transcranial approaches especially in pituitary adenomas

176 patients

CS involvement and whether the CS tumor was approached medial or lateral to the ICA

Medial approach and adding lateral exposure resulted in good outcomes with low morbidity in nonfunctional adenomas. Functional adenomas involving the CS were associated with low rates of hormonal remission necessitating higher rates of additional treatment

137 patients

ER and GTR were correlated with the grade of parasellar extension and intraoperative findings of invasiveness of the CS

With increasing grade of parasellar extension, the likelihood of surgically observed invasion rises and the chance of GTR and ER decreases CS invasion was identified as an independent predictor of unfavorable outcome. Direct removal of the invading tumor, revealed an increased chance of remission

Case-control study

Case-control study

Nishioka et al9

2014

III

Case-control study

55 patients

Consecutive series of acromegalic patients with identified CS invasion who underwent TSS

Woodworth et al15

2014

IV

Case series

36 patients

Extent of resection as a whole and within the CS was assessed

The risk of permanent cranial nerve deficit is low and there is a high chance of improvement of preexisting deficits

20 patients

Parasellar extension of the tumor was measured according to the Knosp Scale and grade of tumor removal was assessed

Compared with transcranial and microscopic TSS, ESS offers a wide exposure for reaching the CS medial wall, which enables tumour tissue removal. Gamma Knife and medical therapy should be supplementary treatment options

Ceylan et al13

2010

IV

Case series

Abbreviations: CS, cavernous sinus; EES, endoscopic endonasal surgery; ER, endocrine remission; GTR, gross total resection; ICA, internal carotid artery; TSS, transsphenoidal surgery.

functioning pituitary adenoma or hypopituitarism. An extended endoscopic transsphenoidal approach with exploration of the left cavernous sinus was performed (Video 15.1). Histopathological examinations revealed a silent adrenocorticotropic hormone (ACTH)-secreting adenoma—subtype 2, MIB1 < 1% positive cells. ▶ Fig. 15.1a shows a preoperative postcontrast T1-weighted coronal MRI, showing a supra- and parasellar mass; the normal pituitary gland was displaced lateral to the right side. ▶ Fig. 15.1b shows a preoperative sagittal MRI, showing the displacement of the optic chiasm and the cystic tumor components. ▶ Fig. 15.1c, d show the 3 months postoperative coronal MRI; the normal pituitary gland and the pituitary stalk are

visible on the right side. On the left side postoperative cystic formations with inserted hemostatic compounds are visible.

15.3 Conclusions We conclude that surgical resection of pituitary adenoma tissue extending/invading the space of the cavernous sinus is feasible and should be considered especially in younger patients with acromegaly. Furthermore, a medial to lateral removal of tumor tissue, following the tumor’s growth, is recommended because direct approach has more risk for cranial nerve and/or ICA injury.

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Fig. 15.1 (a) Preoperative postcontrast T1weighted coronal magnetic resonance imaging (MRI), showing a supra- and parasellar mass, the normal pituitary gland was displaced lateral to the right side. (b) Preoperative sagittal MRI, showing the displacement of the optic chiasm and the cystic tumor components. (c, d) 3months postoperative coronal and sagittal MRI.

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Exploration of the Cavernous Sinus Is Effective During Transsphenoidal Surgery for Pituitary Adenoma [23] de Divitiis E, Cavallo LM, Esposito F, Stella L, Messina A. Extended endoscopic transsphenoidal approach for tuberculum sellae meningiomas. Neurosurgery. 2008; 62(6) Suppl 3:1192–1201 [24] Gardner PA, Kassam AB, Thomas A, et al. Endoscopic endonasal resection of anterior cranial base meningiomas. Neurosurgery. 2008; 63(1):36–52, discussion 52–54 [25] Kitano M, Taneda M, Nakao Y. Postoperative improvement in visual function in patients with tuberculum sellae meningiomas: results of the extended

transsphenoidal and transcranial approaches. J Neurosurg. 2007; 107(2): 337–346 [26] Ajlan A, Achrol AS, Albakr A, et al. Cavernous sinus involvement by pituitary adenomas: clinical implications and outcomes of endoscopic endonasal resection. J Neurol Surg B Skull Base. 2017; 78(3):273–282 [27] Micko AS, Wohrer A, Wolfsberger S, Knosp E. Invasion of the cavernous sinus space in pituitary adenomas: endoscopic verification and its correlation with an MRI-based classification. J Neurosurg. 2015; 122(4):803–811

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Pituitary Adenoma

16 Surgery versus Medical Management: First-Line Treatment for Pituitary Apoplexy Garni Barkhoudarian, Sheri Palejwala, and Daniel F. Kelly Abstract Pituitary apoplexy (PA) has long been considered a surgical emergency for acute-onset symptoms. There is a wide range of symptom severity with which a patient may present. Grading systems to assess PA have demonstrated utility in retrospect, differentiating between surgery and conservative management. Level III evidence-based recommendations include the use of corticosteroid therapy in the acute setting, surgical resection for patients with acute neurological or neuroophthalmic symptoms, and conservative therapy is reasonable for patients with mild neuroophthalmic symptoms or endocrinopathy alone. Keywords: pituitary apoplexy, pituitary adenoma, hemorrhage, endocrinopathy, transsphenoidal surgery

16.1 Introduction Pituitary apoplexy (PA) is an uncommon but serious condition caused by hemorrhage or infarction of a pituitary adenoma or Rathke’s cleft cyst. It occurs with an annual incidence between 0.2 and 0.6%, and affects 2 to 12% of patients with pituitary adenomas.1,2,3,4,5 PA often presents with a combination of acute-onset headaches, vision loss, oculoparesis, and/or endocrine dysfunction. A contemporary review of the literature evaluating 1,202 patients by Briet et al noted the incidence of presenting symptoms to include headaches (73%), diminished visual acuity (68%), hypopituitarism (64%), diminished visual fields (49%), nausea (49%), oculoparesis (48%), and altered level of consciousness/coma (17%).6 One-fourth of apoplexy patients had a known pituitary adenoma.6 However, a prospective natural history study by Arita et al noted, in a cohort of 42 patients with macroadenomas, an apoplexy rate of 9.5% (4 patients) at 5-year follow-up.7 It is important to note the “classic” definition of PA requires the acute onset of symptoms (often a combination of headaches, vision loss, and/or endocrinopathy) along with evidence of hemorrhage or infarction of a pituitary tumor or Rathke’s cleft cyst.8 Often “silent” or “subclinical” subacute or chronic hemorrhage of a pituitary tumor is identified on imaging in patients who are asymptomatic.9 Though some authors contend that all hemorrhagic pituitary tumors be considered as apoplexy, for the purpose of this chapter, these subclinical scenarios of “silent” hemorrhage within an adenoma or Rathke’s cleft cyst will not be considered as such.10,11

16.1.1 Surgical Management of Classic Pituitary Apoplexy The traditional and widely adopted management of classic PA is urgent or semiurgent transsphenoidal surgery and resection of the hemorrhagic tumor or cyst5,8,12,13 (▶ Fig. 16.1). All patients should undergo perioperative endocrine evaluation and are

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often treated with stress-dose corticosteroid replacement (e.g., dexamethasone or hydrocortisone).3,5,12 Since the introduction of microscopic transsphenoidal surgery and especially during the endoscopic era, this operation has become increasingly safe with a low complication rate.14,15,16 Depending on the acuity of the patient’s symptoms, the timing of surgery varies from immediately following presentation to weeks afterward. However, the majority of studies demonstrate clinical benefit if surgery is performed within the first week after PA.3,17 This is also reflected in the Congress of Neurological Surgeons guidelines for the management of nonfunctional pituitary adenomas.18 In a series of 62 patients with apoplexy by Semple et al, visual acuity and visual fields were normal or improved in 85 and 94% of patients, respectively.5 Oculoparesis was normal or improved in all patients. However, only 12% of patients had normal endocrine function and there was a 5% mortality rate. A more contemporary series of 39 patients with PA reported by Gondim et al demonstrated improved visual field deficits and oculoparesis in 74 and 68%, respectively.14 Hypopituitarism improved from 86 to 77% at 6 months. There was no surgical morbidity noted in this study. Given the safety of the modern transsphenoidal operation and the potential for benefit in this patient population, most surgeons will offer surgery to the majority of PA patients.

16.1.2 Conservative Management of Classic Pituitary Apoplexy In the 1970s, it was noted that patients who suffered PA were capable of spontaneous recovery, and, in select cases, could result in remission of hormonal hypersecretion.19,20,21 Hence, conservative management of select PA patients was proposed.21 Maccagnan et al were the first to publish a prospective study assessing the conservative approach for PA patients. In a small series of 12 patients with PA, they were empirically treated with intravenous dexamethasone and monitored closely for neurological decline. Surgery was undertaken only if the patient did not improve neurologically. They noted successful implementation of this strategy in seven (58%) patients who had similar outcomes overall to the five patients who ultimately underwent surgery. This conservative approach for PA has been adopted by numerous pituitary centers internationally, although many centers continue to adhere to the belief that all patients with PA warrant urgent surgery.22 It is generally accepted that apoplexy patients with acute neurological deficits (vision loss or altered mental status) should undergo urgent surgical evacuation and resection of tumor. Conversely, minimally symptomatic patients with hemorrhagic pituitary tumors can be managed conservatively with elective tumor resection as an option in the future. Most patients with PA, however, present somewhere between these extremes, hence the ongoing debate in defining the optimal management.

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Surgery versus Medical Management: First-Line Treatment for Pituitary Apoplexy

Fig. 16.1 Coronal and sagittal pituitary–protocol MRI of a 35-year-old man with a known macroprolactinoma (prolactin > 8,000 ng/mL) on dopamine agonist therapy who presented with acute onset headaches, vision loss, and hypopituitarism. He underwent surgery within 24 hours of presentation with full recovery of vision, but remains with hypopituitarism. (a,b) Preapoplexy pituitary macroadenoma with little signal heterogeneity; (c–f) postapoplexy MRI—(c) precontrast T1 MRI with minimal signal heterogeneity; (d) T2 MRI with T2 signal at apex of tumor suggesting hemorrhagic conversion; (e,f) T1 postcontrast with heterogenetic of signal and fluid-fluid level on coronal and sagittal views; (g,h) 3 months postoperative MRI demonstrates gross-total resection of tumor. Current prolactin level is 7.5 ng/mL.

16.2 Pituitary Apoplexy Grading Scales 16.2.1 Pituitary Apoplexy Score Given the spectrum of PA presentations, the determination as to “mild” or “severe” apoplexy can be often difficult to relate. Given this dilemma, a PA scale (PAS) has been proposed by the United Kingdom Pituitary Apoplexy Guidelines Development Group (▶ Table 16.1).17 This scale places heavy emphasis on level of consciousness (Glasgow coma scale) and visual deficits. Often, visual acuity and visual field deficits accompany each other, resulting in a somewhat inflated score. Endocrine dysfunction is not well captured with this system, except for severe Addisonian crisis that would result in altered mental status. Nevertheless, this scale has been validated in at least one published study, Bujawansa et al.23 This retrospective study of 55 patients was able to capture PAS scores in 84% of patients and noted that the conservatively managed apoplexy patients had a mean score of 1.8 compared to the surgically managed group with 3.8. All patients with PAS greater than 4 required surgical resection.

16.2.2 Pituitary Apoplexy Grading System The PAS is limited by its inability to discern milder presentations of PA, in particular those with endocrine dysfunction alone (▶ Fig. 16.2). Hence, Jho et al published a Pituitary

Table 16.1 Pituitary Apoplexy Scale Variable

Points

Level of consciousness GCS 15 GCS 8–14 GCS 3–7

0 2 4

Visual acuity Normal (premorbid baseline) Reduced—unilateral Reduced—bilateral

0 1 2

Visual field deficits Normal (premorbid baseline) Unilateral defect Bilateral defect

0 1 2

Ocular paresis Absent Present—unilateral Present—bilateral

0 1 2

Abbreviation: GCS, Glasgow Coma Scale. Source: Reproduced with permission from Rajasekaran S, Vanderpump M, Baldeweg S, et al. UK guidelines for the management of pituitary apoplexy. Clin Endocrinol 2011;74:9.

Apoplexy Grading System that addresses patient acuity rather than using an addition point system (▶ Table 16.2).11 As is evident, grades I to III are not captured by the PAS. Grade IV would correlate to a PAS score of 1 or 2. Grade V could correlate to a much wider PAS range (1–10). Nevertheless, this system has a higher resolution at the lower range of the apoplexy spectrum.

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Pituitary Adenoma

Fig. 16.2 Coronal and sagittal pituitary protocol MRI of a 74-year-old woman who presented with acute-onset altered mental status, hyponatremia (Na: 122 mEq/L) and Addisonian crisis. She was resuscitated and returned to baseline without headaches or vision loss. She underwent pituitary MRI 4 days after presentation which demonstrated a hemorrhagic pituitary macroadenoma. She underwent surgical resection 1 month after her presentation without complication. Her endocrinopathy has improved and she requires only hydrocortisone replacement. (a,b) T1 MRI demonstrating signal intensity in pituitary tumor. (c,d) Hypoenhancing tumor with clear enhancement of pituitary gland. (e,f) Three months postoperative MRI demonstrating gross-total resection of tumor.

Table 16.2 Pituitary Apoplexy Grading System Grade

Description

1

No symptoms

2

Symptoms caused by endocrinopathy only

3

Headache (acute-onset new or acute-on-chronic)

4

Ocular paresis (cavernous sinus cranial nerves)

5

Visual acuity or field deficit (or low GCS score not allowing testing)

Abbreviation: GCS, Glasgow Coma Scale. Source: Reproduced with permission from Jho D, Biller B, Agarwalla P, Swearingen B. Pituitary apoplexy: large surgical series with grading system. World Neurosurg 2014;82:781.

Within their cohort of 109 patients, 30% of patients were grade III, 24% were grade IV, and 43% were grade V. When compared to the PAS, only six patients had a PAS ≥ 4. The majority of patients’ PAS score was 0. Additionally, the PA grading system can have subset modifiers (p = prolactinoma, r = Rathke’s cleft cyst, s = sick patients with increased comorbidities). This study was not without limitations, as they included subclinical apoplexy which may have skewed the data in favor of lower acuity patients. Nevertheless, these qualitative modifiers can help

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further modify the decision regarding surgery or conservative management.

16.3 Conservative versus Surgical Management of Pituitary Apoplexy 16.3.1 Literature Review with EvidenceBased Review Published articles in the English language were searched using PubMed and Google Scholar. Search terms included “Pituitary apoplexy,” “conservative,” “surgery,” “medical management,” “non-operative,” and their variations. Studies assessing both cohorts of PA management with appropriate outcomes data were included. A total of eight articles were identified, published between 1993 and 2014, assessing a total of 267 PA patients, 121 treated conservatively and 146 treated surgically.23,24,25,26,27,28,29,30 Time to surgery had a wide range, from 1 day to 3 years, though the majority were early, except for Maccagnan et al which deliberately waited until conservative management failed. There was a clear bias for less acute patients in the conservative cohort. The only study that applied a grading system was

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Surgery versus Medical Management: First-Line Treatment for Pituitary Apoplexy that of Bujawansa et al (PAS) and identified an average of 1.8 for the conservative group compared to 3.8 in the surgical group.23 Although the PA grading system proposed by Jho et al is more granular, the authors noted a major limitation of their study as the patients were identified through a surgical database and many medically treated patients were not captured. These studies are compared in ▶ Table 16.3, including assessment of level of evidence. Overall, the clinical outcomes of both cohorts are similar. Visual acuity recovery (near or complete) was 87% in the

conservative cohort and 73% in the surgical cohort (no statistical difference including when assessing only complete recovery). Visual field recovery was similar as well (79 vs. 66%, not significant). Oculoparesis did demonstrate notable improvement or resolution in the conservative cohort (100 vs. 85%). This may have been due to the lesser acuity in this patient group. There was no difference in the endocrine recovery rate. Interestingly, Sibal et al noted that the tumor recurrence/progression rate was 22% in the conservative group and 4% in the surgical group, suggesting the importance of close monitoring

Table 16.3 Evidence Based Review of comparison studies between surgical and conservative management of pituitary apoplexy Authors

Year

Level of evidence

Total patients

Conservative patients

Surgical patients

Outcomes

Recommendations

Bonicki et al25

1993

IV

40

24

16

Surgical outcomes suggest superior outcomes over observation cohort

Surgical resection of all pituitary apoplexy patients recommended

Maccagnan et al30

1995

IIIa

31

17

14

No significant difference except for pituitary function in tumors that obliterated themselves due to apoplexy

Conservative management is safe for all apoplexy patients as first-line treatment for any severity of PA

Ayuk et al29

2004

III

33

18

15

No significant difference in recovery of visual fields, oculoparesis, or hypopituitarism

Patients with stable or improving visual deficits may be treated conservatively

Sibal et al26

2004

III

45

18

27

Visual acuity, field deficit, and ocular palsy improved or normalized in surgical group (93, 94, and 93%, respectively) and in all conservatively management patients. Endocrine function was normal in 19% of surgical and 11% of conservative patients

Patients with classical pituitary apoplexy, who are without neuroophthalmic signs or exhibit mild and nonprogressive signs, can be managed conservatively in the acute stage

Gruber et al28

2006

III

30

20

10

Surgical cohort had more severe visual symptoms at baseline. Both cohorts demonstrated improvement in visual symptoms and oculoparesis

Early neurosurgical intervention may not be required in most patients presenting with pituitary apoplexy

Dubuisson et al24

2007

IV

24

21

3

Visual fields improved in 92% and oculoparesis in 85% of patients. 92% of patients required long-term hormone replacement. The 3 patients managed conservatively had mild symptoms, had past acute phase, or refused surgery

Complete recovery is possible if the diagnosis is rapidly obtained and adequate management is initiated in time. Surgical results after transsphenoidal approach are in the majority of cases very satisfactory

Leyer et al27

2011

III

44

25

19

At 21 mo, there were no significant differences in terms of endocrine or vision recovery between these two cohorts

The outcome of patients treated with or without surgery for pituitary apoplexy without severe neuroophthalmic deficits seems to be identical

Bujawansa et al23

2014

III

55

22

33

Surgical cohort had more severe visual symptoms at baseline (mean PAS: 3.8 compared to 1.8 in conservative cohort). No difference in visual or endocrine recovery in both cohorts

Patients without VF deficits or whose visual deficits are stable or improving can be managed expectantly without negative impact on outcomes. Clinical severity based on a PAS ≥ 4 appeared to influence management toward emergency surgical intervention

Abbreviation: VF, visual field. prospective study was designed like a single-arm cross-over study, enrolling patients in the surgical cohort only after conservative management failed. Hence, it does not meet full criteria for level II level of evidence.

aThis

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Pituitary Adenoma of these patients with serial imaging.26 It also supports the theory that some tumors can be obliterated from the apoplectic event obviating the need for surgery in these patients.

16.3.2 Evidence-Based Recommendations Most of the studies reviewed were of levels III and IV evidence. The one prospective study, Maccagnan et al, was a unilateral study where surgery was withheld until conservative treatment failed.30 Hence, it is not a true cohort comparison, despite its prospective nature.

Corticosteroid Management—Level III ●

All patients with acute symptoms of PA should be administered stress-dose corticosteroids urgently.

Surgical Management—Level III ●

All patients with acute ophthalmic or neurological deficits with PA should be considered for surgical intervention unless limited by patient comorbidities.

Conservative Management—Level III ●

Patients with mild neuroophthalmic or endocrine dysfunction can be considered for conservative management.

Pituitary Apoplexy Grading Systems—Level III ●

Both the Pituitary Apoplexy Scale and Pituitary Apoplexy Grading System have retrospectively demonstrated utility discerning between surgical and conservative management. These should be used as a tool to help the care team determine the treatment options.

16.4 Conclusions Given the difficulty to perform randomized controlled studies, guidelines for choosing surgical versus conservative management of PA rely on levels III and IV evidence. In patients with acute neuroophthalmic or neurological symptoms, surgery remains the generally accepted treatment option. For patients with mild symptoms or endocrinopathy alone, conservative management is certainly reasonable. Future studies should focus on prospective data assessment as well as utilization and validation of both PA grading systems. Regardless of surgical versus conservative management, prompt assessment of endocrine function and administration of stress-dose glucocorticoids should be part of standard management.

References [1] Fernandez A, Karavitaki N, Wass JA. Prevalence of pituitary adenomas: a community-based, cross-sectional study in Banbury (Oxfordshire, UK). Clin Endocrinol (Oxf). 2010; 72(3):377–382 [2] Raappana A, Koivukangas J, Ebeling T, Pirilä T. Incidence of pituitary adenomas in Northern Finland in 1992–2007. J Clin Endocrinol Metab. 2010; 95(9): 4268–4275 [3] Randeva HS, Schoebel J, Byrne J, Esiri M, Adams CB, Wass JA. Classical pituitary apoplexy: clinical features, management and outcome. Clin Endocrinol (Oxf). 1999; 51(2):181–188

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[4] da Motta LA, de Mello PA, de Lacerda CM, Neto AP, da Motta LD, Filho MF. Pituitary apoplexy. Clinical course, endocrine evaluations and treatment analysis. J Neurosurg Sci. 1999; 43(1):25–36 [5] Semple PL, Webb MK, de Villiers JC, Laws ER, Jr. Pituitary apoplexy. Neurosurgery. 2005; 56(1):65–72, discussion 72–73 [6] Briet C, Salenave S, Bonneville JF, Laws ER, Chanson P. Pituitary apoplexy. Endocr Rev. 2015; 36(6):622–645 [7] Arita K, Tominaga A, Sugiyama K, et al. Natural course of incidentally found nonfunctioning pituitary adenoma, with special reference to pituitary apoplexy during follow-up examination. J Neurosurg. 2006; 104(6):884–891 [8] Onesti ST, Wisniewski T, Post KD. Clinical versus subclinical pituitary apoplexy: presentation, surgical management, and outcome in 21 patients. Neurosurgery. 1990; 26(6):980–986 [9] Findling JW, Tyrrell JB, Aron DC, Fitzgerald PA, Wilson CB, Forsham PH. Silent pituitary apoplexy: subclinical infarction of an adrenocorticotropin-producing pituitary adenoma. J Clin Endocrinol Metab. 1981; 52(1):95–97 [10] Mohr G, Hardy J. Hemorrhage, necrosis, and apoplexy in pituitary adenomas. Surg Neurol. 1982; 18(3):181–189 [11] Jho DH, Biller BM, Agarwalla PK, Swearingen B. Pituitary apoplexy: large surgical series with grading system. World Neurosurg. 2014; 82(5):781–790 [12] Albani A, Ferraù F, Angileri FF, et al. Multidisciplinary management of pituitary apoplexy. Int J Endocrinol. 2016; 2016:7951536 [13] Lubina A, Olchovsky D, Berezin M, Ram Z, Hadani M, Shimon I. Management of pituitary apoplexy: clinical experience with 40 patients. Acta Neurochir (Wien). 2005; 147(2):151–157, discussion 157 [14] Gondim JA, de Albuquerque LAF, Almeida JP, et al. Endoscopic endonasal surgery for treatment of pituitary apoplexy: 16 years of experience in a specialized pituitary center. World Neurosurg. 2017; 108:137–142 [15] Barkhoudarian G, Kelly DF. Complications with Transsphenoidal Surgery: A Review. Transsphenoidal Surgery 2017:315–343 [16] Conger A, Zhao F, Wang X, et al. Evolution of the graded repair of CSF leaks and skull base defects in endonasal endoscopic tumor surgery: trends in repair failure and meningitis rates in 509 patients. J Neurosurg. 2018; 11:1– 15 [17] Rajasekaran S, Vanderpump M, Baldeweg S, et al. UK guidelines for the management of pituitary apoplexy. Clin Endocrinol (Oxf). 2011; 74(1):9–20 [18] Aghi MK, Chen CC, Fleseriu M, et al. Congress of Neurological Surgeons Systematic Review and Evidence-Based Guidelines on the management of patients with nonfunctioning pituitary adenomas: executive summary. Neurosurgery. 2016; 79(4):521–523 [19] Jeffcoate WJ, Birch CR. Apoplexy in small pituitary tumours. J Neurol Neurosurg Psychiatry. 1986; 49(9):1077–1078 [20] McFadzean RM, Doyle D, Rampling R, Teasdale E, Teasdale G. Pituitary apoplexy and its effect on vision. Neurosurgery. 1991; 29(5):669–675 [21] Pelkonen R, Kuusisto A, Salmi J, et al. Pituitary function after pituitary apoplexy. Am J Med. 1978; 65(5):773–778 [22] Vargas G, Gonzalez B, Guinto G, et al. Pituitary apoplexy in nonfunctioning pituitary macroadenomas: a case-control study. Endocr Pract. 2014; 20(12): 1274–1280 [23] Bujawansa S, Thondam SK, Steele C, et al. Presentation, management and outcomes in acute pituitary apoplexy: a large single-centre experience from the United Kingdom. Clin Endocrinol (Oxf). 2014; 80(3):419–424 [24] Dubuisson AS, Beckers A, Stevenaert A. Classical pituitary tumour apoplexy: clinical features, management and outcomes in a series of 24 patients. Clin Neurol Neurosurg. 2007; 109(1):63–70 [25] Bonicki W, Kasperlik-Załuska A, Koszewski W, Zgliczyński W, Wisławski J. Pituitary apoplexy: endocrine, surgical and oncological emergency. Incidence, clinical course and treatment with reference to 799 cases of pituitary adenomas. Acta Neurochir (Wien). 1993; 120(3–4):118–122 [26] Sibal L, Ball SG, Connolly V, et al. Pituitary apoplexy: a review of clinical presentation, management and outcome in 45 cases. Pituitary. 2004; 7(3):157–163 [27] Leyer C, Castinetti F, Morange I, et al. A conservative management is preferable in milder forms of pituitary tumor apoplexy. J Endocrinol Invest. 2011; 34 (7):502–509 [28] Gruber A, Clayton J, Kumar S, Robertson I, Howlett TA, Mansell P. Pituitary apoplexy: retrospective review of 30 patients–is surgical intervention always necessary? Br J Neurosurg. 2006; 20(6):379–385 [29] Ayuk J, McGregor EJ, Mitchell RD, Gittoes NJ. Acute management of pituitary apoplexy–surgery or conservative management? Clin Endocrinol (Oxf). 2004; 61(6):747–752 [30] Maccagnan P, Macedo CL, Kayath MJ, Nogueira RG, Abucham J. Conservative management of pituitary apoplexy: a prospective study. J Clin Endocrinol Metab. 1995; 80(7):2190–2197

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Alternative Treatment Strategies for Atypical and Aggressive Pituitary Adenomas

17 Alternative Treatment Strategies for Atypical and Aggressive Pituitary Adenomas Gregory K. Hong Abstract Pituitary adenomas represent common intracranial tumors with a broad spectrum of clinical behavior; the identification and management of aggressive pituitary adenomas remains clinically challenging. Pituitary adenomas arise from distinct cell types and exhibit heterogeneity with regard to several important clinical variables: invasiveness, growth rate, and recurrence. In an attempt to predict clinically aggressive behavior, the WHO classification of 2004 recognized three distinct categories of pituitary tumors: (1) typical adenomas, (2) atypical adenomas, and (3) pituitary carcinomas. Atypical adenomas represent a minority of pituitary adenomas and are characterized by invasive tumor growth, elevated Ki-67 labeling index, elevated mitotic activity, and extensive nuclear staining for p53. Unfortunately, these criteria proved to be lacking in their ability to predict aggressive behavior and not all tumors which meet criteria for an atypical adenoma proved to be clinically aggressive. The primary challenge remains to identify and predict which adenomas require more intensive surveillance and, when recurrence occurs, what optimal therapy should be. Further identification of predictive biological markers is urgently needed. Keywords: atypical adenoma, temozolomide, transsphenoidal resection

17.1 Introduction Pituitary adenomas (PAs) are common neoplasms with a prevalence of around 90 cases per 100,000 individuals.1 While usually benign in nature, PAs often result in significant morbidity through local invasion and/or disruption of normal pituitary hormone homeostasis.2 Common treatment modalities include transsphenoidal resection (TSR), medical therapy, and radiation therapy. It is recognized that responses to different treatment modalities can be highly variable; many studies over the years have attempted to identify tumor characteristics and features that indicate indolent behavior or predict a favorable response to therapy.3 Revisions to PA classification schemes have occurred over the years in an attempt to categorize tumors according to clinical behavior and characteristics. PAs are distinguished based on size (microadenoma if < 1 cm, macroadenoma if 1–4 cm, giant PA if > 4 cm) and capacity for hormone secretion (nonfunctioning, prolactinoma, Cushing disease, acromegaly, TSH-oma). In 2004, the WHO published a classification system based on immunohistochemical parameters; this system organized pituitary tumors into three broad categories: typical adenomas, atypical adenomas, and pituitary carcinoma.4 Pituitary carcinomas were defined by the presence of metastases. Atypical adenomas demonstrate “invasive” growth and have an “elevated” mitotic index, a Ki-67 labeling index greater than 3%,

and “extensive” nuclear staining for p53. No formal criteria were given to define “elevated” or “extensive”; likewise “invasiveness” was not systematically defined. At that time, it was believed that classifying PA as “atypical” would identify a subset of PA with high propensity for aggressive behavior; this would then help clinical decision making regarding intensity of surveillance and need for/timing of additional therapy (e.g., radiation). Current series indicate a prevalence of 2.7 to 14.8% for PA meeting atypical criteria among all tumors.5,6,7,8,9,10,11,12 Review of data using the 2004 WHO classification system demonstrates that the utility of using an atypical PA phenotype to predict clinical aggressiveness is flawed.13 Attempts to correlate certain features of atypical PA with aggressive clinical behavior have had mixed success.14 Ki-67 is a well-validated marker of cellular proliferation assessed via the MIB-1 antibody; some (but not all) studies suggest a correlation between Ki-67 elevation and aggressive clinical behavior. For example, a Ki-67 index greater than 3% has been associated with invasive behavior of PA15 and some view an index of greater than 10% as a risk factor for malignant potential.16 However, indolent tumors may also demonstrate an elevated Ki-67 index17 and significant variability exists in the methodology for assessing Ki-67 among different groups.18 As such, the utility of Ki-67 index in predicting aggressive clinical behavior remains controversial.14 The utility of p53 immunoreactivity as a predictive marker of clinical aggressiveness is also limited. Abnormalities of p53 expression are characteristic of many tumors and some studies link increased expression of p53 with invasive and/or aggressive behavior of PA.19,20 However, other studies demonstrate no correlation between p53 expression and PA invasion or recurrence.18,21 Furthermore, methodologic concerns exist regarding p53 quantification18 and p53 currently remains an unreliable marker of aggressive behavior in PA.17,22

17.2 Controversy: How to Best Identify PA with Aggressive Potential? The critical issue facing clinicians is determining which PAs have a propensity for aggressive behavior. In an ideal scenario, future aggressive behavior would be predicted at the time of initial surgery based on certain pathological features; aggressive tumors could then be treated with early and intensive therapy to reduce future recurrences and morbidity. Although atypical PAs have features which may correlate with aggressive phenotype, this association is imperfect and many atypical PAs demonstrate indolent behavior. Hence, most agree that the 2004 WHO classification of “atypical” is not predictive of aggressive behavior. As a result, the WHO removed the category of “atypical” PA altogether from its 2017 classification scheme23 and tumor grading is no longer a factor in classifying PA (tumor cell lineage/origin is now the primary factor). While it is noted

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Pituitary Adenoma Table 17.1 Aggressive histological subtypes of pituitary adenoma by lineage Morphologic variant

Adenoma lineage

Silent corticotroph adenoma

Corticotroph

Crooke’s cell adenoma

Corticotroph

Sparsely granulated GH adenoma

Somatotroph

PIT-1 adenoma

Plurihormonal

Densely granulated PrL adenoma (especially in men)

Lactotroph

Abbreviations: GH, growth hormone; PrL, prolactin. Source: Adapted from WHO 2017 Classification of pituitary adenomas.

that tumor invasion and proliferative potential are important, no specific criteria are set forth to evaluate these in a systematic fashion. The 2017 update does recognize that certain histologic subtypes, whether or not they meet previous criteria for an atypical adenoma, are more likely to exhibit aggressive behavior23 (▶ Table 17.1). Furthermore, while no single biomarker reliably predicts aggressiveness, the presence of multiple suggestive biomarkers in conjunction with the extent of invasion can raise suspicion for an aggressive phenotype. A recently proposed classification system,24 separate from the 2017 WHO system, which systematically defined invasion and proliferative capacity, has been prospectively studied in a single-center cohort of 213 PA patients undergoing TSR. This proposed system modified the 2004 WHO classification of atypical adenoma by adding a systematic definition of invasion (a noted flaw of the initial WHO classification14) and standardizing definitions of proliferative biomarkers. Under this classification system, invasion was assessed preoperatively via MRI and considered positive if evidence of cavernous sinus or sphenoid sinus invasion was present. PAs were deemed proliferative if at least two of the following three criteria were present: greater than 2 mitoses per 10 HPF, Ki-67 greater than 3%, greater than 10 nuclei strongly positive for p53 per 10 HPF. Over a mean followup of 3.6 years, PA with both invasive and proliferative characteristics had a 3.72-fold higher risk of progression (radiological regrowth or increase in plasma hormone levels for functional PA) compared to PA lacking both invasive and proliferative characteristics.24 While further data and longer follow-up are needed, this study suggests that the addition of a systematic assessment of invasiveness to assessment of proliferative capacity may help identify a subset of PA with a propensity for recurrence. Although limitations with regard to Ki-67 and p53 methodology still exist, the author finds this classification system advantageous for prognostic purposes when compared to the current 2017 WHO classification which does not systematically assess factors known to influence PA behavior (invasion, proliferative capacity). Given that the WHO no longer recognizes atypical adenomas, this article will focus on the clinical care of patients with PA with aggressive behavior, recognizing that this is the subset of tumors which the WHO had initially attempted to define via their atypical criteria in 2004.

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17.3 Alternative Treatment Strategies for Aggressive Adenomas In general, the initial treatment strategy for aggressive PA is similar to the treatment strategy for usual PA. Medical therapy with a dopamine agonist remains the initial therapy in lactotroph adenomas.25 TSR usually represents the preferred initial therapy in other functional tumors (Cushing disease, acromegaly, TSH-oma) or nonfunctional tumors with current/imminent mass effect26; many times TSR is pursued even if it may not be completely curative, as it can increase responsiveness to medical therapy in functional tumors while immediately relieving mass effect in nonfunctional tumors.27 TSR can also be pursued in medically refractory prolactinomas or patients with significant side effects to medical therapy.25 Similarities also exist in the management of tumor residual or the first recurrence following surgery when comparing aggressive PA to usual PA. Commonly used modalities to address tumor residual or initial recurrence are repeat surgery and/or radiation. Repeat surgery may be a viable option depending on the location of the tumor residual/recurrence, although success rates are lower and complication rates are higher when compared to the initial resection.28 Radiotherapy (RT) is often used to control future tumor growth and limit the potential for future invasive effects. RT can also be effective (in delayed fashion) for controlling hormonal hypersecretion, although rates for control of hormonal secretion are often lower than rates for control of tumor growth.29 Medical therapy is often employed, in combination with RT or repeat surgery, in an attempt to normalize hormone hypersecretion in functional tumors. While the majority of nonfunctional tumors express dopamine receptors,30 the utility of treating nonfunctional PA with dopamine agonists remains uncertain, as only small uncontrolled studies exist to date. In the largest series (n = 79 patients), treatment with dopamine agonists led to tumor shrinkage in 35% of patients.31 Interestingly, no correlation existed between dopamine receptor expression and response to therapy. It is critical to note that aggressive histologic subtypes were excluded from this study, and the included tumors likely had indolent behavior based on the degree of growth over time in addition to almost uniformly low Ki-67 staining. It is likely that response rates of aggressive PA to dopamine agonists would be much lower and many endocrinologists (the author included) do not view dopamine agonists as a viable therapeutic option for aggressive nonfunctioning PA. An in-depth review of treatment of PA is beyond the scope of this chapter; furthermore, recent reviews have highlighted the role of usual treatment strategies in the management of aggressive PAs.3 As such the following text will focus on several alternative treatment strategies particularly relevant to the management of aggressive PA: (1) RT timing, dose, and the role of repeat RT; (2) temozolomide (TMZ) therapy; and (3) promising investigational therapies.

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Alternative Treatment Strategies for Atypical and Aggressive Pituitary Adenomas

17.4 Radiation Therapy for Aggressive Atypical Pituitary Adenomas RT is commonly utilized in the management of PA, usually employed as a means to treat residual and/or recurrent tumor following an initial surgical resection.32 RT modalities include stereotactic radiosurgery (SRS; usually delivered as a single fraction of 12–30 Gy) and fractionated RT (45–54 Gy delivered in 25–30 daily fractions over 5–6 weeks).33 While SRS is often preferred due to patient convenience, fractionated RT can represent a safer choice when a large tumor mass is immediately adjacent to critical neural structures (e.g., optic nerve). The overall goals of RT are to control further tumor growth and, in the case of a functional tumor, to control hormonal hypersecretion. The majority of studies to date indicate a higher degree of efficacy in terms of control of tumor growth compared to control of hormonal hypersecretion.29 Potential side effects include new onset hypopituitarism (~30–50%) and cranial neuropathies (< 5%). Some studies suggest lower rates of hypopituitarism and faster time to endocrine remission for PA treated with SRS compared to fractionated RT; however, whether SRS is truly superior remains uncertain.34,35 To date, there have been no prospective studies examining the role of RT specifically in the management of aggressive PA; hence, the following discussion is based on the general PA literature. Certain RT issues (timing, dose amount, and number) will be discussed in the context of their potential use in the management of aggressive PA. The majority of the discussion will focus on SRS, as this represents the most commonly utilized radiation modality currently.

17.5 Early Radiation Therapy Uncertainty currently exists over the optimal timing of RT following an initial surgery for PA.33 In general, given the concern for radiation-induced hypopituitarism, RT is often withheld until obvious tumor progression is demonstrated via serial imaging, often obtained over months/years. This strategy is attractive as many patients have indolent PA with slow rates of growth. Patients with residual or recurrent nonfunctioning PA may not be at risk for significant adverse clinical effects during their lifetime as the growth of the residual/recurrent tumor mass may occur so slowly that critical structures will never be threatened by mass effect. However, in the case of aggressive PA (presumably with a high likelihood for rapid growth), it would seem advantageous to treat residual (or recurrent) tumor early (i.e., before documented progression) with RT to decrease the chances of significant mass effect or invasion of local structures in the future. No studies to date have specifically examined the role of radiation timing specifically in aggressive PA. A recent retrospective cohort study compared the outcomes of early (< 6 months after TSR) versus late (> 6 months after TSR) SRS in 64 patients with nonfunctioning PA who were followed up for a median of 68.5 months.36 Details of histologic staining were unavailable; hence, it is unknown how many tumors had features suggestive of aggressive behavior (i.e., elevated Ki-67). However, 50% of the patients had undergone more than one resection suggesting

that at least some patients had clinically aggressive tumors. Late SRS increased the chance of tumor progression as well as endocrinopathy when compared to early SRS; of note the increased rate of endocrinopathy was due to tumor growth prior to the receipt of SRS. This study suggests that RT early (within 6 months) after initial TSR may be of advantage; further studies specifically examining the role of RT in aggressive PA are needed.

17.6 Radiation Dose for SRS Choosing the optimal radiation dose for SRS treatment of PA involves balancing the goals of RT (volumetric control, biochemical control, or both) with potential complications (hypopituitarism, cranial neuropathy). In general, for single-fraction SRS, lower doses (12–16 Gy) are employed for nonfunctioning PA (where the goal is volumetric control), while higher doses (> 20 Gy) are employed for secretory PA (where goals are both volumetric control and control of hormonal hypersecretion).33 While uncertainty still exists regarding the optimal SRS dose, several retrospective studies suggest a benefit in terms of both volumetric and biochemical control with increasing doses of SRS.33,37,38 However, it appears this benefit plateaus around 20 Gy for nonfunctioning PA and 25 Gy for hormonally active PA, although there are studies where radiation doses even higher than 25 Gy were associated with improved hormonal control in Cushing disease.38 One could postulate given the demonstrated relationship between radiation dose and efficacy that it would be advantageous to treat aggressive PA with relatively “high” doses of SRS in the hopes of improved volumetric (and biochemical) control in the future (e.g., > 20 Gy for a nonfunctioning aggressive PA). Whether or not patients with aggressive PA would derive overall benefit from “high”-dose SRS remains to be determined in future studies comparing tumor control with risks of RT; of note, this is a notable concern given the known relationship between increasing radiation dose and hypopituitarism/cranial neuropathy.33

17.7 Salvage Radiotherapy Repeat irradiation of previously irradiated PA (i.e., salvage RT) represents an option for management of progressive growth (or persistent hormonal hypersecretion) of aggressive PA that cannot be adequately managed by repeat surgery. Historically salvage RT was rarely used given concerns for radiation-induced damage; early studies noted relatively high rates of temporal lobe necrosis (20%) and hypopituitarism (100%) following repeat salvage RT using conventional RT techniques.39 Recently, SRS has been employed more frequently as salvage RT given the theoretical benefit of less radiation toxicity to surrounding anatomical structures. The largest published series to date involves 29 patients with recurrent PA previously treated with conventional RT who received repeat treatment with SRS.39 Many of these patients had undergone multiple surgeries suggesting that their tumors were likely aggressive; however, pathologic markers of proliferative capacity were not included. Biochemical control was more likely to be achieved in acromegalic patients (88%, n = 8) compared to Cushing disease (25%, n = 4) or prolactinoma (0%, n = 1). Of the nonfunctioning PA patients

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Pituitary Adenoma (n = 7), 85% achieved disease stabilization or shrinkage. There were no complications of cranial neuropathy or temporal lobe necrosis. Although follow-up was limited (reported ~ 12 months), a similar study of 21 patients followed up for 33 months did not demonstrate cranial neuropathy or temporal lobe necrosis in response to salvage SRS RT.40 It should be noted in other studies that patients treated with multiple rounds of SRS had relatively higher rates of cranial neuropathy, although absolute numbers were small.41 Differences in rates of cranial neuropathy after salvage RT may relate to the timing between doses (generally waiting several years between doses is felt to be safest based on animal data42) and the total dose of radiation used. In summary, salvage RT using SRS appears to be a viable treatment option for recurrent PA with a reasonable safety profile based on the limited data to date; whether similar levels of biochemical or volumetric control would be achieved in patients with aggressive PA remains to be determined.

17.8 Chemotherapy Chemotherapy of PA usually represents salvage therapy following failure of multiple courses of surgery, radiation, and conventional medical therapy. With the exception of TMZ, minimal published data exist and response rates to traditional chemotherapeutic regimens have been dismal.43 Agents tested to date (often in combination) include lomustine, etoposide, cisplatin, cyclophosphamide, 5FU, doxorubicin, vincristine, and bleomycin (among others). Given the lack of demonstrated efficacy with traditional chemotherapeutic regimens, the author will focus solely on TMZ, as this remains the only chemotherapeutic agent with some evidence of clinical benefit in the treatment of PA. TMZ is an accepted chemotherapeutic agent for treatment of aggressive PAs which progress despite surgery, radiation, and other conventional antisecretory medical therapies.44 TMZ alkylates DNA resulting in cellular senescence or apoptosis; its

efficacy in the treatment of malignant gliomas is well established.45 TMZ is an attractive chemotherapeutic agent given excellent oral bioavailability and minimal limiting toxicities (e.g., myelosuppression); these toxicities typically resolve with dose reduction. While theoretical concerns exist over long-term adverse effects such as myelodysplastic syndrome or acute myelogenous leukemia, the estimated incidence of these adverse events is less than 0.1%.46 TMZ has been employed in the treatment of PA and carcinomas over the past 10 years; currently over 150 patients have been reported cumulatively in the literature.47,48,49,50,51,52,53,54,55 All tumors treated with TMZ were aggressive tumors refractory to other therapies at the time of TMZ treatment; this should be kept in mind when evaluating the efficacy data concerning TMZ.

17.9 Efficacy of TMZ Judging the true efficacy of TMZ in the treatment of pituitary tumors is difficult for several reasons. Although it has been used for more than 10 years, the total number of treated patients is still relatively low (estimated at < 200 total patients published in the literature with most studies representing small retrospective analyses).44 Lack of standardized treatment regimens (dose and cycle number) and variable definitions of clinical response (i.e., degree of tumor shrinkage vs. disease stability) result in wide variation in published response rates. Data from published series of more than five patients is summarized in ▶ Table 17.2. Some would argue that the primary goal of TMZ therapy should be to stabilize disease/prevent further progression; when one takes this as the goal of therapy, then the cumulative efficacy of TMZ is approximately 73%. The optimal strategy to use TMZ in the treatment of PA remains to be determined. Most studies employ a standard dosage (150–200 mg/m2 × 5 days per 28-day cycle); however, the optimal number of cycles remains to be established (most published series use 9–12 cycles). Several series indicate that

Table 17.2 Temozolomide data Reference

n

Mean cycle no.

Median f/u (mo)

Complete or partial response

Stable dz

Dz progression

Notes

Lasolle et al53

43 (14 pc)

7

16

51% (22/43)

23% (10/43)

26% (11/43)

No correlation w/MGMT, nonfunctional status correlated

Losa et al52

31 (6 pc)

n/a (up to 12)

43

36% (11/31)

45% (14/31)

19% (6/31)

No MGMT correlation

Bengtsson et al47

24 (8 pc)

10

33

46% (11/24)

17% (4/24)

38% (9/24)

+ MGMT correlation

Hirohata et al51

13 (10 pc)

11

n/a

31% (4/13)

15% (2/13)

8% (1/13)

No MGMT correlation, + MSH6 correlation

Raverot et al50

8 (5 pc)

9

n/a

38% (3/8)

25% (2/8)

38% (3/8)

No MGMT correlation

Bush et al55

7

9

n/a

43% (3/7)

43% (3/7)

14% (1/7)

No MGMT correlation; lower than normal TMZ dose used

Losa et al49

6 (1 pc)

10

24

33% (2/6)

33% (2/6)

33% (2/6)

+ MGMT correlation (?)

Bruno et al54

6 (1 pc)

9

6

33% (2/6)

n/a

67% (4/6)

No MGMT correlation

Ceccato et al48

5

11

n/a

No MGMT correlation

Total

143 (45 pc)

40% (2/5)

20% (1/5)

40% (2/5)

42% (60/143)

27% (38/143)

27% (39/ 143)

Abbreviations: Dz, disease; f/u, follow-up; MGMT, O6-methylguanine-DNA methyltransferase; pc, pituitary carcinoma; TMZ, temozolomide.

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Alternative Treatment Strategies for Atypical and Aggressive Pituitary Adenomas response to TMZ is typically evident within the first three cycles50,51; hence, continuing therapy in the absence of a response after three cycles is likely to be unsuccessful. If recurrence/regrowth occurs after a successful response to TMZ (27– 67% recurrence rate47,51,52), the likelihood of response to a second course of TMZ is extremely low.56 In gliomas, a clear benefit has been established by adding concurrent RT to TMZ therapy,45 whether concurrent RT should be pursued with TMZ therapy in PAs is unclear. Furthermore, the response to TMZ in gliomas inversely correlates with expression of O6-methylguanine-DNA methyltransferase (MGMT), an enzyme which repairs the DNA damage induced by TMZ; however, studies examining a correlation between MGMT expression and MGMT promoter methylation have been conflicting to date.57 Similar efforts to correlate other proteins important in DNA mismatch repair (e.g., MSH6) with TMZ responsiveness have also yielded conflicting results.47,51 Some series suggest improved efficacy of TMZ in functional tumors when compared to nonfunctional tumors44; however, it should be noted that the absolute numbers of nonfunctioning tumors are quite low in the published literature preventing any firm conclusions from being drawn. Currently, there is no way to adequately predict which type of pituitary tumor will respond to TMZ.

17.10 Investigational/ Experimental Therapies Peptide receptor radionuclide therapy (PRRT) allows specific targeting of neuroendocrine tissue by coupling a therapeutic radionuclide to a somatostatin analog. This strategy is an effective treatment modality of metastatic gut neuroendocrine tumors which express high levels of somatostatin receptors.58 Given that PAs also express high levels of various somatostatin receptors,59 PRRT represents an attractive treatment option for refractory PAs. Unfortunately, evidence is extremely limited at this point; only four published cases currently exist.60,61,62 Three of the four cases had proliferative features consistent with aggressive behavior. In all cases, the patients had substantial tumor burden; two of the cases had undergone previous RT. All four patients had evidence of somatostatin uptake on pretreatment scans to assess for somatostatin avidity. Response to treatment with stabilization or improvement in tumor burden was seen in two patients (follow-up: 2 and 8 years), while the other two patients had progressive disease which ultimately led to their demise; of note, these two patients did not receive their full course of PRRT due to rapidly worsening clinical condition. While PRRT holds theoretical appeal, its true efficacy remains to be determined and more data are needed. Surgical implantation of polymer wafers impregnated with the chemotherapeutic agent carmustine allows for local cytotoxicity while minimizing systemic toxicity; this strategy has been used with success in gliomas.63 In a series of eight patients with aggressive PA with progressive growth despite multiple

treatment modalities; treatment with implanted carmustine wafers halted tumor progression in six patients, with complete resolution of tumor in three patients (mean follow-up of 19 months).63 While detailed pathologic descriptors are not available, it should be noted that one patient who failed to respond to treatment had an elevated Ki-67 index. Furthermore, another patient with a pituitary carcinoma with an elevated Ki-67 index also failed to respond to carmustine wafer therapy. It remains to be determined in larger studies whether carmustine wafers would be effective in PAs with high proliferative capacity (as measured by Ki-67).

17.11 Proposed Strategy for Identification and Management of Aggressive PA Optimal identification and management of PA with aggressive potential remains controversial. The previous 2004 WHO classification of atypical PA was flawed, and the current 2017 classification system does not specify a means to systemically assess important predictors of clinical behavior (e.g., proliferative capacity of a tumor). Some attempts at classifying PA based on systematic definitions of invasion and proliferation have shown promise; however, absolute numbers and overall clinical experience is small.24 A suggested approach to the management of potentially aggressive PA is outlined in ▶ Fig. 17.1. To save costs, the author favors assessment of proliferative capacity (e.g., Ki67 staining) in select cases where invasion is obvious radiographically and initial histologic review reveals elevated mitoses. Tumors of a histologic subtype known to be more aggressive, or with evidence of invasion and increased proliferative capacity, should be subjected to more intense surveillance with consideration of early RT prior to the development of recurrence. Once recurrence or further growth occurs, either repeat RT or TMZ therapy serves as important second-line treatments. Failure of these two modalities to halt further tumor growth should prompt consideration of experimental therapies as repeat courses of TMZ are rarely effective.

17.12 Conclusions The management of aggressive PA remains a challenging problem for clinicians. Currently, no well-validated system exists that can confidently predict long-term tumor behavior in the early stages of disease. Further studies are urgently needed to identify novel biomarkers with good prognostic performance and to optimize treatment protocols for tumors which progress despite surgery, conventional medical therapy, and RT. Until further knowledge is gained, management is best undertaken by multidisciplinary clinics (neurosurgery, endocrinology, radiation oncology) with significant experience in treating patients with aggressive PA.

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Pituitary Adenoma

Fig. 17.1 Suggested approach to management of aggressive pituitary adenomas. CD, Cushing disease; PRRT, peptide receptor radionuclide therapy; SRS, stereotactic radiosurgery; TMZ, temozolomide; TSR, transsphenoidal resection.

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[44] Halevy C, Whitelaw BC. How effective is temozolomide for treating pituitary tumours and when should it be used? Pituitary. 2017; 20(2):261–266 [45] Stupp R, Hegi ME, Mason WP, et al. European Organisation for Research and Treatment of Cancer Brain Tumour and Radiation Oncology Groups, National Cancer Institute of Canada Clinical Trials Group. Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol. 2009; 10(5):459–466 [46] Dixit S, Baker L, Walmsley V, Hingorani M. Temozolomide-related idiosyncratic and other uncommon toxicities: a systematic review. Anticancer Drugs. 2012; 23(10):1099–1106 [47] Bengtsson D, Schrøder HD, Andersen M, et al. Long-term outcome and MGMT as a predictive marker in 24 patients with atypical pituitary adenomas and pituitary carcinomas given treatment with temozolomide. J Clin Endocrinol Metab. 2015; 100(4):1689–1698 [48] Ceccato F, Lombardi G, Manara R, et al. Temozolomide and pasireotide treatment for aggressive pituitary adenoma: expertise at a tertiary care center. J Neurooncol. 2015; 122(1):189–196 [49] Losa M, Mazza E, Terreni MR, et al. Salvage therapy with temozolomide in patients with aggressive or metastatic pituitary adenomas: experience in six cases. Eur J Endocrinol. 2010; 163(6):843–851 [50] Raverot G, Sturm N, de Fraipont F, et al. Temozolomide treatment in aggressive pituitary tumors and pituitary carcinomas: a French multicenter experience. J Clin Endocrinol Metab. 2010; 95(10):4592–4599 [51] Hirohata T, Asano K, Ogawa Y, et al. DNA mismatch repair protein (MSH6) correlated with the responses of atypical pituitary adenomas and pituitary carcinomas to temozolomide: the national cooperative study by the Japan Society for Hypothalamic and Pituitary Tumors. J Clin Endocrinol Metab. 2013; 98(3):1130–1136 [52] Losa M, Bogazzi F, Cannavo S, et al. Temozolomide therapy in patients with aggressive pituitary adenomas or carcinomas. J Neurooncol. 2016; 126(3): 519–525 [53] Lasolle H, Cortet C, Castinetti F, et al. Temozolomide treatment can improve overall survival in aggressive pituitary tumors and pituitary carcinomas. Eur J Endocrinol. 2017; 176(6):769–777 [54] Bruno OD, Juárez-Allen L, Christiansen SB, et al. Temozolomide therapy for aggressive pituitary tumors: results in a small series of patients from argentina. Int J Endocrinol. 2015; 2015:587893 [55] Bush ZM, Longtine JA, Cunningham T, et al. Temozolomide treatment for aggressive pituitary tumors: correlation of clinical outcome with O(6)-methylguanine methyltransferase (MGMT) promoter methylation and expression. J Clin Endocrinol Metab. 2010; 95(11):E280–E290 [56] Campderá M, Palacios N, Aller J, et al. Temozolomide for aggressive ACTH pituitary tumors: failure of a second course of treatment. Pituitary. 2016; 19 (2):158–166 [57] Raverot G, Castinetti F, Jouanneau E, et al. Pituitary carcinomas and aggressive pituitary tumours: merits and pitfalls of temozolomide treatment. Clin Endocrinol (Oxf). 2012; 76(6):769–775 [58] Dash A, Chakraborty S, Pillai MR, Knapp FF, Jr. Peptide receptor radionuclide therapy: an overview. Cancer Biother Radiopharm. 2015; 30(2):47–71 [59] Hofland LJ, Feelders RA, de Herder WW, Lamberts SW. Pituitary tumours: the sst/D2 receptors as molecular targets. Mol Cell Endocrinol. 2010; 326(1– 2):89–98 [60] Baldari S, Ferraù F, Alafaci C, et al. First demonstration of the effectiveness of peptide receptor radionuclide therapy (PRRT) with 111 In-DTPA-octreotide in a giant PRL-secreting pituitary adenoma resistant to conventional treatment. Pituitary. 2012; 15 Suppl 1:S57–S60 [61] Maclean J, Aldridge M, Bomanji J, Short S, Fersht N. Peptide receptor radionuclide therapy for aggressive atypical pituitary adenoma/carcinoma: variable clinical response in preliminary evaluation. Pituitary. 2014; 17(6):530–538 [62] Komor J, Reubi JC, Christ ER. Peptide receptor radionuclide therapy in a patient with disabling non-functioning pituitary adenoma. Pituitary. 2014; 17(3):227–231 [63] Subach BR, Witham TF, Kondziolka D, Lunsford LD, Bozik M, Schiff D. Morbidity and survival after 1,3-bis(2-chloroethyl)-1-nitrosourea wafer implantation for recurrent glioblastoma: a retrospective case-matched cohort series. Neurosurgery. 1999; 45(1):17–22, discussion 22–23

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Part IV Craniopharyngioma

IV

18 Controversies in Radical Resection versus Subtotal Resection with Radiation in Craniopharyngioma 112 19 The Role of Open and Endoscopic Approaches to Craniopharyngiomas

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20 The Molecular Pathogenesis of Craniopharyngioma and Potential Therapeutic Targets

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18 Controversies in Radical Resection versus Subtotal Resection with Radiation in Craniopharyngioma Taylor J. Abel and James T. Rutka Abstract Significant controversy exists regarding whether radical resection or subtotal resection with radiotherapy is the optimal treatment for craniopharyngioma. While radical gross total resection was the treatment of choice for many years, research in the last decade suggests that planned gross total resection is associated with higher rates of morbidity (e.g., endocrinopathy or neurological deficit) and similar tumor control when compared to subtotal resection with radiotherapy. These findings are based on systematic reviews of prospective and retrospective cohort studies. To date there are no randomized controlled trials evaluating the relative efficacy and treatment-related morbidity of radical resection to subtotal total resection with radiation therapy. Thus, future work is necessary to inform decisions regarding initial therapy for patients with craniopharyngioma. Results of Kraniopharyngeom 2007, a prospective, multinational trial of craniopharyngioma patients, are pending and may help clarify controversy in the field. Keywords: endocrinopathy, radiotherapy, pediatric craniopharyngioma, morbidity, tumor control, radical resection

18.1 Introduction Craniopharyngiomas are histologically benign tumors that occur in the suprasellar region and are thought to originate from the ectodermally derived remnants of Rathke’s pouch and the craniopharyngeal duct.1 Craniopharyngiomas are relatively uncommon brain neoplasms that make up approximately 3% of all intracranial tumors (6–13% in pediatric intracranial tumors) and have an overall incidence of 0.13 per 100,000 personyears.2,3 Though histologically benign, craniopharyngiomas are typically located in the suprasellar and sellar regions and can involve critical structures like the carotid and basilar arteries, pituitary, hypothalamus, and optic apparatus. Given the proximity to these important structures, complete surgical removal of craniopharyngiomas is challenging and often associated with unacceptable morbidity. Neurologic complications of craniopharyngioma resection can include polyendocrinopathy, cognitive impairment, visual impairment, shunt dependence, and other complications.1,4 Therefore, while gross total resection (GTR) of craniopharyngiomas may result in a favorable oncologic outcome, it can be associated with adverse morbidity, which must be considered at the time of initial treatment. Given the relative morbidity of radical surgical resection, treatment approaches that optimize control of tumor-related symptoms and long-term quality of life are now given careful consideration. The best treatment for optimizing quality of life and oncologic control of craniopharyngioma remains unknown and is currently a topic of intense debate. A variety of surgical approaches are currently in use including (1) aggressive surgical removal (attempted GTR); (2) planned subtotal resection

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(STR); (3) planned STR with postoperative radiotherapy (STR + XRT); (3) biopsy with postoperative XRT (BX + XRT); and (4) implantation of intracystic reservoirs for long-term control of tumor cysts often with XRT (cyst drainage [CD]). To date, no prospective randomized controlled trial has compared these different treatment approaches. A majority of the currently available evidence is from retrospective cohort studies, case series, and expert opinion articles. In this chapter, we review the available evidence for both aggressive surgical resection and planned STR plus XRT.

18.2 Current State of Evidence To date, there are no prospective randomized controlled trials evaluating the efficacy, morbidity, or quality of life associated with different initial treatment modalities for craniopharyngioma. ▶ Table 18.1 summarizes recent studies,1,5,6,7,8,9,10 primarily systematic reviews and retrospective cohort studies, comparing radical resection and STR with XRT. Numerous studies have evaluated different treatment approaches, predominantly in the form of retrospective cohort studies, which are reviewed by Ali et al1 and Clark et al5,6; however, there are no studies providing level I evidence and few studies providing level II evidence, with the preponderance of evidence being level III or IV. In 2012, Clark et al systematically reviewed the literature to examine the effect of different pediatric craniopharyngioma resection strategies on treatment-related morbidity.5 The authors stratified results by GTR, STR (or STR + XRT), or BX. The authors found that GTR was associated with higher rates of anterior lobe pituitary dysfunction and panhypopituitarism when compared to BX alone, and that GTR was also associated with higher rates of neurologic deficits and diabetes insipidus. When compared to BX, STR was also associated with increased rates of anterior lobe pituitary dysfunction and panhypopituitarism. However, in contrast to GTR, STR was not associated with postoperative neurological deficits or increased rates of diabetes insipidus. The authors also compared STR to STR + XRT, showing that STR + XRT was associated with a higher rate of panhypopituitarism compared to STR alone. Thus, this work suggests that both GTR and STR are associated with increased rates of endocrine-related morbidity, while GTR is also associated with greater risk of neurological deficit and diabetes insipidus. Given these differences in morbidity profiles, Clark et al next sought to examine the effect of these different treatment modalities on tumor control in the pediatric population, which was published as a follow-up systematic review in 2013.6 Comparing results of GTR, STR, and BX, they found a “small but highly statistically significant” increase in tumor recurrence after STR (without XRT) when compared to GTR. However, when GTR was compared to STR + XRT, there was no difference in PFS at 1- and 5-year follow-up. Thus, this systematic review demonstrated that STR + XRT is associated with similar rates of tumor control when compared to GTR.

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Table 18.1 Summary of recent studies evaluating radical resection or STR with XRT Author (year)

Level of evidence

Design

Treatment modality

Results

Clark et al (2013)6

III

Systematic review

GTR STR STR + XRT

1. PFS similar between GTR and STR + XRT 2. Longer PFS for STR + XRT, than for STR alone

Clark et al (2012)5

III

Systematic review

GTR STR STR + XRT

1. Compared to STR, GTR is associated with higher rates of neurological deficit and diabetes insipidus 2. Compared to biopsy, both STR and GTR are associated with higher rates of pituitary dysfunction

Ali et al (2014)1

III

Systematic review

GTR STR + XRT Biopsy + XRT

1. Authors used a measure “QALY” that combines quality of life and extent of life 2. Biopsy + XRT associated with highest QALY scores at 5 and 10 y

Elowe-Gruau et al (2013)7

II

Prospective cohort

GTR HSS

1. HSS decreases long-term obesity rates 2. HSS is associated with lower rates of endocrine dysfunction 3. HSS is not associated with higher rates of local recurrence

Rao et al (2017)9

III

Retrospective cohort

GTR Biopsy or STR

1. Limited surgery (biopsy or STR) with XRT had equivalent 5-y survival rates as GTR

Wijnen et al (2017)10

III

Retrospective cohort

GTR STR STR + XRT Aspiration

1. Different initial treatment modalities resulted in similar rates of long-term health effects 2. Initial cyst aspiration is associated with significantly lower progression-free survival

Lo at al (2014)8

III

Retrospective cohort

GTR STR STR + XRT Aspiration

1. STR + XRT or aspiration + XRT is associated with highest rates of progression-free survival

Abbreviations: GTR, gross total resection; HSS, hypothalamic-sparing surgery; QALY, quality-adjusted life years; STR, subtotal resection; XRT, radiotherapy.

Taken together, the work by Clark et al suggests that STR + XRT would provide similar tumor control as GTR, with a lower risk of neurological deficit and diabetes insipidus. However, in the work by Clark et al, GTR and STR + XRT were associated with similar rates of anterior pituitary dysfunction and panhypopituitarism, which should be carefully considered prior to initiating treatment. More recently, Ali et al published a systematic review and meta-analysis evaluating outcome of GTR, STR + XRT, BX + XRT, and endoscopic resections for craniopharyngioma.1 The authors used an aggregate measure combining survival and quality of life denoted, quality-adjusted life years (QALY) to evaluate outcomes. At both 5- and 10-year follow-up points, BX + XRT was associated with significantly higher QALY than GTR or STR + XRT. In conjunction with the work by Clark et al, this work provides further evidence against GTR as an initial treatment strategy. It is important to note that STR + XRT also had lower QALY scores than BX + XRT in this study. Some groups have also advocated for hypothalamic-sparing surgery (HSS) as opposed to GTR.7 Elowe-Gruau et al, in 2013, showed lower rates of long-term obesity and endocrine dysfunction when compared to a retrospective comparison group of patients who underwent radical resection.7 The group who underwent HSS had an equivalent rate of local recurrence. Taken together, the available literature suggests that GTR is associated with greater treatment-related morbidity when compared to STR or BX. However, there is also literature that suggests STR + XRT and BX + XRT may provide equivalent or only modestly decreased tumor control when compared to

GTR. The finding that GTR and more limited surgery is associated with similar tumor control is also supported by other recent retrospective cohort studies.8,9 Unfortunately, the bulk of this evidence is level III or lower, and future studies are needed to confirm and augment these findings. There is merit in estimating the potential morbidity of GTR through careful analysis of the preoperative magnetic resonance imaging (MRI) scans of patients with craniopharyngioma. Puget et al examined in detail the MRI findings in 66 children with craniopharyngioma.11 They graded the scans according to the degree of hypothalamic involvement. For patients with severe, bilateral involvement of the hypothalamus, they recommend STR and XRT; but for patients without hypothalamic involvement, GTR is recommended. In the same study, a prospective cohort of 22 patients with craniopharyngioma was examined where the degree of hypothalamic involvement dictated the operative approach. Since the use of this preoperative grading system, the authors claim not to have had any new cases of postoperative hyperphagia, morbid obesity, or behavioral disturbances.

18.3 Case Examples 18.3.1 Case of Gross Total Excision A 10-year-old female presented to hospital with a 2-month history of progressive headaches and visual obscurations. A computed tomographic (CT) scan was performed and showed a calcified tumor in the suprasellar area. An MRI scan

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Fig. 18.1 T1-weighted gadolinium-enhanced sagittal MRI demonstrating solid, calcified sellar mass with cystic extension invaginating into the third ventricle.

Fig. 18.2 T1-weighted gadolinium-enhanced coronal MRI demonstrating cystic third ventricular mass lesion with asymmetric ventricles. There is subtle edema in the right hypothalamus indicating its origin and attachment.

resection of the lesion, and it could be completely removed (▶ Fig. 18.3). The pituitary stalk could not be salvaged. Postoperatively, she required complete endocrine hormone replacement therapy. Following her recovery, she returned to school and her usual activities. Over the course of the next 8 years, she demonstrated progressive weight gain and became morbidly obese. She has entered university and is doing well from a cognitive perspective. Her craniopharyngioma has not recurred, and she has required no other treatment (▶ Fig. 18.4).

18.3.2 Case of Cyst Drainage and Treatment of Hydrocephalus

Fig. 18.3 Intraoperative photomicrograph showing mirror being used to assess the retrochiasmatic space into the third ventricle. Seen in this image is the right anterior cerebral artery (D), the chiasm (A), and the right and left optic tracts (B and C, respectively).

demonstrated a retrochiasmatic craniopharyngioma with a cystic extension into the third ventricle (▶ Fig. 18.1). Coronal MRI illustrated potential attachment to the right hypothalamus (▶ Fig. 18.2). She underwent a unilateral subfrontal approach to

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A 9-year-old female presented with a history of progressively severe headaches, nausea, and vomiting. A CT scan showed a large cystic tumor with sellar calcification. An MRI scan showed obstructive hydrocephalus with periventricular edema from obstruction of the third ventricle by the cystic mass (▶ Fig. 18.5). A ventriculo-peritoneal shunt was placed to control the intracranial pressure. Then, at a later date, an Ommaya reservoir was placed with cyst aspiration. Cytopathology showed cells compatible with craniopharyngioma. Alpha-interferon was then used to treat the cyst on two occasions. Over the next 6 years, the cyst has remained collapsed, and the lesion has not grown (▶ Fig. 18.6). Aside from one shunt blockage from a broken catheter in the cervical region, she has been functioning normally without endocrinological deficit.

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Fig. 18.4 Left: Postoperative T1-weighted sagittal MRI showing complete resection of the craniopharyngioma without recurrence several years after surgery. Right: Postoperative T1weighted coronal MRI showing clear suprasellar region, and resected craniopharyngioma from the right hypothalamus.

Fig. 18.5 Left: Sagittal T1-weighted MRI showing large cystic craniopharyngioma with extension onto the planum sphenoidale subfrontally. Right: Coronal T2-weighted MRI showing cystic mass lesion occupying region of the third ventricle. There is moderate ventricular dilatation.

Fig. 18.6 Left: T1-weighted sagittal MRI postgadolinium showing normal pituitary stalk, and disappearance of cystic lesion after placement of Ommaya reservoir and aspiration. Right: T1-weighted coronal MRI showing Ommaya reservoir dome in left parasagittal region. No cystic mass lesion is seen.

18.4 Conclusions

18.5 Future Directions

Given currently available levels of evidence, it is not possible to make definitive recommendations with regard to treatment strategy (i.e., GTR vs. STR + XRT). The available literature suggests that more limited surgery may be the best strategy for optimizing tumor control and quality of life. The benefit of aggressive resection is uncertain as local recurrence may still occur after GTR and the literature to date suggests similar control rates between GTR and STR + XRT (and in some cases BX + XRT). Given current levels of evidence, treatment should be individualized to maximize quality of life and tumor control.

Prospective randomized-controlled trials comparing GTR, STR + XRT, and BX + XRT are necessary to advance understanding of the optimal treatment strategy for patients with craniopharyngioma. These studies should evaluate tumor control, morbidity, survival rates, and quality of life. Results of Kraniopharyngeom 2007, a prospective, multinational trial of craniopharyngioma patients, are pending and may help clarify controversy in the field.

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References [1] Ali ZS, Bailey RL, Daniels LB, et al. Comparative effectiveness of treatment options for pediatric craniopharyngiomas. J Neurosurg Pediatr. 2014; 13(2): 178–188 [2] Bunin GR, Surawicz TS, Witman PA, Preston-Martin S, Davis F, Bruner JM. The descriptive epidemiology of craniopharyngioma. J Neurosurg. 1998; 89(4): 547–551 [3] Carmel PW, Antunes JL, Chang CH. Craniopharyngiomas in children. Neurosurgery. 1982; 11(3):382–389 [4] Crom DB, Smith D, Xiong Z, et al. Health status in long-term survivors of pediatric craniopharyngiomas. J Neurosci Nurs. 2010; 42(6):323–328, quiz 329–330 [5] Clark AJ, Cage TA, Aranda D, Parsa AT, Auguste KI, Gupta N. Treatment-related morbidity and the management of pediatric craniopharyngioma: a systematic review. J Neurosurg Pediatr. 2012; 10(4):293–301

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[6] Clark AJ, Cage TA, Aranda D, et al. A systematic review of the results of surgery and radiotherapy on tumor control for pediatric craniopharyngioma. Childs Nerv Syst. 2013; 29(2):231–238 [7] Elowe-Gruau E, Beltrand J, Brauner R, et al. Childhood craniopharyngioma: hypothalamus-sparing surgery decreases the risk of obesity. J Clin Endocrinol Metab. 2013; 98(6):2376–2382 [8] Lo AC, Howard AF, Nichol A, et al. Long-term outcomes and complications in patients with craniopharyngioma: the British Columbia Cancer Agency experience. Int J Radiat Oncol Biol Phys. 2014; 88(5):1011–1018 [9] Rao YJ, Hassanzadeh C, Fischer-Valuck B, et al. Patterns of care and treatment outcomes of patients with Craniopharyngioma in the national cancer database. J Neurooncol. 2017; 132(1):109–117 [10] Wijnen M, van den Heuvel-Eibrink MM, Janssen JAMJL, et al. Very long-term sequelae of craniopharyngioma. Eur J Endocrinol. 2017; 176(6):755–767 [11] Puget S, Garnett M, Wray A, et al. Pediatric craniopharyngiomas: classification and treatment according to the degree of hypothalamic involvement. J Neurosurg. 2007; 106(1) Suppl:3–12

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The Role of Open and Endoscopic Approaches to Craniopharyngiomas

19 The Role of Open and Endoscopic Approaches to Craniopharyngiomas Neil Majmundar, Jean Anderson Eloy, and James K. Liu Abstract Maximally safe surgical resection to minimize the risk of recurrence and progression remains the mainstay treatment for craniopharyngiomas. Both microscopic transcranial and endoscopic endonasal surgical approaches are utilized for the treatment of this disease. However, there remains debate over the approach selection paradigm. The choice of approach plays a significant role in obtaining radical resection while minimizing surgical complications. Craniopharyngiomas can present in a variety of sizes, locations, and tumor consistencies. Each tumor has its own distinct features which may favor one specific approach over another. In this chapter, we review transcranial and endoscopic approaches, and discuss the tumor characteristics influencing approach selection. We also discuss key studies comparing these approaches and their outcomes. Keywords: craniopharyngioma, endoscopic endonasal approach, microsurgical, transsphenoidal, skull base surgery

19.1 Introduction Craniopharyngiomas are rare, slow-growing neoplasms thought to originate from embryonic remnants of Rathke’s pouch around the pituitary stalk, spanning from the sella turcica up to the hypothalamus and the floor of the third ventricle.1,2 These tumors have a bimodal presentation affecting children from ages 5 to 14 years and adults from ages 55 to 65 years.1 Despite being histologically benign, craniopharyngiomas cause neurological deficits due to their close proximity to critical neurovascular structures. Due to the intimate involvement with the optic nerves and chiasm, pituitary infundibulum and gland, and often the hypothalamus and third ventricle, surgical resection can carry with it an extremely high morbidity. Despite this, surgical resection remains the first-line therapy and offers the best chance of radical resection and oncologic cure.3,4,5,6,7,8,9,10 There still remain several topics of debate in the treatment of craniopharyngiomas despite the advances made in the treatment of this pathology. These include approach selection, extent of resection, management of recurrence, roles of radiotherapy, and molecular biology including targeted therapies. In this chapter, we focus on the role of open and endoscopic approaches in the treatment of craniopharyngiomas. Significant advances in approaches to the ventral skull base, neuroimaging, hormone replacement therapy, and modern microsurgical and endoscopic techniques have allowed for safer gross or near total resection of craniopharyngiomas, with gross total resection rates ranging from 72.7 to 90%.7,10,11,12,13,14 In cases where tumor is adherent to critical structures, achieving a maximal safe resection or near total resection (> 95%) is the goal in order to preserve function. The surgeon must take into account a

number of factors related to each individual tumor to select a patient-tailored approach that may at times require a combined transcranial and endoscopic approach.

19.2 Approach Selection The optimal surgical approach for craniopharyngiomas is the shortest and most direct corridor which provides maximal exposure and minimal risk for neurovascular complications. Tumor size, tumor location, tumor consistency, surgeon preference, and history of previous resections all largely impact the surgical approach.14 In particular, the relationship of the tumor to key neurovascular structures, including the optic chiasm and tracts, the pituitary infundibulum and gland, the hypothalamus, and third ventricle, plays a significant role in selecting the best approach. The patient’s age and medical history must also be taken into account. These last two factors also impact the extent to which gross total resection should be pursued. In older patients who may have multiple comorbidities, a conservative approach in which the neural structures are decompressed may be warranted. Surgeon comfort and skill level with certain approaches also dictate the “optimal” approach for the patient. A number of classification systems have been devised to classify craniopharyngiomas based on their location, relationship to the infundibulum and hypothalamus, position along the vertical hypophyseal axis, and type of involvement with the third ventricle.15,16,17,18 While these classification systems can be used to aid the development of an algorithm for surgical treatment and approach selection, it is important to recognize that craniopharyngiomas extend into several different “compartments” within the sellar and suprasellar regions, thereby increasing the surgical complexity and necessitating a personalized, tailored approach based on multiple factors.14 The sellar and suprasellar regions can be accessed through a number of different skull base approaches, each with their own distinct advantages and limitations. The traditional open approaches include midline approaches (transbasal subfrontal, frontobasal interhemispheric), anterolateral approaches (pterional, orbitopterional, orbitozygomatic, frontolateral, and supraorbital eyebrow), and lateral approaches (subtemporal, combined petrosal).6,7,13,14,19,20,21 The transsphenoidal (microsurgical) approach provides a transnasal trajectory to the sellar and suprasellar space for midline tumors.14 Over the past decade, the extended endoscopic endonasal approach (EEA) via the transplanum transtuberculum corridor has been developed to provide direct midline exposure to intrasellar/subdiaphragmatic, supradiaphragmatic, and retrochiasmatic craniopharyngiomas extending up to the third ventricle.12,14,15,22,23,24,25,26,27,28, 29,30,31,32,33 Finally, transcortical or transcallosal approaches can be used to access tumors which are entirely intraventricular. In addition to selecting the approach with the most direct route to the tumor, one must also consider an approach that

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Craniopharyngioma allows for better visualization of the tumor interface with the surrounding critical neurovascular structures in order to avoid neurologic damage. In cases of craniopharyngiomas, this includes tumor involvement with the pituitary gland, pituitary stalk, optic nerves and chiasm, hypothalamus, and important arterial perforators. Although there is often debate between choosing an open transcranial approach or an extended EEA, there has been an increased acceptance of EEA for suprasellar and retrochiasmatic craniopharyngiomas.

19.2.1 Anterolateral Approaches Anterolateral open transcranial approaches expose the suprasellar region through a transsylvian or unilateral subfrontal corridor. These generally include the pterional (frontotemporal), orbitozygomatic, lateral supraorbital (frontolateral) approaches.3,6,13,14,21 The pterional and orbitozygomatic approaches are performed through a curvilinear incision behind the hairline, while the lateral supraorbital approach can be performed through an eyebrow or eyelid incision. At our institution we prefer to use the one-piece modified orbitozygomatic approach for suprasellar tumors that extend laterally into the Sylvian fissure. This approach provides an inferior-to-superior surgical trajectory, increases the corridor of exposure, shortens the target distance, and improves the maneuverability of instruments while minimizing brain retraction.14 Anterolateral approaches for retrochiasmatic craniopharyngiomas, which extend up into the third ventricle necessitate a translamina terminalis exposure, especially in cases where the chiasm is prefixed. The narrow corridors between the critical structures in this location increase the risk of neurovascular injury from manipulation. These approaches are generally limited in their ability to provide visualization of the ipsilateral wall of the hypothalamus as well as to the undersurface of the optic chiasm, where many perforators supply the optic apparatus. Blind dissection of the tumor in these two regions can result in potential damage to these critical structures. For this reason, the EEA is believed to be the superior approach for retrochiasmatic tumors, allowing for direct visualization of the undersurface of the chiasm and its perforators.

19.2.2 Midline Approaches Midline transcranial approaches (bifrontal transbasal, frontobasal interhemispheric) offer a direct midline orientation and access to the lamina terminalis, allowing for superior visualization of the both walls of the third ventricle, the hypothalamus, and the interpeduncular cistern.14,19,34 These approaches offer a clear advantage over the anterolateral approaches, where the view of the lamina terminalis is oblique and only allows adequate visualization of the contralateral wall of the third ventricle. Midline approaches also allow direct visualization and access to the prechiasmatic space as well as both carotico-oculomotor and opticocarotid cisterns.14 The lamina terminalis can be opened to access tumors in the retrochiasmatic space extending into the third ventricle. These approaches are favorable for large midline retrochiasmatic craniopharyngiomas situated higher in the vertical hypophyseal axis extending into the third ventricle. In cases where the infrachiasmatic corridor between the diaphragm sella and optic chiasm is narrow, a midline transcranial approach may be more favorable than an EEA.

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However, the major disadvantage with a midline transcranial approach is the inability to directly visualize the undersurface of the optic apparatus, which remains a critical blind spot where the blood supply to the optic chiasm from the perforators of the superior hypophyseal artery reside. At our institution, we favor the modified one-piece extended transbasal approach where we perform a bifrontal craniotomy that includes the anterior wall of the frontal sinus. This provides the lowest basal trajectory along the floor of the anterior cranial fossa thereby avoiding an additional supraorbital bar osteotomy. Following this craniotomy, a subfrontal or an interhemispheric route can be taken to gain access to the lamina terminalis for tumor resection.

19.2.3 Intraventricular Approaches The transcallosal and transventricular approaches are performed with minimal brain retraction for tumors that extend into the anterior third ventricle and lateral ventricle(s).14 A transcortical approach may be considered if the tumor causes hydrocephalus or presents itself to one ventricle. This approach is considered in tumors which are purely intraventricular and do not violate the floor of the third ventricle. At our institution, we prefer the interhemispheric transcallosal approach that provides midline access to either lateral ventricle without having to transgress the cortical surface, thereby reducing the risk of seizures. Despite excellent access to the lateral ventricles, the interhemispheric approach does not allow direct visualization of the suprasellar region and carries the risks of injuring the fornices, the pericallosal arteries, and major veins including the bridging veins and the internal cerebral veins. While these approaches are of limited use in tumors residing mainly in the sellar and suprasellar regions, they can be used to supplement other approaches to remove any intraventricular tumor extension.35,36

19.2.4 Lateral Approaches The lateral approaches include the transpetrosal (combined petrosal) and subtemporal approaches.14,37,38,39,40 These approaches are seldom used in craniopharyngioma surgery and are generally considered in few select cases. The transpetrosal approach allows a posterior to anterior and inferior viewing projection of the optic chiasm, floor of the third ventricle, and the hypothalamus. This approach provides the advantage of avoiding pituitary transposition and allows for tumor removal in cases of retroinfundibular craniopharyngiomas that may extend into retrosellar and retroclival spaces.14 One major disadvantage of this approach is the narrow working corridors it provides, carrying a higher risk for injury to the oculomotor nerve as well as the posterior communicating artery and its perforators.14 Other drawbacks of this approach include the risk of venous infarct (vein of Labbe, superior petrosal sinus), temporal lobe retraction, and operative time. Furthermore, in pediatric cases, the mastoid sinus is not well pneumatized thereby making it technically challenging to perform a mastoidectomy. The subtemporal approach involves a temporal craniotomy that does not require a petrosectomy or mastoidectomy thereby reducing the operative time in comparison to the transpetrosal

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The Role of Open and Endoscopic Approaches to Craniopharyngiomas approach. One major disadvantage is the reduced potential of achieving a gross total resection due to the limited exposure. The subtemporal approach also does not allow for a complete transtentorial division which eliminates the viewing trajectory of the retrochiasmatic space afforded by the transpetrosal approach.14

19.2.5 Endoscopic Endonasal Approaches Over the past decade, endoscopic endonasal techniques have significantly evolved. The previously mentioned traditional transcranial approaches all require some degree of brain retraction, provide narrow working corridors for microsurgical resection, and lack direct visualization and safe access to the retrochiasmatic region. While traditional microscopic speculum-based transsphenoidal approaches offer a direct midline route to intrasellar and subdiaphragmatic tumors, they are restricted by a limited field of view and reduced surgical freedom.14,41,42 The extended EEA, however, provides a significant advantage in certain cases because it eliminates many of the limitations associated with the open transcranial and microscopic transsphenoidal approaches. The extended EEA provides midline exposure to the intrasellar/subdiaphragmatic, supradiaphragmatic, and retrochiasmatic craniopharyngiomas that extend up to the third ventricle without necessitating any brain retraction.14 Purely intrasellar craniopharyngiomas can be accessed with a transsellar approach. The majority of suprasellar supradiaphragmatic craniopharyngiomas are accessed via an extended EEA through the transplanum transtuberculum corridor. In cases of extensive tumors involving multiple intracranial compartments, a combined open approach and EEA may be required in a staged fashion.11,25 Certain centers perform the EEA combined with a keyhole craniotomy in select cases.43 In addition, the EEA serves an important role in cases of recurrence, especially when the first attempt at resection is transcranial, as this strategy provides a fresh and untouched route to the tumor.44 The major advantage of the EEA for retrochiasmatic craniopharyngiomas with third ventricular extension is the direct visualization of the undersurface of the optic nerves, chiasm, and hypothalamus. The undersurface, a blind spot with the open approach, can be accessed from below allowing for bimanual microdissection techniques to dissect the tumor off the chiasm and hypothalamus with direct visualization of the superior hypophyseal artery perforators.33,36 This ability to visualize the undersurface of the chiasm and hypothalamus as well as preserving critical neurovascular structures has significantly reduced the rates of hypothalamic and visual complications.30,32 Factors which make the EEA a less favorable approach include a hypoplastic sphenoid sinus, a narrow intercarotid artery distance, and a narrow infrachiasmatic window. Tumors extending laterally into the Sylvian fissure (> 1 cm lateral to the carotids) and superiorly into the interhemispheric fissure are also not suitable for the EEA. In addition, there is a higher risk of cerebrospinal fluid (CSF) leak with EEA.30 Nonetheless, the rates of CSF leak have decreased significantly as multilayer reconstruction techniques with use of the vascularized pedicled nasoseptal flap have advanced.45,46 The inability to perform direct vascular repair or bypass in cases of arterial injury is also another limitation of the EEA.

19.3 Discussion of Key Studies A direct head-to-head comparison of endoscopic and transcranial techniques is difficult to achieve as certain tumors are inherently more appropriately treated by one approach over another. For example, tumors with lateral extension into the Sylvian fissure would not be appropriately treated with an EEA. Therefore, the majority of key studies are retrospective analyses comparing various outcomes. Below we summarize a few of the most recent and comprehensive studies. These studies among the others (summarized in ▶ Table 19.1) provide Level III and lower evidence for the roles of transcranial and endoscopic approaches. In a large systematic review of 88 published reports, Komotar et al, compared EEA, microscopic transsphenoidal, and transcranial approaches.30 They found the EEA cohort to have lower rates of recurrence, higher rates of gross total resection, improved visual outcomes, and less mortality when compared to the transcranial cohort.30 The transcranial cohort also had a greater rate of seizures and permanent diabetes insipidus.30 As expected, the EEA cohort had a higher rate of CSF leak.30 One significant drawback in this analysis was the previously stated selection bias that exists when deciding the appropriate approach. The authors reported a greater average tumor diameter in patients who underwent an open transcranial approach, while patients with smaller midline tumors underwent an EEA.30 Another retrospective review by Jeswani et al, comparing outcomes at a single institution for 53 cases of midline suprasellar lesions undergoing endoscopic or transcranial approaches found a similar extent of resection between both groups.47 Progression-free survival curves and recurrence rates were also similar between the two groups.47 The transcranial group had a higher rate of cranial nerve injury (optic, oculomotor, trochlear, olfactory, and frontalis branch of the facial nerve), and the endonasal group had a higher rate of CSF leak.47 The authors concluded that surgeon preference was the only factor determining surgical approach at their institution. Moussazadeh et al recently published a single-institution retrospective study comparing 26 cases, 21 EEA and 5 transcranial, for midline craniopharyngiomas in adults.48 The authors demonstrated that the EEA had higher rates of gross total resection, superior visual outcomes, lower rates of recurrence, and fewer complications. Similar to other studies, the transcranial approach was typically used for tumors with a larger diameter. The majority of publications conclude that the EEA and transcranial approach have similar rates of resection. The EEA has been shown to have higher rates of visual improvement as well as higher rates of CSF leak. The transcranial approaches have a higher rate of postoperative seizures. While these studies provide a general idea of outcomes, they also reinforce the notion that the approach must be tailored to each individual tumor.

19.4 Complication Avoidance Appropriate approach selection is critical to complication avoidance. Prior to discussing any technical aspects to complication avoidance, one must first discuss preoperative planning. As mentioned above, certain tumor characteristics will dictate the appropriate approach.

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Craniopharyngioma

Table 19.1 Summary of relevant clinical studies Level of evidence

Study

Description

IV-case series

Yasargil et al 1990. Total removal of craniopharyngiomas3

Retrospective review of 144 patients undergoing microsurgical resection from 1967 to 1989 (130-TC, 14-TS). 90% were completely resected and 7% recurred

IV-case series

Fahlbusch et al 1999. Surgical treatment of craniopharyngiomas: experience with 168 patients6

Retrospective analysis of 148 TC and open TS approaches for tumor resection

IV-case series

Gardner et al 2008. Outcomes following endoscopic, expanded endonasal resection of suprasellar craniopharyngiomas: a case series12

Retrospective review of 16 patients undergoing EEA from 1999–2006. 91% had NTR or GTR, 93% had improvement or recovery with vision, 18% developed panyhypopituitarism, 8% developed permanent DI, and 58% CSF leak rate

III-systematic review

Komotar et al 2012. Endoscopic endonasal compared with microscopic transsphenoidal and open transcranial resection of craniopharyngiomas30

Systematic review of open and endoscopic approaches for adult and pediatric craniopharyngiomas published from 1995–2010

III-retrospective cohort study

Jeswani et al 2016. Comparative analysis of outcomes following craniotomy and expanded endoscopic endonasal transsphenoidal resection of craniopharyngioma and related tumors: a single-institution study47

Retrospective review comparing EEA with open transcranial approaches at a single institution of patients undergoing resection of suprasellar lesions between 2000 and 2013. Similar extent of resection/progression-free survival between both groups, increased risk of CN injury with open transcranial, increased risk of CSF leak with EEA

III-case-control study

Moussazadeh et al 2016. Endoscopic endonasal versus open transcranial resection of craniopharyngiomas: a case-matched singleinstitution analysis48

Retrospective review of 26 cases (21 EEA, 5 TC) at a single institution. Higher rate of GTR (90 vs. 40%), superior visual restoration (63 vs. 0%), decreased incidence of recurrence, and fewer complications with the EEA

III-retrospective cohort study

Wannemuehler et al 2016. Outcomes in transcranial microsurgery versus extended endoscopic endonasal approach for primary resection of adult craniopharyngiomas49

Retrospective review of 21 patients who underwent TC (12) or EEA (9) for resection. Extent of resection was similar. CSF leak in 2 EEA patients. Postop visual improvement 89% in EEA vs. 25% in TC

IV-case series

Park et al 2017. Clinical outcome after extended endoscopic endonasal resection of craniopharyngiomas: Two-institution experience50

Retrospective review of 116 patients undergoing EEA at two institutions between 2010 and 2016. 85% of patients had at least near total resection (> 95%) after EEA. 76% of patients experienced improvement in visual fields postop

IV-case series

Shi et al 2017. Outcome of radical surgical resection for craniopharyngioma with hypothalamic preservation: a single-center retrospective study of 1054 patients51

Retrospective review of 1054 patients undergoing transcranial approaches for resection. GTR in 89.6%, visual improvement in 47.1%, new onset DI in 29.7%

IV-case series

Patel et al 2017. Outcomes after endoscopic endonasal resection of craniopharyngiomas in the pediatric population52

Retrospective review of 16 pediatric patients undergoing EEA from 1995–2016. GTR in 93.8%, normal or improved vision in 69.2%, new-onset DI or panhypopituitarism in 46.7%, new hypothalamic obesity in 28.6%, CSF leak in 18.8%, and a major complication rate of 12.5%

IV-case series

Lauretti et al 2018. Neuroendoscopic treatment of cystic craniopharyngiomas: A Case series with systematic review of the literature53

Case series of eight adult patients with cystic/mixed craniopharyngiomas treated by neuroendoscopy and EVD

IV-case series

Alalade et al 2018. Suprasellar and recurrent pediatric craniopharyngiomas: expanding indications for the extended endoscopic transsphenoidal approach54

Retrospective review of 11 patients undergoing EEA from 2007–2016. GTR in 50, 63.3 DI, 74% with stable or improved visual function

Abbreviations: CN, cranial nerve; CSF, cerebrospinal fluid; EEA, endoscopic endonasal approach; GTR, gross total resection; NTR, near total resection; TC, transcranial; TS, transsphenoidal.

Major complications of the EEA include vascular injury, optic nerve injury, hypothalamic injury, cranial neuropathies, and CSF leak. During exposure, we routinely utilize neuronavigation (with CT angiogram merged with magnetic resonance imaging [MRI]) in order to identify the anterior extent of the transplanum bony exposure. In addition, a micro-Doppler probe may be used to map out the internal carotid arteries during exposure of the ventral skull base. Dural opening must allow for adequate visualization of the tumor, optic nerves, and internal carotid

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arteries. It is also important to create adequate surgical freedom to allow for bimanual extracapsular dissection of the tumor in order to achieve maximally safe resection. If the tumor is cystic, early decompression may facilitate extracapsular dissection. Additional attention must be paid to the branches of the superior hypophyseal artery, with care to avoid any branches supplying the undersurface of the optic chiasm in order to avoid postoperative visual loss. It is also important to maintain the integrity of the membrane of Liliequist to protect the basilar

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The Role of Open and Endoscopic Approaches to Craniopharyngiomas artery and P1 perforators. Meticulous multilayered closure with use of a vascularized pedicled nasoseptal flap is paramount to avoid postoperative CSF leakage. Complications involving the transcranial approaches for craniopharyngiomas in particular typically occur during tumor resection. The involvement of the nearby critical neurovascular structures make resection of these tumors particularly challenging, especially when working in narrower corridors between nerves and vessels. Blind dissection of the tumor from difficult to visualize regions such as the hypothalamus and undersurface of the optic chiasm should be avoided to minimize risk of injury to these structures.

19.5 Case Examples 19.5.1 Case 1: Staged Transbasal and EEA Approach This 19-year-old female presented with progressive headaches and visual loss. MRI demonstrated a giant multicystic craniopharyngioma extending into the suprasellar region, interhemispheric fissure, left Sylvian fissure, and retrochiasmatic region up into the third ventricle resulting in obstructive hydrocephalus (▶ Fig. 19.1a, b). Because the tumor had significant interhemispheric extension with encasement of the pericallosal arteries, and also lateral extension with encasement of the left middle cerebral artery, we felt that the safest approach to resect the most amount of tumor with excellent vascular control was a midline transbasal approach via the interhemispheric fissure with additional access through the lamina terminalis corridor to remove the retrochiasmatic third ventricular component. The anterior cyst in the interhemispheric fissure was carefully dissected away from the engulfed pericallosal arteries (▶ Fig. 19.2a–d). A near total resection of the anterior cyst was

achieved leaving small microscopic remnants adherent to the pericallosal arteries. The retrochiasmatic cyst was decompressed and removed via the lamina terminalis corridor. Unfortunately, the corridor was rather narrow and remnants adherent to the hypothalamus and the undersurface of the optic chiasm were not resected. Postoperative MRI showed greater than 95% removal of the tumor with excellent decompression of the optic chiasm and resolution of hydrocephalus (▶ Fig. 19.1c, d). The patient had restoration of normal vision with normal pituitary function. However, at 3 months after surgery, she presented with progressive headaches and worsening vision due to recurrence of the retrochiasmatic cyst with extension into the third ventricle (▶ Fig. 19.3a, b). An EEA via the transplanum tuberculum corridor was used to resect the recurrent tumor in the retrochiasmatic space. This approach provided a better view of the undersurface of the optic chiasm, hypothalamus and third ventricle (▶ Fig. 19.4a–d). The pituitary stalk was expanded by the tumor and not salvageable. A near-complete tumor removal was achieved leaving a densely calcified remnant that was adherent to the undersurface of the optic chiasm (▶ Fig. 19.3c, d). Postoperatively, the patient had restoration of normal vision and was maintained on hormone replacement therapy. She underwent additional fractionated radiation therapy to the residual tumor that was adherent to the optic chiasm and pericallosal arteries without any recurrence at 2 years after surgery. This case illustrates the importance of having multiple operative approaches in the surgical armamentarium for craniopharyngioma treatment. The initial transbasal approach was chosen because it provided safer dissection of the engulfed pericallosal arteries and left middle cerebral artery. The limited diameter of the lamina terminalis working corridor resulted in residual tumor that progressed with recurrence. However, this limitation was adequately addressed using an extended EEA.

Fig. 19.1 (a, b) Preoperative post-gadolinium magnetic resonance imaging (MRI) of patient in Case Illustration 1 demonstrates a giant multicystic craniopharyngioma occupying the suprasellar and interhemispheric region, and also in the retrochiasmatic third ventricular region with obstructive hydrocephalus. There is encasement of the pericallosal arteries (b, white arrow) in the interhemispheric fissure, and also lateral extension with encasement of the left middle cerebral artery. A transbasal interhemispheric translamina terminalis approach was performed. (c, d) Postoperative post-gadolinium MRI showed approximately 95% removal of the tumor. There was residual tumor adherent to the infrachiasmatic region, hypothalamus, and microscopic residue on portions of the pericallosal arteries.

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Fig. 19.2 Intraoperative photographs of transbasal interhemispheric translamina terminalis approach (patient in Case Illustration 1). (a) Interhemispheric dissection shows cystic tumor (T) engulfing pericallosal A3 vessels. (b) Tumor (T) has been carefully dissected away from the anterior communicating artery (Acom), perforators (AP), A1, A2, and recurrent artery of Heubner (HB). The remaining retrochiasmatic tumor is hidden behind the lamina terminalis (T*). (c) The lamina terminalis is opened posterior to the optic chiasm (OC) to access the tumor (T*). (d) Final view after decompression of the optic chiasm and nerves.

Fig. 19.3 (a, b) Postoperative magnetic resonance imaging (MRI) at 3 months follow-up of patient in Case Illustration 1 shows recurrence of retrochiasmatic cystic craniopharyngioma extending into third ventricle. An endoscopic endonasal transplanum transtuberculum approach was performed to resect the tumor. Near total resection was achieved, leaving a calcified remnant adherent to undersurface of optic chiasm. (c, d) Postoperative MRI 3 months after endoscopic endonasal approach shows stable residual enhancement of microscopic tumor that was adherent to critical structures.

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The Role of Open and Endoscopic Approaches to Craniopharyngiomas

Fig. 19.4 Intraoperative photographs of second stage endoscopic endonasal approach resection of recurrent cystic craniopharyngioma in the retrochiasmatic space (patient in Case Illustration 1). (a) The cyst is decompressed and the tumor (T) is dissected away from undersurface of optic chiasm (OC) and removed from the retrochiasmatic space. (b) After removal of the tumor, the third ventricle (3V) is visualized. Residual calcified tumor (asterisk) is densely adherent to undersurface of optic chiasm (OC). (c) Endoscopic view of third ventricle shows both foramen of Monro. (d) Reconstruction of skull base with nasoseptal flap (NSF).

19.5.2 Case Illustration 2: Limitations and Advantages of EEA for Giant Complex Craniopharyngioma This 56-year-old female presented with progressive headaches, confusion, memory loss, and bitemporal visual field loss. MRI demonstrated a solid, retrochiasmatic craniopharyngioma compressing the optic chiasm with an associated giant right frontal cyst causing significant mass effect (▶ Fig. 19.5a–c). Various surgical approaches were considered including a transbasal subfrontal approach, right orbitozygomatic approach, EEA, and a combined microscopic/EEA. After careful deliberation, it was felt that the optic chiasm would be best decompressed with an EEA with decompression of the frontal cyst. If the cyst wall could not be completely removed with an endonasal approach, a second stage transcranial procedure was anticipated if the cyst recurred. At surgery, the solid, retrochiasmatic component of the tumor was readily dissected off the optic chiasm and hypothalamus. The pituitary stalk was identified at the base of the tumor and was preserved anatomically. Remnants of microscopic calcifications were left adherent to the top of the optic chiasm and the anterior communicating artery complex. The right frontal lobe cyst was decompressed, but the cyst wall was very adherent to the frontal lobe and anterior communicating

artery complex, and could not be safely removed. The solid component of the tumor was completely removed with excellent decompression of the optic chiasm and preservation of the pituitary stalk (▶ Fig. 19.6a–f). Here, a decision was made to preserve the stalk because it was anatomically intact and a complete tumor resection was not achievable. Postoperatively, the patient had restoration of normal vision, preservation of normal pituitary function without requiring hormone replacement therapy, and no CSF leakage. MRI performed at 3 months follow-up showed no evidence of solid tumor recurrence and regression of the right frontal lobe cyst (▶ Fig. 19.5d–f). It appeared that the frontal lobe cyst was well fenestrated into the suprasellar cistern. The patient underwent radiation therapy to the residual tumor. Follow-up imaging at 2 years after surgery and radiation showed regression of the residual enhancing cyst wall and residual tumor in the suprasellar region. This case illustrates the limitations of complete tumor removal via an EEA when superiorly extending cyst walls are adherent to critical structures. However, we felt it was a reasonable first surgical option since it allowed complete removal of the solid component in the retrochiasmatic space with excellent visual and endocrine outcomes. This case also demonstrates the effectiveness of adjuvant radiation therapy to residual tumor after a radical near total removal.

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Fig. 19.5 (a–c) Preoperative magnetic resonance imaging (MRI) of solid retrochiasmatic craniopharyngioma with associated giant right frontal lobe cyst (patient in Case Illustration 2). Removal of the solid retrochiasmatic component was performed with wide fenestration of frontal lobe cyst into suprasellar cistern. (d–f) Postoperative MRI at 3 months follow-up shows regression and collapse of frontal lobe cyst. Optic chiasm is well decompressed and the patient had normal pituitary function with stalk preservation.

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Fig. 19.6 Intraoperative photographs of endoscopic endonasal approach resection of solid retrochiasmatic craniopharyngioma with associated giant right frontal lobe cyst (patient in Case Illustration 2). (a, b) Extracapsular dissection of tumor (T) off the left internal carotid artery (ICA), left posterior communicating artery (Pco), left optic nerve (ON), and optic chiasm (OC). (c) Right frontal cyst (FC) is widely fenestrated into suprasellar cistern. The tumor (T) is very adherent to the optic chiasm. (d) Elevation of the tumor from the top of the pituitary gland (PG) reveals the pituitary stalk (PS) which is able to be preserved. The basilar artery (BA) complex and left oculomotor nerve are visualized. (e, f) Final view after near total resection. The optic chiasm is well decompressed and there is adherent microscopic tumor to the both A1 vessels. The frontal lobe cyst (FC) was also very adherent to the brain and the A1 vessels.

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The Role of Open and Endoscopic Approaches to Craniopharyngiomas

19.6 Conclusions There are a variety of microsurgical and endoscopic approaches that can be used for surgical resection of craniopharyngiomas. While each approach has its advantages and limitations, a personalized, tailored approach to the individual based on multiple factors is crucial in determining the optimal treatment strategy. Knowledge and expertise in both traditional microsurgical and endoscopic endonasal techniques is necessary for the surgical armamentarium for craniopharyngioma management.

[15]

[16]

[17]

[18]

19.7 Suggestions for Future Studies It is rather impossible to conduct a head-to-head prospective randomized clinical trial between open and endoscopic approaches for craniopharyngiomas due to the rarity of this tumor and the variability in tumor sizes, consistency, and extent. It is important to continue long-term radiographic and clinical follow-up of these tumors with consistent reporting of clinical outcomes, including postoperative visual function, endocrine function, body mass index, quality of life, and tumor recurrence. Further investigations should include the role of early postoperative radiation for subtotal or radical subtotal removal of craniopharyngioma, as well as the study of molecular pathways to identify targets for chemotherapeutic agents.

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Craniopharyngioma [38] Al-Mefty O, Ayoubi S, Kadri PA. The petrosal approach for the total removal of giant retrochiasmatic craniopharyngiomas in children. J Neurosurg. 2007; 106(2) Suppl:87–92 [39] Kunihiro N, Goto T, Ishibashi K, Ohata K. Surgical outcomes of the minimum anterior and posterior combined transpetrosal approach for resection of retrochiasmatic craniopharyngiomas with complicated conditions. J Neurosurg. 2014; 120(1):1–11 [40] Hakuba A, Nishimura S, Inoue Y. Transpetrosal-transtentorial approach and its application in the therapy of retrochiasmatic craniopharyngiomas. Surg Neurol. 1985; 24(4):405–415 [41] Jane JA, Jr, Prevedello DM, Alden TD, Laws ER, Jr. The transsphenoidal resection of pediatric craniopharyngiomas: a case series. J Neurosurg Pediatr. 2010; 5(1):49–60 [42] Couldwell WT, Weiss MH, Rabb C, Liu JK, Apfelbaum RI, Fukushima T. Variations on the standard transsphenoidal approach to the sellar region, with emphasis on the extended approaches and parasellar approaches: surgical experience in 105 cases. Neurosurgery. 2004; 55(3):539–547, discussion 547–550 [43] Nagata Y, Watanabe T, Nagatani T, Takeuchi K, Chu J, Wakabayashi T. Fully endoscopic combined transsphenoidal and supraorbital keyhole approach for parasellar lesions. J Neurosurg. 2018; 128(3):685–694 [44] Turel MK, Tsermoulas G, Gonen L, et al. Management and outcome of recurrent adult craniopharyngiomas: an analysis of 42 cases with long-term follow-up. Neurosurg Focus. 2016; 41(6):E11 [45] Strickland BA, Lucas J, Harris B, et al. Identification and repair of intraoperative cerebrospinal fluid leaks in endonasal transsphenoidal pituitary surgery: surgical experience in a series of 1002 patients. J Neurosurg. 2018; 129:425–429

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[46] Hadad G, Bassagasteguy L, Carrau RL, et al. A novel reconstructive technique after endoscopic expanded endonasal approaches: vascular pedicle nasoseptal flap. Laryngoscope. 2006; 116(10):1882–1886 [47] Jeswani S, Nuño M, Wu A, et al. Comparative analysis of outcomes following craniotomy and expanded endoscopic endonasal transsphenoidal resection of craniopharyngioma and related tumors: a single-institution study. J Neurosurg. 2016; 124(3):627–638 [48] Moussazadeh N, Prabhu V, Bander ED, et al. Endoscopic endonasal versus open transcranial resection of craniopharyngiomas: a case-matched singleinstitution analysis. Neurosurg Focus. 2016; 41(6):E7 [49] Wannemuehler TJ, Rubel KE, Hendricks BK, et al. Outcomes in transcranial microsurgery versus extended endoscopic endonasal approach for primary resection of adult craniopharyngiomas. Neurosurg Focus. 2016; 41(6):E6 [50] Park HR, Kshettry VR, Farrell CJ, et al. Clinical outcome after extended endoscopic endonasal resection of craniopharyngiomas: two-institution experience. World Neurosurg. 2017; 103:465–474 [51] Shi X, Zhou Z, Wu B, et al. Outcome of radical surgical resection for craniopharyngioma with hypothalamic preservation: a single-center retrospective study of 1054 patients. World Neurosurg. 2017; 102:167–180 [52] Patel VS, Thamboo A, Quon J, et al. Outcomes after endoscopic endonasal resection of craniopharyngiomas in the pediatric population. World Neurosurg. 2017; 108:6–14 [53] Lauretti L, Legninda Sop FY, Pallini R, Fernandez E, D’Alessandris QG. Neuroendoscopic Treatment of Cystic Craniopharyngiomas: A Case Series with Systematic Review of the Literature. World Neurosurg. 2018; 110:e367–e373 [54] Alalade AF, Ogando-Rivas E, Boatey J, et al. Suprasellar and recurrent pediatric craniopharyngiomas: expanding indications for the extended endoscopic transsphenoidal approach. J Neurosurg Pediatr. 2018; 21(1):72–80

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The Molecular Pathogenesis of Craniopharyngioma and Potential Therapeutic Targets

20 The Molecular Pathogenesis of Craniopharyngioma and Potential Therapeutic Targets Douglas A. Hardesty Abstract Extensive research has now elucidated the molecular underpinnings of both adamantinomatous craniopharyngioma (aCp) and papillary craniopharyngioma (pCp) at the DNA level. As with most benign tumors, single-gene mutations drive these lesions’ pathogenesis; despite similar clinical behaviors and gross appearances during surgery, aCp and pCp have mutually exclusive molecular origins. With aCp, aberrant signaling is found in the beta-catenin pathway, while with pCp, the driving mutation occurs in the BRAF pathway. These identified mutations have opened the possibility of targeted therapy for craniopharyngioma for the first time. The previous commercial development of BRAF inhibitors for metastatic melanoma has led to successful off-label use of these drugs according to reports on patients undergoing salvage therapy for otherwise refractory pCp, and a formal clinical trial is in progress. For aCp patients, molecular therapeutics are not yet commercially available, but they may emerge in coming years. These advances will doubtlessly alter the current paradigm regarding the extent of resection and the role of radiation, once targeted chemotherapeutic agents for these tumors have been proven effective. Keywords: beta-catenin, BRAF, chemotherapy, craniopharyngioma, molecular biology, papillary, pathogenesis, targeted therapy

20.1 Introduction Craniopharyngioma represents a histologically benign tumor with clinically malignant consequences due to its proximity to the optic apparatus and hypothalamus. These tumors tend to adhere to adjacent normal structures and often recur or progress at late follow-up, especially after subtotal resection. The current

treatment paradigm for craniopharyngioma, as discussed by other authors in the chapters of this section, includes maximal safe open microsurgical or endonasal resection and, at times, external beam radiation. Most surgeons who deal with these formidable lesions would agree that additional, improved therapies would be a boon to patients and their physicians alike. Craniopharyngioma is divided histologically into adamantinomatous (aCp) and papillary (pCp) subtypes; both represent World Health Organization Grade I benign tumors. The pCp is found almost exclusively in adults, whereas the aCp is found in a bimodal distribution among children and middle-age adults. At any patient age, aCp is statistically more common than pCp. Many surgical series combine the two histologic diagnoses, as the two tumor subtypes behave in a similar clinical fashion with respect to surgical approaches, morbidity, and recurrence rate.1,2,3 Despite these clinical similarities, molecular studies over the last decade have shown that the histologic subtypes of aCp and pCp demonstrate nonoverlapping and unique genetic mutations. The increased understanding of craniopharyngioma biology, especially pCp biology, has fostered reports of targeted molecular therapy for lesions recalcitrant to traditional therapeutic modalities. In the remainder of this chapter, we review the published literature exploring the molecular biology of craniopharyngiomas and summarize clinical reports to date that have shown promise in the targeted therapy of these difficultto-treat lesions.

20.2 Key Studies and Quality of Evidence To date, no randomized clinical trials have used molecular targeting in craniopharyngioma. The clinical studies reviewed herein (▶ Table 20.1)4,5,6,7,8 wholly constitute level IV evidence,

Table 20.1 Summary of available evidence and key studies for molecular therapy in craniopharyngioma Author (year)

Type of study

Level of evidence

Number of tumors/ patients

Key findings

Sekine et al (2002)4

Translational science

N/A

16 tumors

Beta-catenin (CTNNB1) mutations found in aCp, not in pCp

Brastianos et al (2014)5

Translational science

N/A

92 tumors

Whole-exome sequencing confirms beta-catenin (CTNNB1) mutations in aCp; BRAF mutations implicated for first time in pCp

Brastianos et al (2016)6

Case report

IV

1 patient

First-in-human use of BRAF and MEK inhibitors (dabrafenib and trametinib, respectively) for progressive pCp; good clinical response

Aylwin et al (2016)7

Case report

IV

1 patient

Single-agent BRAF inhibitor (vemurafenib) for pCp; patient responded well but eventually suffered disease progression

Roque and Odia (2017)8

Case report

IV

1 patient

BRAF and MEK inhibitors (dabrafenib and trametinib, respectively) used for progressive pCp; good clinical response

Abbreviations: aCp, adamantinomatous craniopharyngioma; BRAF, B-Raf protooncogene, serine/threonine kinase; MEK, mitogen-activated protein; N/A, not applicable; pCp, papillary craniopharyngioma.

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Craniopharyngioma and conclusions therefore must be made cautiously. However, the translational studies that underpin our molecular knowledge of craniopharyngiomas are of relatively high quality, despite being uncategorized under guidelines for level of evidence.

20.2.1 Driving Gene Mutations and Molecular Pathogenesis in Craniopharyngioma The first formal report of beta-catenin gene mutations (CTNNB1) in aCp was published in the early 2000s using a small set of 10 aCp and 6 pCp specimens.4 These authors already recognized that aCp and pCp appeared genetically different, as none of their analyzed pCp specimens harbored any CTNNB1 mutations, but all 10 aCp did harbor CTNNB1 mutations. Furthermore, localization of expressed beta-catenin was abnormal in aCp with significant nuclear accumulations. Additional studies by Kato et al9 and Buslei et al10 reinforced the concepts of CTNNB1 mutations in aCp, but not pCp, and the abnormal nuclear localization of the protein end-product beta-catenin. Furthermore, nuclear expression of beta-catenin was found to drive target gene overactivation and cellular behavior, such as abnormal cell migration in aCp.11,12 Therefore, in the 2000s, the molecular underpinnings of aCp as a disease of abnormal betacatenin expression, localization, and downstream function were elucidated via the work of these small but important clinical reports. However, little to no understanding of the molecular pathogenesis of pCp had yet been revealed. The landmark translational science publication that built upon these early reports and cemented the molecular divergence between aCp and pCp was that of Brastianos et al5 in 2014. This impactful work was the result of a multicenter collaboration among high-volume tertiary neurosurgical centers in the United States and Egypt. Whole-exome genomic sequencing of aCp and pCp revealed CTNNB1 mutations in nearly all aCp samples; for the first time, pathogenic mutations in BRAF were reported in almost all pCp samples. Mutual exclusivity between CTNNB1 and BRAF mutations in the study of Brastianos et al5 suggested that immunohistochemistry alone could be used to distinguish the two subtypes of craniopharyngioma.13 One subsequent study did reveal rare BRAF mutations coinciding in CTNNB1-mutated aCp, although no CTNNB1 mutations were found in pCp.14 Other groups13,15 have reported complete mutual exclusivity of these mutations, which is concordant with the study of Brastianos et al.5 These single-gene mutations appeared to be the driving force behind tumor pathogenesis, and widespread genetic mutations such as those seen in high-grade neoplasms were not reported. The lack of large-scale chromosomal abnormalities in craniopharyngiomas is similar to other low-grade and pediatric neoplasms as well as prior reports in aCp.16 An exciting concept derived from these data was (off-label) targeted drug therapy against pCp, as BRAF inhibitors were already commercially available for the treatment of BRAF-mutated metastatic melanoma. The later clinical use of these inhibitors for pCp is discussed separately later. Studies completed since the postgenomic discovery era of craniopharyngioma have further elucidated the molecular underpinnings of aCp and pCp beyond simple CTNNB1 and BRAF mutations. For example, the canonical cancer pathway

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MAPK and downstream Sox2 + stem cells have been implicated in the proliferation of pCp as a consequence of abnormal BRAF signaling.17 Beyond DNA-level mutations, aCp and pCp have distinct DNA methylation patterns that correlate perfectly with the traditional histology-based subtypes.15 The RNA transcriptome of aCp has been partially analyzed via microarray gene expression analysis in 15 pediatric patients, and numerous overexpressed molecular pathways with existing smallmolecule or antibody-based inhibitors were identified as future chemotherapeutic targets.18

20.2.2 Early Reports of Targeted Molecular Therapies in Papillary Craniopharyngioma Commercial BRAF inhibitors were already in clinical use at the time of the discovery that aberrant BRAF signaling mediated pCp. Although the standard of care remained surgical resection and/or radiotherapy for patients with these lesions, the use of these inhibitors for salvage therapy in refractory cases of pCp was of immediate interest. To date, no clinical trials or even case series exist for targeted molecular therapy for pCp; the three reports published consist only of single patients at three different centers across the world.6,7,8 Therefore, any conclusions as to safety and efficacy remain tentative until a greater level of evidence is presented. Nevertheless, dramatic responses to BRAF inhibitors in patients with otherwise recalcitrant pCp demonstrate significant promise for a targeted, molecular therapy approach. The same group in the United States that published the original pCp exome-sequencing study reported a single pCp patient harboring the BRAF V600E mutation treated with targeted therapy for the first time in humans.6 This patient had undergone multiple surgeries in a short time period for an unusually clinically aggressive pCp and was subsequently started on the BRAF inhibitor dabrafenib, to which the MEK-pathway inhibitor trametinib (shown to be synergistic in BRAF-mutated melanoma) was also added after a short period. The patient had an immediate and dramatic imaging response (▶ Fig. 20.1) with significant tumor regression and underwent successful subsequent resection and adjuvant radiotherapy 1 month after chemotherapy initiation.6 No recurrence has been reported to date with a published follow-up of 18 months.19 This group has gone on to organize a larger clinical trial (NCT03224767, ClinicalTrials.gov) using combination BRAF–MEK inhibitor therapy, and the trial is currently accruing patients. A group based in England reported the use of a single-agent BRAF inhibitor, vemurafenib, for a patient with similar clinically aggressive pCp.7 After 3 months of therapy, the patient’s vision improved and the recurrent tumor shrank so dramatically as to cause a cerebrospinal fluid leak through a sellar skull base defect and subsequent meningitis. The tumor went on to recur/ progress within the first year despite additional surgery. The number of patients reported is clearly insufficient to make any definitive conclusions, but this may demonstrate that dualagent use of a BRAF inhibitor with a MEK inhibitor, as used by Brastianos et al,6 is more effective than single-agent therapy. Finally, the third patient to date treated with targeted therapy was reported by an American group also using combination

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The Molecular Pathogenesis of Craniopharyngioma and Potential Therapeutic Targets

Fig. 20.1 Postgadolinium MRIs from a 39-year-old man with recurrent BRAF V600E-mutated papillary craniopharyngioma treated at Massachusetts General Hospital. (a) After multiple prior resections over a short period of time, MRI shows recurrence/progression of solid enhancing tumor, and the patient initiated targeted chemotherapy (day 0 of molecular therapy). (b) After use of the oral BRAF inhibitor dabrafenib alone for 17 days, a 52% reduction in enhancing tumor volume is shown. (c) After an additional 14 days of dabrafenib with the addition of MEK inhibitor (trametinib) treatment, MRI at 34 days after initiation of molecular therapy shows a final volumetric reduction in the enhancing mass of 85%. The patient went on to have surgical resection redone and to eventual radiation therapy, with no recurrent disease after 18 months of published follow-up. (Reproduced with permission from Brastianos PK, Shankar GM, Gill CM, et al. Dramatic response of BRAF V600E mutant papillary craniopharyngioma to targeted therapy. JNCI Natl Cancer Inst 2016;108(2):3, by permission of Oxford University Press.)

BRAF–MEK inhibition with dabrafenib and trametinib.8 The patient, also with refractory and progressive pCp, had an excellent clinical and radiographic (magnetic resonance imaging and positron emission tomography) response with minimal toxicity and was stable at 6 months after targeted-agent treatment.

20.2.3 Lack of Available Targeted Agents Limits Progress in Adamantinomatous Craniopharyngioma The excitement and progress of targeted therapy for pCp has unfortunately not been replicated in the most common aCp. Unlike BRAF inhibitors for pCp, no commercially available inhibitor of abnormal beta-catenin signaling for aCp exists to date.20 Normal cell signaling through the Wnt/beta-catenin pathway is essential for life, and indiscriminate targeting of this pathway has not always been successful in preclinical models of multiple cancers.21,22,23,24 Nevertheless, targets downstream of beta-catenin signaling are in development and may eventually show efficacy in aCp; however, these agents likely will have to come to market for more common and better-funded cancer types and be borrowed for off-label use in aCp.22,25

20.3 Conclusions The last two decades have witnessed extensive and muchneeded progress in the understanding of craniopharyngioma molecular pathogenesis. Multiple high-quality studies have demonstrated that the driving mutation behind aCp lies within CTNNB1, the beta-catenin pathway; the less common pCp is driven by BRAF mutations. Targeted therapy for pCp using BRAF inhibitors with or without the addition of a MEK inhibitor is now in its infancy, with several successful case reports and a clinical trial ongoing. With time and better understanding of

downstream pathways, we hope that aCp also can be treated with targeted therapy.

20.4 Future Studies Continued basic science and translational science work will better elucidate the downstream effectors that are unleashed by beta-catenin and BRAF mutations in craniopharyngioma and explain the heterogeneity among these tumors within an individual histologic subset. Larger clinical series will prove or dismiss the utility of BRAF/MEK inhibitors in pCp treatment in the coming years. Eventually, targeted therapy for aCp may become a reality, but effective and safe therapeutics are not yet available and remain in early clinical trials at best.

References [1] Koutourousiou M, Gardner PA, Fernandez-Miranda JC, Tyler-Kabara EC, Wang EW, Snyderman CH. Endoscopic endonasal surgery for craniopharyngiomas: surgical outcome in 64 patients. J Neurosurg. 2013; 119(5):1194–1207 [2] Cavallo LM, Frank G, Cappabianca P, et al. The endoscopic endonasal approach for the management of craniopharyngiomas: a series of 103 patients. J Neurosurg. 2014; 121(1):100–113 [3] Omay SB, Chen YN, Almeida JP, et al. Do craniopharyngioma molecular signatures correlate with clinical characteristics? J Neurosurg. 2018; 128(5):1473– 1478 [4] Sekine S, Shibata T, Kokubu A, et al. Craniopharyngiomas of adamantinomatous type harbor beta-catenin gene mutations. Am J Pathol. 2002; 161(6): 1997–2001 [5] Brastianos PK, Taylor-Weiner A, Manley PE, et al. Exome sequencing identifies BRAF mutations in papillary craniopharyngiomas. Nat Genet. 2014; 46(2): 161–165 [6] Brastianos PK, Shankar GM, Gill CM, et al. Dramatic response of BRAF V600E mutant papillary craniopharyngioma to targeted therapy. J Natl Cancer Inst. 2015; 108(2) [7] Aylwin SJ, Bodi I, Beaney R. Pronounced response of papillary craniopharyngioma to treatment with vemurafenib, a BRAF inhibitor. Pituitary. 2016; 19(5): 544–546

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Craniopharyngioma [8] Roque A, Odia Y. BRAF-V600E mutant papillary craniopharyngioma dramatically responds to combination BRAF and MEK inhibitors. CNS Oncol. 2017; 6 (2):95–99 [9] Kato K, Nakatani Y, Kanno H, et al. Possible linkage between specific histological structures and aberrant reactivation of the Wnt pathway in adamantinomatous craniopharyngioma. J Pathol. 2004; 203(3):814–821 [10] Buslei R, Nolde M, Hofmann B, et al. Common mutations of beta-catenin in adamantinomatous craniopharyngiomas but not in other tumours originating from the sellar region. Acta Neuropathol. 2005; 109(6):589–597 [11] Hölsken A, Buchfelder M, Fahlbusch R, Blümcke I, Buslei R. Tumour cell migration in adamantinomatous craniopharyngiomas is promoted by activated Wnt-signalling. Acta Neuropathol. 2010; 119(5):631–639 [12] Hölsken A, Kreutzer J, Hofmann BM, et al. Target gene activation of the Wnt signaling pathway in nuclear beta-catenin accumulating cells of adamantinomatous craniopharyngiomas. Brain Pathol. 2009; 19(3):357–364 [13] Yoshimoto K, Hatae R, Suzuki SO, et al. High-resolution melting and immunohistochemical analysis efficiently detects mutually exclusive genetic alterations of adamantinomatous and papillary craniopharyngiomas. Neuropathology. 2017(Aug):25 [14] Larkin SJ, Preda V, Karavitaki N, Grossman A, Ansorge O. BRAF V600E mutations are characteristic for papillary craniopharyngioma and may coexist with CTNNB1-mutated adamantinomatous craniopharyngioma. Acta Neuropathol. 2014; 127(6):927–929 [15] Hölsken A, Sill M, Merkle J, et al. Adamantinomatous and papillary craniopharyngiomas are characterized by distinct epigenomic as well as mutational and transcriptomic profiles. Acta Neuropathol Commun. 2016; 4:20

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[16] Yoshimoto M, de Toledo SR, da Silva NS, et al. Comparative genomic hybridization analysis of pediatric adamantinomatous craniopharyngiomas and a review of the literature. J Neurosurg. 2004; 101(1) Suppl:85–90 [17] Haston S, Pozzi S, Carreno G, et al. MAPK pathway control of stem cell proliferation and differentiation in the embryonic pituitary provides insights into the pathogenesis of papillary craniopharyngioma. Development. 2017; 144 (12):2141–2152 [18] Gump JM, Donson AM, Birks DK, et al. Identification of targets for rational pharmacological therapy in childhood craniopharyngioma. Acta Neuropathol Commun. 2015; 3:30 [19] Martinez-Gutierrez JC, D’Andrea MR, Cahill DP, Santagata S, Barker FG, II, Brastianos PK. Diagnosis and management of craniopharyngiomas in the era of genomics and targeted therapy. Neurosurg Focus. 2016; 41(6):E2 [20] Zhang X, Hao J. Development of anticancer agents targeting the Wnt/β-catenin signaling. Am J Cancer Res. 2015; 5(8):2344–2360 [21] Tai D, Wells K, Arcaroli J, et al. Targeting the WNT signaling pathway in cancer therapeutics. Oncologist. 2015; 20(10):1189–1198 [22] Zhan T, Rindtorff N, Boutros M. Wnt signaling in cancer. Oncogene. 2017; 36 (11):1461–1473 [23] Kahn M. Can we safely target the WNT pathway? Nat Rev Drug Discov. 2014; 13(7):513–532 [24] Kim YM, Kahn M. The role of the Wnt signaling pathway in cancer stem cells: prospects for drug development. Res Rep Biochem. 2014; 4:1–12 [25] Apps JR, Martinez-Barbera JP. Molecular pathology of adamantinomatous craniopharyngioma: review and opportunities for practice. Neurosurg Focus. 2016; 41(6):E4

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Part V

21 Resection versus Cyst Fenestration: The Best Treatment for Rathke Cleft Cysts

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Rathke Cleft Cyst and Other Sellar Lesions

22 Headache in Patients with Rathke Cleft Cysts

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23 Rathke Cleft Cyst Surgery: Indications, Outcomes, and Complications

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24 Controversies in the Management of Histiocytosis and Xanthogranulomas

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Rathke Cleft Cyst and Other Sellar Lesions

21 Resection versus Cyst Fenestration: The Best Treatment for Rathke Cleft Cysts Michelle Lin and Gabriel Zada Abstract Rathke cleft cysts (RCCs) are benign epithelial lesions arising in the sellar space. These cysts frequently present with headaches, visual field deficits, and endocrinopathies. For patients presenting with symptomatic RCCs, surgical decompression can alleviate headaches and visual field deficits. Although there is consensus that surgery is the mainstay of therapy for symptomatic patients, goals of initial operative intervention remain somewhat varied and controversial. Despite the benign nature of RCCs, there is an appreciable rate of recurrence following surgical fenestration and drainage. Cyst adherence to the pituitary gland may place patients at risk for postoperative endocrinopathies when complete capsular wall resection is attempted. Therefore, operative goals must balance the risk of recurrence with minimizing development of iatrogenic endocrinopathies or other surgical complications including cerebrospinal fluid leakage. There is question as to whether a more extensive degree of RCC wall resection minimizes recurrence. Certain institutions have observed a decrease in recurrence rates following gross total resections in comparison to decompression with either subtotal resections or cyst fenestration and drainage. Other authors report no difference in recurrence rates following more aggressive resections. Despite some ongoing debate, robust evidence exists showing that gross total RCC resection leads to a significantly higher rate of postoperative endocrinopathies, particularly permanent diabetes insipidus. In pediatric patients or those presenting without preoperative endocrinopathies, the unacceptable risk of postoperative endocrinopathy may prompt surgeons to opt for fenestration alone, especially for first-time operations. Regardless of the extent of resection, all patients should be judiciously monitored for postoperative endocrinopathy and delayed cyst regrowth. Keywords: Rathke cleft cysts, surgical management, operative goals, cyst fenestration, headache

21.1 Introduction Rathke cleft cysts (RCCs) are benign epithelial cysts arising most commonly from the pars intermedia. Histopathology exhibiting ciliated cuboidal epithelium demonstrates these lesions’ likely ectodermal origin; RCCs are thought to arise from remnants of Rathke pouch—an intersection between the embryological oropharynx and diencephalon.1 On imaging, RCCs are often nonenhancing, homogeneous expansions of the sellar and/or suprasellar space without cavernous sinus invasion (▶ Fig. 21.1). Given a prevalence of 11.3% on autopsy,2 these lesions are commonly found incidentally. However, patients harboring these lesions may present with headaches, visual field deficits secondary to mass effect on the optic apparatus, and endocrinopathies.

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The first-line therapy for symptomatic patients is minimally invasive surgical decompression. One of the primary controversies regarding management of RCCs is the optimal extent of resection of the cyst wall. Although RCCs are benign epithelial growths, a substantive proportion have been known to recur, with authors reporting recurrence rates as high as 31%, often depending substantially on the follow-up time.3,4,5,6,7,8 An increased rate of RCC recurrence has been associated with selected subtypes characterized by squamous metaplasia in the cyst wall on histopathological analysis.3 There exists some discussion as to what operative goals and strategies should be employed in efforts to achieve a durable effect on symptoms and minimize the risk of recurrence. While some physicians advocate for gross total resections (GTRs), others espouse a more conservative philosophy of cyst fenestration/marsupialization and drainage with or without maximal safe cyst wall resection. In this chapter, we will review the current discussion surrounding operative goals in surgical management of RCCs, with an emphasis on aggressive resection versus fenestration and drainage.

21.2 Review of Key Studies 21.2.1 Key Studies and Quality of Evidence As previously mentioned, RCCs have an appreciable risk of recurrence following surgical intervention. Due to this risk of recurrence, most surgeons previously attempted complete capsular wall resections under the assumption that cyst wall removal would minimize fluid production and accumulation,9 decreasing the likelihood of recurrence. There is now literature suggesting that an increased extent of resection offers no appreciable benefit in decreasing the rate of recurrence.3,10,11,12 In one of the largest surgical series evaluating RCCs to date, Aho et al reported no difference in rates of recurrence between patients undergoing GTRs compared to those who received decompression alone.3 Likewise, Higgins et al and Wait et al found no differences in rates of recurrence following capsular wall resection compared with cyst fenestration.10,12 There is evidence, however, that calls these findings into question. Kim et al found an increased rate of recurrence in patients who underwent fenestration and drainage alone (p = 0.012).9 Similarly, in a series of 62 patients, Benveniste et al found an increased rate of RCC recurrence in patients who received decompression (18.5%) compared to those who underwent capsular wall resections (0%), although not to a statistically significant extent (p = 0.317).5 Laws and Kanter also advocated for attempts at capsular cyst wall resection whenever possible, in light of a twofold decrease in recurrence rates observed in patients who received radical cyst wall removals at their institution.13

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Resection versus Cyst Fenestration: The Best Treatment for Rathke Cleft Cysts Fig. 21.1 Sellar images in a patient presenting with a Rathke cleft cyst symptomatic for headaches and galactorrhea. (a) Sagittal and (b) coronal postcontrast T1-weighted thin-cut MRI. Imaging demonstrates a 10 × 9 mm cystic structure with suprasellar extension and compression of the optic apparatus. Resolution of the cyst as demonstrated on imaging 3 months status postfenestration and capsular wall biopsy. (c) Sagittal and (d) coronal postcontrast T1-weighted thin-cut MRI).

Despite a clear lack of consensus regarding the association between extent of resection and recurrence rate, there is robust literature demonstrating an increased rate of postoperative complications following more aggressive capsular wall resection.3,10,11,12,14 Moreover, institutions have reported an unacceptably high risk of postoperative endocrinopathy following attempts at GTR.5 Owing to the proximity of the capsular cyst wall to the posterior pituitary gland, rates of permanent postoperative diabetes insipidus (DI) following GTR have been reported in the literature to be as high as 50%.3,5,10 In 2005, Aho et al reported a 42% rate of permanent DI following aggressive resection. This rate decreased to 9% following a change in surgical goals that included stripping less of the cyst wall and arachnoid membrane.3 Despite this less aggressive approach, lack of cyst capsule on postoperative thin-cut (2–3 mm) MR images was nevertheless achieved in 97% of patients in this series. In another series of 61 cases, Higgins et al reported an increased rate of postoperative complications (p = 0.03), including DI, cerebrospinal fluid (CSF) leaks, worsened vision, and hemorrhage following GTR compared to decompression.10 In their series, decompression consisted of either subtotal cyst wall resections or cyst fenestration accompanied by capsular wall biopsy. Subsequently, multiple institutions have since adopted a more conservative philosophy, with surgeons primarily performing cyst fenestrations accompanied by capsular wall biopsies or subtotal resections.4,15,16,17,18,19,20,21 Of these aforementioned series, Fukui et al recently reported a 0% recurrence rate over a follow-up time ranging from 5 to 87 months after fenestration alone, suggesting that extent of resection may not be related to risk of recurrence.4

Given the lack of conclusive evidence that more aggressive procedures reduce RCC recurrence rates, and given the clear evidence of increased rates of postoperative endocrinopathies in patients undergoing more aggressive procedures, cyst fenestration appears to be a preferred and recommended first-line operative goal. Given that symptomatic RCC recurrences necessitating reoperation are not without risk, some surgeons have proposed alternative techniques to minimize the risk of recurrence when performing cyst fenestrations alone. Some authors have advocated for marsupialization of RCCs into the subarachnoid space.22,23 However, this technique necessitates violation of the arachnoid space and is therefore not routinely recommended given the risk of CSF fistula development. Other surgeons have attempted instillation of alcohol into the cyst bed3,24 as a means of chemically cauterizing cuboidal and goblet cells in the cyst wall. Although this practice continues to be performed at some institutions on the basis of anecdotal evidence, the efficacy of alcohol instillation in minimizing recurrence remains unsubstantiated.5,11,12,25 It has been reported that usage of autologous fat grafts and packing of the sella for CSF leak repair are also associated with an increased rate of cyst recurrence (p < 0.001).3 Therefore, in 2010, Wait et al reported an institutional preference to minimize aggressive resections in order to avoid CSF leak development, thereby allowing the surgeons to forego packing of the sellar floor for continuous drainage into the sphenoid sinus.12 Regardless of surgical technique, diligent long-term follow-up with serial magnetic resonance imaging (MRI) is recommended for all patients to ensure early detection of recurrences (▶ Table 21.1).5,9,11,24,26

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Rathke Cleft Cyst and Other Sellar Lesions

Table 21.1 Key studies addressing optimal extent of resection in RCC Fat and fascial packingc

Complication rated

N/A

Yes (p < 0.001)

Yes

No (p = 1.000)

No (p = 0.608)

Yes (p = 0.033)

N/A

N/A

Yes (p = 0.03)

Level of evidence

Study

Number of patients

Gross total vs. decompressiona

Alcohol instillationb

III

Aho et al (2005)3

118

No (p = 0.473)

III

Benveniste et al (2004)5

62

Yes (p = 0.317)

III

Higgins et al (2011)10

61

No (p = 0.36)

III

Kim et al (2004)9

53

Yes (p = 0.012)

N/A

N/A

N/A

IV

Lillehei et al (2011)11

82

N/A

No (p = 0.2)

N/A

N/A

III

Wait et al (2010)12

73

No (p = 1.000)

N/A

N/A

No (p = 1.000)

V

Laws and Kanter (2004)13

N/A

Yes

N/A

N/A

Yes

aDifference

in recurrence rate between gross total resection and decompression found. in recurrence rate following alcohol instillation in the cyst bed found. cDifference in recurrence rate following fat or fascial packing. dDifference in postoperative complication rate found between gross total resection and subtotal resection or decompression. bDifference

21.2.2 Author and Institutional Biases At our home institution, the University of Southern California, all patients presenting for initial surgery undergo cyst fenestration with capsular wall biopsy and subtotal resection of the anterior wall, when possible. Children’s Hospital Los Angeles (CHLA) has adopted the same conservative surgical philosophy for pediatric patients, a population in whom the clinical sequelae of iatrogenic endocrinopathy poses far too high of a risk to outweigh the possible benefits21 of a radical cyst resection. This strategy is in contrast to the University of Virginia Health Science Center, where radical removals have been historically performed if the operating surgeon feels this can be accomplished without inflicting damage to the surrounding structures.13 Comparably, Barrow Neurological Institute does not attempt aggressive resections if intraoperatively the capsular wall is noted to be adherent to either the surrounding pituitary gland or stalk.12 Furthermore, in cases where no CSF leak is observed, the sellar floor is not packed, to allow for continuous drainage into the sphenoid sinus. At our institution, more aggressive and complete RCC wall resection is reserved for recurrent RCCs and are often treated with extended endoscopic approaches and complex reconstruction of the skull base, often including a pedicled nasoseptal flap and autologous grafting using fascia lata and/or fat.

21.3 Case Examples A 33-year-old man initially presented to our hospital with symptoms of hypogonadism and fatigue secondary to an RCC. The patient underwent successful transsphenoidal cyst fenestration with improvement of symptoms. He has since been followed up with clinic visits and thin-section MRIs for 15 years. Despite recurrence of the cyst on MRI (▶ Fig. 21.2a–d), the patient has remained asymptomatic and has not required additional surgery given the stable and asymptomatic nature of the cyst. Therefore, it is crucial to recognize that recurrence does not necessarily translate to the requirement for reoperation. In contrast, a 54-year-old woman presented to our institution 1 year status post cyst fenestration at an outside hospital for a suprasellar RCC causing progressive visual field deficits (▶ Fig. 21.3a, b). She was subsequently treated at our center via an endoscopic extended transtuberculum approach; however,

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this was limited by significant postoperative adhesions from the patient’s initial operation. The cyst was therefore subsequently approached using a right supraorbital/subfrontal craniotomy to allow for successful and safe fenestration (▶ Fig. 21.3c, d). The patient was diligently followed up clinically and radiologically. Unfortunately, the patient developed progressive worsening of visual acuity and was found to have multiple recurrent RCC 3 years after the aforementioned procedure at our institution. In light of the atypically aggressive and recurrent nature of this RCC, a right frontal supraorbital craniotomy for subtotal resection was again performed. The patient continues to be followed up and has experienced no further recurrences to date with stabilization of her symptoms. Therefore, despite our institutions’ bias toward cyst fenestration, in patients with complex, multiple recurrent, atypically aggressive RCCs, surgeons should consider attempting subtotal or gross total cyst resections when possible to minimize the need for reoperation in such patients.

21.4 Conclusions There are different viewpoints as to the contribution of extent of resection in risk of RCC recurrence. For most patients presenting for initial operation, cyst fenestration with capsular wall biopsy or subtotal resection is sufficient and provides durable improvement. A conservative surgical goal appreciably decreases the risks of postoperative endocrinopathy (e.g., DI) and surgical complications including CSF leak. In patients who experience symptomatic recurrence, additional operations confer notable summative risks. However, the morbidity of recurrences can be mitigated with judicious radiological and clinical follow-up which should be employed in all patients regardless of surgical procedure of choice.

21.5 Suggestions for Future Studies Considerable advancements in our understanding of surgical management in RCCs have occurred in recent decades. However, because definitions of recurrence are not standardized, and follow-up times have been inconsistent across studies, good data on long-term follow-up of these lesions remains

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Resection versus Cyst Fenestration: The Best Treatment for Rathke Cleft Cysts

Fig. 21.2 MRI in a patient 14 years following initial surgery for a Rathke cleft cyst demonstrates asymptomatic radiologic recurrence. A 13 × 10 × 13 cm cystic reaccumulation with sellar expansion is appreciated. (a) Sagittal and (b) coronal postcontrast T1-weighted thin-cut MRI. No optic chiasm compression is evident, and the patient remained clinically intact. Follow-up imaging 1 year later. (c) Sagittal and (d) coronal postcontrast T1-weighted thin-cut MRI confirms the stable nature of disease with no change in cyst appearance or size.

Fig. 21.3 A patient presented with a recurrent Rathke cleft cyst previously treated at another institution. A complex cyst measuring 15 × 10 × 13 mm with suprasellar extension and peripheral enhancement was seen. (a) Sagittal and (b) coronal postcontrast T1-weighted thincut MRI. Residual cyst capsule was visualized 6 months after a supraorbital resection, limited by significant intraoperative adhesions. (c) Sagittal and (d) coronal postcontrast T1-weighted thincut MRI.

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Rathke Cleft Cyst and Other Sellar Lesions limited. The efficacy of alcohol cauterization remains insufficiently studied. Likewise, the benefits of continuous drainage into the sphenoid sinus have not been fully explored or understood. Future studies aimed at examining some of the proposed surgical maneuvers and their respective impacts on recurrence would further advance our understanding and would likely contribute to better patient outcomes.

References [1] Harrison MJ, Morgello S, Post KD. Epithelial cystic lesions of the sellar and parasellar region: a continuum of ectodermal derivatives? J Neurosurg. 1994; 80(6):1018–1025 [2] Teramoto A, Hirakawa K, Sanno N, Osamura Y. Incidental pituitary lesions in 1,000 unselected autopsy specimens. Radiology. 1994; 193(1):161–164 [3] Aho CJ, Liu C, Zelman V, Couldwell WT, Weiss MH. Surgical outcomes in 118 patients with Rathke cleft cysts. J Neurosurg. 2005; 102(2):189–193 [4] Fukui I, Hayashi Y, Kita D, et al. Significant improvement in chronic persistent headaches caused by small Rathke cleft cysts after transsphenoidal surgery. World Neurosurg. 2017; 99:362–368 [5] Benveniste RJ, King WA, Walsh J, Lee JS, Naidich TP, Post KD. Surgery for Rathke cleft cysts: technical considerations and outcomes. J Neurosurg. 2004; 101(4):577–584 [6] el-Mahdy W, Powell M. Transsphenoidal management of 28 symptomatic Rathke cleft cysts, with special reference to visual and hormonal recovery. Neurosurgery. 1998; 42(1):7–16, discussion 16–17 [7] Kasperbauer JL, Orvidas LJ, Atkinson JL, Abboud CF. Rathke cleft cyst: diagnostic and therapeutic considerations. Laryngoscope. 2002; 112(10):1836–1839 [8] Fager CA, Carter H. Intrasellar epithelial cysts. J Neurosurg. 1966; 24(1):77– 81 [9] Kim JE, Kim JH, Kim OL, et al. Surgical treatment of symptomatic Rathke cleft cysts: clinical features and results with special attention to recurrence. J Neurosurg. 2004; 100(1):33–40 [10] Higgins DM, Van Gompel JJ, Nippoldt TB, Meyer FB. Symptomatic Rathke cleft cysts: extent of resection and surgical complications. Neurosurg Focus. 2011; 31(1):E2 [11] Lillehei KO, Widdel L, Astete CA, Wierman ME, Kleinschmidt-DeMasters BK, Kerr JM. Transsphenoidal resection of 82 Rathke cleft cysts: limited value of alcohol cauterization in reducing recurrence rates. J Neurosurg. 2011; 114(2): 310–317

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[12] Wait SD, Garrett MP, Little AS, Killory BD, White WL. Endocrinopathy, vision, headache, and recurrence after transsphenoidal surgery for Rathke cleft cysts. Neurosurgery. 2010; 67(3):837–843, discussion 843 [13] Laws ER, Kanter AS. Rathke cleft cysts. J Neurosurg. 2004; 101(4):571–572, discussion 572 [14] Mendelson ZS, Husain Q, Elmoursi S, Svider PF, Eloy JA, Liu JK. Rathke cleft cyst recurrence after transsphenoidal surgery: a meta-analysis of 1151 cases. J Clin Neurosci. 2014; 21(3):378–385 [15] Oyama N, Tahara S, Oyama K, Ishii Y, Teramoto A. Assessment of pre- and postoperative endocrine function in 94 patients with Rathke cleft cyst. Endocr J. 2013; 60(2):207–213 [16] Mukherjee JJ, Islam N, Kaltsas G, et al. Clinical, radiological and pathological features of patients with Rathke cleft cysts: tumors that may recur. J Clin Endocrinol Metab. 1997; 82(7):2357–2362 [17] Madhok R, Prevedello DM, Gardner P, Carrau RL, Snyderman CH, Kassam AB. Endoscopic endonasal resection of Rathke cleft cysts: clinical outcomes and surgical nuances. J Neurosurg. 2010; 112(6):1333–1339 [18] Kim E. Symptomatic Rathke cleft cyst: clinical features and surgical outcomes. World Neurosurg. 2012; 78(5):527–534 [19] Ross DA, Norman D, Wilson CB. Radiologic characteristics and results of surgical management of Rathke cysts in 43 patients. Neurosurgery. 1992; 30(2): 173–178, discussion 178–179 [20] Xie T, Hu F, Yu Y, Gu Y, Wang X, Zhang X. Endoscopic endonasal resection of symptomatic Rathke cleft cysts. J Clin Neurosci. 2011; 18(6):760–762 [21] Zada G, Ditty B, McNatt SA, McComb JG, Krieger MD. Surgical treatment of Rathke cleft cysts in children. Neurosurgery. 2009; 64(6):1132–1137, author reply 1037–1038 [22] Frank G, Sciarretta V, Mazzatenta D, Farneti G, Modugno GC, Pasquini E. Transsphenoidal endoscopic approach in the treatment of Rathke cleft cyst. Neurosurgery. 2005; 56(1):124–128, discussion 129 [23] Marcincin RP, Gennarelli TA. Recurrence of symptomatic pituitary cysts following transsphenoidal drainage. Surg Neurol. 1982; 18(6):448–451 [24] Ogawa Y, Watanabe M, Tominaga T. Prognostic factors of operated Rathke cleft cysts with special reference to re-accumulation and recommended surgical strategy. Acta Neurochir (Wien). 2011; 153(12):2427–2433, discussion 2433 [25] Han SJ, Rolston JD, Jahangiri A, Aghi MK. Rathke cleft cysts: review of natural history and surgical outcomes. J Neurooncol. 2014; 117(2):197–203 [26] Shin JL, Asa SL, Woodhouse LJ, Smyth HS, Ezzat S. Cystic lesions of the pituitary: clinicopathological features distinguishing craniopharyngioma, Rathke cleft cyst, and arachnoid cyst. J Clin Endocrinol Metab. 1999; 84(11):3972– 3982

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Headache in Patients with Rathke Cleft Cysts

22 Headache in Patients with Rathke Cleft Cysts Justin L. Hoskin, Kevin C. J. Yuen, and Kerry L. Knievel Abstract This chapter on headache in patients with Rathke cleft cysts discusses the pathophysiology, clinical context, current treatment recommendations, and future considerations for health care professionals treating patients with Rathke cleft cysts. We describe the expected frequency, location, and severity of presenting headache symptoms in the context of cyst size, location, and imaging findings. We evaluate the current data on skull base surgery and postoperative resolution of headache and discuss the risk of recurrence after surgical intervention. We conclude with a discussion of the need for further randomized controlled trials and the future of treatment of patients who have headache due to Rathke cleft cysts.

a reasonable approach is often conservative management and watchful waiting, although few data are available regarding spontaneous involution of these cysts.5 One small study found that 100% of patients (n = 9) who were treated conservatively had spontaneous involution of the lesion over time.6 However, RCCs can persist in some patients, and some cysts can even enlarge to the extent that they cause severe, medically intractable headaches.11,12,13,14 Current areas of controversy include whether surgical intervention for RCCs is indicated if the only presenting feature is headache (▶ Table 22.1).1,2,4,6,7,8,9,15,16,17,18,19,20,21 Also debatable is whether headache is related to RCC size, type of contents in the RCC, location of the lesion, and appearance on MRI.

Keywords: headache, pituitary, Rathke cleft cyst, recurrence, treatment

22.2 Symptoms

22.1 Introduction Rathke cleft cysts (RCCs) are benign, epithelium-lined intrasellar cystic lesions that arise when the embryonic cleft of the Rathke pouch, a dorsal invagination of the stomodeal ectoderm, fails to regress.1,2 Other theories regarding the pathogenesis of RCCs suggest that the cells of origin are derived from neuroepithelium, endoderm, or metaplastic anterior pituitary cells.2 The epithelium that lines the cyst may include ciliated and goblet cells and thus may contain mucous material of varying viscosities. Regardless of their origin, RCCs are relatively common, affecting an estimated 2 to 26% of the general population.2,3,4 These cysts are often discovered incidentally in asymptomatic patients on magnetic resonance imaging (MRI) (▶ Fig. 22.1) or computed tomography or at autopsy.5,6,7,8 Typically, RCCs are clinically silent. RCCs have been reported to occur in symptomatic patients of all ages, with a mean age at presentation that ranges from 40 to 50 years and with a female preponderance.4,9 It has been estimated that only 5.4% of RCCs will increase in size, while the remainder remain unchanged or decrease in size over time.10 Thus, in the absence of symptoms,

Symptoms of an RCC most commonly include headache, endocrinopathies, and visual impairment.6,21 Unusual symptoms and findings include pituitary apoplexy, hypophysitis, aseptic meningitis, intracystic abscess, sphenoid sinusitis, and empty sella syndrome.3 By far the most common presenting symptom of patients with RCCs is headache, which affects an estimated 44 to 81% of patients.1,8,9,16,18,20,21,22 As many as 35 to 40% of patients with RCCs have headache as their only presenting symptom.9 However, the headache also can be associated with other clinical manifestations, including visual disturbances, hypopituitarism, hyperprolactinemia, and diabetes insipidus.9,18 Headache duration prior to patient presentation varies, and current data are limited. Benveniste et al16 found that the mean duration of headaches was 12.0 ± 25.2 months (range, 1 week to 12 years). In contrast, Fukui et al8 found that the mean period from onset of headaches to patient presentation with an RCC was much longer (41.8 months). Furthermore, the presentation of patients with headache may also vary, but it is typically described as bifrontal or frontotemporal, progressive, throbbing, and accompanied by retroorbital pain.8,23 Nishioka et al18 found that among 27 patients with headache, 85% had a nonpulsating headache. Several authors have attempted to determine whether the headaches are continuous and chronic or

Fig. 22.1 Contrasted sagittal (a) and coronal (b) magnetic resonance images of a patient with a Rathke cleft cyst (*). The pituitary gland in this case is displaced inferiorly. The cyst is touching the optic chiasm (arrow). (Used with permission from Barrow Neurological Institute, Phoenix, AZ.)

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Rathke Cleft Cyst and Other Sellar Lesions

Table 22.1 Summary of available evidence on headache before and after surgical resection of Rathke cleft cysts Author (year)

Type of study

Level of evidence

No. of patients

RCC size

Comments

Voelker et al (1991)2

Case series

IV

155 (137 [88%] treated surgically); 60 (39%) underwent craniotomy; 59 (38%) underwent transsphenoidal approach

–

72 (49%) presented with headache; postoperative information limited, although 15 patients had “resolved” headache, 2 patients had “improved” headache, and 0 patients reported “unchanged” or “worsened” headache

Shin et al (1999)15

Case series

IV

26

16.3 ± 1.2 mm

17 (65%) had headache preoperatively; 82% had headache resolution and 12% remained the same postoperatively

Benveniste et al (2004)16

Case series

IV

62 (56 [90%] had transsphenoidal cyst decompression and biopsy; 6 [10%] had cyst wall resection)

Mean cyst volume: 1.63 ± 1.68 mL (range: 0.06– 5.5 l mL)

44 (71%) presented with headache; postoperatively, 23 (52%) had resolution of headache, 17 (39%) had improvement, 2 (4.5%) were unchanged, and status was undetermined in 2 (4.5%)

Kim et al (2004)9

Case series

IV

53 (all underwent surgery)

17.0 mm; SD: N/A

43 (81%) had preoperative headache; 40 of 43 (93%) had improvement in symptoms

Nishioka et al (2006)17

Case series

IV

37 (27 [73%] underwent surgical intervention)

17.9 ± 7.6 mm (range: 10– 38 mm)

18 (49%) presented with headache preoperatively; 15 patients underwent transsphenoidal surgery and 12 of 15 (80%) had improvement in headache postoperatively

Nishioka et al (2006)18

Case series

IV

46 (33 [72%] underwent surgery)

Max. diameter, range: 10– 38 mm (mean, 17.9 ± 7.6 mm)

27 (59%) presented with headache (23 [85%] had nonpulsating headache, 11 [41%] had sudden episodic headache); postoperatively, 17 of 21 (81%) had improvement in headaches

Raper and Besser (2009)1

Case series

IV

12

Range: 6– 20 mm with 9 (75%) > 10 mm; mean: N/A

8 (67%) presented with headache; postoperative headache data: N/A

Amhaz et al (2010)6

Case series

IV

9 (untreated)

–

7 (78%) had headache on presentation; 5 (56%) had symptom resolution

Kim (2012)19

Case series

IV

40 (33 [83%] had transsphenoidal surgery)

19.6 mm; SD: N/A (range 18–43 mm)

30 (75%) presented with headache preoperatively; 23 of 30 (77%) had improvement or resolution of their headache postoperatively

Oyama et al (2013)20

Case series

IV

94 (91 [97%] underwent transsphenoidal surgery)

–

36 (38%) reported headache preoperatively; postoperative data: N/A

Mendelson et al, 20144

Meta-analysis

IV

1,151 (96% underwent transsphenoidal approach)

Mean diameter: 14.9 mm (SD: N/A)

55% had headache preoperatively (number of patients: N/A); postoperative information: N/A

Chotai et al (2015)21

Case series

IV

87 (all underwent surgery)

Mean cyst volume: 2.4 ± 0.9 mL (range: 0.36– 4.9 mL)

66 (76%) had preoperative headache; rate of improvement highest in intrasellar type (92%) and lowest in suprasellar type (66%)

Cote et al (2015)7

Case series

IV

23 (all underwent transsphenoidal resection)

20 (87%) size > 1 cm; mean: N/A

19 (83%) had preoperative headache; 12 (52%) had postoperative headache

Fukui et al, 20178

Case series

IV

13 (all underwent endoscopic transsphenoidal surgery)

7.0 ± 1.8 mm

13 (100%) had preoperative headache; mean HIT 6 score: 63.9 preoperatively vs. 37.2 postoperatively

Abbreviations: HIT, Headache Impact Test; N/A, not available; RCC, Rathke cleft cyst; SD, standard deviation.

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Headache in Patients with Rathke Cleft Cysts sudden and episodic in nature, but results are mixed.6,8 In a retrospective study by Nishioka et al18 of 46 patients with RCC, the reported headaches frequently consisted of nonpulsating, bilateral, and frontal pain. Their characteristics resembled the characteristics of headaches reported by patients with pituitary adenomas, and the headaches did not correlate with the presence of other symptoms, including the severity of hypopituitarism. Nishioka et al18 also found that about 40% of patients presented with sudden episodic headaches that mimic those of pituitary apoplexy and acute sinus headaches. Thus far, episodic headaches have been found in 16 to 43% of patients complaining of headaches.16,19 A comparison of postsurgical recovery data shows that RCC patients with sudden episodic headaches appear to improve more than patients with chronic headaches; hence, patients with episodic headaches should be considered as surgical candidates.19 Patients’ chronic headache may not be fully improved after surgery, and few published reports show that headache actually worsens after surgical intervention for RCC. Given the high prevalence of chronic and episodic migraines (1–2% and 11–15%, respectively), it is difficult to prove causality because RCCs may be incidentally discovered during a routine secondary headache evaluation.24,25 Nevertheless, in a recent retrospective analysis of 43 patients by Cote et al,7 the investigators found that, if patients were carefully selected, transsphenoidal surgery for RCC may have the potential to decrease the frequency and severity of headaches.

22.3 Pathophysiology of RCCInduced Headaches The proposed mechanisms for sudden-onset headaches remain unclear, although this type of headache may be caused by infarction, hemorrhage, or leakage of cyst contents.16 It is also possible that the increased intrasellar pressure caused by the RCC could cause the development of headaches, as a general correlation has been described between RCC size and headaches.5,26,27 However, the presence of headache has not been correlated with the size of RCCs, as headache is more frequently observed in patients with RCCs who have high intensity and isointensity on T1-weighted MRIs than in patients with RCCs who have low intensity on MRIs, suggesting that higher protein content may play a causal role.17 Another possibility is to view the pathophysiology of RCCs as similar to that of pituitary adenomas, for which two other mechanisms for the headache have been proposed. In patients with pituitary adenomas, headaches may be caused by traction and displacement of the diaphragma sellae by the suprasellar extension of the tumor.9,28 Additionally, patients with pituitary adenomas may have stimulation by the adenoma of pain-sensitive structures, including the cavernous sinus, dural arteries, internal carotid arteries, and the first branch of the trigeminal nerve in the diaphragma sellae.28 Compression and expansion have also been suggested as possible etiologies for headaches, and the mucus material within the cysts has also been thought to be causal. Mucus is a strong stimulator of tissue and can thus cause a foreign-body inflammatory reaction,9,18 which may lead to the subsequent destruction of the pituitary gland and consequently to the

development of hypopituitarism that is frequently irreversible.29 Aseptic meningitis may also develop as a result of rupture of the cystic content into the subarachnoid space or extension of the inflammation to the surrounding structures.30,31 Conversely, sudden episodic headaches had been previously thought to be caused by hemorrhage within the cyst, mimicking pituitary apoplexy.31,32,33

22.4 Size Differences On pathologic examination, the size of the cyst can vary from 2 to 40 mm, with a mean size of 17 mm.3,9,15 Most RCCs are discovered incidentally and are smaller than 20 mm in diameter, with only 18% of cysts found to be greater than 20 mm in diameter.15 There are reports of small RCCs, with a diameter of less than 10 mm, in patients who present with chronic headaches.8 Thus far, no definitive conclusion can be made regarding the presence of headache and the size of the cyst.19

22.5 Location Differences A retrospective study of 155 patients with symptomatic RCC reported that the cyst was found in intrasellar and suprasellar locations in 71% of patients and was enlarged in 80%.2 A more recent meta-analysis found that 52% of RCCs were intrasellar with suprasellar extension, 42% were intrasellar, and 6% were purely suprasellar. The enlargement may be due to an imbalance between secretion and reabsorption of cyst contents.2 Although some evidence indicates that the location of the cyst may play a role in the development of visual disturbance or hyperprolactinemia, anatomical location does not appear to play a role in the development of headache.21 Postoperative headache improvement is highest after removal of intrasellar cysts (92%) and lowest after removal of suprasellar cysts (66%).21

22.6 MRI Findings Several studies have examined MRI features of RCCs because they may determine treatment and relate to postoperative outcomes. Few studies have addressed headache symptoms and specific MRI findings. Nishioka et al17 found that headaches are more frequently observed in patients with high-intensity and isointensity cysts than in those with low-intensity cysts on T1weighted imaging. These patients often described their headaches as episodic. Other studies have found that MRI intensities are highly variable and are related to protein, cholesterol, and mucopolysaccharide concentrations in the cyst fluid.6,9,20 In general, MRI features of RCCs are variable and, thus far, are inconclusive with regard to cyst contents, histologic features, and postoperative outcomes, let alone the features of headache.9

22.7 Treatment Minimal evidence is available regarding nonoperative headache management in patients with RCCs. Nonsteroidal anti-inflammatory drugs and triptans seem to be insufficient to relieve the pain.18 Patients may obtain symptom relief by increasing doses of dexamethasone.21,34 Close monitoring and follow-up have

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Rathke Cleft Cyst and Other Sellar Lesions been proposed for the management of patients whose only symptom is headache. Nishioka et al18 reported on 10 patients who did not undergo surgical intervention for various reasons (e.g., cyst resolution, refusal of surgery, headache as the only complaint, or asymptomatic). Amhaz et al6 found that some patients experienced resolution of their headaches as the cyst regressed. The likelihood of regression of an RCC has not been well quantified, with minimal studies available showing as much as 31% regression in patients for whom conservative management was an option.6,35 Additionally, the mechanism of regression is not well understood. When surgery is required, the most common surgical approach is transsphenoidal, although other approaches are occasionally required.19 No consensus exists on the most effective method of resection that alleviates symptoms.4 With surgery, headache resolution can occur in up to 52 to 82% of patients.16,18 Postoperative improvement of headache, although not resolution, is estimated to occur in 66 to 94% of patients.9,16 Patients with episodic and frontal headaches seem to completely or nearly completely improve, while those with nonfrontal headaches improve at a lower rate (32.5%).18 Some authors have found no difference in the rates of improvement for patients with sudden-onset headaches compared to those with chronic headaches.16 Thus far, few studies have examined headache frequency, severity, and duration both preoperatively and postoperatively. In one retrospective study, researchers conducted a postoperative telephone survey of 23 patients to ask specific questions regarding their headaches.7 These investigators found a significant decrease in the number of patients who had a headache (from 19 to 12, p = 0.02), in the severity of their headaches on a 1 to 10 scale (from 6.4 to 3.4, p = 0.006), and in the monthly frequency of their headaches (from 18.1 to 3.7, p < 0.001). Although these are great results for patients with headaches attributable to RCC, evidence is certainly lacking, and controlled trials regarding improvement in headache scores are needed.

22.8 Rathke Cleft Cysts Recurrence Occasionally, RCCs recur in patients after the initial surgical removal or cyst wall fenestration, with recurrence rates varying from 5 to 33%. Predictors of recurrence have been evaluated and may include RCC enhancement on MRI, extent of cyst removal, cyst location, and the presence of squamous epithelium on pathology.9,35 However, other studies have been unable to identify specific predictors of recurrence.15 Thus far, no evidence has been found in differences in recurrence rates between aggressive surgical approaches and less aggressive approaches.4 Headache does not appear to be a good predictor of RCC recurrence. In patients who required repeat surgical intervention, 80% had improvement or resolution of their headaches after a second surgical procedure.16

22.9 Conclusions Almost 90% of patients with symptomatic RCCs have improvement in their headaches after surgical intervention.16 Nishioka

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et al18 found that episodic headaches greatly improve with surgical intervention. Throughout the literature, there is little debate that headache, if caused by the RCC, will improve after surgery. It is also widely accepted that surgery is indicated when patients present with nonheadache symptoms, such as pituitary deficiencies and visual impairment. The area of debate starts with the benefits of surgery in patients who present with headache as their only symptom. Addressing this question requires additional research in the form of a randomized controlled trial comparing headache severity in patients who receive medical management to headache severity in patients who undergo surgery. However, such a study would be difficult to conduct, as patients would not be blinded to the intervention and would require close follow-up to ensure that no other deficiencies develop during the monitoring period. Such research would also allow for the development of an RCC management algorithm that would include an optimal “wait period” during which, if medical management fails, surgery may be indicated for RCC removal.

22.10 Future Studies Future prospective studies specifically addressing headache and RCC could help describe the quality and quantity of headaches before and after surgery. Another factor that must be considered is whether the RCC is coincidental or causative in regard to a patient’s headache, which can only be teased out with a trial of medical management.6 A trial of headache prophylactic medications, such as those used to prevent migraine and tensiontype headaches, should be considered, especially if features of these primary headaches are present. Interventional treatments, such as peripheral nerve blockade (occipital and trigeminal branches), onabotulinum toxin A, and sphenopalatine ganglion block, may also be options, although these treatments have not been studied for RCC-related headaches. Other factors that should be compared to headache scores and closely studied include the risk of recurrence, MRI features, cyst size, location, and the optimal extent of resection of the RCC. Finally, an additional understanding of the mechanism of regression might allow prediction of the risk of cyst recurrence.

References [1] Raper DM, Besser M. Clinical features, management and recurrence of symptomatic Rathke cleft cyst. J Clin Neurosci. 2009; 16(3):385–389 [2] Voelker JL, Campbell RL, Muller J. Clinical, radiographic, and pathological features of symptomatic Rathke cleft cysts. J Neurosurg. 1991; 74(4):535–544 [3] Naik VD, Thakore NR. A case of symptomatic Rathke cyst. BMJ Case Rep. 2013; 2013:2013 [4] Mendelson ZS, Husain Q, Elmoursi S, Svider PF, Eloy JA, Liu JK. Rathke cleft cyst recurrence after transsphenoidal surgery: a meta-analysis of 1151 cases. J Clin Neurosci. 2014; 21(3):378–385 [5] Aho CJ, Liu C, Zelman V, Couldwell WT, Weiss MH. Surgical outcomes in 118 patients with Rathke cleft cysts. J Neurosurg. 2005; 102(2):189–193 [6] Amhaz HH, Chamoun RB, Waguespack SG, Shah K, McCutcheon IE. Spontaneous involution of Rathke cleft cysts: is it rare or just underreported? J Neurosurg. 2010; 112(6):1327–1332 [7] Cote DJ, Besasie BD, Hulou MM, Yan SC, Smith TR, Laws ER. Transsphenoidal surgery for Rathke cleft cyst can reduce headache severity and frequency. Pituitary. 2016; 19(1):57–64 [8] Fukui I, Hayashi Y, Kita D, et al. Significant improvement in chronic persistent headaches caused by small Rathke cleft cysts after transsphenoidal surgery. World Neurosurg. 2017; 99:362–368

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Headache in Patients with Rathke Cleft Cysts [9] Kim JE, Kim JH, Kim OL, et al. Surgical treatment of symptomatic Rathke cleft cysts: clinical features and results with special attention to recurrence. J Neurosurg. 2004; 100(1):33–40 [10] Sanno N, Oyama K, Tahara S, Teramoto A, Kato Y. A survey of pituitary incidentaloma in Japan. Eur J Endocrinol. 2003; 149(2):123–127 [11] Zada G, Lin N, Ojerholm E, Ramkissoon S, Laws ER. Craniopharyngioma and other cystic epithelial lesions of the sellar region: a review of clinical, imaging, and histopathological relationships. Neurosurg Focus. 2010; 28(4):E4 [12] Zada G. Rathke cleft cysts: a review of clinical and surgical management. Neurosurg Focus. 2011; 31(1):E1 [13] Jahangiri A, Wagner JR, Chin AT, et al. Incidence of headache as a presenting complaint in over 1000 patients with sellar lesions and factors predicting postoperative improvement. Clin Neurol Neurosurg. 2015; 132:16–20 [14] Jung JE, Jin J, Jung MK, et al. Clinical manifestations of Rathke cleft cysts and their natural progression during 2 years in children and adolescents. Ann Pediatr Endocrinol Metab. 2017; 22(3):164–169 [15] Shin JL, Asa SL, Woodhouse LJ, Smyth HS, Ezzat S. Cystic lesions of the pituitary: clinicopathological features distinguishing craniopharyngioma, Rathke cleft cyst, and arachnoid cyst. J Clin Endocrinol Metab. 1999; 84(11):3972– 3982 [16] Benveniste RJ, King WA, Walsh J, Lee JS, Naidich TP, Post KD. Surgery for Rathke cleft cysts: technical considerations and outcomes. J Neurosurg. 2004; 101(4):577–584 [17] Nishioka H, Haraoka J, Izawa H, Ikeda Y. Magnetic resonance imaging, clinical manifestations, and management of Rathke cleft cyst. Clin Endocrinol (Oxf). 2006; 64(2):184–188 [18] Nishioka H, Haraoka J, Izawa H, Ikeda Y. Headaches associated with Rathke cleft cyst. Headache. 2006; 46(10):1580–1586 [19] Kim E. Symptomatic Rathke cleft cyst: clinical features and surgical outcomes. World Neurosurg. 2012; 78(5):527–534 [20] Oyama N, Tahara S, Oyama K, Ishii Y, Teramoto A. Assessment of pre- and postoperative endocrine function in 94 patients with Rathke cleft cyst. Endocr J. 2013; 60(2):207–213 [21] Chotai S, Liu Y, Pan J, Qi S. Characteristics of Rathke cleft cyst based on cyst location with a primary focus on recurrence after resection. J Neurosurg. 2015; 122(6):1380–1389

[22] Eguchi K, Uozumi T, Arita K, et al. Pituitary function in patients with Rathke cleft cyst: significance of surgical management. Endocr J. 1994; 41(5):535–540 [23] Ward TN, St Germain DL, Comi RJ, Cromwell LD. Rathke cleft cyst as a secondary cause of headache: a case report. Cephalalgia. 2001; 21(9):921–923 [24] Katsarava Z, Buse DC, Manack AN, Lipton RB. Defining the differences between episodic migraine and chronic migraine. Curr Pain Headache Rep. 2012; 16(1):86–92 [25] Adams AM, Serrano D, Buse DC, et al. The impact of chronic migraine: The Chronic Migraine Epidemiology and Outcomes (CaMEO) Study methods and baseline results. Cephalalgia. 2015; 35(7):563–578 [26] Kanter AS, Sansur CA, Jane JA, Jr, Laws ER, Jr. Rathke cleft cysts. Front Horm Res. 2006; 34:127–157 [27] Harrison MJ, Morgello S, Post KD. Epithelial cystic lesions of the sellar and parasellar region: a continuum of ectodermal derivatives? J Neurosurg. 1994; 80(6):1018–1025 [28] Abe T, Matsumoto K, Kuwazawa J, Toyoda I, Sasaki K. Headache associated with pituitary adenomas. Headache. 1998; 38(10):782–786 [29] Hama S, Arita K, Nishisaka T, et al. Changes in the epithelium of Rathke cleft cyst associated with inflammation. J Neurosurg. 2002; 96(2):209–216 [30] Mrelashvili A, Braksick SA, Murphy LL, Morparia NP, Natt N, Kumar N. Chemical meningitis: a rare presentation of Rathke cleft cyst. J Clin Neurosci. 2014; 21(4):692–694 [31] Chaiban JT, Abdelmannan D, Cohen M, Selman WR, Arafah BM. Rathke cleft cyst apoplexy: a newly characterized distinct clinical entity. J Neurosurg. 2011; 114(2):318–324 [32] Neidert MC, Woernle CM, Leske H, et al. Ruptured Rathke cleft cyst mimicking pituitary apoplexy. J Neurol Surg A Cent Eur Neurosurg. 2013; 74 Suppl 1: e229–e232 [33] Binning MJ, Liu JK, Gannon J, Osborn AG, Couldwell WT. Hemorrhagic and nonhemorrhagic Rathke cleft cysts mimicking pituitary apoplexy. J Neurosurg. 2008; 108(1):3–8 [34] Steinberg GK, Koenig GH, Golden JB. Symptomatic Rathke cleft cysts. Report of two cases. J Neurosurg. 1982; 56(2):290–295 [35] Rasmussen Z, Abode-Iyamah KO, Kirby P, Greenlee JD. Rathke cleft cyst: a case report of recurrence and spontaneous involution. J Clin Neurosci. 2016; 32: 122–125

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Rathke Cleft Cyst and Other Sellar Lesions

23 Rathke Cleft Cyst Surgery: Indications, Outcomes, and Complications David L. Penn and Edward R. Laws Jr. Abstract With increased use of high-resolution imaging for a plethora of symptoms, deciding whether or not Rathke cleft cysts (RCCs) are symptomatic and warrant surgical intervention has become increasingly controversial. RCCs are benign embryological remnants found in the pars intermedius of the pituitary gland. These benign cysts can grow within the sella and many extend into the suprasellar space exerting mass effect on the diaphragma sellae producing headaches, on the optic chiasm causing decreased visual acuity or field cut, and on the surrounding normal pituitary gland resulting in varying degrees of hypopituitarism. Despite their benign nature, these cysts can grow quite large, and are capable of producing severe symptoms requiring urgent surgical intervention. The liquid contents within the cyst vary from thin serous secretions resembling spinal fluid to thick mucoid, purulent-appearing contents. Because of the varied contents within the cyst, RCCs can have differing appearance on MRI which can make definitive diagnosis challenging. The preoperative evaluation should include full endocrinologic and ophthalmologic testing. Although both transsphenoidal and transcranial surgical approaches exist for successful treatment of these lesions, the transsphenoidal route is predominantly favored for a number of reasons, including low complication rates, faster patient recovery, and improved patient quality of life. Although a number of studies exist examining the natural history of asymptomatic RCCs, demonstrating the dynamic nature of RCCs—growing and regressing spontaneously—there are limited data on the natural history of symptomatic lesions. Keywords: Rathke cleft cyst, transsphenoidal surgery, natural history, surgical outcomes, complications

23.1 Introduction Rathke cleft cysts (RCCs) are benign embryological remnants found in the sellar or suprasellar regions. These lesions were first described by Martin Heinrich Rathke, a German anatomist.1,2 Rathke was instrumental in the description of these cysts through his development of the embryological theory of “backwards metamorphosis” which hypothesized that incipient structures were reabsorbed to give rise to others, and his subsequent discovery of Rathke’s pouch which gives rise to the adenohypophysis. Later work in the 19th and early 20th centuries by Luschka and Goldzieher, respectively, described the first cases of RCCs discovered incidentally postmortem.3,4 Although initially perceived to be rare, further autopsy studies revealed an incidence of small RCCs ranging from 3.7 to 22%.5,6,7,8,9 With increased use of advanced imaging techniques, in particular magnetic resonance imaging (MRI), for a plethora of symptoms, the controversy surrounding surgical intervention for RCCs has

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become more complex. This chapter will review the pathophysiology, clinic presentation and workup, and natural history of RCC in attempt to improve clinical decision making for surgical management of this benign lesion.

23.1.1 Embryology of Rathke Cleft Cysts RCCs are derived from persistence of Rathke’s pouch, a structure that is present on the 24th embryonic day of life and appears as a diverticulum from the dorsal portion of the ectodermal stomodeum or primitive oral cavity.9 Lined by a ciliated, simple columnar epithelium, Rathke’s pouch extends in the cranial direction forming the craniopharyngeal duct while the infundibulum forms as a downgrowth of neuroepithelium from the diencephalon. Around the fifth week of gestation, Rathke’s pouch contacts the infundibulum and around the sixth or seventh week, it separates from the oral cavity.3,10 Between months 3 and 5 of gestation, cells within the anterior wall of Rathke’s pouch proliferate forming the pars anterior of the normal pituitary gland, and the posterior wall becomes the pars intermedia. The median eminence, pituitary stalk, and posterior pituitary lobe derive from the infundibulum. While these normal pituitary structures form, the craniopharyngeal duct obliterates causing involution of the pouch. When involution goes awry, the lumen of this duct persists and an enlarging cyst can form between the pars distalis and pars nervosa, forming a spectrum of cystic lesions, in particular RCCs.

23.1.2 Pathology of Rathke Cleft Cysts As previously mentioned, RCCs are benign cystic lesions that are generally small in size but have been reported to grow as large as 4 cm in maximum diameter.11 The wall of the cyst is often fibrous and tough while the contents within vary greatly from thin and clear (similar to CSF) to gelatinous or mucoid with a proteinaceous, serous, or brown tinge, to thick and milky with a purulent appearance. On histological analysis, the cyst wall has simple cuboidal or columnar epithelium with or without cilia. Mucous-secreting goblet cells can be found occasionally interspersed in the wall. While the earlier description is stereotypical of RCCs, pseudostratified, columnar, and/or ciliated respiratory-type epithelium may be found. There have also been reports of squamous metaplasia that can make RCCs difficult to differentiate from craniopharyngiomas. Other pathological findings include cholesterol clefts, necrotic debris, and keratin. Like many other lesions of the pituitary gland, RCCs can present with hemorrhagic episodes, and when this is the case, histologic analysis may reveal blood or hemosiderin. These histological findings indicate how RCCs may be part of a spectrum of disease arising from the craniopharyngeal duct, along with craniopharyngiomas.

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Rathke Cleft Cyst Surgery: Indications, Outcomes, and Complications

23.2 Clinical Presentation and Workup 23.2.1 Presenting Symptoms Similar to other lesions of the sella and pituitary gland, RCCs commonly present with headaches, visual loss, or endocrinopathy. In addition, with increased use of advanced imaging techniques, such as MRI, the discovery of all pituitary lesions, including RCCs for a myriad of symptoms, likely unrelated to the lesion, is more predominant.12 Symptoms are caused as the cyst grows and exerts increasing mass effect on the surrounding structures. The headache caused by RCCs can be attributed to stretching of the overlying diaphragm sellae resulting in activation of pain fibers within the dura.13 These headaches are often referred to the frontal or occipital regions; however, increased use of MRI for all headache types has made it more difficult to differentiate incidental lesions from lesions causing headache. Compression of the optic apparatus can result in different types of visual deficits, most commonly bitemporal hemianopsia from midchiasmal compression, or even decreased acuity or color vision. Lastly, endocrinopathies tend to result from compression of the normal pituitary gland resulting in decreased pituitary function, ranging from hypogonadism to hypocortisolism. One exception is hyperprolactinemia which results from compression of the pituitary stalk and decreased dopaminergic inhibitory signals from the hypothalamus. Another way RCCs can manifest clinically is with signs and symptoms of meningitis. Case reports detailing patients

presenting with both aseptic and bacterial meningitis thought to be associated with the presence of an RCC have been published.14,15,16 The pathogenesis of aseptic meningitis is believed to occur from rupture or leakage of the cyst contents into the subarachnoid space. There is an association between the presence of a pituitary lesion, including RCCs or adenomas, and pituitary abscesses and meningitis; however, the mechanism for this association is unclear.17,18 Additional rare presentations of RCCs include lymphocytic hypophysitis and intracystic hemorrhage.19,20,21

23.2.2 Radiological Workup Patients with concerns for any pituitary lesion should undergo an appropriate radiological workup including MRI with and without gadolinium contrast with high-resolution pituitary sequences. Although computed tomographic (CT) scan can be useful in the acute setting to rule out hemorrhage within the sella and for operative planning, for definitive diagnosis of RCCs this modality does not provide adequate soft-tissue detail. CT findings demonstrate a low-density cystic mass that can arise in the sella or suprasellar region, sometimes revealing a rim of contrast enhancement thought to be secondary to noninfectious inflammation.22 As previously described, the contents of RCCs can vary greatly, and therefore, so can their signal characteristics on all MRI sequences (▶ Fig. 23.1). Cysts containing serous fluids can appear hypointense on T1-weighted and hyperintense on T2-weighted imaging, while mucoid cysts are hyperintense on T1-weighted sequences and more iso- to

Fig. 23.1 MRI demonstrating pathologyconfirmed Rathke cleft cyst. (a) Patient presenting with headache and MRI demonstrating a hypointense cystic lesion in the sella on T1-weighted postcontrast imaging. There is mass effect on the normal pituitary gland which is displaced posteriorly and superiorly. White arrow heads demonstrate enlargement of the sella, indicating the cyst contents may be under pressure, resulting in bone remodeling and stretching of the diaphragma sellae. (b) Patient presenting with blurred vision in the right eye found to have an isodense cystic lesion on T1weighted postcontrast imaging. The lesion is located superior to the normal gland and causing bowing of the optic chiasm above (yellow arrowheads). (c) Patient with acute-onset, severe headache and hypopituitarism found to have a cystic, T1-weighted hyperintense lesion on T1weighted precontrast imaging (arrow). Presentation and radiographic and operative findings were consistent with an apoplectic Rathke’s cleft cyst. (d) Patient presenting with debilitating headaches, decreased visual acuity, and fatigue, with a cystic lesion in the pars intermedius. The border between the cyst and the anteriorly displaced adenohypophysis is observed (white arrowheads). There is stretching of the pituitary stalk (arrow) as well, demonstrating the cyst contents may be under pressure causing both headaches and hypopituitarism.

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Fig. 23.2 Correlation of MRI and intraoperative findings. (a–c) Patient presenting with bitemporal hemianopsia and hypopituitarism found to have a large sellar cyst compressing the optic chiasm. (a) T1-weighted precontrast sagittal sequence showing hyperintense material within the cystic lesion. There is some heterogeneity to the contents as noted in the inferior portion of the cyst (arrow). (b) Postcontrast sequence demonstrating a similar appearing heterogeneous T1-weighted hyperintense cyst with very minimal peripheral enhancement, likely representing the normal pituitary gland (arrowheads); (c) demonstrates intraoperative image of the thick, purulent-appearing cyst contents under pressure. (d, e) Patient presenting with headaches found to have a sellar cyst extending into the suprasellar region. (d) Postcontrast T1-weighted coronal image demonstrating a hypointense cystic lesion extending from the sella into the suprasellar region; (e) demonstrates the intraoperative findings with a thin, mucoid cyst contents being extruded under mild pressure.

hypointense on T2-weighted sequences (▶ Fig. 23.2).23,24,25 Gadolinium contrast administration can reveal very mild enhancement of the wall of the cyst. Imaging signs for differentiation of RCCs on MRI are generally based on anatomical location. For example, small RCCs can usually be found in the pars intermedius between the anterior and posterior pituitary lobes. Larger RCCs can oftentimes be identified as being located superiorly to the pituitary gland and diaphragm sellae. As cysts become increasingly larger and exert greater mass effect on surrounding structures, this subtle anatomical localization can be difficult to identify.

23.2.3 Ophthalmologic Workup Patients with subacute visual loss who do not present with acute visual changes, requiring more urgent operations, should undergo full neuroophthalmologic evaluation. This helps establish a preoperative baseline and can help establish appropriate care in the case of permanent deficits. Complete evaluation should include assessment of visual acuity and color vision, Humphrey Automated Perimetric Assessment of Visual Fields, evaluation for pupillary response and ophthalmoparesis, and

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Optical Coherence Tomography to assess structural changes in the retinal nerve fiber layer.

23.2.4 Endocrinologic Workup As with all lesions of the sella and suprasellar regions, patients with RCCs should undergo complete endocrine workup with laboratory tests checking all pituitary hormone levels. Subclinical deficiencies discovered on this workup should be replaced preoperatively, in particularly, hypothyroidism and hypocortisolemia. Patients with low thyroid function receive levothyroxine and adrenal-insufficient patients are treated with perioperative hydrocortisone that can be tapered to physiologic doses in the postoperative period.

23.3 Surgical Intervention 23.3.1 Indications and Approach Surgical intervention for RCCs is indicated for many of the symptoms previously described and is particularly effective for symptoms resultant from mass effect of the cyst. There are two

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Rathke Cleft Cyst Surgery: Indications, Outcomes, and Complications predominant approaches that can be used for removal of RCCs: transsphenoidal and transcranial. The transsphenoidal approach can be performed with the operative microscope; however, endoscopic endonasal surgery has gained increasing popularity. There exist pros and cons of any surgical technique. Advantages of the operative microscope include improved depth perception with increased bimanual technique and a lighted corridor down the space created by the nasal speculum; however, disadvantages include a smaller field of vision, limited illumination from instruments and hands, as well as placement of the light outside the surgical field, and collision of instruments with the microscope. The primary advantage of the endoscopic approach includes increased lighting and panoramic view with the endoscope being placed within the surgical field, while disadvantages include loss of depth perception when working with a two-dimensional endoscope. Although both procedures are safe and effective for removal of RCCs, data regarding whether or not one procedure improves outcomes are difficult to analyze because of inconsistencies across multiple analyses and lack of control regarding surgeon experience with the various tools.20,26,27,28 While it can be difficult to resect the cyst capsule using a transsphenoidal operation, adequate decompression of the cyst and relief of mass effect can be achieved. Because of the technique required to attempt removal of the cyst wall from a transsphenoidal approach, there can be significant amount of traction on the capsule, without adequate visualization of the adhesions to the surrounding normal structures. This can result in severe hypopituitarism, in particular, diabetes insipidus and adrenal insufficiency. There are a number of transcranial operations that are effective for resection of RCCs including transsylvian and subfrontal approaches that can be chosen based on the specific morphology of the cyst and its relation to the surrounding normal anatomy. The primary advantage of transcranial surgery for RCCs is that it allows more careful dissection of the cyst capsule from the surrounding neurovascular structures, in particular the optic chiasm. In addition, when the cyst capsule can be completely resected, there is a decreased likelihood of cyst recurrence. Despite these advantages of transcranial surgery, there are increased risks associated with larger and prolonged surgical procedures which must be considered to provide patients with optimal treatment. Almost as important as choosing the appropriate indication for surgical intervention of RCCs is appropriately determining the goal of a planned procedure. In many cases, the primary goal of surgical intervention is decompression of the mass effect of the cyst to relieve symptoms such as headache, visual loss, and hypopituitarism. This goal can easily be accomplished by drainage of the cyst contents; however, without resection of the cyst wall, there is a higher risk of recurrence.29,30,31 If the only goal is to drain the cyst contents, the transsphenoidal approach is likely more appropriate, given the ease and low risk of this procedure. Obliteration of the cyst wall can be attempted by exposure to hydrogen peroxide.29 Furthermore, if a CSF leak is not encountered during the procedure, it is possible to leave the sellar defect open which allows the cyst contents to drain into the sphenoid sinus, preventing reaccumulation and recurrent mass effect. In many cases of recurrence, repeated transsphenoidal drainage may be appropriate to treat symptomatic lesions, again based on the ease and low risk of this approach;

Table 23.1 Symptom improvement after transsphenoidal surgery for Rathke cleft cysts Study

Level of evidence

Headache

Vision

Hypopituitarism

Benveniste et al (2004)28

IV

90.9%

70.0%

28.0%

Kim et al (2004)30

IV

93.0%

59–68%

17–77%

(2005)26

14–18%

IV

–

98.0%

Fleseriu et al (2009)34

IV

90.9%

–

Wait et al (2010)31

IV

89.1%

96.4%

38.0–100%

Kim (2012)29

IV

76.7%

87.0%

16.7–56.3%

IV

60.9%

–

–

Aho et al

Cote et al

(2016)32

however, in patients who have had complications with prior procedures, with extremely high risk of a difficult-to-repair CSF leak or multiple recurrences, a transcranial operation would likely be more appropriate because it carries a significantly lower risk of CSF leak and improved access to resect the cyst capsule, preventing further recurrence.

23.3.2 Surgical Outcomes Surgical resection of RCCs is most successful for symptoms of mass effect, such as headaches, visual loss, and hypopituitarism (▶ Table 23.1). Current literature demonstrates that transsphenoidal surgery for RCCs can be successful in treating headaches, with reports detailing rates of improvement of preoperative headaches ranging from 57 to 91%.28,29,31,32,33,34 Similar success is achieved with transsphenoidal surgery for RCCs with regard to visual outcomes with improvement achieved in 75 to 98%.26, 28,29,31 Despite the success of treating headaches and visual loss from RCCs, endocrinologic outcomes have been less successful. Authors variably report outcomes based on particular endocrine axes and new deficits. Considering all hormonal axes, the improvement in hypopituitarism ranges from 14 to 100%.26,28,29, 31 Rates of new anterior pituitary hormone deficit and diabetes insipidus range from 7.5 to 21% and 4 to 19%, respectively.26,28, 29,31 Benveniste et al examined the effect of postoperative endocrinopathy when performing decompression compared to aggressive cyst resection, demonstrating in the latter a statistically significant increase in both anterior and posterior pituitary dysfunction.28 Recurrence rates requiring reoperation range from 5.0 to 11.0%.26,28,29,31 Risk of recurrence has been shown to be associated with a number of factors, including enhancement of the cyst wall, the presence of chronic inflammation or stratified epithelium, the presence of squamous metaplasia, degree of cyst wall resection, and insertion of abdominal fat graft.26,28,30,35,36 In our most recent series of 865 patients who underwent a total of 948 transsphenoidal procedures, 108 of these were performed for pathologically confirmed RCCs in 99 patients. Of these procedures, 80.6% (n = 87) of patients presented with headaches, 32.4% (n = 35) presented with visual disturbances, and 22.2% (n = 24) presented with signs of hypopituitarism. Improvement of preoperative headaches and visual symptoms was achieved in 77.0 and 77.1%, respectively, and 12.6% of patients had stable postoperative headaches and 32.6% had stable postoperative vision. Only one patient had worsening of

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Rathke Cleft Cyst and Other Sellar Lesions preoperative vision. Our incidence of transient and permanent postoperative diabetes insipidus was 15.7% (n = 17) and 10.2% (n = 11), respectively. Of the 99 patients examined, 9.1% (n = 9) experienced symptomatic cyst recurrence necessitating reoperation.

23.3.3 Complications Reported complication rates for transsphenoidal surgery of RCCs are relatively low. CSF leak rates have been reported to range from 0 to 2.5%.26,28,29,31,34 Reports of postoperative visual field loss are also very low. One study reported visual field loss secondary to overpacking of the sella with fat graft and one report of postoperative hematoma causing vision loss.31 There are also reports of minor complications associated with harvesting of abdominal fat.28,31 There are no reports of carotid injury or mortality directly associated with surgical procedures in the current literature. In our own series, there was a 0.9% (n = 1) incidence of persistent postoperative CSF leak requiring reoperation, 1.9% (n = 2) incidence of meningitis, and 1.9% (n = 2) incidence of postoperative hematomas. There was a 4.6% (n = 5) incidence of delayed postoperative epistaxis. No patients experienced internal carotid artery injury or mortality.

23.4 Natural History versus Surgery When deciding to operate on any lesion or disease process, it is important that the risk of clinical deterioration or morbidity and mortality associated with the procedure itself is lower than the risk posed by the pathology. With increased use of high-resolution imaging technologies, such as CT and MRI, incidental and asymptomatic pituitary masses, including RCCs, are being discovered at higher frequencies, requiring close examination of the natural history of asymptomatic RCCs.12 One large cohort of 248 incidental pituitary masses examined in Japan included 94 patients with asymptomatic RCCs followed with serial MRI over a time period ranging from 6 to 93 months, with a mean follow-up of 38.9 months.37 Of the patients followed up, 76.5% (n = 72) demonstrated stability of the lesion and 15.9% (n = 15) demonstrated decreased size of the lesion. Only 5.3% (n = 5) of the population followed up exhibited increased cyst size on MRI. Two patients exhibited both increase and decrease of the cyst on serial imaging, indicating that these lesions possess a dynamic natural history. Five of these patients underwent transsphenoidal resection of the cyst. Another series of 61 patients with incidentally discovered RCCs has been reported. In this group, 69% (n = 42) of patients were observed to remain clinically and radiographically stable over a 9-year period.26 In addition to changing size of these lesions, there are a number of case reports detailing patients who have experienced spontaneous involution of presumed RCCs.38,39,40,41

23.5 Conclusions Data regarding the natural history of symptomatic RCCs are lacking, presumably because these patients have undergone surgery in a shorter, more expedited, time period preventing

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longer observation. Lack of these data, with frequent use of high-resolution imaging techniques, makes it difficult to assess which RCCs are the direct causation of symptoms, in particular, headache. Our practice has one patient with debilitating headache and a presumed RCC that we were planning to resect. The patient presented the day prior to the procedure for repeat MRI for neuronavigation purposes and the cyst had spontaneously resolved while the headaches persisted. Such cases make surgical decision making a challenge. Despite high rates of success with symptomatic relief, increased knowledge of the natural history and causality of symptoms associated with these lesions is necessary to improve patient selection for surgery.

References [1] Chun IKH, Ojumah N, Loukas M, Oskouian RJ, Tubbs RS. Martin Heinrich Rathke (1793–1860) and his pouch and cyst. Childs Nerv Syst. 2018; 34(3): 377–379 [2] Rathke H. Ueber die Entstehung der Glandula pituitaria. Archiv für Anatomie. Physiologie und Wissenschaftliche Medicin. 1838; 40:482–485 [3] Trifanescu R, Ansorge O, Wass JA, Grossman AB, Karavitaki N. Rathke’s cleft cysts. Clin Endocrinol (Oxf). 2012; 76(2):151–160 [4] Goldzieher M. Über Sektionsbefunde bei Diabetes insipidus. Verh Dtsch Ges Pathol. 1913; 16:281–287 [5] Bayoumi ML. Rathke’s cleft and its cysts. Edinburgh Med J. 1948; 55(12):745– 749 [6] Shanklin WM. On the presence of cysts in the human pituitary. Anat Rec. 1949; 104(4):379–407 [7] Shanklin WM. The incidence and distribution of cilia in the human pituitary with a description of microfollicular cysts derived from Rathke’s cleft. Acta Anat (Basel). 1951; 11(2–3):361–382 [8] Teramoto A, Hirakawa K, Sanno N, Osamura Y. Incidental pituitary lesions in 1,000 unselected autopsy specimens. Radiology. 1994; 193(1):161–164 [9] Fager CA, Carter H. Intrasellar epithelial cysts. J Neurosurg. 1966; 24(1):77– 81 [10] Voelker JL, Campbell RL, Muller J. Clinical, radiographic, and pathological features of symptomatic Rathke’s cleft cysts. J Neurosurg. 1991; 74(4):535–544 [11] Chuang CC, Chen YL, Jung SM, Pai PC. A giant retroclival Rathke’s cleft cyst. J Clin Neurosci. 2010; 17(9):1189–1191 [12] Scangas GA, Laws ER, Jr. Pituitary incidentalomas. Pituitary. 2014; 17(5):486– 491 [13] Rizzoli P, Iuliano S, Weizenbaum E, Laws E. Headache in patients with pituitary lesions: a longitudinal cohort study. neurosurgery. 2016; 78(3):316–323 [14] Berlit P, Keyvani K, Herring A, Krämer M. Recurrent bacterial meningitis perpetuated by an infected Rathke’s cleft cyst. Fortschr Neurol Psychiatr. 2015; 83(10):e14–e16 [15] Maniec K, Watson JC. Spontaneous rupture, disappearance, and reaccumulation of a Rathke’s cleft cyst. Case Rep Endocrinol. 2011; 2011:549262 [16] Mrelashvili A, Braksick SA, Murphy LL, Morparia NP, Natt N, Kumar N. Chemical meningitis: a rare presentation of Rathke’s cleft cyst. J Clin Neurosci. 2014; 21(4):692–694 [17] Domingue JN, Wilson CB. Pituitary abscesses. Report of seven cases and review of the literature. J Neurosurg. 1977; 46(5):601–608 [18] Jain KC, Varma A, Mahapatra AK. Pituitary abscess: a series of six cases. Br J Neurosurg. 1997; 11(2):139–143 [19] Nishikawa T, Takahashi JA, Shimatsu A, Hashimoto N. Hypophysitis caused by Rathke’s cleft cyst. Case report. Neurol Med Chir (Tokyo). 2007; 47(3):136– 139 [20] Zada G. Rathke cleft cysts: a review of clinical and surgical management. Neurosurg Focus. 2011; 31(1):E1 [21] Nishioka H, Ito H, Miki T, Hashimoto T, Nojima H, Matsumura H. Rathke’s cleft cyst with pituitary apoplexy: case report. Neuroradiology. 1999; 41(11):832– 834 [22] Okamoto S, Handa H, Yamashita J, Ishikawa M, Nagasawa S. Computed tomography in intra- and suprasellar epithelial cysts (symptomatic Rathke cleft cysts). AJNR Am J Neuroradiol. 1985; 6(4):515–519 [23] Pisaneschi M, Kapoor G. Imaging the sella and parasellar region. Neuroimaging Clin N Am. 2005; 15(1):203–219

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Rathke Cleft Cyst Surgery: Indications, Outcomes, and Complications [24] Nakasu Y, Isozumi T, Nakasu S, Handa J. Rathke’s cleft cyst: computed tomographic scan and magnetic resonance imaging. Acta Neurochir (Wien). 1990; 103(3–4):99–104 [25] Sumida M, Uozumi T, Mukada K, Arita K, Kurisu K, Eguchi K. Rathke cleft cysts: correlation of enhanced MR and surgical findings. AJNR Am J Neuroradiol. 1994; 15(3):525–532 [26] Aho CJ, Liu C, Zelman V, Couldwell WT, Weiss MH. Surgical outcomes in 118 patients with Rathke cleft cysts. J Neurosurg. 2005; 102(2):189–193 [27] Barkhoudarian G, Zada G, Laws ER. Endoscopic endonasal surgery for nonadenomatous sellar/parasellar lesions. World Neurosurg. 2014; 82(6) Suppl:S138–S146 [28] Benveniste RJ, King WA, Walsh J, Lee JS, Naidich TP, Post KD. Surgery for Rathke cleft cysts: technical considerations and outcomes. J Neurosurg. 2004; 101(4):577–584 [29] Kim E. Symptomatic Rathke cleft cyst: clinical features and surgical outcomes. World Neurosurg. 2012; 78(5):527–534 [30] Kim JE, Kim JH, Kim OL, et al. Surgical treatment of symptomatic Rathke cleft cysts: clinical features and results with special attention to recurrence. J Neurosurg. 2004; 100(1):33–40 [31] Wait SD, Garrett MP, Little AS, Killory BD, White WL. Endocrinopathy, vision, headache, and recurrence after transsphenoidal surgery for Rathke cleft cysts. Neurosurgery. 2010; 67(3):837–843, discussion 843 [32] Cote DJ, Besasie BD, Hulou MM, Yan SC, Smith TR, Laws ER. Transsphenoidal surgery for Rathke’s cleft cyst can reduce headache severity and frequency. Pituitary. 2016; 19(1):57–64

[33] Jahangiri A, Wagner JR, Chin AT, et al. Incidence of headache as a presenting complaint in over 1000 patients with sellar lesions and factors predicting postoperative improvement. Clin Neurol Neurosurg. 2015; 132:16–20 [34] Fleseriu M, Yedinak C, Campbell C, Delashaw JB. Significant headache improvement after transsphenoidal surgery in patients with small sellar lesions. J Neurosurg. 2009; 110(2):354–358 [35] Kasperbauer JL, Orvidas LJ, Atkinson JL, Abboud CF. Rathke cleft cyst: diagnostic and therapeutic considerations. Laryngoscope. 2002; 112(10):1836–1839 [36] Lillehei KO, Widdel L, Astete CA, Wierman ME, Kleinschmidt-DeMasters BK, Kerr JM. Transsphenoidal resection of 82 Rathke cleft cysts: limited value of alcohol cauterization in reducing recurrence rates. J Neurosurg. 2011; 114(2): 310–317 [37] Sanno N, Oyama K, Tahara S, Teramoto A, Kato Y. A survey of pituitary incidentaloma in Japan. Eur J Endocrinol. 2003; 149(2):123–127 [38] Al Safatli D, Kalff R, Waschke A. Spontaneous involution of a presumably Rathke’s cleft cyst in a patient with slight subclinical hypopituitarism: a case report and review of the literature. Case Rep Surg. 2015; 2015:971364 [39] Cheng L, Guo P, Jin P, Li H, Fan M, Cai E. Spontaneous involution of a Rathke cleft cyst. J Craniofac Surg. 2016; 27(8):e791–e793 [40] Kim CW, Hwang K, Joo JD, Kim YH, Han JH, Kim CY. Spontaneous involution of Rathke’s cleft cysts without visual symptoms. Brain Tumor Res Treat. 2016; 4(2):58–62 [41] Rasmussen Z, Abode-Iyamah KO, Kirby P, Greenlee JD. Rathke’s cleft cyst: a case report of recurrence and spontaneous involution. J Clin Neurosci. 2016; 32:122–125

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24 Controversies in the Management of Histiocytosis and Xanthogranulomas Christina E. Sarris and Ruth E. Bristol Abstract Histiocytoses are a group of disorders involving the malignant proliferation of antigen-presenting cells. Although histiocytoses are more common in pediatric patients than in adult patients, their diagnosis and treatment should be familiar to all neurosurgeons. Langerhans cell histiocytosis, Erdheim-Chester disease, and juvenile xanthogranuloma are all histiocytic disorders that can affect the neuraxis and, in particular, the skull base. It is critical for the skull base surgeon to select the proper surgical approach for biopsy and, when necessary, resection of these lesions. Transcranial open biopsies were once the standard of care, but transsphenoidal and intraventricular approaches via endoscopy are becoming more commonplace and may be preferable. Once a diagnosis of one of the aforementioned histiocytoses is made, management strategies are variable and debated on the basis of the diagnosis and extent of the disease. Keywords: diabetes insipidus, Erdheim–Chester disease, histiocytosis, juvenile xanthogranuloma, Langerhans cell, pituitary stalk

24.2 Langerhans Cell Histiocytosis 24.2.1 Overview LCH is primarily found in pediatric patients. It is characterized histologically by the malignant proliferation of the Langerhans cells of the reticuloendothelial system, which function as antigen-presenting cells. With great variability in its presentation, LCH can range from clinically significant disease progression over time, affecting numerous different organ systems, to small self-resolving lesions.2,5 LCH involvement of the CNS can result in debilitating consequences. Although LCH is usually observed within the context of multiorgan involvement, there are some cases in which LCH is associated with isolated CNS lesions. Infiltration and dysfunction of the pituitary gland or hypothalamus occur in 10 to 40% of patients. Diabetes insipidus (DI) is the most common neurologic presentation of the disease. In up to 10% of cases, other areas of the brain are involved as well, including the cerebellum, cerebral hemispheres, and choroid plexus.1

24.2.2 Imaging Characteristics

24.1 Introduction Histiocytoses are disorders involving the proliferation of cells derived from macrophages or dendritic cells, which process and present antigens to lymphocytes.1,2 Although adult patients with histiocytoses are infrequently encountered by neurosurgeons, the practitioner should be familiar with their presentation, evaluation, and management. The pediatric neurosurgeon, however, may regularly encounter patients with histiocytoses. As a disease group, histiocytoses are variable and range from isolated cutaneous lesions, with no adverse clinical outcomes, to disseminated multisystem pathologies. Classically, histiocytoses were divided into Langerhans cell and non–Langerhans cell disorders. More recently, this classification scheme has been revisited.2 However, for the purpose of this chapter, we will discuss the following histiocytoses in light of their relation to the central nervous system (CNS): Langerhans cell histiocytosis (LCH), Erdheim–Chester disease (ECD), and juvenile xanthogranuloma (JXG). Many of these histiocytoses, when investigated on magnetic resonance imaging (MRI), have pathologies based in the sella, with thickened pituitary stalks and other characteristic neuroimaging features. It is critical for the skull base surgeon to select the proper surgical approach for biopsy and, when necessary, resection of these lesions. Transcranial open biopsies were once the standard of care,3 but transsphenoidal and intraventricular approaches via endoscopy are becoming more commonplace and may be preferable.4 Once a diagnosis of LCH, ECD, or JXG is made, management strategies for the specific histiocytosis are variable and debated on the basis of the diagnosis and extent of the disease.

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Although imaging findings characteristic of LCH are not specific, they are valuable in cases when the diagnosis is unclear in the absence of a history of LCH or extracranial disease.6 In general, neuroimaging is not performed unless clinical indications exist, including neurologic symptoms or endocrinopathies. Craniofacial lesions are the most common findings on imaging, with lesions involving the skull, skull base, and maxillofacial bones found in 50 to 80% of patients.7 Intracranially, classic imaging findings in patients with LCH of the CNS include increased size of the sella, infundibular thickening, and the absence of posterior pituitary intensity on MRI. Laurencikas et al6 reviewed a group of pediatric patients with LCH and found that the most common MRI pathology was involvement of the globus pallidus and dentate nucleus of the cerebellum, followed by hypothalamic–pituitary abnormalities, such as a thickened stalk and the absence of the posterior pituitary “bright spot.” All patients in this series who developed DI had hypothalamic–pituitary axis MRI changes. In a cohort of 31 patients, Porto et al8 found the most common MRI changes in LCH to be osseous lesions in 17 (55%), followed by enlargement of the pineal gland in 14 (45%), thickened pituitary stalk in 10 (32%), and signal changes of the dentate nucleus in 9 (29%). In another large retrospective review of 98 patients with LCH, investigators sought to study MRI changes over time in the patients with both LCH and DI.9 There were two radiologic findings common to these patients: a thickened infundibulum was present in approximately 84%, and posterior pituitary hyperintensity was absent in 10%. Of note, follow-up imaging findings indicated mixed changes during and after treatment, with some patients experiencing progressive pituitary atrophy and others having normal findings. It is critical for the physician to be aware of clinical and

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Controversies in the Management of Histiocytosis and Xanthogranulomas Table 24.1 Summary of key studies for diagnosis and management of histiocytosis and xanthogranulomas Author (year)

Level of evidence

No. of patients

Key findings

Davidson et al (2008)5

IV

44

Most common LCH presentation was localized skull mass; only 5% presented with isolated H-P axis involvement

Varan et al (2008)9

IV

98

Thickened infundibulum in 84% of patients with LCH and DI

Laurencikas et al (2011)6

IV

29

Most common MRI findings in LCH were involvement of GP and dentate, followed by hypothalamic or pituitary abnormalities

Jinguji et al (2013)4

IV

11

Endoscopic stalk biopsy not associated with further deterioration in pituitary function after biopsy

Abbreviations: DI, diabetes insipidus; GP, globus pallidus; H-P, hypothalamic–pituitary; LCH, Langerhans cell histiocytosis; MRI, magnetic resonance imaging.

radiographic findings suggestive of DI in this patient population. Prosch et al10 recommended that all patients with DI obtain dedicated pituitary MRI sequences. Patients with LCH can also develop panhypopituitarism or partial hypopituitarism with no evidence of DI.11

24.2.3 Presentation LCH can affect numerous different organ systems, and patients with LCH are therefore extremely variable in presentation (▶ Table 24.1).4,5,6,9 Most patients will generally present with involvement of the bony skeleton, which can cause pain, deformity, or fracture.1 Skin lesions are the second most common finding. These patients, however, will not usually present to a neurosurgeon unless there is a finding of an obvious calvarial lesion or neurologic or endocrinologic symptoms with neuroimaging findings of concern. Most patients with LCH who demonstrate CNS involvement already have multiorgan disease. However, some patients may present initially with neurologic symptoms.10 Symptoms can include endocrinopathies (e.g., DI, growth hormone deficiency, panhypopituitarism),12 cognitive deficits, ataxia, dysarthria, and psychological complaints.13,14,15 In a 30-year review of patients with LCH treated at Children’s Hospital Los Angeles, Davidson et al5 identified and examined 44 pediatric patients for disease location, treatment, and outcomes. This series is the largest neurosurgical series of pediatric patients with craniospinal LCH. The most common presentation was a localized skull mass, which was usually tender upon palpation. Only two patients (5%) presented with isolated involvement of the hypothalamic–pituitary axis, with imaging demonstrating contrast-enhancing lesions. These patients had unifocal LCH that did not progress. Autopsy studies show that hypothalamic–pituitary axis infiltration is present in 5 to 50% of children with LCH and that the most common presenting endocrinopathy is DI.16,17 The incidence of DI ranges from 10 to 50% in patients with LCH.18,19,20 Anterior pituitary deficiencies can also develop, with growth hormone deficiency and gonadotropin deficiency being the most common.10,21 Patients with LCH may initially present for treatment of a hormonal abnormality, or these problems may surface months or years after diagnosis of LCH.16

24.2.4 Diagnosis The skull base surgeon is likely to become involved in the diagnosis of LCH when a patient presents with an obvious cranial lesion or with a neurologic or endocrinologic deficit and

imaging findings that are of concern. The diagnosis and management of a patient who presents with central DI and a thickened pituitary stalk on imaging, for example, poses a challenge for the practitioner. In the absence of a known LCH diagnosis, tissue sampling is necessary. However, given the morbidity that can result from CNS biopsy, surgeons should ensure that there are no other safe targets for tissue sampling. The surgical considerations for biopsy of the pituitary stalk will be discussed in a following section. The medical literature has demonstrated that most patients with LCH who present with DI are likely to develop extracranial lesions within the first year of diagnosis, which obviates the need for such biopsies.5,10 However, the practitioner should begin with cerebrospinal fluid (CSF) studies for alpha-fetoprotein and beta-human chorionic gonadotropin5 to evaluate for possible germinoma, particularly because that diagnosis is more likely in pediatric patients. CSF cytology can also be helpful in identifying lymphoma. More recently, molecular testing for the BRAF-V600E mutation in peripheral blood or CSF has been studied, and positive results can support a diagnosis of LCH.22 Some authors suggest that, if this workup has negative results and the patient is otherwise stable, the patient can be followed up conservatively with MRI every 3 to 6 months for 5 years.10,23

Staging After a diagnosis of LCH is confirmed, treatment is determined on the basis of disease staging. Traditional staging for LCH is contingent on whether the patient has single-system disease or multisystem disease.1 Patients should undergo positron emission tomography or computed tomography screening to identify the extent of the disease.

Management The discussion of treatment options will be limited to the management of patients with LCH of the CNS. For patients with CNS mass lesions (e.g., meninges, choroid plexus, hypothalamic–pituitary axis, brain parenchyma), isolated lesions are generally treated with resection. In contrast, multifocal lesions are treated with vinblastine and prednisone.22 Retrospective series have suggested that lesions in the skull base, sinuses, and orbit predispose patients to an increased risk of developing DI and that treating them with systemic chemotherapy helps decrease that risk.24,25 Considerable debate remains in terms of developing the best treatment plan for sellar or hypothalamic–pituitary axis LCH. Patients who have presented with unifocal LCH in this area have been treated with

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Rathke Cleft Cyst and Other Sellar Lesions

Fig. 24.1 Coronal T1-weighted magnetic resonance image with contrast of the brain, demonstrating an enhancing sellar mass. Transsphenoidal biopsy was consistent with Langerhans cell histiocytosis. (Used with permission from Barrow Neurological Institute, Phoenix, AZ.)

complete resection,26,27 with biopsy followed by radiation,28 or with biopsy followed by radiation and corticosteroid therapy.29 Given the detrimental location that these lesions sometimes occupy, often with substantial adherence to surrounding brain tissue, the provider must carefully decide how best to treat the patient.

24.2.5 Management of Diabetes Insipidus One of the most challenging debates is the management of DI caused by LCH. Mixed results have been found in patients who have undergone radiation of the hypothalamic–pituitary axis.30,31,32 Some studies have suggested that initiating chemotherapy may help prevent the development of DI,18 whereas others found no improvement in DI among children who were treated with chemotherapy.18,33,34 Surgical resection can lead to improvement of DI. Nishio et al35 resected a pituitary LCH lesion, and the patient had partial improvement of preoperative DI. However, given the surgical proximity of the disease to the posterior pituitary, any surgical treatment may also result in worsened or new-onset DI.

Case Presentation An 11-year-old boy with no clinically significant medical history presented to his primary care physician with several months of increased thirst and urination. These symptoms were initially noticed by his parents, who found that, when the child was riding on a motocross track, he had to stop approximately every 10 minutes to urinate and drink water. He ultimately underwent an endocrinologic evaluation, and treatment with desmopressin, thyroid replacement therapy, and corticosteroid therapy was initiated. A subsequent MRI of the brain

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Fig. 24.2 Sagittal T1-weighted magnetic resonance image with contrast (same patient as in ▶ Fig. 24.1), demonstrating a primarily infundibular mass. (Used with permission from Barrow Neurological Institute, Phoenix, AZ.)

demonstrated an enhancing, primarily infundibular mass approximately 1.0 cm in diameter (▶ Fig. 24.1 and ▶ Fig. 24.2). The patient underwent a transsphenoidal biopsy of the lesion, which was well tolerated. The pathology report was consistent with LCH.

24.3 Erdheim–Chester Disease ECD is a non-LCH disease affecting multiple organs and involving the bones. It is less common than LCH in the pediatric population. Like LCH, its clinical course is variable, and outcomes are largely dependent on the extent of the disease. The pathognomonic features of the disease are symmetrical sclerosis of bones36 and histologic findings of foamy histiocytes that distinguish the disease from LCH.37 CNS lesions are variable but frequently affect the pituitary and hypothalamus. Like patients with LCH, patients with CNS lesions may present with DI and hypopituitarism. CNS involvement is generally associated with a poor prognosis.37 At least 60 cases have been reported in the medical literature.36 Endocrine symptoms may precede diagnosis, but neuroimaging often fails to detect any evidence of the disease. In the cases that have been documented, findings are variable and can sometimes involve pituitary stalk thickening, a tumor-like mass, or the absence of signal of the posterior pituitary.36 When managing a patient with ECD, even when neurologic involvement is obvious, the practitioner can generally make a diagnosis on the basis of the biopsy of non-CNS tissue. However, there have been reports of isolated sellar lesions, consistent with ECD, in patients who received a diagnosis on the basis of pituitary biopsy with no extracranial involvement.38 Few cases exist in the medical literature in which neurosurgical biopsies were performed for initial diagnosis, and typically in such cases the disease presentation in other organ systems (usually bone) was not recognized.36,38 The neurosurgeon

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Controversies in the Management of Histiocytosis and Xanthogranulomas should recognize that, if ECD is diagnosed on biopsy, a further systemic workup, including long-bone imaging, must be undertaken. There are also documented cases of patients with ECD who have presented with obstructive hydrocephalus39 and spinal epidural masses40 requiring more neurosurgical intervention. Given the rarity of ECD, there is no standard best treatment for patients with this diagnosis. Therapies have included bisphosphonates,41 tyrosine kinase inhibitors,42,43 interferon alpha,37 cladribine,44 and even stem cell transplantation.45 Arnaud et al37 found that the presence of CNS involvement was the sole independent predictor of poor survival in their study of 53 patients with biopsy-proven ECD. The data from this group also suggest that treating ECD patients with interferon-alpha, PEGylated interferon-alpha, or both improves survival, with interferon-alpha indicated as the first-line therapy.

24.4 Juvenile Xanthogranuloma JXG is another non-LCH disease that usually affects children by 4 years of age.46 Children typically present with small yellow or brown cutaneous papules, and the disease course is benign. The CNS is one of the most common sites of extracutaneous manifestation. The true incidence of JXG in the CNS is unknown, because if the process of the disease is similar to that of skin lesions with frequent spontaneous regression, many patients may never have neurologic symptoms.46 Patients with JXG may present with single or multiple lesions in numerous locations, including the sella and pituitary. The first-line neurosurgical treatment for JXG is resection in symptomatic patients, occasionally followed by adjuvant chemotherapy or radiotherapy for residual disease.

24.5 Surgical Considerations for Histiocytoses The skull base surgeon will often encounter pediatric patients who have a thickened pituitary stalk of unknown etiology and may be asked to help obtain tissue for diagnosis. In addition to the histiocytoses LCH, ECD, and JXG, which can present in this manner, lesions in this region can also include craniopharyngiomas, lymphomas, germ cell tumors, lymphocytic hypophysitis, sarcoidosis, and tuberculosis. Classically, pituitary stalk biopsies have been encouraged when the stalk diameter is greater than 6.5 to 7.0 mm,47,48,49 despite the surgical risk of disrupting the neural tracts that run through this critical region as well as the increased risk of a CSF leak and anterior pituitary dysfunction. Delaying or avoiding biopsy, however, can lead to clinically significant neurologic, endocrinologic, and systemic morbidity in terms of disease progression. Transcranial approaches were once common for biopsy of the pituitary stalk, but endoscopic transsphenoidal or intraventricular approaches have become increasingly popular.4 Jinguji et al4 reported on 11 patients who underwent endoscopic biopsy of thickened pituitary stalks, 7 with transsphenoidal approaches and 4 with intraventricular approaches. None of these patients had any further deterioration in pituitary function after biopsy. The authors recommended use of the transsphenoidal approach for biopsies associated with intrasellar

lesions or lesions localized to the pituitary stalk and use of intraventricular approaches for lesions that protrude from the infundibulum. Kinoshita et al,49 considering that the posterior pituitary lobe is in continuity with the stalk, recently reported a series of 11 patients who underwent posterior pituitary lobe biopsies rather than stalk biopsies in an effort to obtain a diagnosis and prevent development or worsening of hormonal function. Their data demonstrated that the posterior pituitary lobe specimens provided a histologic diagnosis in all cases. Ten of the 11 patients had DI at presentation, and the patient without DI did not develop signs or symptoms of disease after the biopsy. They suggested posterior pituitary lobe biopsy over stalk biopsy in cases with MRI evidence of swelling of the posterior pituitary lobe and disappearance of the bright spot on T1 images, which indicates an abnormal posterior gland.

24.6 Conclusions The histiocytoses are a rare, diverse group of disorders found primarily in the pediatric population. Although histiocytoses are uncommon, it is probable that a neurosurgeon will eventually encounter patients with CNS manifestations of the disease. A proper systemic workup and approach to diagnosis will assist in appropriate management and help avoid unnecessary harm to this group of patients. It is important for practitioners to become familiar with the particular imaging findings associated with CNS histiocytosis; the options for biopsy and, when necessary, resection; and the subsequent multidisciplinary treatment strategies that may be required.

References [1] Henter JI, Tondini C, Pritchard J. Histiocyte disorders. Crit Rev Oncol Hematol. 2004; 50(2):157–174 [2] Emile JF, Abla O, Fraitag S, et al. Histiocyte Society. Revised classification of histiocytoses and neoplasms of the macrophage-dendritic cell lineages. Blood. 2016; 127(22):2672–2681 [3] Beni-Adani L, Sainte-Rose C, Zerah M, et al. Surgical implications of the thickened pituitary stalk accompanied by central diabetes insipidus. J Neurosurg. 2005; 103(2) Suppl:142–147 [4] Jinguji S, Nishiyama K, Yoshimura J, et al. Endoscopic biopsies of lesions associated with a thickened pituitary stalk. Acta Neurochir (Wien). 2013; 155(1): 119–124, discussion 124 [5] Davidson L, McComb JG, Bowen I, Krieger MD. Craniospinal Langerhans cell histiocytosis in children: 30 years’ experience at a single institution. J Neurosurg Pediatr. 2008; 1(3):187–195 [6] Laurencikas E, Gavhed D, Stålemark H, et al. Incidence and pattern of radiological central nervous system Langerhans cell histiocytosis in children: a population based study. Pediatr Blood Cancer. 2011; 56(2):250–257 [7] Chaudhary V, Bano S, Aggarwal R, et al. Neuroimaging of Langerhans cell histiocytosis: a radiological review. Jpn J Radiol. 2013; 31(12):786–796 [8] Porto L, Schöning S, Hattingen E, Sörensen J, Jurcoane A, Lehrnbecher T. Central nervous system imaging in childhood Langerhans cell histiocytosis - a reference center analysis. Radiol Oncol. 2015; 49(3):242–249 [9] Varan A, Cila A, Akyüz C, Kale G, Kutluk T, Büyükpamukçu M. Radiological evaluation of patients with pituitary Langerhans cell histiocytosis at diagnosis and at follow-up. Pediatr Hematol Oncol. 2008; 25(6):567–574 [10] Prosch H, Grois N, Prayer D, et al. Central diabetes insipidus as presenting symptom of Langerhans cell histiocytosis. Pediatr Blood Cancer. 2004; 43(5): 594–599 [11] Balaguruswamy S, Chattington PD. Partial hypopituitarism and Langerhans cell histiocytosis. BMJ Case Rep. 2011 pii: bcr0720103203 [12] Donadieu J, Rolon MA, Thomas C, et al. French LCH Study Group. Endocrine involvement in pediatric-onset Langerhans’ cell histiocytosis: a populationbased study. J Pediatr. 2004; 144(3):344–350

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Rathke Cleft Cyst and Other Sellar Lesions [13] Haupt R, Nanduri V, Calevo MG, et al. Permanent consequences in Langerhans cell histiocytosis patients: a pilot study from the Histiocyte Society-Late Effects Study Group. Pediatr Blood Cancer. 2004; 42(5):438–444 [14] Mittheisz E, Seidl R, Prayer D, et al. Central nervous system-related permanent consequences in patients with Langerhans cell histiocytosis. Pediatr Blood Cancer. 2007; 48(1):50–56 [15] Van’t Hooft I, Gavhed D, Laurencikas E, Henter JI. Neuropsychological sequelae in patients with neurodegenerative Langerhans cell histiocytosis. Pediatr Blood Cancer. 2008; 51(5):669–674 [16] Kurtulmus N, Mert M, Tanakol R, Yarman S. The pituitary gland in patients with Langerhans cell histiocytosis: a clinical and radiological evaluation. Endocrine. 2015; 48(3):949–956 [17] Aricò M, Egeler RM. Clinical aspects of Langerhans cell histiocytosis. Hematol Oncol Clin North Am. 1998; 12(2):247–258 [18] Grois N, Flucher-Wolfram B, Heitger A, Mostbeck GH, Hofmann J, Gadner H. Diabetes insipidus in Langerhans cell histiocytosis: results from the DAL-HX 83 study. Med Pediatr Oncol. 1995; 24(4):248–256 [19] Dunger DB, Broadbent V, Yeoman E, et al. The frequency and natural history of diabetes insipidus in children with Langerhans-cell histiocytosis. N Engl J Med. 1989; 321(17):1157–1162 [20] Sims DG. Histiocytosis X; follow-up of 43 cases. Arch Dis Child. 1977; 52(6): 433–440 [21] Dean HJ, Bishop A, Winter JS. Growth hormone deficiency in patients with histiocytosis X. J Pediatr. 1986; 109(4):615–618 [22] Yeh EA, Greenberg J, Abla O, et al. North American Consortium for Histiocytosis. Evaluation and treatment of Langerhans cell histiocytosis patients with central nervous system abnormalities: current views and new vistas. Pediatr Blood Cancer. 2018; 65(1) [23] Mootha SL, Barkovich AJ, Grumbach MM, et al. Idiopathic hypothalamic diabetes insipidus, pituitary stalk thickening, and the occult intracranial germinoma in children and adolescents. J Clin Endocrinol Metab. 1997; 82(5): 1362–1367 [24] Grois N, Fahrner B, Arceci RJ, et al. Histiocyte Society CNS LCH Study Group. Central nervous system disease in Langerhans cell histiocytosis. J Pediatr. 2010; 156(6):873–881.e1 [25] Grois N, Prayer D, Prosch H, Minkov M, Pötschger U, Gadner H. Course and clinical impact of magnetic resonance imaging findings in diabetes insipidus associated with Langerhans cell histiocytosis. Pediatr Blood Cancer. 2004; 43(1):59–65 [26] Czech T, Mazal PR, Schima W. Resection of a Langerhans cell histiocytosis granuloma of the hypothalamus: case report. Br J Neurosurg. 1999; 13(2):196–200 [27] d’Avella D, Giusa M, Blandino A, Angileri FF, La Rosa G, Tomasello F. Microsurgical excision of a primary isolated hypothalamic eosinophilic granuloma. Case report. J Neurosurg. 1997; 87(5):768–772 [28] Ober KP, Alexander E, Jr, Challa VR, Ferree C, Elster A. Histiocytosis X of the hypothalamus. Neurosurgery. 1989; 24(1):93–95 [29] Tibbs PA, Challa V, Mortara RH. Isolated histiocytosis X of the hypothalamus. Case report. J Neurosurg. 1978; 49(6):929–934 [30] Broadbent V, Gadner H. Current therapy for Langerhans cell histiocytosis. Hematol Oncol Clin North Am. 1998; 12(2):327–338 [31] Minehan KJ, Chen MG, Zimmerman D, Su JQ, Colby TV, Shaw EG. Radiation therapy for diabetes insipidus caused by Langerhans cell histiocytosis. Int J Radiat Oncol Biol Phys. 1992; 23(3):519–524

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Part VI Other Cranial Tumors

25 Surgical Approach Selection for Skull Base Chordoma

154

26 Chordoma Genetics and Tumor Phenotype Profiles

167

27 Surgery versus Radiation versus Observation: What Treatment Is Best for Skull Base Paraganglioma? 174

VI

28 Management of Chondrosarcoma of the Cranial Base

182

29 Natural History and Treatment Strategies for Posterior Fossa Epidermoids

188

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Other Cranial Tumors

25 Surgical Approach Selection for Skull Base Chordoma Paul A. Gardner, Ahmed Jorge, Juan C. Fernandez-Miranda, Eric W. Wang, and Carl H. Snyderman Abstract The primary and most effective treatment for chordoma is complete removal. In some regions of the spine, this can be achieved as an en bloc resection; however, this is impossible for any but the smallest of chordomas in the cranial base. Often, these tumors are intimately associated with one or both petrous or cavernous carotid arteries, the abducens nerve, pituitary gland, clival dura, and even the vertebrobasilar system. As a result, piecemeal resection is necessary to achieve complete resection without injury to neural and vascular structures. Nevertheless, every large study has correlated gross total resection (GTR) with improved prognosis. True GTR should include resection of any involved bone or dura with the widest possible margins. This may require more than one approach to achieve. Regardless of approach, reconstruction after clival dural resection is a significant challenge and source of complications. This, however, should not alter the goals of surgery. Historically, traditional open approaches such as the extended subfrontal, orbitozygomatic, transpetrous, and far lateral craniotomies provided the standard for resection of chordomas. However, endoscopic endonasal approaches are rapidly becoming the preferred option for these tumors given their direct access to this midline tumor with minimal neurovascular manipulation. Finally, surgeon experience plays a large role in the ability to achieve complete resection with acceptable morbidity and may affect choice of approach. Keywords: surgical approach, cerebrospinal fluid leak, chordoma, complication, resection, skull base

25.1 Introduction Gross total resection (GTR) is a key factor that has been consistently associated with tumor-free survival in chordoma. As a result, complete resection of chordoma should be the goal of any surgical approach. This goal is often challenged by involvement of critical neurovascular structures, most commonly the abducens nerve, internal carotid arteries (ICAs), lower cranial nerves, and the vertebrobasilar vessels. Additional risks of tumor resection, depending on location, range from effects on pituitary function to olfaction to hearing to craniocervical stability. These morbidities must be considered along with the ability to achieve maximal resection in selecting an approach. Chordomas require the surgical team to be facile and familiar with a multitude of approaches to provide each patient with the best option. Naturally, surgeons are biased by their training and comfort with certain approaches, and their ability to provide the best resection with lowest risk should naturally follow their experience and ability. However, an evaluation of the published results of available approaches, performed by experts in each, has the potential to drive the future training of surgeons to allow for idealized care of these challenging tumors.

154

25.2 Review 25.2.1 Methods We identified a total of 881 potential skull base chordoma publications in a PubMed search for relevant keywords including approach, surgery, management, treatment, or prognosis. Dates were constrained to all articles published within the last 10 years (2008–2018) and only major articles published since 1997. Only chordomas of the skull base were included. Animal studies and articles that referred to biochemical pathways, pharmacological treatment, socioeconomic, policy issues, etc. were excluded based on title or abstract information as they offered little to no recommendations or conclusions regarding surgical approaches. Case reports were eliminated from our search as there are multiple higher-level evidence case series and cohort studies already investigating chordoma approaches and with enough sample size to provide more robust recommendations and conclusions. Non-English language articles were also excluded. Finally, we found 49 studies that satisfied the earlier-mentioned inclusion and exclusion criteria. We organized these studies in ▶ Table 25.1, where the level of evidence column is based on the definitions presented by Fisher et al.1 Most large case series provide one consistent conclusion: complete resection provides the best long-term prognosis.4,13,29,35 This is consistent across studies and approaches and confirmed by several meta-analyses.4,13,25,27 The literature does not provide any studies that directly compare approaches for chordoma resection.2,13,16,21 As a result, the only comparisons are between individual case series, which are rarely based on a single approach. The largest meta-analysis available did compare approaches and concluded that anterior midline approaches such as the endoscopic endonasal approach provide superior rates of GTR with fewer complications.27 This level III evidence supports the primary use of endoscopic endonasal surgery (EES) for chordomas. Such reviews fail to account for selection bias of surgical approach and temporal changes in management with a recent proliferation of literature on endonasal approaches to clival chordomas. Regardless, the switch to endoscopic approaches has been accepted by most experts for clival lesions due to superior anatomic accessibility of these midline lesions, deep in the skull base. One aspect of surgical approach which is rarely discussed is the learning curve associated with each technique. With laparoscopic cholecystectomy, the only significant factor in surgical outcome was experience with that specific procedure.51 Koutourousiou et al showed a clear learning curve using EES for chordoma, evolving over 60 cases with increasing degrees of GTR without an increase in complications over time.26 Di Maio et al showed similar improvements over time by comparing results in a later cohort of 95 tumors managed with largely “open” approaches.12 Given that this same learning curve is present for any approach and tumor, surgeon experience and comfort with an approach is a key factor that is not easily

Year 1997

2007

2014

2009

2010

2013

2008

Authors

Al-Mefty and Borba2

Almefty et al3

Amit et al4

Arbolay et al5

Carrabba et al6

Chibbaro et al7

Cho et al8 19

54

60

2

196

67

23

Patients

IV

IV

IV

IV

IV

IV

IV

Level of evidence

Multiple approaches used (e.g., transsphenoidal, orbitozygomatic, pterional) Total: 16% Subtotal: 58% Partial: 26%

Endoscopic endonasal Total: 65% Subtotal: 17% Partial: 19%

Endoscopic endonasal (17) and open (anterior or lateral, 43). Endoscopic Total: 59% Partial: 41% Open Total: 84% Partial: 16% Note: endoscopic and open groups are not comparable due to selection bias

Transsphenoidal endoscopic Total: 50% Partial: 50%

Open surgery (114), transsphenoidal (4), and endoscopic (68). Total: N/A Subtotal: N/A Partial: N/A

Approaches N/A Total: 45% Subtotal: N/A Partial: N/A

Multiple surgical approaches Total: 43% Subtotal: 48% Partial: 9%

Approach and degrees of tumor resection

CN deficits (42)

CSF leak (8), meningitis (14)

Endoscopic: CSF leak(24), tension pneumocephalus (6), intracranial hematoma (6), CN palsy (47), hematoma (6), Open: 33% morbidity

None reported

Open surgery: CSF leak (12), meningitis (10), CN deficit (20), endocrine disorder (7). Transsphenoidal: Meningitis (7), endocrine disorder (7). Endoscopic: CSF leak (11), hydrocephalus (4), CN deficit (4)

N/A

CSF leak (4), meningitis (9), oronasal fistula (13), CN deficit (26)

Operative complications (%)

Table 25.1 Relevant articles discussing surgical approaches for chordoma of the skull base using search methodology described in “Methods” section

Progression-free survival rate of 40% at 5 y

11% recurred

No recurrence in a median follow-up time of 16 mo for the endoscopic subgroup. For the open approach subgroup, the mortality rate was 24% in a mean follow-up period of 5 y

N/A

5-year disease-free survival was 94% for total resection for any approach. Subgroup approach analysis not available

A 10-year survival rate of 59%

24% recurrence. Mean diseasefree interval was 14.4 mo

Recurrence and survival rates

Chordomas are much more aggressive and exhibit lower survival rates than those from chondrosarcomas

Extended endonasal approach for centrally located lesions or as an adjunct. Systematic radiotherapy in all patients

Although the open approach is associated with higher rates of morbidity and higher rates of total resections (the latter likely to selection bias), the authors favor the endoscopic approach

The endoscopic approach is a promising technique for tumors with clivus involvement

Complete resection is associated with better outcomes. Adjuvant radiotherapy improves survival for partial resections

Radical surgical resection and radiotherapy are the optimal treatment for chordomas

Radical excision and postoperative radiation are recommended

Conclusions/Recommendations

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155

156

Year

2001

2004

2008

2012

1999– 2011

2011

2008

2010

2016

Authors

Colli and Al-Mefty9

Couldwell et al10

Dehdashti et al11

Di Maio et al12

Di Maio et al13

Eid et al14

Fatemi et al15

Fraser et al16

Garzaro et al17

Table 25.1 (continued)

9

7

14

7

807

95

12

18

53

Patients

IV

IV

IV

IV

IV (metaanalysis)

IV

IV

IV

IV

Level of evidence

3D-endoscopic transnasal transsphenoidal Total: 67% Subtotal: 11% Partial: 22%

Endonasal > 95%: 71% Partial: 29%

Endoscopic endonasal transsphenoidal Total: 43% Subtotal: 43% Partial: 14%

Approaches N/A Subtotal: 86% Biopsy: 14%

Multiple approaches across studies Total: 0–74% Subtotal: N/A Partial: N/A

Multiple approaches (e.g., subfrontal, orbitozygomatic, anterior and posterior transpetrosal) but no endoscopic endonasal Total: 71% Subtotal: N/A Partial: N/A

Expanded endoscopic endonasal Total: 58% Subtotal: 42%

Transsphenoidal Total: 12 Subtotal: N/A Partial: N/A

Multiple approaches (e.g., cranioorbitozygomatic, maxillotomy, transsphenoidal) Total: 45% Subtotal: 28% Partial: 26%

Approach and degrees of tumor resection

CSF leak (22) and CN palsy (11)

No CSF leaks, pulmonary embolus (14), diplopia (57), CN deficits (14)

CSF leak (57), CN deficit (71), adrenal insufficiency (7), meningitis (7), transient diabetes insipidus (7)

N/A

N/A

From 1988 to 1999: CN involvement (48), vascular (14), CSF or wound (2), systemic (2) From 2000 to 2011: CN involvement (10), vascular (3), CSF or wound (16), systemic (0)

CSF leak (33), tension pneumocephalus (8), hematoma (8), hemiparesis (8), hydrocephalus (8)

CSF fistula (6), internal carotid hemorrhage (17), hemiparesis (6), CN deficit (11)

CSF leak (9), hydrocephalus (4), seizures (6), meningitis (2), CN involvement (45), pneumocephalus (2), basal ganglia infarction (2), quadriparesis (2)

Operative complications (%)

N/A

29% recurrence rate and a mean disease-free period of at least 18 mo on the remaining cohort

Recurrence rate of 14% within a median follow-up period of 20 mo

71% recurrence rate with a 14% mortality rate and a mean follow-up period of 88 mo

68% recurrence rate with an average disease-free interval of 45 mo

5-y overall survival was significantly higher in the second era (93 vs. 64%)

0% recurrence during a median follow-up period of 16 mo

N/A

Mortality rate of 14% and a 5-y recurrence rate of 51%

Recurrence and survival rates

3D vision complements the dissection and skull repair stages of the endoscopic approach

There is a significant relationship between tumor size and total resection success. Tumors with a volume bigger than 80 cm3 or a diameter bigger than 4 cm are more difficult to remove endonasally

Endoscopy is an excellent tool for tumor removal and assessment of resection

Subtotal resection and adjunctive radiotherapy or radiosurgery resulted in favorable outcomes

Complete excision is associated with improved survival

Aggressive tumor removal strategies involving modern skull base approaches are qualitatively different and confer at the very least similar outcomes as their older counterparts

The endoscopic endonasal approach can be used as an alternative to centrally located clival chordomas

The majority of chordomas can be successfully accessed via the extended transsphenoidal approach

Total resection and adjuvant radiotherapy resulted in better prognosis. Chordoma histology and patient’s age were not significant in determining prognosis

Conclusions/Recommendations

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Year 2016

2010

2009

2010

2015

2011

2017

Authors

Gui et al18

Holzmann et al19

Hong Jiang et al20

Ito et al21

Jahangiri et al22

Kano et al23

Kim et al24

Table 25.1 (continued)

37

71

50

19

12

13

161

Patients

IV

IV

IV

IV

IV

IV

IV

Level of evidence

Transclival endoscopic endonasal in combination with transcavernous (91%) Total: 67%a Subtotal: 33%a

Stereotactic radiosurgery as primary, adjuvant, or salvage treatment. After radiosurgery: Total: 3% Partial: 32% Stable: 32% Progression: 32%

Multiple approaches (e.g. endonasal transsphenoidal, transoral, craniotomy) Total: 52% Subtotal: N/A Partial: N/A

Multiple approaches (e.g., transsphenoidal, orbitozygomatic, petrosal, transcondylar) including one endoscopic endonasal Total: 74% Subtotal: 21% Partial: 5%

Endonasal transseptal transsphenoidal (9) and endoscopic transoropharyngeal (3) Total: 58% Subtotal: 33% Partial: 8%

Transnasal transclival Total or subtotal: 92% Partial: 8%

Transnasal endoscopic (124), open cranial base (11), staged using both (26). Total: 24% Subtotal: 53% Partial: 18%

Approach and degrees of tumor resection

CSF leak (17), meningitis (1), CN palsy (2)

Adverse radiation effects (9), abducens neuropathy (3), facial neuropathy (1), trigeminal and abducens neuropathy (1), anterior pituitary dysfunction (3)

Meningitis (12), CSF leak (12), CN neuropathies (6), diabetes insipidus (4)

CSF leak (16), CN deficits (26)

No severe bleedings, infections, motor or visual deficits. Dura defect (8%), nasal dryness (75%), eye dryness (42%)

Cavernous sinus bleeding (15), CSF fistula (8)

CSF leak (7), infection (2), CN deficit (11), internal carotid rupture (1), brain stem infarction (1), hydrocephalus (1)

Operative complications (%)

Recurrence rates of 19% during a mean follow-up period of 33 mo

73% survival rate after a follow-up period of 10 y with a median survival time of 14 y

49% remained disease-free or stable at a follow-up of 41 mo

The recurrence rate was 58% with a 5-y progression-free survival of 48%

All patients who received a total or subtotal resection and post-op radiation were recurrence free in a follow-up period of 6 mo to 3 y

100% disease-free rate for all patients who underwent a gross total resection with a follow-up period of 18 mo

16% recurrence rate among total resection subgroup and 64% recurrence rate in the remaining two groups with a follow-up period of 39 mo

Recurrence and survival rates

A central tumor without laterality is associated with higher rates of total resection

Stereotactic radiosurgery is a possible treatment for small chordomas along with surgical resection in some cases

Total resection is associated with decreased recurrence rates

Long-term management was achieved. Radiosurgery was used in 21% of cases

Combination of endoscopic approach and post-op radiation therapy

The transnasal transclival approach was a successful approach; however, large-size dural reconstructions were difficult

The authors developed a novel classification method for the selection of the surgical approach. This method might improve resection degree

Conclusions/Recommendations

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157

158 Year 2011

2012

2016

2014

2014

2017

2017

Authors

Komotar et al25

Koutourousiou et al26

Labidi et al27

Ouyang et al28

Rachinger et al29

Rahme et al30

Ramm-Pettersen et al31

Table 25.1 (continued)

10

17

47

77

1,050 (metaanalysis)

60

766 (systematic review)

Patients

III

IV

IV

IV

III

IV

III

Level of evidence

Endoscopic transsphenoidal (6) and followed up untreated (4). Endoscopic: Total: 67% Subtotal: N/A Partial: N/A

Endoscopic endonasal Total: 53% Subtotal: N/A Partial: N/A

The majority with transsphenoidal (40%), transfacial (17%), and retrosigmoid (17%). Total: 15% Partial: 81% Extended biopsy: 4%

Endonasal, pterional, retrosigmoid, suboccipital. Total: 33% Subtotal: 48% Partial: 12%

Purely anterior midline (6 studies, n = 116, e.g., endoscopic, microscopic, transseptal) vs. transcranial (10 studies, n = 495, e.g., pterional, subfrontal) Purely midline Total: 61% Mixed: N/A Total: 42%

Endoscopic endonasal Total: 67% Subtotal: 15% Partial: 18%

Endoscope assisted (127) vs. open microscope-assisted (639). Endoscopic: Total: 61% Subtotal: 27% Open: Total: 48% Subtotal: 48%

Approach and degrees of tumor resection

CSF leak (17), CN neuropathies (83)

Three out of four patients remain disease free in a mean of 94 mo

Recurrence rate of 29% with a mean follow-up of 63 mo

The median progression-free survival was 7.3 y. Recurrence noted in 55% of cohort

“Complication rates in the lower ends,” only one specifically mentioned: CN deficit (17)

CSF leak (35), CN palsy (29), meningitis (18), post-op stroke (12)

5-y overall survival was 93, 61, and 16% for the total, subtotal, and partial resection groups, respectively. 32% of the cases died of tumor recurrence

Recurrence rate of 38% and overall survival of 74% with a mean follow-up period of 52 mo for the overall cohort

Recurrence rate of 33%, mean recurrence period of 14 mo and mean follow-up of 18 mo

Mortality rate 5% (endoscopic) vs. 22% (open) with a 5-y survival of 66% for the open cases (no survival reported for endoscopic). Recurrence rates 40% (open) vs. 17% (endoscopic)

Recurrence and survival rates

CSF leak (5), hematoma (5), hemiparesis (4), cerebral infarction (3), epilepsy (2), meningitis (2), CN deficit (5)

Purely midline: CSF leak (22), CNS infection (2), CN deficit (8). Mixed: CSF leak (10), CNS infection (6 CN deficit (16)

CSF leak (20), meningitis (3), CN palsy (7), carotid injury (3), pontine hemorrhage (2), hematoma (2), SIADH (2), sinus infection (2), pulmonary embolism (2)

Endoscopic: CN deficit (1), CSF leak (5), pneumonia (0), meningitis (1), diabetes insipidus (1), infection (0), hydrocephalus (1). Open: CN deficit (24), CSF leak (11), pneumonia (2), meningitis (6), diabetes insipidus (2), infection (4), hydrocephalus (2)

Operative complications (%)

Endoscopic transsphenoidal is an acceptable choice for the treatment of chordomas while a “wait and scan” can be an alternative as well in very specific patients

Total resection with adjuvant radiotherapy improves outcomes

Complete resection improves survival

Extend of resection is correlated with outcome.

Anterior midline approaches were associated with higher total resection rates and lower complications

Larger tumor volumes, tumor location, and previously treated were significant factors in outcomes

Endoscopic approach had significantly higher percentage of total resection and fewer complications and lower recurrence rates

Conclusions/Recommendations

Controversies in Skull Base Surgery | 04.06.19 - 14:45

Year 2011

2007

2001

2010

2014

2010

2009

2009

Authors

Saito et al32

Samii et al33

Sekhar et al34

Sen et al35

Shidoh et al36

Solares et al37

Stippler et al38

Takahashi et al39

Table 25.1 (continued)

32

20

4

18

71

42

49

6

Patients

IV

IV

IV

III

IV

IV

IV

IV

Level of evidence

Multiple approaches (e.g., transpetrosal, transoral, transsphenoidal) Subtotal: 41% Partial: 59%

Endoscopic endonasal Total: 67% Subtotal: 17% Partial: 17%

Transnasal endoscopic Total: 75% Subtotal: N/A% Partial: N/A%

Transoral (9) vs. endoscopic endonasal (9) Transoral: Total: 11% Subtotal: 44% Partial: 44% Endonasal: Total: 33% Subtotal: 22% Partial: 44%

Multiple approaches (e.g., subfrontal, transmaxillary, transcervical, transpetrosal) including endoscopic endonasal. Total: 58% Incomplete: 42%

Multiple approaches (e.g., subfrontal, frontotemporal, petrosal) but not including endoscopic. Total: 59% Subtotal: 28% Partial: 11%

Multiple approaches (e.g., transethmoidal, pterional, retrosigmoid) Total: 49% Subtotal: 51%

Endoscopic endonasal Total: 50% Subtotal: 17% Partial: 33%

Approach and degrees of tumor resection

Hemiparesis (7), meningitis (7), CSF leak (7), CN deficit (5), wound infection (2), post-op hemorrhage (2)

CSF leak (25), brainstem hemorrhage (5%), transient hemiparesis (10)

N/A

Transoral: CSF leak (22) pharyngeal fistula (11). Endonasal: CSF leak (33), meningitis (22), diabetes insipidus (11), infarction (11)

Hydrocephalus (13), hemiparesis (8), brain infarction (3), hematoma (1), CSF leak (20)

CSF leak (26), vessel injury (12), CN deficit (33), major stroke (5), death (12)

CSF leak (5), meningitis (5), postop hemorrhage (5), hydrocephalus (5), brain edema (5)

CSF leak (67), transient diabetes insipidus (17), meningitis (17), infarction (17)

Operative complications (%)

76% survival rate for no radiotherapy compared to 86% for radiotherapy within a mean follow-up period of 36 mo

Recurrence seen in 10% of patients from the total resection subgroup during a mean follow-up period of 13 mo

68%b of patients were disease free with a mean follow-up of 32 mob

N/A

5-y survival of 75%. 49% recurrence

35% recurrence at 5 y

The 5-y survival rate was 65%

N/A

Recurrence and survival rates

Survival rates were improved with surgical removal and post-op radiotherapy

Disease progression and recurrence were significantly associated with percentage of tumor resection

Transnasal endoscopic approach to the sphenoclival region is possible

The endonasal approach results in higher total resections; however, complications were higher in the endonasal group mainly due to a more involved management of subdural invasion

Radical resection improves survival

Radical excision and radiotherapy of remnants is an acceptable treatment. The main cause of death was attributed to vascular complications

While it increases morbidity, radical surgery also increases the recurrence-free interval

Resection using the endoscopic endonasal approach yielded a total resection for the majority of patients with few complications

Conclusions/Recommendations

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159

160 Year 2014

2012

2012

2006

2014

2017

2010

Authors

Tamura et al40

Tan et al41

Taniguchi et al42

Tzortzidis el al43

Vellutini et al44

Wang et al45

Wu et al46

Table 25.1 (continued)

106

238

26

74

4

14

24

Patients

IV

III

IV

IV

IV

IV

IV

Level of evidence

Subdural approaches for most cases Total: 10% Subtotal: 48% Partial: 16%

Anterior midline (51, e.g., microscopic and endoscopic endonasal, transmaxillary) and lateral (187, e.g., transpetrous, zygomatic) Anterior midline: Total: 8% Subtotal: 41% Partial: 51% Lateral: Total: 13% Subtotal: 58% Partial: 55%

All underwent a transsphenoidal, with some undergoing transsphenoidal + transpterygoid (7) and transsphenoidal + transpterygoid + retropharyngeal (2) Total: 50% Subtotal: 27% Partial: 23%

Multiple approaches (e.g., subfrontal, frontotemporal orbitozygomatic transcavernous) Total: 72% Subtotal: 28%

Transsphenoidal using a side-view endoscope. Total: 100%

Transnasal Total: 50% Partial: 50%

Multiple approaches (e.g., transsphenoidal, craniofacial, orbitozygomatic) including endoscopic endonasal. Total: 67% Subtotal: 25% Partial: 8%

Approach and degrees of tumor resection

N/A

Meningitis (8), CSF leak (4), stroke (3), hydrocephalus (2), death (0.4) (only overall complications available)

Fistula (23), meningitis (12), endocrine disorder (4), stroke (8), death (12), pneumocephalus (8), epistaxis (4), pulmonary embolism (1)

CSF leak (1), hydrocephalus (1), CN deficit (4), deep vein thrombosis (3), pulmonary emboli (1), stroke (1), sinus infection (1), death (3)

CSF leak (25), CN palsy (25)

CSF leak (21), hydrocephalus (7), CN deficit (7)

CSF leak (2), CN palsy (25), hypopituitarism (4), diabetes insipidus (4)

Operative complications (%)

Recurrence rate of 53 and 88% at 5 and 10 y, respectively

For both approaches, the overall survival period was 111 and 99 mo for the total and subtotal subgroups, respectively (partial unavailable)

N/A

Recurrence-free survival rate was 31% at 10 y

100% symptom free for a mean follow-up period of 21 mo

Disease-free survival is 71% (5) for first-time cases vs. 29% (2) for a revision case

5-y survival rate and progression-free survival rate was 47%

Recurrence and survival rates

A total resection, when compared to a subtotal, is significantly associated with better survival

The anterior midline approach, in comparison to the lateral approach, was significantly associated with higher total resection rates

Lateral extensions and previous surgery for chordoma are associated with poorer outcomes

An aggressive resection is recommended and results in a longer tumor-free period

A side-view endoscope option should be considered in the transsphenoidal approach

Endoscopic resection of clival chordomas is a safe and viable alternative to the open approach

Aggressive surgical removal, using various techniques, results in better outcomes

Conclusions/Recommendations

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2012

2008

2008

2018

Yasuda et al47

Yoneoka et al48

Zhang et al49

Zoli et al50 65

7

13

40

Patients

IV

IV

IV

IV

Level of evidence

Endoscopic Transsphenoidal Total: 59% Subtotal: 35% Partial: 6%

Endoscopic endonasal Total: 86% Subtotal: 14%

Approach N/A Subtotal: 62% Partial: 38%

Multiple approaches (endoscopically, 5) with multimodalities in some cases. Total: 43% Subtotal: 48% Partial: 10%

Approach and degrees of tumor resection

CSF leak (3), CN deficit (6), ICA injury (3)

N/A

N/A

CSF leak (11).

Operative complications (%)

26% recurrence. 77% survival at 5 y and 57% survival at 10 y (Kaplan–Meyer analysis)

Disease-free survival is 86% for a mean follow-up period of 21 mo

A 5-y survival rate was 83%

Disease progressed in 18% of the total, 11% of the subtotal, and 75% of the partial approach subgroups. Mean follow-up period was 48, 40, and 68 mo, respectively

Recurrence and survival rates

Extended endonasal approach is an acceptable approach for a chordoma

The nasoendoscopic approach provides an advantageous visualization of deeper anatomic structures

Outcomes using surgery with local irradiation or with stereotactic radiosurgery are comparable to proton beam therapy

Multimodal surgery and proton therapy resulted in improved outcomes

Conclusions/Recommendations

Abbreviations: CSF, cerebrospinal fluid; CN, cranial nerve; ICA, internal carotid artery; SIADH, syndrome of inappropriate antidiuretic hormone secretion; N/A, not available. Definitions for resection rates: total, absence of tumor; subtotal, resection of > 90 to 95% of tumor; partial, resection of < 90 to 95% of tumor. aSeries mixes chordomas (37) and chondrosarcoma (5). bThese numbers are combined with other pathologies of the sphenoid sinus.

Year

Authors

Table 25.1 (continued)

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161

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Other Cranial Tumors

Fig. 25.1 Sagittal FLAIR (a) and axial T2-weighted (b) MRI images showing a small, largely interdural chordoma (arrow) causing an abducens palsy in an 11-year-old girl. Given its largely midline location and direct access behind the sphenoid sinus, an endoscopic endonasal approach was chosen for resection.

quantified when considering the optimal approach. Therefore, while recent literature favors EES for many chordomas, this does not take into account an individual surgeon’s experience with the approach. One additional inference can be drawn from the literature, that no single approach is best for all tumors. Koutourousiou et al found that inferolateral tumors had a greater risk of residual/recurrent tumor following EES and would therefore benefit from a combination of approaches.26 Many of the open series also include ventral midline approaches, either transoral or transsphenoidal (microscopic, nonendoscopic).22,25,36,39,45 This heterogeneity reflects not only surgeon preference and experience but also the complementary benefits of multiple approaches. In the end, the surgeon must choose the approach or approaches that provide the best option for achieving GTR. This may vary by center with similar results. Hopefully over time, training in all approaches will become standardized allowing more equanimity in the decision of best approach, based on tumor extent, anatomic relationships, and reconstruction options.

25.3 Case Examples Traditional approaches to the clivus are based on a division of the clivus into thirds around the neural foramina. The upper third, including anything at or above the trigeminal nerve and Meckel’s cave can be accessed via an orbitozygomatic approach. Middle third tumors (between the trigeminal and jugular foramina) require a transpetrosal approach (anterior or posterior, depending on epicenter and extension). Lower third tumors, below the jugular foramen, are treated with a far lateral or extreme lateral approach. Naturally, these can be combined or staged for tumors which cross these borders and subfrontal approaches can provide midline access to the majority of the clivus. Endonasal approaches to the clivus utilize different landmarks for divisions of the clivus. The upper and middle clivus are divided by the floor of the sella; the middle and lower clivus are divided by the floor of the sphenoid sinus. The endonasal approach provides access to all three divisions; access to the superior clivus requires transposition of the pituitary gland.52

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25.3.1 Case 1: Upper Clival Chordoma An 11-year-old girl presented with long-standing diplopia, a left abducens nerve palsy, and mild headache. Magnetic resonance imaging shows an upper clival tumor, largely intradural, which imaging characteristics suspicious for chordoma (▶ Fig. 25.1). She underwent EES, including bilateral posterior clinoid resection via an interdural, transcavernous pituitary transposition, wide dural resection, and multilayer reconstruction with a vascularized nasoseptal flap. Postoperative imaging shows a complete resection with no evidence of recurrence (▶ Fig. 25.2). She was referred for strabismus surgery 3 months postoperatively as her abducens nerve did not stimulate intraoperatively despite being anatomically intact.

25.3.2 Case 2: Craniocervical Junction Chordoma A 26-year-old man presented with occipital headache and dysarthria related to a right hypoglossal nerve palsy. Imaging showed an extensive craniocervical junction chordoma extending lateral to the right hypoglossal canal, involving the condyle and mastoid, dens and atlantoaxial ligaments (▶ Fig. 25.3). He underwent a combined, two-stage resection, consisting of EES to remove the midline tumor to the condyle and hypoglossal canals bilaterally, followed by a right far lateral approach to resect the remainder of the tumor in the condyle, lateral to the hypoglossal canal, followed by posterior occipito-cervical fixation. Postoperative imaging (▶ Fig. 25.4) showed a complete resection and he had partial improvement of his hypoglossal palsy with preservation of swallowing function.

25.3.3 Case 3: Panclival Chordoma A 27-year-old man presented with diplopia and headache with partial oculomotor and abducens nerve palsies. Imaging showed a giant chordoma, centered around the upper clivus, but involving the entire clivus (▶ Fig. 25.5). EES, including

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Surgical Approach Selection for Skull Base Chordoma

Fig. 25.2 Postoperative, sagittal FLAIR (a) and axial T2-weighted (b) MRI images show complete resection via endoscopic endonasal approach. There is a robust nasoseptal flap (arrow) seen supporting the skull base defect created by the wide margin of resection.

Fig. 25.3 Axial T2-weighted MRI sequences showing an extensive craniocervical junction chordoma with involvement of the lower clivus, atlantoaxial ligaments, and condyle which required a two-stage resection via endoscopic endonasal approach (EEA) (arrow, a) followed by a far lateral and transmastoid approach (arrow, b).

Fig. 25.4 Postoperative, T2-weighted axial MRI sequences showing complete resection of the tumor in ▶ Fig. 25.3. The patient has a Foley balloon (arrow, a) to support the multilayer endonasal reconstruction, including a nasoseptal flap and fat graft to fill the mastoid defect created by tumor removal via a far lateral approach (arrow, b).

resection of invaded dura of the sellar floor, dorsum sellae, and entire clivus, was performed with GTR. He did well initially but developed delayed nasoseptal flap necrosis with meningitis 2 weeks after surgery. This was treated with debridement and

placement of a vascularized inferior turbinate/lateral nasal wall flap as well as intravenous antibiotic therapy. He has been well without wound breakdown or evidence of recurrence following proton beam irradiation (▶ Fig. 25.6).

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Other Cranial Tumors

Fig. 25.5 Axial T2 (a) and postcontrast (b), T1weighted axial MRI images showing a large, panclival chordoma. Sagittal, postcontrast T1weighted MRI (c) and sagittal CT angiogram (d) reconstruction show the extent of clival involvement. The upper and midclivus are obliterated by the tumor and the pituitary cannot be easily identified. An endoscopic endonasal approach was chosen given the midline location and extent of clival involvement.

Fig. 25.6 Axial T2 (a), postcontrast, T1-weighted (b) axial and sagittal (c) MRI images following endoscopic endonasal resection of a large, panclival chordoma. There is a robustly enhancing inferior turbinate flap (arrow) which replaced the previously nonenhancing and necrotic nasoseptal flap. In addition, the intact pituitary gland and stalk can be clearly identified (arrowhead, c).

25.4 Conclusions Currently, there is lack of level I evidence to guide treatment of skull base chordoma. However, there is consensus among large case series that GTR provides a clear survival benefit. In addition, there is some early level III evidence in the form of metaanalyses that suggests that EES may provide greater degrees of resection with lower morbidity. However, this must be tempered by case selection bias and evidence that, even in large

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EES series, there are cases which require combined approaches for complete resection. This, combined with the consistent evidence supporting GTR and significant learning curve for endoscopic transclival approaches, leads to the conclusion that EES can be considered as a first-line option for clival chordoma, but no single approach can be recommended, only that complete resection should be the goal of any surgical treatment. Due to the complexity of these surgeries and the association of GTR with experience, chordomas should be treated at centers with

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Surgical Approach Selection for Skull Base Chordoma significant experience. Referral is appropriate when adequate resources or experience is not available, regardless of approach.

25.5 Future Studies In order to avoid the bias of retrospective reviews, a multicenter prospective, randomized controlled trial would be necessary to directly compare approaches; however, given the rarity of chordoma, this is impractical. Case–control comparative (prospective or retrospective) outcome studies between expert centers are the most reasonable option to provide a greater level of evidence to guide approach selection. In addition, expert opinion pieces, anatomic studies, and clinical studies showing location of residual tumor would help detail anatomic and technical limitations of each approach so that treating physicians can determine which approach is best for each individual tumor. Training programs should incorporate teaching of all approaches so that the next generation of surgeons is best equipped to manage patients with chordoma.

References [1] Fisher CG, Wood KB. Introduction to and techniques of evidence-based medicine. Spine. 2007; 32(19) Suppl:S66–S72 [2] Al-Mefty O, Borba LAB. Skull base chordomas: a management challenge. J Neurosurg. 1997; 86(2):182–189 [3] Almefty K, Pravdenkova S, Colli BO, Al-Mefty O, Gokden M. Chordoma and chondrosarcoma: similar, but quite different, skull base tumors. Cancer. 2007; 110(11):2457–2467 [4] Amit M, Na’ara S, Binenbaum Y, et al. Treatment and outcome of patients with skull base chordoma: a meta-analysis. J Neurol Surg B Skull Base. 2014; 75(6):383–390 [5] Arbolay OL, González JG, González RH, Gálvez YH. Extended endoscopic endonasal approach to the skull base. Minim Invasive Neurosurg. 2009; 52 (3):114–118 [6] Carrabba G, Dehdashti AR, Gentili F. Surgery for clival lesions: open resection versus the expanded endoscopic endonasal approach. Neurosurg Focus. 2008; 25(6):E7 [7] Chibbaro S, Cornelius JF, Froelich S, et al. Endoscopic endonasal approach in the management of skull base chordomas–clinical experience on a large series, technique, outcome, and pitfalls. Neurosurg Rev. 2014; 37(2):217–224, discussion 224–225 [8] Cho YH, Kim JH, Khang SK, Lee J-K, Kim CJ. Chordomas and chondrosarcomas of the skull base: comparative analysis of clinical results in 30 patients. Neurosurg Rev. 2008; 31(1):35–43, discussion 43 [9] Colli B, Al-Mefty O. Chordomas of the craniocervical junction: follow-up review and prognostic factors. J Neurosurg. 2001; 95(6):933–943 [10] Couldwell WT, Weiss MH, Rabb C, Liu JK, Apfelbaum RI, Fukushima T. Variations on the standard transsphenoidal approach to the sellar region, with emphasis on the extended approaches and parasellar approaches: surgical experience in 105 cases. Neurosurgery. 2004; 55(3):539–547, discussion 547–550 [11] Dehdashti AR, Karabatsou K, Ganna A, Witterick I, Gentili F. Expanded endoscopic endonasal approach for treatment of clival chordomas: early results in 12 patients. Neurosurgery. 2008; 63(2):299–307, discussion 307–309 [12] Di Maio S, Rostomily R, Sekhar LN. Current surgical outcomes for cranial base chordomas: cohort study of 95 patients. Neurosurgery. 2012; 70(6):1355– 1360, discussion 1360 [13] Di Maio S, Temkin N, Ramanathan D, Sekhar LN. Current comprehensive management of cranial base chordomas: 10-year meta-analysis of observational studies. J Neurosurg. 2011; 115(6):1094–1105 [14] Eid AS, Chang UK, Lee SY, Jeon DG. The treatment outcome depending on the extent of resection in skull base and spinal chordomas. Acta Neurochir (Wien). 2011; 153(3):509–516 [15] Fatemi N, Dusick JR, Gorgulho AA, et al. Endonasal microscopic removal of clival chordomas. Surg Neurol. 2008; 69(4):331–338

[16] Fraser JF, Nyquist GG, Moore N, Anand VK, Schwartz TH. Endoscopic endonasal transclival resection of chordomas: operative technique, clinical outcome, and review of the literature. J Neurosurg. 2010; 112(5):1061–1069 [17] Garzaro M, Zenga F, Raimondo L, et al. Three-dimensional endoscopy in transnasal transsphenoidal approach to clival chordomas. Head Neck. 2016; 38 Suppl 1:E1814–E1819 [18] Gui S, Zong X, Wang X, et al. Classification and surgical approaches for transnasal endoscopic skull base chordoma resection: a 6-year experience with 161 cases. Neurosurg Rev. 2016; 39(2):321–332, discussion 332–333 [19] Holzmann D, Reisch R, Krayenbühl N, Hug E, Bernays RL. The transnasal transclival approach for clivus chordoma. Minim Invasive Neurosurg. 2010; 53(5–6):211–217 [20] Hong Jiang W, Ping Zhao S, Hai Xie Z, Zhang H, Zhang J, Yun Xiao J. Endoscopic resection of chordomas in different clival regions. Acta Otolaryngol. 2009; 129(1):71–83 [21] Ito E, Saito K, Okada T, Nagatani T, Nagasaka T. Long-term control of clival chordoma with initial aggressive surgical resection and gamma knife radiosurgery for recurrence. Acta Neurochir (Wien). 2010; 152(1):57–67, discussion 67 [22] Jahangiri A, Chin AT, Wagner JR, et al. Factors predicting recurrence after resection of clival chordoma using variable surgical approaches and radiation modalities. Neurosurgery. 2015; 76(2):179–185, discussion 185–186 [23] Kano H, Iqbal FO, Sheehan J, et al. Stereotactic radiosurgery for chordoma: a report from the North American Gamma Knife Consortium. Neurosurgery. 2011; 68(2):379–389 [24] Kim YH, Jeon C, Se Y-B, et al. Clinical outcomes of an endoscopic transclival and transpetrosal approach for primary skull base malignancies involving the clivus. J Neurosurg. 2017(June):1–9 [25] Komotar RJ, Starke RM, Raper DMS, Anand VK, Schwartz TH. The endoscopeassisted ventral approach compared with open microscope-assisted surgery for clival chordomas. World Neurosurg. 2011; 76(3–4):318–327, discussion 259–262 [26] Koutourousiou M, Gardner PA, Tormenti MJ, et al. Endoscopic endonasal approach for resection of cranial base chordomas: outcomes and learning curve. Neurosurgery. 2012; 71(3):614–624, discussion 624–625 [27] Labidi M, Watanabe K, Bouazza S, et al. Clivus chordomas: a systematic review and meta-analysis of contemporary surgical management. J Neurosurg Sci. 2016; 60(4):476–484 [28] Ouyang T, Zhang N, Zhang Y, et al. Clinical characteristics, immunohistochemistry, and outcomes of 77 patients with skull base chordomas. World Neurosurg. 2014; 81(5–6):790–797 [29] Rachinger W, Eigenbrod S, Dützmann S, et al. Male sex as a risk factor for the clinical course of skull base chordomas. J Neurosurg. 2014; 120(6):1313–1320 [30] Rahme RJ, Arnaout OM, Sanusi OR, Kesavabhotla K, Chandler JP. Endoscopic approach to clival chordomas: the northwestern experience. World Neurosurg. 2018; 110:e231–e238 [31] Ramm-Pettersen J, Frič R, Berg-Johnsen J. Long-term follow-up after endoscopic trans-sphenoidal surgery or initial observation in clivus chordomas. Acta Neurochir (Wien). 2017; 159(10):1849–1855 [32] Saito K, Toda M, Tomita T, Ogawa K, Yoshida K. Surgical results of an endoscopic endonasal approach for clival chordomas. Acta Neurochir (Wien). 2012; 154(5):879–886 [33] Samii A, Gerganov VM, Herold C, et al. Chordomas of the skull base: surgical management and outcome. J Neurosurg. 2007; 107(2):319–324 [34] Sekhar LN, Pranatartiharan R, Chanda A, Wright DC. Chordomas and chondrosarcomas of the skull base: results and complications of surgical management. Neurosurg Focus. 2001; 10(3):E2 [35] Sen C, Triana AI, Berglind N, Godbold J, Shrivastava RK. Clival chordomas: clinical management, results, and complications in 71 patients. J Neurosurg. 2010; 113(5):1059–1071 [36] Shidoh S, Toda M, Kawase T, et al. Transoral vs. endoscopic endonasal approach for clival/upper cervical chordoma. Neurol Med Chir (Tokyo). 2014; 54(12):991–998 [37] Solares CA, Grindler D, Luong A, et al. Endoscopic management of sphenoclival neoplasms: anatomical correlates and patient outcomes. Otolaryngol Head Neck Surg. 2010; 142(3):315–321 [38] Stippler M, Gardner PA, Snyderman CH, Carrau RL, Prevedello DM, Kassam AB. Endoscopic endonasal approach for clival chordomas. Neurosurgery. 2009; 64(2):268–277, discussion 277–278 [39] Takahashi S, Kawase T, Yoshida K, Hasegawa A, Mizoe JE. Skull base chordomas: efficacy of surgery followed by carbon ion radiotherapy. Acta Neurochir (Wien). 2009; 151(7):759–769 [40] Tamura T, Sato T, Kishida Y, et al. Outcome of clival chordomas after skull base surgeries with mean follow-up of 10 years. Fukushima J Med Sci. 2015; 61 (2):131–140

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Other Cranial Tumors [41] Tan NCW, Naidoo Y, Oue S, et al. Endoscopic surgery of skull base chordomas. J Neurol Surg B Skull Base. 2012; 73(6):379–386 [42] Taniguchi M, Kohmura E. Endoscopic endonasal removal of laterally extended clival chordoma using side-viewing scopes. Acta Neurochir (Wien). 2012; 154 (4):627–632 [43] Tzortzidis F, Elahi F, Wright D, Natarajan SK, Sekhar LN. Patient outcome at long-term follow-up after aggressive microsurgical resection of cranial base chordomas. Neurosurgery. 2006; 59(2):230–237, discussion 230–237 [44] Vellutini EA, Balsalobre L, Hermann DR, Stamm AC. The endoscopic endonasal approach for extradural and intradural clivus lesions. World Neurosurg. 2014; 82(6) Suppl:S106–S115 [45] Wang L, Wu Z, Tian K, et al. Clinical features and surgical outcomes of patients with skull base chordoma: a retrospective analysis of 238 patients. J Neurosurg. 2017; 127(6):1257–1267 [46] Wu Z, Zhang J, Zhang L, et al. Prognostic factors for long-term outcome of patients with surgical resection of skull base chordomas-106 cases review in one institution. Neurosurg Rev. 2010; 33(4):451–456

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[47] Yasuda M, Bresson D, Chibbaro S, et al. Chordomas of the skull base and cervical spine: clinical outcomes associated with a multimodal surgical resection combined with proton-beam radiation in 40 patients. Neurosurg Rev. 2012; 35(2):171–182, discussion 182–183 [48] Yoneoka Y, Tsumanuma I, Fukuda M, et al. Cranial base chordoma–long term outcome and review of the literature. Acta Neurochir (Wien). 2008; 150(8): 773–778, discussion 778 [49] Zhang Q, Kong F, Yan B, Ni Z, Liu H. Endoscopic endonasal surgery for clival chordoma and chondrosarcoma. ORL J Otorhinolaryngol Relat Spec. 2008; 70 (2):124–129 [50] Zoli M, Milanese L, Bonfatti R, et al. Clival chordomas: considerations after 16 years of endoscopic endonasal surgery. J Neurosurg. 2018; 128(2):329–338 [51] Zucker KA, Bailey RW, Gadacz TR, Imbembo AL. Laparoscopic guided cholecystectomy. Am J Surg. 1991; 161(1):36–42, discussion 42–44 [52] Fernandez-Miranda JC, Gardner PA, Rastelli MM, Jr, et al. Endoscopic endonasal transcavernous posterior clinoidectomy with interdural pituitary transposition. J Neurosurg. 2014; 121(1):91–99

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Chordoma Genetics and Tumor Phenotype Profiles

26 Chordoma Genetics and Tumor Phenotype Profiles William L. Harryman and Anne E. Cress Abstract Chordoma genetics and tumor phenotype profiles are emerging areas of interest in efforts to develop effective therapies for this highly recurrent tumor. Chordoma is a relatively rare (1.4% of primary malignant bone tumors), slow-growing, locally invasive, and frequently metastatic bone tumor found in the sacrum, mobile spine, and skull base (clivus). Chordomas have demonstrated distant metastasis to lung, liver, bone, and lymph nodes in up to 48% of patients. Current treatment is surgery followed by ionizing radiation (IR) with good initial response rates; however, the tumors are radiation resistant, dose-limited by surrounding tissue tolerance, often recur or metastasize, and are refractory to conventional chemotherapeutic agents due to low proliferation (< 10% Ki-67 staining). Since 2007, several studies have been published investigating genomic changes that may account for the development of chordoma. The genetic alterations include the discovery of genetic risk factors by several groups of single nucleotide polymorphisms (SNPs) in the exon of brachyury (T), a transcription factor essential for notochord development. Overall, chordoma has general patterns of genome instability reflected in copy number variation (CNV), further represented as chromosome losses, aneuploidy, chromothripsis, and gene fusions. Because a predominant pattern has not yet emerged, it is likely that DNA damage response (DDR) defects may play a role and provide a synthetic lethal approach for adjuvants to surgery and radiation therapy. Since DDR heterogeneity exists in chordoma, an integrated approach to defining tumor subtypes will greatly advance the prevention of recurrent disease.

representative of malignant tumors.10 Although once considered a low metastatic risk, chordomas have demonstrated distant metastasis to lung, liver, bone, and lymph nodes in up to 48% of patients.11,12,13 Current treatment is surgery followed by ionizing radiation (IR). While initial response rates can be good, the tumors are radiation resistant,1,14 dose limited by surrounding tissue tolerance,1,15 and often recur or metastasize.14,16

26.2 Etiology Human chordomas are believed to arise from primitive remnants of the notochord (NC)—a transient structure found along the midline of embryos that is segmented and guided by Sonic Hedgehog (SHH).17 During embryonic morphogenesis, the NC differentiates, triggered by brachyury,18 into segments that form the primitive vertebrae. The NC is further differentiated into the nucleus pulposus (NP); the gelatinous inner core of the intervertebral disks, anulus fibrosus (AF), a fibrous capsule that surrounds the NP and consists of concentric lamellae of collagen fibers; and the superior and inferior cartilaginous end plates, situated at the articular surfaces of the intervertebral disk and the adjacent vertebrae.17,19,20,21 The brachyury transcription factor is expressed only in chordoma,18 and occurs in any tissue or lesion derived from the NC.3 The immature NP contains NC cells that are larger than NP cells and that contain both large, highly vacuolated chondrocytes and small chondroblasts inherited from the NC.19,22 These NC cells are composed of an extensive actin cytoskeletal network.22,23 When the smaller NP cells were separated by

Keywords: chordoma, brachyury, PTEN, single nucleotide polymorphisms, copy number variations, cohesive cluster phenotype, ionizing radiation, radiation resistant phenotype

26.1 Introduction Chordomas account for 1.4% of all primary malignant bone tumors,1,2 0.4% of all intracranial tumors, 0.2% of skull base tumors, and 17% of primary bone tumors of the spine, most commonly at the C1–C2 level.3 Originally thought to occur predominantly in the sacrum, chordomas are equally distributed between three primary locations: 29.2% in the sacrum, 32% in the skull base, and 32.8% in the mobile spine (cervical, thoracic, and lumbar).3 Other researchers have suggested “hot spots” at the upper spine (skull base: 20–30%) and lower spine (sacrococcygeal: 50–60%)4 or, alternately, in the sacrococcygeal area (50%), the skull base (35%), and vertebral bodies (15%).5 Chordomas are reported, most often, to originate in an extra-axial distribution within soft tissue between vertebrae.5,6,7 Chordoma histologically suggests a low-grade neoplasm1; however, unlike other malignant neoplasms, chordomas are slow-growing, radioresistant, locally aggressive and invasive, and highly recurrent tumors. Chordoma frequently exhibits the cohesive cluster phenotype8,9 (▶ Fig. 26.1) and a clinical progression

Fig. 26.1 3D image of α6 integrin and actin in chordoma cells. A chordoma 3D cohesive cluster fixed and stained for F-actin (green), α6 integrin (red), and DNA (blue).

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Other Cranial Tumors fluorescence-activated cell sorting (FACS), the sorted NC-like cells express lower mRNA levels of type-I collagen, biglycan, TIMP1, HSP70, and c-fos, and did not express demonstrable mRNA levels of decorin, lumican, several MMPs, or interleukin (IL)-1β via quantification by reverse transcription-polymerase chain reaction (RT-PCR).22 A greater number of these NC-like cells also expressed higher levels of α6, α1, and β1 integrin subunits as compared to small NP cells.22 After initiating and guiding vertebral column formation, the NC disappears, sometimes leaving cellular remnants in the NP.24 Most models of chordoma tumorigenesis suggest that NC cell remnants are responsible for chordoma development.24,25 However, the presence of NC remnants in humans is much more frequent than the occurrence of chordoma, and researchers believe that NC remnants often stay dormant, only becoming malignant when stimulated by a mutation, environmental factor, or other event.21,24 Researchers have reported cases suggesting a link between benign notochordal cell tumor (BNCT)— NC remnants that have the potential to become malignant—and chordoma.26 Moreover, the locations of BNCT and chordoma completely overlap. These findings indirectly support the premise that BNCT is a precursor of chordoma.26

26.3 Review 26.3.1 Genetic Markers in Chordoma Since 2007, a number of studies (▶ Table 26.1) have been published investigating genomic changes that may account for the development of chordoma. The genetic alterations include the discovery by several groups of single nucleotide polymorphisms (SNPs) in the exon of brachyury (T), a transcription factor essential for NC development.27 The SNPs are associated with increased risk of chordoma as determined by familial studies. It is less clear whether these are associated with sporadic chordoma. The search for hotspot mutations or mutation drivers is less compelling since a predominant pattern has not yet emerged, despite several independent attempts using a variety of molecularly based approaches with fresh surgical samples (▶ Table 26.2). Instead, the pattern of genome instability is observed with copy number variation (CNV) emerging as a common theme. CNV represented as chromosome losses, and aneuploidy, chromothripsis, and gene fusion have been reported.27,32,33,34,35 The loss of PTEN and CDKN2A and CDKN2B as part of the chromosome losses was reported in several studies.27,36 The predominance of CNV in the slow-growing but lethal chordoma is similar to the pattern

Table 26.1 Genomic alterations in chordoma Analysis

Technique

Specimen

Summary of findings

Reference

Cytogenetic abnormalities

Molecular cytogenetics (iFISH) for p53, TGF-β, VEGF, and bFGF/FGF2 loci

7 primary tumors and 11 recurrences

Chr 1, 2, 7 alterations are in primary tumors and recurrences. Chr 6 alterations only in the primary tumor

28

Germline CNV

High-resolution array CGH

4 families with > 3 cases of chordoma

Unique duplications on Chr 6; complex genomic rearrangements

29

Recurrent copy number alterations

Array comparative CGH, verified by qRT-PCR

21 sporadic chordomas

Copy number losses of CDKN2A, CDKN2B on Chr 9 (80% cases); one copy loss of PTEN on Chr 10 (80% cases)

30

Whole exome sequencing of T and an association study

Sanger sequencing of T exons in individuals with chordoma and ancestrymatched controls

40 chordoma and 358 controls

Strong association of SNP rs 2305089 and chordoma risk; SNP located in DNA binding domain of T

27

Whole genome SNP microarray

Flash frozen surgical specimens; confirmed results by IHC

21 clival chordoma and 1 chordoma from C1 to C2 vertebrae

Deletion of CDKN2A, CDKN2B, MTAP on Chr 9. Chr 3 aneuploidy; chromothripsis on Chr 22 and 7

30

865 hot spot mutations in 111 oncogenes

Sequenom iPLEX genotyping with validation by Sequenom hME genotyping

45 chordoma tumor samples

7 of the 45 contained at least one mutation. Mutations in CDKN2A and PTEN occurred in areas of Chr loss

31

Whole exome sequencing of T and an association study

Compared familial chordoma and sporadic cases of chordoma

24 familial cases, 103 sporadic cases, and 160 controls

Three SNPs significantly associated with risk: rs2305089 rs1056048 rs3816300

32

Screened for mutations in 48 cancer genes

Hot spot cancer panel (Illumina), deep sequencing

9 chordomas

11-point mutations found in three genes (KIT, KDR, and TP53). None of detected mutations found in all samples

33

13 skull base chordomas

Chr 1, 7, 10, 13, and 17 aberrations; SNP rs2305089; and recurrent mutations in MUC4, NBPF1, NPIPB15; and gene fusion (SAMD5-SASH1)

34

Whole exome and whole transcriptome sequencing

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Table 26.2 Gene products in chordoma growth, proliferation, and metastasis Gene product

Human tissue

Cell lines

Summary

Reference

T (Brachyury)

Yes

U-CH2

“Expression of PI3K/Akt pathway genes was upregulated in Brachyury highexpression tumors; suppression of PI3K signaling reduced Brachyury expression and inhibition of cell growth”

39

STAT3

Yes

U-CH1 GB 60 CH 8

“The level of phosphorylated Stat3 expression correlated with the survival and severity of the disease.… The expression of Stat3 signaling cascade was inhibited in all chordoma cell lines after treatment with SD-1029 (a novel inhibitor of Stat3)”

40,41

Yes

CH 8 GB 60 U-CH1

“The key components of the Src/Stat3 signaling cascade, including Stat3, pStat3, Src, pSrc, Bcl-xL, and myeloid cell leukemia-1 were all highly expressed in chordomas”

Yes

n/a

“EGFR is frequently and the most significantly activated RTK in chordomas”

Yes

n/a

“Chordomas displayed predominately a strong expression of EGFR presented with intense and diffuse cytoplasm membrane positivity.… The EGFR immunopositivity was found in 134 out of 145 cases (92.4%)…”

Yes

U-CH1

“The EGFR inhibitor tyrphostin (AG 1478) inhibited proliferation of the chordoma cell line U-CH1 in vitro and diminished EGFR phosphorylation in a dose-dependent manner, a finding supported by inhibition of phosphorylated Erk1/2. p-Akt was suppressed to a much lesser degree in these experiments. These data implicate aberrant EGFR signaling in the pathogenesis of chordoma

Yes

n/a

“The expression of PTEN in sacral chordoma was significantly lower than that in adjacent normal tissues… PTEN-negative expression … was associated with tumor invasion into the surrounding muscles”

Yes

U-CH1 U-CH2

“Loss of heterozygosity of the PTEN gene, which is seen in a subset of chordomas, is correlated with more aggressive in vitro behavior (than wildtype PTEN) and strongly correlates with increased Ki-67 proliferative index”

No

MUGCHOR1 U-CH1

Phenotypic-specific analysis showed genomic and transcription differences in specific gene products for subtyping and linked to chordoma cell development

EGFR

PTEN

UCHL3, ALG11, 2PP2BC

observed in slow-growing prostate cancers, which contain a predominance of chromothripsis37 and gene fusions.38 Complex alterations in genetic material has been linked to defective DNA damage responses (DDRs) in other tumors, which is an actionable target for treatment.

26.3.2 DNA Damage Response and the Cohesive Cluster Phenotype Our current work focuses on the DDR to radiation therapy and how to make radiotherapy a more effective modality.9 Eke et al showed that chordoma cells in tissue culture are aggressive yet slow growing and contain cohesive clusters as monolayers of cells.36 Since cell adhesion can be protective in epithelial tumor cell populations,8 and chordoma displays epithelial features, we examined the epithelial adhesion characteristics of the chordoma population and determined if DDRs were consistent across the population. The cohesive cluster phenotype facilitates metastasis and can provide increased radiation resistance over single cells or strands of cells8 due to cell-adhesion mediation, including expression of cytokeratin 8 and 18 in tumor cell clusters, as well as α6 integrin and actin (as shown in ▶ Fig. 26.1). Previous work by others showed that β1 integrin is a determining factor in radiation resistance,35,36 occurring due to blockage of β1 integrin function or its associated downstream signaling via focal adhesion kinase and integrin-linked

42,43,44

45,46

47

kinase.48 Identifying whether laminin-binding β1 integrins (α3β1, α6β1) are involved in IR responses in chordoma can allow targeting of specific molecular pathways to inhibit the DDR and increase IR effectiveness. In our recent study, the DDR of human U-CH1 chordoma cells to IR was determined in both individual cells and cell clusters (▶ Fig. 26.2). An integrin ligand mimetic, HYD1, which inhibits cluster formation, and AIIB2, a function-blocking β1 integrinspecific antibody, were tested to identify effects on IR response and survival. The DDR was estimated by the time-dependent detection of three DDR indicators (γH2AX, pKAP1, and pATM) in the U-CH1 cells. If chordoma cohesive clusters demonstrate a muted DDR to IR as compared to the coexisting single-cell monolayer, then targeting the integrin-mediated adhesion complex was postulated to increase the effectiveness of IR and perhaps reduce chordoma recurrence. Immunofluorescence microscopy verified that only 15% of U-CH1 clustered cells were γH2AX or pKAP1 positive (vs. 80% of nonclustered cells) 2 hours following 2-Gy IR. In contrast, both tumor cell lines were uniformly defective in pATM response. HYD1, a synthetic ECM ligand, inhibited DDR through an unresolved γH2AX response. β1 integrin-blocking antibody (AIIB2) decreased cell survival by 50% and approximately doubled the IR-induced cell kill at all IR doses observed at 2 and 4 weeks posttreatment. These results suggest that a heterogeneity of DDR to IR exists within a chordoma population and altering the adhesion phenotype can

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Other Cranial Tumors

Fig. 26.2 Cohesive chordomas express lamininbinding integrin on plasma membrane. Human chordoma, 42 resections from 23 different patients (de-identified) were stained using AA6NT antibody. The dark staining (α6 integrin) in 98% of the cases was either (a) cytoplasmic in noncohesive clusters or (b) on the plasma membrane in cohesive clusters.

sensitize chordoma to IR. An important consideration in planning a treatment strategy would include targeting all the relevant phenotypes. Blocking integrin function alone and/or as an adjuvant to IR may eradicate chordomas containing the cohesive cluster phenotype.9

26.4 Gene Products and Tumor Phenotypes Researchers looking at gene expression differences (minimum of twofold change) between chordoma, soft-tissue sarcoma, and chondrosarcoma49 found that chordomas express α3 and β4 integrins (which necessarily includes α6) as well as brachyury and other genes, while the other two do not (small sample size). Type II collagen, fibronectin, matrix metalloproteinase 9 (MMP-9) and 19, and aggrecan—among many others—are expressed by both chordoma and chondrosarcoma (compared to soft-tissue sarcoma).49 MMPs are the primary secreted proteinases necessary for extracellular matrix (ECM) degradation in many physiological and pathological tissue remodeling processes, including wound healing, embryo implantation, tumor invasion, metastasis, and angiogenesis.50,51,52,53 MMP-9 (gelatinase-B) is an endopeptidase capable of degrading the ECM and basement membrane that has been implicated in tumor cell invasion,52,53 likely as a mediator for angiogenesis, working with vascular endothelial growth factor (VEGF).53 Schwab et al suggested both MMP-9 and MMP-19 are involved in matrix metabolism and degradation.49 Two transcription factors influencing MMPs are IL-1β and transforming growth factor (TGF)-β. IL-1β stimulates, whereas TGF-β inhibits MMP gene expression.54 Chen et al found that the expression of VEGF and MMP-9 was significantly higher in sacral chordomas than in adjacent normal tissues (p = 0.05).53 Patients with MMP-9 expression showed poorer prognosis than those with negative MMP-9 (median: 24 vs. 70.5 months, p = 0.019), while the difference of continuous disease-free survival rates between the VEGF-positive group and the VEGF-negative group was not statistically significant (39.5 vs. 28.5 months, p = 0.938).22 Another lesser examined protein, aggrecan, has also been shown to have a role in invasiveness and metastasis of tumors, generally as a tumor supressor.55 Aggrecan is a proteoglycan, also known as cartilage-specific proteoglycan core protein (CSPCP) or chondroitin sulfate proteoglycan-1. The encoded protein is an integral part of the ECM in cartilage tissue, and

170

it withstands compression in cartilage. Aggrecan plays an important role in mediating chondrocyte–chondrocyte and chondrocyte–matrix interactions through its ability to bind hyaluronan.56 Aggrecan levels are high in the immature NP, and while the inner AF of mature discs is also high in aggrecan, the outer AF is mostly decorin and fibromodulin.19 Mature NP cells in humans are small and produce an aggrecan-rich matrix,57 with a different gene expression profile and metabolic activity from articular cartilage.19 In comparison with other connective tissue tumors, chordomas express greater higher quantities of genes for collagen II, aggrecan, fibromodulin, cartilage-linking protein, and cartilage oligomeric matrix protein, characteristic of the ECM and of hyaline cartilage.10,18,58 Chordomas also demonstrate higher expression of the chondrogenic transcription factor SOX9, fibronectin, MMP9, and MMP19.10 Chordomas have been shown to express estrogen receptor alpha and progesterone receptor beta, which are associated with tumor progression.59 In another study, high levels of TGF-α and basic fibroblast growth factor expression were linked to higher rates of recurrence, and it was suggested that high fibronectin expression could be a marker of aggressive biological behavior.10 STAT3 is a cytoplasmic transcription factor activated by cytokines and growth factor receptors.40 In one study, expression of STAT3 was evaluated in 70 chordoma samples.41 All samples showed nuclear staining for phosphorylated STAT3, with higher levels of phosphorylated STAT3 expression correlated with decreased survival and severity of the disease (high staining < 50% mortality).41 Yang et al found that both phosphorylated and total STAT3, and phosphorylated and total Src (a protooncogene encoding a tyrosine kinase), were expressed in chordoma tissues and chordoma cell lines, as well as the antiapoptotic proteins Bcl-xL and MCL-1, which were regulated by activated STAT3.40 In contrast to chordoma cell lines and tissues, there was no expression of phosphorylated and total STAT3, or phosphorylated and total Src, in normal intervertebral disc.40 Src (c-Src) is a protooncogene (a nonreceptor tyrosine kinase) that has been linked through expression and activity to advanced malignancy and reduced survival in several human cancers.60 There are nine other enzymes with homology to Src that have been identified and are known as the Src family kinases (SFKs).60 SFKs interact directly with receptor tyrosine kinases (RTKs), G-protein-coupled receptors, steroid receptors, signal transducers, and activators of transcription and molecules involved in cell adhesion and migration, interactions that lead to many and diverse biological functions: proliferation, cell

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Chordoma Genetics and Tumor Phenotype Profiles growth, differentiation, cell shape, motility, migration, angiogenesis, and survival.60,61 Src levels are often elevated in human neoplasia when compared to adjacent normal tissues, and these levels are believed to increase with the stage of disease.60,61 Similarly, increased Src protein kinase activity has been observed in numerous human cancer cell lines derived from these tumors.61 Activity of Src may be increased through direct or indirect interaction with RTKs, such as epidermal growth factor receptor (EGFR), platelet-derived growth factor receptor (PDGFR), fibroblast growth factor receptor (FGFR), colony-stimulating factor-1 receptor (CSF-1R), HER2/neu, and hepatocyte growth factor receptor (c-Met).61 As an example, researchers have shown that the combination of EGFR and Src expression in fibroblasts leads to a synergism of tumorigenicity when compared with expression of EGFR or Src alone.61 Dewaele et al found that EGFR is a frequently (and most significantly) activated RTK in chordomas.42 Moreover, with EGFR activation, the tumors commonly reveal coactivation of alternative RTK—the consistent activation of AKT, the frequent loss of the tumor suppressor PTEN allele, and the recurrent activation of upstream RTK and of downstream effectors like mammalian target of rapamycin (mTOR).42 Together, these data indicate that the phosphoinositide 3-kinase (PI3K)/AKT pathway is an important mediator of transformation in chordomas.42 In a study of 145 clival (base of skull) chordomas (74 primary chordoma, and 71 from recurrent tumors), Akhavan-Sigari et al found that PDGFR-α, EGFR, c-Met, and CD-34 were detected in 100, 92, 100, and 59% of cases, respectively.43 PDGFR-α and cMet staining was of moderate to strong intensity in all cases, while total EGFR staining was variable (immunopositivity was found in 134 out of 145 cases [92.4%]: 11 tumors had no expression [7.6%], 15 were mild [score 1; 10.3%], 33 were moderate [score 2; 22.7%], and 86 were strongly expressed [scores 3–6; 59.3%]).43 In their study, all chordoma samples were positive for PDGFR-α, with moderate (score 2) (27; 19%) to strong (score 3) (118; 81%) staining.43 C-Met also was expressed in all chordomas, with moderate (score 2) (26; 18%) to strong (scores 3–6) (119; 82%) staining.43 The researchers concluded that a relationship between EGFR expression, PDGFR-α, c-Met, and CD-34 was detected.43 Shalaby et al looked at the possible role of EGFR in chordoma pathogenesis44 in 173 samples from 160 patients (160 primary tumors, 13 recurrences and/or metastases), taken from the sacrococcygeum (n = 94), the mobile spine (n = 16), and base of the skull (n = 50). In the skull base chordomas, 52/68 (76%) showed immunoreactivity, while 27/46 (59%) of non–skull base chordomas showed immunoreactivity, which when combined yields 79/114 (69%) overall immunoreactivity.44 These researchers also noted that PTEN expression, as assessed by immunohistochemistry, was missing in 19 (13%) of 147 chordomas (16 [84%] of these were EGFR FISH negative, while only 1 case was EGFR FISH positive, and 2 were noninformative).44 AkhavanSigari et al found that EGFR, inducible nitric oxide synthase (iNOS), and Ki-M1 P were expressed in 92.40, 82.0, and 98.6% of primary, and in 98.0% of recurrent lesions in skull base chordomas.62 Higher EGFR expression correlated with younger patient age. Lesions with a higher expression of iNOS demonstrated significantly higher Ki-M1 P scores in both primary and recurrent lesions compared to those with lower iNOS expression.62 In recurrent lesions, higher EGFR expression was associated with

significantly poorer prognosis than those with lower EGFR expression (p = 0.031).62 Furthermore, lesions with a higher level of iNOS and Ki-M1 P expression demonstrated significantly poorer prognosis than those with lower iNOS and KiM1 P expression.62 Phosphatase and tensin homolog deleted on chromosome ten (PTEN) is a tumor suppressor gene that locates on chromosome 10q23 and encodes proteins regulating various signal transduction pathways and modulating cell growth processes, cell migration, and apoptosis.45 Lee et al added to this that loss of heterozygosity of the PTEN gene, which is seen in a subset of chordomas, is correlated with more aggressive in vitro behavior (than wild-type PTEN) and strongly correlates with increased Ki-67 proliferative index.46 Likewise, Choy et al found that 17 of 21 chordoma samples displayed copy loss at PTEN, and it was inferred that a loss of heterozygosity PTEN (as well as SMARCB1 and CDKN2A) might play a significant role in chordoma genesis.31 Dewaele et al reported that PTEN is an important negative regulator of the AKT/mTOR pathway, which when suppressed contributes to phosphorylation of AKT and activation of downstream effectors.42 They noted that PTEN loss is also frequently found in chordomas. Chen et al found that expression of PTEN in sacral chordoma was significantly lower than in adjacent normal tissues, while the levels of mTOR expression in sacral chordoma were significantly higher than in adjacent normal tissues (p = 0.000, p = 0.030).45 Furthermore, the positive expression of mTOR correlates with negative expression of PTEN in sacral chordoma (p = 0.021), and that PTEN-negative expression and mTOR-positive expression were associated with tumor invasion into the surrounding muscles (p = 0.038, p = 0.014).45 PTEN is a negative regulator of the PI3K signal transduction pathway. Sitting downstream of PI3K is the mTOR, which phosphorylates a series of downstream effectors involved in protein biosynthesis, ribosome biogenesis, and transcription of genes crucial to cell growth. The PI3K–AKT–mTOR pathway is an important cellular pathway involved in cell growth, tumorigenesis, cell invasion, and drug response. Negative expression of PTEN may result in increased mTOR activity,45 which, as described earlier, increases chordoma tumor invasion and metastasis.

26.5 Author Bias The references used here were restricted to peer-reviewed manuscripts using both cell lines and tissue in the analysis. The research literature relevant to chordoma biology was viewed through the lens of knowing characteristics of other epithelial human tumors, such as prostate and some bladder tumors, that are slow growing, yet have aggressive phenotypes. In addition, the perspective of needing an integrated view of the genotype and the phenotype of both the tumor and the tumor microenvironment was brought to the work, as well as the concept of DDR heterogeneity.

26.6 Conclusions Chordomas arise from undifferentiated remnants of the primitive NC1,63 and express epithelial-type characteristics4 and a low growth fraction, indicative of slow-growing disease.

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Other Cranial Tumors Chordomas impinge on critical nerve functions present within the clival, vertebral, and sacral regions13 and can locally invade surrounding laminin-rich muscle. Although they are slow growing and low grade, chordomas are highly recurrent, aggressive, locally invasive, and prone to metastasize to the lungs, bone, and the liver.13 Current therapy consists of surgical removal of the tumor and postoperative radiation therapy,1,24 but tumors frequently recur, limiting the efficacy of the approach. Chordoma is refractory to conventional chemotherapeutic agents due to low proliferation (< 10% Ki-67 staining).1,64 Since 2007, several studies have been published investigating genomic changes that may account for the development of chordoma. The genetic alterations include the discovery of a genetic risk factor by several groups of SNPs in the exon of brachyury (T), a transcription factor essential for NC development. Overall, chordoma has a pattern of genome instability reflected in CNV, further represented as chromosome losses, aneuploidy, chromothripsis, and gene fusions. These complex rearrangements of the genetic material suggest major defects in part, of DDR or repair (defects detected in other slow-growing cancer subtypes) or defects in structural requirements or organelles to maintain chromosome order. Independent of the molecular genesis of chordoma, a critical barrier to the development of effective therapeutic strategies is the lack of understanding of the radiation-resistant phenotype. The potential heterogeneity of DDR likely exists because of the reported complex phenotypes within chordoma. Multiplexing the biopsy tissue with specific lineage markers would aid our understanding of the tumor damage repair subtypes that would require a specialized combination treatment. While integrin β1-dependent cell adhesion is an established mechanism in epithelial-type tumors for overcoming resistance to IR35,36 and can be exploited to eradicate the tumor, understanding the heterogeneity of DDR in the tumors would greatly add to the ability to use known DDR inhibitors in a synthetic lethal approach. It is likely that combinations of agents will be required to target the relevant DDR pathways early in order to prevent recurrence. Current research to define the DDR subtypes using a multiplex approach in a single biopsy holds promise for selecting the best adjuvants to surgery and radiation therapy.

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Chordoma Genetics and Tumor Phenotype Profiles [36] Eke I, Deuse Y, Hehlgans S, et al. β1 Integrin/FAK/cortactin signaling is essential for human head and neck cancer resistance to radiotherapy. J Clin Invest. 2012; 122(4):1529–1540 [37] Fraser M, Sabelnykova VY, Yamaguchi TN, et al. Genomic hallmarks of localized, non-indolent prostate cancer. Nature. 2017; 541(7637):359–364 [38] Wang X, Qiao Y, Asangani IA, et al. Development of peptidomimetic inhibitors of the ERG gene fusion product in prostate cancer. Cancer Cell. 2017; 31(4): 532–548.e7 [39] Otani R, Mukasa A, Shin M, et al. Brachyury gene copy number gain and activation of the PI3K/Akt pathway: association with upregulation of oncogenic Brachyury expression in skull base chordoma. J Neurosurg. 2018; 128(5): 1428–1437 [40] Yang C, Hornicek FJ, Wood KB, et al. Blockage of Stat3 with CDDO-Me inhibits tumor cell growth in chordoma. Spine. 2010; 35(18):1668–1675 [41] Yang C, Schwab JH, Schoenfeld AJ, et al. A novel target for treatment of chordoma: signal transducers and activators of transcription 3. Mol Cancer Ther. 2009; 8(9):2597–2605 [42] Dewaele B, Maggiani F, Floris G, et al. Frequent activation of EGFR in advanced chordomas. Clin Sarcoma Res. 2011; 1(1):4 [43] Akhavan-Sigari R, Abili M, Gaab MR, et al. Immunohistochemical expression of receptor tyrosine kinase PDGFR-, c-Met, and EGFR in skull base chordoma. Neurosurg Rev. 2015; 38(1):89–98, discussion 98–99 [44] Shalaby A, Presneau N, Ye H, et al. The role of epidermal growth factor receptor in chordoma pathogenesis: a potential therapeutic target. J Pathol. 2011; 223(3):336–346 [45] Chen K, Mo J, Zhou M, et al. Expression of PTEN and mTOR in sacral chordoma and association with poor prognosis. Med Oncol. 2014; 31(4):886 [46] Lee D-H, Zhang Y, Kassam AB, et al. Combined PDGFR and HDAC inhibition overcomes PTEN disruption in chordoma. PLoS One. 2015; 10(8): e0134426 [47] El-Heliebi A, Kroneis T, Wagner K, et al. Resolving tumor heterogeneity: genes involved in chordoma cell development identified by low-template analysis of morphologically distinct cells. PLoS One. 2014; 9(2):e87663 [48] Hoshino A, Costa-Silva B, Shen T-L, et al. Tumour exosome integrins determine organotropic metastasis. Nature. 2015; 527(7578):329–335 [49] Schwab JH, Boland PJ, Agaram NP, et al. Chordoma and chondrosarcoma gene profile: implications for immunotherapy. Cancer Immunol Immunother. 2009; 58(3):339–349 [50] Aznavoorian S, Murphy AN, Stetler-Stevenson WG, Liotta LA. Molecular aspects of tumor cell invasion and metastasis. Cancer. 1993; 71(4):1368–1383

[51] Kleiner DE, Stetler-Stevenson WG. Matrix metalloproteinases and metastasis. Cancer Chemother Pharmacol. 1999; 43(1) Suppl:S42–S51 [52] Forsyth PA, Wong H, Laing TD, et al. Gelatinase-A (MMP-2), gelatinase-B (MMP-9) and membrane type matrix metalloproteinase-1 (MT1-MMP) are involved in different aspects of the pathophysiology of malignant gliomas. Br J Cancer. 1999; 79(11–12):1828–1835 [53] Chen KW, Yang HL, Lu J, et al. Expression of vascular endothelial growth factor and matrix metalloproteinase-9 in sacral chordoma. J Neurooncol. 2011; 101(3):357–363 [54] Yadav L, Puri N, Rastogi V, Satpute P, Ahmad R, Kaur G. Matrix metalloproteinases and cancer - roles in threat and therapy. Asian Pac J Cancer Prev. 2014; 15(3):1085–1091 [55] Binder MJ, McCoombe S, Williams ED, McCulloch DR, Ward AC. The extracellular matrix in cancer progression: role of hyalectan proteoglycans and ADAMTS enzymes. Cancer Lett. 2017; 385:55–64 [56] Kiani C, Chen L, Wu YJ, Yee AJ, Yang BB. Structure and function of aggrecan. Cell Res. 2002; 12(1):19–32 [57] Hornicek FJ, Schwab JH. Chordomas and chondrosarcomas of the axial skeleton: emerging therapies and future directions. –In: Harsh G, Vaz-Guimaraes F, eds. Chordomas and Chondrosarcomas of the Skull Base and Spine. 2nd ed. Academic Press; 2018:411–418 [58] Güdük M, Özek MM. Molecular biology and genetics of chordomas. In: Özek MCG, Maixner W, Sainte-Rose C, eds. Posterior Fossa Tumors in Children. Cham, Switzerland: Springer; 2015:675–682 [59] Camacho-Arroyo I, González-Agüero G, Gamboa-Domínguez A, Cerbón MA, Ondarza R. Progesterone receptor isoforms expression pattern in human chordomas. J Neurooncol. 2000; 49(1):1–7 [60] Wheeler DL, Iida M, Dunn EF. The role of Src in solid tumors. Oncologist. 2009; 14(7):667–678 [61] Irby RB, Yeatman TJ. Role of Src expression and activation in human cancer. Oncogene. 2000; 19(49):5636–5642 [62] Akhavan-Sigari R, Gaab MR, Rohde V, et al. Expression of vascular endothelial growth factor receptor 2 (VEGFR-2), inducible nitric oxide synthase (iNOS), and Ki-M1 P in skull base chordoma: a series of 145 tumors. Neurosurg Rev. 2014; 37(1):79–88 [63] Shen J, Shi Q, Lu J, et al. Histological study of chordoma origin from fetal notochordal cell rests. Spine. 2013; 38(25):2165–2170 [64] von Witzleben A, Goerttler L, Lennerz J, et al. In chordoma, metastasis, recurrences, Ki-67 index, and a matrix-poor phenotype are associated with patients’ shorter overall survival. Eur Spine J. 2015:1–9

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27 Surgery versus Radiation versus Observation: What Treatment Is Best for Skull Base Paraganglioma? Gregory P. Lekovic, Kevin A. Peng, Eric P. Wilkinson, William H. Slattery, and Kathryn Y. Noonan Abstract Although paragangliomas are rare, histologically benign neoplasms, they have the potential to cause serious morbidity and mortality when located in the skull base region.1,2,3,4 Due to the challenging nature of these tumors, ideal clinical management is often a topic of debate. Recommended management options included observation, radiation therapy, surgery, or a combination of any of these techniques. All possible treatment modalities carry substantial risks due to the close proximity to the lower cranial nerves, internal carotid artery, jugular bulb, and vertebral arteries. Tumors can also be locally aggressive causing multiple lower cranial neuropathies and other nearby injuries when left alone. A Dutch study of a 50-year-old cohort of patients shows that there is no difference in mortality between paraganglioma patients and the normal population regardless of the treatment modality applied.5 Management decisions need to be tailored to each individual patient. Therapies are impacted based on the location and the size of the tumor. Keywords: paraganglioma, subtotal resection, radiotherapy, surgery, management, glomus tumor, radiation therapy

27.1 Introduction Although paragangliomas are rare, histologically benign neoplasms, they have the potential to cause serious morbidity and mortality when located in the skull base region.1,2,3,4 Mortality rates associated with these tumors have previously been reported as high as 13%; however, with improved treatment options they are now usually less than 3%.6,7,8 Due to the challenging nature of these tumors, ideal clinical management is often a topic of debate. Recommended management options included observation, radiation therapy, surgery, and a combination of any of these techniques. This chapter will discuss the literature on the treatment of skull base paragangliomas and briefly review the contemporary House Ear Clinic approach to these tumors.

involved.12,14 The estimated incidence of head and neck paragangliomas is 1 out of 30,000.15 Head and neck paragangliomas are classified based on location. They are known as glomus tympanicums, glomus jugulares, glomus vagales, and carotid body paragangliomas arising from the tympanic plexus, the adventitia of the jugular bulb, or the ganglia of the vagus nerve, or the bifurcation of the carotid artery, respectively. There are numerous classification systems to help stratify the severity of disease and can be viewed in ▶ Table 27.1.8

27.3 Diagnosis and Workup Clinical presentation can vary depending on the location of the tumor. Carotid body tumors are the most common, comprising 60% of head and neck paragangliomas followed by jugular paragangliomas (23%), vagal paragangliomas (13%), and tympanic paragangliomas (6%).12 Skull base tumors are more common in females with a ratio reported as high as 6:113 and are usually seen in the fifth to sixth decades.16 The most common presenting symptoms are conductive hearing loss and pulsatile tinnitus.13,17 Cranial neuropathies are present in about 10% of cases upon presentation.13 One percent to 5% of tumors secrete catecholamine and therefore patients should be asked about headaches, flushing, palpitations, and hypertension.6,18,19 Catecholamine secretion is rare in head and neck tumors; so, when present it should raise suspicion for multiplicity.12 Computed tomography (CT) and magnetic resonance imaging (MRI) are essential for staging of disease and treatment planning. Glomus tympanicum tumors are limited to the middle ear and mastoid and can be differentiated from glomus jugulare tumors by assessing for erosion of the lateral plate of the jugular fossa. Table 27.1 Head and neck paragangliomas classification schemes Fisch

Tympanic PGL

Type A

Limited to middle ear cleft

Type B

Limited to tympanomastoid area

Jugular PGL

Type C

Involvement of infralabyrinthine compartment of temporal bone and extending to petrous apex

Type D

Intracranial extension

Vagal PGL

Type A

Confined to neck

Type B

Contact with jugular foramen

Type C

Extended into/beyond jugular foramen without intracranial extension

I

Splaying of the carotid bifurcation with little attachment to vessels

II

Partial involvement of carotid vessels

III

Complete involvement of carotid vessels

27.2 Background Paragangliomas arise from the chemoreceptor system and can be found originating from any extra-adrenal chromaffin cells. Tumors arising in the head and neck are almost always derived from parasympathetic tissue and therefore rarely secrete catecholamines.9 They are typically benign and sporadic but can be linked to genetic abnormalities in over one-third of cases.10 Hereditary tumors are commonly associated with succinate dehydrogenase mutations and are seen in an autosomal dominant pattern with incomplete penetrance and genomic imprinting.10,11 They can be malignant in around 3% of cases.12,13 Paragangliomas are located in the head and neck in up to 69% of cases, but rates vary depending on the genetic mutation

174

Netterville

Shamblin’s

Carotid body PGL

Abbreviation: PGL, paragangliomas.

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Surgery versus Radiation versus Observation: What Treatment Is Best for Skull Base Paraganglioma? MRI can help determine if there is intradural tumor extension by better evaluating the tumor–brain interface. PET/CT can help assess for additional tumors. It is important to have a thorough understanding of the skull base anatomy, as this can be altered by large tumors. The internal carotid artery is often closely associated with paragangliomas and can be best identified in the neck and traced superiorly. The genu of the petrous internal carotid is superior and medial to the orifice of the Eustachian tube. Middle ear landmarks may be obscured or eroded by the mass. The jugular foramen can be divided into the pars nervosa and the pars vascularis.

27.4 Management Controversies 27.4.1 Overview Management of skull base paragangliomas can be complex and therapy plans need to be tailored to each individual patient. Therapies are impacted based on the location and the size of the tumor. Fisch class A and class B tympanomastoid lesions can often be removed surgically with minimal morbidity or mortality.20,21,22 Thus, complete surgical excision is the mainstay of treatment in this location when there are no medical contraindications to surgery. Fisch class C and class D, vagal paragangliomas, and carotid body tumors on the other hand, can be more complex to treat. All possible treatment modalities carry substantial risks due to proximity to the lower cranial nerves, internal carotid artery, jugular bulb, and vertebral arteries. Tumors can also be locally aggressive causing multiple lower cranial neuropathies and other nearby injuries when left alone. A Dutch study of a 50-year-old cohort of patients show that there is no difference in mortality between paraganglioma patients and the normal population regardless of the treatment modality applied.5 Current therapeutic options include observation, surgery, radiation, or a combination of any of these approaches.

27.4.2 Observation Case Illustration A 75-year-old female presented with upper airway obstruction due to an enlarging paraganglioma involving the skull base and carotid sheath; she had a history of repeated transoral cauterization of the mass for 8 years prior. Digital subtraction angiogram of the carotid artery demonstrates a large neck paraganglioma with vascular blush consistent with a large carotid body tumor (▶ Fig. 27.1a–c). The patient was offered definitive treatment consisting of angiography with balloon test occlusion of the internal carotid artery followed by carotid sacrifice or extracranial–intracranial bypass and resection of tumor. However, she refused intervention in lieu of continued conservative management. One month later, she expired from carotid blow out. Twenty-five years ago, van der Mey et al published a landmark paper reporting on the “wait-and-see” approach for jugular paragangliomas. They found a high rate of treatment-related complications with no overall survival benefit in the treatment group when compared to the observation cohort. Interestingly, they also noticed a narrowing of this gap as technology developed and treatment options improved. Many authors advocate for the “wait-and-see” treatment approach depending on patient presentation.23,24,25,26,27,28,29,30 Several studies have retrospectively reviewed their data and found that elderly patients, asymptomatic patients, small tumors, and patients with contralateral cranial neuropathies benefit from a trial of observation.23,24,27,28 A review of the literature demonstrates that although up to 20% of tumors shrink, 38 to 60% of tumors will grow with a course of observation.23,24,25,28 If the age of the patient was less than 50 years, there was a higher proportion of tumors with growth.24 Rates of tumor-related complications in the observation cohorts were reported between 12 and 33%.26,27,28 Growth rates were variable by location of

Fig. 27.1 AP (a) and lateral (b) digital subtraction angiography of the right carotid artery demonstrating large mass with mass effect on the carotid artery; late-phase study demonstrates vascular blush consistent with paraganglioma (c).

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Table 27.2 Observational studies with relevant findings Author (year)

Type (n)

Length of follow-up (y)

Key findings

Cranial nerve defects

Level of evidence*

van der Mey et al (1992)26

All (50)

13.5

No tumor-related death

18%

II

Jansen et al (2000)25

All (48)

4.2

40% no growth Growth rate: 1.0 mm/y

0%

II

Prasad et al (2014)28

All (47)

3–5 +

92% (22/24) no growth in 3 y 83% (10/12) no growths in 5 y 45% (5/11) no growth in 5 + y

30%

II

Langerman et al (2012)

All (43)

5

62% no growth Growth rate: 0.2 cm3/y

12% (on presentation)

II

Carlson et al (2015)22

J (16)

6.5

58% no growth Growth rate: 0.4 cm3/y No tumor-related deaths

53%

II

Jansen et al (2017)24

All (159)

4.25

44% growing tumors (70/157) Age < 50 y was a risk factor for growth 32% eventually requiring other treatment modalities

8% with cranial nerve paresis

II

23

Abbreviations: All, all types of head and neck paragangliomas; J, jugular foramen paragangliomas. retrospective studies investigating outcome of disease.

*All

paragangliomas and the individual study parameters. Growth rates ranged from 0.2 to 1.6 mm/year.23,24,27,28 The wait-and-see approach has gained popularity and is now more commonly applied. Yearly MRI scans are recommended in all wait-and-see patients. Unlike other histologically benign tumors, long-term close monitoring of these patients is required because a 3 to 5% rate of malignant transformation has been reported as well as a late propensity to grow.31 ▶ Table 27.2 summarizes key studies describing the wait-andsee approach in skull base paragangliomas.

27.4.3 Surgery Case Illustration A 57-year-old male presented with severe, disabling pulse-synchronous tinnitus; conductive hearing loss; and hyperacusia. MRI demonstrated a 1.8-cm right jugular foramen mass. The patient was initially treated with CyberKnife stereotactic radiosurgery (SRS) to a dose of 27 Gy in three fractions of 9 Gy. He experienced no complications from radiosurgery but also had no relief in his tinnitus and hyperacusis. Eighteen months after radiosurgery, the patient was offered partial resection of the middle-ear component of tumor in the hopes of relieving his symptoms. The patient experienced a vocal cord palsy following preoperative embolization. He then underwent transjugular craniotomy for definitive resection of the tumor. Postoperatively, the patient compensated well from his vocal cord palsy but experienced continued disabling tinnitus in spite of neartotal resection of tumor (▶ Fig. 27.2a–c). Surgical resection has been the traditional approach to managing head and neck paragangliomas over the past several decades. It is the only option that can offer a cure; however, it comes with a risk of substantial morbidity and mortality.3,32,33, 34,35 Various surgical approaches are available depending on the size of the tumor and the location. Accurate tumor staging facilitates planning of therapy.

176

Tympanomastoid Paragangliomas Surgery remains the primary therapeutic approach in Fisch A and B tumors because complete control of disease can be achieved with minimal complications.20,21,22,28,36 Carlson et al reported a 100% control rate in 115 tympanomastoid paragangliomas over a mean follow-up period of 30 months.22 Less than 2% of patients experienced temporary facial paresis and less than 1% had a postoperative cerebrospinal fluid leak. Complete surgical excision is the mainstay of treatment in this location when there are no medical contraindications to surgery.

Jugular Paragangliomas Jugular paragangliomas are surgically very challenging to treat and can be associated with high rates of postoperative cranial nerve deficits.3,20,33,34,37,38,39 Gross total resection is possible in up to 91% of cases but is limited by cranial nerve, vascular, or intracranial involvement.3,20,33,34,35,39 With aggressive surgical management authors reported 95 to 98% rates of tumor control with mortality rates less than 3%.3,20,34 In a recent study by Prasad et al, injury rate in the lower cranial nerve doubled for IX, X, XI, and XII postoperatively with most authors reporting injury rates between 20 and 40% after surgery. See ▶ Table 27.3 for additional details. Due to the high rates of morbidity with aggressive surgical resection and promising data from observation and radiation patients, some authors are now advocating for a less aggressive surgical subtotal resection approach.17,29,30,35,38,39,40,41 Nicoli et al published a review of 36 jugulotympanic paragangliomas patients managed with a conservative surgical approach and found a slightly higher (15%) recurrence rate but with much lower postoperative cranial nerve defects (6%).39 These patients can be treated with postoperative radiation or monitored with serial imaging.

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Surgery versus Radiation versus Observation: What Treatment Is Best for Skull Base Paraganglioma?

Fig. 27.2 Axial (a) and coronal (b) T1-weighted contrast-enhanced MRI of the brain demonstrating a right-side glomus jugular prior to treatment. The patient subsequently underwent embolization (c) and resection for control of symptoms of tinnitus and hyperacusis. Postoperative coronal contrast-enhanced MRI demonstrates near-total resection of tumor (d).

Table 27.3 Surgical studies with relevant findings Author (year)

Type (n)

Netterville et al (1998)42

V (46)

Jackson et al (2001)3

All (182)

Fayad et al (2010)33

% GTR

Key findings

CN defects

Level of evidence

100% surgical tumor control

100% Vagal nerve cut in 37/40 cases

IV

90% 168/182

5.5% (10) recurrence rate 2.7%(5) mortality rate 4.5% (3/66) CSF leak

New deficits for CNs IX, X, XI, and XII occurred in 39, 25, 26, and 21% of cases, respectively

IV

J (67)

81%

4.2% CSF leak 33% with early complications 40% with late complications

CN deficiencies in 18.9% of cases 12% with persistent facial weakness

IV

Borba et al (2010)34

J (34)

91%

17.6% with CSF leak 94.2% tumor control

17.6% with new CN deficits

IV

Carlson et al (2015)27

T (115)

93.9%

100% control rate 0.9% with carotid injury 0.9% CSF leak

1.7% facial paresis (temporary)

IV

Prasad et al (2016)20

JT (185)

90% 166/185

8% CSF leak 2.4% (4) of GTR with recurrence

23% (43) patients with post-op facial deficits

IV

Li et al (2016)35

J (48)

54% 26/48

0% mortality 14.5% (7) CSF 12.5% (6) tracheostomy 12.5% (6) tumor recurrence/ regrowth

New deficits for CN VII, IX–X, XI, and XII occurred in 29% (15), 31% (16), 6% (3), and 8% (4), respectively

IV

Nicoli et al (2017)39

JT (36)

72% 26/36

15% local recurrence rate

6% CN deficits

IV

Abbreviations: All, all types of head and neck paragangliomas; CN, cranial nerve; CSF, cerebrospinal fluid; GTR, gross total resection; J, jugular paragangliomas; JT, jugulotympanic paragangliomas; T, tympanic paragangliomas; V, vagal.

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Vagal Paragangliomas

27.4.4 Radiation

Vagal paragangliomas are difficult to resect without vagal nerve injury and postoperative vocal cord paralysis.7,29,42 In a study by Netterville et al reviewing surgically treated vagal paragangliomas, they found 37 of the 40 patients required surgical resection of the vagus nerve.42 Suárez et al conducted a systematic review of 61 studies including 226 vagal paragangliomas.7 On average, the vagus nerve was preserved in only 4.3% (11) of surgically treated patients; however, the majority of studies in the literature report surgery as the primary approach to therapy.7,30 Given the morbidity of vagus nerve palsy, we advocate a more conservative approach to these tumors and prefer radiosurgery as the primary mode of treatment when treatment is necessary.

Case Illustration

Carotid Body Paragangliomas Carotid body paragangliomas may be treated with observation, surgery, or radiotherapy; however, like vagal paragangliomas the primary approach published in the literature is surgical.29,43,44 Suárez et al conducted a systematic review of carotid body paragangliomas. Out of 2,302 carotid body tumors, only 127 (5.5%) were not approached with surgery. They reported similar long-term control rates of 93.8 and 94.5% for the surgery and radiation cohorts, respectively.43

A 77-year-old female presented with vertigo; MRI was obtained demonstrating a right jugular foramen mass consistent with glomus jugulare (▶ Fig. 27.3a). She was treated with stereotactic radiotherapy with a prescription dose of 25 fractions of 180 cGy at the 87% isodose line. Tumor volume was 6.32 cc. Although the patient experienced complete loss of hearing at 2-year follow-up, her tumor was controlled and in fact at 5-year followup MRI, it had decreased in size to 1.4 × 1.5 × 1.8 cm. At 9 years posttreatment, the patient began to complain of hemifacial spasm followed by HB6/6 facial palsy the following year. In addition, she developed hoarseness of her voice and difficulty swallowing. Laryngoscopy confirmed paralysis of the right vocal cord. Follow-up MRI and CT of the temporal bone 10 years after salvage radiotherapy demonstrated progression of disease with mass measuring 2.7 × 4.5 × 1.7 cm (▶ Fig. 27.3b–d). The patient was offered arytenoid reduction, hypopharyngoplasty, and cricopharyngeal myotomy in order to improve her swallowing, but refused; she was unable to tolerate oral nutrition, failed to thrive, and was placed on hospice care. Radiation therapy is widely accepted as a viable treatment option for patients with head and neck paragangliomas because it can achieve high tumor control rates with limited

Fig. 27.3 (a) Axial T1-weighted contrastenhanced MRI of the brain demonstrating a heterogeneously enhancing mass centered on the right jugular foramen consistent with glomus jugulare. Follow-up imagings including axial T1weighted gadolinium-enhanced MRI (b) and axial and coronal temporal bone CT (c, d, respectively) demonstrate progression of disease.

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Table 27.4 Radiotherapy studies with relevant findings Author (year)

n

Length of follow-up (mo)

Radiation type

Key findings

CN defects

Level of evidence

Winford et al (2017)46

J (15)

39

SRS

12% of tumor with growth No correlation between Fisch’s classification and growth

IV

Chen (2010)56

J (15)

43

GKS

20% of tumors with growth 33% unchanged 47% shrinking

IV

Patel et al (2017)53

J (35)

37

SRS

Marchetti et al (2017)47

All (21)

Gilbo et al (2014)48

All (156)

138

Hafez et al (2016)54

J (22)

56

Dobberpuhl et al (2016)49

J (12)

Genc (2010)57 Galland-Girodet et al (2014)51

20% nonserviceable hearing

IV

100% control rate

30% with CN impairment 10% hearing loss

IV

Radiation SRS IMRT

96% tumor control 1 malignant transformation

20% of patients with complications including hearing loss

IV

14% (3/22)

IV

27.6

SRS

100% control

No change in PTA or WR

IV

J (18)

52.7

GKS

94% tumor control

All (130)

91 (median)

EBRT

96% control over 5 y

86% report subjective hearing loss

IV

IV

Abbreviations: All, all head and neck paragangliomas; CN, cranial nerve; EBRT, external beam radiation therapy; GKS, Gamma Knife surgery; IMRT, intensity-modulated radiotherapy; J, jugular; PTA, pure tone average; SRS, stereotactic radiosurgery; WR, word recognition.

complications.13,42,43,44,45,46,47,48,49,50,51,52 In the past, radiation therapy was reserved for elderly patients or those too ill to undergo a major resection, but as radiation techniques improve and long-term results become more available, this approach has gained popularity. Patients undergoing radiation therapy can be treated with external beam radiation therapy (EBRT) or SRS. SRS allows for delivery of radiation precisely to the tumor bed with steep drop-off in surrounding tissues. The majority of recently published studies are reporting on SRS which includes both gamma-knife and cyber-knife results. In a recent meta-analysis of over 300 patients treated with SRS, there was a 97% rate of tumor control.45 The goal of radiation therapy is to arrest growth. Tumor control is defined as nongrowing tumors which includes stable or shrinking paragangliomas. Radiation therapy achieves tumor control in 88 to 100% of patients.16,45,46,47,48,49,50,51,52 The drawback to radiation therapy is that it can cause both early and late complications. Reported complication rates are generally lower than complications observed in surgery cohorts, but it may be too early in the follow-up period to fully understand the longterm effects.7 Progression of cranial nerve defects or new defects was reported in 5 to 20% of patients.47,50,53,54 Radiation therapy may also rarely induce malignant transformation of tumors.48,51 Radiation in the past has been significantly more ototoxic; however, newer techniques have reported increased hearing preservation. Galland-Girodet et al published a cross-sectional study of radiated skull base paragangliomas which showed 86% of patients noted long-term subjective hearing loss.51 The cochlear nerve is radiosensitive and can suffer damage even with limited exposure. More recently, in a study by Patel et al, serviceable hearing was reported in 80% of radiated patients after SRS with a 37-month average follow-up period.53

Additional radiosurgery references and information can be found in ▶ Table 27.4 and ▶ Table 27.5.

27.5 Author Institutional Biases Overall, our institution has seen a relative increase in the proportion of patients with jugular and vagal paraganglioma treated primarily with SRS, whereas carotid body tumors and tympanomastoid paraganglioma are still primarily treated surgically. Observation is often recommended for patients with small tumors without progression, patients with significant comorbidities, or asymptomatic tumors. Because gross total resection of jugular paraganglioma in particular is associated with high rates of lower cranial nerve palsy, we routinely recommend subtotal resection in order to minimize new cranial neuropathy. Conversely, a more aggressive surgical approach is recommended for patients with jugular paraganglioma presenting with lower cranial nerve deficits. The charts of patients undergoing evaluation and treatment for head and neck paraganglioma from 2013 to 2018 were reviewed, revealing 47 patients undergoing 51 procedures. A total of 37 surgical procedures were performed on 36 patients (there was one reoperation for recurrence of glomus jugulare). Tympanomastoid paraganglioma accounted for 19 patients; these were all treated surgically via transmastoid and/or transcanal approaches. Glomus jugulare, vagale, and carotid body tumors comprised the remainder of the surgical patients (n = 15, 1, and 1, respectively). We routinely recommend preoperative embolization prior to surgery for jugular and vagal paraganglioma. In our experience, embolization for carotid body tumors and tympanomastoid paragangliomas is of limited benefit.

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Table 27.5 Large reviews Author (year)

n

Key findings

J (869)

STR—69% control rate GTR—86% control rate STR + SRS—71% control rate SRS—95% control rate with largest proportion of Fisch D

Suárez et al (2014)43

J (1084) V (226)

Surgical: 78% tumor control 2.4% mortality Radiotherapy: 91.5% tumor control 2.6% mortality

Guss et al (2011)45, a

J (300 +)

95% of patients with clinical control 97% of patients with tumor control

Ivan et al

(2011)16

CN defects

Level of evidence Meta-analysis Level III

Jugular PGL (p < 0.001): Surgical: 0.9 CN defects (averaged) per patient Radiotherapy: 0.08 CN defects (averaged) per patient Vagal PGL: CN X deficits in 96% of surgical patients postoperatively. No comparison to radiotherapy possible

Systematic review Level III

Meta-analysis Level III

Abbreviations: J, jugular; CN, cranial nerve; GTR, gross-total resection; PGL, paragangliomas; SRS, stereotactic radiosurgery; STR, subtotal resection; V, vagal. aVariable follow-up but most studies less than 3 years.

New cranial nerve deficits were seen in two patients with jugular tumors, including one vocal cord paresis after embolization, and one temporary facial nerve paresis following rerouting of the facial nerve. Two patients with glomus jugulare had failed radiation treatment prior to surgery (both treated remotely). There was one mortality associated with a patient with prior external beam radiation at an outside institution who developed a malignant peripheral nerve sheath tumor of the vagus nerve. Fourteen patients with glomus jugulare were treated with SRS primarily (n = 11) or after planned subtotal resection (n = 3). Although both modalities have been utilized, over the past 5 years, there has been an increased utilization of Cyber Knife radiosurgery over Gamma Knife, primarily owing to greater ease with treating tumors extending into the neck and with larger treatment volumes necessitating hypofractionation. There were no complications associated with SRS treatment. All patients are followed up postoperatively with serial imaging. Patients undergoing near- or subtotal resection may benefit from SRS; however, this may be safely deferred until residual tumor demonstrates growth on serial imaging. This approach has been reported by several authors and demonstrates lower complication rates and arrested growth of the tumor.38,39,55 Wanna et all published a review of 12 patients treated conservatively and found no tumor growth over 44 months of followup when greater than 80% of the tumor was surgically resected.38,40 “Up-front” planned/staged radiosurgery after partial resection was performed in three patients to alleviate symptoms including otalgia, pulsatile tinnitus, or conductive hearing loss while preserving cranial nerve function.

27.6 Conclusions Head and neck paragangliomas are extremely challenging to treat. The majority are benign tumors; so, it is imperative to

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select a therapy that is going to provide better outcomes than the natural course of the disease. Additionally, it is difficult to predict morbidity because the tumors that cause neuropathies are not limited to growing tumors. Management decisions are impacted by many factors including location and size of tumor, age of patient, comorbid diseases, tumor multiplicity, or even suspicion of malignancy. All treatment options need to be carefully considered and therapy tailored to the needs of the patient.

References [1] Brown JS. Glomus jugulare tumors revisited: a ten-year statistical follow-up of 231 cases. Laryngoscope. 1985; 95(3):284–288 [2] Spector GJ, Fierstein J, Ogura JH. A comparison of therapeutic modalities of glomus tumors in the temporal bone. Laryngoscope. 1976; 86(5):690–696 [3] Jackson CG, McGrew BM, Forest JA, Netterville JL, Hampf CF, Glasscock ME, III. Lateral skull base surgery for glomus tumors: long-term control. Otol Neurotol. 2001; 22(3):377–382 [4] Ghani GA, Sung YF, Per-Lee JH. Glomus jugulare tumors–origin, pathology, and anesthetic considerations. Anesth Analg. 1983; 62(7):686–691 [5] de Flines J, Jansen J, Elders R, et al. Normal life expectancy for paraganglioma patients: a 50-year-old cohort revisited. Skull Base. 2011; 21(6):385–388 [6] Makiese O, Chibbaro S, Marsella M, Tran Ba Huy P, George B. Jugular foramen paragangliomas: management, outcome and avoidance of complications in a series of 75 cases. Neurosurg Rev. 2012; 35(2):185–194, discussion 194 [7] Suárez C, Rodrigo JP, Bödeker CC, et al. Jugular and vagal paragangliomas: Systematic study of management with surgery and radiotherapy. Head Neck. 2013; 35(8):1195–1204 [8] Brackmann D, Shelton C, Arriaga M. Otologic Surgery. 4th ed. Philadelphia, PA: Elsevier; 2017. Available at: http://content.wkhealth.com/linkback/openurl?sid=WKPTLP:landingpage&an=00129492–201606000–00002. Accessed December 13, 2018 [9] Hussain I, Husain Q, Baredes S, Eloy JA, Jyung RW, Liu JK. Molecular genetics of paragangliomas of the skull base and head and neck region: implications for medical and surgical management. J Neurosurg. 2014; 120(2):321–330 [10] Gimenez-Roqueplo A-P, Dahia PL, Robledo M. An update on the genetics of paraganglioma, pheochromocytoma, and associated hereditary syndromes. Horm Metab Res. 2012; 44(5):328–333 [11] Williams MD. Paragangliomas of the head and neck: an overview from diagnosis to genetics. Head Neck Pathol. 2017; 11(3):278–287

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Surgery versus Radiation versus Observation: What Treatment Is Best for Skull Base Paraganglioma? [12] Taïeb D, Kaliski A, Boedeker CC, et al. Current approaches and recent developments in the management of head and neck paragangliomas. Endocr Rev. 2014; 35(5):795–819 [13] Jackler R, Brackmann D. Neurotology. 2nd ed. Philadelphia, PA: Mosby, Inc.; 2005 [14] Malec K, Cenda P, Brzewski P, Kuchta K, Dobosz P, Modrzejewski M. Paragangliomas of head and neck - a surgical challenge. J Craniomaxillofac Surg. 2017; 45(1):127–130 [15] Erickson D, Kudva YC, Ebersold MJ, et al. Benign paragangliomas: clinical presentation and treatment outcomes in 236 patients. J Clin Endocrinol Metab. 2001; 86(11):5210–5216 [16] Ivan ME, Sughrue ME, Clark AJ, et al. A meta-analysis of tumor control rates and treatment-related morbidity for patients with glomus jugulare tumors. J Neurosurg. 2011; 114(5):1299–1305 [17] Ibrahim R, Ammori MB, Yianni J, Grainger A, Rowe J, Radatz M. Gamma Knife radiosurgery for glomus jugulare tumors: a single-center series of 75 cases. J Neurosurg. 2017; 126(5):1488–1497 [18] Friedman R. Lateral Skull Base Surgery: The House Clinical Atlas. New York, NY: Thieme; 2012 [19] Scheick SM, Morris CG, Amdur RJ, Bova FJ, Friedman WA, Mendenhall WM. Long-term Outcomes After Radiosurgery for Temporal Bone Paragangliomas. Am J Clin Oncol. 2018; 41(3):223–226 [20] Prasad SC, Mimoune HA, Khardaly M, Piazza P, Russo A, Sanna M. Strategies and long-term outcomes in the surgical management of tympanojugular paragangliomas. Head Neck. 2016; 38(6):871–885 [21] Sanna M, Fois P, Pasanisi E, Russo A, Bacciu A. Middle ear and mastoid glomus tumors (glomus tympanicum): an algorithm for the surgical management. Auris Nasus Larynx. 2010; 37(6):661–668 [22] Carlson ML, Sweeney AD, Pelosi S, Wanna GB, Glasscock ME, III, Haynes DS. Glomus tympanicum: a review of 115 cases over 4 decades. Otolaryngol Head Neck Surg. 2015; 152(1):136–142 [23] Langerman A, Athavale SM, Rangarajan SV, Sinard RJ, Netterville JL. Natural history of cervical paragangliomas: outcomes of observation of 43 patients. Arch Otolaryngol Head Neck Surg. 2012; 138(4):341–345 [24] Jansen TTG, Timmers HJLM, Marres HAM, Kunst HPM. Feasibility of a waitand-scan period as initial management strategy for head and neck paraganglioma. Head Neck. 2017; 39(10):2088–2094 [25] Jansen JC, van den Berg R, Kuiper A, van der Mey AG, Zwinderman AH, Cornelisse CJ. Estimation of growth rate in patients with head and neck paragangliomas influences the treatment proposal. Cancer. 2000; 88(12):2811–2816 [26] van der Mey AG, Frijns JH, Cornelisse CJ, et al. Does intervention improve the natural course of glomus tumors? A series of 108 patients seen in a 32-year period. Ann Otol Rhinol Laryngol. 1992; 101(8):635–642 [27] Carlson ML, Sweeney AD, Wanna GB, Netterville JL, Haynes DS. Natural history of glomus jugulare: a review of 16 tumors managed with primary observation. Otolaryngol Head Neck Surg. 2015; 152(1):98–105 [28] Prasad SC, Mimoune HA, D’Orazio F, et al. The role of wait-and-scan and the efficacy of radiotherapy in the treatment of temporal bone paragangliomas. Otol Neurotol. 2014; 35(5):922–931 [29] Moore MG, Netterville JL, Mendenhall WM, Isaacson B, Nussenbaum B. Head and neck paragangliomas: an update on evaluation and management. Otolaryngol Head Neck Surg. 2016; 154(4):597–605 [30] González-Orús Álvarez-Morujo RJ, Arístegui Ruiz MÁ, da Costa Belisario J, Martinez Guirado T, Scola Yurrita B. Head and neck paragangliomas: experience in 126 patients with 162 tumours. Acta Otorrinolaringol Esp. 2015; 66 (6):332–341 [31] Harrison L, Corbridge R. Active surveillance management of head and neck paragangliomas: case series and review of the literature. J Laryngol Otol. 2017; 131(7):580–584 [32] Forbes JA, Brock AA, Ghiassi M, Thompson RC, Haynes DS, Tsai BS. Jugulotympanic paragangliomas: 75 years of evolution in understanding. Neurosurg Focus. 2012; 33(2):E13 [33] Fayad JN, Keles B, Brackmann DE. Jugular foramen tumors: clinical characteristics and treatment outcomes. Otol Neurotol. 2010; 31(2):299–305 [34] Borba LAB, Araújo JC, de Oliveira JG, et al. Surgical management of glomus jugulare tumors: a proposal for approach selection based on tumor relationships with the facial nerve. J Neurosurg. 2010; 112(1):88–98

[35] Li D, Zeng X-J, Hao S-Y, et al. Less-aggressive surgical management and longterm outcomes of jugular foramen paragangliomas: a neurosurgical perspective. J Neurosurg. 2016; 125(5):1143–1154 [36] Düzlü M, Tutar H, Karamert R, et al. Temporal bone paragangliomas: 15 years experience. Rev Bras Otorrinolaringol (Engl Ed). 2016:[Epub ahead of print] [37] Odat H, Shin SH, Odat MA, Alzoubi F. Facial nerve management in jugular paraganglioma surgery: a literature review. J Laryngol Otol. 2016; 130(3):219– 224 [38] Wanna GB, Sweeney AD, Carlson ML, et al. Subtotal resection for management of large jugular paragangliomas with functional lower cranial nerves. Otolaryngol Head Neck Surg. 2014; 151(6):991–995 [39] Nicoli TK, Sinkkonen ST, Anttila T, Mäkitie A, Jero J. Jugulotympanic paragangliomas in southern Finland: a 40-year experience suggests individualized surgical management. Eur Arch Otorhinolaryngol. 2017; 274(1):389–397 [40] Wanna GB, Sweeney AD, Haynes DS, Carlson ML. Contemporary management of jugular paragangliomas. Otolaryngol Clin North Am. 2015; 48(2):331–341 [41] Mazzoni A, Zanoletti E. Observation and partial targeted surgery in the management of tympano-jugular paraganglioma: a contribution to the multioptional treatment. Eur Arch Otorhinolaryngol. 2016; 273(3):635–642 [42] Netterville JL, Jackson CG, Miller FR, Wanamaker JR, Glasscock ME. Vagal paraganglioma: a review of 46 patients treated during a 20-year period. Arch Otolaryngol Head Neck Surg. 1998; 124(10):1133–1140 [43] Suárez C, Rodrigo JP, Mendenhall WM, et al. Carotid body paragangliomas: a systematic study on management with surgery and radiotherapy. Eur Arch Otorhinolaryngol. 2014; 271(1):23–34 [44] Gad A, Sayed A, Elwan H, et al. Carotid body tumors: a review of 25 years experience in diagnosis and management of 56 tumors. Ann Vasc Dis. 2014; 7(3):292–299 [45] Guss ZD, Batra S, Limb CJ, et al. Radiosurgery of glomus jugulare tumors: a meta-analysis. Int J Radiat Oncol Biol Phys. 2011; 81(4):e497–e502 [46] Winford TW, Dorton LH, Browne JD, Chan MD, Tatter SB, Oliver ER. Stereotactic radiosurgical treatment of glomus jugulare tumors. Otol Neurotol. 2017; 38(4):555–562 [47] Marchetti M, Pinzi V, Tramacere I, Bianchi LC, Ghielmetti F, Fariselli L. Radiosurgery for paragangliomas of the head and neck: another step for the validation of a treatment paradigm. World Neurosurg. 2017; 98(2): 281–287 [48] Gilbo P, Morris CG, Amdur RJ, et al. Radiotherapy for benign head and neck paragangliomas: a 45-year experience. Cancer. 2014; 120(23):3738–3743 [49] Dobberpuhl MR, Maxwell S, Feddock J, St Clair W, Bush ML. Treatment outcomes for single modality management of glomus jugulare tumors with stereotactic radiosurgery. Otol Neurotol. 2016; 37(9):1406–1410 [50] Genç A, Bicer A, Abacioglu U, Peker S, Pamir MN, Kilic T. Gamma knife radiosurgery for the treatment of glomus jugulare tumors. J Neurooncol. 2010; 97 (1):101–108 [51] Galland-Girodet S, Maire J-P, De-Mones E, et al. The role of radiation therapy in the management of head and neck paragangliomas: impact of quality of life versus treatment response. Radiother Oncol. 2014; 111(3):463–467 [52] Schuster D, Sweeney AD, Stavas MJ, et al. Initial radiographic tumor control is similar following single or multi-fractionated stereotactic radiosurgery for jugular paragangliomas. Am J Otolaryngol. 2016; 37(3):255–258 [53] Patel NS, Link MJ, Driscoll CLW, Pollock BE, Lohse CM, Carlson ML. Hearing outcomes after stereotactic radiosurgery for jugular paraganglioma. Otol Neurotol. 2017; 1(24) [54] Hafez RFA, Morgan MS, Fahmy OM. An intermediate term benefits and complications of gamma knife surgery in management of glomus jugulare tumor. World J Surg Oncol. 2016; 14(1):36 [55] Willen SN, Einstein DB, Maciunas RJMC, Megerian CA. Treatment of glomus jugulare tumors in patients with advanced age: planned limited surgical resection followed by staged gamma knife radiosurgery: a preliminary report. Otol Neurotol. 2005; 26(6):1229–1234 [56] Chen PG, Nguyen JH, Payne SC, Sheehan JP, Hashisaki GT. Treatment of glomus jugulare tumors with gamma knife radiosurgery. Laryngoscope. 2010; 120(9):1856–1862 [57] Genc A, Bicer A, Abacioglu U, Peker S, Pamir MN, Kilic T. Gamma knife radiosurgery for the treatment of glomus jugulare tumors. J Neurooncol. 2010; 97: 101–110

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Other Cranial Tumors

28 Management of Chondrosarcoma of the Cranial Base Jonathan A. Forbes, Vijay K. Anand, and Theodore H. Schwartz Abstract Skull base chondrosarcomas (CSAs) are locally invasive neoplasms that often exhibit indolent growth patterns and are prone to delayed recurrence following surgery and/or radiation therapy. The management of CSAs of the cranial base varies widely and is influenced by tumor morphology, underlying histopathologic features, and preferences of the treating institution. With increased understanding of the biology of CSA, the argument for maximal safe cytoreduction has gained traction. Open microsurgical resection is well established as an effective method to extend longevity in patients with CSA. Choice of open surgical corridor varies by tumor morphology and surgeon preference. Because associated open surgical corridors often involve microdissection of tumor through narrow spaces between involved cranial nerves, progressive utilization of expanded endonasal approaches for treatment of these neoplasms has been reported. While early series have demonstrated promising results, long-term outcome data are limited. Postoperative radiation therapy has been associated with a decreased risk of tumor recurrence in some settings. However, choice and method of postoperative radiotherapy varies widely by institution. Keywords: chondrosarcoma, cranial base, open microsurgical, endoscopic endonasal, radiotherapy, radiosurgery, protonbeam radiotherapy

28.1 Introduction Skull base chondrosarcomas (CSAs) are locally invasive neoplasms that often exhibit indolent growth patterns and are prone to delayed recurrence following surgery and/or radiation therapy.1,2 The prevalence of these tumors in the general population is low; CSAs have been estimated to comprise 0.15% of all intracranial tumors and 6% of all skull base neoplasms.2 CSAs originate from regions encompassing the petrooccipital, sphenooccipital, and sphenopetrosal synchondroses.1 Owing to a shared origin in the cranial base and common clinical presentation, CSAs have often been grouped with chordomas (CHs) in historical reports. While there is overlap in the radiologic features of CSA and CH, CSA is typified by erosion of involved bone on CT imaging with occasional foci of calcification involving the tumor matrix.2,3 In contrast to CHs, which often arise from the anatomic midline, CSAs tend to exhibit a paramedian origin.4 MR imaging of CSA often demonstrates high-signal on T2weighted sequences and moderate to intense enhancement on postcontrast T1-weighted sequences.5 While radiologic features of the two pathologies can be similar, the practice of empiric administration of stereotactic radiosurgery (SRS) for neoplasms suspected to be CSA based on radiologic appearance alone has been reported.6 Important histologic and prognostic differences exist between CSAs and CHs. CSAs are believed to originate from sporadic, malignant transformation of chondrocytes, or chondrocyte-

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progenitor cells, that reside in cranial base synchondroses.5 Relating to this mesenchymal origin, pathologic specimens from CSAs stain negative for the epithelial markers cytokeratin and epithelial membrane antigen—markers that are routinely positive in CH.7 Both CHs and CSAs stain positive for S-100 protein. Despite the immunohistologic specifications described earlier, pathologic differentiation between the two can occasionally be difficult— especially in differentiation of chondroid CHs from chondrosarcoma.8,9 Proper designation is important, as the 5- and 10-year survival rates associated with CSA are higher than those associated with CH (including the chondroid variant) and many authors have advocated a lower threshold to initiate postoperative radiation therapy with the latter pathology.3,10,11 While pathologic confirmation is essential in optimizing adjuvant treatment, it is important to note that considerable biologic variability exists within the designation of CSA. Several histopathologic subtypes have been identified; however, cranial base CSAs are most often identified as either the conventional or mesenchymal variety. While often assigned a low-grade characterization, mesenchymal CSAs are known to be significantly more biologically aggressive than the conventional subtype—with an average life expectancy reported in one study at 28 months.12,13,14 Conventional CSAs can exist as grade I (well differentiated), grade II (moderately differentiated), and grade III (poorly differentiated).15 Of the 512 patients identified in the meta-analysis provided by Bloch and Parsa et al, 452 patients possessed the conventional subtype, while 60 patients harbored the mesenchymal subtype.1 The recurrence rate was noted to be significantly higher in patients with the mesenchymal subtype (63 vs. 16%). Grade III CSAs are rare—in the aforementioned meta-analysis, 364 patients with conventional CSAs had grade I tumors, 80 patients had grade II tumors, and 8 patients had grade III tumors.1 In this study, the rate of recurrence was higher in the grade III group (33%) than grades I and II (15 and 16%, respectively), but statistical significance was not reached.

28.2 Open Microsurgical Treatment Open microsurgical resection is well established as an effective method to extend longevity in patients with CSA.2,16,17,18,19 Surgery provides a histologic diagnosis and can help reduce the dose of radiation to critical structures when postoperative XRT is deemed necessary.20 Given the proclivity for neural compression without invasion exhibited by CSAs, surgical resection also offers potential for improvement of preoperative cranial nerve deficits.16 Still it is widely recognized that aggressive attempts at gross total surgical resection of CSAs are associated with considerable risks to adjacent neural and vascular structures. In earlier series, the biology of CSA was incompletely understood and occasionally interposed with that of the more aggressive and prevalent CH.12,21 Many initial reports advocated radical excision as the most oncologically sound approach; in some cases, authors tolerated considerable postoperative neurologic

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Management of Chondrosarcoma of the Cranial Base

Fig. 28.1 (a) Axial T1-weighted, postcontrast MRI obtained prior to surgery demonstrates a right lateral temporal bone mesenchymal skull base chondrosarcoma with involvement of the infratemporal fossa, temporal bone, mandible, and parapharyngeal space. (b) Axial T1-weighted, postcontrast imaging obtained following a subtemporal-infratemporal fossa approach with lateral temporal bone resection, mandibular condylectomy, and free flap reconstruction. Gross total resection of the tumor was achieved. (Figure used with permission from Shaan M. Raza, MD, Department of Neurosurgery, The University of Texas M.D. Anderson Cancer Center.)

deficit to achieve this goal.22 Sekhar et al reported results in 22 patients with CSA who underwent aggressive surgical resection with rates of intraoperative vascular injury in 14% and new injury to cranial nerves 5 and 6 in 23 and 18%, respectively.21 A subsequent report by the same group described intentional and unintentional sacrifice of the internal carotid artery in 6 of 47 patients treated with revascularization in attempts to maximize extent of resection.18 A 2006 series by Brackmann and Teufert reported successful gross total resection in 100% of eight patients with CSA who underwent surgery. The 5- and 10-year overall survival rate was noted to be 100% in all patients not lost to follow-up; however, new postoperative cranial nerve deficits were reported in all eight patients.2 With increased understanding of the natural history of CSA, the argument for maximal safe cytoreduction and preference for subtotal resection over gross total resection and neurologic deficit in treatment has gained traction. In a 2005 series of 33 patients by Oghalai et al, the authors noted an increased risk of recurrence when postoperative radiation was not given, but not with incomplete tumor resection.23 The strategy of maximal safe cytoreduction was also advocated by Samii et al who felt that, given the good long-term prognosis of these tumors, the goals of surgery should be designed around maximizing quality of life.17 In the most recent compilation reporting treatment of CSA at four tertiary care centers, Carlson et al described achieving gross total resection in 27% of patients, with only one reported death during a mean follow-up interval of 6 years.16 Choice of open surgical corridor varies by tumor morphology and surgeon preference. CSAs of the skull base demonstrate considerable anatomic variability and are known to involve multiple compartments; it has been reported that 64% arise in the middle fossa alone, 14% involve both the middle and posterior fossa, 14% occur in the anterior fossa, and 7% originate in the posterior fossa.2 The vast majority of historical reports of resection of CSAs describe variations of pterional (including FTOZ), subfrontal/transbasal, subtemporal/infratemporal, retrosigmoid, transpetrosal, and transfacial surgical approaches— often used in combination. Surgeon preference is an important variable; Brackmann and Teufert reported use of an infratemporal fossa approach in 88% of his patient population.2 Wanebo et al favored orbitozygomatic craniotomy in 78% of patients.19 Crockard et al utilized a variety of approaches, most commonly

a pterional craniotomy in 35%.12 ▶ Fig. 28.1 demonstrates an example of resection of a right lateral temporal bone CSA with infratemporal extension via a subtemporal–infratemporal fossa approach. In recent years, there has been progressive utilization of expanded endonasal approaches for treatment of these neoplasms, which will be discussed in the ensuing passage.6,24 Rates of gross total resection, postoperative neurologic morbidity, adjuvant radiotherapy, and overall survival in various large open microsurgical series are presented in ▶ Table 28.1.

28.3 Endoscopic Endonasal Treatment Despite the proven effectiveness of open approaches, the associated surgical corridors often involve microdissection of tumor through narrow spaces between involved cranial nerves, with high attendant rates of subtotal resection and neurologic morbidity. These issues have led many cranial base surgeons to seek an alternative surgical approach.24 Over the past 25 years, advances in endoscopic technology and understanding have progressed to allow more comprehensive access to the skull base from the endonasal route.25,26 The ability to expeditiously remove tumor-infiltrated bone and access deep-seated regions of tumor extension without the need for aggressive brain retraction made endonasal techniques an appealing alternative to traditional open approaches. The typical soft consistency and relative avascularity of CSAs proved well suited to resection via the endoscopic endonasal route.27 Early case reports provided cautionary examples of postoperative cerebrospinal fluid (CSF) leakage following resection of CSAs with intradural extension.28 With increased experience and technological advancements, including the introduction of the vascularized nasoseptal flap, the rate of postoperative CSF leak has decreased dramatically in recent years.6,24 The first large case series of chondrosarcomas was provided by Mesquita Filho et al in 2014.24 While this study was limited by selection bias (only 5 of 19 surgical patients with CSA were selected for analysis—specifically those with extension to the cerebellopontine angle) and poor long-term follow-up data, the relatively high rate of gross total resection with no reported postoperative neurologic deficit provided reason for

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Other Cranial Tumors

Table 28.1 Largest modern series of open surgical treatment for resection of cranial base chondrosarcoma Study (year)

Pt/Sx

Av. Sx/ Pt

New post-op deficit

CSF leaka

GTR

% MSNC or Gr III

5Y RFS

10Y RFS

5Y OS

10Y OS

Post-op XRT

LEO

Carlson et al (2016)16

55/NS

NS

11 (24%)

3 (6%)

12 (27%)

2 (4%)

70%

56%

NS

NS

30 (64%)

IV

Samii et al (2009)17

25/39

1.56

NS (33%)b

4 (16%)

19 (76%)

0 (0%)

NS

NS

95%

95%

8 (32%)

IV

Tzortzidis et al (2006)18

47/72

1.53

c

1 (2%)

29 (62%)

2 (4%)

52%

32%

NS

NS

NS

IV

Wanebo et al (2006)19

23/43

1.87

5 (22%)

2 (9%)

NSd

NS

NS

NS

93%

71%

10 (43%)

IV

Brackmann and Teufert (2006)2

8/9

1.13

8 (100%)

1 (13%)

8 (100%)

NS

NS

NS

100%e

100%f

2 (25%)

IV

Crockard et al (2001)12

17/NS

NS

4 (24%)

2 (12%)

NSf

2 (12%)

NS

NS

14 (82%)

13 (76%)

4 (24%)

IV

Abbreviations: Pt, number of patients; Sx, number of surgeries; Av. Sx/Pt, average number of surgeries per patient; CSF, cerebrospinal fluid; GTR, effective gross total resection; MSNC, number of tumors graded as mesenchymal subtype; Gr III, number of tumors designated grade III CSA; 5Y RFS, 5-year recurrence-free survival; 10Y RFS, 10-year recurrence-free survival; 5Y OS, 5-year overall survival; 10Y OS, 10-year overall survival; Post-op XRT, number of patients who underwent postoperative radiation therapy; LEO, level of evidence; NS, not specified. aCSF leakage reported as a percentage of number of patients with leakage over total number of patients (total number of surgeries not figured in to calculation). bNeurologic complications were not described on an individual basis. Authors-reported new neurologic deficits immediately following surgery appeared in 33.3%. The reported rate of persistent surgery-related deficit in the study was 11.1%. cResults presented in Table 3 by Tzortzidis et al indicated 32 patients (68%) had “partially recovered” central nervous system (CNS) palsy, while 2 patients (4%) suffered from a permanent CNS palsy. dNS. Report describes 7 patients who underwent GTR of tumor without initial radiation therapy, but does not specify degree of resection in remaining 16 patients. eOne patient lost to follow-up over initial 10-year postoperative period. fReported greater than 90% removal in 14 of 17 patients.

optimism.24 Moussazadeh et al followed up with a series of eight patients treated with endonasal resection in 2015; the authors noted that five additional patients were treated via a transcranial route during this time because of significant lateral petrous extension.27 In this series, greater than 95% resection was achieved in five of eight patients with one postoperative CSF leak and no new postoperative neurologic deficits. In contrast to the open, microsurgical series of CSAs listed in ▶ Table 28.1, postoperative radiation was administered to 100% of patients in both aforementioned endonasal series. Recently, Hasegawa et al released data on 19 consecutive patients who underwent endoscopic endonasal resection of CSA of the skull base. Gross total resection was achieved in 79% of patients with only one postoperative CSF leak (5%). The rate of immediate postoperative neurologic deficit was 3 (16%), although there were zero permanent neurologic deficits.29 Postoperative radiation therapy was administered only in 21% of the patient population; however, as with the other endonasal series, long-term follow-up data are lacking. Rates of gross total resection, postoperative neurologic morbidity, adjuvant radiotherapy, and overall survival in the aforementioned endonasal series are presented in ▶ Table 28.2. In contrast to the various strategies often employed for open microsurgery, the endoscopic, endonasal techniques used for resection of CSAs are more consistent across various series. Inherent in this approach is the need to begin with a transsphenoidal window. A nasoseptal flap is harvested from the opposite side. In the event a transmaxillary corridor is deemed necessary (e.g., tumor extension to the petrous ICA), a complete

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ethmoidectomy and sphenoidotomy is required.30 A wide antrostomy provides access to the posterior wall of the maxillary sinus, which can be removed to allow mobilization of the contents of the pterygopalatine fossa. Lateral tumor extension sometimes requires an associated anterior petrosectomy, which can be performed following additional exposure of the infrasphenoidal clivus.24,30,31 Lesions that involve the lower clivus and extend to the infratemporal fossa often require a transpterygoid extension and/or mobilization of the Eustachian tube.24 ▶ Fig. 28.2 demonstrates an example of resection of petroclival CSA with cavernous sinus extension via expanded endonasal approach. Deciding whether or not to proceed via traditional open microsurgical approach or endoscopic endonasal approach for resection of CSA can be a complicated process. Knowledge of associated limitations is of paramount importance. Tumor extension lateral to the course of the cranial nerves represents a relative contraindication to sole use of an endoscopic endonasal approach. In their series of endonasal endoscopic resection of CSAs and CHs, Kim et al evaluated the extent of sagittal and lateral tumor extension on tumor resectability.31 They noted that tumor extension lateral to the cavernous/paraclival ICA, cisternal trigeminal nerve, and hypoglossal canal significantly increased the likelihood of subtotal resection; a significant difference was not detected, however, with regard to rostrocaudal clival involvement.31 While many agree that lateral extension makes gross total resection more challenging, opinions on the topic of surgical selection are not uniform.24,27 Moussazadeh et al reported that open approaches in their series were chosen

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Management of Chondrosarcoma of the Cranial Base

Table 28.2 Large modern series of endoscopic endonasal treatment for resection of cranial base chondrosarcoma Study (year)

Pts/Sxs

Av. Sx/ Pt

New postop deficit

CSF leaka

GTR

% MSNC or Grade III

5Y RFS

10Y RFS

5Y OS

10Y OS

Post-op XRT

LEO

Hasegawa et al (2017)29

19/20

NS

3 (16%)b

1 (5%)

15 (79%)

1 (5%)

NS

NS

NS

NS

4 (21%)

IV

Moussazadeh et al (2015)27

8/10

1.25

0 (0%)

1 (12.5%)

NSc

NS

NS

NS

NS

NS

8 (100%)

IV

Mesquita Filho et al (2014)24

5/8

1.6

0 (0%)

0 (0%)

3 (60%)

2 (40%)

NS

NS

NS

NS

5 (100%)

IV

Abbreviations: Pts, number of patients; Sx, number of surgeries; Av. Sx/Pt, average number of surgeries per patient; CSF, cerebrospinal fluid; GTR, effective gross total resection; MSNC, number of tumors graded as mesenchymal subtype; grade III, number of tumors designated grade III CSA; 5Y RFS, 5-year recurrence-free survival; 10Y RFS, 10-year recurrence-free survival; 5Y OS, 5-year overall survival; 10Y OS, 10-year overall survival; Post-op XRT, number of patients who underwent postoperative radiation therapy; LEO, level of evidence; NS, not specified. aCSF leakage reported as a percentage of number of patients with leakage over total number of patients (total number of surgeries not figured in to calculation). bEach of the three new, postoperative neurologic deficits resolved with time. Rate of new, permanent neurologic deficits in this study reported at 0%. cAuthors reported > 95% resection in 5 of 8 patients treated (63%).

Fig. 28.2 Axial T1-weighted, postcontrast images obtained pre- (a) and postoperatively (b) following gross total resection of petroclival skull base chondrosarcoma with cavernous sinus extension via expanded endonasal route.

when tumors exhibited a significant lateral petrous extension and were felt to be poorly accessible from a paramedian endoscopic corridor.27 Mesquita Filho et al and Hasegawa et al have advocated the use of endoscopic endonasal approaches as the initial surgical corridor in all cases of petroclival chondrosarcoma.24,29 In another recent large, multi-institutional series by Carlson et al, expanded endonasal approaches were used only in 11% of the patient population.16 It is likely that optimal treatment of these complicated tumors in ensuing years will require surgical teams well versed in both traditional open microsurgical strategies and contemporary expanded endonasal approaches.

28.4 Role of Radiation Therapy The low incidence of cranial base CSAs makes systematic, unbiased analysis difficult, which contributes to variation in treatment patterns. This is especially true with choice and method of adjuvant therapy following resection of CSAs—where great variability has been reported in the literature.12,18,24,27,29 Currently, there is no compelling evidence to support chemotherapy in CSAs, although it is sometimes considered on an individual basis following failure of surgery and/or radiation therapy.20 Given the relatively radioresistant nature of CSAs, high doses of conventional radiation therapy, often in excess of

60 Gray, have been proposed to achieve tumor control.17 In some of the older series, morbidity and occasional mortality secondary to radiation-related complications were noted. In the series by Tzortzidis et al, two patients died as a result of radiotherapy complications; one patient from radionecrosis secondary to fractionated radiation and the other from unspecified malignant transformation in the irradiated field.18 In recent years, advances in stereotactic and heavy-particle radiotherapy have allowed for safer deposition of greater amounts of radiation.20 SRS utilizes convergence of multiple radiation beams to maximize delivery of radiation to the tumor bed, with minimization of radiation to surrounding critical structures. SRS is often limited by volume; even the most vocal proponents of its use choose to withhold therapy when maximal tumor diameter exceeds 35 mm.32 Tumors that are too large or too close to critical structures are often considered for fractionated radiotherapy. However, many authors have described the standard use of postoperative SRS for residual or recurrent tumor and its safety profile is well documented.6,19 Proton-beam radiotherapy (PBRT) is another form of radiation therapy often considered during multimodality treatment of cranial base CSA. PBRT utilizes the Bragg peak effect to achieve a steep gradient of radiation delivery.33 With this technology, proton beams travel through tissue with minimal dose deposition until a terminal

185

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Other Cranial Tumors peak of energy transfer occurs at a precalculated depth. The dose deposited before this Bragg peak is approximately 30% of the maximum dose; the dose deposited beyond the peak is close to zero.33 This is in contradistinction to photon-based radiation therapy, where exponential decrease of deposited dose is noted with increasing depth. There is some evidence to suggest that PBRT is superior to IMRT and fractionated SRS with regard to long-term local control of CSA.34 Some experts have gone as far to refer to PBRT as the standard of care for postoperative radiotherapy in CSA.33 Newer forms of heavy-particle radiotherapy are currently being investigated for use in CSA.20 Carbon-ion radiation therapy is of particular interest, as carbon-ion beams result in two to three times the relative biological effectiveness of more conventional methods of irradiation.35 Both PBRT and carbon-ion radiation therapy are limited by extremely high start-up costs and referral to a center with capability for particle irradiation can be impractical. The question of true superiority of these modalities over more traditional inexpensive methods remains. Various algorithms exist when deciding if and how to proceed with postoperative radiotherapy following resection of CSAs. Crockard et al chose to stratify the decision to proceed with postoperative radiotherapy based on CSA subtype: conventional lowgrade CSAs were observed—with preference given to repeat surgery for recurrence, whereas mesenchymal CSA were treated similar to CHs and routinely treated with a combination of radiosurgery and conventional radiotherapy following surgery.12 Tzortzidis et al advocated postoperative radiation therapy for residual tumor, but did not differentiate between the various forms.18 Hasegawa et al recommended against routine postoperative radiotherapy following radiologic gross total resection of CSA and reported high rates of tumor control by utilizing radiosurgery (15–16 Gy prescribed to margin) in selective cases where residual tumor is present following surgery.29 Sekhar et al reported the following surgical strategy for residual tumor: if the patient was young and the remnant was greater than 2 cm, repeat surgery was recommended; if a small (< 2 cm) remnant was visible on postoperative MRI or the patient was older, the decision was often made to proceed with SRS or PBRT.21 In a large meta-analysis by Bloch and Parsa, the 5-year rate of recurrence was noted to be significantly lower following surgery and radiation than with either surgery alone or radiation alone.1 While numerous studies report good results with postoperative SRS or PBRT, the question of choice and method of postoperative radiotherapy is clouded by a natural postoperative history that is incompletely understood.6,36 Samii et al reported 95% 10-year overall survival despite only choosing to utilize postoperative radiotherapy in 32% of patients treated.17 However, there is good data to suggest that the long-term control with postoperative radiotherapy is high. In a landmark report, Hug et al achieved a 5-year rate of progression-free survival in patients with CSA who underwent PBRT of 75% with a 5-year survival rate of 100%.36 More recently, Kano et al reported a 10year rate of progression-free survival for patients with CSA who underwent SRS at 70%; 78% of patients in this study were alive at a median follow-up of 75 months.6 Of note, five patients in this study were treated with empiric XRT in the absence of histologic confirmation.36 It is our current practice to recommend postoperative PBRT in all patients with histologically verified CSA following resection.27

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28.5 Future Directions In light of the great variability in clinical strategies discussed earlier, future studies should seek to form a more unified algorithm regarding treatment. While recent reports are reflective of a shift toward increased utilization of endoscopic endonasal approaches for these tumors, additional long-term data are needed. In the future, it is likely that additional data points (e.g., subtype classification, molecular targets) distinct from the gross histopathologic diagnosis of CSA will be evaluated when considering adjuvant radiotherapy and overall prognosis. Research meant to assess the effect of various radiation/or chemotherapy protocols on the mesenchymal variety, which appears to be significantly more aggressive than the conventional subtype, may be particularly beneficial.

28.6 Conclusions Skull base chondrosarcomas are locally invasive neoplasms that often exhibit indolent growth patterns and are prone to delayed recurrence following surgery and/or radiation therapy. Historically, a number of surgical approaches have been used for resection; application of these strategies varies greatly by treating institution. Recent studies appear to demonstrate a shift toward increased utilization of endoscopic endonasal procedures. Radiation is often considered following resection of CSAs, although individual protocols also vary greatly. Currently, there is no compelling evidence to support the use of chemotherapy in CSAs, although it is sometimes considered on an individual basis following failure of surgery and/or radiation therapy.

References [1] Bloch O, Parsa AT. Skull base chondrosarcoma: evidence-based treatment paradigms. Neurosurg Clin N Am. 2013; 24(1):89–96 [2] Brackmann DE, Teufert KB. Chondrosarcoma of the skull base: long-term follow-up. Otol Neurotol. 2006; 27(7):981–991 [3] Almefty K, Pravdenkova S, Colli BO, Al-Mefty O, Gokden M. Chordoma and chondrosarcoma: similar, but quite different, skull base tumors. Cancer. 2007; 110(11):2457–2467 [4] Meyers SP, Hirsch WL, Jr, Curtin HD, Barnes L, Sekhar LN, Sen C. Chondrosarcomas of the skull base: MR imaging features. Radiology. 1992; 184(1):103–108 [5] Mohyeldin A, Prevedello DM, Jamshidi AO, Ditzel Filho LF, Carrau RL. Nuances in the treatment of malignant tumors of the clival and petroclival region. Int Arch Otorhinolaryngol. 2014; 18 Suppl 2:S157–S172 [6] Kano H, Sheehan J, Sneed PK, et al. Skull base chondrosarcoma radiosurgery: report of the North American Gamma Knife Consortium. J Neurosurg. 2015; 123(5):1268–1275 [7] Holton JL, Steel T, Luxsuwong M, Crockard HA, Revesz T. Skull base chordomas: correlation of tumour doubling time with age, mitosis and Ki67 proliferation index. Neuropathol Appl Neurobiol. 2000; 26(6):497–503 [8] Korten AG, ter Berg HJ, Spincemaille GH, van der Laan RT, Van de Wel AM. Intracranial chondrosarcoma: review of the literature and report of 15 cases. J Neurol Neurosurg Psychiatry. 1998; 65(1):88–92 [9] Lanzino G, Dumont AS, Lopes MB, Laws ER, Jr. Skull base chordomas: overview of disease, management options, and outcome. Neurosurg Focus. 2001; 10(3):E12 [10] Gay E, Sekhar LN, Rubinstein E, et al. Chordomas and chondrosarcomas of the cranial base: results and follow-up of 60 patients. Neurosurgery. 1995; 36(5): 887–896, discussion 896–897 [11] Watkins L, Khudados ES, Kaleoglu M, Revesz T, Sacares P, Crockard HA. Skull base chordomas: a review of 38 patients, 1958–88. Br J Neurosurg. 1993; 7 (3):241–248 [12] Crockard HA, Cheeseman A, Steel T, et al. A multidisciplinary team approach to skull base chondrosarcomas. J Neurosurg. 2001; 95(2):184–189

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Management of Chondrosarcoma of the Cranial Base [13] Evans HL, Ayala AG, Romsdahl MM. Prognostic factors in chondrosarcoma of bone: a clinicopathologic analysis with emphasis on histologic grading. Cancer. 1977; 40(2):818–831 [14] Gelderblom H, Hogendoorn PC, Dijkstra SD, et al. The clinical approach towards chondrosarcoma. Oncologist. 2008; 13(3):320–329 [15] Rosenberg AE, Nielsen GP, Keel SB, et al. Chondrosarcoma of the base of the skull: a clinicopathologic study of 200 cases with emphasis on its distinction from chordoma. Am J Surg Pathol. 1999; 23(11):1370–1378 [16] Carlson ML, O’Connell BP, Breen JT, et al. Petroclival chondrosarcoma: a multicenter review of 55 cases and new staging system. Otol Neurotol. 2016; 37 (7):940–950 [17] Samii A, Gerganov V, Herold C, Gharabaghi A, Hayashi N, Samii M. Surgical treatment of skull base chondrosarcomas. Neurosurg Rev. 2009; 32(1):67–75, discussion 75 [18] Tzortzidis F, Elahi F, Wright DC, Temkin N, Natarajan SK, Sekhar LN. Patient outcome at long-term follow-up after aggressive microsurgical resection of cranial base chondrosarcomas. Neurosurgery. 2006; 58(6):1090–1098, discussion 1090–1098 [19] Wanebo JE, Bristol RE, Porter RR, Coons SW, Spetzler RF. Management of cranial base chondrosarcomas. Neurosurgery. 2006; 58(2):249–255, discussion 249–255 [20] Amichetti M, Amelio D, Cianchetti M, Giacomelli I, Scartoni D. The treatment of chordoma and chondrosarcoma of the skull base with particular attention to radiotherapy. Clin Oncol. 2017; 2(1195):1–7 [21] Sekhar LN, Pranatartiharan R, Chanda A, Wright DC. Chordomas and chondrosarcomas of the skull base: results and complications of surgical management. Neurosurg Focus. 2001; 10(3):E2 [22] Neff B, Sataloff RT, Storey L, Hawkshaw M, Spiegel JR. Chondrosarcoma of the skull base. Laryngoscope. 2002; 112(1):134–139 [23] Oghalai JS, Buxbaum JL, Jackler RK, McDermott MW. Skull base chondrosarcoma originating from the petroclival junction. Otol Neurotol. 2005; 26(5):1052–1060 [24] Mesquita Filho PM, Ditzel Filho LF, Prevedello DM, et al. Endoscopic endonasal surgical management of chondrosarcomas with cerebellopontine angle extension. Neurosurg Focus. 2014; 37(4):E13

[25] Arbolay OL, González JG, González RH, Gálvez YH. Extended endoscopic endonasal approach to the skull base. Minim Invasive Neurosurg. 2009; 52 (3):114–118 [26] Klossek JM, Ferrie JC, Goujon JM, Fontanel JP. Endoscopic approach of the pterygopalatine fossa: report of one case. Rhinology. 1994; 32(4):208–210 [27] Moussazadeh N, Kulwin C, Anand VK, et al. Endoscopic endonasal resection of skull base chondrosarcomas: technique and early results. J Neurosurg. 2015; 122(4):735–742 [28] Li MC, Guo HC, Chen G, Kong F, Zhang QH. Meningitis caused by Enterococcus casseliflavus with refractory cerebrospinal fluid leakage following endoscopic endonasal removal of skull base chondrosarcoma. Chin Med J (Engl). 2011; 124(20):3440 [29] Hasegawa H, Shin M, Kondo K, et al. Role of endoscopic transnasal surgery for skull base chondrosarcoma: a retrospective analysis of 19 cases at a single institution. J Neurosurg. 2017; 7:1–10 [30] Hofstetter CP, Singh A, Anand VK, Kacker A, Schwartz TH. The endoscopic, endonasal, transmaxillary transpterygoid approach to the pterygopalatine fossa, infratemporal fossa, petrous apex, and the Meckel cave. J Neurosurg. 2010; 113(5):967–974 [31] Kim YH, Jeon C, Se YB, et al. Clinical outcomes of an endoscopic transclival and transpetrosal approach for primary skull base malignancies involving the clivus. J Neurosurg. 2017; 2:1–9 [32] Martin JJ, Niranjan A, Kondziolka D, Flickinger JC, Lozanne KA, Lunsford LD. Radiosurgery for chordomas and chondrosarcomas of the skull base. J Neurosurg. 2007; 107(4):758–764 [33] Mitin T, Zietman AL. Promise and pitfalls of heavy-particle therapy. J Clin Oncol. 2014; 32(26):2855–2863 [34] Debus J, Schulz-Ertner D, Schad L, et al. Stereotactic fractionated radiotherapy for chordomas and chondrosarcomas of the skull base. Int J Radiat Oncol Biol Phys. 2000; 47(3):591–596 [35] Ebner DK, Kamada T. The emerging role of carbon-ion radiotherapy. Front Oncol. 2016; 6:140 [36] Hug EB, Loredo LN, Slater JD, et al. Proton radiation therapy for chordomas and chondrosarcomas of the skull base. J Neurosurg. 1999; 91(3):432–439

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Other Cranial Tumors

29 Natural History and Treatment Strategies for Posterior Fossa Epidermoids Steven B. Carr, Omar Arnaout, and Charles Teo Abstract In this chapter, we discuss the natural history of posterior fossa epidermoids and review optimal treatment strategies and the factors related to recurrence. Epidermoid tumors have a tendency to arise in juxtaposition to the skull base of the posterior fossa, are slow growing, and result from trapped ectodermal tissue in the central nervous system during development. They grow at a linear rate and only rarely behave in a malignant fashion. The infrequent reports of recurrence after apparent gross macroscopic removal is largely due to undetected residual remnants and intentional residual that is found to be densely adherent to neurovascular structures. Maximal safe surgical resection is the gold standard and the mainstay of treatment. We discuss the surgical strategies most beneficial to optimally treating patients in whom these tumors are found. Keywords: epidermoid, craniotomy, treatment, surgery, resection, keyhole, endoscope, recurrence

29.1 Introduction The surgical management of intracranial epidermoid tumors is both straightforward and challenging. They are thought to arise from trapped ectodermal cells within the central nervous system during embryogenesis and grow at a linear growth rate similar to that of skin, rather than the exponential growth rate seen in true neoplasms.1,2 Hence, epidermoids are considered benign lesions that necessitate treatment due mostly to the mass effect that arises from their growth. Other clinical manifestations include seizures, mostly seen with supratentorial lesions, cranial neuropathy, including trigeminal neuralgia when the fifth cranial nerve is involved, and aseptic meningitis with rupture of these cysts into the subarachnoid space. They tend to occur at the skull base, most commonly in the posterior fossa, although they may be found anywhere in the cranial cavity, both intra and extra-axial and even intradiploic. MRI characteristics are almost diagnostic. These lesions are generally slightly hyperintense or isointense to gray matter on the T1weighted sequence, depending on the lipid content, and often have a heterogeneous center. On the T2-weighted sequence, they are isointense to cerebrospinal fluid, and on diffusionweighted imaging they have markedly restricted diffusion and hence are hyperintense. Although they typically do not enhance, the capsule and surrounding structures sometimes take up gadolinium in the presence of inflammation. In this chapter, we discuss what factors are relevant to achieving an optimal outcome for patients with posterior fossa epidermoids and how these lesions are ideal for the application of keyhole neurosurgical principles. The natural history of epidermoids is related to their biological origin. These lesions are thought to derive from surface ectoderm and migrate via vesicle folds along neurovascular

188

structures to eventually settle in their typical paramedian or lateral skull base location. While epidermoids can be found in any intracranial compartment, the most common location is the posterior fossa, specifically the cerebellopontine angle (CPA).3,4 Epidermoid cysts are composed of keratinizing stratified squamous epithelium, with an inner constitution of keratin, desquamated cell debris, and cholesterol.5 Their growth pattern is similar to the growth pattern of skin, following a stepwise maturation pattern and linear growth rate, and they tend to spread along subarachnoid planes. The outer capsule of the lesion is what is believed to be the part that causes growth, hence the temptation for surgeons, wishing to minimize risk of recurrence, to strive for complete capsule resection. Neurosurgeons have been publishing their surgical experience with epidermoids since the early modern neurosurgical history.6 Current thinking still regards epidermoid tumors as almost exclusively surgical lesions. However, because these lesions can be adherent to neurovascular structures and aggressive removal of such adherent remnants of these otherwise benign lesions can be harmful, some authors argue that adherent residual tumor should be left behind.7 However, it is likely that this conservative surgical approach explains in part the tendency of these lesions to regrow. A recent retrospective series evaluating a single institution’s surgical results of posterior fossa epidermoid tumors found an 84% increase in the recurrence rate where total removal was not achieved.8 Disturbingly, there are a growing number of case reports of malignant transformation of epidermoid cysts to squamous cell carcinoma, which further complicates surgical decision making.9,10,11,12,13 Thus, in this chapter we address the surgical strategy, principles, and tools best suited for safely maximizing surgical resection, while minimizing the risk of recurrence, poor neurologic outcome, and poor prognosis associated with rare malignant transformation.

29.2 Review The mainstay of treatment for epidermoids is maximal safe surgical resection. As discussed by Samii et al,14 operative morbidity prior to the more modern era was high given the adherence of these lesions to cranial nerves, delicate vasculature, and the brainstem pia mater. Consequently, several authors advocated a more conservative approach of intentionally leaving behind the capsule or at least those parts that were densely adherent to important structures.7,15,16,17,18 Further justification for a subtotal resection is the relative biological inert nature of these tumors that have been known to take decades to recur. However, over time our knowledge about these lesions has evolved, and so too have our tools. The development of higher resolution imaging techniques, surgical navigation, intraoperative neuromonitoring, high-definition microscopy, and endoscopy has been useful addition to the surgeon’s armamentarium. Thus, the contrary approach proposes attempt at gross total

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Natural History and Treatment Strategies for Posterior Fossa Epidermoids resection, including total removal of the capsule to minimize the risk of recurrence. When epidermoid tumors do recur, they tend to be more difficult to remove, possibly due to scarring and longer duration of tumor presence with associated inflammatory response.19,20,21 Hence, remission rates following resection for a recurrent epidermoid are significantly lower than those for virgin cases (see ▶ Table 29.1).

Several groups who adopted a more aggressive surgical strategy found a significant enough benefit in tumor remission and low enough operative morbidity to recommend total removal as the standard goal when treating posterior fossa epidermoids.8,26 Al-Mefty and coworkers20 reported they were able to achieve total removal of the tumor and associated capsule in 73% of patients who harbored even giant epidermoids and

Table 29.1 List of key studies and level of evidence Study

Cases

Endoscope use

Extent of resection

Remission rate

Follow-up duration

Hasegawa et al (2016)22

22

No

GTR/NTR

82%

100%

2 mo–9 y

STR

18%

100%

46%

94%

47

No

GTR STR

54%

90%

Gopalakrishnan et al (2014)8

38

No

GTR

62%

91%

STR

38%

7%

Raghunath et al (2013)24

15

GTR

33%

100%

NTR/STR

67%

100%

GTR

52%

77%

STR

48%

73%

GTR

75%

100%

STR

25%

60%

GTR

22%

100%

STR

78%

43%

GTR

57%

100%

STR

43%

85%

GTR

63%

100%

STR

37%

66%

GTR

57%

95%

STR

43%

65%

GTR

75%

100%

STR

25%

70%

GTR

19%

15%

STR

81%

Overall

GTR

8%

100%

STR

92%

100%

GTR

Posterior fossa cases not separately analyzed

Schiefer and Link (2008) Akar et al (2003)15 Tancredi et al (2003)17 Kobata et al (2002)26 Mallucci et al, 199927 Talacchi et al (1998)28 Samii et al (1996)14 deSouza et al (1989)29 Berger and Wilson (1985)7

24 20 9 30 8 28 40 30 13

No No No No No No No No No

Level of evidence

18%

IV

Overall

Yawn et al (2016)23

No

New neuro deficit

3.5 y

0%

9.4 y

11%

IV

0% IV

Overall 1.4 y

13%

IV

Overall 4.3 y

15%

IV

18% 6y

20%

IV

60% 14.5 y

22%

IV

Overall 11.5 y

NR

IV

4.8 y

25%

IV

Overall 8.6 y

11%

IV

Overall 5.7 y

10%

IV

Overall NR

40%

IV

Overall 4.5 y

0%

IV

0%

Endoscopic assisted Aboud et al (2015)20

34

Yes (13)

IV

STR Tuchman et al (2014)30

13

Yes (all)

GTR/NTR

54%

STR

46%

NR

6

Yes (all)

GTR

83%

STR

17%

100%

Chowdhury et al (2013)32

14

Yes (3)

GTR/NTR STR

79% 21%

Chowdhury and Haque, (2012)33

1

Yes (all)

GTR STR

Ebner et al (2010)25

7

Safavi-Abbasi et al (2008)34

12

Schroeder et al (2004)35

8

Yes (some) Yes (all)

0%

IV

0%

Peng et al (2014)31

Yes (all)

NR

100%

3.2 y

40%

IV

100% 100%

3.3 y

0%

IV

N/A

N/A

2 mo

N/A

IV

100%

100%

Total

15%

N/A

NR

0%

IV

GTR

85%

N/A

GTR

75%

N/A

STR

25%

N/A

GTR

38%

100%

STR

62%

100%

0%

33% 2.3 y

17%

IV

Overall 3.3 y

66%

IV

0%

189

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Other Cranial Tumors reported improvements in clinical status (Karnofsky Performance Score) postoperatively compared to their preoperative baseline. Of note, they were only able to achieve a gross total resection in 17% of cases that presented as recurrences, underscoring the importance of achieving the best resection possible in the initial resection. Schiefer and Link36 validated this report when reporting on 24 patients with CPA epidermoids, of whom 16% had new permanent deficits, and all but 1 were reported as relatively minor. Minimally invasive keyhole approaches are extremely applicable to these tumors given their soft, flaky consistency and avascular interior. In keeping with this concept, several authors have reported on the usefulness of the endoscope in surgical resection of epidermoids. One group reported that the use of endoscopic-assisted techniques in combination with standard microsurgical resection was beneficial in 85% of cases, which led to more complete resections.30 Abolfotoh et al37 reported that by using the endoscope, residual tumor was discovered in 69% of patients with CPA tumors (of several types) in whom the surgeons believed they had achieved a gross total resection with the microscope. Schroeder et al35 described their series of eight patients with CPA epidermoid tumors, in whom 100% benefitted from endoscopic-assisted surgery. Their use of the endoscope ranged from inspection of the surgical site (four patients) to tumor removal under endoscopic visualization (four patients). All eight patients did well without evidence of recurrence at last follow-up. Although standard microsurgical resection followed by endoscopic assistance to discover and remove hidden components is the most common practice, a few authors have reported their experience with pure endoscopic visualization, that is, without the use of the microscope. In a series of six patients with CPA epidermoids, Peng and colleagues31 achieved similar resection rates as other series but reported one complication related to endoscope positioning which led to facial nerve paralysis and permanent hearing loss. This was likely endoscope related as their operative strategy was similar to most, in that adherent capsule was left attached to neurovascular structures. Another

group33 described their experience resecting a left CPA epidermoid under pure endoscopic visualization, with a good clinical and radiographic result. However, their follow-up was limited to only the immediate postoperative period, and they were also forced to leave behind particularly adherent capsule components. Both radiation therapy and stereotactic radiosurgery (SRS) have been tried to treat particularly difficult epidermoids in uncommon scenarios. Davies and colleagues38 reported on their experience treating multiple recurrent epidermoid tumors with radiation therapy. Their recommended algorithm suggested epidermoid tumors should only be radiated after at least three surgical attempts or rarely when two attempts had resulted in worsening neurological status or patient reticence for more surgery. Parikh et al39 reported a single case of a recurrent epidermoid treated with radiotherapy after an initial subtotal resection with no regrowth after a follow-up period of 2 years. An article by Nagasawa and colleagues9 reviewing the existing literature on the use of radiation for epidermoid tumors which had undergone malignant transformation found that survival doubled from 6.6 months to 12.7 months when radiation therapy was added to surgical resection. SRS has also been used in an attempt to control the regrowth of epidermoids. A recent retrospective study40 reviewing 12 patients who underwent SRS either after a single surgical resection (2 patients) or as standalone therapy (10 patients) showed that none of the treated tumors progressed. However, the mean follow-up was relatively short at 2 years for radiologic and 5 years for clinical follow-up. An additional three patients were reported in another case series41 who were treated with either surgery first (one patient) or SRS as standalone therapy (two patients). Radiological follow-up varied between 6 and 34 months, but no clinical or radiographic worsening was observed.

29.3 Case Example This is a patient with a right-side posterior fossa epidermoid with brainstem compression (▶ Fig. 29.1). We elected for a right

Fig. 29.1 Case example of a right posterior fossa epidermoid. Preoperative (a) T1-weighted axial, (b) T2-weighted axial, and (c) diffusion-weighted imaging axial MRI slices are provided.

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Natural History and Treatment Strategies for Posterior Fossa Epidermoids

Fig. 29.2 Intraoperative screen shots from the case examples demonstrating the (a) microscopic view and the (b) endoscopic view.

retrosigmoid craniotomy for resection of the lesion using an endoscopic-assisted approach (▶ Fig. 29.2). The operative video demonstrates surgical removal of the contents of the cyst. After microscopic resection of the lesion, an endoscopic-assisted technique is used to inspect for cyst remnants.

29.4 Conclusions As a general guideline, we recommend a surgical approach for the primary treatment of epidermoid tumors of the posterior fossa with the goal of complete safe resection of both contents and capsule. Given the consistency and vascularity of these tumors and their location within and around important neurovascular structures, we strongly recommend achieving this using keyhole principles and endoscopic-assisted techniques. Almost all posterior fossa epidermoids can be accessed through a small retrosigmoid or other suboccipital craniotomy, and the endoscope helps the surgeon identify important anatomy early in the surgery, see around corners, inspect for residual tumor, and sometimes obviate the need for combined approaches. Although the use of angled visualization is intuitive, further studies are required to make definitive evidence-based statements. Naturally, every patient and epidermoid tumor is different, and in some patients it may be prudent to leave behind densely adherent tumor capsule and accept the higher likelihood of recurrence and the need for further surgery over fixed neurological deficits, especially given the slow-growing nature of these lesions. Long-term follow-up studies are required to accurately document the true natural history of surgically resected epidermoid tumors.

References [1] Alvord EC, Jr. Growth rates of epidermoid tumors. Ann Neurol. 1977; 2(5): 367–370 [2] Toglia JU, Netsky MG, Alexander E, Jr. Epithelial (epidermoid) tumors of the cranium. Their common nature and pathogenesis. J Neurosurg. 1965; 23(4): 384–393 [3] Yamakawa K, Shitara N, Genka S, Manaka S, Takakura K. Clinical course and surgical prognosis of 33 cases of intracranial epidermoid tumors. Neurosurgery. 1989; 24(4):568–573 [4] Osborn AG. Intracranial lesions (differential diagnosis by anatomical location): cerebellopontine angle and internal auditory canal. In: Osborn AG, ed. Handbook of Neuroradiology. St. Louis, MO: Mosby Year Book; 1991:344–349 [5] Hassaneen W, Sawaya R. Epidermoid, dermoid, and neurenteric cysts. In: Winn HR, ed. Youmans Neurological Surgery, 6th ed. Philadelphia, PA: Elsevier Saunders; 2011:1523–1528

[6] Love JG, Kernohan JW. Dermoid and epidermoid tumors (cholesteatomas) of central nervous system. JAMA. 1936; 107:1876–1883 [7] Berger MS, Wilson CB. Epidermoid cysts of the posterior fossa. J Neurosurg. 1985; 62(2):214–219 [8] Gopalakrishnan CV, Ansari KA, Nair S, Menon G. Long term outcome in surgically treated posterior fossa epidermoids. Clin Neurol Neurosurg. 2014; 117: 93–99 [9] Nagasawa D, Yew A, Spasic M, Choy W, Gopen Q, Yang I. Survival outcomes for radiotherapy treatment of epidermoid tumors with malignant transformation. J Clin Neurosci. 2012; 19(1):21–26 [10] Mascarenhas A, Parsons A, Smith C, Molloy C, Jukes A. Malignant squamous cell carcinoma arising in a previously resected cerebellopontine angle epidermoid. Surg Neurol Int. 2017; 8:186 [11] Solanki SP, Maccormac O, Dow GR, Smith S. Malignant transformation of residual posterior fossa epidermoid cyst to squamous cell carcinoma. Br J Neurosurg. 2017; 31(4):497–498 [12] Pikis S, Margolin E. Malignant transformation of a residual cerebellopontine angle epidermoid cyst. J Clin Neurosci. 2016; 33:59–62 [13] Vellutini EA, de Oliveira MF, Ribeiro AP, Rotta JM. Malignant transformation of intracranial epidermoid cyst. Br J Neurosurg. 2014; 28(4):507–509 [14] Samii M, Tatagiba M, Piquer J, Carvalho GA. Surgical treatment of epidermoid cysts of the cerebellopontine angle. J Neurosurg. 1996; 84(1):14–19 [15] Akar Z, Tanriover N, Tuzgen S, Kafadar AM, Kuday C. Surgical treatment of intracranial epidermoid tumors. Neurol Med Chir (Tokyo). 2003; 43(6):275– 280, discussion 281 [16] Gormley WB, Tomecek FJ, Qureshi N, Malik GM. Craniocerebral epidermoid and dermoid tumours: a review of 32 cases. Acta Neurochir (Wien). 1994; 128(1–4):115–121 [17] Tancredi A, Fiume D, Gazzeri G. Epidermoid cysts of the fourth ventricle: very long follow up in 9 cases and review of the literature. Acta Neurochir (Wien). 2003; 145(10):905–910, discussion 910–911 [18] Lunardi P, Missori P, Innocenzi G, Gagliardi FM, Fortuna A. Long-term results of surgical treatment of cerebello-pontine angle epidermoids. Acta Neurochir (Wien). 1990; 103(3–4):105–108 [19] Netsky MG. Epidermoid tumors. Review of the literature. Surg Neurol. 1988; 29(6):477–483 [20] Aboud E, Abolfotoh M, Pravdenkova S, Gokoglu A, Gokden M, Al-Mefty O. Giant intracranial epidermoids: is total removal feasible? J Neurosurg. 2015; 122(4):743–756 [21] Chung LK, Beckett JS, Ong V, et al. Predictors of outcomes in fourth ventricular epidermoid cysts: a case report and a review of literature. World Neurosurg. 2017; 105:689–696 [22] Hasegawa M, Nouri M, Nagahisa S, et al. Cerebellopontine angle epidermoid cysts: clinical presentations and surgical outcome. Neurosurg Rev. 2016; 39 (2):259–266, discussion 266–267 [23] Yawn RJ, Patel NS, Driscoll CL, et al. Primary epidermoid tumors of the cerebellopontine angle: a review of 47 cases. Otol Neurotol. 2016; 37(7):951–955 [24] Raghunath A, Devi BI, Bhat DI, Somanna S. Unusual complications of a benign tumour - our experience with midline posterior fossa epidermoids. Br J Neurosurg. 2013; 27(1):69–73 [25] Ebner FH, Roser F, Thaher F, Schittenhelm J, Tatagiba M. Balancing the shortcomings of microscope and endoscope: endoscope-assisted technique in microsurgical removal of recurrent epidermoid cysts in the posterior fossa. Minim Invasive Neurosurg. 2010; 53(5–6):218–222 [26] Kobata H, Kondo A, Iwasaki K. Cerebellopontine angle epidermoids presenting with cranial nerve hyperactive dysfunction: pathogenesis and long-term

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Other Cranial Tumors

[27]

[28]

[29] [30]

[31] [32]

[33]

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surgical results in 30 patients. Neurosurgery. 2002; 50(2):276–285, discussion 285–286 Mallucci CL, Ward V, Carney AS, O’Donoghue GM, Robertson I. Clinical features and outcomes in patients with non-acoustic cerebellopontine angle tumours. J Neurol Neurosurg Psychiatry. 1999; 66(6):768–771 Talacchi A, Sala F, Alessandrini F, Turazzi S, Bricolo A. Assessment and surgical management of posterior fossa epidermoid tumors: report of 28 cases. Neurosurgery. 1998; 42(2):242–251, discussion 251–252 deSouza CE, deSouza R, da Costa S, et al. Cerebellopontine angle epidermoid cysts: a report on 30 cases. J Neurol Neurosurg Psychiatry. 1989; 52(8):986–990 Tuchman A, Platt A, Winer J, Pham M, Giannotta S, Zada G. Endoscopicassisted resection of intracranial epidermoid tumors. World Neurosurg. 2014; 82(3–4):450–454 Peng Y, Yu L, Li Y, Fan J, Qiu M, Qi S. Pure endoscopic removal of epidermoid tumors of the cerebellopontine angle. Childs Nerv Syst. 2014; 30(7):1261–1267 Chowdhury FH, Haque MR, Sarker MH. Intracranial epidermoid tumor; microneurosurgical management: an experience of 23 cases. Asian J Neurosurg. 2013; 8(1):21–28 Chowdhury FH, Haque MR. Endoscopic assisted microsurgical removal of cerebello-pontine angle and prepontine epidermoid. J Neurosci Rural Pract. 2012; 3(3):414–419

[34] Safavi-Abbasi S, Di Rocco F, Bambakidis N, et al. Has management of epidermoid tumors of the cerebellopontine angle improved? A surgical synopsis of the past and present. Skull Base. 2008; 18(2):85–98 [35] Schroeder HWS, Oertel J, Gaab MR. Endoscope-assisted microsurgical resection of epidermoid tumors of the cerebellopontine angle. J Neurosurg. 2004; 101(2):227–232 [36] Schiefer TK, Link MJ. Epidermoids of the cerebellopontine angle: a 20-year experience. Surg Neurol. 2008; 70(6):584–590, discussion 590 [37] Abolfotoh M, Bi WL, Hong CK, et al. The combined microscopic-endoscopic technique for radical resection of cerebellopontine angle tumors. J Neurosurg. 2015; 123(5):1301–1311 [38] Davies JM, Trinh VT, Sneed PK, McDermott MW. Radiotherapy for recurrent epidermoid cyst. J Neurooncol. 2013; 112(2):307–313 [39] Parikh S, Milosevic M, Wong CS, Laperriere N. Recurrent intracranial epidermoid cyst treated with radiotherapy. J Neurooncol. 1995; 24(3):293–297 [40] El-Shehaby AMN, Reda WA, Abdel Karim KM, Emad Eldin RM, Nabeel AM. Gamma knife radiosurgery for cerebellopontine angle epidermoid tumors. Surg Neurol Int. 2017; 8:258 [41] Vasquez JA, Fonnegra JR, Diez JC, Fonnegra A. Treatment of epidermoid tumors with gamma knife radiosurgery: case series. Surg Neurol Int. 2016; 7 Suppl 4:S116–S120

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Part VII Cranial Nerve Schwannoma

30 Indications for and Outcomes of Radiosurgery in Trigeminal and Jugular Foramen Schwannomas

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31 Challenges of Applying Endoscopic Techniques for Cranial Nerve Schwannomas

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32 Management of Cranial Nerve III, IV, and VI Schwannomas 205 33 Treatment of Facial Pain in Patients with Trigeminal Schwannoma

VII

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Cranial Nerve Schwannoma

30 Indications for and Outcomes of Radiosurgery in Trigeminal and Jugular Foramen Schwannomas Andrew Faramand, Ajay Niranjan, Hideyuki Kano, and L. Dade Lunsford Abstract This chapter will discuss the outcomes and indications of Gamma Knife stereotactic radiosurgery (SRS) in the management of trigeminal and jugular foramen schwannomas. The treatment options considered in the management of lower cranial nerve schwannomas are observation with serial imaging, surgery, and stereotactic radiosurgery. Surgical resection is often considered the first-line treatment option, particularly when there is symptomatic mass effect. Stereotactic radiosurgery is a noninvasive, outpatient procedure that can be used as a primary treatment option, or as an adjuvant modality following incomplete tumor resection. SRS is associated with high tumor control rates, high rates of symptom improvement, and low risks of complications. Keywords: Gamma Knife, radiosurgery, schwannomas, cranial nerves, trigeminal, jugular foramen

Surgical resection has been the standard treatment option for NVS. Resection is often indicated when there is a symptomatic mass effect, or when there is diagnostic uncertainty. Complete tumor resection is often curative. However, despite the advances of skull base surgery, surgery remains associated with higher rates of morbidity, particularly with lower cranial nerve schwannomas.10,13 Gamma Knife SRS (GKSRS) provides an effective and noninvasive tool in the primary or adjuvant management of skull base neoplasms. GKSRS has been shown to achieve high tumor control and low complication rates.14,15 However, because of the rarity of this problem, relatively few reports in the literature discuss the long-term outcomes of radiosurgery in the management of NVS. In this chapter, we discuss the indications and outcomes of GKSRS in the management of NVS. Additionally, we present two cases on NVS managed with radiosurgery.

30.2 Discussion 30.1 Introduction Schwannomas are typically benign tumors composed of Schwann cells that produce the myelin sheath covering peripheral nerves. The most common site of origin is cranial nerve VIII, the vestibulocochlear nerve. In autopsy series, 3 to 4% of all autopsies demonstrated the presence of cranial nerve schwannomas.1 In 1982, Nedzelski and Tator used the term “nonacoustic neuroma” or “nonvestibular schwannoma” in their description of eight cases involving patients who underwent surgery for these tumors.2 Nonvestibular schwannomas (NVS) account for less than 10% of all intracranial schwannomas, and less than 0.5% of all intracranial tumors.3 Symptoms secondary to these tumors are often related to either the dysfunction of the nerve of origin or due to the mass effect on the surrounding structures. Trigeminal schwannomas (TSs) are the second most common intracranial schwannomas, and they account for up to 0.3% of intracranial tumors, and 8% of intracranial schwannomas.4 Trigeminal nerve dysfunction resulting in facial pain or sensory loss is the most common manifestation of this tumor.5 Jugular foramen schwannomas (JFSs) refer to tumors arising from Schwann cells covering the 9th, 10th, or 11th cranial nerves around the jugular foramen. They comprise around 3 to 4% of all intracranial schwannomas.6,7 The most common symptoms of JFS are swallowing dysfunction, hoarseness of the voice, and hearing loss.8 Three treatment options are usually considered for the management of these tumors: surveillance with serial imaging, surgical resection, and stereotactic radiosurgery (SRS).5,7,9,10,11, 12 Although longitudinal reports on the natural history of these tumors are lacking, it is still considered reasonable to observe these tumors with serial imaging if they are discovered incidentally, and are asymptomatic.12

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The treatment goals for NVS highly depend on the tumor presentation. However, the management strategy should be individualized to each patient in order to balance tumor control with minimal morbidity and mortality. Observation is often considered when the tumor is small and discovered incidentally. Fisher et al observed the progression of untreated NVS in patients with neurofibromatosis type II (NFII).16 They concluded that because of the slow tumor growth, observation of NVS is recommended until growth on serial imaging is documented and loss of function is threatened. In contrast, O’Reilly et al recommended early treatment of NVS.17 In their series, in five out of nine patients with NVS, a 5% per year tumor growth rate was observed. They reported that symptom progression was a strong indicator for high growth rate. Complete surgical resection provides the highest rate of longterm tumor control and provides a tissue sample for pathological diagnosis. However, attempts for complete resection are associated with an increased incidence of neurologic deficits. Zeng et al reported on 133 patients who underwent surgical resection for JFS.10 In their series, gross total resection was achieved in 80.5% of patients, with almost 10% of patients experiencing tumor recurrence or progression at a mean follow-up of 108 months. Additionally, worsening or new onset cranial nerve deficits occurred in 36.1% of patients. The perioperative mortality rate was 1.5%.10 Fukuda et al described 15 patients who underwent surgical resection of JFS.18 Complete resection was achieved in 10 patients; however, nine patients had tumor recurrence or progression at a mean of 32 months after resection. Day et al reported complete resection in 73% of patients who underwent surgery for TSs.19 In most patients, preoperative symptoms persisted or worsened after resection. Goel at al reported worsening trigeminal nerve dysfunction in 27% of patients after resection.20 Jeong et al noted worsening hyperesthesia in the majority of 49 patients who underwent surgical resection of trigeminal schwannomas.21

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Indications for and Outcomes of Radiosurgery in Trigeminal and Jugular Foramen Schwannomas

Table 30.1 Overview of selected series discussing outcomes of GKSRS in the management of TS Study

N

Location

Tumor volume in cm3 (median)

Margin dose (Gy) (median)

Tumor control (%)

Improvement in symptoms (%)

Worsening or new onset cranial nerve deficit (%)

Follow-up (mo) (median)

Level of evidence

Sheehan et al (2007)

26

CN V

3.96

15

88

72

12

48.5

IV

Phi et al (2007)

22

CN V

4.1

13.3

95

Facial pain: 73 Facial numbness: 11 Diplopia: 67

27

46

IV

Kano et al14 (2009)

33

CN V

5.4

82 (10 y)

33

Facial pain: 3 Facial numbness: 3

54

IV

Yianni et al (2012)15

74

CN V

5.3

16.4 (mean)

93 (5 y) 79 (10 y)

15

Facial numbness: 8.6 Diplopia: 2

48.2

IV

Hasegawa et al23 (2013)

53

CN V

6

14

87

49

10

98

IV

Sun et al (2013)24

52

CN V

7.2

13.9 (mean)

86.5

67.3

Facial pain: 1.9 Facial numbness: 1.9

61

IV

Abbreviations: CN, cranial nerve; GKSRS, Gamma Knife stereotactic radiosurgery; TS, trigeminal schwannoma.

GKSRS is a well-established primary or adjuvant treatment modality in the management of multiple intracranial pathologies. It is often indicated in patients with small to moderate size lesions and is also a good option in patients with symptoms related to cranial nerve dysfunction, as it provides patients with the greatest chance of symptom improvement. In the presence of significant brain stem or fourth ventricle compression, surgery is often considered. For larger tumors, partial surgical resection followed by SRS is an effective option. In 1993, Pollock et al published the first report on the use of GKSRS in the management of NVS.22 In their series, six patients with trigeminal schwannomas and five patients with JFS underwent GKSRS. Tumor control was achieved in all patients with TS, and in 75% of patients with JFS. None of the patients developed new or worsening cranial nerve deficits.

30.2.1 Trigeminal Schwannomas Hasegawa et al reported 53 patients with TS treated with GKSRS. Sixty-four percent of their cohort underwent GKSRS as the primary management option. The median tumor volume treated was 6 cc and the median margin dose utilized was 14 Gy. Tumor control was achieved in 87% of patients after a median of 98month follow-up. Symptoms improved in 49% of patients, and 10% developed new onset or worsening preexisting deficits.23 Yianni et al reported 74 patients who underwent GKSRS for TS.15 Tumor control was achieved in 93% of patients after 5 years, with 15% of patients reporting symptoms improvement, and 9% reporting new onset or worsening facial numbness at a median follow-up of 48 months. Sun et al reported 52 patients with TS using GKSRS.24 They reported a tumor control rate of 86.5% at a median follow-up of 5 years. Near-complete regression was noted in 15.4%, shrinkage in 62%, unchanged tumor size in 9.6%, and tumor progression in 13.5% of patients. We evaluated the outcomes of GKSRS in 33 trigeminal schwannoma patients who underwent GKSRS at the University of Pittsburgh Medical Center in Pittsburgh. The median patient

age was 49.5 years. Eleven patients had prior tumor resection. The median radiosurgery target volume was 4.2 cc and the median dose to the tumor margin was 15 Gy. The rate of progression-free survival (PFS) at 1, 5, and 10 years after SRS was 97, 82, and 82%, respectively. Factors associated with improved PFS included female sex, smaller tumor size, and a root or ganglion-type tumors. Symptoms improved in 33% of patients including facial numbness and pain, in some cases. Patients with no history of prior resection were more likely to experience symptom improvement. ▶ Table 30.1 presents a literature of GKSRS in the management of trigeminal schwannomas. ▶ Fig. 30.1 presents the intraoperative and follow-up images of a patient with TS treated with primary GKSRS.

30.2.2 Jugular Foramen Schwannomas Multiple reports have demonstrated the high tumor response rates and low complication rates achieved with the use of radiosurgery as a primary or an adjuvant therapy in the management of JFS. Martin et al reported 34 patients with JFS treated with GKSRS.25 In 13 patients, GKSRS was the primary treatment modality, while 21 patients had previously undergone prior tumor resection. At a median follow-up of 84 months, two tumors demonstrated progression requiring further intervention. The actuarial tumor control rate was 97% at 5 years and 94% at 10 years. Symptom improvement was documented in 20% of patients, while only one patient reported worsening symptoms attributed to an increase in tumor volume. Peker et al identified 17 patients with a mean age of 44 years who underwent GKSRS of JFS.26 In five patients, GKSRS was the primary management option. At a mean follow-up of 64 months, tumor control was achieved in all patients. Symptom improvement was documented in 35%, and in 6% new onset or worsening hoarseness was reported. In a multi-institutional study conducted in Japan, Hasegawa et al reported the outcomes of 117 patients with JFS treated with GKSRS.8 Tumor control was

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Cranial Nerve Schwannoma Fig. 30.1 Intraoperative and follow-up MRI of a 69-year-old female patient who was found to have an asymptomatic contrast-enhancing lesion in the distribution of the right trigeminal nerve. With 2 years of observation, the tumor doubled in size and volume. (a) Intraoperative axial, coronal, and sagittal T1-weighted images with IV contrast. The patient underwent GKSRS for this enlarging tumor with microcystic change in the temporal lobe as well as the prepontine lesion. The lesion was treated with 12.5 Gy to the 50% isodose line (yellow line) using multiple isocenters to target the tumor measuring 5 cc in volume. (b) Axial and coronal T1-weighted images with IV contrast performed 4 years after GKSRS demonstrate more than 70% regression in tumor volume. The patient remained asymptomatic and neurologically intact on examination.

Table 30.2 Overview of selected series discussing the outcomes of GKSRS in the management of JFS Study

N

Location

Tumor volume in cm3 (median)

Margin dose (Gy) (median)

Tumor control (%)

Improvement in symptoms (%)

Worsening or new onset cranial nerve deficit (%)

Follow-up (mo) (median)

Level of evidence

Martin et al (2007)25

34

JF

4.2

14

94

20

3

83

IV

Peker et al (2012)26

17

JF

5.9

13

100

35

Hoarseness: 5.9

64 (mean)

IV

Hasegawa et al (2016)8

117

JF

4.9

12

91 (5 y) 89 (3 y)

Hoarseness: 66 Swallowing: 63

17

52

IV

Kano et al (2018)14

92

JF

4.1

12.5

87 (5 y) 82 (10 y)

29

7

51

IV

Abbreviation: GKSRS, Gamma Knife stereotactic radiosurgery; JF, jugular foramen; JFS, jugular foramen schwannoma.

achieved in 89% of patients at a median follow-up of 52 years. Symptom improvement was documented in 66% of patients with preexisting hoarseness and in 63% of patients who had swallowing difficulties. Symptomatic deterioration was documented in 17% of patients. This deterioration was transient in 10% and persistent in 7% of patients. Persistent deterioration was attributed to tumor progression in 4% and to adverse radiation effects in 3% of patients. In 2017, we reported the outcomes of GKSRS in 94 patients with JFS as part of an international multi-institutional study sponsored by the International Gamma Knife Research Foundation.14 In 51 patients, GKSRS was the initial procedure, while 41 patients had at least one prior tumor resection. The median tumor volume was 4.1 cc and the median margin dose was 12.5 Gy. Median follow-up after GKSRS was 51 months. Tumor

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control was achieved in 87% of patients (regression observed in 51% of patients, and stability in 33%). The PFS was 93% at 3 years, 87% at 5 years, and 82% at 10 years. In univariate analysis, only dumbbell-shaped tumor (extension extracranially via the jugular foramen) was associated with worse PFS. Twenty-seven patients (32%) with pretreatment neurological deficits had improvement. After GKSRS, 14 patients (15%) had delayed onset of additional cranial nerve deficits. In seven patients, this worsening was attributed to definable tumor growth. In the remaining seven patients, worsening was attributed to adverse radiation effects, and these were managed with temporary oral corticosteroids. ▶ Table 30.2 presents the relevant literature discussing the outcomes of GKSRS in the management of JFS. ▶ Fig. 30.2 presents the pre-resection, intraoperative, and follow-up images of a patient with JFS treated with adjuvant GKSRS.

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Indications for and Outcomes of Radiosurgery in Trigeminal and Jugular Foramen Schwannomas

Fig. 30.2 Pre-resection, postresection, and GKSRS intraoperative MRI of a 39-year-old male who presented with history of several months of imbalance, swallowing difficulties, right hearing loss, headaches, and blurry vision (a) demonstrates the axial and coronal T1-weighted MRI with IV contrast demonstrating a heterogeneously enhancing right cerebellopontine angle lesion extending extracranially through the jugular foramen. A two-stage resection was performed, and pathology revealed a vagal nerve schwannoma with a KI-67 of 2%. (b) Axial and coronal T1weighted MRI demonstrating tumor residual after resection. (c) Axial, coronal, and sagittal MRI used for treatment planning using 15 Gy at the 50% isodose line (yellow line) to target the residual tumor measuring 2.75 cc in volume.

30.3 Conclusions Management options for trigeminal and lower cranial nerve schwannomas are observation, surgical resection, and radiosurgery. The ideal management option depends on patient presentation and tumor size. Surgery is often indicated when patients present with symptoms related to tumor mass effect. Radiosurgery can be used as an initial procedure in small to moderate size tumors, or as an adjuvant option following partial tumor resection. GKSRS is associated with high tumor control rates, higher rates of preservation, or improvement of existing cranial

nerve function, and low rates of new or worsening cranial nerve deficits.

References [1] Schneider J, Warzok R, Schreiber D, Güthert H. [Tumors of the central nervous system in biopsy and autopsy material. 7th communication: neurinomas and neurofibromatoses with CNS involvement]. Zentralbl Allg Pathol. 1983; 127 (5–6):305–314 [2] Elsharkawy M, Xu Z, Schlesinger D, Sheehan JP. Gamma Knife surgery for nonvestibular schwannomas: radiological and clinical outcomes. J Neurosurg. 2012; 116(1):66–72

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Cranial Nerve Schwannoma [3] Pollock BE, Foote RL, Stafford SL. Stereotactic radiosurgery: the preferred management for patients with nonvestibular schwannomas? Int J Radiat Oncol Biol Phys. 2002; 52(4):1002–1007 [4] Peker S, Bayrakli F, Kiliç T, Pamir MN. Gamma-knife radiosurgery in the treatment of trigeminal schwannomas. Acta Neurochir (Wien). 2007; 149(11): 1133–1137, discussion 1137 [5] Kano H, Niranjan A, Kondziolka D, Flickinger JC, Dade Lunsford L. Stereotactic radiosurgery for trigeminal schwannoma: tumor control and functional preservation clinical article. J Neurosurg. 2009; 110(3):553–558 [6] Samii M, Babu RP, Tatagiba M, Sepehrnia A. Surgical treatment of jugular foramen schwannomas. J Neurosurg. 1995; 82(6):924–932 [7] Ryu SM, Lee JI, Park K, et al. Optimal treatment of jugular foramen schwannomas: long-term outcome of a multidisciplinary approach for a series of 29 cases in a single institute. Acta Neurochir (Wien). 2017; 159(8):1517–1527 [8] Hasegawa T, Kato T, Kida Y, et al. Gamma Knife surgery for patients with jugular foramen schwannomas: a multiinstitutional retrospective study in Japan. J Neurosurg. 2016; 125(4):822–831 [9] Cavalcanti DD, Martirosyan NL, Verma K, et al. Surgical management and outcome of schwannomas in the craniocervical region. J Neurosurg. 2011; 114 (5):1257–1267 [10] Zeng XJ, Li D, Hao SY, et al. Long-term functional and recurrence outcomes of surgically treated jugular foramen schwannomas: a 20-year experience. World Neurosurg. 2016; 86:134–146 [11] Sedney CL, Nonaka Y, Bulsara KR, Fukushima T. Microsurgical management of jugular foramen schwannomas. Neurosurgery. 2013; 72(1):42–46, discussion 46 [12] Niranjan A, Barnett S, Anand V, Agazzi S. Multimodality management of trigeminal schwannomas. J Neurol Surg B Skull Base. 2016; 77(4):371–378 [13] Netterville JL, Civantos FJ. Rehabilitation of cranial nerve deficits after neurotologic skull base surgery. Laryngoscope. 1993; 103(11, Pt 2) Suppl 60:45–54 [14] Kano H, Meola A, Yang HC, et al. Stereotactic radiosurgery for jugular foramen schwannomas: an international multicenter study. J Neurosurg. 2018; 129 (4):928–936 [15] Yianni J, Dinca EB, Rowe J, Radatz M, Kemeny AA. Stereotactic radiosurgery for trigeminal schwannomas. Acta Neurochir (Wien). 2012; 154(2):277–283

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[16] Fisher LM, Doherty JK, Lev MH, Slattery WH, III. Distribution of nonvestibular cranial nerve schwannomas in neurofibromatosis 2. Otol Neurotol. 2007; 28 (8):1083–1090 [17] O’Reilly BF, Mehanna H, Kishore A, Crowther JA. Growth rate of non-vestibular intracranial schwannomas. Clin Otolaryngol Allied Sci. 2004; 29(1):94–97 [18] Fukuda M, Oishi M, Saito A, Fujii Y. Long-term outcomes after surgical treatment of jugular foramen schwannoma. Skull Base. 2009; 19(6):401–408 [19] Day JD, Fukushima T. The surgical management of trigeminal neuromas. Neurosurgery. 1998; 42(2):233–240, discussion 240–241 [20] Goel A, Muzumdar D, Raman C. Trigeminal neuroma: analysis of surgical experience with 73 cases. Neurosurgery. 2003; 52(4):783–790, discussion 790 [21] Jeong SK, Lee EJ, Hue YH, Cho YH, Kim JH, Kim CJ. A suggestion of modified classification of trigeminal schwannomas according to location, shape, and extension. Brain Tumor Res Treat. 2014; 2(2):62–68 [22] Pollock BE, Kondziolka D, Flickinger JC, Maitz A, Lunsford LD. Preservation of cranial nerve function after radiosurgery for nonacoustic schwannomas. Neurosurgery. 1993; 33(4):597–601 [23] Hasegawa T, Kato T, Iizuka H, Kida Y. Long-term results for trigeminal schwannomas treated with gamma knife surgery. Int J Radiat Oncol Biol Phys. 2013; 87(5):1115–1121 [24] Sun J, Zhang J, Yu X, et al. Stereotactic radiosurgery for trigeminal schwannoma: a clinical retrospective study in 52 cases. Stereotact Funct Neurosurg. 2013; 91(4):236–242 [25] Martin JJ, Kondziolka D, Flickinger JC, Mathieu D, Niranjan A, Lunsford LD. Cranial nerve preservation and outcomes after stereotactic radiosurgery for jugular foramen schwannomas. Neurosurgery. 2007; 61(1):76–81, discussion 81 [26] Peker S, Sengöz M, Kılıç T, Pamir MN. Gamma knife radiosurgery for jugular foramen schwannomas. Neurosurg Rev. 2012; 35(4):549–553, discussion 553 [27] Sheehan J, Yen CP, Arkha Y, Schlesinger D, Steiner L. Gamma knife surgery for trigeminal schwannoma. J Neurosurg. 2007; 106:839–845 [28] Phi JH, Paek SH, Chung HT, et al. Gamma Knife surgery and trigeminal schwannoma: is it possible to preserve cranial nerve function? J Neurosurg. 2007; 107(4):727–732

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Challenges of Applying Endoscopic Techniques for Cranial Nerve Schwannomas

31 Challenges of Applying Endoscopic Techniques for Cranial Nerve Schwannomas Rachel Blue, Tracy M. Flanders, and John Y.K. Lee Abstract In recent years, neurosurgeons have increasingly utilized the endoscope in skull base surgery, first starting with pituitary adenomas but gradually tackling craniopharyngiomas, chordomas, and schwannomas. With the addition of this visualization tool, smaller cranial openings, panoramic visualization of cranial anatomy, and at times a more extensive tumor resection have been made possible. In this chapter, we will summarize the advantages of the endoscope and describe the different cranial nerve schwannomas resected using the endoscope: vestibular schwannomas, trigeminal schwannomas, jugular foramen schwannomas, and schwannomas of the orbit and paranasal sinuses. We will then investigate challenges that are encountered with endoscopic resection of these tumors. Such challenges include two dimensionality, maneuverability, and surgical instrumentation. Keywords: endoscopy, cranial nerve schwannoma, endoscopic skull base surgery, cerebellopontine angle, endonasal, retrosigmoid, endoscopic-assisted, endoscopic challenges, skull base surgery

31.1 Introduction The operative endoscope was first described in 1879, but its more modern use for skull base surgery was pioneered first by rhinologists1 and then by neurosurgeons.2 Since that time, the use of endoscopes in neurosurgery has grown exponentially.3 The endoscope enables a panoramic view and enhances visualization around anatomical corners that are not safely accessed with the operative microscope alone. Although the endoscope was initially employed by otorhinolaryngologists and neurosurgeons working in conjunction, eventually neurosurgeons have employed the endoscope on their own in various lateral skull base procedures as well.4 The introduction of the pneumatic holding arms enables the endoscope to remain in a fixed position while operating.5,6 The improved surgical vantage point provided with endoscopy improves the neurosurgeon’s understanding of the pathological anatomy. In particular, use of the endoscope facilitates a safer visualization of Meckel’s cave, the internal acoustic meatus, the dorsal aspect of neurovascular structures, and cranial nerve junctions along the brainstem.7 Quantitative analysis in cadaveric studies comparing endoscopic and microscopic approaches in the skull base demonstrated a nearly twofold increase in field of view in the endoscope compared to the microscope.8 Endoscopy has been lauded as a means of achieving smaller craniotomies without compromising the surgical field; notably, maximal safe resection of skull base tumors is still possible.7,9,10,11,12,13 However, the use of the endoscope for cranial nerve schwannoma resection still presents some challenges. This chapter is aimed at further exploring these challenges.

31.2 Review 31.2.1 Endoscopic Resection of Schwannomas The endoscope is a great addition to or replacement for the microscope in schwannoma resection. ▶ Table 31.1 highlights the spectrum of schwannoma resection that can be achieved with the endoscope. The next few sections will discuss the role of endoscopy for vestibular schwannomas, trigeminal schwannomas, and jugular foramen schwannomas, in particular.

Vestibular Schwannomas Surgical approaches to vestibular schwannomas with microsurgical techniques are well established—retrosigmoid, translabyrinthine, and middle fossa. The addition of the endoscope,

Table 31.1 Summary of endoscopic resection of schwannomas Authors (year)

Schwannoma location

Number of cases

Level of evidence

King and Wackym (1999)26

Vestibular

78

IV

Magnan et al (2002)16

Vestibular

119

IV

Gerganov et al (2005)30

Vestibular

18

IV

Göksu et al (2005)15

Vestibular

60

IV

Hori et al (2006)31

Vestibular

33

IV

Gerganov et al (2010)25

Vestibular

30

IV

Kumon et al (2012)32

Vestibular

28

IV

Chovanec et al (2013)33

Vestibular

39

IV

Iacoangel et al (2013)38

Vestibular

10

IV

Wang et al (2017)34

Vestibular

22

IV

Abolfotoh et al (2015)9

Vestibular Trigeminal Jugular foramen

13 2 3

IV

Samii et al (2014)18

Trigeminal

20

IV

Raza et al (2014)35

Trigeminal

4

IV

Taniguchi et al (2005)24

Jugular foramen

3

IV

Samii et al (2015)23

Jugular foramen

16

IV

Samii et al (2016)36

Jugular foramen

5

IV

Ali et al (2013)21

Paranasal

3

IV

Har-El (2005)37

Orbital

1

IV

Lee et al (2012)20

Orbital

1

IV

199

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Cranial Nerve Schwannoma however, improves on some of the limitations of each approach, primarily as an endoscope-assisted procedure. The retrosigmoid approach provides excellent cephalocaudal and medial visualization of vestibular schwannomas, but its weakness is difficulty visualizing the lateral fundus of the internal acoustic canal (IAC), as retraction of the cerebellum is limited in young patients with tight brain. Tumor can remain in this corner, and hidden air cells that need to be occluded can hide in this challenging corner. Hence, use of the endoscope as an adjunct is particularly useful in this situation. In addition, endoscopy can provide earlier visualization of the tumor bed at its origin from the brainstem to the porus acusticus, although the senior author (J.Y.K.L.) has not found the endoscope to be as useful for facial nerve identification as compared to others.14 Multiple studies have demonstrated the feasibility and efficacy of endoscopic-assisted and fully endoscopic vestibular schwannoma resection with regard to overall tumor resection, facial nerve preservation, hearing preservation, operative time, and postoperative complications.9,14,15,16 Although authors have described a fully endoscopic resection of vestibular schwannoma, the senior author (J.Y.K.L.) generally finds the binocular three-dimensional perspective of the microscope to be more efficient for routine vestibular schwannoma surgery, and finds the major value of the endoscope in vestibular schwannoma resection to be visualization of the lateral fundus of the internal acoustic canal (▶ Fig. 31.1).

Vestibular Schwannoma - IAC visualization

a

b

c

d

e

f

Trigeminal Schwannomas Trigeminal schwannomas are the second most common intracranial schwannoma after vestibular schwannomas. The course of the trigeminal nerve is complex, traversing multiple intracranial compartments. There are several possible trajectories for potential resections of tumors involving this nerve, including extradural transkeyhole supraorbital, transpterygoid, extradural transkeyhole subtemporal, anterior petrosectomy, and retrosigmoid with suprameatal extension.17,18 Each of these approaches allows for access to different divisions of the trigeminal nerve, and choice of approach depends on anatomic configuration at presentation as well as surgeon preference.17 In patients with a predominant cerebellopontine angle component of the trigeminal schwannoma and a smaller portion in Meckel’s cave, an endoscopic-assisted retrosigmoid, suprameatal approach (EA-RISA) for trigeminal schwannoma resection has been described. This approach is an extension of the approach initially described by Samii and allows for a retrosigmoid approach followed by suprameatal drilling and exposure.19 However, the endoscope can be used to visualize the tumor traveling anteriorly toward Meckel’s cave and thus potentially achieve a more radical tumor resection. It was found to be feasible and safe for dumbbell trigeminal schwannoma resection compared to the more established RISA approach.18 Another excellent use of the endoscope is in patients who present with tumor extending along the V2/ V3 branches of the trigeminal nerve, originating from Meckel’s cave, and without a cerebellopontine angle component. In these patients, a fully endonasal, endoscopic, transpterygoid, infratemporal fossa approach can be used for patients with trigeminal schwannomas where the bulk of the tumor is extracranial (Case 2 (p. 202)).

200

Fig. 31.1 T1 postcontrast axial MRI of a patient with a left-sided vestibular schwannoma, preresection (a) and postresection (b). Anatomical visualization with the zero-degree endoscope, initial view (c), and final view (d). Improved lateral fundus visualization with the 30-degree angled endoscope (e, f).

Orbital and Paranasal Schwannomas Schwannomas of the orbit and sinonasal cavity are rare, accounting for 1 to 2% of tumors in the orbit, and some of these can be approached via an endoscopic endonasal approach for resection.20,21,22 This surgical approach to the orbit is best employed when the schwannoma lies medial to the optic nerve. The intimate proximity of the optic nerve, the ciliary ganglion, the ophthalmic artery, and the origin of the extraocular muscles can be fairly challenging.20 There is a paucity of published literature on endoscopic resection of these tumors and a case example has been presented later in this chapter (Case 3 (p. 202)).

Jugular Foramen Schwannoma Jugular foramen schwannomas are rare tumors and may arise from cranial nerves IX, X, or XI, or the sympathetic chain.23 Endoscopic-assisted resection using a lateral suboccipital approach has been described as a technique to limit bone resection and thereby mitigate the potential danger of cerebrospinal fluid leak, cranial nerve damage, and venous outflow.24

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Challenges of Applying Endoscopic Techniques for Cranial Nerve Schwannomas Recently, endoscopic-assisted retrosigmoid infralabyrinthine and endoscopic-assisted transcervical approaches have been described with excellent outcomes in regard to lower cranial nerve preservation.23

31.2.2 Challenges in Endoscopic Resection Endoscope Design The endoscope provides the surgeon with a wide panoramic view when placed through narrow cavities or apertures in the brain; however, one of the challenges is how to bring instruments in and out of the field. When neurosurgeons work with ENT surgeons, or when the single surgeon holds the endoscope, the endoscope can be moved in parallel with the surgical instrument. This allows the instrument to be visualized as it enters the nose or cerebellopontine angle, for example, but this type of in and out movement is not always possible. An endoscope may be “parked” with a rigid holder. In these situations, the surgical instrument is not seen until it is slightly past the tip of the endoscope as the angle of view is approximately 45 degrees from the axis of the endoscope for total view of 90 degrees. In some instances, inadvertent damage to surrounding cranial nerves or brain parenchyma is possible. In endonasal approaches, where the surrounding anatomy is largely noneloquent, mucosal, and bony, the potential for damage of delicate structures is much lower than that in the cerebellopontine angle, where the planes of access are potential spaces surrounded by delicate neurovascular structures. The neurosurgeon must balance an optimized view of distal structures with loss of visualization of instruments passing through the surgical field. Inadvertent movement of the endoscope or of surgical instruments risks damage to the brainstem, cranial nerves, and vessels. Another challenge with endoscopy and skull base surgery is that drilling of the skull base is a common means of improving exposure. Bone dust created by drilling obscures the endoscopic view and can blind the surgeon. Frequent irrigation and clearing of the scope are required to prevent thermal damage to tissues and fogging of the visual field.25,26

Technique and Maneuverability The addition of the endoscope into the surgical field, an already limited space, results in the problem of “sword fighting,” and a unique set of instruments must be used.27 In some surgical approaches, a stereotypic approach, such as the “triangle method,” can be employed (endoscope at top of equilateral triangle and suction in left side of triangle and working instrument such as dissector, bipolar, or scissors in right side of triangle).4 In other cases, however, the endoscope needs to be in parallel as in approaches to pineal via paramedian supracerebellar infratentorial.28 Experimentation with positioning of the endoscope with a rigid holder for advanced endoscope techniques requires time and patience. Additional challenges with endoscopy include orientation. When using the angled lenses of certain endoscopes, the working angle is distinct from the angle of visualization, which can lead to surgeon disorientation. Hence, the senior author’s recommendation to early neurosurgeons is to start with zerodegree endoscope as much as possible and only to move to

angled endoscopes if absolutely necessary. In quantitative cadaveric studies comparing maneuverability between microscopic and endoscopic approaches, endoscopic approaches have significantly decreased overall freedom of movement.8 This challenge can be overcome with dedicated angled instrumentation and careful thoughtfulness about placement of endoscope. Another challenge is the two-dimensionality of the endoscope, leading to a loss of perceived depth while operating. The absence of depth lends itself to surgeon disorientation, which carries potential catastrophic consequences with injury to neurovascular structures outside the field of view of the endoscope. Several different techniques have been described for fixation and movement of the endoscope. The senior author, J.Y.K.L., utilizes the Mitaka pneumatic holding arm to allow for easy fixation and fluid movement during the operation. Other authors have described combined microscope and endoscopic “freehand” techniques, in which the assistant surgeon holds the endoscope, while the senior surgeon operates with two hands.9 A one-handed endoscopic technique has also been employed with the suction attached to the endoscope in one hand and operative instruments in the other hand.29 For surgeons who prefer the microscope, the endoscope can be utilized as an adjunct for visualization of the surgical site at select stages of the resection.

31.3 Case Examples The following case examples performed by the senior author, J. Y.K.L., illustrate the various challenges with endoscopic approaches to cranial nerve schwannomas.

31.3.1 Case 1 Patient A is a 65-year-old male presenting with the following right-sided symptoms: generalized weakness, tongue burning and tingling, change in taste, and facial numbness. He also endorsed dizziness, gait imbalance, and difficulty with phonation. An MRI brain was obtained and revealed bilateral trigeminal schwannomas (▶ Fig. 31.2a). He was taken to the operating room for. A retrosigmoid craniotomy was performed and the lateral surface of the tumor was identified and debulked with the ultrasonic aspirator. The tumor capsule was gradually identified, and the trigeminal, cochlear, vestibular, and facial nerves were dissected off the tumor. The tumor had pushed the facial nerve caudal to the vestibular nerve, and by the end of the resection, the facial nerve was in its expected anatomical location. The tumor was carefully dissected away from the tentorium and the trochlear nerve. The tumor had many unusual cysts, which were evacuated. The endoscopic portion of the case was the involvement of the tumor with Meckel’s cave. At this point, the endoscope was used as an adjunct to the operating microscope to enhance visualization of this deep anatomical region (▶ Fig. 31.2c–h). The 30-degree angled endoscope provided excellent visualization into Meckel’s cave, and the canal dissector and pituitary ring curettes (with attached suction) were used to evacuate the tumor. Tumor cells were positive for S100 and negative for epithelial membrane antigen (EMA), and the final pathological diagnosis was trigeminal schwannoma. A postoperative MRI revealed gross total resection (▶ Fig. 31.2b).

201

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Cranial Nerve Schwannoma Case 1: Trigeminal Schwannoma

a

b

with careful dissection in and around the region of the carotid arteries and optic nerve. The tumor was debulked, and the capsule was pulled into itself. The superior plane was dissected along the temporal lobe dura, and the middle fossa floor identified. The tumor was pulled down and dissected; the V2 branch was identified at the foramen rotundum as it exited Meckel’s cave and subsequently cut. The specimen was sent to pathology, and immunohistochemical stains were positive for S100 and glial fibrillary acidic protein (GFAP), negative for EMA, and Ki67 stains less than 1% of cells; schwannoma was confirmed. A postoperative MRI was obtained and revealed tumor resection with minimal residual dural enhancement (▶ Fig. 31.3b).

31.3.3 Case 3 CN

PV

PV T

c

d

PV

PV

T

e

f

PV

PV M

g

M

h

Fig. 31.2 T1 postcontrast axial MRI of Case 1, patient with bilateral trigeminal schwannomas, preoperatively (a) and postoperatively (b) with right-sided gross total resection. Intraoperative endoscopic images from Case 1, pretumor resection (c, e) and posttumor resection (d, f). Visualization into Meckel’s cave, pre- (g) and posttumor resection (h). CN, trigeminal nerve; M, Meckel’s cave; PV, petrosal vein; T, tumor.

31.3.2 Case 2 Patient B is a 57-year-old female presenting with left facial and ear pain. An MRI brain was obtained showing concern for an infratemporal V2 trigeminal schwannoma (▶ Fig. 31.3a). The patient was taken to the operating room for resection. A maxillary antrostomy was performed above the canine tooth via Caldwell-Luc approach. The mucosa was resected posteriorly and dissection was performed along the posterior maxilla into the infratemporal fossa. The large schwannoma of this area was noted and extradural resection of the tumor was accomplished using a two-surgeon, four-handed technique

202

Patient C is a 64-year-old female presenting with progressive loss of vision who previously underwent attempted surgical resection by another surgeon for a right orbital apex tumor with incomplete resection. A brain MRI was obtained demonstrating an orbital apex tumor with scar formation (▶ Fig. 31.4a). The patient was taken to the operating room for an endoscopic endonasal orbital tumor resection. A posterior septectomy was performed and bilateral maxillary, ethmoid, sphenoid, and frontal sinuses were opened. A sphenoidotomy and complete septostomy was performed, and the tumor was visualized. It was clear that as the tumor had grown, anatomic distortion of the bone as well as optic nerve/ canal compression had occurred. The tumor had clearly extended into the anterior cranial fossa. The lamina papyracea of the right side was identified, and scarring from the prior surgery was noted on the posterior aspect. The cavernous portion of the internal carotid artery, tuberculum sellae, and optic nerve were identified. The bone was carefully drilled and removed under the optic nerve through the sellae, and the optic nerve was dissected back toward the globe. The bone from the medial orbital wall was removed, and dissection was continued all the way to the prior scarred region and down to the superior orbital fissure. Brisk venous bleeding was encountered, consistent with the cavernous sinus, and packed with Gelfoam. Bony removal through the inferior orbital floor connected the sinus opening the anterior superior aspect of the orbit down to the middle of the inferior aspect of the orbit. At this point, the size of the drill bit limited the ability to safely drill around the optic nerve. The frontal lobe dura was then reflected almost 90 degrees down to the periorbita, which was then reflected down to the optic canal. The optic nerve sheath was opened distally toward the prior scar, and a gray soft tissue mass, consistent with schwannoma, was identified superiorly. Angled scopes were used for better visualization of the medial orbital wall and the orbital apex. The tumor had compressed the optic nerve superiorly and laterally, and was removed using pituitary ringed curettes. It was recognized that for further resection, the prior scar mass would have to be opened. After careful consideration, it was decided not to cut through the scar/medial rectus in attempts to resect additional tumor more anteriorly. Tumor was cleared from the posterior orbital apex going into the optic nerve canal and foramen entering the anterior skull base. This intradural tumor was thus removed. A postoperative MRI was obtained and revealed a right intraconal mass, partially resected, with expected residual neoplasm (▶ Fig. 31.4b).

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Challenges of Applying Endoscopic Techniques for Cranial Nerve Schwannomas

Case 2: V2 Trigeminal Schwannoma

a

Fig. 31.3 T1 postcontrast axial MRI of Case 2, patient with left-sided infratemporal V2 trigeminal schwannoma, preresection (a) and postresection (b) with minimal residual dural enhancement.

b

31.4 Conclusions and Suggestions for Future Studies

Case 3: Orbital Apex Schwannoma

a

The current literature for endoscopic procedures in the skull base is comprised only of limited case series studies and cadaveric studies with surgeon commentary (expert opinion). We strongly believe that this evidence, while limited, clearly demonstrates that when used appropriately, the addition of the endoscope into the neurosurgical repertoire can greatly improve surgical outcomes and tumor resection without increasing morbidity and mortality. It is essential for surgeons to be properly trained in the endoscopic technique, potentially utilizing cadaveric models for study and practice. As the technique becomes increasingly utilized, further prospective analysis of outcomes would strengthen the case for endoscopic utilization in the skull base.

b AEA

MRM

PEA ON

MRM ON OP

OP

c

d

e

f

Fig. 31.4 T1 postcontrast axial MRI of Case 3, patient with a right-sided orbital apex schwannoma, preresection (a) and postresection (b) with expected residual neoplasm. Endoscopic view of a cadaveric dissection of the right medial intraconal orbital apex (c, d). Retraction of the medial rectus muscle inferiorly in the posterior orbital apex allows identification of the optic nerve as it courses anteriorly (c); further inferior retraction of the medial rectus muscle, the course of the optic nerve along the superior half of the muscle can be appreciated (d). AEA, anterior ethmoid artery; MRM, medial rectus muscle; ON, optic nerve; OP, optic protuberance; PEA, posterior ethmoid artery. Intraoperative endoscopic view of the orbital apex (e) with visualization of the inferior division of oculomotor nerve (f).

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Cranial Nerve Schwannoma [10] Cappabianca P, Cavallo LM, Esposito F, de Divitiis E, Tschabitscher M. Endoscopic examination of the cerebellar pontine angle. Clin Neurol Neurosurg. 2002; 104(4):387–391 [11] Halpern CH, Lang SS, Lee JY. Fully endoscopic microvascular decompression: our early experience. Minim Invasive Surg. 2013; 2013:739432 [12] Jennings CR, O’Donoghue GM. Posterior fossa endoscopy. J Laryngol Otol. 1998; 112(3):227–229 [13] Miyazaki H, Deveze A, Magnan J. Neuro-otologic surgery through minimally invasive retrosigmoid approach: endoscope assisted microvascular decompression, vestibular neurotomy, and tumor removal. Laryngoscope. 2005; 115(9):1612–1617 [14] Setty P, D’Andrea KP, Stucken EZ, Babu S, LaRouere MJ, Pieper DR. Endoscopic resection of vestibular schwannomas. J Neurol Surg B Skull Base. 2015; 76(3): 230–238 [15] Göksu N, Yilmaz M, Bayramoglu I, Aydil U, Bayazit YA. Evaluation of the results of endoscope-assisted acoustic neuroma surgery through posterior fossa approach. ORL J Otorhinolaryngol Relat Spec. 2005; 67(2):87–91 [16] Magnan J, Barbieri M, Mora R, et al. Retrosigmoid approach for small and medium-sized acoustic neuromas. Otol Neurotol. 2002; 23(2):141–145 [17] Komatsu F, Komatsu M, Di Ieva A, Tschabitscher M. Endoscopic approaches to the trigeminal nerve and clinical consideration for trigeminal schwannomas: a cadaveric study. J Neurosurg. 2012; 117(4):690–696 [18] Samii M, Alimohamadi M, Gerganov V. Endoscope-assisted retrosigmoid intradural suprameatal approach for surgical treatment of trigeminal schwannomas. Neurosurgery. 2014; 10 Suppl 4:565–575, discussion 575 [19] Samii M, Tatagiba M, Carvalho GA. Retrosigmoid intradural suprameatal approach to Meckel’s cave and the middle fossa: surgical technique and outcome. J Neurosurg. 2000; 92(2):235–241 [20] Lee JY, Ramakrishnan VR, Chiu AG, Palmer J, Gausas RE. Endoscopic endonasal surgical resection of tumors of the medial orbital apex and wall. Clin Neurol Neurosurg. 2012; 114(1):93–98 [21] Ali ZS, Lang S, Adappa ND, Barkley A, Palmer JN, Lee JYK. Expanded endoscopic endonasal treatment of primary intracranial tumors within the paranasal sinuses. ISRN Minim Invasive Surg. 2013; 2013:5 [22] Wang Y, Xiao LH. Orbital schwannomas: findings from magnetic resonance imaging in 62 cases. Eye (Lond). 2008; 22(8):1034–1039 [23] Samii M, Alimohamadi M, Gerganov V. Surgical treatment of jugular foramen schwannoma: surgical treatment based on a new classification. Neurosurgery. 2015; 77(3):424–432, discussion 432 [24] Taniguchi M, Kato A, Taki T, et al. Endoscope assisted removal of jugular foramen schwannoma; report of 3 cases. Minim Invasive Neurosurg. 2005; 48(6): 365–368

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[25] Gerganov VM, Giordano M, Herold C, Samii A, Samii M. An electrophysiological study on the safety of the endoscope-assisted microsurgical removal of vestibular schwannomas. Eur J Surg Oncol. 2010; 36(4):422–427 [26] King WA, Wackym PA. Endoscope-assisted surgery for acoustic neuromas (vestibular schwannomas): early experience using the rigid Hopkins telescope. Neurosurgery. 1999; 44(5):1095–1100, discussion 1100–1102 [27] Little AS, Almefty KK, Spetzler RF. Endoscopic surgery of the posterior fossa: strengths and limitations. World Neurosurg. 2014; 82(3)(–)(4):322–324 [28] Uschold T, Abla AA, Fusco D, Bristol RE, Nakaji P. Supracerebellar infratentorial endoscopically controlled resection of pineal lesions: case series and operative technique. J Neurosurg Pediatr. 2011; 8(6):554–564 [29] Cutler AR, Kaloostian SW, Ishiyama A, Frazee JG. Two-handed endoscopicdirected vestibular nerve sectioning: case series and review of the literature. J Neurosurg. 2012; 117(3):507–513 [30] Gerganov VM, Romansky KV, Bussarsky VA, Noutchev LT, Iliev IN. Endoscopeassisted microsurgery of large vestibular schwannomas. Minim Invasive Neurosurg. 2005; 48(1):39–43 [31] Hori T, Okada Y, Maruyama T, Chernov M, Attia W. Endoscope-controlled removal of intrameatal vestibular schwannomas. Minim Invasive Neurosurg. 2006; 49(1):25–29 [32] Kumon Y, Kohno S, Ohue S, et al. Usefulness of endoscope-assisted microsurgery for removal of vestibular schwannomas. J Neurol Surg B Skull Base. 2012; 73(1):42–47 [33] Chovanec M, Zvěřina E, Profant O, et al. Impact of video-endoscopy on the results of retrosigmoid-transmeatal microsurgery of vestibular schwannoma: prospective study. Eur Arch Otorhinolaryngol. 2013; 270(4):1277–1284 [34] Wang ZY, Jia H, Yang J, Tan HY, Wu H. A combination use of endoscope and microscope in cerebral pontine angle surgery [in Chinese]. Zhonghua Er Bi Yan Hou Tou Jing Wai Ke Za Zhi. 2017; 52(2):85–88 [35] Raza SM, Donaldson AM, Mehta A, Tsiouris AJ, Anand VK, Schwartz TH. Surgical management of trigeminal schwannomas: defining the role for endoscopic endonasal approaches. Neurosurg Focus. 2014; 37(4):E17 [36] Samii M, Alimohamadi M, Gerganov V. Endoscope-assisted retrosigmoid infralabyrinthine approach to jugular foramen tumors. J Neurosurg. 2016; 124(4):1061–1067 [37] Har-El G. Combined endoscopic transmaxillary-transnasal approach to the pterygoid region, lateral sphenoid sinus, and retrobulbar orbit. Ann Otol Rhinol Laryngol. 2005; 114(6):439–442 [38] Iacoangeli M, Salvinelli F, Di Rienzo A, et al. Microsurgical endoscopy-assisted presigmoid retrolabyrinthine approach as a minimally invasive surgical option for the treatment of medium to large vestibular schwannomas. Acta Neurochir (Wien). 2013; 155(4):663–670

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Management of Cranial Nerve III, IV, and VI Schwannomas

32 Management of Cranial Nerve III, IV, and VI Schwannomas Jai Deep Thakur, Christopher Storey, Anil Nanda, and Hai Sun Abstract Cranial nerve III, IV, and VI schwannomas can present a multitude of questions regarding when and how to operate on them. Not only the surrounding anatomy and location but also the symptoms are important to the surgical decision making. The decision between surgical resection and stereotactic radiosurgery can weigh heavily on the surgeon. Due to the ophthalmoplegia involved, the ability for vision correction by an ophthalmologist needs to be integrated into the decision making. Only purely cisternal lesions with surrounding arachnoid layer will allow for good recovery with total resection. More cavernous involvement should then advocate for lateral resection and decompression with adjunctive stereotactic radiosurgery. For smaller lesions with correctable vison, a wait and watch approach can be utilized with or without stereotactic radiosurgery. Keywords: schwannoma, trochlear nerve, oculomotor nerve, abducens nerve

32.1 Introduction Due to the rarity of schwannomas of the third, fourth, and sixth cranial nerves, the expected natural history is extrapolated from the benign nature of schwannomas of the eighth and fifth cranial nerves. The chief controversy arises on when and if to operate. Open surgery runs the risk of new or worsened extraocular movement palsy. Radiosurgery provides a method to hopefully halt progression or shrink the tumor with lower risk of nerve damage. Monitoring for growth runs the risk of sudden onset of permanent nerve palsy. The entire clinical picture of the patient must be considered for treatment. The lesions associated with these three cranial nerves can arise from multiple locations along the nerves, which can be

Table 32.1 List of studies reviewed for CN III and CN IV schwannomas Study

Level of evidence

Outcome

Furtado and Hegde2

IV

Subtotal resection for improved outcomes

Langlois et al6

IV

SRS response same as vestibular schwannoma

Elsharkawy et al7

IV

SRS response same as vestibular schwannoma

Elmalem et al8

IV

No surgery if small

Cunha et al9

IV

Only surgery if causing deficit other than CN IV palsy. Subtotal resection better

divided into three regions: cisternal, cavernous, and intraorbital regions1 (▶ Fig. 32.1). The lesions can also track along the nerve to occupy multiple regions. Each location carries its own risks and surgical strategies. Based on the region where the lesion develops, the signs and symptoms can vary widely. All the data that exist in the literature are level IV due to the rare nature of these pathologies (▶ Table 32.1, ▶ Table 32.2). In this chapter, we summarize the existing literature on signs and symptoms associated with these tumors and treatment outcomes. Based on this evidence, recommendations on treatment strategies are made.

32.2 Review 32.2.1 Cranial Nerve III The published literature on schwannomas associated with CN III is limited to case reports (▶ Table 32.1). Furtado and Hegde2 reviewed and summarized these case reports and showed a total of 54 reported cases. The average age of these patients was 38 years and there was a slight female predominance. The leading signs and symptoms of these patients were diplopia (42%), followed by headache (32%), ptosis (27%), vison loss (13%), hemiparesis (7%), and facial numbness (4%). They noted several reports of an arachnoid plane for dissection for cisternal and cavernous lesions. There was only an 11% rate of improvement in third nerve palsy with surgery, and five of the six patients who improved only had partial resection. There was a 50% rate of worsening of diplopia. Gamma Knife radiosurgery did not improve third nerve function even with tumor shrinkage on follow-up. Surgical indication for an oculomotor nerve schwannoma requires a multifactorial analysis. The goal of the surgery is for neural decompression. A thorough review of the imaging is required to find points of compression in the supraorbital fissure or the cisternal cavernous transition. The caliber of the ipsilateral cavernous carotid should be reviewed. Smaller caliber (Hirsch Grade 3) likely bodes well for improvement of neural function after decompression. The meningioma literature that supports sinus decompression with lateral resection and stereotactic radiosurgery for the residual may be relevant.3,4,5

CN III Table 32.2 Systematic review of literature comparing SRS and microsurgery for treatment of CN VI schwannoma Total patients

Data available for n patients

Clinical improvement

No improvement or clinical deterioration

Radiological control (no growth or shrinkage)

SRS series11

16

11

73%

27%

91%

Surgical series1

32

32

45%

55%

100%

CN IV

Abbreviation: SRS, stereotactic radiosurgery.

Abbreviation: SRS, stereotactic radiosurgery.

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Cranial Nerve Schwannoma

Fig. 32.1 Tumor location based on anatomic consideration. Based on the current literature, we classified tumors along the course of the abducens nerve as it traverses intracranially. (a) The image shows anatomic considerations along the course of the nerve. The abducens nerve is labeled as 5. The nerve is shown to originate from the brainstem, traversing through Dorello’s canal anteriorly up to its passage from the superior orbital fissure to supply the lateral rectus. Relevant structures along the course include (1) optic nerve; (2) anterior clinoid process; (3) V1 entering into the superior orbital fissure; (4) V2 entering into the foramen rotundum; (5) cranial nerve VI in the cavernous segment; (6) V3 entering into the foramen ovale; (7) gasserian ganglion; (8) Dorello’s canal; (9) brainstem; (10) orbital segment of abducens nerve; (11) cavernous segment of abducens nerve; (12) cisternal segment of abducens nerve, showing sixth nerve schwannoma as it originates in the (b) cisternal, (c) cisterocavernous, (d) cavernous sinus proper, (e) caverno-orbital, and (f) orbital locations.

If patients are older or have significant morbidities, then one may lean away from surgery. If these patients have acceptable oculomotor palsy and are okay with prevention of progression, then Gamma Knife radiosurgery may be a better option. Langlois et al6 and Elsharkawy et al7 compared their case series against others and concluded that nonvestibular schwannomas respond to Gamma Knife similarly to vestibular schwannomas, although they only included a single oculomotor nerve schwannoma. Asymptomatic patients should always be monitored with imaging without intervention or one could consider Gamma Knife to prevent progression or sudden oculomotor nerve palsy.

32.2.2 Cranial Nerve IV The choice for intervention is different from CN IV versus III and VI due to the number of extraocular muscles innervated and the relative ease of correcting CN IV palsy by ophthalmology (▶ Table 32.1). Elmalem et al8 reviewed 30 patients with trochlear nerve schwannoma with an average age of 51 years and a

206

male predominance. The symptoms were led by fourth nerve palsy (97%) and followed by headache (23%). Most of the lesions occurred in the ambient and perimesencephalic cisterns.6 Only two patients received open surgery and one received radiosurgery. Due to the isolated muscle involvement in 67%, patients were treated with prism diopters or strabismus surgery. Due to ease of correcting vision with a fourth nerve palsy, surgery is rarely indicated when tumor is small and has no mass effect. Cunha et al reviewed 34 surgical cases of trochlear nerve schwannoma. Fifty percent presented with trochlear nerve palsy, which is significantly lower than the above ophthalmology series.9 Seventy-one percent of patients who presented without trochlear nerve palsy developed a new one postoperatively, with only a 17% rate of improvement at last follow-up. Of the patients who presented with a trochlear nerve palsy, only 6% showed improvement at last follow-up. Of note, the single patient that improved had subtotal resection. This surgical review had a 43% rate of hemiplegia due to the larger size and mass effect, which likely played a role in the decision to proceed with surgery.

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Management of Cranial Nerve III, IV, and VI Schwannomas

32.2.3 Cranial Nerve VI CN VI schwannoma is a rare entity and even described as possibly the least common among the ocular motor nerves (▶ Table 32.2).10 Just over 40 patients have been reported so far in the literature.1 The first case reported was in 1981 by BingHuan.1 It is seen most commonly in middle-aged adults. A recent systematic review reported mean age at the diagnosis to be 44 ± 16.5 years, with a very slight predilection toward females (52%).1 As the origin of tumor can be variable, clinical symptomatology usually follows the anatomical occupancy of the tumor (▶ Fig. 32.1). Most common presenting symptoms are usually headaches, diplopia, and abducens nerve palsy. More severe signs and symptoms of this pathology have been noted with concomitant development of increased intracranial pressure and hydrocephalus. Cerebellopontine angle location can certainly present with facial symptoms, hearing loss, and cerebellar symptomatology. These tumors can mimic acoustic neuromas. Rarely, taste and swallowing dysfunction are affected. CN III, V, and VI have been described to be co-affected in a primarily cavernous sinus location. Orbital tumors will naturally have vision issues among the principal complaint with some patients also presenting with proptosis. There have been two recent systematic reviews evaluating the role of surgery and radiosurgery in affecting outcomes of CN VI schwannomas.1,11 Highlights from review of literature thus far are stated below.1,10,11,12,13,14,15,16,17,18,19,20,21,22 Sun et al performed a systematic review of the microsurgical resection of CN VI schwannomas.1 The majority series consists of case reports. They analyzed the factors associated with CN VI

recovery after the surgical intervention. This study did not analyze any other performance status of these patients before and after the surgical intervention. Thirty-two patients were included from 29 reports. The overall CN VI improvement was reported in 45% of tumors. Tumor extension in the cavernous sinus was significantly associated with lesser likelihood of postsurgical CN VI recovery. Large tumor size (> 2.5 cm), female gender, and solid consistency of tumor showed a strong trend toward poor recovery pattern of CN VI. Gross total resection (GTR) showed a trend of better CN VI outcomes at long-term follow-up. It appears that the surgical series of CN VI schwannomas has a better overall rate of CN VI functional recovery than the surgical series for CN III and CN IV. In addition, GTR of CN VI schwannoma was associated with better CN recovery, whereas subtotal resection of CN III and IV schwannomas had better CN outcome. The discrepancy is probably due to the fact that the series of CN VI schwannomas had higher portion of cisternal tumors (33%). The relative ease of dissecting arachnoid plane among cisternal tumors may contribute to the high rate of GTR and better CN function outcomes. An obvious limitation of this study is that overall functional outcomes were not analyzed among these patients.

32.3 Case Example 32.3.1 Cranial Nerve VI Schwannoma1 An 18-year-old white female presented with progressively worsening left-sided frontoparietal visual problems (left eye floaters and double vision on left lateral gaze) and left-sided facial numbness and tingling for more than 2 months (▶ Fig. 32.2).

Fig. 32.2 Neuroimaging and histopathologic evaluation. Magnetic resonance imaging showing (a) axial view showing encapsulated heterogeneous mass with epicenter in the left cavernous sinus; (b) coronal T1-weighted contrast showing encasement of the cavernous segment of the internal carotid artery by the mass with narrowing, along with contralateral displacement of the artery (arrow); (c) sagittal view showing the extension of the mass to the ipsilateral left orbital apex; (d) angiogram showing stenosis of the internal carotid artery secondary to the mass; (e, f) postoperative magnetic resonance scans showing extent of surgical resection in axial and coronal view, respectively; (g) hematoxylin–eosin staining showing Antoni A (left) and Antoni B (right) patterns and (h) immunohistochemical evaluation showing positivity to S100 staining, consistent with a schwannoma.

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Cranial Nerve Schwannoma Visual exam was evident for left CN VI palsy with anisocoria. Magnetic resonance imaging showed an encapsulated heterogeneous mass measuring 3.1 cm × 3.2 cm × 2.6 cm with its epicenter in the region of the left cavernous sinus encasing the cavernous internal carotid artery (ICA) with subsequent narrowing and displacement of the artery to the contralateral side (yellow arrow). There was extension of the lesion to the posterior aspect of the left orbital apex. Digital subtraction angiography confirmed concentric stenosis of the ICA secondary to the mass. The patient underwent neuronavigation-guided left orbitozygomatic craniotomy. Intraoperatively, the mass was confirmed to arise from the abducens nerve. A large part of the cystic portion of the tumor along with the solid part was removed en bloc, whereas smaller fragments were removed in a piecemeal fashion. The postoperative course was uneventful and there was complete resolution of the CN VI palsy and anisocoria. At 1-year follow-up, there was no evidence of recurrence.

32.4 Conclusions Schwannomas arising from CN III, IV, and VI are rare and can present with mild to severe neurological symptoms. Given the scarce patient population, there is lack of higher level of evidence, which makes it difficult to come up with a reliable treatment algorithm. Even though CN III supplies more extraocular muscles than CN IV/VI, treatment decisions may not be made solely based on that criterion. Rather, the treatment strategy depends on the holistic clinical picture and radiological characteristics. Here are a few important points to consider when treating patients with these conditions: ● Schwannomas are benign tumors and the outcome of these patients merits excellent quality of life. Surgical treatment poses a significant risk for functional decline and should be only considered for patients with tumors that cause significant mass effect to neurovascular structures and cerebrospinal fluid obstruction. Incidentally found tumors that cause no mass effect or hydrocephalus usually required no treatment and can be monitored with serial imaging. ● Surgical resection has only a small chance to improve cranial neuropathy associated with these tumors. Patient who presents with diplopia and has small tumor may be referred to an ophthalmologist for prisms. The correction of diplopia should not be the goal of surgical treatment. ● Subtotal resection of these tumors seems safe for these patients especially when the tumor involves the cavernous sinus. GTR should only be attempted if the tumor is purely cisternal. Due to the benign nature of these tumors, debulking is usually sufficient treatment for these lesions. Preservation of the existing function and hence the maintenance of the quality of life should be goal of the surgical treatment. Finally, minimally symptomatic tumors and tumors with predominant cavernous component may benefit from radiosurgery as an initial treatment.

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References [1] Sun H, Sharma K, Kalakoti P, et al. Factors associated with abducens nerve recovery in patients undergoing surgical resection of sixth nerve schwannoma: a systematic review and case illustration. World Neurosurg. 2017; 104:883–899 [2] Furtado SV, Hegde AS. Management of oculomotor nerve schwannomas in two different locations: surgical nuances and comprehensive review. Neurosurg Rev. 2012; 35(1):27–34, discussion 34–35 [3] Abdel-Aziz KM, Froelich SC, Dagnew E, et al. Large sphenoid wing meningiomas involving the cavernous sinus: conservative surgical strategies for better functional outcomes. Neurosurgery. 2004; 54(6):1375–1383, discussion 1383–1384 [4] Couldwell WT, Kan P, Liu JK, Apfelbaum RI. Decompression of cavernous sinus meningioma for preservation and improvement of cranial nerve function. Technical note. J Neurosurg. 2006; 105(1):148–152 [5] Hirsch WL, Sekhar LN, Lanzino G, Pomonis S, Sen CN. Meningiomas involving the cavernous sinus: value of imaging for predicting surgical complications. AJR Am J Roentgenol. 1993; 160(5):1083–1088 [6] Langlois AM, Iorio-Morin C, Masson-Côté L, Mathieu D. Gamma Knife stereotactic radiosurgery for nonvestibular cranial nerve schwannomas. World Neurosurg. 2018; 110:e1031–e1039 [7] Elsharkawy M, Xu Z, Schlesinger D, Sheehan JP. Gamma Knife surgery for nonvestibular schwannomas: radiological and clinical outcomes. J Neurosurg. 2012; 116(1):66–72 [8] Elmalem VI, Younge BR, Biousse V, et al. Clinical course and prognosis of trochlear nerve schwannomas. Ophthalmology. 2009; 116(10):2011–2016 [9] Cunha M, Miranda M, Cecconello G. Trochlear nerve schwannoma: case report and literature review. Available at: https://www.researchgate.net/publication/317641791_Trochlear_Nerve_Schwannoma_Case_Report_and_Literature_Review. Accessed March 5, 2018 [10] Nakamura M, Carvalho GA, Samii M. Abducens nerve schwannoma: a case report and review of the literature. Surg Neurol. 2002; 57(3):183–188, discussion 188–189 [11] Prasad GL, Sharma MS, Kale SS, Agrawal D, Singh M, Sharma BS. Gamma Knife radiosurgery in the treatment of abducens nerve schwannomas: a retrospective study. J Neurosurg. 2016; 125(4):832–837 [12] Park JH, Cho YH, Kim JH, Lee J-K, Kim CJ. Abducens nerve schwannoma: case report and review of the literature. Neurosurg Rev. 2009; 32(3):375–378, discussion 378 [13] Wang M, Huang H, Zhou Y. Abducens nerve schwannoma in cerebellopontine angle mimicking acoustic neuroma. J Craniofac Surg. 2015; 26(2):589–592 [14] Vachata P, Sames M. Abducens nerve schwannoma mimicking intrinsic brainstem tumor. Acta Neurochir (Wien). 2009; 151(10):1281–1287 [15] Erlich SA, Tymianski M, Kiehl T-R. Cellular schwannoma of the abducens nerve: case report and review of the literature. Clin Neurol Neurosurg. 2009; 111(5):467–471 [16] Shibao S, Hayashi S, Yoshida K. Dumbbell-shaped abducens schwannoma: case report. Neurol Med Chir (Tokyo). 2014; 54(4):331–336 [17] Kim I-Y, Kondziolka D, Niranjan A, Flickinger JC, Lunsford LD. Gamma Knife surgery for schwannomas originating from cranial nerves III, IV, and VI. J Neurosurg. 2008; 109 Suppl:149–153 [18] Lo PA, Harper CG, Besser M. Intracavernous schwannoma of the abducens nerve: a review of the clinical features, radiology and pathology of an unusual case. J Clin Neurosci. 2001; 8(4):357–360 [19] Rato RMF, Correia M, Cunha JP, Roque PS. Intraorbital abducens nerve schwannoma. World Neurosurg. 2012; 78(3)(–)(4):375.e1–375.e4 [20] Mariniello G, de Divitiis O, Caranci F, Dones F, Maiuri F. Parasellar schwannomas: extradural vs extra-intradural surgical approach. Oper Neurosurg (Hagerstown). 2018; 14(6):627–638 [21] Moses JE, Vermani N, Bansal SK. Preoperative clinico-radiological diagnosis of schwannoma arising from cavernous segment of abducens nerve. Neurol India. 2011; 59(3):471–473 [22] Peciu-Florianu I, Tuleasca C, Comps J-N, et al. Radiosurgery in trochlear and abducens nerve schwannomas: case series and systematic review. Acta Neurochir (Wien). 2017; 159(12):2409–2418

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Treatment of Facial Pain in Patients with Trigeminal Schwannoma

33 Treatment of Facial Pain in Patients with Trigeminal Schwannoma John P. Sheehy and Zaman Mirzadeh Abstract Facial pain accompanies the presentation of many patients with skull base tumors, including nearly one-fourth of those with trigeminal schwannomas. The management of facial pain in these patients is not so much controversial as it is highly nuanced. Although preoperative pain improves in most patients undergoing surgery and in approximately two-thirds of patients undergoing radiotherapy, a few patients will develop new or worsened pain after treatment. In managing tumor-associated pain, it is critical to distinguish between trigeminal neuralgia (lancinating, electrical pain that is classically paroxysmal but may also have a constant component) and trigeminal neuropathic pain (burning, aching pain that is more often constant and associated with sensory loss). If surgical resection or radiotherapy fails to ameliorate the pain, patients with medication-resistant trigeminal neuralgia may be treated with therapies targeting the trigeminal root or gasserian ganglion. However, patients with refractory trigeminal neuropathic pain require procedures targeting higher-order neurons in the somatosensory pathway. Although our focus in this chapter is on facial pain in patients with trigeminal schwannomas, these considerations are broadly applicable to patients with facial pain caused by other benign skull base tumors. Keywords: facial pain, skull base tumor, trigeminal neuralgia, trigeminal neuropathic pain, trigeminal schwannoma

33.1 Introduction In 13 published series of patients with trigeminal schwannomas, facial pain was reported in 118 of 464 patients (25%) (▶ Table 33.1).1,2,3,4,5,6,7,8,9,10,11,12,13 The characteristics of the pain were varied and not uniformly reported. Some authors speculate that the location of trigeminal nerve compression by the tumor appears, at least in part, to determine the type of pain: a neuralgia-like syndrome is more common with tumors abutting the nerve segment from the root entry zone to the gasserian ganglion, and pain atypical of neuralgia is more common in tumors affecting the ganglion and more distal sites.1,14 Although some facial pain might be difficult to characterize, the distinction between trigeminal neuralgia and trigeminal neuropathic pain is critical to the management of facial pain in patients with skull base tumors. Trigeminal neuropathic pain is a burning, aching pain associated with sensory loss caused by injury to the first-order neurons of the trigeminal nerve. Trigeminal neuralgia is a lancinating, electrical pain that is classically paroxysmal (TN1) but may also have a predominant constant component (TN2) putatively caused by abnormal first-order activation (TN1) and higher-order deafferentation (TN2).15 Facial pain will frequently resolve with direct treatment of the schwannoma. A comprehensive literature review combining data from multiple nonoverlapping case series showed that, in surgical series, facial pain improved in 49 of 58 patients (84%)

(▶ Table 33.2),1,3,4,5,9,13 and in stereotactic radiosurgical series, facial pain improved in 28 of 43 patients (65%) (▶ Table 33.3).6,7, 8,10,12 Treating the trigeminal schwannoma will occasionally have a negative impact on facial pain. Three of 183 patients (2%) without preoperative facial pain developed new pain after surgical resection.1,3,4,5,9,13 New pain also developed in 5 of 105 patients (5%) without pain who underwent stereotactic radiosurgery, although this pain was transient in 3 cases.6,7,8,10,12,16 Furthermore, 4 of 43 patients (9%) with pain who underwent stereotactic radiosurgery experienced worse pain after the procedure.6,7,8,10,12,16 With these data in mind, one should consider four possible scenarios regarding facial pain in the context of the goals of care when treating patients with trigeminal schwannomas or other skull base tumors: (1) pain management in the poor surgical candidate, (2) maximizing pain relief with surgical therapy, (3) managing unresolved preoperative facial pain after surgery, and (4) managing new pain after tumor treatment. Throughout these distinct scenarios, the distinction between trigeminal neuralgia (lancinating, electrical pain) and neuropathic facial pain (aching, burning pain) is critical. Patients with other benign skull base tumors that cause facial pain exhibit a pain response similar to that of those with trigeminal schwannomas after surgical and radiosurgical treatment.14,17,18,19,20,21,22,23 The following discussion can therefore be more broadly applicable to these tumors as well. Very few data beyond case reports are available regarding the direct treatment of facial pain in patients with trigeminal schwannomas or any other skull base tumor, and thus the following treatment recommendations are guided by expert opinion (▶ Table 33.4). We are indebted to the members of the

Table 33.1 Incidence of facial pain with trigeminal schwannomas in 13 series Case series

Level of evidence

No. of patients

No. with facial pain

%

McCormick et al (1988)1

IV

14

8

57

Samii et al (1995)2

IV

12

3

25

Day and Fukushima (1998)3

IV

38

13

34

Al-Mefty et al (2002)4

IV

25

14

56

Goel et al (2003)5

IV

73

15

21

Peker et al (2007)7

IV

15

3

20

Phi et al (2007)8

IV

22

11

50

(2007)6

IV

26

11

42

Kano et al (2009)10

IV

33

8

24

Zhang et al (2009)9

IV

42

3

7

Fukaya et al (2010)11

IV

57

8

14

Sun et al (2013)12

IV

52

10

19

Chen et al (2014)13

IV

55

11

20

464

118

25

Sheehan et al

Combined

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Cranial Nerve Schwannoma Table 33.2 Facial pain outcomes after microsurgical resection of trigeminal schwannomas

Table 33.3 Facial pain outcomes after radiosurgical treatment of trigeminal schwannomas

Surgical series

Fraction improved

Fraction new

Radiosurgery series

Fraction improved

Fraction worse

Fraction newa

McCormick et al (1988)1

7/8 (88%)

0/8 (0%)

0/6 (0%)

0/3 (0%)

1/12 (8%)

12/13 (92%)

0/13 (0%)

1/25 (4%)

Peker et al (2007)7

2/3 (67%)

Day and Fukushima (1998)3

Phi et al (2007)8

8/11 (73%)

0/11 (0%)

2/11 (18%)

8/11 (73%)

0/11 (0%)

1/11 (9%)

Sheehan et al (2007)6

7/11 (64%)

3/11 (27%)

0/15 (0%)

Goel et al (2003)5

11/15 (73%)

0/15 (0%)

0/58 (0%)

Kano et al (2009)10

2/8 (25%)

1/8 (13%)

1/25 (4%)

Zhang et al (2009)9

Not reported

Not reported

1/39 (3%)

Sun et al (2013)12

9/10 (90%)

0/10 (0%)

1/42 (2%)

Chen et al (2014)13

11/11 (100%)

0/11 (0%)

0/44 (0%)

Combined

28/43 (65%)

4/43 (9%)

5/105 (5%)

49/58 (84%)

0/58 (0%)

3/183 (2%)

Note: Values are number/total (percentage). aAlthough five patients experienced new pain, the pain was transient in three cases.

Al-Mefty et al

(2002)4,a

Combined

Fraction worse

Note: Values are number/total (percentage). discrepancy in patient numbers in the Al-Mefty et al series is present in the original publication. The missing cases appear to be caused by missing outcome data for those patients.

aThe

Table 33.4 Summary of treatment options Trigeminal neuralgia pain

Trigeminal neuropathic pain

Gamma Knife ● Minimally invasive ● Target tumor or nerve root ● Total radiation dose ● May need repeat therapy ● Delayed effect Percutaneous rhizotomy ● Minimally invasive, but ablative ● Radiofrequency, glycerol, or balloon ● Balloon rhizotomy contraindicated if tumor in Meckel’s cave ● Immediate impact ● Less durable than microvascular decompression Microvascular decompression ● Most durable relief ● Offending vessel frequently found even in patients with tumor ● More invasive ● Increased morbidity profile in repeat craniotomy

Reversible techniques: Peripheral nerve stimulation ● Least invasive ● Effective for localized, superficial target Deep brain stimulation ● Targets ventral posteromedial nucleus of thalamus or periaqueductal gray ● Scalable Nucleus caudalis epidural stimulation ● Electrode over high cervical spine placed laterally over affected side ● Scalable Intrathecal drug delivery system ● Catheter tip at C1 ● Allows versatility of different drug combinations ● Scalable Ablative techniques: Percutaneous computed tomography–guided trigeminal tractotomy and nucleotomy ● Percutaneous technique ● Small lesion; may be less effective than open nucleus caudalis ablation Open nucleus caudalis ablation ● Most invasive technique ● Larger lesion; more likely to be effective

American Association of Neurological Surgeons–Congress of Neurological Surgeons (AANS/CNS) Joint Section on Pain for much of this guidance (personal communications with AANS/ CNS Joint Pain Section Google Group, private online discussion forum, January to March 2018).

33.2 Trigeminal Neuralgia Patients with trigeminal neuralgia report electrical or lancinating pain, which is classically paroxysmal. The pain may (TN2) or may not (TN1) have a predominant constant component, which does not significantly affect treatment considerations in these patients. For patients with trigeminal neuralgia, the first-line treatment is medical therapy with anticonvulsants, and specific

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considerations relate to patients with medication-refractory trigeminal neuralgia.

33.2.1 Medication-Refractory Trigeminal Neuralgia in the Poor Surgical Candidate with Trigeminal Schwannoma If the patient is not a candidate for craniotomy, less invasive options include stereotactic radiosurgery and percutaneous rhizotomy. As noted above, direct stereotactic radiosurgery to the tumor provides pain relief in nearly two-thirds of patients with trigeminal schwannomas. One case series of patients with skull

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Treatment of Facial Pain in Patients with Trigeminal Schwannoma base tumors and facial pain examined cases treated with Gamma Knife (Elekta AB) radiosurgery for pain control (not tumor control), when the target was the nerve root itself or only that portion of the tumor containing the nerve.24 At a median 55-month follow-up, five of seven patients were painfree without medication. The onset of relief is delayed with stereotactic radiosurgery, so percutaneous rhizotomy may be preferable for immediate alleviation of pain. Stereotactic lesioning can be performed with radiofrequency lesioning, glycerol, or balloon compression; however, balloon compression is contraindicated if the tumor is within Meckel’s cave.15 The duration of efficacy observed in patients without skull base tumors indicates that these radiosurgical and percutaneous options will likely provide temporary relief lasting several years, but patients may require re-treatment in the long term.15

33.2.2 Maximizing Trigeminal Neuralgia Relief with Surgery As described above, surgical resection improved facial pain in 49 of 58 (84%) patients with trigeminal schwannoma,1,3,4,5,9,13 although the exact number of patients with trigeminal neuralgia is not known. Some series suggest that patients with trigeminal neuralgia have a better chance of improving with surgery than those with other forms of facial pain.4,25 The presence of a skull base tumor may indirectly cause vascular compression that results in trigeminal neuralgia. In a series of 35 patients with skull base tumors, vascular compression of the trigeminal nerve was found in 15 patients, all but 1 of whom improved with decompression and resection.23 These findings lead us to recommend vigilance for identifying vascular compression during surgical resection of trigeminal schwannomas in patients with trigeminal neuralgia.

33.2.3 Treating Persistent Trigeminal Neuralgia following Tumor Treatment Some patients have trigeminal neuralgia that does not resolve after tumor treatment with surgery or radiosurgery. For patients whose quality of life is significantly affected and for whom medical therapy is not helpful, several surgical options are available. The first consideration is surgical exploration to decompress an offending blood vessel at the root entry zone. If no compressive vessel is found, a partial sensory rhizotomy (internal neurolysis, compression of nerve) may be performed. Two cases have been reported of patients with trigeminal neuralgia and small, previously irradiated trigeminal schwannomas who underwent surgical exploration.26 In both cases, a compressive vessel was found and microvascular decompression resulted in pain relief. If a craniotomy is not appropriate, radiosurgical and percutaneous options are available to treat trigeminal neuralgia. The results in patients without tumors indicate that the relief provided by these therapies would likely be of shorter duration than the relief provided by microvascular decompression.15

33.2.4 New Trigeminal Neuralgia after Tumor Treatment The putative pathophysiology of new trigeminal neuralgia indicates that it is unlikely to occur after surgical resection. If new

postoperative facial pain is definitive and clinically consistent with trigeminal neuralgia, the possibility of new vascular compression at the root entry zone should be considered (perhaps from redundant blood vessels previously stretched by the tumor). If medical management fails, surgical therapy might entail re-exploration or the use of a less invasive procedure (Gamma Knife or percutaneous rhizotomy).

33.3 Trigeminal Neuropathic Pain Trigeminal neuropathic pain has burning or aching characteristics, with associated sensory loss that is thought to result from damage to the trigeminal nerve. With this type of pain, treatment that can result in further damage to the nerve is not recommended. Therapy (either ablative or reversible) should be targeted upstream in the pain pathway.

33.3.1 Trigeminal Neuropathic Pain in the Poor Surgical Candidate Diverse medical therapies are available for trigeminal neuropathic pain (e.g., anticonvulsants, local anesthetics, antidepressants, and opioids), but treatment is challenging and frequently limited by systemic adverse effects.15 Trigeminal neuropathic pain and its extreme form, anesthesia dolorosa, are notoriously difficult to treat. If medical therapy is not effective, a range of less invasive surgical procedures that might be optimized for poor surgical candidates are available and are described in the subsequent sections.

33.3.2 Maximizing Trigeminal Neuropathic Pain Relief during Therapy Although the mechanism is not clear, at least some patients with a likely neuropathic facial pain syndrome have improved after surgical resection or radiosurgery of their tumors.4,25 Because trigeminal neuropathic pain is secondary to first-order deafferentation, this relief might be the result of the return of afferent signal from first-order neurons after resolution of compression. Further damage to the nerve should be avoided during surgery. With stereotactic radiosurgery, the nerve root should not be targeted along with the tumor in patients with neuropathic facial pain.

33.3.3 Treating New or Persistent Trigeminal Neuropathic Pain after Therapy Numerous surgical options exist for treating patients with neuropathic facial pain, and most of these treatments target the afferent sensory pathway at the second-order neuron level and above. These therapies can be characterized as reversible or ablative neuromodulation. Reversible therapies include intrathecal medication delivery through a high-cervical catheter,27 nucleus caudalis stimulation (using a high-cervical epidural electrode), and deep brain stimulation of the ventral posteromedial nucleus of thalamus and periaqueductal gray.28 These reversible scalable therapies target the second- and third-order

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Cranial Nerve Schwannoma neurons of the pain pathway. One additional reversible therapy, which targets first-order neurons, is facial peripheral nerve stimulation. This type of reversible therapy is limited to patients whose neuropathic pain is localized to superficial regions on the face that can be covered with a peripheral subcutaneous electrode. The ablative approaches, although irreversible and with the risk of long-term return of pain, may be more effective than the reversible therapies. One ablative approach is percutaneous computed tomography–guided trigeminal tractotomy and nucleotomy, wherein a radiofrequency probe is used to ablate part of the nucleus caudalis and trigeminal tract at the cervicomedullary junction.29 A more extensive ablation (associated with more postoperative pain but also more likely to result in relief of facial pain) may be performed with open nucleus caudalis ablation, which targets more of the nucleus caudalis through a posterior suboccipital craniectomy and C1 laminectomy.30 All of these therapies have both risks and benefits. We favor attempting a reversible, less invasive procedure before resorting to more invasive ablative surgery.

33.4 Conclusions Facial pain is a common presenting symptom in patients with trigeminal schwannomas. In many cases, the pain will improve after surgical or radiosurgical treatment, but some patients will have persistent pain and others will develop new pain. The distinction between trigeminal neuralgia and trigeminal neuropathic pain is critical to the further treatment of facial pain in these patients. Trigeminal neuralgia necessitates treatment directed at the trigeminal nerve root and ganglion. Trigeminal neuropathic pain necessitates therapy targeting higher-order neurons.

References [1] McCormick PC, Bello JA, Post KD. Trigeminal schwannoma. Surgical series of 14 cases with review of the literature. J Neurosurg. 1988; 69(6):850–860 [2] Samii M, Migliori MM, Tatagiba M, Babu R. Surgical treatment of trigeminal schwannomas. J Neurosurg. 1995; 82(5):711–718 [3] Day JD, Fukushima T. The surgical management of trigeminal neuromas. Neurosurgery. 1998; 42(2):233–240, discussion 240–241 [4] Al-Mefty O, Ayoubi S, Gaber E. Trigeminal schwannomas: removal of dumbbell-shaped tumors through the expanded Meckel cave and outcomes of cranial nerve function. J Neurosurg. 2002; 96(3):453–463 [5] Goel A, Muzumdar D, Raman C. Trigeminal neuroma: analysis of surgical experience with 73 cases. Neurosurgery. 2003; 52(4):783–790, discussion 790 [6] Sheehan J, Yen CP, Arkha Y, Schlesinger D, Steiner L. Gamma knife surgery for trigeminal schwannoma. J Neurosurg. 2007; 106(5):839–845 [7] Peker S, Bayrakli F, Kiliç T, Pamir MN. Gamma-knife radiosurgery in the treatment of trigeminal schwannomas. Acta Neurochir (Wien). 2007; 149(11): 1133–1137, discussion 1137

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[8] Phi JH, Paek SH, Chung HT, et al. Gamma Knife surgery and trigeminal schwannoma: is it possible to preserve cranial nerve function? J Neurosurg. 2007; 107(4):727–732 [9] Zhang L, Yang Y, Xu S, Wang J, Liu Y, Zhu S. Trigeminal schwannomas: a report of 42 cases and review of the relevant surgical approaches. Clin Neurol Neurosurg. 2009; 111(3):261–269 [10] Kano H, Niranjan A, Kondziolka D, Flickinger JC, Dade Lunsford L. Stereotactic radiosurgery for trigeminal schwannoma: tumor control and functional preservation Clinical article. J Neurosurg. 2009; 110(3):553–558 [11] Fukaya R, Yoshida K, Ohira T, Kawase T. Trigeminal schwannomas: experience with 57 cases and a review of the literature. Neurosurg Rev. 2010; 34(2):159– 171 [12] Sun J, Zhang J, Yu X, et al. Stereotactic radiosurgery for trigeminal schwannoma: a clinical retrospective study in 52 cases. Stereotact Funct Neurosurg. 2013; 91(4):236–242 [13] Chen LF, Yang Y, Yu XG, et al. Operative management of trigeminal neuromas: an analysis of a surgical experience with 55 cases. Acta Neurochir (Wien). 2014; 156(6):1105–1114 [14] Bullitt E, Tew JM, Boyd J. Intracranial tumors in patients with facial pain. J Neurosurg. 1986; 64(6):865–871 [15] Burchiel KJ. Surgical Management of Pain. 2nd ed. New York, NY: Thieme; 2014 [16] Huang CF, Kondziolka D, Flickinger JC, Lunsford LD. Stereotactic radiosurgery for trigeminal schwannomas. Neurosurgery. 1999; 45(1):11–16, discussion 16 [17] Cho KR, Lee MH, Im YS, et al. Gamma knife radiosurgery for trigeminal neuralgia secondary to benign lesions. Headache. 2016; 56(5):883–889 [18] Squire SE, Chan MD, Furr RM, et al. Gamma knife radiosurgery in the treatment of tumor-related facial pain. Stereotact Funct Neurosurg. 2012; 90(3): 145–150 [19] Tanaka S, Pollock BE, Stafford SL, Link MJ. Stereotactic radiosurgery for trigeminal pain secondary to benign skull base tumors. World Neurosurg. 2013; 80(3–4):371–377 [20] Chang JW, Kim SH, Huh R, Park YG, Chung SS. The effects of stereotactic radiosurgery on secondary facial pain. Stereotact Funct Neurosurg. 1999; 72 Suppl 1:29–37 [21] Huang CF, Tu HT, Liu WS, Lin LY. Gamma Knife surgery for trigeminal pain caused by benign brain tumors. J Neurosurg. 2008; 109 Suppl:154–159 [22] Barker FG, II, Jannetta PJ, Babu RP, Pomonis S, Bissonette DJ, Jho HD. Longterm outcome after operation for trigeminal neuralgia in patients with posterior fossa tumors. J Neurosurg. 1996; 84(5):818–825 [23] Liu P, Liao C, Zhong W, Yang M, Li S, Zhang W. Symptomatic trigeminal neuralgia caused by cerebellopontine angle tumors. J Craniofac Surg. 2017; 28 (3):e256–e258 [24] Régis J, Metellus P, Dufour H, et al. Long-term outcome after gamma knife surgery for secondary trigeminal neuralgia. J Neurosurg. 2001; 95(2):199–205 [25] Alfano GJ. There are no routine patients. Am J Nurs. 1975; 75(10):1804–1807, 1822 [26] Miller JP, Acar F, Burchiel KJ. Trigeminal neuralgia and vascular compression in patients with trigeminal schwannomas: case report. Neurosurgery. 2008; 62(4):E974–E975, discussion E975 [27] Hayek SM, Sweet JA, Miller JP, Sayegh RR. Successful management of corneal neuropathic pain with intrathecal targeted drug delivery. Pain Med. 2016; 17 (7):1302–1307 [28] Green AL, Owen SL, Davies P, Moir L, Aziz TZ. Deep brain stimulation for neuropathic cephalalgia. Cephalalgia. 2006; 26(5):561–567 [29] Raslan AM. Percutaneous computed tomography-guided radiofrequency ablation of upper spinal cord pain pathways for cancer-related pain. Neurosurgery. 2008; 62(3) Suppl 1:226–233, discussion 233–234 [30] Rahimpour S, Lad SP. Surgical options for atypical facial pain syndromes. Neurosurg Clin N Am. 2016; 27(3):365–370

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Part VIII Sinonasal Malignancies

34 Induction Therapy for Esthesioneuroblastoma

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35 Surgical Approach for Esthesioneuroblastoma: Controversy in Approach Selection

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36 What Is the Role of Surgery for Adenoid Cystic Carcinoma?

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37 Proton versus Photon Therapy for Sinonasal Malignancies: Pros and Cons of Each Method

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Sinonasal Malignancies

34 Induction Therapy for Esthesioneuroblastoma Sheri K. Palejwala, Christopher H. Le, and G. Michael Lemole Jr. Abstract The impact of induction radiation and chemotherapy in the treatment of esthesioneuroblastoma has been inconclusive and unreliably reproduced, such that no definitive conclusions can yet be drawn regarding the potential benefits on survival and disease freedom. It is possible that the addition of induction therapy might prove beneficial to a subset of patients, yet it is unclear which patients stand to gain from such treatments and who might be harmed either from treatment complications, delayed or indefinitely postponed surgery, or incomplete resections. At this time, the cornerstone of esthesioneuroblastoma management remains an aggressive, clear-margin resection and adjuvant radiation therapy. Ultimately, a randomized trial is necessary, between patients who receive neoadjuvant therapy and those who undergo upfront surgical resection, controlling for Kadish stage and Hyams grade, while maintaining extensive resection, comparing morbidity, disease-free, and overall survival. Keywords: chemotherapy, esthesioneuroblastoma, induction therapy, neoadjuvant, radiation

reviews have demonstrated statistically worsened overall survival with more advanced modified Kadish staging.14,22,28 Other staging systems include an adaptation of the popular TNM system, proposed by Biller et al, that better accounts for nodal involvement and metastasis than the original Kadish stages.27,30 Dulguerov and Calcaterra modified the system set forth by Biller and colleagues, by breaking down the more limited-extent tumors.31 Nevertheless, the Kadish system, either with the Morita modification or with clarification regarding lymph node involvement, remains the most popular basis of disease classification used in the current literature.18,27

34.2.2 Histological Classification Histopathological stratification, based on Hyams grading, has also been shown to be an important prognosticator, both for overall prognosis and for treatment response.14,32,33 In brief, the Hyams grading is derived from histological differentiation, ranging from grades I to IV, and is based on cellular architecture, extracellular matrix, pleomorphism, mitotic rates, necrosis, and calcifications.32,33

34.3 Current Management 34.1 Introduction Esthesioneuroblastoma, or olfactory neuroblastoma, is an uncommon, malignant, neuroendocrine tumor that arises from olfactory neurosecretory cells near the cribriform plate.1,2,3,4 It was first described by Berger et al, in 1924, as L’esthésioneuroépithéliome olfactif.5 Since then, several hundred cases have been described in small case series, single-institution reviews, and meta-analyses.1,2,3,4,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24,25,26 Most cases of esthesioneuroblastoma are diagnosed at advanced stages, at which point the tumor is already quite extensive, largely due to its nonspecific symptoms and overall rarity.13,15,27 Patients typically present with generalized complaints including congestion and sinusitis-like symptoms that make diagnosis challenging.13,15,27 Since most esthesioneuroblastomas have greater extension and even intracranial invasion at the time of diagnosis, these advanced stage tumors become more arduous to treat.1,2,15,18,28,29

34.2 Classification of Esthesioneuroblastoma 34.2.1 Radiographic Classification In 1976, Kadish et al described the first, and most widely used, staging system for esthesioneuroblastoma. It includes three tiers: stage A, disease limited to the nasal cavity; stage B, inclusion of the paranasal sinuses; and stage C, extension beyond the cribriform plate and paranasal sinuses.27 This was later modified by Morita and co-workers to include stage D, involvement of cervical lymph nodes and distant metastases.18 Analyses of large database studies as well as single-institution

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Radical surgical resection, with disease-free margins, is a strong predictor of tumor freedom and prevention of both local and distal recurrence.10,15,16,34 Positive surgical margins in anterior skull base tumors were found to double local recurrence rates and cut survival in half.10,34 Furthermore, the use of craniofacial approaches led to over a twofold improvement in disease-free survival.10,12,22,34 Expectedly, after its introduction, craniofacial resection became the gold standard in the treatment of esthesioneuroblastoma.2,8,10,16,22,24 The standard of care for the treatment of esthesioneuroblastomas is currently held to be craniofacial resection with histologically proven disease-free margins, and the use of adjuvant radiotherapy.2,6,8,10,16,20,24 The use of chemotherapy, neoadjuvant therapy, neck dissection, and cervical irradiation, however, remains controversial.1,9,10,12,19,21

34.3.1 Craniofacial Resection Esthesioneuroblastoma has an established propensity for being locally aggressive with the possibility of distal metastases, and the potential for decades-delayed recurrences.1,2,9,20 Radical surgical resection, with clear margins, is a strong predictor of disease freedom.10,15,16,34 In an effort to prolong disease-free survival, most advocate for radical resection with clear margins, which has been shown to double disease-free survival, especially in the setting of advanced Kadish tumors.1,10,16,34 The widespread use of craniofacial approaches has improved our ability to obtain complete resections with histologically disease-free margins, even in the setting of extensive, high Kadish stage tumors.2,8,10,16,22,24 Craniofacial resection has been shown to increase progression-free survival from 37.5 to 82%.10,12,22,34 As such, craniofacial approaches quickly became the gold standard for the surgical treatment of esthesioneuroblastoma.2,8,10,16 However, transfacial

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Induction Therapy for Esthesioneuroblastoma approaches, in particular, have fallen largely out of favor, while endoscopic approaches have gained popularity, both for cosmesis and for reduction in morbidity.2,3,8,10,16,24,35

34.3.2 Endoscopic Approaches Yuen et al first described the use of an endoscopic approach in the treatment of esthesioneuroblastoma in 1997.35 Since then multiple studies have not only reproduced its feasibility but also, in some cases, demonstrated its superiority.2,8,10,16 The use of endoscopy can provide greater visualization of tumor margins and critical structures, as well as preserve cosmesis.36 Equipoise, and in some instances superiority, has been demonstrated with endoscopic-only or endoscopic-assisted approaches, as compared to transcranial approaches, for complete margin-free resection, albeit with the ever-present caveat of careful patient selection.3 Several series have shown excellent results with transcranial, endoscopic-assisted approaches, including clear surgical margins, and long-term disease-free and overall survival, while minimizing complications.2,8,10,16,24 Many studies report significantly lower rates of adverse events in those patients undergoing endoscopic-only surgical approaches, in contrast to open transcranial or transfacial surgical resections.2,8,16,26 In some cases, endoscopic-only approaches did not compromise extent of resection even in the setting of extensive Kadish C disease,8 though many studies did not reproduce the same results.10,16,26 Nevertheless, the addition of endoscopic approaches can augment the likelihood of margin-free resection without the added morbidity of transfacial approaches.

34.3.3 Adjuvant Radiation Therapy Despite the favorable outcomes with extensive resection, single-modality treatment, including surgery in isolation, led to poor results and higher rates of both local recurrence and distal metastatic disease.13,15 In addition to radical resection, the highest control rates were found with the addition of radiation therapy. Dulguerov et al performed a meta-analysis of 26 studies with 390 patients, which ultimately showed the best outcomes in esthesioneuroblastoma occurred when margin-free resection was followed by radiotherapy; this has also been corroborated by several large studies.2,10,20 As such, most advocate for aggressive surgical resection to be followed by 55 to 65 Gy of radiation therapy.20,31,37 More recently, proton-beam radiation has been shown to have similar outcomes in disease-free survival, with a reduction in the adverse events associated with photon-beam therapy. Specifically, the rate of ocular side effects, including blindness, are significantly lower in the setting of proton-beam therapy, though there is still a notable risk of radiation necrosis and wound complications.7,37

34.3.4 Role of Chemotherapy The addition of chemotherapy, however, has been controversial, where many groups reserve its use for recurrent or systemically disseminated disease.10,15,22,38 However, more recent studies have shown a benefit with concomitant postoperative chemotherapy for patients with high Kadish stage disease.23 Most chemotherapy regimens include the use of etoposide and a

platinum-based agent such as cisplatin or carboplatin, which have been found to have excellent results, especially in the setting of lymph node involvement and distant metastases.13,38 Other regimens include the use of cyclophosphamide and vincristine, which have also demonstrated good long-term control rates.1,9,12 McElroy and colleagues described a particular subset of patients, with high Hyams grade and advanced Kadish stage esthesioneuroblastomas, who have shown favorable objective responses to platinum-based chemotherapy, used as induction, concomitant, and salvage therapy.39 The discrepancy in reported chemotherapy efficacy can potentially be attributed to only some subtypes of esthesioneuroblastomas, especially those with histological characteristics attributable to a greater Hyams grades, that demonstrate a particular chemosensitivity.38,39 Ultimately, there has been no reliable and reproducible benefit of systemic chemotherapy reported in the literature, and a randomized trial to tease out its potential benefits and toxicities is warranted.13,15,22,23,40,41

34.3.5 Neck Irradiation Another area of concern for advanced Kadish stage esthesioneuroblastomas has been the presence of lymph node involvement. The rates of cervical lymph node metastasis have been reported as high as 33%, and can present over a decade after control of the primary disease.17,19 Advanced Kadish stage disease, even with adequate local control, has been shown to have delayed cervical node metastasis in up to 16% of cases, only one-third of whom are salvaged with additional therapy.17 One study demonstrated no neck recurrence in those patients undergoing elective neck radiation, while 44% of those who did not undergo cervical radiotherapy experienced neck recurrence.19 Because of this, some argue in favor of, and have shown good results with, prophylactic neck irradiation in locally aggressive Kadish B and C disease.19 Others reserve the use of cervical radiation, used in conjunction with neck dissection, for cases of disease recurrence.1 Neck irradiation is not without morbidity, however, including such complications as mucositis, dermatitis, esophagitis, and dysphagia that could require gastrostomy.17,19 The role of prophylactic neck radiation remains controversial, and the risk of potential distant recurrence must be weighed against the adverse events associated with radiotherapy.1,19

34.4 Induction Therapy 34.4.1 Proposed Protocols One proposed method of decreasing preoperative tumor volume and improving surgical extent of resection is the use of neoadjuvant therapy. The University of Virginia team, in particular, advocates the use of neoadjuvant therapy.1,9,12,21 Their goal is to reduce the tumor burden to make a margin-free resection more feasible while simultaneously minimizing the surgical footprint.1,9 Their most recently published series includes 50 patients who had strict adherence to their protocol of neoadjuvant therapy. All Kadish A and B patients received 50 Gy of radiotherapy followed by craniofacial resection 4 to 6 weeks later.1 Kadish C

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Sinonasal Malignancies patients underwent preoperative radiation and six cycles of chemotherapy with cyclophosphamide and vincristine sulfate, while some patients had the addition of doxorubicin, followed by craniofacial resection.1,9

34.4.2 Neoadjuvant Radiotherapy On review of patients undergoing preoperative radiation treatment, the authors noted only 4.8% of patients had interval tumor progression in the preoperative period and one-third had no significant tumor reduction.9 Two-thirds, however, had at least 20% reduction in tumor volume, preoperatively, where nearly half had greater than 50% decrease in tumor volume. Additionally, those that had a significant (≥ 20%) reduction in tumor burden with neoadjuvant therapy were significantly more likely to have disease-free survival than nonresponders.9 One of the drawbacks of neoadjuvant radiotherapy, however, is the confounding nature of radiation changes on histopathology, which can impede obtaining clear surgical planes, and potentially damage already sensitized vital structures and confuse the ability to achieve histological margin-free resections.29,42

34.4.3 Induction Chemotherapy Kim et al described nine patients who were given induction chemotherapy with etoposide, ifosfamide, and cisplatin; the patients demonstrated an 82% response rate, but 37% rate of neutropenic fevers after each cycle, and resulted in only an 18month median survival.43 Similarly, a multi-institution study demonstrated a 74% response rate with induction chemotherapy, yet no definitive benefits in terms of disease-free or overall survival.44 In contrast, several other studies have shown no discernible benefit, with either tumor reduction or prognosis, with the use of neoadjuvant chemotherapy.7,22,37 It should be noted that a consistent protocol was not used in most studies, and a direct comparison of the use of chemotherapy, while controlling for tumor stage and grade, is justified.

34.4.4 Outcomes of Neoadjuvant Chemoradiation The University of Virginia group, in their most recent 28-year review, reported an 87 and 83% 5- and 15-year disease-free survival, respectively, which is significantly higher than studies that show the “gold standard” approach of complete craniofacial resection followed by adjuvant radiotherapy.1,20 However, earlier reports, from the same group, were somewhat contradictory with a 10-year survival of 54% with the same treatment protocol, which has survival estimates more consistent with other published findings.9 A meta-analysis by Broich et al studied 945 patients and demonstrated a 72.5% 5-year survival for combined therapy, while Dulguerov et al analyzed 390 patients and showed surgery and radiation conferred a 65% 5-year survival.20,45 Interestingly, 5year survival with the addition of chemotherapy was lower at 51%.20 This can likely be attributed to the use of chemotherapy for palliation and “unresectable” cases by many groups. Many have proposed concern for the higher potential rates of complications that may incur from radiation and

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chemotherapy, and might delay or even prevent extensive resection, which remains the mainstay of esthesioneuroblastoma treatment.1,2,10,16 The University of Virginia group, however, noted that there was no significant difference between complication rates in the setting of induction therapy in contrast to adjuvant therapy. They reported a 10% cerebrospinal fluid leak rate, 17% complication rate from chemotherapy, including myocardial infarction, and a 15% incidence of radiation-induced orbital complications.1 In contradiction, two patients from the University of Pennsylvania with advanced-stage esthesioneuroblastoma who underwent concurrent neoadjuvant chemoradiation developed multiple side effects, including grade 1–2 dermatitis, grade 4 mucositis, soft tissue infection, neutropenic sepsis, and early cessation of radiation therapy in one patient. Ultimately, the authors argued that despite the complications of induction therapy, there was no delay in surgical resection, performed 8 to 12 weeks after completion of neoadjuvant therapy. Conclusions regarding any potential benefit of the therapies, however, cannot be drawn from the short 24- to 30-month follow-up period.46 Review of published studies thus far indicates neoadjuvant radiation and chemotherapy has inconclusive and unreproducible efficacy.

34.5 Postoperative Adjuvant Treatment The goals of oncologic treatment, especially in the modern era, are to improve rates of curative treatment and disease freedom while minimizing treatment impact and associated complications. This is particularly challenging with aggressive, malignant tumors, such as esthesioneuroblastomas, that are both locally and distally aggressive with a potential for long-delayed recurrences. In an effort to expedite definitive resection and minimize potential side effects, our treatment algorithm consists of upfront definitive resection, with clear margins, when possible, followed by radiation therapy. Chemotherapy is reserved for cases with lymph node involvement, metastatic disease, salvage therapy, or palliation. Neck dissection and radiation are similarly used in the setting of cervical lymph node disease. We highlight two patients who were treated using our aforementioned protocol.

34.5.1 Case Presentations Case 1 A 55-year-old female presented with 7 months of epistaxis from a nasal mass diagnosed as esthesioneuroblastoma on biopsy. MRI revealed a right-sided tumor with involvement of the cribriform plate (▶ Fig. 34.1). The patient underwent complete resection with histologically negative margins and dural resection via an endoscopic endonasal approach for her Kadish C, Hyams grade II, esthesioneuroblastoma. Reconstruction was performed with an autologous fascia lata graft and vascularized nasoseptal flap. Postoperatively, the patient received 54 Gy of radiation treatment, complicated by grade 1 dermatitis, grade 2 mucositis, and mild nasal crusting. She has remained diseaseand symptom-free at the time of her last follow-up, 44 months after surgery (▶ Fig. 34.2).

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Induction Therapy for Esthesioneuroblastoma

Fig. 34.1 (a) Sagittal, (b) axial, and (c) coronal T1-weighted contrasted MRI, respectively, demonstrating a right-sided nasal mass involving the cribriform plate and extending into the frontal sinus.

Fig. 34.2 (a) Axial and (b) coronal T1-weighted contrasted MRI 38 months after surgery without evidence of recurrent or residual tumor.

Case 2 A 61-year-old male, with a several-decade history of chronic sinusitis, presented with a 5-month history of nasal congestion, decreased sense of taste and smell, intermittent yellow nasal drainage, scant epistaxis, left ptosis, and medial periorbital edema. Nasal endoscopy revealed a 7-cm nasal mass, and biopsy demonstrated esthesioneuroblastoma. On imaging, there was a homogeneously enhancing, erosive left skull base lesion with extension into the right nasal cavity, bilateral ethmoid, left maxillary, frontal, and sphenoid sinuses with anterior cranial fossa extension and leptomeningeal enhancement (▶ Fig. 34.3). Two mildly enlarged fludeoxyglucose (FDG)-avid parapharyngeal lymph nodes were also seen on PET-CT. He subsequently underwent a combined level-1 transbasal and endoscopic endonasal approach for complete, margin-free resection, for his Kadish D, Hyams grade III, esthesioneuroblastoma. The skull base was repaired with vascularized pericranium.

This was followed by intensity-modulated radiation therapy (IMRT) with 54 Gy to the tumor bed and 70 Gy to the neck, with two cycles of cisplatin and etoposide concurrently. After completing his therapy, 3.5 months after surgery, he had no radiographic evidence of residual or recurrent disease (▶ Fig. 34.4). PET-CT 6 months after surgery revealed decreased size and activity of the parapharyngeal nodes as well. His postoperative course was, however, complicated by radiation-induced dysphagia, treated with temporary PEG tube placement, and nasal crusting, managed with periodic debridements and antibiotics when indicated. Unfortunately, his course was further complicated by delayed breakdown of his skull base reconstruction with eventual neofrontal sinus development, leading to a frontal epidural collection that ultimately required several revisions, including cranioplasties and a vascularized myofascial flap. His disease-free interval was only 26 months with distant intracranial recurrence requiring salvage concomitant chemotherapy and radiation.

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Fig. 34.3 (a,b) Coronal and (c,d) axial T1weighted contrasted MRI showing large, avidly enhancing skull base mass centered in the left nasal cavity. The lesion abuts and laterally displaces the left orbit and has extensive intracranial invasion with leptomeningeal enhancement but without evidence of cavernous sinus invasion.

34.6 Conclusions The advantages of neoadjuvant radiation and chemotherapy in the treatment of esthesioneuroblastoma have been inconclusive and unreliably reproducible across institutions, such that no definitive conclusions can yet be made regarding the potential benefits of such therapies. Although the addition of induction therapy might benefit a subset of patients, it is heretofore unclear which patients stand to gain from such treatments, and

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which might be harmed either with complications, delayed surgery, or incomplete resections. At this time, the gold standard in the treatment of esthesioneuroblastoma remains an extensive resection, with a goal of surgical cure, and the addition of adjuvant radiation therapy. A randomized trial, controlling for Kadish stage and Hyams grade, comparing morbidity, disease-free interval, and overall survival, between patients who receive neoadjuvant therapy and those who do not, is warranted.

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Fig. 34.4 (a,b) Coronal and (c,d) axial T1weighted contrasted MRI 3.5 months after surgery and concurrent chemoradiation showing extensive resection without evidence of residual or recurrent disease.

References [1] Loy AH, Reibel JF, Read PW, et al. Esthesioneuroblastoma: continued followup of a single institution’s experience. Arch Otolaryngol Head Neck Surg. 2006; 132(2):134–138 [2] Komotar RJ, Starke RM, Raper DMS, Anand VK, Schwartz TH. Endoscopic endonasal compared with anterior craniofacial and combined cranionasal resection of esthesioneuroblastomas. World Neurosurg. 2013; 80(1–2):148– 159 [3] Devaiah AK, Andreoli MT. Treatment of esthesioneuroblastoma: a 16-year meta-analysis of 361 patients. Laryngoscope. 2009; 119(7):1412–1416 [4] Song CM, Won TB, Lee CH, Kim DY, Rhee CS. Treatment modalities and outcomes of olfactory neuroblastoma. Laryngoscope. 2012; 122(11):2389–2395 [5] Berger L, Luc R, Richard D. L’esthesioneuroepitheliome olfactif. Bull Assoc Fr Etud Cancer. 1924; 13:410–421 [6] Tajudeen BA, Arshi A, Suh JD, et al. Esthesioneuroblastoma: an update on the UCLA experience, 2002–2013. J Neurol Surg B Skull Base. 2015; 76(1):43–49 [7] Herr MW, Sethi RK, Meier JC, et al. Esthesioneuroblastoma: an update on the massachusetts eye and ear infirmary and massachusetts general hospital experience with craniofacial resection, proton beam radiation, and chemotherapy. J Neurol Surg B Skull Base. 2014; 75(1):58–64 [8] Folbe A, Herzallah I, Duvvuri U, et al. Endoscopic endonasal resection of esthesioneuroblastoma: a multicenter study. Am J Rhinol Allergy. 2009; 23 (1):91–94

[9] Polin RS, Sheehan JP, Chenelle AG, et al. The role of preoperative adjuvant treatment in the management of esthesioneuroblastoma: the University of Virginia experience. Neurosurgery. 1998; 42(5):1029–1037 [10] Zafereo ME, Fakhri S, Prayson R, et al. Esthesioneuroblastoma: 25-year experience at a single institution. Otolaryngol Head Neck Surg. 2008; 138(4):452– 458 [11] Hollen TR, Morris CG, Kirwan JM, Amdur RJ, Werning JW, Vaysberg MW. Esthesioneuroblastoma of the nasal cavity. Vestn Otorinolaringol. 2015; 38:84 [12] Levine PA, McLean WC, Cantrell RW. Esthesioneuroblastoma: the University of Virginia experience 1960–1985. Laryngoscope. 1986; 96(7):742–746 [13] McLean JN, Nunley SR, Klass C, Moore C, Müller S, Johnstone PA. Combined modality therapy of esthesioneuroblastoma. Otolaryngol Head Neck Surg. 2007; 136(6):998–1002 [14] Miyamoto RC, Gleich LL, Biddinger PW, Gluckman JL. Esthesioneuroblastoma and sinonasal undifferentiated carcinoma: impact of histological grading and clinical staging on survival and prognosis. Laryngoscope. 2000; 110(8):1262– 1265 [15] Gruber G, Laedrach K, Baumert B, Caversaccio M, Raveh J, Greiner R. Esthesioneuroblastoma: irradiation alone and surgery alone are not enough. Int J Radiat Oncol Biol Phys. 2002; 54(2):486–491 [16] Liu JK, O’Neill B, Orlandi RR, Moscatello AL, Jensen RL, Couldwell WT. Endoscopic-assisted craniofacial resection of esthesioneuroblastoma: minimizing facial incisions–technical note and report of 3 cases. Minim Invasive Neurosurg. 2003; 46(5):310–315

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Sinonasal Malignancies [17] Ferlito A, Rinaldo A, Rhys-Evans PH. Contemporary clinical commentary: esthesioneuroblastoma: an update on management of the neck. Laryngoscope. 2003; 113(11):1935–1938 [18] Foote RL, Morita A, Ebersold MJ, et al. Esthesioneuroblastoma: the role of adjuvant radiation therapy. Int J Radiat Oncol Biol Phys. 1993; 27(4):835–842 [19] Monroe AT, Hinerman RW, Amdur RJ, Morris CG, Mendenhall WM. Radiation therapy for esthesioneuroblastoma: rationale for elective neck irradiation. Head Neck. 2003; 25(7):529–534 [20] Dulguerov P, Allal AS, Calcaterra TC. Esthesioneuroblastoma: a meta-analysis and review. Lancet Oncol. 2001; 2(11):683–690 [21] Levine PA, Gallagher R, Cantrell RW. Esthesioneuroblastoma: reflections of a 21-year experience. Laryngoscope. 1999; 109(10):1539–1543 [22] Resto VA, Eisele DW, Forastiere A, Zahurak M, Lee DJ, Westra WH. Esthesioneuroblastoma: the Johns Hopkins experience. Head Neck. 2000; 22(6):550– 558 [23] Eich HT, Müller RP, Micke O, Kocher M, Berthold F, Hero B. Esthesioneuroblastoma in childhood and adolescence. Better prognosis with multimodal treatment? Strahlenther Onkol. 2005; 181(6):378–384 [24] Manthuruthil C, Lewis J, McLean C, Batra PS, Barnett SL. Endoscopic endonasal management of olfactory neuroblastoma: a retrospective analysis of 10 patients with quality of life measures. World Neurosurg. 2016; 90:1–5 [25] Koka VN, Julieron M, Bourhis J, et al. Aesthesioneuroblastoma. J Laryngol Otol. 1998; 112(7):628–633 [26] Petruzzelli GJ, Howell JB, Pederson A, et al. Multidisciplinary treatment of olfactory neuroblastoma: Patterns of failure and management of recurrence. Am J Otolaryngol. 2015; 36(4):547–553 [27] Kadish S, Goodman M, Wang CC. Olfactory neuroblastoma. A clinical analysis of 17 cases. Cancer. 1976; 37(3):1571–1576 [28] Jethanamest D, Morris LG, Sikora AG, Kutler DI. Esthesioneuroblastoma: a population-based analysis of survival and prognostic factors. Arch Otolaryngol Head Neck Surg. 2007; 133(3):276–280 [29] Eriksen JG, Bastholt L, Krogdahl AS, Hansen O, Joergensen KE. Esthesioneuroblastoma–what is the optimal treatment? Acta Oncol. 2000; 39(2):231–235 [30] Biller HF, Lawson W, Sachdev VP, Som P. Esthesioneuroblastoma: surgical treatment without radiation. Laryngoscope. 1990; 100(11):1199–1201 [31] Dulguerov P, Calcaterra T. Esthesioneuroblastoma: the UCLA experience 1970–1990. Laryngoscope. 1992; 102(8):843–849 [32] Bell D, Saade R, Roberts D, et al. Prognostic utility of Hyams histological grading and Kadish-Morita staging systems for esthesioneuroblastoma outcomes. Head Neck Pathol. 2015; 9(1):51–59

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[33] Hyams V. Olfactory neuroblastoma (Case 6). In: Batsakis J, Hyams V, Morales A, eds. Special Tumors of the Head and Neck. Chicago, IL: ASCP Press; 1982:24–29 [34] Patel SG, Singh B, Polluri A, et al. Craniofacial surgery for malignant skull base tumors: report of an international collaborative study. Cancer. 2003; 98(6): 1179–1187 [35] Yuen APW, Fan YW, Fung CF, Hung KN. Endoscopic-assisted cranionasal resection of olfactory neuroblastoma. Head Neck. 2005; 27(6):488–493 [36] Batra PS, Citardi MJ, Worley S, Lee J, Lanza DC. Resection of anterior skull base tumors: comparison of combined traditional and endoscopic techniques. Am J Rhinol. 2005; 19(5):521–528 [37] Nichols AC, Chan AW, Curry WT, Barker FG, II, Deschler DG, Lin DT. Esthesioneuroblastoma: the massachusetts eye and ear infirmary and massachusetts general hospital experience with craniofacial resection, proton beam radiation, and chemotherapy. Skull Base. 2008; 18(5):327–337 [38] Goldsweig HG, Sundaresan N. Chemotherapy of recurrent esthesioneuroblastoma. Case report and review of the literature. Am J Clin Oncol. 1990; 13(2): 139–143 [39] McElroy EA, Jr, Buckner JC, Lewis JE. Chemotherapy for advanced esthesioneuroblastoma: the Mayo Clinic experience. Neurosurgery. 1998; 42(5): 1023–1027, discussion 1027–1028 [40] Dias FL, Sá GM, Kligerman J, et al. Complications of anterior craniofacial resection. Head Neck. 1999; 21(1):12–20 [41] Kim HJ, Kim CH, Lee BJ, et al. Surgical treatment versus concurrent chemoradiotherapy as an initial treatment modality in advanced olfactory neuroblastoma. Auris Nasus Larynx. 2007; 34(4):493–498 [42] Constantinidis J, Steinhart H, Koch M, et al. Olfactory neuroblastoma: the University of Erlangen-Nuremberg experience 1975–2000. Otolaryngol Head Neck Surg. 2004; 130(5):567–574 [43] Kim DW, Jo YH, Kim JH, et al. Neoadjuvant etoposide, ifosfamide, and cisplatin for the treatment of olfactory neuroblastoma. Cancer. 2004; 101(10):2257–2260 [44] Modesto A, Blanchard P, Tao YG, et al. Multimodal treatment and long-term outcome of patients with esthesioneuroblastoma. Oral Oncol. 2013; 49(8): 830–834 [45] Broich G, Pagliari A, Ottaviani F. Esthesioneuroblastoma: a general review of the cases published since the discovery of the tumour in 1924. Anticancer Res. 1997; 17 4A:2683–2706 [46] Sohrabi S, Drabick JJ, Crist H, Goldenberg D, Sheehan JM, Mackley HB. Neoadjuvant concurrent chemoradiation for advanced esthesioneuroblastoma: a case series and review of the literature. J Clin Oncol. 2011; 29(13):e358–e361

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Surgical Approach for Esthesioneuroblastoma: Controversy in Approach Selection

35 Surgical Approach for Esthesioneuroblastoma: Controversy in Approach Selection Jamie J. Van Gompel and Jeffrey Janus Abstract Typically, the rarer a lesion is, the more controversy surrounds its management. There are several reasons for this. Firstly, no large series exist to give us accurate clinical data on management. Secondly, there is a plethora of institutional competition for these rare and interesting cases. Lastly, heterogeneity at presentation prevents one from accurately assessing the available literature. All the aforementioned certainly apply to esthesioneuroblastoma (ENB). This chapter attempts to provide an outline of the current controversies in ENB management; however, one must look no further than variability in disease presentation and in the definitions surrounding the tumor to find controversy. Here, we present our thoughts in the light of current literature. Keywords: esthesioneuroblastoma, olfactory neuroblastoma, skull base

35.1 Introduction Esthesioneuroblastoma (ENB)1 is a very uncommon skull base tumor that goes by a variety of names, including olfactory neuroblastoma, olfactory esthesioneuroblastoma, esthesioneurocytoma, and olfactory placode tumor. The World Health Organization (WHO) recently suggested that olfactory neuroblastoma should supplant the term esthesioneuroblastoma; however, the latter is still more frequently used than the former, so the transition continues. ENBs are rare nasal neoplasms with an incidence of 0.4 per 1,000,000 people.2 These masses represent 3% of intranasal malignant neoplasms, and because of their rarity and infrequent encounters clinically, the treatment paradigms vary considerably from institution to institution, and furthermore from country to country. Thus, a multitude of ways exists to manage these tumors. As stated by Biller et al,3 “There is no reason to believe that the biologic behavior of this tumor is different from other related neurogenic neoplasms; therefore, the observed high incidence of local recurrence is directly related to inadequate resection margins.” Therefore, the controversy regarding this tumor really is not endoscopic versus open surgery for ENB; however, the controversy exists in the surgical thought process and ability of the individuals involved in treating these lesions. While some are able to achieve a margin-negative resection in a facile manner with endoscopic surgical acumen, some are not. Transparency of margin status and frequent, methodical sampling is paramount; anything less is a disservice to the patient. Thus, while the promise of a nonoperative solution for these complex tumors is still on the horizon, the core oncologic principle of a margin-negative resection is resolute with ENB, so long as the surgery to remove such a lesion falls within a reasonable complication profile. In this current chapter, we

attempt to expose current controversies in ENB management that do not compromise this core principle. Many prognostic criteria have been established for olfactory neuroblastomas; however, Kadish staging4 (and more recently modified Kadish staging)5 (▶ Table 35.1) has continued to be important in prognostication. Modified Kadish staging effectively represents a graded system of progressive skull base involvement. Kadish A represents tumors involving only the nasal cavity, whereas Kadish B tumors involve the paranasal sinuses. Kadish C tumors extend either into the orbit or subfrontally through the subfrontal dura into the olfactory bulbs. The modification system by Morita et al from the Mayo Clinic includes metastatic tumor to either regional lymph nodes or distant disease, and is labelled Kadish D.5 This staging system appears to correlate well with overall survival as advanced locoregional disease and lymph node involvement correlates with poorer outcome.6 There are three current staging systems, namely the modified Kadish system, the Biller et al system, and the Dulguerov and Calcaterra system, the latter two incorporating TNM classification which is currently not as widely used as Kadish staging (▶ Table 35.1).3,10 In addition to the correlation of advanced stage to survival, other clinical and histopathologic correlatives have been realized. Age greater than 65 years at diagnosis further decreases overall survival.7 Kane et al as well as Van Gompel et al have reported high Hyams grade pathology certainly correlates with a poor prognosis.8,9 The first and perhaps largest controversy regarding ENB is the initial management. Many institutions follow a treatment strategy in which, after a biopsy confirms the diagnosis, upfront chemotherapy and radiation (neoadjuvant) are administered to sterilize the surgical field, reduce the size of the potential resection, or improve the disease resectability.11,12,13 Although this strategy appears to have good overall disease control, all patients regardless of pathology or extent of disease are exposed to aggressive chemotherapy and radiation when in fact this may not be necessary in some. Our preference has been an upfront surgical strategy that assesses disease grade and extent Table 35.1 Kadish staging Modified Kadish (Morita et al)

Biller et al

Dulguerov and Calcaterra

A: Confined to nasal cavity

T1: Nasal/paranasal sinuses

T1: Nasal/paranasal sinuses

B: Extends to paranasal sinus

T2: Periorbital/ anterior fossa extension

T2: Erosion of cribriform plate

C: Local extension beyond sinus

T3: Brain involvement, resectable margins

T3: Periorbital/ anterior fossa extension

D: Distant metastasis

T4: Unable to obtain negative margins; unresectable

T4: Brain involvement

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Fig. 35.1 Treatment algorithm.

of disease at presentation.9 Our treatment algorithm is summarized in ▶ Fig. 35.1. Upon presentation, typically an intranasal biopsy is performed once a nasal obstructive mass or mass associated with epistaxis in the nasal cavity is encountered. This typically confirms the diagnosis. Subsequently, a decision is to be made whether the mass is resectable or not. If the tumor is resectable, our strategy then goes onto an endoscopic approach which typically encompasses most Kadish A and B disease and some Kadish C disease. However, if it is believed that the margins may be compromised, or if we do not have the ability to get negative margins, we perform an open craniofacial resection with endoscopic assistance, which does constitute a fair amount of Kadish C patients. If a patient does not have resectable disease upon presentation, we then initiate preoperative neoadjuvant treatment, which typically consists of platinum-based therapies utilized as induction therapy. If there is a response to neoadjuvant therapy and there is a possibility for margin-negative resection, then the patient goes on to surgery. If there is no response, they are not typically offered surgery. In patients that have a lower grade tumor (Hyams grade 1 or 2) and the margins are negative on final pathology, we give them the option of pursuing radiation or alternatively being observed. In patients that are observed, we typically see a higher frequency of recurrence despite the lower Hyams grade and margin-negative status. However, the recurrences are typically manageable and salvage therapies are effective in these patients. The patients that have positive margins or Hyams grade 3 or 4 are immediately treated with radiation in all cases, and chemotherapy in select cases after the skull base heals. Typically, this occurs between 4 and 8 weeks after the operation. In cases where regional disease is observed on initial presentation with positive cervical nodes present on exam, neck dissection concomitant with primary tumor resection and then subsequent neck irradiation are offered.

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Radiation paradigms for these tumors include intensitymodulated therapies in which a patient that has negative margins at the time of surgery with a completely resected lesion will receive 55.8 Gy of IMRT (intensity-modulated radiation therapy) over 6 to 6.5 weeks. Patients with positive margins receive 63 to 70 Gy over 7 to 8 weeks. This is administered in a dose per fraction allowing less than 200 cGy to the retina, optic nerve margin, and brainstem. In patients with cervical node involvement, the dissected side typically receives 60 Gy and the nondissected side 54 Gy. Gamma Knife boost radiation therapy was used for a period of time; however, this did not show efficacy and is typically not done currently for adjuvant therapy. Gamma Knife does have a role in the treatment of local recurrence, for which it is administered in doses of 12 to 15 Gy.14,15 As stated previously, our surgical approach is predicated on the ability to achieve wide safe surgical margins and does not favor an endoscopic versus an open approach. In addition, we believe that open dural repair is reassuring for larger tumors, particularly those involving the upper posterior inner table of the frontal sinus, as well as those involving the dura over the top of the orbit and/or optic nerves. One unanswered question currently is the position of the frontal lobes after endoscopic resection when compared to an open resection, and the impact of radiation on these structures. After a purely endoscopic approach, the repair results in prolapse and compression of the gyrus rectus on the repair, classically resulting in low-lying frontal lobes. Conversely, in an open craniofacial resection, during which the frontal lobes are contracted, a phenomenon of “shortening” of the cranial fossa is observed where the frontal lobes appear lifted upward from the fovea ethmoidalis. Interestingly, this may in fact bring the frontal lobes out of the radiation field as opposed to cases with endoscopic repair in which the frontal lobes typically push down or even herniate beyond their natural position into the location of the olfactory bulbs. This

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Surgical Approach for Esthesioneuroblastoma: Controversy in Approach Selection may in fact have some long-term disadvantage in patients that receive radiation after endoscopic skull base surgery, potentially contributing to mild cognitive dysfunction. However, alternatively this may reduce local recurrence. When evaluating the literature on ENB, it is critical to carefully review the patient inclusion and exclusion criteria, as it is surprising to find the distinct variances between institutions. For instance, some institutions distinctly exclude Kadish D patients from surgical outcome studies stating that these tumors are incurable. Furthermore, other tertiary institutions have historically excluded Hyams grade 4 lesions, stating it is too difficult to distinguish these reliably from sinonasal undifferentiated carcinoma (SNUC). Although controversy regarding this histopathological conundrum exists, the ability to reliably distinguish these two tumors exists and thus they should be included in surgical outcome studies. That said, older studies are fraught with mixed populations of high grade Hyams lesions, SNUC, and patients presenting with metastatic disease that were improperly screened. Beyond this, as we go forward with molecular medical classification of these tumors, it will become more confusing. For example, INI-1-deficient lesions carry a particularly poor diagnosis and are not predictable by pathology and these series will never incorporate their presence molecularly. It is also critical to understand that reported endoscopic series typically have a preponderance of smaller tumors with lower Kadish staging. Comparing these smaller tumors with better prognosis to larger ones with a selection bias for open approach and a poor prognosis is not equivocal. It is critical to understand that there may be differences with these minimally invasive approaches in terms of what is currently reported.

35.2 Upfront Neoadjuvant Therapy Compared to Postoperative Selective Therapy In a chapter on controversies in ENB treatment, it is appropriate to discuss the pros and cons of neoadjuvant therapy versus surgical resection as an initial treatment strategy. One disadvantage of neoadjuvant therapy is the perceived higher risk of wound healing when the following surgery is coupled with postoperative radiation. Additionally, neoadjuvant therapy may mislead the pathologic margins of the tumor as it sterilizes the tumor margin. Furthermore, it may affect ultimately the final pathologic Hyams grade of the tumor by causing more necrosis and confusing the pathology with treatment effect. In our experience, we believe if radiation and chemotherapy are selectively given to patients based on margin status and pathologic grading, a certain proportion of patients who would have received neoadjuvant radiation and chemotherapy are sometimes spared radiation and often spared chemotherapy. Patients who receive neoadjuvant therapy, especially with larger tumors, and are unfortunate enough to develop induced multisystem organ failure from the chemotherapy may be precluded from a surgical option secondary to health. It is important to realize that neoadjuvant therapy certainly influences the number of patients making it to surgery and can worsen the health of patients to the point of precluding them from

surgery. The advantages of upfront neoadjuvant therapy, however, include the potential reduced risk of operative seeding to the nasal cavity, which can be important in these types of tumors since en-bloc resection cannot typically be performed. It also may improve margin resectability. However, again there is question as to whether or not negative margins are able to be accurately assessed on a histopathologic level in patients with preoperative neoadjuvant therapy.

35.3 Salvage Therapy Recurrence is a common problem, even after a satisfactory surgical resection of ENB. In roughly half of those patients experiencing recurrence, disease will arise as local recurrence at the margins of the resection or intracranially. If this recurrence is surgically operable with the minimal risk, we recommend initial upfront reoperation followed by radiation therapy if radiation has not been given after the initial resection. An additional effective therapy, which we have reported previously, is stereotactic irradiation, if the lesion is amenable. This appears to be extremely effective at controlling disease.14,15 In patients with regional recurrence in the lymph nodes, we perform select neck dissection followed by neck irradiation, with a slightly higher dose to the diseased side, as stated previously. In patients with distant metastasis, obviously chemotherapy is the first line of treatment in these patients with a plethora of agents reported. When comparing surgical modalities such as an endoscopic approach, an open craniofacial approach, or a combined endoscopic-assisted craniofacial approach, what becomes increasingly clear is that surgeon comfort with each approach, accomplishment of the operative goals, and achieving a margin-negative resection will yield the best results. There have been three reports relevant to this subject currently in the literature. Initial meta-analysis performed by Komotar et al included studies from 1985 to 2010 that categorized resections by craniofacial (open, n = 318 patients), cranionasal (combined, n = 33), or endoscopic (n = 102) approach.16 In this study, the authors reported a much higher percentage of the patients in the open group were higher Kadish stage, which is a major contributor to recurrence, as stated previously. The authors also reported a higher rate of prior surgery in the open group, as well as a higher rate of perioperative radiation therapy in the endoscopic group, which has also been shown to reduce recurrence.16,17 In the end, this study concluded that the study populations are too different to understand with a meta-analysis; however, it is presumed that in cases that can be done with any technique, the technique of resection likely plays little role in long-term outcome, but may impact overall quality of life.16 We agree with this statement. The major drawback of this study was that no follow-up was reported and we can presume it to be shorter for the endoscopic group, thereby building in some intrinsic bias toward survival with less follow-up. Another study with a similar data set and patients by Fu et al reported a total of 486 patients with open procedures and 123 patients with endoscopic procedures, with a mean follow-up of 67.8 months in the open group and 52.4 months in the endoscopic.18 This study concluded that there was an improved outcome in overall survival for Hyams grade 3/4 and for Kadish C disease for those undergoing endoscopic procedures, but obviously there is a large bias in recurrence for a group (endoscopic) that

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Sinonasal Malignancies at 52.4 months has nearly 18 months less follow-up than the average time to recurrence (52–68 months).18 Harvey et al reported a retrospective six-center study comparing endoscopic to open approaches in 109 patients.19 They reported that staged matched survival was better in their endoscopic group; however, the experience of the endoscopic surgeons in that group may have outweighed those performing the open approaches.19 The conclusions drawn from their study again is that marginnegative resection is most essential as they were more frequently able to achieve a margin-negative resection endoscopically.19 This likely has to do with selection bias of open approaches used for tumors in which margin-negative resection may not be possible, but none the less demonstrate there is likely no worse outcome with endoscopic approaches when all things are equal, with the potential of life gains.19

35.4 Conclusions In the end, in our practice, when an endoscopic approach can be performed we choose to do it, as the chance of a cranial infection and the need for an additional incision are unnecessary and probably do worsen the patient’s quality of life. Further, with a pure endoscopic approach, there is an opportunity to potentially preserve smell. The axiom of performing whatever approach necessary to achieve negative margins has translated to many tumors being managed endonasally, avoiding a craniotomy except for select cases where extent of disease or challenging access dictates use.

References [1] Berger L, Luc G, Richard D. L’Esthesioneuroepitheliome Olfactif. Bull Assoc Fr Etud Cancer. 1924; 13:410–421 [2] Theilgaard SA, Buchwald C, Ingeholm P, Kornum Larsen S, Eriksen JG, Sand Hansen H. Esthesioneuroblastoma: a Danish demographic study of 40 patients registered between 1978 and 2000. Acta Otolaryngol. 2003; 123(3): 433–439

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[3] Biller HF, Lawson W, Sachdev VP, Som P. Esthesioneuroblastoma: surgical treatment without radiation. Laryngoscope. 1990; 100(11):1199–1201 [4] Kadish S, Goodman M, Wang CC. Olfactory neuroblastoma. A clinical analysis of 17 cases. Cancer. 1976; 37(3):1571–1576 [5] Morita A, Ebersold MJ, Olsen KD, Foote RL, Lewis JE, Quast LM. Esthesioneuroblastoma: prognosis and management. Neurosurgery. 1993; 32(5):706–714, discussion 714–715 [6] Dias FL, Sa GM, Lima RA, et al. Patterns of failure and outcome in esthesioneuroblastoma. Arch Otolaryngol Head Neck Surg. 2003; 129(11):1186–1192 [7] Dulguerov P, Allal AS, Calcaterra TC. Esthesioneuroblastoma: a meta-analysis and review. Lancet Oncol. 2001; 2(11):683–690 [8] Kane AJ, Sughrue ME, Rutkowski MJ, et al. Posttreatment prognosis of patients with esthesioneuroblastoma. J Neurosurg. 2010; 113(2):340–351 [9] Van Gompel JJ, Giannini C, Olsen KD, et al. Long-term outcome of esthesioneuroblastoma: hyams grade predicts patient survival. J Neurol Surg B Skull Base. 2012; 73(5):331–336 [10] Dulguerov P, Calcaterra T. Esthesioneuroblastoma: the UCLA experience 1970–1990. Laryngoscope. 1992; 102(8):843–849 [11] Levine PA, Debo RF, Meredith SD, Jane JA, Constable WC, Cantrell RW. Craniofacial resection at the University of Virginia (1976–1992): survival analysis. Head Neck. 1994; 16(6):574–577 [12] Levine PA, Gallagher R, Cantrell RW. Esthesioneuroblastoma: reflections of a 21-year experience. Laryngoscope. 1999; 109(10):1539–1543 [13] Levine PA, McLean WC, Cantrell RW. Esthesioneuroblastoma: the University of Virginia experience 1960–1985. Laryngoscope. 1986; 96(7):742–746 [14] Van Gompel JJ, Carlson ML, Pollock BE, Moore EJ, Foote RL, Link MJ. Stereotactic radiosurgical salvage treatment for locally recurrent esthesioneuroblastoma. Neurosurgery. 2013; 72(3):332–339, discussion 339–340 [15] Van Gompel JJ, Link MJ, Sheehan JP, et al. Radiosurgery is an effective treatment for recurrent esthesioneuroblastoma: a multicenter study. J Neurol Surg B Skull Base. 2014; 75(6):409–414 [16] Komotar RJ, Starke RM, Raper DM, Anand VK, Schwartz TH. Endoscopic endonasal compared with anterior craniofacial and combined cranionasal resection of esthesioneuroblastomas. World Neurosurg. 2013; 80(1)(–)(2): 148–159 [17] Ow TJ, Hanna EY, Roberts DB, et al. Optimization of long-term outcomes for patients with esthesioneuroblastoma. Head Neck. 2014; 36(4):524–530 [18] Fu TS, Monteiro E, Muhanna N, Goldstein DP, de Almeida JR. Comparison of outcomes for open versus endoscopic approaches for olfactory neuroblastoma: a systematic review and individual participant data meta-analysis. Head Neck. 2016; 38 Suppl 1:E2306–E2316 [19] Harvey RJ, Nalavenkata S, Sacks R, et al. Survival outcomes for stage-matched endoscopic and open resection of olfactory neuroblastoma. Head Neck. 2017; 39(12):2425–2432

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What Is the Role of Surgery for Adenoid Cystic Carcinoma?

36 What Is the Role of Surgery for Adenoid Cystic Carcinoma? David William Hsu, Marvin Bergsneider, and Marilene B. Wang Abstract Adenoid cystic carcinoma (ACC) is an aggressive salivary gland malignancy found in the head and neck with an unpredictable clinical course. ACC is locally invasive and has a high propensity for perineural invasion and can involve the cranial base. Clinical characteristics may entail an indolent growth rate, but a relentless course featuring multiple local recurrences and distant, delayed metastases, most notably involving the lung, liver, and bone. Once detected in the sinonasal cavity and along the skull base, these tumors can progress to cause soft-tissue involvement, bone destruction, skull base invasion, or cranial nerve dysfunction, and thus worsening prognosis. Current literature focuses on primary surgery and adjuvant radiation therapy management. For ACC involving the skull base, this therapeutic approach is thought to be best for patient’s care. Surgical management involving the skull base relies on balancing maximal resection with minimal morbidity. Current, 5-year survival rates range between 64 and 91% and 10-year survival rates range between 37 and 65%. Furthermore, local recurrences are quoted to be between 12 and 40%. Higher tumor stage and skull base involvement have been linked to shorter disease-free survival. Local recurrences often involve the cranial base, as negative margins are difficult to achieve given the proximity to critical neural and vascular structures. Thus, it is important to discuss the role of surgery in the management of ACC involving the skull base and the efficacy of the current approach on outcomes. Keywords: adenoid cystic carcinoma, paranasal sinus, skull base surgery, perineural invasion, endonasal approach

36.1 Introduction Adenoid cystic carcinoma (ACC) is an aggressive salivary gland malignancy found in the head and neck with an unpredictable clinical course.1 ACC can arise in both major and minor salivary glands and can be located in the tongue, trachea, palate, larynx, and most notably for its potential for skull base involvement, the paranasal sinuses.2 ACC is locally invasive and has a high propensity for perineural invasion (PNI), such as trigeminal branches if involving the cranial base. Clinical characteristics may entail an indolent growth rate, but a relentless course featuring multiple local recurrences and distant, delayed metastases, most notably involving the lung, liver, and bone.2 In the literature, 5-year survival rates range between 64 and 91% and 10-year survival rates range between 37 and 65%.3 Furthermore, local recurrences are quoted to be between 12 and 40%, and distant metastases, which are thought to be the primary cause of reduced survival, occur in 20 to 64% of cases.3 Thus, ACC is very difficult to manage due to its indolent, unpredictable course and associated poor long-term survival.

Like many sinonasal malignancies, ACC of the paranasal sinuses can remain undetected for long periods of time with minimal symptoms.4 Once detected, these tumors can progress to cause soft-tissue involvement, bone destruction, skull base invasion, or cranial nerve dysfunction, and thus worsening prognosis.5 Management of ACC of the head and neck has been extensively studied, but remains unclear and still requires more analysis.2 Current literature focuses on primary surgery and adjuvant radiation therapy management.2 For ACC involving the skull base, this therapeutic approach is thought to be best for patient care.6 While ACC is considered to be radiosensitive, the literature has shown that radiation alone is not effective.7 Thus, although surgery is believed to be crucial in its management, more has to be elucidated due to the unpredictable clinical course and difficulty in obtaining clear margins. Furthermore, the relative scarcity of ACC involving the skull base makes analysis of case series challenging. Surgical management involving the skull base relies on balancing maximal resection with minimal morbidity.4 Higher tumor stage and skull base involvement have been linked to shorter disease-free survival (DFS).3 Local recurrences often involve the cranial base, as negative margins are difficult to achieve given the proximity to critical neural and vascular structures. Here, we discuss the role of surgery in the management of ACC involving the skull base and the efficacy of the current approach on outcomes.

36.2 Literature Review The current literature evaluating surgical management and outcomes of ACC with skull base involvement is mainly composed of level III evidence at best (▶ Table 36.1). Table 36.1 Summary of literature Authors

Year

Title

Level of evidence

Pitman et al8

1998

The role of skull base surgery for the treatment of adenoid cystic carcinoma of the sinonasal tract

IV

Ramakrishna et al9

2016

Adenoid cystic carcinoma of the skull base: results with an aggressive multidisciplinary approach

III

Lupinetti et al6

2007

Sinonasal adenoid cystic carcinoma: The M.D. Anderson Cancer Center experience

III

Amit et al10

2013

Adenoid cystic carcinoma of the nasal cavity and paranasal sinuses: a meta-analysis

III

Unsal et al12

2017

Sinonasal adenoid cystic carcinoma: a populationbased analysis of 694 cases

III

225

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Sinonasal Malignancies Pitman et al performed an early study from Pittsburgh on the outcomes of ACC involving the skull base.8 They performed a retrospective review of 35 patients undergoing surgery and radiation for T34 tumors with a median follow-up of 48 months. Orbital invasion was seen in 37% of patients, and intracranial involvement was seen in 34% of patients. Overall, 46% of patients had positive margins after surgery. For patients who required skull base surgery, the DFS was 41% at 3 years with a local recurrence rate of 36%. The status of surgical margins, the presence of PNI, the presence of orbital invasion, and the site of the primary tumor and the histologic grade of the tumor demonstrated no statistically significant correlation with recurrence, metastases, or survival. Lastly, DFS rate was 6% in patients who required salvage surgery after adequate initial treatment. In this early study, Pitman el al concluded that skull base surgery helps with excision of advanced stage lesions, but its effect on survival is limited given the high local recurrence rate.8 Furthermore, they concluded that the extent of resection must take into consideration the potential morbidity when the tumor involves vital surrounding neurovascular structures. Describing the MD Anderson Cancer Center experience through a retrospective review, Ramakrishna et al evaluated the overall survival (OS) and progression-free survival (PFS) in 51 patients with ACC involving the skull base with a mean follow-up of 8.2 years.9 They utilized an aggressive multidisciplinary approach of primary surgery and adjuvant radiotherapy. Their surgical strategy was mostly open craniofacial approaches due to advanced T stage, and maximal resection until negative margins were achieved or until the risk of neurological complications became high. Eighty percent of their patients presented with a T4b stage, and 46% presented with cavernous sinus involvement. Furthermore, they examined subsites of primary orbit, primary anterior cranial base/sinonasal cavity, and primary maxillary/infratemporal/pterygopalatine fossa. The OS was 15.6 years, with a 5- and 10-year OS rate of 78 and 50%, respectively.9 The PFS was 7.3 years with a 5- and 10year PFS rate of 46.7 and 21%, respectively. Gross total resection was obtained in 75% of patients, and 49% had microscopically negative margin at the first operation. They described a 2- and 5-year local control rate of 86 and 82%, respectively. In both univariate and multivariate analysis, achievement of microscopic negative margins showed a significant OS advantage in both primary operations and reoperations for recurrence.9 However, negative margins did not affect PFS, which they attributed to variability of disease progression. PNI showed a statistically significant OS disadvantage of 10 years and PFS of 4 years. Adjuvant radiation provided significant advantage in OS and PFS for initial management, whereas adjuvant chemotherapy at any stage and radiation in the setting of recurrence did not. Finally, adjuvant radiation alone showed an OS disadvantage of 10 years. Focusing on skull base involvement, they evaluated the variables of cavernous sinus invasion and tumor primary site. They showed that these two variables did not significantly affect OS and thus concluded that a maximal resection strategy should be applied regardless of tumor location. They did not analyze any other skull base involvement variables. Overall, Ramakrishna et al concluded that primary surgery with adjuvant radiation increases OS and PFS and that PNI and

226

positive margins serve as negative prognostic factors.9 They describe an improved OS of ACC of the skull base when compared to previously published literature (OS range of 4–8 years). Lastly, they attribute the improvements in oncologic outcomes to improved multidisciplinary surgical strategies and more effective adjuvant therapy. Ramakrishna et al built upon the findings of the MD Anderson Cancer Center experience described by Lupinetti et al in 2007.6 In the retrospective chart review of 105 patients with sinonasal ACC over a 14-year period, Lupinetti et al found that surgical resection with adjuvant radiation therapy offered overall local control with a 5-year OS and disease-specific survival (DSS) rate of 62.9 and 70.9%, respectively.6 The overall recurrence rate was 56.3% with a local recurrence rate of 30.5%. In their cohort, 65% of patients presented with T4 disease, with 27.6% of cases with tumor extending to the skull base and 23.8% invading the skull base. Analysis of variables that affect survival showed that tumors of the sphenoid, skull base invasion, advanced T stage, and histological solid type decreased OS. For management, they showed that surgery with adjuvant radiation provided a statistically significant advantage compared to surgery alone, radiation alone, and chemotherapy, based on their Kaplan–Meier survival analysis.6 Amit et al performed a meta-analysis looking at paranasal and nasal cavity ACC to identify variables that affect survival outcomes.10 They identified 15 studies, comprising 520 patients (99 from an ACC international study group) with a median follow-up of 60 months. There was heterogeneity among the studies, but they showed that 78% of patients in their study presented with advanced stage (III–IV) based on studies that provided demographics. Lastly, in studies that described skull base involvement, they noted skull base invasion in 51.8% of patients (83 of 160 patients).10 The overall 5-year OS and DSS in the meta-analysis were 62 and 67%, respectively, with a local recurrence rate of 36.6%.10 The DFS at 5 years was 43% overall and 53% in the international cohort. As for variables that affected survival, they showed a significant difference in OS and DSS based on tumor site: ethmoid or sphenoid sinus involvement leads to a low DSS of 25%. Overall, PNI did not significantly affect OS or DSS, but led to a lower DFS. Positive margins, on the other hand, negatively affected survival. They also showed no difference in OS and DSS in patients with skull base invasion. Further multivariate analysis of only the international group showed that intraorbital invasion, dural invasion, and cavernous sinus invasion had no significant difference in OS and DSS.10 Interestingly, Amit et al noted that there was no significant difference in 5-year OS when comparing surgery alone versus surgery followed by adjuvant radiotherapy versus primary chemoradiation.10 In their discussion, while they alluded to studies describing the benefits of local control with surgery and adjuvant radiation,11 they called for more prospective studies to verify the management paradigm for paranasal ACC. Unsal et al performed a retrospective population-based study based on the Surveillance, Epidemiology and End Results (SEER) database over a 40-year period and identified 694 cases of sinonasal ACC.12 Overall, the 5-, 10-, and 20-year DSS rates were 66.5, 41.1, and 17.6%, respectively. 50.8% of cases involved T4 tumors.

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What Is the Role of Surgery for Adenoid Cystic Carcinoma? When analyzing DSS based different variables, T stage showed no statistically significant results. The rates, however, were stark for T4 tumors, with 58% DSS at 5 years and 3.0% at 10 years.12 The variable that significantly affected DSS was the presence of distant metastasis, with a 44.5% decrease in DSS at 5 years. The study also examined 5-, 10-, and 15-year OS based on location. Notably, the OS of ACC involving the frontal sinus was 25% at 5 years, 25% at 10 years, and 25% at 15 years; for the sphenoid sinus, OS was 53.3, 6.3, and 0%, respectively.12 Tumors involving the nasal cavity, ethmoid, and maxillary showed better survival trends. There was no explicit OS or DSS analysis based on margin status or skull base/orbital/perineural involvement. In their analysis of management of sinonasal ACC, patients who underwent surgical therapy alone had 5-, 10-, and 20-year DSS rates of 72.5, 54.2, and 36.8%, respectively.12 Cases were treated with combined surgery and radiotherapy showed 5-, 10-, and 20-year DSS rates of 73.5, 44.2, and 15.5%, respectively. These findings were statistically significant when compared to DSS rates for no treatment and to radiation alone. Tumors treated only with radiotherapy exhibited 5-, 10-, and 20-year DSS rates of 37.3, 10.8, and 0.0%, respectively. Ultimately, the study concluded that surgery improves survival and that adjuvant radiotherapy may prolong 5-year disease-free interval, but may not impact long-term survival given ACC’s indolent course and tendency to recur.12

36.3 Author and Institutional Biases For treatment of ACC involving the skull base, we support primary surgery with adjuvant radiation. We support en bloc

Fig. 36.1 Preoperative coronal T1-weighted MRI scan showing extensive skull base involvement.

resection of the tumor and resection to negative margins whenever feasible. We also support avoiding damage to critical neurovascular structures to prevent subsequent morbidity. Thus, resection may be limited by cavernous sinus, carotid artery, or orbital involvement. Depending on tumor size and location, we utilize an endoscopic approach, open approach, or a combined approach. For tumors grossly involving dura, we resect dura and are able to reconstruct the skull base with various techniques.4 For tumors involving the trigeminal nerve or Vidian nerve, resection up to their respective skull base foramina is feasible. For tumors involving the orbit and the orbital contents, consideration of orbital exenteration must be weighed against the morbidity in the setting of OS rates as described earlier. Discussion and treatment planning should involve a multidisciplinary tumor board.

36.4 Case Example A 52-year-old man presents with decreasing vision and numbness of the face as well as sixth nerve palsy. On imaging, he was found to have a large tumor involving the clivus, sphenoid sinus, invading right cavernous sinus and orbit, ethmoid sinuses, and maxillary sinus more on the right side (▶ Fig. 36.1). He underwent an endoscopic, endonasal, transsphenoidal approach to the anterior skull base with expanded sphenoidectomy, exposure of right cavernous sinus, orbit, resection of malignant sinonasal–skull base tumor, decompression of optic nerve, and reconstruction of the skull base with a nasoseptal flap. Intraoperative findings showed there was tumor attached to the lamina papyracea and appeared to be invading the infratemporal fossa and tracking along the orbit and optic nerve. The right cavernous sinus, clivus, and carotid artery were identified, and there was invasion of the tumor in the right cavernous sinus, right opticocarotid recesses, and clival carotids. The intracavernous genu segment of the internal carotid artery was further exposed, and the tumor was tenaciously adherent and could not be dissected away from the internal carotid artery as it emerged from the clival segment. Intraoperative photos show exposure of the right carotid (▶ Fig. 36.2). A postoperative image was obtained (▶ Fig. 36.3).

Fig. 36.2 Intraoperative photo showing right carotid area involvement of tumor.

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Sinonasal Malignancies recurrence and that higher T-stage and PNI is associated with metastatic failure.3 In conclusion, patients with ACC involving the skull base are at higher risk for local recurrence and have a lower OS risk, and surgery with the goal of full oncologic resection but limiting morbidity still has an important role in its primary management.

36.6 Suggestions for Future Studies

Fig. 36.3 Postoperative coronal T1-weighted MRI scan showing postsurgical findings.

36.5 Conclusions ACC, including those that have skull base involvement, is an aggressive disease with an unpredictable clinical course. Its management is further complicated when involving the skull base. In this review of studies, we show a 5-year OS range of 62 to 78% and a 5-year DFS range of 41 to 73.5%. Local recurrence rates ranged between 18 and 36%. In the largest single-center study of ACC involving the skull base, Ramakrishna et al had the most compelling results in support of aggressive surgery with adjuvant radiation.9 Their OS was 15.6 years, with a 5- and 10-year OS rate of 78 and 50%, respectively, and local recurrence rate of 18%. Furthermore, while the study cohort was heterogeneous, Unsal et al showed a significant increase in overall 5-, 10-, and 20-year DSS rate when surgery was the primary therapy when compared to radiation only.12 On the other hand, Amit et al showed that there was no significant difference in 5-year OS based on treatment modality.10 This may be due to the heterogeneity of their meta-analysis, but their findings do raise the question of the role of surgery or any treatment modality on OS. Regardless, surgery does play a significant role in the treatment of ACC involving the skull base in improving 5-year overall and DSS. Factors that decrease survival for ACC involving the skull base require more study. Positive margins and primary location of ACC in the paranasal sinuses have been shown to have a negative prognostic value, but there is conflicting data on the effect of PNI. Furthermore, several studies have shown that various skull base involvement, whether cavernous sinus, intraorbital invasion, or dural invasion, did not affect survival. However, one study looking at head and neck ACC as a whole has shown that skull base involvement does increase the rate of local

228

Current therapies for ACC involving the skull base provide improved outcomes when compared to previously described, but still remain limited in terms of long-term survival. However, it is unlikely that more aggressive surgery is beneficial to patients in terms of survival and prevention of recurrence. Areas of future study still remain and include evaluating the role of adjuvant chemotherapy, improving radiation therapy techniques, examining molecular markers to stratify high-risk patients, and developing potential targeted therapies. As shown here, most studies are retrospective level III evidence, and thus, there is a need for multicenter controlled, randomized studies exploring different treatment algorithms. Improving techniques in molecular characterization of ACC could identify and stratify high-risk patients who may benefit from more intensive adjuvant therapies.

References [1] Conley J, Dingman DL. Adenoid cystic carcinoma in the head and neck (cylindroma). Arch Otolaryngol. 1974; 100(2):81–90 [2] Bradley PJ. Adenoid cystic carcinoma of the head and neck: a review. Curr Opin Otolaryngol Head Neck Surg. 2004; 12(2):127–132 [3] Jang S, Patel PN, Kimple RJ, McCulloch TM. Clinical outcomes and prognostic factors of adenoid cystic carcinoma of the head and neck. Anticancer Res. 2017; 37(6):3045–3052 [4] Castelnuovo P, Turri-Zanoni M, Battaglia P, Antognoni P, Bossi P, Locatelli D. Sinonasal malignancies of anterior skull base: histology-driven treatment strategies. Otolaryngol Clin North Am. 2016; 49(1):183–200 [5] Howard DJ, Lund VJ. Reflections on the management of adenoid cystic carcinoma of the nasal cavity and paranasal sinuses. Otolaryngol Head Neck Surg. 1985; 93(3):338–341 [6] Lupinetti AD, Roberts DB, Williams MD, et al. Sinonasal adenoid cystic carcinoma: the M. D. Anderson Cancer Center experience. Cancer. 2007; 110(12): 2726–2731 [7] Rhee CS, Won TB, Lee CH, et al. Adenoid cystic carcinoma of the sinonasal tract: treatment results. Laryngoscope. 2006; 116(6):982–986 [8] Pitman KT, Prokopakis EP, Aydogan B, et al. The role of skull base surgery for the treatment of adenoid cystic carcinoma of the sinonasal tract. Head Neck. 1999; 21(5):402–407 [9] Ramakrishna R, Raza SM, Kupferman M, Hanna E, DeMonte F. Adenoid cystic carcinoma of the skull base: results with an aggressive multidisciplinary approach. J Neurosurg. 2016; 124(1):115–121 [10] Amit M, Binenbaum Y, Sharma K, et al. Adenoid cystic carcinoma of the nasal cavity and paranasal sinuses: a meta-analysis. J Neurol Surg B Skull Base. 2013; 74(3):118–125 [11] Mendenhall WM, Morris CG, Amdur RJ, Werning JW, Hinerman RW, Villaret DB. Radiotherapy alone or combined with surgery for adenoid cystic carcinoma of the head and neck. Head Neck. 2004; 26(2):154–162 [12] Unsal AA, Chung SY, Zhou AH, Baredes S, Eloy JA. Sinonasal adenoid cystic carcinoma: a population-based analysis of 694 cases. Int Forum Allergy Rhinol. 2017; 7(3):312–320

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Proton versus Photon Therapy for Sinonasal Malignancies: Pros and Cons of Each Method

37 Proton versus Photon Therapy for Sinonasal Malignancies: Pros and Cons of Each Method Emad Youssef Abstract Radiotherapy is commonly used to treat sinonasal malignancies, whether in an adjuvant setting after surgical resection or as a definitive treatment for locally advanced tumors. Delivery of a tumoricidal dose of radiation is usually limited by the complex regional anatomy with surrounding critical structures, namely, the optic nerves, chiasm, and brainstem. Photon therapy has been used for many years to treat sinonasal malignancies. Two-dimensional conventional therapy and threedimensional conformal therapy were used initially. Intensitymodulated radiotherapy demonstrated noticeably improved clinical outcomes and reduced the incidence of adverse effects, mainly vision impairment. Photons and protons act in a similar biological way by damaging DNA, resulting in cell death. Proton therapy has some dosimetric advantages compared with photon therapy, namely, a Bragg peak and a sharper lateral dose distribution (i.e., sharper dose falloff) due to the heavier particle mass of protons. Both of these factors allow for deposition of most of the proton radiation energy within the target volume and sparing of the surrounding organs at risk. Technical improvements in photon and proton therapy have helped improve the clinical outcome of patients undergoing radiotherapy to treat sinonasal malignancies. Future studies are warranted to examine the role of systemic therapy in further improving the therapeutic ratio of radiotherapy in the management of these challenging tumors. Keywords: Bragg peak, intensity-modulated radiotherapy, photons, protons, sinonasal malignancy, therapeutic ratio

37.1 Introduction Radiotherapy is frequently used in an adjuvant setting after resection of an early-stage sinonasal malignancy, and it can be used as the primary treatment for patients who are not candidates for definitive surgery. However, radiotherapy for sinonasal malignancies represents a significant challenge for treating physicians because of the following factors: ● The sinonasal regional anatomy is complex, with surrounding critical structures such as the optic nerves, chiasm, pituitary gland, and temporal lobes. ● Local recurrence is the predominant pattern of recurrence. Most marginal recurrences are located at the level of the eyes or adjoining region of the brain, which may suggest the difficulty of administering an adequate radiation dose in this region when attempting to protect the optic structures, brainstem, and brain.1 ● Local tumor control is the main determinant of cure. Patients who have local recurrence are more likely to die of their disease, which highlights the value of adequate local therapy. ● High-dose radiation (range: 60–70 Gy) is needed for tumor control, whether in a primary setting or in an adjuvant

●

setting, and it is especially necessary in locally advanced cases. This range exceeds the tolerance dose of most surrounding critical structures, most importantly, the optic structures, which have a tolerance dose in the range of 50 to 55 Gy.2 Platinum-based chemotherapy is used commonly as a radiation sensitizer. Although its role in affecting the tolerance of the optic structures is still undefined, it may have an adverse effect on the tolerance of optic structures to radiotherapy.3

37.2 Review 37.2.1 Photon Therapy Photon therapy has been used for many years to treat sinonasal malignancies. Clinical studies using conventional two-dimensional (2D) and three-dimensional (3D) conformal techniques were used initially with reported local control rates of 45 to 83%.3,4,5,6 The lowest control rate was associated with locally advanced tumors. These techniques were associated with significant vision impairment or blindness (range, 0–20%), which correlated with the radiation dose to the optic structures.6,7 Intensity-modulated radiotherapy (IMRT) is a technique of planning and delivery of photons that helps deliver a high dose of radiation that is needed for tumor control with a relatively smaller dose to surrounding critical structures. Compared to conventional 2D and 3D conformal therapy, IMRT demonstrated noticeably improved clinical outcomes and reduced the incidence of vision impairment with local tumor control rates between 56 and 78%. No severe optic nerve toxicity was noted when the dose received by optic nerves and chiasm was limited to 54 Gy using conventional fractionation (1.8–2.0 Gy daily dose; ▶ Table 37.1).8,9,10,11 Chen et al12 reported data on 127 patients with sinonasal malignancies; the study focused on the differences between 2D, 3D, and IMRT techniques used between 1960 and 2005. They studied the effect of photon therapy techniques on outcome. All techniques achieved comparable local control rates (55.9, 67.0, and 69.6% for 2D, 3D, and IMRT, respectively), but IMRT reduced the incidence of grade III or higher visual toxicity (20, 9, and 0% for 2D, 3D, and IMRT, respectively). Several technical factors may help to improve tumor coverage and spare optic structures when using IMRT. An increased number of beams and segments, noncoplanar setup (i.e., multiple beams delivered from different axes and angles), and image guidance during delivery using conebased beam computed tomography help improve target volume coverage and spare the surrounding organs at risk. Helical tomotherapy is a relatively new IMRT technique based on helical delivery of radiation; it has been shown to generate superior target volume homogeneity and may result in better sparing of optic structures.13

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Sinonasal Malignancies

Table 37.1 Treatment results using IMRT Author

N

Histology

Modality

Median follow-up

LCR

Late toxicity

Comments

Level of evidence

Daly et al (2007)8

36

12 SCC 7 EN 5 ACC 5 AC 5 UC 2 others

IMRT, dose 60–70 Gy

51 mo (surviving patients)

2 y, 62% 5 y, 58%

No G3 ocular toxicity 1 xerophthalmia 1 lacrimal stenosis 1 cataract 9 nonocular late toxicity

89% had surgical resection before radiation

IV

Madani et al (2009)9,a

84

54 AC 17 SCC 9 EN 4 ACC

IMRT, dose 70 Gy 75 PORT 9 definitive RT

40 mo (surviving patients)

3 y, 74.9% 5 y, 70.7%

1 G3 visual impairment 3 asymptomatic brain necrosis 1 lacrimal duct stenosis

29% T4 11 reirradiated for recurrent tumorsb

IV

Dirix et al (2010)10,c

40

31 AC 4 NEC 2 EN 2 SCC 1 UC

IMRT, dose 60–66 Gy

30 mo (surviving patients)

2 y, 76%

No G3 or G4 toxicities

All patients had surgical resection before radiation

III

Wiegner et al (2012)11,d

52

28 SCC 7 EN 7 UC 5 ACC 1 AC 4 others

IMRT, dose 66–74.4 Gy

30.9 mo (surviving patients)

2 y, 75%

1 G3 ON 1 G3 corneal ulcer 1 G3 ORN 1 G3 epistaxis 2 G3 hearing loss due to cisplatin

10% unresectable tumors

IV

Abbreviations: AC, adenocarcinoma; ACC, adenoid cystic carcinoma; EN, esthesioneuroblastoma; G3/4, grade III/IV; IMRT, intensity-modulated radiotherapy; LC, local control; LCR, local control rate; MM, mucosal melanoma; NEC, neuroendocrine carcinoma; ON, optic neuropathy; ORN, osteoradionecrosis; PORT, postoperative radiotherapy; RT, radiotherapy; SCC, squamous cell carcinoma; UC, undifferentiated carcinoma. aCommon Terminology Criteria for Adverse Events (CTCAE) version 2.0. bOne patient who had reirradiation had osteoradionecrosis and brain necrosis. cPatients who had three-dimensional radiation at the same institute had a 2-year LCR of 67% and a 15.8% rate of radiation-induced retinopathy. dCTCAE version 3.0.

37.2.2 Proton Therapy Proton therapy is a relatively newer modality of external-beam radiotherapy. Photons and protons act in a similar biological way by damaging DNA, which results in cell death. Protons have a relative biological effectiveness (RBE) that is slightly higher than photons according to the International Commission on Radiation Units and Measurements.14 Proton therapy has some dosimetric advantages that make it useful for treating sinonasal tumors. The dose depth distribution for proton therapy is characterized by a sharp increase in dose deposited at the end of the particle range, a dosimetric phenomenon known as a Bragg peak (▶ Fig. 37.1), which helps reduce the exit dose beyond the tumor. Protons also have a sharper lateral dose distribution (i.e., sharper dose falloff) due to their heavier particle mass compared to that of photons. Both of these factors allow for deposition of most of the proton radiation energy within the target volume and for sparing of the surrounding organs at risk.15 Intensity-modulated proton therapy plans can be generated either by single-field optimization (individually optimizing the spot intensities of each beam) or by multiple-field optimization (simultaneous optimization of all beam intensities).16 Intensitymodulated proton therapy results in a greater dose conformity and smaller integral dose with less neutron production compared with that of passive-scatter proton therapy, whereby the proton beam is spread by using either single-scattering or double-scattering foils.17 ▶ Table 37.2 summarizes data from selected studies with a minimum follow-up of 24 months that showed proton therapy compared favorably to IMRT.18,19,20,21,22,23

230

Proton Spread-out proton peak 22 MV X-rays 22 MeV electrons 200 kV X-rays 60

Co Y-rays

Fig. 37.1 Bragg peak and spread-out Bragg peak for a proton beam in comparison with photon and electron dose distributions. (Copyright of International Journal of Otolaryngology and made available under the CC BY 2.0 [http://creativecommons.org/licenses/by-nc-sa/2.0/].)15

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Proton versus Photon Therapy for Sinonasal Malignancies: Pros and Cons of Each Method

Table 37.2 Treatment results using proton therapy Author

N

Histology

Modality

Median follow-up

LCR

Late toxicity

Comments

Level of evidence

Truong et al (2009)18,a

20

10 SCC 7 ACC 2 NEC 1 AC

PT, 65% BID

27 mo (surviving patients)

2 y, 86%

No G3 or G4 ocular toxicity 1 G5 CSF leak 3 G2–3 nasal fibrosis

All sphenoid sinus tumors, 35% underwent partial resection before radiation

IV

Zenda et al (2011)19

39

11 SCC 9 ON 6 MM 13 others

PT

45.5 mo (all patients)

1 y, 77%

12.8% G3 or higher 1 related death due to CSF leakage

All T4

IV

Fukumitsu et al (2012)20

17

11 SCC 2 ACC 2 AC 2 others

PT

57 mo (surviving patients)

2 y, 35%

2 G3 or higher (brain necrosis and ipsilateral blindness)

T4 or recurrent, all unresectable

IV

Okano et al (2012)21

13

7 ON 3 SCC 3 others

IC followed by PT

56.5 mo (all patients)

10/13 CR

No late toxicity observed

All T4b, prospective nonrandomized study

IV

Russo et al (2016)22

54

SCC

PT (median dose, 72.8 Gy RBE)

82 mo (surviving patients)

5 y, 80%; 10 local recurrence

9 G3 and 6 G4 Mostly wound adverse events

2 had vision loss, 1 had maxillary sarcomatoid carcinoma 9 y after therapy

IV

Dagan et al (2016)23

84

23 ON 22 SCC 14 ACC 8 AC 14 Others

PT BID

32.4 mo (surviving patients)

3 y, 83%

24% had G3 or higher toxicities

Death attributed to therapy in 3 patients

IV

Abbreviations: AC, adenocarcinoma; ACC, adenoid cystic carcinoma; BID, twice-daily fractionation; CR, complete response; CSF, cerebrospinal fluid; G3/ 4/5, grade III/IV/V; IC, induction chemotherapy; LCR, local control rate; MM, mucosal melanoma; NEC, neuroendocrine carcinoma; ON, olfactory neuroblastoma; PT, proton therapy; RBE, relative biological effectiveness; SCC, squamous cell carcinoma. aToxicity was scored using the National Cancer Institute Common Toxicity Criteria v 3.0 (CTC) grading system (http://ctep.cancer.gov).

Russo et al22 reported their experience with 54 patients with locally advanced sinonasal squamous cell carcinoma (SCC) who were treated with proton therapy at their institution. The median follow-up time was 82 months in surviving patients. Ten patients had local recurrence, and the 5-year actuarial local control rate was 80%. Treatment toxicity was scored using the Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Fourteen patients (26%) experienced one or more grade II late ocular and visual adverse effects; the most common was nasolacrimal stenosis (5 patients), followed by retinopathy (2 patients). There were 9 (16%) grade III and 6 (11%) grade IV toxicities (5 patients had flap reconstruction for sinonasal cutaneous fistula and 1 patient had orbital exenteration for protrusion of titanium mesh that was used before radiation for orbital floor reconstruction). Two patients with tumor involvement of the optic nerve at diagnosis experienced expected vision loss. One patient received a diagnosis of spindle cell sarcomatoid carcinoma in the maxillary sinus 9 years after the completion of radiation. Holliday and Frank24 reported data on 16 patients; 13 patients had received proton therapy after resection and 3 patients received proton therapy as definitive treatment. The median follow-up time was 10.2 months. The median radiation dose was 62 Gy (RBE). Of the 13 patients who had surgery before proton therapy, 1 had local recurrence; 1 of the 3 patients who had definitive therapy had progressive disease. No grade IV or V toxicities were reported. One patient had grade III dermatitis.

Altered Fractionation Dagan et al23 reported their experience with 84 patients with sinonasal malignancies. The most common histologies were olfactory neuroblastoma (23%), followed by SCC (22%) and adenoid cystic carcinoma (17%). Among these patients, 70% had either T3 or T4 tumors, and 87% were treated in an adjuvant setting after surgical resection. All patients were treated using dose-intensified hyperfractionated intensity-modulated proton therapy (1.2 Gy [RBE] twice/day) and weekly cisplatin. The median proton therapy dose was 73.8 Gy (RBE). At a median follow-up of 2.7 years for surviving patients, the 3-year actuarial local control rate was 83%, which is higher than historical rates reported for IMRT.9,11 Twelve patients had local recurrence, and 50% of local recurrences were marginal. Unfortunately, 24% of patients developed grade III complications or higher according to the CTCAE version 4.0 grading system. Two patients developed unilateral vision loss, and 7 patients developed bone or soft-tissue necrosis. Death was attributed in part to radiotherapy in 3 patients. Although the results of local control reported by Dagan et al23 are encouraging, some concerns about this treatment regimen have been raised by the pattern of relapse being marginal in 50% of patients, the relatively short followup, and the high incidence of complications.

Neoadjuvant Chemotherapy Okano et al21 reported data on 13 patients with T4b sinonasal malignancies (7 patients with olfactory neuroblastoma, 3 with

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Sinonasal Malignancies SCC, and 1 each with adenocarcinoma, undifferentiated carcinoma, and small cell carcinoma). All 13 patients received neoadjuvant chemotherapy using docetaxel, cisplatin, and S-1 (TPS) for 3 cycles followed by proton therapy either alone or concurrent with cisplatin. The total dose of proton therapy was 65 cobalt Gy equivalents (GyE) for 4 to 5 fractions per week in a 2.5-GyE once-daily fractionation. Eleven patients achieved a complete response. Median follow-up was 56.5 months. Local relapse developed in 3 patients (2 lesions within the radiation field and 1 marginal lesion). No brain damage or blindness occurred. The small number of patients and the heterogeneity of the histology of these patients are limitations for these encouraging results, which may prove valid in future studies.

37.2.3 Combined Protons and Photons ▶ Table 37.3 summarizes the results of studies using combined photons and protons for sinonasal malignancies with excellent local control and minimal side effects.25,26,27,28 Resto et al28 reported data on 102 patients with different histologies (32% SCC, 29% carcinoma with neuroendocrine features, and 20% adenoid cystic carcinoma) who were treated using surgery (20% had complete resection, 49% underwent partial resection, and 31% underwent biopsy only). The median total dose was 71.6 Gy. The authors reported 5-year actuarial local control rates of 95, 82, and 87% for complete resection, partial resection, and biopsy only, respectively. They did not report on ocular toxicity or any other adverse effects.

37.2.4 Comparative Studies Several dosimetry studies suggested that proton therapy dosimetry is superior in sparing normal structures and possibly in providing better tumor coverage.29,30 However, no randomized controlled study has been reported that indicates whether this dosimetric advantage will translate to better clinical outcomes. Randomized controlled trials comparing photon therapy with proton therapy among patients with sinonasal malignancies are difficult to design, and it is difficult to accrue patients to such trials, mainly because of different pathologic types and institutional biases. In 2014, Patel et al31 published a systematic review and metaanalysis of 41 noncomparative observational studies to compare the clinical outcomes of patients treated with charged particles (the majority of studies used proton therapy) with those of patients who received photon therapy. Although the authors excluded studies that were published before 1990 to ensure that the analysis incorporated modern radiotherapy, more than 50% of the photon therapy studies that were included used conventional 2D or 3D conformal therapy. The median follow-up for both groups was comparable (38 months for charged particles and 40 months for photons). At 5 years, the pooled overall survival was higher for patients receiving charged particles (relative risk [RR]: 1.51, 95% CI: 1.14–1.99, p = 0.0038), but locoregional control did not differ between the two groups (RR: 1.06, 95% CI: 0.68–1.67, p = 0.79). There were significantly more neurologic toxic effects in the charged-particle therapy group than in the

Table 37.3 Treatment results using combined photons and protons Author

N

Histology

Modality

Median follow-up

LCR

Late toxicity

Comments

Level of evidence

Fitzek et al (2002)25,a

19

9 ON 10 NEC

Photons + protons, concomitant boost

45 mo (patients not specified)

5 y, 88%

2 patients with soft tissue or bone necrosis 1 patient with CSF leakage

4 patients had MRI-detected radiationinduced brain damage

II

Pommier et al (2006)26

23

ACC

Photons + protons

64 mo (surviving patients)

5 y, 93%

10 G3 toxicity 1 G5 toxicity CSF leakage

12 patients had MRI-detected radiationinduced brain damage

IV

Weber et al (2006)27,b

36

10 SCC 10 ACC 9 ON 2 STS 5 others

Photons + protons, BID

52.4 mo (surviving patients)

4 patients had local recurrence

5.6% G3 visual or ocular toxicity

Study was designed to address visual outcome

IV

Resto et al (2008)28

102

33 SCC 20 ACC 30 NEC 13 STS 6 AC

Photons + protons

5.1 y (surviving patients)

5 y (82–95%), based on extent of surgical resection

Not reported

Study was designed to investigate the role of surgery

III

Abbreviations: AC, adenocarcinoma; ACC, adenoid cystic carcinoma; BID, twice-daily fractionation; CSF, cerebrospinal fluid; G3/5, grade III/V; LCR, local control rate; MRI, magnetic resonance imaging; NEC, neuroendocrine carcinoma; ON, olfactory neuroblastoma; SCC, squamous cell carcinoma; STS, soft-tissue sarcoma. aRadiation-induced complications were graded according to the Radiation Therapy Oncology Group (RTOG) LENT-SOMA scales. bUsed RTOG LENT-SOMA and the National Cancer Institute Common Toxicity Criteria v 2.0 (CTC) grading system (http://ctep.cancer.gov).

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Proton versus Photon Therapy for Sinonasal Malignancies: Pros and Cons of Each Method photon therapy group (p = 0.0002). Upon subgroup analysis of relatively smaller numbers of patients comparing proton therapy with IMRT, they reported that patients undergoing proton therapy had a higher disease-free survival at 5 years and higher locoregional control at longest follow-up. The authors did not report a comparison of toxic effects between the two subgroups. This analysis is confounded by selection bias (e.g., including a higher proportion of patients with high-risk histology in the photon group), institutional and patient preferences, heterogeneity of techniques, and subgroup analysis limitations.

37.3 Conclusions Sinonasal malignancies are a heterogeneous group of tumors with different inherent radiosensitivities. Accurate pathologic diagnosis and proper imaging are critical for proper target volume delineation, regardless of whether photons or protons are used. Proton therapy has dosimetry advantages, but its widespread usage is limited by the relatively higher cost needed for initial setup and maintenance. Technical improvements in photon therapy, namely, IMRT and image-guided radiotherapy, have helped improve the radiation therapeutic ratio of this option.

37.4 Suggestions for Future Studies Future studies using systemic therapy in different combinations with either photons or protons are warranted to improve local control and survival. Such research should also focus on reducing radiation-induced toxicity.

References [1] Porceddu S, Martin J, Shanker G, et al. Paranasal sinus tumors: Peter MacCallum Cancer Institute experience. Head Neck. 2004; 26(4):322–330 [2] Mayo C, Martel MK, Marks LB, Flickinger J, Nam J, Kirkpatrick J. Radiation dose-volume effects of optic nerves and chiasm. Int J Radiat Oncol Biol Phys. 2010; 76(3) Suppl:S28–S35 [3] Homma A, Oridate N, Suzuki F, et al. Superselective high-dose cisplatin infusion with concomitant radiotherapy in patients with advanced cancer of the nasal cavity and paranasal sinuses: a single institution experience. Cancer. 2009; 115(20):4705–4714 [4] Mendenhall WM, Amdur RJ, Morris CG, et al. Carcinoma of the nasal cavity and paranasal sinuses. Laryngoscope. 2009; 119(5):899–906 [5] Logue JP, Slevin NJ. Carcinoma of the nasal cavity and paranasal sinuses: an analysis of radical radiotherapy. Clin Oncol (R Coll Radiol). 1991; 3(2):84–89 [6] Roa WH, Hazuka MB, Sandler HM, et al. Results of primary and adjuvant CTbased 3-dimensional radiotherapy for malignant tumors of the paranasal sinuses. Int J Radiat Oncol Biol Phys. 1994; 28(4):857–865 [7] Pommier P, Ginestet C, Sunyach M, et al. Conformal radiotherapy for paranasal sinus and nasal cavity tumors: three-dimensional treatment planning and preliminary results in 40 patients. Int J Radiat Oncol Biol Phys. 2000; 48 (2):485–493 [8] Daly ME, Chen AM, Bucci MK, et al. Intensity-modulated radiation therapy for malignancies of the nasal cavity and paranasal sinuses. Int J Radiat Oncol Biol Phys. 2007; 67(1):151–157 [9] Madani I, Bonte K, Vakaet L, Boterberg T, De Neve W. Intensity-modulated radiotherapy for sinonasal tumors: Ghent University Hospital update. Int J Radiat Oncol Biol Phys. 2009; 73(2):424–432

[10] Dirix P, Vanstraelen B, Jorissen M, Vander Poorten V, Nuyts S. Intensitymodulated radiotherapy for sinonasal cancer: improved outcome compared to conventional radiotherapy. Int J Radiat Oncol Biol Phys. 2010; 78(4):998– 1004 [11] Wiegner EA, Daly ME, Murphy JD, et al. Intensity-modulated radiotherapy for tumors of the nasal cavity and paranasal sinuses: clinical outcomes and patterns of failure. Int J Radiat Oncol Biol Phys. 2012; 83(1):243–251 [12] Chen AM, Daly ME, Bucci MK, et al. Carcinomas of the paranasal sinuses and nasal cavity treated with radiotherapy at a single institution over five decades: are we making improvement? Int J Radiat Oncol Biol Phys. 2007; 69(1):141–147 [13] Chen AM, Sreeraman R, Mathai M, Vijayakumar S, Purdy JA. Potential of helical tomotherapy to reduce dose to the ocular structures for patients treated for unresectable sinonasal cancer. Am J Clin Oncol. 2010; 33(6):595–598 [14] Li Z. Prescribing, recording, and reporting proton beam therapy. JICRU. 2007; 7(2):1–210 [15] Cianchetti M, Amichetti M. Sinonasal malignancies and charged particle radiation treatment: a systematic literature review. Int J Otolaryngol. 2012; 2012: 325891 [16] Zhu XR, Poenisch F, Li H, et al. A single-field integrated boost treatment planning technique for spot scanning proton therapy. Radiat Oncol. 2014; 9:202 [17] McKeever MR, Sio TT, Gunn GB, et al. Reduced acute toxicity and improved efficacy from intensity-modulated proton therapy (IMPT) for the management of head and neck cancer. Linchuang Zhongliuxue Zazhi. 2016; 5(4):54 [18] Truong MT, Kamat UR, Liebsch NJ, et al. Proton radiation therapy for primary sphenoid sinus malignancies: treatment outcome and prognostic factors. Head Neck. 2009; 31(10):1297–1308 [19] Zenda S, Kohno R, Kawashima M, et al. Proton beam therapy for unresectable malignancies of the nasal cavity and paranasal sinuses. Int J Radiat Oncol Biol Phys. 2011; 81(5):1473–1478 [20] Fukumitsu N, Okumura T, Mizumoto M, et al. Outcome of T4 (International Union against Cancer Staging System, 7th edition) or recurrent nasal cavity and paranasal sinus carcinoma treated with proton beam. Int J Radiat Oncol Biol Phys. 2012; 83(2):704–711 [21] Okano S, Tahara M, Zenda S, et al. Induction chemotherapy with docetaxel, cisplatin and S-1 followed by proton beam therapy concurrent with cisplatin in patients with T4b nasal and sinonasal malignancies. Jpn J Clin Oncol. 2012; 42(8):691–696 [22] Russo AL, Adams JA, Weyman EA, et al. Long-term outcomes after proton beam therapy for sinonasal squamous cell carcinoma. Int J Radiat Oncol Biol Phys. 2016; 95(1):368–376 [23] Dagan R, Bryant C, Li Z, et al. Outcomes of sinonasal cancer treated with proton therapy. Int J Radiat Oncol Biol Phys. 2016; 95(1):377–385 [24] Holliday EB, Frank SJ. Proton radiation therapy for head and neck cancer: a review of the clinical experience to date. Int J Radiat Oncol Biol Phys. 2014; 89(2):292–302 [25] Fitzek MM, Thornton AF, Varvares M, et al. Neuroendocrine tumors of the sinonasal tract. Results of a prospective study incorporating chemotherapy, surgery, and combined proton-photon radiotherapy. Cancer. 2002; 94(10): 2623–2634 [26] Pommier P, Liebsch NJ, Deschler DG, et al. Proton beam radiation therapy for skull base adenoid cystic carcinoma. Arch Otolaryngol Head Neck Surg. 2006; 132(11):1242–1249 [27] Weber DC, Chan AW, Lessell S, et al. Visual outcome of accelerated fractionated radiation for advanced sinonasal malignancies employing photons/protons. Radiother Oncol. 2006; 81(3):243–249 [28] Resto VA, Chan AW, Deschler DG, Lin DT. Extent of surgery in the management of locally advanced sinonasal malignancies. Head Neck. 2008; 30(2): 222–229 [29] Lomax AJ, Goitein M, Adams J. Intensity modulation in radiotherapy: photons versus protons in the paranasal sinus. Radiother Oncol. 2003; 66(1):11–18 [30] Mock U, Georg D, Bogner J, Auberger T, Pötter R. Treatment planning comparison of conventional, 3D conformal, and intensity-modulated photon (IMRT) and proton therapy for paranasal sinus carcinoma. Int J Radiat Oncol Biol Phys. 2004; 58(1):147–154 [31] Patel SH, Wang Z, Wong WW, et al. Charged particle therapy versus photon therapy for paranasal sinus and nasal cavity malignant diseases: a systematic review and meta-analysis. Lancet Oncol. 2014; 15(9):1027–1038

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Part IX Surgical Approaches and Techniques

38 Controversies in Skull Base Reconstruction Techniques

236

39 The Role of Lumbar Drains in Skull Base Surgery

245

40 The Role of Postoperative Antibiotics in Endoscopic Endonasal Surgery

250

41 Does Otorhinolaryngology Collaboration Improve Outcomes in Endonasal Skull Base Surgery? 254

IX

42 Controversies in Outcome Measures of Skull Base Surgery

258

43 To Bypass or Not? The Role of Revascularization in Skull Base Surgery

264

44 Transcranial versus Endoscopic Repair of Lateral Sphenoid Recess Encephaloceles

274

45 Cranioplasty Techniques

282

46 The Future of Robotics in Skull Base Surgery

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38 Controversies in Skull Base Reconstruction Techniques Chad A. Glenn, Thomas A. Ostergard, and Michael E. Sughrue Abstract Reconstruction of skull base defects requires a vast knowledge of the available repair techniques. Not only must the surgeon know what options are available, but he or she must also know how and when to employ them. In this chapter, we provide a historical perspective on the evolution of modern repair techniques. A review of reconstructive materials, including free tissue grafts/autografts, vascularized intranasal and local extranasal flaps, distant extranasal rotational flaps, and revascularized free flaps is provided. We place a special emphasis on the development of free tissue grafts/autografts as well as vascularized intranasal and local extranasal flaps, as these are frequently the first-line option. Specific topics of controversy are addressed. (1) The use of vascularized intranasal and local extranasal flaps following endoscopic endonasal skull base surgery is now widespread and has led to improvement in the reported postoperative leak rates. However, it is unclear if a flap is required in all cases, especially in the setting of a low flow leak. (2) There is great variation in opinion on the effectiveness of lumbar drain placement for prevention of a fluid leak following skull base surgery. While likely beneficial in some patients, the benefits of drain use in the setting of a multilayered repair technique including a vascularized flap are less obvious. (3) With the advent of vascularized flaps for skull base reconstruction, the utility of antibiotic prophylaxis in all cases has come into question. Currently, there is no agreed upon postoperative regimen and furthermore some have argued against antibiotic prophylaxis entirely. Keywords: skull base reconstruction, free tissue grafts, vascularized flaps, cerebrospinal fluid leak, lumbar drain, antibiotic prophylaxis

38.1 Introduction The best skull base operation is undone by a poor reconstruction. There is much variation in the techniques used to repair skull base defects. Variation is expected, however, given the unique challenges posed by various pathologies and anatomic locations. The skull base surgeon is faced with many approach choices with each having pros and cons. The choices have expanded even further as the utilization of endonasal skull base approaches has gained popularity. In fact, over the last 20 years, endonasal approaches have been accepted as a reasonable alternative to open approaches in selected patients.1 Similar to open approach paradigms, the model of a multidisciplinary surgical team has been utilized for endonasal approaches. The otolaryngologist and the neurosurgeon have classically worked together furthering this field through advancement in endoscopic approach techniques and surgical tools. Historically, endoscopic endonasal skull base surgery was associated with a cerebrospinal fluid (CSF) leak rate of 20% with morbid complications resulting from infection.2,3,4 The most significant advancement furthering the field of endonasal skull

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base surgery was likely the development of the nasoseptal flap.5 The vascularized flap has made endonasal approaches comparable to open approaches for many pathologies in many aspects, including infection.3,6 However, posterior fossa pathologies, especially those located lateral to the internal auditory canal or jugular foramen, remain best treated by open lateral approaches.7,8,9 Whether considering an open or endoscopic reconstruction, the goals are the same. Broadly stated, these goals include separation of the brain from the outside world to prevent CSF leak and subsequent sequelae, functional preservation of important neurovascular structures, and achievement of an acceptable cosmetic outcome. While these goals are straightforward, determining the best method of achieving them is not always clear. The size, location, and nature of the anatomic defect must also be considered. The presence or absence of a CSF leak greatly affects the repair methods used. When a CSF leak is present, it must be determined if the leak is low or high flow, as more rigorous reconstructive techniques are required for highflow leaks. Allografts, autografts, or free tissue transfers; locoregional or rotational vascularized tissue flaps; and free flaps all play a vital role in the armamentarium of skull base repair techniques. Beyond the array of options, skull base reconstruction is also made difficult by the fact that there is no universally agreed upon protocol for even a single approach, let alone all of the approaches. An exhaustive description of all the reported techniques is beyond the scope of this chapter. However, we would like to review the common reconstruction options and address certain controversial issues in more detail.

38.2 A Rationale for Approach Selection Perhaps the most significant factor in deciding between open and endoscopic approaches is the experience of the surgical team. There is no doubt that adoption of new techniques requires a learning curve before optimal outcomes are achieved. This theme has historically rung true in the field of endoscopic endonasal skull base surgery. Beyond obvious anatomic location limitations that dictate the approach needed, at many centers it is the comfort and experience of the surgical team that is guiding the decision to perform an open or endoscopic approach. The development of the nasoseptal flap provided the impetus for expanding the use of endonasal skull base approaches.3,6 The proposed benefits of endoscopic techniques have been well defined. These include minimization of brain retraction and cranial nerve manipulation.10 Traditionally, the offset to these benefits was a higher rate of CSF leak and increased risk of infection.2, 3 Technical improvements and the use of vascularized flaps have made the results of endoscopic skull base surgery comparable to open approaches for some pathologies.3,6 Beyond the nasoseptal flap, several other vascularized intranasal flaps have been described. These are presented in summary later. There is significant overlap in the reconstruction strategies following open and endoscopic endonasal approaches. In fact,

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Controversies in Skull Base Reconstruction Techniques many of these strategies that were originally employed in open approaches have been adapted for intranasal use. Familiar examples of this trend include the pericranial flap and the temporoparietal fascia flap (TPFF).11 With a wealth of reconstruction options, defects may be reconstructed from “above” and “below” when necessary. It behooves any skull base surgeon to at least be knowledgeable of the various reconstruction techniques that may be needed when the first-line or “what we usually do” method is not an option.

38.3 Reconstructive Materials: An Overview There are several materials that are used in reconstructing the skull base common to both open and endonasal approaches. Autologous free graft materials include fascia (temporalis or fascia lata), muscle (temporalis), abdominal fat, and bone (splitthickness calvarium or iliac crest). In general, free grafts (mucoperiosteal/mucoperichondrial) and pedicled flaps (intra- or extranasal) represent the majority of commonly utilized techniques for intranasal pathologies. Revascularized or rotational flaps may be used when more straightforward methods of reconstruction have failed. A tenet of skull base reconstruction includes a multilayered repair. All of the aforementioned graft materials are frequently used in combination with each other or with synthetic dural substitutes (e.g., acellular dermis). Tissue adhesives and glues commonly serve to bolster repair layers. The multilayered techniques used in endonasal repairs mirror the multilayer sutured closures that are performed for open approaches.

38.4 Free Tissue Grafts/Autografts Free tissue grafts are defined as tissue harvested from a donor site which is then transferred to a recipient site for implantation.1 The main advantages of using free tissue grafts are the simplicity of graft harvest and minimal donor site morbidity. These grafts are further distinguished by the fact that they have no blood supply of their own and therefore rely on angiogenesis.12 This is important because use of a free autograft requires implantation into a well-vascularized recipient for the graft to incorporate. Use of a free tissue autograft in a poorly vascularized area (e.g., in a patient who has already undergone radiation to the site or during a repeat operation) may lead to a higher incidence of postoperative CSF leak even in smaller defects.3,13,14 In addition, in the setting of obvious infection, the avascular nature of these tissues necessitates their removal in most cases. When sizing a free tissue graft, it is worth considering that these tissues often shrink over time. For example, abdominal fat grafts have been shown to shrink roughly 50% following implantation.12,15,16,17 Commonly utilized free tissue grafts include nasal mucoperiosteal/mucoperichondrial grafts, muscle, fascia, and abdominal fat.1 These tissues are frequently used as a primary or adjunct layer of dural repair depending on the clinical setting. While synthetic dural grafts may be used in place of fascia, abdominal fat is frequently utilized as buttress to hold autologous or synthetic dural graft materials in place until healing occurs. Tissue adhesives and glues may also be used as bolsters to counteract the effects of gravity.

Table 38.1 Summary of intranasal and local extranasal flaps Intranasal flaps

Local extranasal flaps

Posteriorly pedicled nasoseptal flap5 Bilateral20

Temporoparietal fascia flap21 Endoscopically assisted

Posteriorly pedicled MTF22

Pericranial flap Endoscopically assisted23

Posteriorly pedicled ITF21

Occipital galeopericranial flap18

Anteriorly pedicled lateral nasal/ septal flap13,24

Palatal flap25 Facial buccinator flap26

Abbreviations: ITF, inferior turbinate flap; MTF, middle turbinate flap.

Although less commonly required for endonasal skull base surgeries, free bone autografts obtained from split thickness calvarial bone or the ethmoidal perpendicular plate may be used in cases of elevated intracranial pressure.1,18 The primary purpose of these rigid reconstructions is to prevent brain herniation into the defect. Common indications include middle fossa bony defects with encephalocele and cosmetic deformity resulting from defects of the anterior table of the frontal sinus as well as obstructive sleep apnea or morbid obesity.1,18,19

38.5 Vascularized Intranasal and Local Extranasal Flaps for Reconstruction In the last 10 years, there has been a revolution in the development of vascularized flaps available for endonasal reconstruction (▶ Table 38.1). While there is agreement in the literature that the posteriorly pedicled nasoseptal flap is a first-line choice for most repairs, there are nevertheless clinical scenarios where its use is not possible.3 Therefore, knowledge of the additional vascularized flap options is important. We provide a brief description of the various types of flaps later.

38.5.1 Posteriorly Pedicled Nasoseptal Flap The sphenopalatine artery pedicled nasoseptal flap is considered to be the workhorse flap for endoscopic endonasal reconstruction of large dural defects.3,6 Since its first description in 2006, the nasoseptal flap has been customized to suit a wide array of skull base approaches.5 The robust vascularity, ease of harvest, and ability to preserve olfaction in the majority of cases make this flap appealing.27 A modification of this technique to include bilateral nasal septal flaps has been described to cover defects larger than the surface area provided by a single nasoseptal flap.20,28 Methods for customizing the width and length of the standard nasoseptal flap have been described.29 Larger defects may necessitate extending the initial inferior cut to include the lateral nasal wall, extending the flap width significantly. The length of the flap is also easily customized to reach more distant defects. This is done by extending the inferior and superior cuts anteriorly as desired up to the septocolumellar junction.29

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38.5.2 Posteriorly Pedicled Inferior Turbinate Flap and Middle Turbinate Flap Named for pedicle arteries of the same name, the middle and inferior turbinate flaps have been described as alternatives to the nasoseptal flap for repair of smaller defects.3,22 In general, these flaps are shorter and as such their use is limited to dural defects in relative proximity to the pedicle. Harvesting of the middle turbinate flap is technically demanding and results in a relatively small flap that is most useful for anterior or sellar defects less than 1 cm.11,14 The inferior turbinate flap also has a limited surface area and is restricted in its arc of rotation, making its use primarily restricted to repair of small midsellar and clival dural defects.3,11,14,30 Extended inferior turbinate flaps have been described incorporating the nasal floor, increasing the flap’s surface area significantly.30

38.5.3 Anteriorly Pedicled Lateral Nasal Wall Flap and Nasoseptal Flap Based on branches of the facial and anterior ethmoidal arteries, the anteriorly pedicled lateral nasal wall flap was developed as an alternative to the posteriorly pedicled nasoseptal flap and the inferior and middle turbinate flaps.24 In comparison to the aforementioned flaps, the pedicle to the anterior nasoseptal flap is located more anteriorly and superiorly, making it ideal for anterior skull base defects. The authors who developed this flap recommend its use for reconstruction of large anterior defects when a posteriorly pedicled nasoseptal flap is unavailable.24 Others have reported additional anteriorly based flaps for reconstruction of the frontal beak when the length of a posterior nasoseptal flap would be insufficient.13 Arterial supply to the anterior septum is not as robust and as such the anteriorly pedicled nasoseptal flap is bipedicled, receiving blood supply from the superior labial and nasopalatine arteries.

38.5.4 Pericranial Flaps The pericranial flap is robust and versatile. It is widely used for a variety of indications. This flap consists of the pericranium and subgaleal tissue. It may be modified to include the galea aponeurotica (i.e., galeopericranial flap).1 This is a bipedicled flap receiving its blood supply from the supraorbital and supratrochlear arteries. It may be tailored to specific coverage needs spanning from the anterior cranial fossa to the sella.3 The pericranial flap may be used in a variety of ways. Traditional open approaches following cranialization of the frontal sinus allow for subfrontal graft placement. In recent years, the endoscopically assisted or minimally invasive pericranial flap has been described.11,23,31 In this variation on the open technique, the flap is tunneled through a nasionectomy to enter the nasal cavity. Lastly, the so-called moneybox slot technique in which a frontal osteotomy is performed at the superior margin of the frontal sinus to allow subfrontal pericranial graft placement without disruption of the sinus drainage pathway represents an additional method to utilize this flap when exposure of the frontal sinus is unwarranted.32

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38.5.5 Temporoparietal Fascia Flap Similar to the pericranial flap, the TPFF originally described in open approaches has been adapted for endonasal repair techniques when more straightforward nasal repair options are unavailable.21 This flap is composed of a thin fascial layer deep to the fatty layer of the scalp but just superficial to the temporalis fascia. It receives arterial supply from the superficial temporal artery. The TPFF is widely versatile and may be used to reconstruct defects along the orbit, midface, auricle, and lateral skull base.1,33 Its use as a pedicled vascular flap for endonasal reconstruction has also been described. Extensive dissection and endonasal exposure is required to successfully maneuver this flap into the nasal cavity via the pterygopalatine fossa.11 Primarily used for clival or parasellar defects, the TPFF is frequently inadequate for more anteriorly located dural defects.14

38.5.6 Rescue Flaps In the situation that the aforementioned flaps are all unavailable, there are additional extranasal flap options. Owing to the relatively infrequent use of these techniques, we have chosen not to describe them in great detail. Additional technical information regarding the greater palatine artery palatal flap, the facial artery buccinator flap, and the split-calvarial osteopericranial flap may be reviewed in other studies.18,25,26,31

38.6 Distant Extranasal Rotational Flaps Extranasal flaps can be rotated from sites inferior to the skull base. These reconstruction options are notable for robust vasculature and the ability to harvest a relatively thick graft with a large surface area. For patients undergoing irradiation, these flaps are often outside of the radiation field and therefore important reconstruction options to keep in mind. Due to their traditional use in head and neck surgery, otolaryngologists are often most familiar with construction of these flaps. In recent years, routine use of these techniques has declined due to the availability of excellent local extranasal flaps and improvements in free flap techniques. There can be significant difficulty in extending these flaps to such long distances from their vascular pedicle, especially when they require rotation around the clavicle.34,35 Depending on the surgical positioning, use of these techniques can require patient repositioning, which significantly complicates reconstruction and increases total surgical time. Similar to other rotational flaps, these flaps are categorized by the nutrient artery. Currently, these are often used for patients who are thought to be poor candidates for the prolonged operative times associated with free flap transfer.36,37,38 Latissimus dorsi flaps are based on the thoracodorsal artery, a branch of the subscapular artery. Their use for reconstruction in the head and neck was first described by Quillen in 1978.39 To maintain the vascular supply, it is transposed through the axilla and between the pectoralis muscles. Following transposition, there are noticeable morbid functional deficits which may eventually be offset by hypertrophy of the teres minor muscle.40,41 The lower trapezius flap42,43,44 is based on either the dorsal scapular artery45 or transverse cervical artery.43,46 This flap can

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Controversies in Skull Base Reconstruction Techniques reconstruct both cutaneous and subcutaneous defects in the lateral skull base region. If the other cervical musculature is intact, there should not be noticeable functional morbidity after mobilization of the trapezius.47 Pectoralis major flaps are based on the thoracoacromial artery, a branch of the axillary artery.48 After dissecting the pectoralis major free from its attachments, it is rotated upward across the clavicle. This significantly limits the ability to reach defects at the skull base and is often only considered viable for tissue defects inferior to the external auditory canal.37,49 Technique modifications have been described extending the reach of this flap above the temporal line.36 Significant functional morbidity following resection of pectoralis major for reconstruction is uncommon.50

38.7 Revascularized Free Flaps Free flaps are commonly cited as preferable to rotational flaps for skull base reconstruction.48,51,52,53,54,55,56,57,58 Free flaps have been shown to have lower overall complication rates and higher healing rates when compared to rotational flaps.48,52,56,57 Revascularized free flaps combine many of the benefits of distant rotational flaps without many of the limitations. Similar to distant rotational flaps, they are not included in the radiation field and should have a normal vasculature. Unlike distant rotational flaps, they have significantly more reach due to the lack of a tethering neurovascular complex. When using a rotation flap, the distal portion has the poorest blood supply, but is unfortunately likely to be the portion covering the defect.48 For rotational flaps without an accompanying neck dissection, tunneling of the flap can cause pedicle compression.57 The clear drawback to revascularized free flaps is the significant increase in technical difficulty. However, revascularization significantly expands the options for potential donor sites, thus allowing surgeons to choose a donor site with the least morbidity. In addition, the ability of two surgical teams to work in parallel has been shown to significantly decrease surgical time.59 The first free flap used in clinical practice was the gastroomental free flap, based on the gastroepiploic artery.60 Interestingly, this first report was performed for coverage of a large scalp defect. This flap consists of omentum with or without a portion of gastric mucosa. Similar to the rectus abdominis flap, it can be harvested in parallel and provides a long vascular pedicle for reimplantation. Given the consistency of this flap, it conforms well to defects with a complex three-dimensional shape. However, its use in reconstruction of skull base defects is less common.60,61,62,63,64,65 For skull base reconstruction, the traditional “workhorse” free flap is the rectus abdominis flap.66,67,68,69,70 This flap is based on the deep inferior epigastric artery and can be harvested with muscle, fascia, and a large cutaneous portion if needed. This technique has many benefits. Except for prone positioning, this flap can be prepared and harvested in parallel to cranial surgery. It is comparatively easy to harvest and provides a long vascular pedicle for reimplantation. The main downside of this flap is its large bulk, which is even greater in obese patients. There is also a long-term risk of development of a ventral abdominal hernia.66,67,68,69,70 The latissimus free flap has been used frequently in skull base reconstruction.70,71,72,73,74 For the largest defects, scapular and

latissimus free flaps can be combined into the so-called axillary megaflap.75,76,77 These flaps can provide any desired combination of tissues, including scapular bone if needed. There are two main downsides of using this technique. It usually requires patient repositioning without the ability for the two surgical teams to work in parallel. The latissimus flap has a long vascular pedicle for reimplantation. However, the scapular free flap has a short vascular pedicle that can require an interposition graft, adding repair time. The initial muscle bulk of the latissimus flap will diminish following denervation atrophy, leading to shrinkage of the flap and potential incompetence. Flaps can also be created from the forearm, based on the radial artery.57,70,78,79 Given the functional importance of musculature in this region, these are usually harvested with only fascia and skin, providing a relatively small flap with significantly less bulk than the free flap techniques described earlier. There are objective functional deficits following flap harvest, but do not appear to correlate with subjective patient complaints of functional loss.80 Lastly, in recent years, reconstruction has also been performed with the anterolateral thigh flap, which is based on perforators from the lateral femoral circumflex artery.59,70

38.8 What Are the Controversies? 38.8.1 Endoscopic Endonasal Skull Base Reconstruction: Is a Flap Always Necessary? The options for skull base reconstruction are vast. The reconstruction method chosen is often dictated by the surgery team’s preference, as multiple techniques may be appropriate in a given patient. The goal of any reconstruction is to separate the brain from the outside world. The most obvious indicator of this goal not being met is CSF leakage intraoperatively or in the perioperative period. Intraoperatively, CSF leaks may be described as absent, low flow, or high flow, described in further detail later. In the absence of CSF leak, relatively simple repair techniques often suffice. For endonasal procedures, this may consist of synthetic dural replacement or free mucosal graft along with appropriate buttressing. Smaller defects are the most commonly encountered variety in all clinical settings.4 In the setting of low-flow CSF leaks without communication with a ventricle or cistern, fat grafts, mucosal grafts, and/or fascia lata are frequently adequate.2 Furthermore, authors have reported that when a low-flow CSF leak was present intraoperatively, use of a synthetic dural onlay graft was sufficient for reconstruction.2 In general, multilayered closure techniques using a variety of free grafts and/or synthetic materials for smaller defects (< 1 cm) have proven successful for long time repair in more than 90% of cases.3,81 The low morbidity and ease of harvesting technique have led some to utilize a nasoseptal flap as part of a multilayered reconstruction in all cases of low-flow CSF leak, supplementing the reconstruction with either abdominal fat or fascia lata, or both, depending on the size and location of the dural defect.14 Utilizing this approach, a postoperative CSF leak of just 2.1% was obtained. While it seems likely that a more extensive, and frequently more invasive, repair strategy may minimize the overall rate of

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Surgical Approaches and Techniques CSF leak among all patients, it is apparent from the literature that for many patients with a weeping, low-flow CSF leak, more limited repairs often suffice. In the setting of a small defect with a high-flow leak, more extensive repairs including vascularized flaps are warranted. As alluded to earlier, when deciding the best reconstruction option, surgeons must consider not only the robustness of a CSF leak but also the size of the dural defect. Utilization of free grafts alone in larger defects (> 3 cm) is associated with higher rates of CSF leak.3 Reconstruction of large defects following intradural tumor resection is made difficult by high-flow CSF leaks, a frequent lack of graft supporting structures, and the potential for early hydrocephalus.4 For high-flow CSF leaks or dural defects greater than 3 cm, a multilayer repair including a vascularized flap is frequently the best option.25 Beyond the robustness of intraoperative CSF leak and the size of the dural defect, there are other factors to consider. One is the location and nature of the dural defect, irrespective of the size. For example, an anterior fossa dural defect with bony ledges available to support the graft material in the epidural space is favorable for limited reconstruction, while repair of a similar defect without bony ledges for graft support requires additional techniques.14 In a series of 12 patients reporting outcomes following repair of anterior skull base dural defects greater than 2 cm, a CSF leak rate of 0% was obtained using a single layer of acellular dermal allograft.82 The graft was positioned intracranially with the margins of the graft tucked into the epidural space over the bony margins of the defect. However, depending on the nature of the skull base defect, such a technique may not be tenable. In these situations, multiple repair layers serve to bolster one another until a stable seal is achieved. In a large review, the postoperative CSF leak rate following all endoscopic endonasal approaches was 8.5%.6 In general, the use of vascularized flap in conjunction with a multilayered reconstruction prevented CSF leak in all but 6% of cases. In comparison, free tissue grafts as part of a multilayered repair resulted in a CSF leak of 18%. In the anterior cranial fossa, a successful dural repair was achieved in 92%, regardless of the reconstructive technique utilized. In subgroup analysis, however, use of a vascularized flap was associated with a lower CSF leak rate when compared to free tissue grafts. In the same review, dural defects near the clivus were associated with a 20% rate of CSF leak. Similarly, the best results were achieved with vascularized flaps as compared to free tissue flaps. In a recent series reporting outcomes after endoscopic endonasal resection of primary skull base malignancies involving the clivus, nasoseptal flaps were used in all cases regardless of whether or not an intraoperative CSF leak was encountered.8 Despite immediate postoperative lumbar drain placement in those with an intraoperative leak, the CSF leak rate for all patients was 16.7%. In a meta-analysis examining outcomes after endoscopic endonasal repair of large dural defects in 609 patients, 54% underwent reconstruction with free graft materials and 46% with vascularized flaps.3 The overall CSF leak rate was 11.5%. In subgroup analysis, the CSF leak rate for those undergoing repair with free grafts was 15.6% compared to a leak rate of 6.7% when a vascularized repair was utilized. The use of multilayered closure techniques along with vascularized flaps appears to confer the least chance of developing a postoperative CSF leak.

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Recently, surgeons have begun to expand endoscopic endonasal approaches to include tumors in the petroclival region.7,10,83, 84 Early studies primarily examined surgical treatment of extradural inflammatory lesions, but since that time surgeons have begun to expand these approaches to include intradural petroclival tumors. While the overall CSF leak rate following the majority of endoscopic endonasal approaches is 8.5 to 11.5%, the risk of CSF leak following resection of intradural tumors in the petroclival region is 22 to 41% despite the use of vascularized flaps.3,6, 10,83 It is worth noting that the methods described are relatively recent and likely subject to the steep learning curve common to the introduction of new endoscopic endonasal techniques. However, by comparison, a CSF leak of just 4% has been reported following open approaches to petroclival meningiomas.85 Other disease-specific factors that have been reported to increase the likelihood of developing a postoperative CSF leak include meningioma or craniopharyngioma resection, Cushing disease, pseudotumor cerebri, obstructive sleep apnea, and morbid obesity.1 The extensive bony and dural removal inherent to meningioma resection; the opening of cisterns and communication with the third ventricle common to craniopharyngioma removal; the poor wound healing frequently experienced by patients with Cushing disease; and the elevated intracranial pressure associated with pseudotumor, obstructive sleep apnea, and obesity all provide the setup for perioperative CSF leak. In these clinical settings, authors strongly support the use of vascularized flaps as part of the multilayered reconstruction.3,25,31 Other secondary considerations for the use of vascularized flaps include the need for cranial irradiation to the site of repair or in revision surgery.14 In cases of reoperation, a nasoseptal flap may not be available. Realization of this fact preoperatively is necessary to decide which reconstruction options are available. For defects in the anterior cranial fossa, the endoscopically assisted pericranial flap is a repair option as it provides a large surface area for repair.14,23 However, this technique requires additional cranial incisions and results in a facial scar.86 For more posteriorly located sellar defects, the middle turbinate or inferior turbinate flap may be adequate for smaller defects, while larger defects may be repaired using the TPFF.14,21 While less commonly reported, a series of 16 patients with intranasal dural defects in whom a nasoseptal flap was not a repair option, utilization of a pericranial flap, a TPFF, or an inferior turbinate flap resulted in a postoperative CSF leak rate of 0%.14 When cancer is present within the nasal septum or within the resection margins, the nasoseptal flap is no longer a repair option. The use of abdominal fat as a primary repair technique in this situation has been described with excellent results.86 In a series of 29 patients with malignant sinonasal tumors resected endoscopically via a transcribriform approach, dural reconstruction was performed using an abdominal fat graft and fibrin glue in combination with nasal packing. No vascularized flaps were utilized. The postoperative CSF leak rate was 3.5% which occurred in one patient. The authors describe their technique of sizing the fat graft to extend 1 cm beyond the bony margins in all directions and to be at least 2 cm in thickness. The largest defect repaired in this series measured 3.5 cm in length by 2.6 cm in width. It is also worth noting that while only a single patient developed a postoperative CSF leak, 23 (79.3%) patients underwent postoperative radiotherapy to the tumor site.

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Controversies in Skull Base Reconstruction Techniques

38.8.2 Does a Lumbar Drain Prevent a Postoperative Leak? In endoscopic endonasal skull base surgery, the indications and timing of lumbar drain placement vary significantly. Analysis of studies comparing outcomes following endoscopic endonasal skull base surgery with or without lumbar drain placement is made difficult to compare as the criteria to place a lumbar drain varies among surgeons, being subject to interpretation of the leak being high flow or low flow. In addition, the timing of lumbar drain placement is debated with both preventative and wait-and-see strategies reported.8,10,14 In general, authors advocate for lumbar drain use when a persistent CSF leak occurs resulting from arachnoidal opening, during a skull base exposure with a tumor greater than 3 cm, or in repeat operations.2,14 On the other side of the argument, an analysis of the complications of 65 patients who underwent prospective lumbar drain placement prior to endoscopic anterior skull base surgery was performed.87 The overall CSF leak was 6.2%. However, the authors report a 12.3% complication rate attributable to lumbar drain placement, including three cases of hospital readmission. The authors question whether or not this is an acceptable risk to the patient. Common complications from lumbar drain placement include infection, spinal headache, nerve root irritation, and pneumocephalus.2 The prolonged immobilization associated with lumbar drain use also places patients at risk for thromboembolic and pulmonary complications.29 Others report not using a lumbar drain in any case, opting to endoscopically repair cases of persistent postoperative CSF leak.29,86 There is a general trend for a more extensive multilayered closure technique (incorporating vascularized flaps) to be utilized when the perceived risk of CSF leak is enough to prompt lumbar drain placement in the surgeon’s mind.2 This fact makes it challenging to determine if the addition of a lumbar drain results in a lower rate of CSF leak when a more extensive repair technique is concomitantly utilized. In the setting of a postoperative CSF leak, lumbar drains have been shown to be an effective initial therapy. However, the benefits of lumbar drain placement on postoperative CSF leak reduction are less clear when vascularized flaps are used in the reconstruction.6 For example, in a series of 42 patients with primary clival malignancies, the authors utilized a vascularized flap as a part of the reconstruction in all patients regardless of whether or not an intraoperative CSF leak was encountered.8 Overall, a CSF leak occurred in seven (16.7%) patients. In the 19 (45.2%) patients noted to have an intraoperative CSF leak secondary to intradural tumor, a lumbar drain was placed at the time of surgery. Despite reconstruction using a vascularized flap and CSF diversion using a lumbar drain perioperatively, 4 (21.1%) of the 19 patients still developed a postoperative CSF leak, requiring additional surgical repair. The other three patients (who did not undergo lumbar drain placement as no leak was noted intraoperatively) developed a postoperative CSF leak despite reconstruction using a vascularized flap. In a meta-analysis examining the effect of lumbar drain placement on postoperative CSF leak recurrence following endoscopic repair of CSF rhinorrhea, the authors concluded that lumbar drains did not lower rates of postoperative CSF leak recurrence.88 In addition, subgroup analysis of CSF leaks resulting from anterior skull

base resections found that lumbar drains did not affect the rate of successful repair. Despite compelling arguments questioning the effectiveness of lumbar drains and the acknowledgement of a notable complication rate, intraoperative or postoperative lumbar drain placement in the presence of a CSF leak may benefit some patients. When vascularized flaps are used as part of a multilayered reconstruction, the benefits of lumbar drain placement appear less obvious. At present, there is no agreed upon algorithm for the indications and timing of lumbar drain placement. For further details on the role of lumbar drains in skull base surgery, see Chapter 39.

38.8.3 Should Antibiotic Prophylaxis Be Used? As the nasal cavity is nonsterile, concerns for development of intracranial infection following endoscopic skull base approaches is warranted. Despite this, the risk of infection has been reported to be comparable to that of open approaches in recent analyses.89 A modern review of 1,000 endonasal skull base procedures reported an infection rate of just 1.8%.90 Although the infection rates appear to be comparable to open approaches, there is currently no agreed upon management algorithm for antibiotic prophylaxis.89 Authors hypothesize that the most significant contributor to developing postoperative meningitis is development of a CSF leak with the risk of meningitis in those with a leak being 66% compared to just 4.5% in those without a postoperative leak.91 It follows, therefore, that achieving a watertight repair is a key component in infection prevention. As means to this end, the nasoseptal flap has reduced CSF leaks in several series compared to surgeries performed prior to its inception.92,93,94 In a large analysis, authors reported a 0% incidence of postoperative bacterial meningitis when vascularized flaps were used in the reconstruction of skull base defects.3 The rate of postoperative meningitis was 0 to 14% in cases where free tissue grafts were used for dural reconstruction in lieu of vascularized flaps. However, as noted by others, the incidence of postoperative meningitis was not included in all studies analyzed.86 There is a great variety of approaches to minimizing postoperative infection with some authors advocating specific regimens and others reporting the theoretical advantages of avoiding postoperative antibiotics, namely, masking meningitis.86,89,95 Authors have raised concern over liberal use of antibiotics due to concern for development of antibiotic-resistant meningitis as well as the frequently encountered side effects of these medications. Interestingly, in a study examining postoperative meningitis, there was no difference in mortality between patients who developed meningitis due to bacteria that were either susceptible or resistant to the prophylactic regimen.96 The concerns for increased mortality associated with antibiotic-resistant bacterial meningitis while logical have not been demonstrated to affect clinical outcomes. Typical management strategies include intravenous antibiotics at the time of surgery alone or for 24 hours postoperatively. Oral antibiotics are continued until nasal packing is removed. In an article surveying the infectious protocols following endonasal skull base surgery of 10 different institutions, 10 unique postoperative antibiotic treatment algorithms were reported.89

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Surgical Approaches and Techniques While it appears that some form of prophylactic antibiotics are used in nearly all institutions, the optimal postoperative treatment regimen is entirely unclear.

38.9 Conclusions The reconstruction of skull base defects remains a challenge in skull base surgery. The optimal methods for reconstruction are dependent on characteristics of the defect as well as the clinical setting. The location, size, and flow of CSF from the defect must all be taken into account. In addition, for patients with a history of irradiation or in those with upcoming irradiation, a more extensive reconstruction using vascularized flaps is recommended. Lastly, the experience of the surgical team also dictates the reconstruction method.

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[18] Engle RD, Butrymowicz A, Peris-Celda M, Kenning TJ, Pinheiro-Neto CD. Split-calvarial osteopericranial flap for reconstruction following endoscopic anterior resection of cranial base. Laryngoscope. 2015; 125(4):826–830 [19] Battaglia P, Turri-Zanoni M, Castelnuovo P, Prevedello DM, Carrau RL. Brain herniation after endoscopic transnasal resection of anterior skull base malignancies. Neurosurgery. 2015; 11 Suppl 3:457–462, discussion 462 [20] Nyquist GG, Anand VK, Singh A, Schwartz TH. Janus flap: bilateral nasoseptal flaps for anterior skull base reconstruction. Otolaryngol Head Neck Surg. 2010; 142(3):327–331 [21] Fortes FS, Carrau RL, Snyderman CH, et al. Transpterygoid transposition of a temporoparietal fascia flap: a new method for skull base reconstruction after endoscopic expanded endonasal approaches. Laryngoscope. 2007; 117(6): 970–976 [22] Prevedello DM, Barges-Coll J, Fernandez-Miranda JC, et al. Middle turbinate flap for skull base reconstruction: cadaveric feasibility study. Laryngoscope. 2009; 119(11):2094–2098 [23] Zanation AM, Snyderman CH, Carrau RL, Kassam AB, Gardner PA, Prevedello DM. Minimally invasive endoscopic pericranial flap: a new method for endonasal skull base reconstruction. Laryngoscope. 2009; 119(1):13–18 [24] Hadad G, Rivera-Serrano CM, Bassagaisteguy LH, et al. Anterior pedicle lateral nasal wall flap: a novel technique for the reconstruction of anterior skull base defects. Laryngoscope. 2011; 121(8):1606–1610 [25] Zanation AM, Thorp BD, Parmar P, Harvey RJ. Reconstructive options for endoscopic skull base surgery. Otolaryngol Clin North Am. 2011; 44(5): 1201–1222 [26] Rivera-Serrano CM, Oliver CL, Sok J, et al. Pedicled facial buccinator (FAB) flap: a new flap for reconstruction of skull base defects. Laryngoscope. 2010; 120 (10):1922–1930 [27] Kim SW, Park KB, Khalmuratova R, Lee HK, Jeon SY, Kim DW. Clinical and histologic studies of olfactory outcomes after nasoseptal flap harvesting. Laryngoscope. 2013; 123(7):1602–1606 [28] Shin JH, Kang SG, Kim SW, et al. Bilateral nasoseptal flaps for endoscopic endonasal transsphenoidal approach. J Craniofac Surg. 2013; 24(5):1569– 1572 [29] Liu JK, Schmidt RF, Choudhry OJ, Shukla PA, Eloy JA. Surgical nuances for nasoseptal flap reconstruction of cranial base defects with high-flow cerebrospinal fluid leaks after endoscopic skull base surgery. Neurosurg Focus. 2012; 32(6):E7 [30] Choby GW, Pinheiro-Neto CD, de Almeida JR, et al. Extended inferior turbinate flap for endoscopic reconstruction of skull base defects. J Neurol Surg B Skull Base. 2014; 75(4):225–230 [31] Kim GG, Hang AX, Mitchell CA, Zanation AM. Pedicled extranasal flaps in skull base reconstruction. Adv Otorhinolaryngol. 2013; 74:71–80 [32] Majer J, Herman P, Verillaud B. “Mailbox Slot” pericranial flap for endoscopic skull base reconstruction. Laryngoscope. 2016; 126(8):1736–1738 [33] Reyes C, Mason E, Solares CA. Panorama of reconstruction of skull base defects: from traditional open to endonasal endoscopic approaches, from free grafts to microvascular flaps. Int Arch Otorhinolaryngol. 2014; 18 Suppl 2: S179–S186 [34] Chang DW, Langstein HN, Gupta A, et al. Reconstructive management of cranial base defects after tumor ablation. Plast Reconstr Surg. 2001; 107(6): 1346–1355, discussion 1356–1357 [35] Liu JK, Niazi Z, Couldwell WT. Reconstruction of the skull base after tumor resection: an overview of methods. Neurosurg Focus. 2002; 12(5):e9 [36] Resto VA, McKenna MJ, Deschler DG. Pectoralis major flap in composite lateral skull base defect reconstruction. Arch Otolaryngol Head Neck Surg. 2007; 133(5):490–494 [37] Moore BA, Wine T, Netterville JL. Cervicofacial and cervicothoracic rotation flaps in head and neck reconstruction. Head Neck. 2005; 27(12):1092–1101 [38] Patel NS, Modest MC, Brobst TD, et al. Surgical management of lateral skull base defects. Laryngoscope. 2016; 126(8):1911–1917 [39] Quillen CG, Shearin JC, Jr, Georgiade NG. Use of the latissimus dorsi myocutaneous island flap for reconstruction in the head and neck area: case report. Plast Reconstr Surg. 1978; 62(1):113–117 [40] Russell RC, Pribaz J, Zook EG, Leighton WD, Eriksson E, Smith CJ. Functional evaluation of latissimus dorsi donor site. Plast Reconstr Surg. 1986; 78(3): 336–344 [41] Spear SL, Hess CL. A review of the biomechanical and functional changes in the shoulder following transfer of the latissimus dorsi muscles. Plast Reconstr Surg. 2005; 115(7):2070–2073 [42] McCraw JB, Magee WP, Jr, Kalwaic H. Uses of the trapezius and sternomastoid myocutaneous flaps in head and neck reconstruction. Plast Reconstr Surg. 1979; 63(1):49–57

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Controversies in Skull Base Reconstruction Techniques [43] Rosen HM. The extended trapezius musculocutaneous flap for cranio-orbital facial reconstruction. Plast Reconstr Surg. 1985; 75(3):318–327 [44] Uğurlu K, Ozçelik D, Hüthüt I, Yildiz K, Kilinç L, Baş L. Extended vertical trapezius myocutaneous flap in head and neck reconstruction as a salvage procedure. Plast Reconstr Surg. 2004; 114(2):339–350 [45] Netterville JL, Wood DE. The lower trapezius flap. Vascular anatomy and surgical technique. Arch Otolaryngol Head Neck Surg. 1991; 117(1):73–76 [46] Chandrasekhar B, Terz JJ, Kokal WA, Beatty JD, Gottlieb ME. The inferior trapezius musculocutaneous flap in head and neck reconstruction. Ann Plast Surg. 1988; 21(3):201–209 [47] Yang HJ, Lee DH, Kim YW, Lee SG, Cheon YW. The trapezius muscle flap: a viable alternative for posterior scalp and neck reconstruction. Arch Plast Surg. 2016; 43(6):529–535 [48] Neligan PC, Mulholland S, Irish J, et al. Flap selection in cranial base reconstruction. Plast Reconstr Surg. 1996; 98(7):1159–1166, discussion 1167– 1168 [49] Schusterman MA, Kroll SS. Reconstruction strategy for temporal bone and lateral facial defects. Ann Plast Surg. 1991; 26(3):233–242 [50] Merve A, Mitra I, Swindell R, Homer JJ. Shoulder morbidity after pectoralis major flap reconstruction for head and neck cancer. Head Neck. 2009; 31 (11):1470–1476 [51] Disa JJ, Rodriguez VM, Cordeiro PG. Reconstruction of lateral skull base oncological defects: the role of free tissue transfer. Ann Plast Surg. 1998; 41(6): 633–639 [52] Neligan PC, Boyd JB. Reconstruction of the cranial base defect. Clin Plast Surg. 1995; 22(1):71–77 [53] Jones TR, Jones NF. Advances in reconstruction of the upper aerodigestive tract and cranial base with free tissue transfer. Clin Plast Surg. 1992; 19(4): 819–831 [54] Chang DW, Robb GL. Microvascular reconstruction of the skull base. Semin Surg Oncol. 2000; 19(3):211–217 [55] Besteiro JM, Aki FE, Ferreira MC, Medina LR, Cernea C. Free flap reconstruction of tumors involving the cranial base. Microsurgery. 1994; 15 (1):9–13 [56] Califano J, Cordeiro PG, Disa JJ, et al. Anterior cranial base reconstruction using free tissue transfer: changing trends. Head Neck. 2003; 25(2):89–96 [57] Teknos TN, Smith JC, Day TA, Netterville JL, Burkey BB. Microvascular free tissue transfer in reconstructing skull base defects: lessons learned. Laryngoscope. 2002; 112(10):1871–1876 [58] Pusic AL, Chen CM, Patel S, Cordeiro PG, Shah JP. Microvascular reconstruction of the skull base: a clinical approach to surgical defect classification and flap selection. Skull Base. 2007; 17(1):5–15 [59] Hanasono MM, Sacks JM, Goel N, Ayad M, Skoracki RJ. The anterolateral thigh free flap for skull base reconstruction. Otolaryngol Head Neck Surg. 2009; 140(6):855–860 [60] McLean DH, Buncke HJ, Jr. Autotransplant of omentum to a large scalp defect, with microsurgical revascularization. Plast Reconstr Surg. 1972; 49(3):268– 274 [61] Barrow DL, Nahai F, Tindall GT. The use of greater omentum vascularized free flaps for neurosurgical disorders requiring reconstruction. J Neurosurg. 1984; 60(2):305–311 [62] Costantino PD, Shamouelian D, Tham T, Andrews R, Dec W. The laparoscopically harvested omental free flap: a compelling option for craniofacial and cranial base reconstruction. J Neurol Surg B Skull Base. 2017; 78 (2):191–196 [63] Ikuta Y. Autotransplant of omentum to cover large denudation of the scalp. Case report. Plast Reconstr Surg. 1975; 55(4):490–493 [64] Yamaki T, Uede T, Tano-oka A, Asakura K, Tanabe S, Hashi K. Vascularized omentum graft for the reconstruction of the skull base after removal of a nasoethmoidal tumor with intracranial extension: case report. Neurosurgery. 1991; 28(6):877–880 [65] Panje WR, Pitcock JK, Vargish T. Free omental flap reconstruction of complicated head and neck wounds. Otolaryngol Head Neck Surg. 1989; 100(6): 588–593 [66] Olsen KD, Meland NB, Ebersold MJ, Bartley GB, Garrity JA. Extensive defects of the sino-orbital region. Results with microvascular reconstruction. Arch Otolaryngol Head Neck Surg. 1992; 118(8):828–833, discussion 859–860 [67] Bridger GP, Baldwin M. Anterior craniofacial resection for ethmoid and nasal cancer with free flap reconstruction. Arch Otolaryngol Head Neck Surg. 1989; 115(3):308–312 [68] Urken ML, Catalano PJ, Sen C, Post K, Futran N, Biller HF. Free tissue transfer for skull base reconstruction analysis of complications and a classification

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scheme for defining skull base defects. Arch Otolaryngol Head Neck Surg. 1993; 119(12):1318–1325 Izquierdo R, Leonetti JP, Origitano TC, al-Mefty O, Anderson DE, Reichman OH. Refinements using free-tissue transfer for complex cranial base reconstruction. Plast Reconstr Surg. 1993; 92(4):567–574, discussion 575 Clayman GL, DeMonte F, Jaffe DM, et al. Outcome and complications of extended cranial-base resection requiring microvascular free-tissue transfer. Arch Otolaryngol Head Neck Surg. 1995; 121(11):1253–1257 Barrow DL, Nahai F, Fleischer AS. Use of free latissimus dorsi musculocutaneous flaps in various neurosurgical disorders. J Neurosurg. 1983; 58(2):252– 258 Robson MC, Zachary LS, Schmidt DR, Faibisoff B, Hekmatpanah J. Reconstruction of large cranial defects in the presence of heavy radiation damage and infection utilizing tissue transferred by microvascular anastomoses. Plast Reconstr Surg. 1989; 83(3):438–442 Jones NF, Hardesty RA, Swartz WM, Ramasastry SS, Heckler FR, Newton ED. Extensive and complex defects of the scalp, middle third of the face, and palate: the role of microsurgical reconstruction. Plast Reconstr Surg. 1988; 82 (6):937–952 Taniguchi Y, Tamaki T, Yoshida M, Uematsu Y. Reconstruction of a scalp and skull defect with free latissimus dorsi myocutaneous flap following dermatofibrosarcoma protuberans. J Orthop Surg (Hong Kong). 2002; 10 (2):206–209 Hallock GG. The combined parascapular fasciocutaneous and latissimus dorsi muscle conjoined free flap. Plast Reconstr Surg. 2008; 121(1):101–107 Belousov AE, Kichemasov SD, Kochish AY, Pinchuk VD. Vascularized megaflaps. Ann Plast Surg. 1993; 31(1):54–59 Aviv JE, Urken ML, Vickery C, Weinberg H, Buchbinder D, Biller HF. The combined latissimus dorsi-scapular free flap in head and neck reconstruction. Arch Otolaryngol Head Neck Surg. 1991; 117(11):1242–1250 Lin AC, Lin DT. Reconstruction of lateral skull base defects with radial forearm free flaps: the double-layer technique. J Neurol Surg B Skull Base. 2015; 76 (4):257–261 Burkey BB, Gerek M, Day T. Repair of the persistent cerebrospinal fluid leak with the radial forearm free fascial flap. Laryngoscope. 1999; 109(6):1003– 1006 Brown MT, Couch ME, Huchton DM. Assessment of donor-site functional morbidity from radial forearm fasciocutaneous free flap harvest. Arch Otolaryngol Head Neck Surg. 1999; 125(12):1371–1374 Hegazy HM, Carrau RL, Snyderman CH, Kassam A, Zweig J. Transnasal endoscopic repair of cerebrospinal fluid rhinorrhea: a meta-analysis. Laryngoscope. 2000; 110(7):1166–1172 Germani RM, Vivero R, Herzallah IR, Casiano RR. Endoscopic reconstruction of large anterior skull base defects using acellular dermal allograft. Am J Rhinol. 2007; 21(5):615–618 Pinheiro-Neto CD, Paluzzi A, Fernandez-Miranda JC, et al. Extended dissection of the septal flap pedicle for ipsilateral endoscopic transpterygoid approaches. Laryngoscope. 2014; 124(2):391–396 Hofstetter CP, Singh A, Anand VK, Kacker A, Schwartz TH. The endoscopic, endonasal, transmaxillary transpterygoid approach to the pterygopalatine fossa, infratemporal fossa, petrous apex, and the Meckel cave. J Neurosurg. 2010; 113(5):967–974 Nanda A, Javalkar V, Banerjee AD. Petroclival meningiomas: study on outcomes, complications and recurrence rates. J Neurosurg. 2011; 114(5):1268– 1277 Fonmarty D, Bastier PL, Lechot A, Gimbert E, de Gabory L. Assessment of abdominal fat graft to repair anterior skull base after malignant sinonasal tumor extirpation. Otolaryngol Head Neck Surg. 2016; 154(3):540–546 Ransom ER, Palmer JN, Kennedy DW, Chiu AG. Assessing risk/benefit of lumbar drain use for endoscopic skull-base surgery. Int Forum Allergy Rhinol. 2011; 1(3):173–177 Ahmed OH, Marcus S, Tauber JR, Wang B, Fang Y, Lebowitz RA. Efficacy of perioperative lumbar drainage following endonasal endoscopic cerebrospinal fluid leak repair. Otolaryngol Head Neck Surg. 2017; 156(1): 52–60 Johans SJ, Burkett DJ, Swong KN, Patel CR, Germanwala AV. Antibiotic prophylaxis and infection prevention for endoscopic endonasal skull base surgery: our protocol, results, and review of the literature. J Clin Neurosci. 2017 Kono Y, Prevedello DM, Snyderman CH, et al. One thousand endoscopic skull base surgical procedures demystifying the infection potential: incidence and description of postoperative meningitis and brain abscesses. Infect Control Hosp Epidemiol. 2011; 32(1):77–83

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[94] Ivan ME, Iorgulescu JB, El-Sayed I, et al. Risk factors for postoperative cerebrospinal fluid leak and meningitis after expanded endoscopic endonasal surgery. J Clin Neurosci. 2015; 22(1):48–54 [95] Brown SM, Anand VK, Tabaee A, Schwartz TH. Role of perioperative antibiotics in endoscopic skull base surgery. Laryngoscope. 2007; 117(9): 1528–1532 [96] Korinek AM, Baugnon T, Golmard JL, van Effenterre R, Coriat P, Puybasset L. Risk factors for adult nosocomial meningitis after craniotomy role of antibiotic prophylaxis. Neurosurgery. 2006; 59:126–133

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The Role of Lumbar Drains in Skull Base Surgery

39 The Role of Lumbar Drains in Skull Base Surgery Nathan T. Zwagerman, Carl Snyderman, Eric W. Wang, Paul A. Gardner, and Juan C. Fernandez-Miranda Abstract The role of lumbar drains for cerebral spinal fluid (CSF) diversion during skull base surgery has been controversial due to lack of a standardized protocol and proven efficacy. There is wide variation in how lumbar drains are used and the pathology they are associated with. Many surgeons, however, use them routinely for a wide variety of approaches and reconstructions. The seemingly endless variables result in much confusion and misleading information. This chapter aims to evaluate the best evidence available for the use of lumbar drains in skull base surgery and presents guidance on when and how to use them based on the available data. Keywords: lumbar drains, CSF leak, skull base, endoscopic endonasal, CSF diversion, suprasellar, anterior cranial fossa, posterior cranial fossa

39.1 Introduction Lumbar drains during and after skull base surgery have historically been used for brain relaxation and to prevent postoperative cerebral spinal fluid (CSF) leaks. However, this practice is controversial, as there are not only potential benefits but also harms that may occur with lumbar drain use. Moreover, there is no universal standard of use or duration. Many authors use lumbar drains in every case and others may not use them at all. Some authors use them during the case and remove them after, and some place them at the end of the case for drainage during the postoperative period. Furthermore, lumbar drains may be used from 1 to 7 days with variable draining rates. The goal of this chapter is to discuss the available evidence and present a comprehensive review of the current state of lumbar drains within skull base surgery and provide a resource for others to use in the future.

39.2 Review The role of CSF diversion has been described in a variety of skull base procedures ranging from open to endoscopic endonasal approaches.1,2,3 The benefits of lumbar drain use stem from the ability to increase brain relaxation and decrease brain retraction injuries as well as to aid reconstruction by reducing intracranial-related pressure on the repair.4,5,6 The objective for lumbar drainage of CSF is to allow for a low resistance method of controlled CSF egress to decrease intracranial pressure during and after the surgery permitting the skull base defect and wound closure to heal without increased tension from intracranial pressure and prevent CSF fistula formation. Unfortunately, there are risks associated with lumbar drain placement which can include minor and major complications.7 The most common risks associated with lumbar drainage of CSF include low pressure–type headache, nausea, and vomiting which can range from 13 to 63% of cases.8,9,10 Infections and meningitis rates range from 4 to 10% of cases.11 The risk of infection increases

with duration of drain placement.12 Some of the unusual but major complications include neurological deficits due to overdrainage with tonsillar herniation, acute or delayed intracranial hypotension, intracranial venous thrombosis, tension pneumocephalus, lumbar nerve root irritation, cranial nerve palsy, and retained catheters.13,14,15,16,17,18,19,20 Also, indirect risks of patient immobilization must be accounted for including pneumonia, deep venous thrombosis, and urinary tract infections.

39.3 Discussion of Evidence CSF leak and brain retraction injuries remain one of the major challenges in skull base surgery.21,22,23,24 Vascularized tissue has become the foundation for reconstruction.25,26,27 Horiguchi et al compared patients who underwent endoscopic endonasal surgery (EES) with nasoseptal flap reconstruction and those who underwent EES with fat graft or fascia lata reconstruction, and found there was a significant difference in CSF leak rates (9.5 and 27.3%, respectively).28 This is in agreement with other studies that reported low CSF leak rates with vascular flap reconstruction ranging from 0 to 5.7% leak rate.6,29 As a result, current skull base surgery for the most commonly performed procedures provides a much lower risk of CSF leak than previously described.30,31 Based on potential risks for serious complications of lumbar drainage, the low rate of CSF leak with current reconstruction techniques, and the wide variation in its application, the necessity of lumbar drains after skull base surgery remains unclear. Given the differences in technique and surgeons’ preference, it is difficult to assess the utility of lumbar drainage for brain relaxation during surgery. For the purpose of this chapter, we will focus on lumbar drainage for postoperative CSF leaks. A retrospective transcranial study indicated that the rates of postoperative CSF leakage were 35% in patients with no perioperative lumbar drain and 12% in patients with lumbar drains.2 A study evaluating reconstruction techniques for posterior fossa surgery indicated that lumbar drains did not significantly alter postoperative CSF leaks in this setting.32 Another study looked at a large group of patients with CSF fistulae from spinal and cranial surgeries as well as traumatic causes and showed the rate of CSF leak at 6% when lumbar drain is used.10 However, there have been no prospective studies assessing the usefulness of lumbar drains in skull base surgery. The endoscopic skull base literature has been more productive recently to address this question and an important confounder is identifying CSF leaks as high flow or low flow. A practical definition of “high-flow CSF leak” is one that violates a ventricle or cistern and requires a more robust reconstruction.33,34 Clinical practice varies widely (▶ Table 39.1). Some studies suggest that lumbar drains do not need to be routinely used since the advent of the nasoseptal flap. Garcia-Navarro et al indicated that there was no association between lumbar drain usage and postoperative CSF leak, but they did note that grade III leaks (suprasellar or transclival defects) had a higher risk of CSF leak (12%) in their series. Consequently, these authors

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Table 39.1 Clinical studies of lumbar drains in skull base surgery Study

Surgery

Type

Level of evidence

Lumbar drain protocol

Outcome

Bien et al (2007)2

Open

Retrospective cohort study

III

72 h with drain at shoulder

Significant lower CSF leak with drain

Stoker et al (2012)32

Open

Retrospective case series

IV

Kept in place until patient leaves the hospital

No statistical difference

Patel et al (2010)34

Endonasal

Retrospective case series

IV

3 d, 10 mL/h

CSF leak rate of 3%

Eloy et al (2012)29

Endonasal

Retrospective case series

IV

NA

No lumbar drain, no CSF leaks

Ackerman et al (2013)8

Endonasal

Retrospective case series

IV

3 d, 10–15 mL/h

4.9% leak rate with lumbar drain

Garcia-Navarro et al (2013)35

Endonasal

Retrospective case series

IV

24–48 h, 5 mL/h

No difference

Cohen et al (2018)41

Endonasal

Retrospective case series

IV

48 h, 5 mL/h

Lumbar drain may help decrease CSF leaks in obese patients

Zwagerman et al (2016)40

Endonasal

Prospective randomized controlled trial

I

72 h, 10 mL/h

Lumbar drain significantly reduces CSF leaks in large defects of the anterior and posterior fossa

Abbreviation: CSF, cerebral spinal fluid.

continued to recommend perioperative CSF drainage in these patients.35 A retrospective review by Eloy et al looked at 59 patients who underwent endoscopic repair of high-flow CSF leaks with a nasoseptal flap but without lumbar drain. Their study indicated no postoperative CSF leaks. The majority (42 patients) had sellar or suprasellar pathology, with only 14 anterior cranial fossa lesions and 3 clival defects.29 Bakhsheshian et al performed a review of several studies evaluating lumbar drains in the endoscopic endonasal repair of CSF leaks and indicated no clear benefit of lumbar drainage.36 However, they did not mention size or location of the defects. A review of 25 consecutive patients with suprasellar meningioma who underwent EES at a single institution where lumbar drain was routinely used indicated that the only postoperative leaks that they had were in two patients who did not receive lumbar drains as a result of obesity and they concluded that lumbar drains may help prevent leaks in patients with elevated BMI.37 Another recent review on lumbar drain usage in endoscopic skull base surgery concluded that there is much variation regarding lumbar drains and there is no definitive protocol or evidence for or against usage.38 Finally, a meta-analysis of the role of lumbar drains in endonasal skull base surgery indicated that the available evidence is of poor quality given the variable locations, leak types, tumor types, and defect sizes among the studies.39 Our skull base group at the University of Pittsburgh has performed the first and only randomized and prospective trial noting pathology type, location, and defect size. All 170 participants in the study had “high-flow” leaks. CSF was drained at 10 cc/hour for 72 hours. The study was concluded early (the proposed sample size was 200) as a result of the clear benefit of lumbar drain placement. The overall postoperative CSF leak rate was 8.2% for those in the lumbar drain group versus 21.2% in the nonlumbar drain group (p = 0.017). In 106 patients where defect size was measured intraoperatively, a larger defect was associated with postoperative CSF leak (6.2 vs. 2.9 cm2, p = 0.03).

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A post-hoc secondary analysis of the location of the dural defect and its effect on postoperative CSF leak rates indicated that patients with suprasellar tumors had a decreased risk of postoperative CSF leak compared to patients with tumors of the anterior or posterior fossa (7 vs. 20% vs. 22% leak rate, p = 0.019). These leak rates were from all the tumors within this location (combining lumbar drain patients and no drain patients). This difference on leak rate based on location remained significant for patients in the no-drain group (9.5 vs. 35% vs. 31%, p = 0.032), but was not observed any longer in the lumbar drain cohort (4.7 vs. 11 vs. 13%, p = 0.50).40 In summary, the CSF leak rates with and without drain were 4.7 and 9.5% for suprasellar lesions, 11 and 35% for anterior skull base tumors, and 13 and 31% for posterior skull base lesions, respectively. This study also evaluated confounding effects such as body mass index (BMI), previous surgery, type of flap used, as well as age, and found no other variables that were significantly associated with CSF leaks. In conclusion, size and location of the defect, which are often related to each other (suprasellar defects are typically smaller than anterior and posterior skull base defects), were the main risk factors, and they can be significantly modified with the use of lumbar drains, particularly in larger defects at the anterior and posterior skull base. Complication management of patients with lumbar drains is both preventative and reactionary. A CT of the head immediately after the operation in patients with lumbar drains can help identify problems. In some cases, patients with significant pneumocephalus after an operation had the lumbar drain kept clamped or the amount of CSF drainage was reduced to 5 mL/hour. This was also done in cases of brain edema/hemorrhage. In the aforementioned series, two patients complained of post–lumbar drain headaches and were treated with blood patching. One patient suffered from a retained catheter which was managed conservatively without intervention.

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The Role of Lumbar Drains in Skull Base Surgery

Fig. 39.1 Tuberculum meningioma. (a) T1-contrasted MRI sagittal/coronal views indicating a dural-based mass with suprasellar extension and focused on the tuberculum sella. (b) Intraoperative imaging depicting the dural opening for resection through an endoscopic endonasal approach. (c) Postoperative T1-contrasted MRI sagittal and coronal views indicating complete resection of the mass.

39.4 Author and Institutional Bias

39.5.2 Case 2

The largest limitation of the research presented here is that the surgical approach and resection technique (wide exposure and extensive resection) as well as the closure technique were performed by the two lead neurosurgeons sharing similar philosophy. Other possible techniques exist and the data may not translate outside of the University of Pittsburgh where other surgeons may perform more limited exposures and resections (smaller skull base defect) and have also had excellent results with different closure techniques. We will present two cases of skull base surgeries where we believe lumbar drains may or may not be helpful to reduce postoperative CSF leaks.

A 64-year-old right-handed woman presented after a motor vehicle accident and was found to have a midline dural-based lesion overlapping the posterior olfactory groove and planum (▶ Fig. 39.2a, b). This was observed for 2 years when growth was noted. She was presented with options for radiation or surgery, and she elected for surgery. She underwent an endoscopic endonasal approach for resection of her lesion. Surgery was uneventful and she was discharged on postoperative day 4. Her closure was performed with an inlay collagen matrix, followed by an onlay fascia lata graft and nasoseptal flap. Given the location and size of the dural defect, she was given a lumbar drain to drain 10 cc/hour for 72 hours. She did not have any complications and was seen at her 6month appointment with some diminished smell and taste but no radiographic tumor (▶ Fig. 39.2c). Her pathology indicated WHO grade I meningioma. The treatment for each pathology was tailored to each patient-specific situation. In cases where previous surgery, wound healing concerns, and previous radiation effects may affect reconstruction, the use of a lumbar drain may help facilitate healing as well, and patients with a BMI higher than 40 are at increased risk of CSF leak.

39.5 Case Studies 39.5.1 Case 1 A 58-year-old female presented with right temporal vision loss and headaches. She was found to have a dural-based sellar and suprasellar lesion with compression of the optic chiasm (▶ Fig. 39.1a). She had a medical history of obesity and diabetes but otherwise was independent and continued to work as a secretary. She was taken to the operating room for an endoscopic endonasal approach for resection of the lesion. Surgery was uneventful and she was discharged from the hospital on postoperative day 3 with improvement in her vision. Her closure included an inlay collagen graft, onlay fascia lata graft, and a nasoseptal flap (▶ Fig. 39.1b). Given the small dural opening and suprasellar location of the tumor, a lumbar drain was not used. Her pathology indicated WHO grade I meningioma. On 6month follow-up, she had complete resolution of her vision loss, no headaches, and had intact sense of smell and taste with no residual tumor on MRI (▶ Fig. 39.1c).

39.6 Conclusions Lumbar drains have been shown to be beneficial for the reduction of postoperative CSF leaks in selected cases where the defect is large or if the defect resides in the anterior or posterior cranial fossa. Lumbar drains may also be beneficial in the setting of morbid obesity, previous surgery, or irradiation where wound healing may be an issue. Routine lumbar drain placement for sellar or suprasellar pathology may not be beneficial in the setting of vascularized reconstruction.

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Fig. 39.2 MRI with contrast of an olfactory/planum meningioma. (a) Preoperative T1-contrasted coronal MRI indicating a midline dural-based lesion. (b) Preoperative T1-contrasted sagittal MRI indicating a dural-based lesion extending from the olfactory groove to the planum. (c) Postoperative T1-contrasted coronal MRI indicating complete resection of the midline lesion.

39.7 Suggestions for Future Studies Future research is needed to evaluate the role of lumbar drainage in the setting of large suprasellar lesions with extension into the ventricle which may create high-flow leaks. Further research will help identify whether specific pathologies are more prone to postoperative CSF leaks than others. Research continues to evolve surrounding nursing care for lumbar drain patients and to help reduce the consequences of immobility.

References [1] Allen KP, Isaacson B, Purcell P, Kutz JW, Jr, Roland PS. Lumbar subarachnoid drainage in cerebrospinal fluid leaks after lateral skull base surgery. Otol Neurotol. 2011; 32(9):1522–1524 [2] Bien AG, Bowdino B, Moore G, Leibrock L. Utilization of preoperative cerebrospinal fluid drain in skull base surgery. Skull Base. 2007; 17(2):133–139 [3] Laing RJ, Smielewski P, Czosnyka M, Quaranta N, Moffat DA. A study of perioperative lumbar cerebrospinal fluid pressure in patients undergoing acoustic neuroma surgery. Skull Base Surg. 2000; 10(4):179–185 [4] Moza K, McMenomey SO, Delashaw JB, Jr. Indications for cerebrospinal fluid drainage and avoidance of complications. Otolaryngol Clin North Am. 2005; 38(4):577–582 [5] Viswanathan A, Whitehead WE, Luerssen TG, Jea A. Use of lumbar drainage of cerebrospinal fluid for brain relaxation in occipital lobe approaches in children: technical note. Surg Neurol. 2009; 71(6):681–684, discussion 684 [6] Zanation AM, Carrau RL, Snyderman CH, et al. Nasoseptal flap reconstruction of high flow intraoperative cerebral spinal fluid leaks during endoscopic skull base surgery. Am J Rhinol Allergy. 2009; 23(5):518–521 [7] Governale LS, Fein N, Logsdon J, Black PM. Techniques and complications of external lumbar drainage for normal pressure hydrocephalus. Neurosurgery. 2008; 63(4) Suppl 2:379–384, discussion 384 [8] Ackerman PD, Spencer DA, Prabhu VC. The efficacy and safety of preoperative lumbar drain placement in anterior skull base surgery. J Neurol Surg Rep. 2013; 74(1):1–9 [9] Liang B, Shetty SR, Omay SB, et al. Predictors and incidence of orthostatic headache associated with lumbar drain placement following endoscopic endonasal skull base surgery. Acta Neurochir (Wien). 2017; 159(8):1379– 1385 [10] Shapiro SA, Scully T. Closed continuous drainage of cerebrospinal fluid via a lumbar subarachnoid catheter for treatment or prevention of cranial/spinal cerebrospinal fluid fistula. Neurosurgery. 1992; 30(2):241–245

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[11] Kitchel SH, Eismont FJ, Green BA. Closed subarachnoid drainage for management of cerebrospinal fluid leakage after an operation on the spine. J Bone Joint Surg Am. 1989; 71(7):984–987 [12] Scheithauer S, Bürgel U, Bickenbach J, et al. External ventricular and lumbar drainage-associated meningoventriculitis: prospective analysis of timedependent infection rates and risk factor analysis. Infection. 2010; 38(3): 205–209 [13] al-Mefty O. Prolonged lumbar spinal drainage after the resection of tumors of the skull base: a cautionary note. Neurosurgery. 1992; 30(1):144 [14] Cain RB, Patel NP, Hoxworth JM, Lal D. Abducens palsy after lumbar drain placement: a rare complication in endoscopic skull base surgery. Laryngoscope. 2013; 123(11):2633–2638 [15] Francel PC, Persing JA, Cantrell RW, Levine PA, Newman SA. Neurological deterioration after lumbar cerebrospinal fluid drainage. J Craniofac Surg. 1992; 3(3):145–148 [16] Kim YS, Kim SH, Jung SH, Kim TS, Joo SP. Brain stem herniation secondary to cerebrospinal fluid drainage in ruptured aneurysm surgery: a case report. Springerplus. 2016; 5:247 [17] Manley GT, Dillon W. Acute posterior fossa syndrome following lumbar drainage for treatment of suboccipital pseudomeningocele. Report of three cases. J Neurosurg. 2000; 92(3):469–474 [18] Miglis MG, Levine DN. Intracranial venous thrombosis after placement of a lumbar drain. Neurocrit Care. 2010; 12(1):83–87 [19] Roland PS, Marple BF, Meyerhoff WL, Mickey B. Complications of lumbar spinal fluid drainage. Otolaryngol Head Neck Surg. 1992; 107(4):564–569 [20] Samadani U, Huang JH, Baranov D, Zager EL, Grady MS. Intracranial hypotension after intraoperative lumbar cerebrospinal fluid drainage. Neurosurgery. 2003; 52(1):148–151, discussion 151–152 [21] Borg A, Kirkman MA, Choi D. Endoscopic endonasal anterior skull base surgery: a systematic review of complications during the past 65 years. World Neurosurg. 2016; 95:383–391 [22] Dehdashti AR, Stofko D, Okun J, Obourn C, Kennedy T. Endoscopic endonasal reconstruction of skull base: repair protocol. J Neurol Surg B Skull Base. 2016; 77(3):271–278 [23] McCoul ED, Anand VK, Singh A, Nyquist GG, Schaberg MR, Schwartz TH. Long-term effectiveness of a reconstructive protocol using the nasoseptal flap after endoscopic skull base surgery. World Neurosurg. 2014; 81(1):136–143 [24] Thorp BD, Sreenath SB, Ebert CS, Zanation AM. Endoscopic skull base reconstruction: a review and clinical case series of 152 vascularized flaps used for surgical skull base defects in the setting of intraoperative cerebrospinal fluid leak. Neurosurg Focus. 2014; 37(4):E4 [25] Hadad G, Bassagasteguy L, Carrau RL, et al. A novel reconstructive technique after endoscopic expanded endonasal approaches: vascular pedicle nasoseptal flap. Laryngoscope. 2006; 116(10):1882–1886 [26] Moyer JS, Chepeha DB, Teknos TN. Contemporary skull base reconstruction. Curr Opin Otolaryngol Head Neck Surg. 2004; 12(4):294–299 [27] Nameki H, Kato T, Nameki I, Ajimi Y. Selective reconstructive options for the anterior skull base. Int J Clin Oncol. 2005; 10(4):223–228

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The Role of Lumbar Drains in Skull Base Surgery [28] Horiguchi K, Murai H, Hasegawa Y, Hanazawa T, Yamakami I, Saeki N. Endoscopic endonasal skull base reconstruction using a nasal septal flap: surgical results and comparison with previous reconstructions. Neurosurg Rev. 2010; 33(2):235–241, discussion 241 [29] Eloy JA, Kuperan AB, Choudhry OJ, Harirchian S, Liu JK. Efficacy of the pedicled nasoseptal flap without cerebrospinal fluid (CSF) diversion for repair of skull base defects: incidence of postoperative CSF leaks. Int Forum Allergy Rhinol. 2012; 2(5):397–401 [30] Gardner PA, Kassam AB, Snyderman CH, et al. Outcomes following endoscopic, expanded endonasal resection of suprasellar craniopharyngiomas: a case series. J Neurosurg. 2008; 109(1):6–16 [31] Gardner PA, Kassam AB, Thomas A, et al. Endoscopic endonasal resection of anterior cranial base meningiomas. Neurosurgery. 2008; 63(1):36–52, discussion 52–54 [32] Stoker MA, Forbes JA, Hanif R, et al. Decreased rate of CSF leakage associated with complete reconstruction of suboccipital cranial defects. J Neurol Surg B Skull Base. 2012; 73(4):281–286 [33] Esposito F, Dusick JR, Fatemi N, Kelly DF. Graded repair of cranial base defects and cerebrospinal fluid leaks in transsphenoidal surgery. Neurosurgery. 2007; 60(4) Suppl 2:295–303, discussion 303–304 [34] Patel MR, Stadler ME, Snyderman CH, et al. How to choose? Endoscopic skull base reconstructive options and limitations. Skull Base. 2010; 20 (6):397–404 [35] Garcia-Navarro V, Anand VK, Schwartz TH. Gasket seal closure for extended endonasal endoscopic skull base surgery: efficacy in a large case series. World Neurosurg. 2013; 80(5):563–568

[36] Bakhsheshian J, Hwang MS, Friedman M. What is the evidence for postoperative lumbar drains in endoscopic repair of CSF leaks? Laryngoscope. 2015; 125(10):2245–2246 [37] Cohen S, Jones SH, Dhandapani S, Negm HM, Anand VK, Schwartz TH. Lumbar drains decrease the risk of postoperative cerebrospinal fluid leak following endonasal endoscopic surgery for suprasellar meningiomas in patients with high body mass index. Oper Neurosurg (Hagerstown). 2018; 14(1):66–71 [38] Stokken J, Recinos PF, Woodard T, Sindwani R. The utility of lumbar drains in modern endoscopic skull base surgery. Curr Opin Otolaryngol Head Neck Surg. 2015; 23(1):78–82 [39] D’Anza B, Tien D, Stokken JK, Recinos PF, Woodard TR, Sindwani R. Role of lumbar drains in contemporary endonasal skull base surgery: meta-analysis and systematic review. Am J Rhinol Allergy. 2016; 30(6):430–435 [40] Zwagerman NT, Shin SS, Wang EW, Fernandez Miranda JC, Snyderman C, Gardner P. Does lumbar drainage reduce postoperative cerebrospinal fluid leak after endoscopic endonasal skull base surgery? A prospective, randomized controlled trial. J Neurosurg. 2018; 1:1–7 [Epub ahead of print] [41] Cohen S, Jones SH, Dhandapani S, Negm HM, Anand VK, Schwartz TH. Lumbar drains decrease the risk of postoperative cerebrospinal fluid leak following endonasal endoscopic surgery for suprasellar meningiomas in patients with high body mass index. Oper Neurosurg (Hagerstown). 2018; 14(1):66–71

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40 The Role of Postoperative Antibiotics in Endoscopic Endonasal Surgery Erin K. Reilly, Marc R. Rosen, James J. Evans, and Mindy R. Rabinowitz Abstract The role of postoperative antibiotics in endoscopic endonasal surgery is controversial. Despite the routine use of prophylaxis, there is no evidence-based algorithm for antibiotic therapy after surgery. The main argument in favor of antibiotics is the clean contaminated nature of the nasal and sinus cavities. Violation of the sterile intracranial cavity during skull base surgery is another supportive factor. Furthermore, the eradication of bacteria in an open wound would theoretically minimize the risk of infection, stimulate healing, and accelerate recovery. Support against antibiotic therapy stems from the lack of postoperative infectious complications. In addition, the side effects of long-term antibiotic use are not benign and contribute to bacterial resistance. The current literature fails to demonstrate a beneficial effect of routine antibiotic use after endoscopic endonasal surgery. Keywords: antibiotics, endoscopic sinus surgery, skull base

40.1 Introduction Endoscopic endonasal surgery (EES) includes a broad spectrum of procedures ranging from opening up the sinus cavities to extensive skull base resection. The surgical indications vary from anatomical deformities to malignant neoplasms, with everything from polyps to recurrent infection in between. While the purpose of each case may differ, the fundamentals of EES surgery remain the same. The primary goal is to preserve the natural function of the nasal cavity while removing diseased tissue. Postoperatively the objective is to reduce mucosal inflammation, promote the return of ciliary function, and maintain the patency of the sinus cavities. There is no standardized protocol for postoperative care and specifically, there is no evidence-based algorithm for antibiotic therapy after surgery. The current literature fails to demonstrate a beneficial effect of routine antibiotic use following EES. The main argument in favor of antibiotics is the clean contaminated nature of the nasal and sinus cavities. Violation of the sterile intracranial cavity during skull base surgery is another supportive factor. Furthermore, the eradication of bacteria in an open wound would theoretically minimize the risk of infection, stimulate healing, and accelerate recovery. Support against antibiotic therapy stems from the lack of postoperative infectious complications. In addition, the side effects of long-term antibiotic use are not benign and contribute to bacterial resistance.

40.2 Topic Review Historically, the indication for antibiotics was to prevent toxic shock syndrome as a sequela of nasal packing. There are a few studies looking at the need for antimicrobials following septoplasty with nasal packing, but these have failed to demonstrate

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a reduction in adverse events or improvement in outcomes.1 These results have been corroborated by articles looking at nasal packing in the setting of epistaxis. However, no literature exists on the use of antibiotic therapy with regard to nasal packing after endoscopic sinus surgery. One factor that needs to be considered is the environment of the surgical site. A clean contaminated wound is one in which the respiratory or alimentary tract is entered. It is considered contaminated because these areas are colonized by normal bacterial flora. This classification applies to the nasal and sinus cavities, as they are continuous with the gastrointestinal and pulmonary systems. In theory, reducing the burden of microorganisms in the operating bed would aid in the reduction of postoperative infections. As a result, guidelines have been established in an attempt to provide a standardized approach to the use of antimicrobials to prevent surgical-site infections. The American Society of Health-System Pharmacists (ASHP) concludes that “antimicrobial prophylaxis is preferred for patients undergoing clean contaminated head and neck surgery except tonsillectomy or functional endoscopic sinus procedures.”2 It is important to note that these recommendations apply only to antibiotics given at the time of surgery and no such guidelines for postoperative treatment exist. There is evidence both for and against antibiotic therapy after routine endoscopic sinus surgery in the literature. Three randomized control trials are consistently cited to support this debate and they all target patients with chronic rhinosinusitis. Annys et al studied 202 patients who received either placebo or Cefuroxime twice a day for 10 days postoperatively.3 There was no significant difference between the two groups with regard to infection, endoscopic, or symptom scores.3 Jiang et al analyzed 71 patients who received placebo or Augmentin three times a day for 3 weeks after surgery. Once again there was no difference in symptom or endoscopic scores between the two groups. Additionally, nasal cultures were taken before and after treatment. While there was no difference in the rate of positive cultures, the actual types of bacteria found pre- and postoperatively were distinct in both groups. Thus, they concluded that any bacteria identified after surgery grows de novo.4 Finally, Albu and Lucaciu evaluated 75 patients who also received Augmentin but only twice a day for 2 weeks versus placebo.5 In contrast to the previous studies, a statistically significant difference in endoscopic scores was noted for the treatment group but only at the fifth and twelfth postoperative day. Outcomes were studied up to the 21st and 30th day. Symptoms of nasal blockage and discharge improved in the antibiotic group but exclusively on the fifth day. Other symptoms including facial pain, anosmia, and headache did not reach significance throughout the study period. As a result, the authors concluded that antibiotics may only be effective during the early crusting and immediate healing phase.5 A recent meta-analysis compiled these studies and concluded that the data were “unable to demonstrate a statistically significant reduction of infection, symptoms scores or endoscopic scores to support the routine

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The Role of Postoperative Antibiotics in Endoscopic Endonasal Surgery use of postoperative prophylactic antibiotics following endoscopic sinus surgery.”6 For patients who suffer from chronic rhinosinusitis, endoscopic sinus surgery can be quite successful. Yet some patients develop recurrent infections despite adequate drainage. The question is, “are these infections arising de novo or are certain bacteria refractory to surgery.” A study by Bhattacharyya et al analyzed the difference between cultures obtained 6 weeks after endoscopic sinus surgery in a noninfected state and those same patients during an acute exacerbation with mucopurulent secretions. They found that of the 36 bacterial isolates, only 9 (25%) were identified at baseline. The difference in organisms was statistically significant and the authors concluded that infections occurring after surgery are not due to regrowth or overgrowth of colonizing flora but rather due to pathogenic and de novo bacteria.7 Another study by Jervis-Bardy et al evaluated whether bacteria cultured at the time of surgery was predictive of postoperative infection.8 Infection was defined as frank pus, thick mucus, or abnormal crusting plus a positive microbiology culture. Of the 48 patients who had an acute infection at the time of surgery, 28 (58.3%) developed an infection within 90 days of surgery. 87.5% of patients who were cultured for Staphylococcus aureus at the time of surgery progressed to an infection with S. aureus later on. In contrast, only 31.6% of those who grew “other” bacteria during surgery developed a postoperative infection. These authors concluded instead that postoperative infection is the result of persistent S. aureus refractory to surgery rather than de novo. It is important to note that 25% of patients who had no evidence of infection at the time of surgery developed one postoperatively.8 The aforementioned studies show that it is difficult to predict postoperative recovery based on intraoperative findings. Even with eradication of all purulent material during endoscopic sinus surgery, the presence of retained secretions, blood, and crusting may predispose to an infective environment. Temporary ciliary dysfunction and loss of mucosal integrity also occur. Furthermore, the surgical site is exposed to airborne pathogens during a time of critical healing. Topical rather than oral antibiotics have been suggested to help with these factors. Topical therapies carry the additional benefits of mechanical debridement, direct delivery to diseased mucosa, and avoidance of systemic side effects. Unfortunately, there is insufficient evidence to support the use of antibiotic irrigations in postsurgical patients.9 One argument against routine antibiotic therapy after EES is the lack of serious infectious complications. A study in Japan investigating over 50,000 standard sinus cases revealed the most common complication to be orbital injury, followed by hemorrhage and cerebrospinal fluid (CSF) leak. Infectious complications including meningitis and toxic shock syndrome were cited at 0.9%.10 Even with regard to endoscopic skull base surgery, the rate of infectious complications is slightly higher but remains low in comparison to other problems. A retrospective review of 800 patients found a 1.9% incidence of infection within 30 days.11 It is rarely possible to predict poor outcomes, although some literature claims those with malignancy, intraoperative CSF leaks, or lumbar drains had a higher incidence of intracranial infection. Nonetheless, complications early on are typically influenced by surgery itself, while those that develop later are caused by the underlying disease process.

A systematic review by Coughlan et al in 2015 summarizes most of the earlier findings. They discuss the use of prophylaxis immediately prior to surgery, postoperative oral antibiotics, topical agents, evidence for antimicrobial agents with nasal packing, and the significance of comorbid conditions. They conclude that the current data remain inconclusive with regard to antibiotic use in the perioperative period.12 Endoscopic skull base surgery is a related but separate circumstance to discuss. In contrast to the sinuses, there are several differences that need to be considered. First of all, the intracranial space is sterile and the natural barrier to a contaminated nasal cavity may be violated. Next, reconstruction is often required and a variety of graft materials can be used. Transgression of dura without adequate repair increases the likelihood of CSF leak. This carries a risk of meningitis due to a persistent connection with the brain. Once again, there is no consensus on the use of antimicrobials after endoscopic pituitary or cranial base procedures. Even with regard to open neurosurgical procedures, controversy exists. However, there is convincing evidence that perioperative antibiotic prophylaxis is effective in lowering skin incision infection rate in craniotomies but not in preventing nosocomial meningitis.13 Unfortunately, there are no randomized clinical trials looking at the use of antimicrobials after endoscopic skull base surgery. A study by Brown et al prospectively reviewed 90 patients over 2 years who underwent endoscopic anterior skull base procedures. All individuals received 24 to 48 hours (depending on when nasal packing was removed) of cefazolin or, if allergic, vancomycin or clindamycin. There were no cases of meningitis documented, even in those with an intraoperative CSF leak or lumbar drain. It is important to note that all patients included received intranasal gentamicin rinses for 2 weeks postoperatively and a total of 38 patients received additional antimicrobials for sinusitis during the first 3 months.14 There are three studies looking specifically at transsphenoidal surgery. Little and White reviewed 442 patient who underwent a microscopic approach and received cefuroxime 30 minutes prior to surgery and 8 hours after.15 No patients developed an intracranial infection within 30 days. However, three patients developed delayed meningitis ranging from 2 to 9 months afterward. All three of them had intraoperative CSF leaks. The authors concluded that perioperative antibiotics prevent perioperative meningitis by sterilizing the spinal fluid seeded by nasal flora during surgical extirpation of the lesion. In contrast, delayed meningitis is related to persistent spinal fluid leakage and is unlikely to be influenced by a dose of antibiotics at the time of surgery.15 Thus, the use of antimicrobials becomes less significant and instead there is an emphasis on good surgical technique and proper repair. Somma et al retrospectively analyzed 145 patients who were given cefazolin or clarithromycin 30 minutes prior and 8 hours after endoscopic transsphenoidal surgery.16 Subjects were followed for one year, and no cases of meningitis occurred. One patient developed a CSF leak on postoperative day 7 requiring a week of intravenous cefazolin plus vancomycin. Interestingly, they excluded high-risk patients who required longer antibiotic prophylaxis due an extended surgery, simultaneous sinus surgery, and surgery for CSF leak; heavy smokers; and patients with diabetes or Cushing syndrome.16 A similar article by Orlando et al retrospectively reviewed 170 patients who were

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Table 40.1 Key studies and level of evidence Article title

Main author

Study type

Level of evidence

The role of antibiotic therapy and nasal packing in septoplasty

Gioacchini1

Systematic review

II

Clinical practice guidelines for antimicrobial prophylaxis in surgery

Bratzler2

Systematic review

I

Short-term effects of antibiotics after endoscopic sinus surgery

Annys3

Randomized trial

I

Postoperative antibiotic care after functional endoscopic sinus surgery

Jiang4

Randomized trial

I

Prophylactic antibiotics in endoscopic sinus surgery: a short follow-up study

Albu5

Randomized trial

I

Prophylactic perioperative antibiotic use in endoscopic sinus surgery

Saleh6

Systematic review

I

Should topical antibiotics be routinely used following sinus surgery?

Al-Bar9

Systematic review

II

The role of antibiotics in endoscopic sinus surgery

Coughlan12

Systematic review

II

Role of perioperative antibiotics in endoscopic skull base surgery

Brown14

Case series (no control)

IV

Short-duration, single-agent antibiotic prophylaxis for meningitis in transsphenoidal surgery

Little and White15

Case series (no control)

IV

Efficacy of ultra-short single-agent regimen antibiotic chemoprophylaxis in reducing the risk of meningitis in patients undergoing endoscopic endonasal transsphenoidal surgery

Somma16

Case series (no control)

IV

Retrospective analysis of a new antibiotic chemoprophylaxis regimen in 170 patients undergoing endoscopic endonasal transsphenoidal surgery

Orlando17

Retrospective study

III

administered ceftazidime, ceftazidime plus amikacin, or ceftriaxone plus amikacin. A total of 145 patients received this prophylaxis for 3 days, while 25 high-risk patients (defined as smokers with a history of recurrent respiratory tract infections) started prophylaxis 24 to 48 hours prior to surgery. Only one patient developed meningitis on postoperative day 4 and he had an intraoperative CSF leak repaired at the time of the procedure. Three patients were medically treated for sphenoid sinusitis, only one was symptomatic and the other two were diagnosed incidentally by imaging. Four patients developed a CSF leak requiring reoperation but no infectious complications developed. The choice of antimicrobials in this article was justified because these drugs reach levels in CSF that are sufficient to inhibit Staphylococcus and gram-negative bacilli. However, the authors do comment on the increased cost of this regimen and suggest using it only in high-risk patients.17 Each study used a different type of antimicrobial but had similar outcomes, suggesting that prophylaxis is meaningless. In addition, each study lacked a control group, further questioning whether antimicrobials are even necessary. It is well established that antibiotics are not benign medications. They are costly, contribute to the development of resistance, and have the potential to cause harmful side effects. While the use of antibiotics is aimed at minimizing morbidity, it can in fact contribute to it. Ideally an antimicrobial agent is one that is safe, inexpensive, has minimal adverse effects and covers common sinonasal pathogens. Additionally for skull base surgery, an agent that penetrates the CSF is necessary. However, there is no consensus on the type, dose, length, and route of antibiotic for any endonasal procedure. Cefazolin is the preferred agent for prophylaxis due to its good safety profile, low cost, favorable duration of action, CSF penetration, and adequate bacterial coverage against gram-positive organisms. Penicillin and cephalosporin-based medications are outpatient oral equivalents. But what happens when a patient is allergic? Which situations warrant broad-spectrum coverage? Should a polyp case be treated the same as an acute sinusitis? All of these

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questions are left unanswered. ▶ Table 40.1 highlights the relevant research studies cited in this chapter and demonstrates that the data are clearly insufficient to make an evidence-based consensus regarding antibiotics after EES.

References [1] Gioacchini FM, Alicandri-Ciufelli M, Kaleci S, Magliulo G, Re M. The role of antibiotic therapy and nasal packing in septoplasty. Eur Arch Otorhinolaryngol. 2014; 271(5):879–886 [2] Bratzler DW, Dellinger EP, Olsen KM, et al. American Society of Health-System Pharmacists, Infectious Disease Society of America, Surgical Infection Society, Society for Healthcare Epidemiology of America. Clinical practice guidelines for antimicrobial prophylaxis in surgery. Am J Health Syst Pharm. 2013; 70 (3):195–283 [3] Annys E, Jorissen M. Short term effects of antibiotics (Zinnat) after endoscopic sinus surgery. Acta Otorhinolaryngol Belg. 2000; 54(1):23–28 [4] Jiang RS, Liang KL, Yang KY, et al. Postoperative antibiotic care after functional endoscopic sinus surgery. Am J Rhinol. 2008; 22(6):608–612 [5] Albu S, Lucaciu R. Prophylactic antibiotics in endoscopic sinus surgery: a short follow-up study. Am J Rhinol Allergy. 2010; 24(4):306–309 [6] Saleh AM, Torres KM, Murad MH, Erwin PJ, Driscoll CL. Prophylactic perioperative antibiotic use in endoscopic sinus surgery: a systematic review and meta-analysis. Otolaryngol Head Neck Surg. 2012; 146(4):533–538 [7] Bhattacharyya N, Gopal HV, Lee KH. Bacterial infection after endoscopic sinus surgery: a controlled prospective study. Laryngoscope. 2004; 114 (4):765–767 [8] Jervis-Bardy J, Foreman A, Field J, Wormald PJ. Impaired mucosal healing and infection associated with Staphylococcus aureus after endoscopic sinus surgery. Am J Rhinol Allergy. 2009; 23(5):549–552 [9] Al-Bar MH, Kuperan A, Casiano RR. Should topical antibiotics be routinely used following sinus surgery? Laryngoscope. 2014; 124(12):2653–2654 [10] Suzuki S, Yasunaga H, Matsui H, Fushimi K, Kondo K, Yamasoba T. Complication rates after functional endoscopic sinus surgery: analysis of 50,734 Japanese patients. Laryngoscope. 2015; 125(8):1785–1791 [11] Kassam AB, Prevedello DM, Carrau RL, et al. Endoscopic endonasal skull base surgery: analysis of complications in the authors’ initial 800 patients. J Neurosurg. 2011; 114(6):1544–1568 [12] Coughlan CA, Bhandarkar ND, Bhandarkar N. The role of antibiotics in endoscopic sinus surgery. Curr Opin Otolaryngol Head Neck Surg. 2015; 23(1):47–52 [13] Korinek AM, Baugnon T, Golmard JL, van Effenterre R, Coriat P, Puybasset L. Risk factors for adult nosocomial meningitis after craniotomy: role of antibiotic prophylaxis. Neurosurgery. 2008; 62 Suppl 2:532–539

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The Role of Postoperative Antibiotics in Endoscopic Endonasal Surgery [14] Brown SM, Anand VK, Tabaee A, Schwartz TH. Role of perioperative antibiotics in endoscopic skull base surgery. Laryngoscope. 2007; 117(9):1528–1532 [15] Little AS, White WL. Short-duration, single-agent antibiotic prophylaxis for meningitis in trans-sphenoidal surgery. Pituitary. 2011; 14(4):335–339 [16] Somma T, Maraolo AE, Esposito F, et al. Efficacy of ultra-short single agent regimen antibiotic chemo-prophylaxis in reducing the risk of meningitis in

patients undergoing endoscopic endonasal transsphenoidal surgery. Clin Neurol Neurosurg. 2015; 139:206–209 [17] Orlando R, Cappabianca P, Tosone G, Esposito F, Piazza M, de Divitiis E. Retrospective analysis of a new antibiotic chemoprophylaxis regimen in 170 patients undergoing endoscopic endonasal transsphenoidal surgery. Surg Neurol. 2007; 68(2):145–148, discussion 148

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41 Does Otorhinolaryngology Collaboration Improve Outcomes in Endonasal Skull Base Surgery? Kyle VanKoevering, Ricardo L. Carrau, Daniel M. Prevedello, and Bradley A. Otto Abstract Traditionally, endonasal skull base surgery has been performed collaboratively with a neurosurgeon and otorhinolaryngologist operating as co-surgeons. While there are several advantages to co-surgeon cases (expanded expertise, multiple opinions, additional hands for complex cases, etc.), the need to coordinate schedules and build advanced working relationships often makes this difficult. In spite of a comprehensive literature review, there is a stark paucity of valuable data on outcomes in skull base surgery as related to co-surgeon experience. We highlight the limited level IV and level V data to discuss the potential limitations and benefits in detail. While there can be several challenges to creating a co-surgical approach, the authors strongly believe that the development of a dedicated, multidisciplinary skull base team of subspecialties (otorhinolaryngology, neurosurgery, ophthalmology, endocrinology, radiation oncology, and medical oncology, etc.) allows for better coordination, seamless scheduling, improved operative and postoperative care, and likely results in better outcomes for patients. Keywords: skull base team, multidisciplinary, co-surgeon

41.1 Introduction Over the past two decades, endoscopic endonasal skull base surgery (ESBS) has exponentially grown as a modality to treat challenging disorders of the ventral skull base. From the initial efforts related to pituitary surgery, both otorhinolaryngologists and neurosurgeons have fostered the expansion of the field with respect to improved access, superior visualization, tumor extirpation, and skull base reconstruction. Commonplace to most of these advances is the reliance of a team-based model that typically includes a member from each of the specialties. Although the history of endoscopy is beyond the scope of this chapter, it is important to recognize that the utilization of the endoscope in both neurosurgery and otorhinolaryngology dates back to the early 20th century. Advances in endoscope design, especially the Hopkins rod lens system in 1960, allowed for the expansion of neuroendoscopic procedures beyond the ventricular system and heralded the development of new minimally invasive neurosurgical procures and endoscope-assisted microsurgery.1 In otorhinolaryngology, Messerklinger and a number of other pioneers throughout the world forged the development of modern rhinology and endoscopic sinus surgery (ESS) through the use of the endoscope.1,2 Ultimately, the development of ESBS is related to the convergent experience of neuroendoscopy and ESS, along with the recognition that the sinonasal cavity serves as the corridor with the least potential morbidity to many lesions involving the skull base. Although it seems intuitive that an otolaryngologist with subspecialty rhinology and skull base surgery training should

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prove to be an asset not only to the patient but also to their neurosurgical colleagues, there is a paucity of supporting evidence. This is likely a result of the inherent difficulty related to studying such a question, especially in centers that consider such teamwork essential.

41.2 Review Currently, there is no objective data regarding the benefit (or lack thereof) of collaborative endonasal management of skull base tumors. McLaughlin et al provided an excellent review of teamwork in skull base surgery. As noted in their review, the complexity of skull base pathology makes necessary a comprehensive, collaborative approach involving medical and surgical subspecialties, especially neurosurgery and otorhinolaryngology. The review legitimizes the team-based approach, noting the continued trend toward subspecialization among surgeons and the inability of such providers to deliver holistic care. Also reviewed is the importance of determining team structure and processes in order to foster the best possible collaboration.3

41.3 Advantages When considering comprehensive disease management, perhaps the most obvious situation where an otorhinolaryngologist’s role is critical relates to advanced sinonasal tumors. These tumors have required co-surgical approaches with neurosurgeons and otolaryngologists for decades through complex open resections. Traditionally, extirpation of these lesions required open transcranial approaches for management of the skull base and intracranial compartment combined with transfacial approaches to clear the nasal disease. It is this collaborative relationship that has continued to serve as the foundation for the co-surgical approach as most programs have transitioned to primarily endonasal skull base teams. Furthermore, advanced sinonasal malignancies that can be managed endoscopically may also present with cervical metastasis which may require concomitant neck dissection by the otorhinolaryngologist. Postoperatively, many of these patients require adjuvant radiation treatment, which is best overseen by a head and neck surgeon, and continued surveillance is critical for these patients. Endoscopic examinations can readily be performed in an otolaryngology clinic, with biopsies and debridement as needed to monitor for recurrence. Regarding those conditions that historically have fallen under the purview of the neurosurgeon, the otorhinolaryngologist’s role may vary widely among skull base centers. With appropriate training and equipment, it may be arguably more convenient for a neurosurgeon to manage simple skull base lesions (i.e., routine pituitary macroadenomas) utilizing the endonasal corridor. However, there remains significant potential value for the otolaryngologist even for these “simple” endonasal cases preoperatively, intraoperatively, and postoperatively.

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Does Otorhinolaryngology Collaboration Improve Outcomes in Endonasal Skull Base Surgery?

41.4 Preoperative Preoperatively, the otorhinolaryngologist can evaluate the fitness of the sinonasal cavity for the indicated procedure. Those patients with sinonasal symptoms can be screened for objective evidence of inflammatory or infectious disease. In the case of microbial infections, the otolaryngologist may optimize the preoperative management via culture-directed antibiotics. This may prevent the subsequent and unexpected staging of procedures in those cases where the infection would have otherwise gone unnoticed or nonspecifically managed. Chronic rhinosinusitis (CRS) is reported in up to 4.9% of the U.S. population.4 Nyquist et al recently reported their experience in performing ESBS in patients with concomitant CRS. In their study, no acute or chronic infectious complications were noted among patients who underwent traditional ESS with concurrent ESBS.5 As opposed to CRS, acute bacterial sinusitis poses a potential intracranial risk, and adequate antimicrobial therapy is generally required to resolve the infection and reduce the risk of meningitis. In fact, Nyquist et al staged five such procedures in their study.5 Furthermore, disease processes such as a fungal ball require surgical removal as the treatment of choice via ESS. In the event of unresolved bacterial sinusitis or fungal ball at the time of a planned ESBS, it is prudent to stage the procedures and perform the necessary surgery to treat the infection in the sinonasal cavity during the first stage. Prior to managing these conditions surgically, appropriate diagnosis (via endoscopy and imaging) and medical management may either avoid staged procedures or at least better predict the likelihood. The otorhinolaryngologist’s role is critical in this setting. Endoscopy, as routinely performed in rhinology clinics, also can help identify other potential challenges in the preoperative setting. For example, the presence of septal perforation, severe deviation, previous ESS, or other disorders that decrease the integrity of the sinonasal mucosa may preclude the utilization of a nasoseptal flap or necessitate alternative endonasal

approaches in a way that may not be appreciated from imaging alone.

41.5 Intraoperative The creation of an adequate sinonasal corridor is essential in gaining sufficient access to skull base lesions while minimizing risk to adjacent neurovascular structures. Although avoiding damage to neural tissue and major vessels is the primary consideration, the maintenance of normal sinonasal physiology is also important to postoperative quality of life and potential delayed complications. Maintenance of normal paranasal sinus drainage pathways and avoidance of olfactory epithelial damage are just two examples where anatomical and physiological expertise can improve outcomes. Given the familiarity of most otolaryngologists with ESS techniques, especially those routinely performing ESBS, the creation of the corridor fits naturally and expeditiously into their skill set. Although no data exist regarding the benefit of such a co-surgeon experience in ESBS, the benefits of collaboration between neurosurgery and otorhinolaryngology for acoustic neuromas have been documented. Similar to the approach used during ESBS by many centers, the surgeon best acquainted with the regional particularities of a given phase of the case performs that aspect, maximizing the anatomic expertise.3,6 Depending on the skill set of the team members, the otorhinolaryngologist may additionally be best suited to provide dynamic endoscopy for the duration of the neurosurgical dissection. Dynamic endoscopy aids in the spatial orientation of the surgeon by providing caudal visualization of instruments as they enter the cavity. The continual repositioning of the scope also helps develop a better three-dimensional understanding of the relevant anatomy and to continually acquire the best vantage for the neurosurgeon. This is advantageous over scope holders that do not allow for continual, seamless optimization (▶ Fig. 41.1).1

Fig. 41.1 Intraoperative setup with the otolaryngology co-surgeon providing dynamic endoscopy for the two-hand neurosurgical dissection of a sinonasal malignancy. Note that each surgeon utilizes an individual highresolution monitor to maximize ergonomic efficiency.

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Surgical Approaches and Techniques Outside of the skull base literature, there are some data to suggest that co-surgeon experience significantly improves patient outcomes beyond simple efficiency measures. Mallory et al demonstrated that co-surgeons in bilateral mastectomies not surprisingly reduce operative time.7 However, Haddock et al further demonstrated that co-surgeon microvascular breast reconstruction not only improves operative time but also significantly reduces hospital length of stay and wound complications.8 This suggests that the presence of two co-surgeons not only improves efficiency but potentially that four eyes and two minds working collaboratively may help reduce potential mistakes, diminish fatigue, and maximize management of unexpected intraoperative events, ultimately improving patient outcomes. Although debatable, the perspective of an otorhinolaryngologist as the co-surgeon, as opposed to a second neurosurgeon, may enhance such collaboration by broadening the perspective of the team.

41.5.1 Postoperative In the majority of ESBS cases, the trauma caused in the sinonasal cavity is the primary source of postoperative morbidity. Hence, in the early postoperative phase following ESBS, debridement and postoperative protocols designed to promote healing of the skull base and sinonasal cavity are imperative to quality of life. Nonetheless, complications such as rhinosinusitis, synechiae, anosmia, epistaxis, nasal congestion, and septal perforation may occur.9 Similar to the trend noted by others, Little et al found that sinonasal quality of life decreased following ESBS, reaching a nadir at 2 weeks. However, this improved back to baseline at 3 months.9,10 Prolonged use of nasal splints, use of absorbable nasal packing, and the development of sinusitis were all associated with decreased quality of life. As previously noted, familiarity with in-office debridement techniques, as well as with the diagnosis and management of rhinosinusitis, would seem to be advantageous (▶ Fig. 41.2). It is interesting to note, however, that the presence of an otorhinolaryngologist did not correlate to quality of life outcomes in this study. One potential explanation for this relates to selection bias, as in one center, only those patients with more complicated nasal corri-

dors or postoperative sequelae were referred to the otorhinolaryngologist.9

41.6 Challenges Although the advantages of collaborative surgical management are readily apparent to many skull base centers, there do exist several challenges. Depending on surgical practices and facilities, coordinating surgical schedules between the otolaryngologist and neurosurgeon can be challenging, and at times prohibitive to expedient patient care. Billing challenges can further complicate co-surgeon experience. In spite of recent advances in endonasal skull base surgery, there remain no formal billing codes. Utilizing existing codes or unlisted codes while applying co-surgeon modifiers often limits insurance reimbursement and can significantly affect the co-surgeon relationship. Building a multidisciplinary team also requires a deliberate, hospital-supported effort to bring several specialties together, maximize communication, and avoid gaps in care. The team needs a surgical leader and wide commitment.3 This is even more evident for co-surgical cases, where a highly collaborative, seamless relationship demands shared decision making and must be intentionally developed between the otolaryngologist and neurosurgeon.

41.7 Author and Institutional Biases At our institution, our skull base surgery center was founded upon a team-based model. Accordingly, we maximize every opportunity to work together, even in cases where the procedure could be reasonably performed alone. Although there exists significant overlap in our clinical interests, our neurosurgeons and otorhinolaryngologists possess unique skill sets that fall outside of the interests and capabilities of the other. Our otorhinolaryngologists are intimately involved in all phases of care. They evaluate patients preoperatively and determine fitness for surgery, comanage a weekly multidisciplinary planning meeting, perform the approach to the skull base, assist in the reconstruction, and follow up the patient as long as necessary to foster the best possible outcome, especially with regard to sinonasal function.

41.8 Conclusions

Fig. 41.2 Postoperative crusting and debris 1 week after expanded endonasal approach for a clival lesion. This patient required extensive in-office debridement to reduce sinonasal morbidity.

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Currently, there exist no data upon which one can objectively determine the value of an otorhinolaryngologist to a skull base team performing ESBS. For practical and ethical reasons, such data may never exist and it would be difficult to properly perform a comparative study. Our program relies heavily on a team-based approach and the value added by otorhinolaryngologists, as described earlier, is evident to all members of our multidisciplinary team. In our experience, the initial investment in creating a dedicated skull base surgical team and multidisciplinary program takes concerted effort, but subsequently limits the scheduling as well as relational and billing challenges while likely maximizing outcomes for the patient. However, each team must critically evaluate its own skill set, clinical interests, and goals in choosing whether or not to include an otorhinolaryngologist.

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Does Otorhinolaryngology Collaboration Improve Outcomes in Endonasal Skull Base Surgery?

References [1] Prevedello DM, Doglietto F, Jane JA, Jr, Jagannathan J, Han J, Laws ER, Jr. History of endoscopic skull base surgery: its evolution and current reality. J Neurosurg. 2007; 107(1):206–213 [2] Varshney R, Zawawi F, Tewfik MA, Frenkiel S. Endoscopy - An Advancement in Sinus and Skull Base Surgery. In: Endoscopy. InTech; 2013:1–19. doi: 10.5772/52749 [3] McLaughlin N, Carrau RL, Kelly DF, Prevedello DM, Kassam AB. Teamwork in skull base surgery: an avenue for improvement in patient care. Surg Neurol Int. 2013; 4(1):36–36 [4] Bhattacharyya N. Incremental health care utilization and expenditures for chronic rhinosinusitis in the United States. Ann Otol Rhinol Laryngol. 2011; 120(7):423–427 [5] Nyquist GG, Friedel ME, Singhal S, et al. Surgical management of rhinosinusitis in endoscopic-endonasal skull-base surgery. Int Forum Allergy Rhinol. 2015; 5(4):339–343

[6] Tonn J-C, Schlake H-P, Goldbrunner R, Milewski C, Helms J, Roosen K. Acoustic neuroma surgery as an interdisciplinary approach: a neurosurgical series of 508 patients. J Neurol Neurosurg Psychiatry. 2000; 69(2): 161–166 [7] Mallory MA, Losk K, Camuso K, Caterson S, Nimbkar S, Golshan M. Does “two is better than one” apply to surgeons? Comparing single-surgeon versus co-surgeon bilateral mastectomies. Ann Surg Oncol. 2016; 23(4): 1111–1116 [8] Haddock NT, Kayfan S, Pezeshk RA, Teotia SS. Co-surgeons in breast reconstructive microsurgery: what do they bring to the table? Microsurgery. 2017; 242 Suppl I:172 [9] Little AS, Kelly D, Milligan J, et al. Prospective validation of a patient-reported nasal quality-of-life tool for endonasal skull base surgery: the anterior skull base nasal inventory-12. J Neurosurg. 2013; 119(4):1068–1074 [10] Pant H, Bhatki AM, Snyderman CH, et al. Quality of life following endonasal skull base surgery. Skull Base. 2010; 20(1):35–40

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42 Controversies in Outcome Measures of Skull Base Surgery Gill E. Sviri, Shuli Brammli-Greenberg, and Ziv Gil Abstract Outcome measures in skull base surgery have a major role in guiding the different treatment modalities available for a particular patient. The literature has been confined largely to describing surgical functional outcomes conducted by treating surgeons, using very general scales in a poorly designed retrospective fashion that includes a mixture of pathology and location. Recently, there has been increasing interest regarding patient report outcome measures (PROM) and Health-Related Quality of Life (HRQOL) measures in skull base surgery that are considered to be more accurate for QOL assessment. However, studies in this field demonstrate significant methodological weaknesses related to study design, sample size, data analysis, and mono-method bias. Nevertheless, disease-specific HRQOL measurement scales are now emerging, and a validated process might provide a better assessment of outcomes in skull base surgery. Keywords: outcome, skull base, quality of life, morbidity, complication rate, measurement, acoustic neuroma

42.1 Introduction Outcome measurement, sometimes called performance measurement, has become standard in modern medicine and is an important method for defining quality of care and treatment efficacy, which are the main goals of clinical trials and a key guide to modern evidence-based and patient-centered medicine.1,2,3,4,5,6,7,8 From an economic perspective, one way that systems dealt with the inefficiency of health care systems is using outcome measures as a tool in the hands of the system navigators. Market failures that enhance inefficiency stem, to a large extent, from information gaps among the various players in the system. One way to deal with the existing information gaps is to increase the information by measuring the performance of the system, which is intended to provide relevant information to health care directors, decision makers, and policy makers. This measurement also impacts the incentive plan for service providers and, above all, improves the service and treatment provided. In skull base surgery, tumors have been associated in the past with a relatively high mortality rate. Therefore, success has been judged in accordance with mortality rate.7 The surgical treatment of skull base tumors has undergone major advances in recent years, such as introduction of the operative microscope, multiplane imaging, improved neuroanesthesia, interdisciplinary skull base approaches, and improved postoperative care.9 As a result, the mortality rates have markedly decreased; however, outcome measurements in skull base surgery are still focused on mortality, complication rate, and the extent of tumor resection, as clinical studies have focused mainly on surgical approach and complications.10,11

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42.1.1 History and Definition of Outcome and Performance Measures Measurement is vital to produce a health care system that achieves remarkable results. Without measurement and transparency, clinicians, institutions, patients, and society cannot readily evaluate the value achieved in the health care system. Measurement has been associated with important improvements in providers’ use of evidence-based strategies and patients’ health outcomes. Perhaps most important, measures have altered the culture of health care delivery for the better, with a growing acceptance that clinical practice can be objectively assessed and improved.12 In recent years, there has been heightened awareness for the successful management of patient care. To enhance quality of care as well as productivity, departments and hospitals can use their operations and management to adapt and thrive in current conditions. In the Organization for Economic Co-operation and Development (OECD), new programs and policies focus on development of new performance measures, quality, and accreditation. In 1998, the Joint Commission launched its ORYX initiative, the first national program for the measurement of hospital quality, which initially required the reporting only of nonstandardized data on performance measures. In 2002, accredited hospitals were required to collect and report data on performance for at least two of four core measure sets (acute myocardial infarction, heart failure, pneumonia, and pregnancy); these data were made publicly available. This only occurred, however, when the Centers for Medicare and Medicaid Services (CMS) began financially penalizing hospitals that did not report to the CMS the same performance data they collected for the Joint Commission. The CMS began its own public reporting in the years 2004–2005 when performance measurement became routine in the management of hospitals in the United States and later on in the whole world.13 Performance measures are aimed to provide a quantitative basis for clinicians, organizations, and planners the right tools to improve outcomes. Measures are divided according to their overall goal: 1. To measure a particular outcome. 2. To assess a process. 3. To screen or flag a function that is used to monitor the quality of care, clinical services, or organizational function. Achievements of national goals lead to hospital compensation and sharing of outcome data with the public, all of which aim to enhance quality of care of the whole health care system. Such programs may be initiated at the institutional or departmental levels when national programs cannot recapitulate directly the patients’ requirements. Moreover, most program indicators are clinical and concentrate on quality of treatment rather than performance of activity and general health care service. The basic definition of health care measures typically includes delivery of services that are clustered around three

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Controversies in Outcome Measures of Skull Base Surgery main components: diagnosis, treatment, and outcome. In skull base surgery, the outcome of treatment is defined according to the goal of treatment: cure, prevention of disease, or palliation. For each patient, the multidisciplinary team should determine which is the most suitable treatment option (e.g., radiotherapy, surgery, or observation [OBS]). In this chapter, we will focus on general treatment, which is focused on a specific episode or event requiring care with the goal of improvement of outcome using the efficiency of treatment as a tool. University hospitals present additional aims, as a large percentage of their resources are devoted to operate training programs, academic and research missions, as well as patient care. Surgeons usually share the same objective functions that are defined by the following five goals, by order of importance: 1. Best practice custom for the patient. 2. Best service for patients (patient-centeredness). 3. Educating new generations of doctors. 4. Promoting of science in the clinical area of the department. 5. Maintaining high satisfaction of the staff.

42.1.2 Patient-Centered Care Patient-centeredness is defined as “respectful of and responsive to individual patient preferences, needs, and values and ensuring that patient values guide all clinical decisions.”14 It is designed as a central tenet of health care delivery with the idea that care should be designed around patients’ needs, preferences, circumstances, and well-being. In recent years, patient-centered care has received high priority by several OECD member countries. The professional literature emphasizes the importance of patient-centered care to the performance of health systems. There is evidence that patient-centered care improves quality indices, patients’ satisfaction, self-welfare, and mental health. Patient-centered care also contributes to the system at the organization level, where it improves medical staff’s work satisfaction, reduces costs, and enhances efficiency of health service usage, as it decreases misuse of medical services and increases the success rate of diagnosis.15,16,17,18,19,20,21,22,23,24,25 Research by the Picker Institute has delineated eight dimensions of patient-centered care, including (1) respect for the patient’s values, preferences, and expressed needs; (2) information and education; (3) access to care; (4) emotional support to relieve fear and anxiety; (5) involvement of family and friends; (6) continuity and secure transition between health care settings; (7) physical comfort; and (8) coordination of care.26 Unfortunately, in the traditional department-based organizational structure of a university hospital, patients can often be neglected as a result of fragmented systems of care. Therefore, the correct approach should be the development of measures that prioritize patient’s primacy. This emphasizes that the measures always put the patient as the top priority. In its 2013 report, the English Department of Health summarized this idea by saying that hospitals should move toward making the quality of care as important as the quality of treatment. This means putting patients first and foremost in any health care managerial environment.27

42.2 General Instruments for Estimation of Outcome 42.2.1 Traditional Outcome Measures in Skull Base Surgery Several measuring outcome scales, such as the modified Rankin score (mRS),28 the Karnofsky performance score (KPS),29 and the Glasgow Outcome Scale (GOS),30 have been commonly used by skull base surgeons to measure outcome.31 GOS ranges from 1 to 5 (where 1 is death and 5 is a functional good recovery). It was introduced and used extensively in studies for traumatic head injury and aneurismal rupture outcome studies. GOS is a common outcome measurement tool that is used in skull base surgery by itself or in its extended form.31 KPS is an index of patients’ general well-being that is used in general oncology as a standard way of measuring the ability of cancer patients. Its score ranges from 0 to 100. A higher score means the patient is less disabled and the lower score makes him more dependent. KPS is used to determine a patient’s prognosis, measure changes in a patient’s ability to function, or decide if a patient could be included in a clinical trial. It has become the standard tool for outcome measurement in skull base surgery.31 mRS is a commonly used scale for measuring the degree of disability or dependence in the daily activities of people who have suffered a stroke or other causes of neurological disability. It has become a standard use in clinical outcome measures for stroke clinical trials.32 All these scales were designed as universal measuring tools for head injury, subarachnoid hemorrhage, stroke, and oncology decision making. The scales were also founded on the basis of disease parameters only, and do not necessarily address the illness on multiple aspects of individuals’ well-being.33,34,35 Tumors localized in the skull base induce problems that are not addressed by these rough caregiver-driven assessments of the patient’s functional state. Issues such as imbalance, cosmetic defects, impaired nasal breathing, peripheral hearing loss, chewing, swallowing, neck pain, and headache are not evaluated by these scales. Furthermore, many of the reports are biased as surgeons usually review their outcome in a retrospective chart review study, conducting a subjective assessment of the outcome. This type of outcome assessment is neither reliable nor accurate. Moreover, these scales have been shown to be subject to poor interobserver evaluation, making it difficult to compare the effectiveness of different surgical methods and radiation therapy.36,37

42.2.2 Quality-of-Life Outcome Measures in Skull Base Surgery Since extended skull base surgery has been reported to be associated with poor quality of life (QOL)38 and the emerging trend of modern traditional therapy technique that enables tumor control with minimal impact on QOL,7,39 attention started to shift to QOL and health-related quality of life (HRQOL) outcome measures.31,36,40,41,42 Currently, there are numerous definitions of QOL, but there is general agreement that it involves the patient’s perception of his or her outcome (patient report outcome measurement, PROM). The World Health Organization’s (WHO) definition of QOL states that it is an individual’s

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Surgical Approaches and Techniques perception of his or her position in life in the context of his or her own culture and value systems.43 QOL is not necessarily congruent with health, function, impairment, or disability, although each of these may affect a person’s QOL.44 Therefore, what is considered acceptable can be vastly different for each patient, as a person can have a severe disability or have poor objective health and yet enjoy a high QOL.45 A subset of QOL is the HRQOL that explicitly links a person’s health function with his or her QOL.46 Most HRQOL scales measure the following seven basic dimensions of QOL: physical concerns, functional ability, family wellbeing, emotional well-being, treatment satisfaction, sexuality/ intimacy (including body image), and social functioning. QOL outcome measurement tools can be divided into generic and disease specific. Generic measures are global assessments of HRQOL and are useful for comparisons within and between different conditions. Of these generic scales, the most widely used is the SF-36 which is a shortened version of a battery of 149 health status questions developed and tested on a population of over 22,000 patients.47 Eleven questions were selected to produce a questionnaire that could be completed in less than 10 minutes. SF-36 attempts to capture aspects of health that are important to all patients. Eight subscales are used which include physical and social functioning, mental health, pain, and general health. SF-36 has been shown to be valid, reliable, and responsive to changes in health in different conditions.48 In neurosurgical practice, it has been used to quantify significant morbidity, following complex intracranial procedures, and differentiate patients with a “good outcome” following aneurysmal subarachnoid hemorrhage and stroke.38,49,50,51 Generic scales are, however, not sensitive to a patient’s changing clinical status and do not necessarily focus on specific outcomes of a particular disease, although valuable as a gross estimate of functional status. Disease-specific scales are more responsive to clinical changes and are more appropriate for clinical trials in which specific therapeutic interventions are being evaluated.

42.3 Outcome Measures in Anterior and Mediolateral Skull Base Surgery In recent years, there has been a significant increase in the numbers of HRQOL reports with regard to skull base literature. This was mainly driven by endoscopic endonasal surgeons and radiotherapists, as the extended endonasal approach became an alternative to craniotomy,52,53,54,55 and stereotactic radiosurgery (SRT) became an alternative to microsurgery (MS) in the treatment of acoustic neuroma (AN).56,57 However, only few studies have addressed QOL issues in lateral and anterolateral skull base surgery. In a recent systemic review of literature by Kirkman et al31 on QOL in anterior skull base, only 29 quality studies were found out of 486 studies on anterior skull base surgery. In 59% of them (17 out of 29), high diversity of skull base tumors was included, and 34% incorporated tumors in two or more anatomical regions (anterior, middle, lateral, and/or posterior cranial fossa). A variety of surgical approaches were used, including open and endoscopic. Kirkman et al31 found KPS to be the most commonly used (45%) outcome measurement tool. As discussed previously, KPS provides a gross estimate functional status,

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does not address major aspects that might influence HRQOL, and is not a PROM. Also, the studies that used KPS as an outcome measurement scale had significant diversity with a variety of pathologies, anatomical locations, surgical approaches, and lengths of follow-up. Many studies did not specify the surgical approach used, while some assessed KPS only preoperatively or postoperatively. Those results clearly demonstrated the limitations of an outcome study in the skull base. The most notable HRQOL outcome measuring tool for skull base surgery is the Anterior Skull Base Questionnaire (ASBQ).52, 58 ASBQ has been found to predict the postoperative QOL of different groups of patients undergoing skull base tumor surgery.52 ASBQ is a PROM rather than clinician-reported outcome measure, and this importance was illustrated by a study using ASBQ where a poor correlation was found between a patient’s self-rating and the surgeon’s perception of that patient’s QOL.54 The ASBQ questionnaire was introduced by Gil et al58 in 2003, and it is widely used to assess QOL in patients with tumors in the anterior skull base.52,53,54,55,59,60,61,62,63 The structure of the questionnaire assesses the impact of various factors on aspects of QOL and specific symptoms. It includes a total of 35 items related to the following distinct domains: role of performance, vitality, physical functioning, social adaptation, impact upon emotions, pain, and specific symptoms. The scores for each item range from 1 (poor) to 5 (excellent), and thus the total score ranges from 35 to 175 (higher scores are better). In addition, ASBQ has more general questions on mood, energy levels, and pain, and questions are phrased to detect changes from preoperative levels.52,58 In comparing patient and surgeon ratings with respect to a patient’s QOL, ASBQ scores had good correlations between mean scores reported by patients and their caregivers.54 Only in the specific symptoms domain did caregivers significantly overrate patient scores. Within individual patient– caregiver pairs, there was an overall significant agreement between patients’ and caregivers’ perceptions of QOL, and a significant agreement in all domains except the domains of effect of emotions (minor correlation) and pain (no correlation). Another disease-specific HRQOL scale widely used in endonasal surgery is the Sinonasal Outcome Test (SNOT)-22.59,60,64,65, 66,67 It is a 22-item self-reporting questionnaire that was originally designed for the assessment of QOL related to benign sinonasal disease. Each item is a specific symptom that the patient rates from 0 (no problem) to 5 (as bad as it can be), depending on how much (severity and frequency) each symptom troubles the patient. In this regard, it is not tailored for patients undergoing skull base surgery, because it assesses ear-related symptoms and sneezing but not for symptoms such as sense of smell and taste, nasal crusting, and nasal whistling that are especially relevant for endonasal skull base surgery. Nevertheless, use of the SNOT-22 has shown improvement in sinonasal morbidity following surgery in five skull base surgery studies.59,60,61

42.4 Outcome Measure in Acoustic Neuroma 42.4.1 Traditional Outcome Measures In contrast to anterior skull base, the traditional outcome measurements for AN are stratified and clear. This is related to the

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Controversies in Outcome Measures of Skull Base Surgery fact that AN is a single pathology with standard measurable outcomes of facial nerve function and hearing. The following three treatment modalities are practiced among AN patients. SRT, MS, and the OBS.68,69 There is a consensus that symptomatic tumors larger than 3 cm should be treated with MS; however, the management of tumors smaller than 3 cm not only varies but is also controversial. No significant difference in outcomes was seen between MS and SRT. The local control rates with MS was estimated at 97 to 98% (for gross total removal),70 which is similar to SRT.71,72 The hearing preservation rate was reported to be between 49 and 51%,69,70 and was highly dependent on the size of the tumor, whereas SRT showed slightly better results in the first couple of years after surgery and deteriorated later on.71,73 Similar comparable results were reported for preservation of facial nerve function, and the differences between SRT and MS were not significant. They were estimated to be 95 to 98% for good facial nerve function (House–Brachmann grades I–III),71,72,74,75 after SRS, and 90% for smaller tumors (< 20 mm) after MS.76 Although hundreds of clinical studies have measured outcomes for treatment options, most of the outcome studies were limited in scope. Some were retrospective in nature, many had relatively short follow-up time, and there are real randomized controlled clinical trials to compile any of the treatment modalities.76,77,78,79,80,81

42.4.2 Quality-of-Life Outcome Measures in Acoustic Neuroma Given the difficulty in randomizing treatments for prospective studies and the limitations that currently exist in outcomes research with regard to patients with AN, some authors have suggested76,80 that QOL/HRQOL measures can have a potentially important role in guiding treatment, decision making, and management protocols for AN. Most QOL studies for AN have used the general and generic SF-36 scale. The Dizziness Handicap Inventory, Glasgow Balance Inventory, Health Status Questionnaire, and Hearing Handicap Inventory have also been used; however, they are not specific to AN and were not validated.82 The Penn Acoustic Neuroma Quality of Life (PANQOL) scale is a recent AN disease-specific QOL instrument validated by Shaffer et al83 and Medina et al.84 This survey assesses patient-perceived QOL across the following domains: hearing, balance, facial symptoms, anxiety, energy, pain, and general health. Subscores are used to calculate a composite QOL score. This scale was proved to be more accurate in detecting changes in hearing-associated QOL than the conventional generic scale.82 Although functional preservation of facial nerve and hearing preservation outcomes remain an important issue because of the significant physical and psychological consequences for a patient’s QOL, studies revealed that traditionally objective outcome measurements such as facial nerve function, hearing, and tumor growth have no significant correlation to QOL.84,85,86 However, vertigo and instability were significantly associated with decreased QOL.85,86 On the contrary, there is no consensus with respect to the findings on the impact of different treatment modalities on QOL. Robinett et al82 reported using the PANQOL scale and said that QOL for OBS was not significantly

higher than the MS group between 0 and 5 years; although the OBS group reported higher hearing, balance, and facial nerve– related QOL compared with the MS group, anxiety, energy, and general health subscores tended to be lower in OBS, which may account for this discrepancy. On the contrary, Medina et al84 found that OBS was associated with a higher PANQOL score when compared with SRT and MS. Using generic scale, Breivik et al85 reported that OBS patients had lower QOL scores, whereas both Kelleher et al40 and Sandooram et al87 reported higher QOL in OBS than MS. Di Maio and Akagami79 found no difference between treatment groups. During a systemic review conducted by Gauden et al,81 who were looking into QOL studies in AN, the authors concluded that there is no evidence yet to support that QOL measurements are the favorites of any of the treatment modalities for AN. In a recent international multicenter cross-sectional study comparing MS, SRT, and OBS using PANQOL scale, the differences in HRQOL outcomes were small. The study found that diagnosis of AN by itself, rather than the treatment strategy, has the most significant impact on QOL.88 These mixed results outline the controversy in AN outcome measures and highlights the need for further studies to better evaluate this topic.

42.5 Conclusions Measuring surgical outcomes has been indirectly associated with improving outcomes of care. However, in skull base surgery, this issue is far behind other fields of medicine. This is largely due to frequent poor study designs, priority given to studies focusing on new surgical techniques and case series, and high rates of retrospective studies where outcome was measured by mortality rate, GOS, KPS, and mRS where surgeons reviewed their patients and subjectively assessed the outcome. QOL and HRQOL have become widely accepted in medicine for outcome assessment, and PROMs were validated to give a different perspective on outcome and be more indicative of patient well-being. The penetration of these tools for outcome measures of skull base surgery remains a challenge.

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[75] Selch MT, Pedroso A, Lee SP, et al. Stereotactic radiotherapy for the treatment of acoustic neuromas. J Neurosurg. 2004; 101 Suppl 3:362–372 [76] Bloch O, Sughrue ME, Kaur R, et al. Factors associated with preservation of facial nerve function after surgical resection of vestibular schwannoma. J Neurooncol. 2011; 102(2):281–286 [77] Tschudi DC, Linder TE, Fisch U. Conservative management of unilateral acoustic neuromas. Am J Otol. 2000; 21(5):722–728 [78] Irving RM, Beynon GJ, Viani L, Hardy DG, Baguley DM, Moffat DA. The patient’s perspective after vestibular schwannoma removal: quality of life and implications for management. Am J Otol. 1995; 16(3):331–337 [79] Di Maio S, Akagami R. Prospective comparison of quality of life before and after observation, radiation, or surgery for vestibular schwannomas. J Neurosurg. 2009; 111(4):855–862 [80] Sughrue ME, Yang I, Aranda D, et al. Beyond audiofacial morbidity after vestibular schwannoma surgery. J Neurosurg. 2011; 114(2):367–374 [81] Gauden A, Weir P, Hawthorne G, Kaye A. Systematic review of quality of life in the management of vestibular schwannoma. J Clin Neurosci. 2011; 18(12): 1573–1584 [82] Robinett ZN, Walz PC, Miles-Markley B, Moberly AC, Welling DB. Comparison of long-term quality-of-life outcomes in vestibular schwannoma patients. Otolaryngol Head Neck Surg. 2014; 150(6):1024–1032 [83] Shaffer BT, Cohen MS, Bigelow DC, Ruckenstein MJ. Validation of a diseasespecific quality-of-life instrument for acoustic neuroma: the Penn Acoustic Neuroma Quality-of-Life Scale. Laryngoscope. 2010; 120(8):1646–1654 [84] Medina MD, Carrillo A, Polo R, et al. Validation of the Penn Acoustic Neuroma Quality-of-Life Scale (PANQOL) for Spanish-speaking patients. Otolaryngol Head Neck Surg. 2017; 156(4):728–734 [85] Breivik CN, Varughese JK, Wentzel-Larsen T, Vassbotn F, Lund-Johansen M. Conservative management of vestibular schwannoma–a prospective cohort study: treatment, symptoms, and quality of life. Neurosurgery. 2012; 70(5): 1072–1080, discussion 1080 [86] Martin HC, Sethi J, Lang D, Neil-Dwyer G, Lutman ME, Yardley L. Patientassessed outcomes after excision of acoustic neuroma: postoperative symptoms and quality of life. J Neurosurg. 2001; 94(2):211–216 [87] Sandooram D, Hornigold R, Grunfeld B, et al. The effect of observation versus microsurgical excision on quality of life in unilateral vestibular schwannoma: a prospective study. Skull Base. 2010; 20(1):47–54 [88] Soulier G, van Leeuwen BM, Putter H, et al. Quality of life in 807 patients with vestibular schwannoma: comparing treatment modalities. Otolaryngol Head Neck Surg. 2017; 157(1):92–98

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43 To Bypass or Not? The Role of Revascularization in Skull Base Surgery Justin R. Mascitelli, Sirin Gandhi, and Michael T. Lawton Abstract To bypass or not is a question that must be answered when faced with extensive skull base tumors with vascular involvement. This question may arise when planning a tumor resection, but it may also arise in an unplanned setting in response to a major vascular injury during tumor resection. Tumors may be malignant or benign, and some vessels may already be narrowed to the point of causing ischemia. There has been a trend over the past 20 years for less use of bypass in the setting of skull base oncologic disease for reasons such as extreme poor prognosis associated with extensive malignant skull base tumors and the increasing use of stereotactic radiation for benign skull base tumors. However, there are still scenarios where bypass is useful, such as vascular insufficiency and vascular injury.

principles of oncologic treatment; and (3) a tumor (benign or malignant) already occluding a major artery and causing the patient to have ischemic symptoms (or preoperative evidence of significantly reduced cerebrovascular reserve). The second scenario is in response to inadvertent vessel injury that occurs during tumor resection. The offending surgery may be open or endonasal. An injured artery can be either within the circle of Willis or more distal. Occasionally, an injured vein will also require revascularization. In either instance, bypass will be emergent or urgent and there will be less opportunity for planning. In this chapter, we discuss both types of bypasses, the indications for each, and the controversies surrounding the implementation of these planned and unplanned bypasses.

Keywords: anastomosis, bypass, graft, iatrogenic injury, ischemia, pseudoaneurysm, resection, revascularization, tumor, vascular injury

43.2 Topic Review 43.2.1 Discussion of Key Studies and Quality of Evidence

43.1 Introduction Although rarely needed, cerebral revascularization in patients who have skull base oncologic disease may be used in two general scenarios: planned and unplanned (▶ Table 43.1). The first is a bypass performed in anticipation of a radical skull base tumor resection and planned sacrifice of a large extracranial or intracranial vessel. Tumors may be benign, with vascular encasement, or they may be extensive, recurrent, and malignant. The involved artery is usually the internal carotid artery (ICA) or the dominant vertebral artery (VA). The circle of Willis is frequently incompetent, which eliminates the option of vessel occlusion. The bypass is performed in a controlled, planned setting prior to vessel occlusion and tumor resection. Yang et al1 delineated the indications for a planned bypass as threefold: (1) a benign tumor encasing a major artery, vein, or sinus that cannot be dissected free for complete resection without damaging the vessel; (2) a malignant tumor involving a major artery, for which complete resection is the preoperative goal based on the

Table 43.1 Indications for bypass in skull base oncologic disease Planned or elective

Unplanned or emergent

Benign tumor with vascular encasement or infiltration

Vascular injury during tumor resection

●

Large artery at the skull base (ICA or VA)

Injury during endonasal surgery

●

Dural venous sinus

Injury during open surgery

Malignant tumor involving a major artery at the skull base Vascular insufficiency secondary to tumor-related arterial occlusion Abbreviations: ICA, internal carotid artery; VA, vertebral artery.

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The evidence for bypass in patients with skull base oncologic disease is minimal and is limited to case series, case reports, and expert opinions. Fortunately, most neurosurgeons will rarely encounter either an extensive skull base tumor that mandates a bypass or a vascular injury that occurs during tumor surgery. Thus, there are no large, multicohort studies comparing different treatment modalities, and there are certainly no prospective randomized controlled trials. The largest case series are summarized in ▶ Table 43.2 and ▶ Table 43.3.1,2,3,4,5,6,7,8,9,10,11 Numerous insights can be gleaned from these studies. In the scenario of planned resection and vessel sacrifice, nearly all the patients in all the available studies received a high-flow bypass for replacement of the ICA (not an STA-to-MCA [superficial temporal artery–to–middle cerebral artery] bypass). With respect to benign disease involving vascular encasement, there has been a shift over time from extensive tumor resection to more conservative resection followed by adjuvant radiation for residual disease,12 which has reduced the number of patients requiring bypass surgery. This shift is exemplified by changes in patient volume and attitude toward treatment approaches over time at a single treatment center.1,7 Also performed increasingly rarely in recent years is aggressive resection of tumors involving the dural venous sinuses, accompanied by attempted venous reconstruction.10,11,13 With respect to malignant disease, the outcomes of such an aggressive approach in patients with extensive, recurrent, high-grade malignancies are poor, which may not justify this approach.8 This change is exemplified by the changes in attitude at another institution over time.2,8 In some rare circumstances, such as locally advanced recurrent nasopharyngeal carcinoma, an aggressive approach to revascularization may still be warranted.9 Overall, however, an aggressive approach is most successful in a highly select population of patients with specific types of tumors.1

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To Bypass or Not? The Role of Revascularization in Skull Base Surgery

Table 43.2 Key studies and level of evidence: planned bypass prior to tumor resection or vessel occlusion Author (year)

Level of evidence

Title

No. of patients

Type of bypass

Outcomes

Comments

Lawton and Spetzler (1996)2

IV

Internal carotid artery sacrifice for radical resection of skull base tumors

N = 10 (out of 300 patients with anterior skull base tumors): 9 malignant 1 benign (meningioma)

10 patients had tumor resection, ICA sacrifice, and bypass: 4 ICA–SVG–MCA 1 cervical to supraclinoid ICA 3 petrous to supraclinoid ICA 2 Bonneta

Postop GOS score decreased in 4 patients; postop complications noted in 3 patients (2 ischemia, 1 CSF leak)

ICA preservation is preferable for patients with benign tumors, whereas radical tumor resection and ICA sacrifice are preferable for patients with malignant tumors

Brisman et al (1997)3

IV

Results of surgery for head and neck tumors that involve the carotid artery at the skull base

N = 17 with head and neck malignancies

17 patients had tumor resection (all bypasses were high flow): 7 with ICA preservation 7 with ICA sacrifice and bypass 3 with ICA sacrifice without bypass

65% (11/17) of patients had an overall good outcome at 2.1 y; postop ischemia was noted in 2 patients with a bypass (1 had permanent neurological morbidity; 1 died)

Most patients requiring ICA sacrifice had recurrent disease ICA preservation has lowest risk of stroke ICA sacrifice and bypass are best for patients with advanced or recurrent disease if necessary to obtain a meaningful resection; outcomes are worst for ICA sacrifice without bypass

Chazono et al (2003)4

IV

Extracranial-intracranial bypass for reconstruction of internal carotid artery in the management of head and neck cancer

N = 8 with head and neck cancer

3 single-stage ECA–RAG–M2 1 single-stage V3– RAG–M2 4 two-stage (STAto-M3, followed by ICA–M2 graft)

1 of the 4 patients who underwent a singlestage procedure developed a perioperative infarction leading to permanent neurologic disability (hemiplegia) 3 patients had diseasefree survival for > 4 y

The 2-stage procedure may protect against ischemia, and radical tumor or carotid resection may be the only modality that offers any hope of a cure

Sekhar et al (2008)7

IV

Cerebral revascularization for ischemia, aneurysms, and cranial base tumors

N = 130 patients: 79 meningioma 7 chondrosarcoma 7 chordoma 5 adenoid cystic carcinoma 32 miscellaneous

101 SVG graft 29 RAG graft

63% (82/130) GTR 95.4% (124/130) demonstrated immediate graft patency 2 patients had delayed occlusion 1.5% (2/130) of deaths were related to surgery 13.1% of deaths were related to disease progression or recurrence

Previous publications from this treatment center5,6 were omitted due to presumed overlap with this study

Kalani et al (2013)8

IV

Cerebral revascularization and carotid artery resection at the skull base for treatment of advanced head and neck malignancies

N = 18 with skull base cancer: 4 sarcoma 14 carcinoma

7 ipsilateral EC–IC with SVG 1 ipsilateral EC–IC with RAG 3 Bonnet bypass with SVG 7 Bonnet bypass with RAG

11.1% (2/18) patients with surgery-related mortality 16.7% (3/18) patients with bypass-related morbidity 33.3% (6/18) patients with tumor resection– related morbidity mean LOS, 11.8 mo; median LOS, 8 mo; mean length of followup, 137 mo All 18 patients had died of cancer or cancer-related causes

Even with maximal surgical intervention, morbidity and mortality were too high to justify this approach, but it might be considered in patients with low-grade malignancies

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Table 43.2 (continued) Author (year)

Level of evidence

Title

No. of patients

Type of bypass

Outcomes

Comments

Yang et al (2014)1

IV

Cerebral revascularization for difficult skull base tumors: a contemporary series of 18 patients

N = 18 patients with skull base tumors: 6 benign tumors with ICA or VA encasement 5 malignant tumors with ICA or VA involvement 4 ischemia due to vessel narrowing 3 intraoperative injuries

All bypasses were high flow

72.2% (13/18) patients had GTR No perioperative strokes or graft occlusions 1 delayed graft stenosis that was repaired 83.3% (15/18) of patients with good outcome (mRS score ≤ 2) 3 deaths (1 postop, 2 disease-related)

High-flow bypass is a good option for certain difficult skull base tumors

Chan et al (2016)9

IV

Extracranial/intracranial vascular bypass and craniofacial resection: new hope for patients with locally advanced recurrent nasopharyngeal carcinoma

N = 28 with locally advanced (rT3–rT4) recurrent NPC

First stage: ECA–RAG–MCA or CCA–RAG–MCA bypass followed by an ICA sacrifice Second stage: Combined craniofacial tumor resection

46.4% (13/28) of patients with GTR with 42.6-mo median follow-up; 17.8% (5/28) patients with local recurrence; 52% patients with a 5year overall survival; no change in mean global health score, but reduction in physical function score; most common morbidity was speech and swallowing difficulty

This approach was reasonable for locally advanced recurrent NPC with satisfactory local tumor control and survival and reasonable QOL

Abbreviations: CCA, common carotid artery; CSF, cerebrospinal fluid; EC, extracranial; ECA, external carotid artery; GOS, Glasgow Outcome Scale; GTR, gross total resection; IC, intracranial; ICA, internal carotid artery; LOS, length of survival; MCA, middle cerebral artery; mRS, modified Rankin scale; NPC, nasopharyngeal carcinoma; postop, postoperative; QOL, quality of life; RAG, radial artery graft; STA, superficial temporal artery; SVG, saphenous vein graft; VA, vertebral artery. aBonnet bypass: a contralateral STA–MCA with an SVG or RAG interposition graft that courses over the top of the head.

In the scenario of unplanned bypass for iatrogenic vessel injury, the evidence is even sparser. In 2014, Rangel-Castilla et al14 published a series with a total of eight patients in whom such bypasses were successfully completed for vascular injury (▶ Table 43.4).14 The rest of the surgical literature on the topic consists of case reports and expert opinions,15,16,17,18 especially regarding bypass for venous injury.19 Endovascular therapy has certainly improved over time; thus, many vascular complications, especially those that occur during endonasal surgery, can be managed with endovascular techniques.20 Frequently, however, the only endovascular option is parent vessel occlusion (PVO), and each patient should be evaluated for bypass to prevent cerebral ischemia.

43.2.2 Biases of Authors and Institutions Despite a growing trend in oncology treatment for more conservative tumor resection and liberal use of postoperative radiation for residual tumor, some tumors with vascular encasement will still require aggressive resection. For these cases, we advocate for the use of an aggressive approach toward revascularization, both arterial and venous. However, for patients with extensive, recurrent, and malignant skull base

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tumors, we advocate the use of a more cautious approach (▶ Fig. 43.1). In the latter category, patients should be extensively evaluated preoperatively, including for life expectancy and for the feasibility of obtaining gross total resection. Even if these two factors are favorable, patients require extensive counseling about the high complication rate (with a morbidity estimated at >50% and estimated survival of 25). However, CSF opening pressures or radiographic signs suggestive of benign intracranial hypertension were not consistently reported in these reviews. Due to the association between LSR encephaloceles and benign intracranial hypertension, a workup for benign intracranial hypertension preoperatively and use of CSF diversion therapy during the postoperative course should be considered due to the increased success in CSF leak repair in this patient subset (93 vs. 82%; intervention [acetazolamide or CSF shunt system] vs. no intervention26).

44.2.2 Open Transcranial versus Transnasal Endoscopic Approaches No studies to date have been conducted directly comparing open transcranial to endoscopic transpterygoid approaches. Conclusions regarding the most effective approach are deduced from case series and surgeon experience (levels IV–V evidence) and inferred from the anterior skull base literature (level III evidence). The majority of literature since Bolger introduced the endoscopic transpterygoid approach in 1999 has been dominated by case series replicating Bolger’s technique with 91 to 100% overall success rate (▶ Table 44.1). The only overall treatment failure was reported by Lai et al in a case that already had three previous surgical failures via transsphenoid approaches and they reported that a true transpterygoid approach was not utilized as the operation was performed prior to Bolger’s publication.27 Definitive treatment of this case was not reported.

Studies reporting success of open transcranial approaches have been confined to case reports (▶ Table 44.2, level V evidence). Four case reports described proceeding with an open transcranial approach due to previous endoscopic failures. However, three of the four endoscopic failures employed the restrictive midline transsphenoid approach.20,21,36,37 These failures should not be referenced as examples of the limitations of an endoscopic approach due to the limitations of the midline transsphenoid approach to the LSR previously discussed. Samadian et al did report a failure of an endoscopic transpterygoid approach performed by the authors themselves due to limited visualization of the skull base defect, which was followed by successful treatment via an open transpterional craniotomy approach.21 This initial failure likely reflected the authors’ inexperience with the endoscopic transpterygoid approach rather than a limitation of the technique itself, as adequate removal of the pterygoid process results in wide exposure of the LSR. The minimal invasiveness of the endoscopic approach also has the advantage of lower complication rates and less consequential morbidities seen with open approaches. While direct comparisons of complication rates between transcranial and endoscopic approaches to the LSR cannot be made given the limited literature, open transcranial approaches have shown to incur higher rates of complications and significant morbidities within the anterior skull base literature. Komotar et al’s systematic review revealed that open approaches are associated with significantly higher rates of meningitis, abscesses, sepsis, and perioperative mortality.8 Open approaches also have higher potential for external scars, memory deficits, hemorrhage, seizures, cerebral edema, and osteomyelitis given the external incisions, craniotomy, and temporal lobe retraction in order to gain appropriate exposure to the LSR.41,42,43 Complications associated with the endoscopic transpterygoid approach are limited to meningitis risks and injuries to structures within the pterygopalatine fossae which include the pterygopalatine ganglion, vidian nerve, V2, and the internal maxillary artery leading to the potential for facial and/or palatal hypoesthesia, dry eyes, and/or epistaxis. The rate of meningitis in endoscopic transpterygoid approaches was similar to those of other endoscopic anterior skull base approaches (2 vs. 1.1%, respectively) reported by Komotar et al8 (▶ Table 44.3). Due to the high success rate and low morbidity, the endoscopic transpterygoid approach should be considered the primary approach for repair of LSR encephaloceles. The question remains, however, whether open transcranial approaches still play a role in addressing LSR encephaloceles, specifically for the following indications: encephaloceles in the setting of epilepsy, endoscopic failures, and especially large encephaloceles.

44.2.3 Seizures While the endoscopic transpterygoid approach has proven to be an effective technique to address LSR encephaloceles, debate remains whether this approach has a role in treating temporal lobe epilepsy (TLE) with an associated encephalocele. The contributing role of an encephalocele in the setting of TLE has yet to be fully clarified; current theories suggest that seizures are triggered by traction of herniated temporal lobe parenchyma with secondary local effects of inflammation and gliosis. Refractory seizures can also be attributed to grander scale cerebral

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Table 44.1 Study characteristics of endoscopic transpterygoid repairs of LSR encephaloceles Author

Year

N

Age (y)

F

M

Location

Approach

F/u months

Success rate

Level of evidence

Lai et al27

2002

12

52.3 (19–73)

7

5

LSR (8) MSL (4)

TP

32 (12–69)

92%

IV

Al-Nashar et al11

2004

7

33–80

5

2

LSR

TP

28 (12–79)

100%

IV

Pasquini et al19

2004

4

61 (48– 73)

3

1

LSR

TP (3) TS (1)

18 (10–26)

100%

IV

Bolger12

2005

9

53.1

6

3

LSR

TP

14.5 (1–25)

100%

IV

Bachmann- Harildstad et al28

2006

1

76

0

1

LSR

TP

12

100%

V

Tami29

2006

6

NR

NR

NR

LSR

TP

1–44

100%

IV

Castelnuovo et al3

2007

15

60.3 (34–75)

9

6

LSR

TP (9) TS (6)

37.6

100%

IV

Tomazic and Stammberger23

2009

5

51.2 (44–62)

4

1

LSR

TP (3) TES (2)

6.5 (1–18)

60% primary 100% overall

IV

Forer and Sethi30

2010

8

51 (40– 64)

5

3

LSR

TP

1–84

90% primary 100% overall

IV

Hofstetter et al31

2010

4

48–64

3

1

LSR

TP

30 (7–44)

75% primary 100% overall

IV

Muscatello et al32

2010

2

54–67

1

1

LSR

TP (2)

10–19

50% primary 100% overall

V

Tabaee et al22

2010

13

57.1 (36–78)

8

5

LSR

TP (3) TS (5) TES (5)

56.4 (8– 144)

85% primary 100% overall

IV

Alexander et al33

2012

11

56 (43– 65)

8

3

LSR

TP

10.8 (2–29)

92% primary 100% overall

IV

Schmidt et al34

2012

4

52–59

4

0

LSR

TP

6–42

100%

IV

Martínez Arias et al35

2015

5

59 (37– 72)

4

1

LSR

TP

81 (18– 132)

80% primary 100% overall

IV

El Tarabishi et al16

2016

7

40.1 (30–51)

5

2

LSR

TSR

41.5 (35– 52)

100%

IV

Zoli et al24

2016

23

52 (26– 73)

16

7

LSR

TP

84 (4–167)

100%

IV

Abbreviations: LSR, lateral sphenoid recess; MSL, medial sphenoid line; NR, not reported; TES, transethmosphenoid approach; TP, transpterygoid approach; TS, transsphenoid approach; TSR, transsphenoid retrograde approach.

parenchymal malformations including heterotopia, diffuse cortical dysplasia, and schizencephaly. Optimal surgical treatment for refractory TLE with an associated encephalocele has not yet been established. Some data have shown that isolated reduction of an encephalocele in the setting of TLE absent of major parenchymal malformations has successfully resolved TLE.44,45 However, other authors advocate for an open transcranial approach with an anterior lobectomy to better identify and resect the prospective epileptogenic zone. Faulkner et al reviewed cases reported in the literature of seizures with associated encephaloceles, which included subsites beyond the

276

sphenoid sinus. It was found that of the cases of TLE with an associated encephalocele, 67% underwent lobectomy while 33% underwent treatment limited to the reduction of the encephalocele. Both groups were 100% seizure free in their respective follow-up.45 This may suggest that attempting a less invasive approach initially, such as an endoscopic transpterygoid approach, is reasonable while reserving open transcranial lobectomies for refractory cases. Due to the limited cases reported in the literature, more investigation is needed regarding this topic to better elucidate appropriate treatment options for TLE with encephaloceles.

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Table 44.2 Study characteristics of open transcranial repair LSR encephalocelesa Author

Age (y) gender

F/u months

Approach

Size of defect (mm)

Closure

Lumbar drain

Complications

Vergoni et al (2001)38

75 M

12

Transtemporal

NR

Multilayer: PC + MF + D

NR

NR

Bikmaz et al (2005)39

57 M

24

Transpterional

15

Multilayer: DS + M

Yes

None

Gürkanlar et al (2007)36

44 F

42

Transpterional

NR

Multilayer: TF + TM

NR

NR

Sare et al (2009)37

52 F

24

Subtemporal

NR

Multilayer: DS + AF

NR

None

Prabhu et al (2011)20

50 M, 42 M

6, 6

Transtemporal

15, 10

Multilayer: DPC + T + M + AF; DPC + FL + B + AF

Yes

NR

Samadian et al (2012)21

23 F

12

Transpterional

3

Multilayer: TF + B

NR

None

54 F

60

Subtemporal

NR

Multilayer: PC + M

Yes

None

Keric et al

(2013)40

Abbreviations: AF, autologous fat; B, bone; D, dura; DPC, dural primary closure; DS, dural substitute; FL, fascia lata; M, muscle; MF, muscle fascia; NR, not reported; PC, pericranium; T, titanium mesh; TF, temporalis fascia; TM, temporalis muscle. aAll studies reported are case reports, level V evidence.

44.2.4 Endoscopic Approach Failures The endoscopic transpterygoid approach has proven to produce a high level of efficacy with an overall success rate of 91 to 100%. As previously discussed since the endoscopic transpterygoid approach was introduced, open transcranial approaches have been reported only in four cases where previous endoscopic approaches had failed.20,21,36,37 Only one of these cases was a result of a failed endoscopic transpterygoid approach.21 Open transcranial approaches do offer direct visualization of skull base defects but can still have limitations in exposure as the LSR is located deep within the middle cranial fossae. In contrast, the exposure offered by the endoscopic transpterygoid approach and visualization provided by endoscopes offer a broad field of view with magnification that may offer an advantage for primary and revision cases. The wide exposure and magnified visualization allows for accurate localization of the encephalocele(s) and definitive skull base defect repair, which sometimes cannot be identified with imaging or open approaches (▶ Fig. 44.1b). Castelnuovo et al, Forer and Sethi, and Alexander et al have reported a combined seven cases of successful implementation of the endoscopic transpterygoid approach in revising failed transcranial approaches further illustrating the utility of the transpterygoid approach in even challenging revision cases.3,30,33

44.2.5 Large Encephaloceles Within the anterior skull base literature, some may consider using an open approach to address large and/or multifocal skull base defects. This approach offers the advantage of direct repair of dural defects, addressing multiple subsites simultaneously, and treatment of any surrounding pathology.41 The majority of isolated LSR encephaloceles have been shown to be attributed to benign intracranial hypertension where the size of the skull base defect is typically limited in size. Literature review demonstrated that the size of the skull base defect was similar between open and endoscopic approaches (▶ Table 44.2, ▶ Table 44.3) and therefore not a defining indication to proceed

with a particular approach. In cases of large skull base defects spanning outside the confines of the LSR, a primary open approach to effectively address the multiple subsites simultaneously should be considered.

44.3 Case Example 44.3.1 History A 62-year-old woman reported 3 weeks of intermittent headaches and left-side clear salty rhinorrhea exacerbated with leaning over (▶ Fig. 44.1). She had history of mild blunt head trauma without loss of consciousness 2 days prior to the onset of her aforementioned symptoms. At the transferring hospital, the nasal discharge was confirmed to be CSF with a positive beta-2 transferrin test. A 1-week trial of bed rest and a lumbar drain at an outside hospital was unsuccessful. The patient was then transferred to our facility for definitive management. Throughout her course, she maintained stable vitals without meningismus and complete blood counts and electrolytes remained within normal limits.

44.3.2 Imaging Computed tomography (CT) imaging revealed bilateral lateral pneumatization of her sphenoid sinus with a 5-mm left LSR skull base defect lateral to the foramen rotundum. Magnetic resonance imaging (MRI) exhibited an associated left LSR encephalocele involving the cortex of the medial aspect of the left inferior temporal gyrus (▶ Fig. 44.2).

44.3.3 Surgical Approach The patient was placed under general anesthesia with oral endotracheal intubation. A slow infusion over 10 minutes of 10 mL of 0.1% sodium fluorescein was injected intrathecally. Topical nasal decongestion was applied with 0.05% oxymetazoline and intraoperative image guidance was employed.

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Table 44.3 Endoscopic transpterygoid repair technique and complications Author

Year

N

Size of defect (mm)

Lai et al27

2002

12

1–9

Multilayer: FL + NM

NR

NR

Al-Nashar et al11

2004

7

NR

Multilayer: DS + NM; DS + NM + AF

1/7

NR

Pasquini et al19

2004

4

NR

Multilayer: AF + NM; B + NM; DS + AF + NM

NR

None

Bolger12

2005

9

NR

Multilayer: B + FL + AF

NR

Partial anesthesia palate (1)

Bachmann-Harildstad et al28

2006

1

4

Multilayer: AF + FL + NM

1/1

None

Tami29

2006

6

NR

NR

6/6

Temporary partial anesthesia palate (1), temporary dry eye (1)

Castelnuovo et al3

2007

15

2–8

Monolayer: AF Multilayer: DS + MT; DS + NC

0/15

None

Tomazic and Stammberger23

2009

5

6–10

Multilayer: AF + FL + AC; AF + FL; FL + NC; FL + AF

NR

Partial anesthesia palate (1), meningitis (1), brain abscess (1)

Forer and Sethi30

2010

8

NR

Multilayer: AF + NC + NM + AF; AF + B + NM + AF

0/8

NR

Hofstetter et al31

2010

4

NR

Multilayer: AF + NC + FL

2/4

Dry eyes/palate numbness (1)

Muscatello et al32

2010

2

NR

Multilayer: DS + B + NM; DS + NM

0/2

None

Tabaee et al22

2010

13

NR

Multilayer: B + FL; FL + MT; B + AF; AC + TF; AF + DS

8/13

Meningitis (1), facial paresthesias (1)

Alexander et al33

2012

11

NR

Monolayer: DS Multilayer: DS + B; DS + B + AF; DS + AF + NSF

5/11

NR

Schmidt et al34

2012

4

NR

Monolayer: DS Multilayer: DS + AF; DS + NM + AF; DS + NM

1/4 (VP shunt)

None

Closure

Lumbar drain

Complications

Martínez Arias et al35

2015

5

NR

Multilayer: FL + MT

0/5

None

El-Tarabishi et al16

2016

7

6–10

Multilayer: AF + FL + NC + AF + NM

7/7

None

Zoli et al24

2016

23

NR

Multilayer: B + AF + NM; C + AF + NM

1/23

Post-op seizure (1)

Abbreviations: AF, autologous fat; AC, auricular cartilage; B, bone; C, cartilage; DS, dural substitute; FL, fascia lata; MT, middle turbinate mucosa; NC, nasal cartilage; NM, nasal mucosa; NR, not reported; NSF, nasal septal flap; TF, temporalis fascia. aOf the six patients who did not have a lumbar drain, five patients were placed on acetazolamide. The one patient who did not receive postoperative intervention had normal intracranial pressure.

Sinonasal injections with 1% lidocaine with 1:100,000 epinephrine was performed on the left side at the axilla and anterior head of the middle turbinate. A left-side maxillary antrostomy, total ethmoidectomy, and a wide sphenoidotomy were performed for initial exposure. Through the transethmoid and transsphenoid nasal corridor, the encephalocele was partially visualized with a 30-degree endoscope, but there was limited exposure for instrumentation (▶ Fig. 44.1a; Video 44.1). Attention was then directed to the ascending process of the palatine bone at the junction of the posterior maxillary sinus wall. Vertical mucoperiosteal-releasing incisions were made 5 mm anterior to the posterior attachment of the middle turbinate just anterior to the crista ethmoidalis from the nasal floor and along the lateral nasal wall. The periosteum was then

278

elevated posteriorly to expose the crista ethmoidalis and the sphenopalatine neurovascular bundle exiting the sphenopalatine foramen. A 2-mm rongeur (2-mm Osteo Punch Rongeur, Koros) was used to remove the posterior maxillary sinus wall starting at the sphenopalatine foramen and proceeding in a medial to lateral direction. Great care was utilized during this dissection to avoid violating the underlying fascia. Once the pterygopalatine fossae was widely exposed, the fascia was incised with a beaver blade and bluntly dissected away from the fossae fat to expose underlying neurovascular structures. We obtained early vascular control and isolated the distal internal maxillary artery with a maxillary ostium seeker. The distal segment was then ligated with bipolar cautery and sharply divided. Bipolar cautery was used to reduce the pterygopalatine fat

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Fig. 44.2 CT and MRI with gadolinium imaging with axial, coronal, and sagittal views. The encephalocele and associated skull base defect is visualized within the left lateral sphenoid recess (arrow). Extensive pneumatization of the sphenoid sinus lateral to foramen rotundum (asterisk) and vidian canal (caret) is appreciated and best visualized on coronal CT view.

Fig. 44.3 A 4-month postoperative view of the skull base repair. The graft is well integrated and the lateral sphenoid recess has fully mucosalized with no evidence of a CSF leak.

to the anterior face of the pterygoid process. The pterygoid process was further exposed with a freer elevator safely dissecting away the sphenopalatine ganglion, V2, and vidian nerve. The periosteum overlying the pterygoid process was sharply incised and bluntly dissected to expose the anterior face of the pterygoid process. The anterior face of the pterygoid process can have varying thickness where a ronguer or a drill can be utilized to

remove this bone to expose the LSR. On this particular case, we removed a large portion of the pterygoid process with a 2-mm ronguer (2-mm Osteo Punch Rongeur, Koros) and addressed the thicker bone inferiorly with a 15-degree fluted burr drill (Diego fluted barrel burr, Olympus) to fully expose the LSR. With the broad exposure created by the transpterygoid approach, an additional encephalocele in a more anterior lateral position was identified within the LSR that was not found on imaging or with the wide sphenoidotomy (▶ Fig. 44.1b). The prolapsed encephaloceles were reduced with bipolar cautery to the level of the skull base defects. The lateral recess was stripped of mucosa exposing the underlying bone surrounding the skull base defects. The skull base defects were measured and an extracranial reconstruction was performed with an extracellular matrix graft (Biodesign Duraplasty Graft, Cook Medical) sized to have 1 cm overlap around the skull base defects. Dural sealant (Adherus Dural Sealant, Hyper Branch Medical Technology) was used to secure the graft in place. The graft was then buttressed with bioresorbable packing (Nasopore, Stryker) in the sphenoid sinus. The patient was hospitalized for 7 days postoperatively. She did not experience any postoperative complications. The lumbar drain was kept in place for 6 days and the patient was kept on bed rest for 7 days. At the fourth month postoperative appointment, the graft was noted to be well integrated and mucosalized with no signs of a CSF leak (▶ Fig. 44.3).

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44.4 Conclusions Encephaloceles of the LSR have been historically challenging to address. The endoscopic transpterygoid approach revolutionized the management of the LSR encephaloceles with an overall success rate of 91 to 100% across several case series. This approach provides a straight trajectory and wide exposure of the LSR that delivers excellent visualization to allow for accurate identification of the encephalocele and precise skull base defect repair and is associated with markedly less morbidity compared to more invasive open approaches. The endoscopic transpterygoid approach has become the treatment of choice for primary management of LSR encephaloceles and should be highly considered in revision cases. Open transcranial approaches can be considered in cases of especially large skull base defects spanning multiple subsites and in refractory TLE.

44.5 Author Biases The authors have developed a robust neurosurgery–otolaryngology skull base team at the University of Arizona for a multitude of skull base pathologies. Utilizing the expertise of the otolaryngologist and neurosurgeon in their respective fields and familiarity of their respective anatomy as well as taking the time to develop team dynamics, the authors employ the endoscopic transnasal approach for a wide range of pathologies including sinonasal and skull base tumors, CSF leaks of all etiologies, and pituitary lesions. With this experience, the authors are familiar and comfortable with the transpterygoid approach and use this approach exclusively for LSR encephaloceles. Lack of familiarity with the pterygopalatine fossae anatomy may result in injury to the neurovascular structures within the pterygopalatine fossae or inadequate removal of the pterygoid process, leading to limited LSR exposure and thus compromise the success of skull base repair.

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[36]

[37]

[38]

[39]

[40]

sphenoid meningoencephalocele resection. Our experience. Acta Otorrinolaringol Esp. 2015; 66(1):1–7 Gürkanlar D, Akyuz M, Acikbas C, Ermol C, Tuncer R. Difficulties in treatment of CSF leakage associated with a temporal meningocele. Acta Neurochir (Wien). 2007; 149(12):1239–1242 Sare GM, Varma A, Green K, Herwadkar A, Gnanalingham KK. Pneumococcal meningitis secondary to intra-sphenoidal encephalocoele. Acta Neurochir (Wien). 2009; 151(1):103–104 Vergoni G, Antonelli V, Veronesi V, Servadei F. Spontaneous cerebrospinal fluid rhinorrhoea in anteromedial temporal occult encephalocele. Br J Neurosurg. 2001; 15(2):156–158 Bikmaz K, Cosar M, Iplikcioglu AC, Dinc C, Hatiboglu MA. Spontaneous cerebrospinal fluid rhinorrhoea due to temporosphenoidal encephalocele. J Clin Neurosci. 2005; 12(7):827–829 Keric N, Burger R, Elolf E, Wrede A, Rohde V. Temporobasal, transsphenoidal meningoencephalocele becoming symptomatic with spontaneous cerebrospinal fluid rhinorrhea: diagnostic work-up and microsurgical

[41]

[42]

[43]

[44]

[45]

strategy. J Neurol Surg A Cent Eur Neurosurg. 2013; 74 Suppl 1:e111– e115 Scholsem M, Scholtes F, Collignon F, et al. Surgical management of anterior cranial base fractures with cerebrospinal fluid fistulae: a single-institution experience. Neurosurgery. 2008; 62(2):463–469, discussion 469–471 Tosun F, Gonul E, Yetiser S, Gerek M. Analysis of different surgical approaches for the treatment of cerebrospinal fluid rhinorrhea. Minim Invasive Neurosurg. 2005; 48(6):355–360 Yıldırım AE, Dıvanlıoglu D, Cetinalp NE, Belen AD. Endoscopic endonasal repair of spontaneous sphenoid sinus lateral wall meningocele presenting with cerebrospinal fluid leak. J Neurosci Rural Pract. 2014; 5(2):168–170 Abou-Hamden A, Lau M, Fabinyi G, et al. Small temporal pole encephaloceles: a treatable cause of “lesion negative” temporal lobe epilepsy. Epilepsia. 2010; 51(10):2199–2202 Faulkner HJ, Sandeman DR, Love S, Likeman MJ, Nunez DA, Lhatoo SD. Epilepsy surgery for refractory epilepsy due to encephalocele: a case report and review of the literature. Epileptic Disord. 2010; 12(2):160–166

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45 Cranioplasty Techniques Salvatore Lettieri and Christine Oh Abstract There are three main controversies within the realm of cranioplasty: timing, material, and placement. The discussion in regard to timing includes immediate or delayed. Cranioplasty materials have evolved with a significant expansion in the alloplastic options available and a variety of studies evaluating the benefit of autologous bone compared to alloplastic materials. The utilization of the autologous bone and its timing is also a point of discussion. There has been significant promise in the development of patient-specific implants. The third topic of which there is considerable debate is placement. Specifically, should the cranioplasts be placed in an anatomic or in a nonanatomic position? This chapter will discuss all these points and review the current literature regarding type of material, timing, and placement for cranioplasty. Keywords: cranioplasty, decompressive craniectomy, craniofacial reconstruction, autologous bone, alloplastic materials, syndrome of the trephined

45.1 Introduction Cranioplasty is performed to reconstruct the skull and potentially correct and prevent complications associated with a cranial defect, most often in the setting of decompressive craniectomies in the setting of trauma, medically intractable intracranial hypertension, or cancer resection. After craniectomy, patients are at risk for further neurotrauma due to absence of a protective bony skull and are subject to hydrocephalus, subdural hematoma, hemorrhage, infection, cerebrospinal fluid (CSF) leak, or seizures.1 Cranioplasty can facilitate neurologic recovery by restoring intracranial pressure dynamics and increased activity. Some controversies surrounding cranioplasty include timing, material used, and placement.

45.2 Timing of Cranioplasty The timing of cranioplasts needs to be taken into consideration for all patients and is an ongoing topic of debate.2,3,4 The placement of immediate cranioplasty would be ideal; however, there are often mitigating circumstances that preclude immediate placement of a cranioplasty material. For example, a patient undergoing a decompressive craniectomy thus allowing the brain to expand will not be able to undergo an immediate cranioplasty. The other issues would be patients who are unstable for various reasons, especially in the setting of traumatic injuries. The cranioplasty material, if autologous bone, would then need to be saved and stored for later use. There are a number of circumstances that the cranioplasty can be immediately performed. For example, a patient undergoing a full-thickness calvarial bone graft for craniofacial reconstruction purposes can undergo an immediate cranioplasty with materials that are available given the craniectomy is created for bone graft material and a clean defect amenable to immediate coverage. This is

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very commonly done for midface reconstruction for both children and adults. It is a bit more difficult, however, for patients who have undergone a cancer resection or have chronically infected wounds, especially in irradiated areas. The major factor considered for delayed cranioplasty is the theoretical concern of the syndrome of the trephined. This has been described in anecdotal cases and exists; however, it should be noted that the syndrome of the trephined does not occur in all patients; and in fact, it occurs in a relatively small percentage.5,6,7,8 The concern for this particular symptom has been raised as a major issue with regard to the immediate cranioplasty reconstruction. The problem with performing such cranioplasts in all patients for concern of syndrome of the trephined is that it does not take into account that there are relatively more associated risks for patients with poor wound beds. There are circumstances where patients have had a previous cranioplasty, in which the materials become infected and subsequently explanted, with each surgery serially increasing the future need for reoperation. Patients with a clinical history significant for infection, radiation, or trauma with ischemic changes require standard wound care management prior to undergoing any cranioplasty reconstruction procedures. The best course of action for such patients is to remove all of the infected material and the alloplastic material, and then to allow the soft-tissue bed to heal. This algorithm is applicable to any chronic wound. Best management involves allowing the wound to heal and be cleared of infection and contamination followed by cranioplasty and softtissue reconstruction to cover the defect.9,10,11 Soft-tissue coverage options include tissue expansion or regional rotational scalp flaps or free tissue transfer.9,10,12 ▶ Fig. 45.1 depicts a patient who underwent staged cranioplasty with inlay titanium mesh and a free tissue transfer for soft-tissue coverage. The immediate placement of various types of cranioplasty materials may lead to infection or erosion; hence, patience is required. The thought of foregoing a clean, well-vascularized wound bed because of concern of the syndrome of the trephined needs to be taken into consideration given its rarity.5,7 For example, wound healing problems and crushed degloving injuries of the head or radiation are more common and predictable with regard to their symptomatology and wound healing issues within the patient population when compared to the incidence of neurologic decline secondary to syndrome of the trephined. It is a safe and best practice to allow the wound bed to heal. The phases of wound healing and timing must also be taken into consideration for cranioplasty. During the course of the first 3 months after a craniectomy has been performed, there is still a remodeling phase that is occurring, and bleeding may increase if a scalp flap or soft-tissue coverage is to be dissected off the dura with or without a dural reconstruction. A safe waiting period prior to cranioplasty is 3 months, at a minimum, for elevation of the flap. Once the 3-month time period has passed, the amount of bleeding with the flap elevation is less with decreased risk of complications such as bleeding and need for more significant dural reconstruction or repair. A relatively safe practice with regard to the timing of reconstruction would be

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Fig. 45.1 Patient who underwent decompressive craniectomy with delayed cranioplasty and soft-tissue reconstruction given a significant soft-tissue defect. Cranioplasty was completed with inlay titanium anatomic mesh covered with a free anterolateral thigh flap reconstruction.

to take into account the viability of the wound bed and also the underlying pathology. If there is extensive edema or swelling of the brain, the cranioplasty material would need to be set aside. If there is infection or a significant scalp defect, there needs to be immediate autologous soft-tissue coverage, with either a scalp rotational flap or free tissue transfer. There will most likely be contamination of the wound; therefore, the likelihood of implant infection increases, and also this would lend itself toward a delayed cranioplasty. In the setting of clean wounds and minimal to no edema of the underlying brain, it would be a safe practice to perform an immediate cranioplasty.

45.3 Materials The choice of materials available for cranioplasty has evolved over the past 20 years. Traditionally, the materials most commonly utilized were methylmethacrylate or autologous bone. Since that time, there have been a number of other materials that have been used.13,14,15,16,17,18,19,20,21,22,23 Historically, the ideal material to use was autologous bone given that it is always readily available. The autologous bone that is used in a delayed fashion may be stored in either one of two methods. This would be either implantation in abdominal subcutaneous fat or freezing. There are pros and cons to both methods. In the emergent setting, the bone will often be set aside, placed in a freezer, and

treated with various hospital protocols. There, however, is a time limit for the utilization of this bone; there is an increased risk of bone desiccation with longer duration of storage (▶ Fig. 45.2). The other issue is if the patient transfers hospitals, the protocols for the transfer of the bone to another facility are often fraught with logistic issues and cannot be reliable for cranioplasty use. The other option, if time permits, would be to place the bone material into the subcutaneous abdominal tissue. There are a number of advantages to this.24,25 An obvious advantage is that the bone will “never be lost.” The patient can go to a new facility and still have the bone. A more significant benefit is that the autologous bone will often integrate with the soft tissue and be of useful viability for further cranioplasty usage. There is, however, the possibility of some demineralization or “softening” of the edges of the bone, which can increase rates of complications and reoperation.20 There was no set time for the placement of the bone, if it is stored in the subcutaneous abdominal fat, although 3 months is often the utilized time frame for cranioplasty with bone stored in the freezer. The other materials used have evolved to patient-specific implants. Patient-specific implants can be of various materials, such as polyether ether ketone (PEEK), porous polyethylene, or titanium. Historically, methylmethacrylate custom implants were used, but this has been replaced by newer materials. There have been ample studies in the past few years with utilization of the PEEK implant, as this is a material which has

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Fig. 45.2 Pediatric patient who underwent decompressive craniectomy following a motor vehicle collision. Patient’s bone flap was stored in the freezer and cranioplasty with the autologous bone was performed at 3 months. Patient underwent simultaneous dural repair with DuraGen (Integra LifeSciences, Plainsboro, NJ).

at least the same strength as the bone; and the contour and shape of the bone can be created anatomically.17,19,22 There has been a significant increase in the popularity of PEEK implants for cranioplasty in recent years. Regardless of the type of material used, patient-specific implants now seem to be the future of cranioplasty. The techniques for the creation of patient-specific implants is based on historical data and database computed tomography (CT), in addition to using mirror images.26 For example, a patient with a unilateral defect that extends across the parietal or the temporoparietal skull can have an implant created based on the mirror image CT scan. It can be more difficult to reconstruct midline vertex or frontal defects. Both of these areas have aesthetic concerns and the creation of the patient-specific implant will use historical data or a premorbid CT scan to create the implant. These implants will often be form-fitting and require minimal to no adjustment (▶ Fig. 45.3). One advantage of the PEEK implant is that the material can be contoured near perfectly with a burr, whereas the other materials are not amenable to such a simple solution for an improved aesthetic contour.

45.4 Implant Placement The placement of the cranioplasty material is another important consideration. Clearly, with the patient-specific implants

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and also the autologous bone, the implant will be placed anatomically. There is a choice, however, to place implants in a nonanatomic fashion. There are some circumstances that will lend themselves to the need for nonanatomic implants. This would be if there were a significant resection of part of the brain which will leave a deficit that would need to be compensated. A nonanatomic implant will help obliterate the resultant dead space. The other option would be that if the patient has had a craniectomy with a tumor and also had significant radiation, there will be minimal to no expansion of the brain to compensate for the dead space deep to the implant. Nonanatomic placement of implant material will also need to be considered. For example, patient has an immediate cranioplasty because the scalp is viable or there is a free tissue transfer to cover the area, the dura is thickened, and the brain will not reliably expand and this will leave considerable dead space.9,10,12,27,28 The other issue is that there will be “sharp edges” on the deep side from the inner table (▶ Fig. 45.1). Nonanatomic inlay placement of materials can be utilized in such a scenario. In contrast to this, anatomic positioning of the material will help with contracture of the scalp, as it is repaired. For example, if the incision or the scalp flap is close to the bony “ledge,” then there is a propensity for the scar to widen if it “falls off” this ledge. Anatomic placement of the implant will assist with this (▶ Fig. 45.3). The notion that implants should always be placed

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Fig. 45.3 Patient underwent decompressive craniectomy following a traumatic injury and delayed cranioplasty with a patient-specific polyether ether ketone (PEEK) implant. The PEEK implant required no adjustment with an excellent contour and aesthetic outcome.

in an anatomic position for aesthetic purposes need to be set aside. The physiology of the underlying brain and dura or dural reconstruction, in addition to coverage, should take precedence. For example, a free tissue transfer that is performed to cover the area may be bulky and may push down against the brain in such a fashion that it would cause a physiologic affect. An implant, however, that is placed in an anatomic fashion may push this area out too much and not allow the brain to expand or have a potential for compromise of the flap and ultimate flap necrosis and failure, subjecting the patient to additional surgeries. Careful consideration must be taken in performing cranioplasty to allow for the normal physiology of the underlying brain and dura in parallel with successful coverage of the defect.

45.5 Conclusions There is a shift in regard to choice of ideal cranioplasty material from autologous banked bone historically to anatomic patient-

specific alloplastic materials in recent years. This does not discount autologous bone as a frequently utilized material, but technical advancements in the development of alloplastic cranioplasty allow for a promising future of cranioplasty, especially with the advent of PEEK implants. Albeit such advancements, surgeons must remain cognizant of preexisting clinical history and must maintain best practice especially in the setting of infection, chronic wounds, and failed reconstructions ensuring expectant wound management and consideration of the wound bed allowing for successful cranioplasty reconstruction. Future studies can aim to focus on improving the level of evidence available for cranioplasty timing. There is also a lack of literature on outcomes and complications associated with placement (anatomic vs. nonanatomic) of cranioplasty material and thus can be an area of ongoing research. Please refer to ▶ Table 45.1 for a breakdown of the level of evidence with the study types. This table will help summarize the types of studies available.

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Table 45.1 Review of studies with level of evidence Reference

Study design

Level of evidence

Sample size

Materials used

Results

Quah et al (2016)3

Prospective multinational trial

II

70 patients (25 early, 45 delayed)

Autologous bone, titanium, acrylic, PEEK

Early cranioplasty in noninfected wound beds is safe

Malcolm et al (2016)2

Systematic review

III

3,126 patients (321 studies included)

Autologous bone, alloplastic materials

Early cranioplasty defined as < 90 d has greater odds ratio of hydrocephalus in the trauma population

Paredes et al (2015)11

Prospective study

II

55 patients

Autologous bone, PEEK, methylmethacrylate

Earlier surgery defined as < 85 d and larger bone defects results in improved clinical functional outcomes

Halani et al (2017)1

Systematic review

III

205 patients (decompressive craniectomy defects)

Not specified

Early cranioplasty may improve neurologic outcomes by possible improvement in cerebral blood flow

Reddy et al (2014)23

Retrospective review

III

195 patients

Autologous bone, alloplastic materials

Preoperative radiation is a strong predictor of postoperative complications with cranioplasty and there is an increased risk of hardware exposure in the setting of preoperative infection

Iaccarino et al (2015)29

Prospective study

II

96 patients

Autologous bone, PEEK, polymethylmethacrylate, hydroxyapatite

Alloplastic cranioplasty materials have a lower rate of overall complications

Fu et al (2016)16

Retrospective review

III

41 patients

Autologous bone, polymethylmethacrylate, PEEK, alloplastic unspecified, titanium

There is no increase in intracranial pressure with cranioplasty in the pediatric population and alloplastic materials are safe

Piitulainen et al (2015)20

Retrospective review

III

100 patients

Autologous bone, bioactive fiber, hydroxyapatite, PEEK

Use of autologous bone resulted in a 40% failure rate with removal of the bone secondary to infection or resorption

Abbreviation: PEEK, polyether ether ketone.

References [1] Halani SH, Chu JK, Malcolm JG, et al. Effects of cranioplasty on cerebral blood flow following decompressive craniectomy: a systematic review of the literature. Neurosurgery. 2017; 81(2):204–216 [2] Malcolm JG, Rindler RS, Chu JK, Grossberg JA, Pradilla G, Ahmad FU. Complications following cranioplasty and relationship to timing: a systematic review and meta-analysis. J Clin Neurosci. 2016; 33:39–51 [3] Quah BL, Low HL, Wilson MH, et al. Is there an optimal time for performing cranioplasties? Results from a prospective multinational study. World Neurosurg. 2016; 94:13–17 [4] Xu H, Niu C, Fu X, et al. Early cranioplasty vs. late cranioplasty for the treatment of cranial defect: a systematic review. Clin Neurol Neurosurg. 2015; 136:33–40 [5] Abdou A, Liu J, Carroll M, Vivaldi G, Rizzo JR, Im B. Motor and neurocognitive recovery in the syndrome of the trephined: a case report. Ann Phys Rehabil Med. 2015; 58(3):183–185 [6] Annan M, De Toffol B, Hommet C, Mondon K. Sinking skin flap syndrome (or syndrome of the trephined): a review. Br J Neurosurg. 2015; 29(3):314–318 [7] Ashayeri K, M Jackson E, Huang J, Brem H, R Gordon C. Syndrome of the trephined: a systematic review. Neurosurgery. 2016; 79(4):525–534 [8] Jeyaraj P. Importance of early cranioplasty in reversing the “syndrome of the trephine/motor trephine syndrome/sinking skin flap syndrome”. J Maxillofac Oral Surg. 2015; 14(3):666–673 [9] Kim YH, Youn SK, Kim JT, Kim SW, Yi HJ, Kim CY. Treatment of the severely infected frontal sinus with latissimus dorsi myocutaneous free flaps. J Craniofac Surg. 2011; 22(3):962–966 [10] Lee JC, Kleiber GM, Pelletier AT, Reid RR, Gottlieb LJ. Autologous immediate cranioplasty with vascularized bone in high-risk composite cranial defects. Plast Reconstr Surg. 2013; 132(4):967–975 [11] Paredes I, Castaño-León AM, Munarriz PM, et al. Cranioplasty after decompressive craniectomy. A prospective series analyzing complications and clinical improvement. Neurocirugia (Astur). 2015; 26(3):115–125

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[12] Kumar AR, Tantawi D, Armonda R, Valerio I. Advanced cranial reconstruction using intracranial free flaps and cranial bone grafts: an algorithmic approach developed from the modern battlefield. Plast Reconstr Surg. 2012; 130(5): 1101–1109 [13] Al-Tamimi YZ, Sinha P, Trivedi M, et al. Comparison of acrylic and titanium cranioplasty. Br J Neurosurg. 2012; 26(4):510–513 [14] Brandicourt P, Delanoé F, Roux FE, Jalbert F, Brauge D, Lauwers F. Reconstruction of cranial vault defect with polyetheretherketone implants. World Neurosurg. 2017; 105:783–789 [15] Fearon JA, Griner D, Ditthakasem K, Herbert M. Autogenous bone reconstruction of large secondary skull defects. Plast Reconstr Surg. 2017; 139(2):427– 438 [16] Fu KJ, Barr RM, Kerr ML, et al. An outcomes comparison between autologous and alloplastic cranioplasty in the pediatric population. J Craniofac Surg. 2016; 27(3):593–597 [17] Jonkergouw J, van de Vijfeijken SE, Nout E, et al. Outcome in patient-specific PEEK cranioplasty: a two-center cohort study of 40 implants. J Craniomaxillofac Surg. 2016; 44(9):1266–1272 [18] Lindner D, Schlothofer-Schumann K, Kern BC, Marx O, Müns A, Meixensberger J. Cranioplasty using custom-made hydroxyapatite versus titanium: a randomized clinical trial. J Neurosurg. 2017; 126(1):175–183 [19] O’Reilly EB, Barnett S, Madden C, Welch B, Mickey B, Rozen S. Computedtomography modeled polyether ether ketone (PEEK) implants in revision cranioplasty. J Plast Reconstr Aesthet Surg. 2015; 68(3):329–338 [20] Piitulainen JM, Kauko T, Aitasalo KM, Vuorinen V, Vallittu PK, Posti JP. Outcomes of cranioplasty with synthetic materials and autologous bone grafts. World Neurosurg. 2015; 83(5):708–714 [21] Plum AW, Tatum SA. A comparison between autograft alone, bone cement, and demineralized bone matrix in cranioplasty. Laryngoscope. 2015; 125(6): 1322–1327 [22] Punchak M, Chung LK, Lagman C, et al. Outcomes following polyetheretherketone (PEEK) cranioplasty: systematic review and meta-analysis. J Clin Neurosci. 2017; 41:30–35

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Cranioplasty Techniques [23] Reddy S, Khalifian S, Flores JM, et al. Clinical outcomes in cranioplasty: risk factors and choice of reconstructive material. Plast Reconstr Surg. 2014; 133 (4):864–873 [24] Corliss B, Gooldy T, Vaziri S, Kubilis P, Murad G, Fargen K. Complications after in vivo and ex vivo autologous bone flap storage for cranioplasty: a comparative analysis of the literature. World Neurosurg. 2016; 96:510– 515 [25] Fan MC, Wang QL, Sun P, et al. Cryopreservation of autologous cranial bone flaps for cranioplasty: a large sample retrospective study. World Neurosurg. 2018; 109:e853–e859

[26] Nout E, Mommaerts MY. Considerations in computer-aided design for inlay cranioplasty: technical note. Oral Maxillofac Surg. 2018; 22(1):65–69 [27] Honeybul S, Janzen C, Kruger K, Ho KM. The impact of cranioplasty on neurological function. Br J Neurosurg. 2013; 27(5):636–641 [28] Kumar AR, Bradley JP, Harshbarger R, et al. Warfare-related craniectomy defect reconstruction: early success using custom alloplast implants. Plast Reconstr Surg. 2011; 127(3):1279–1287 [29] Iaccarino C, Viaroli E, Fricia M, Serchi E, Poli T, Servadei F. Preliminary results of a prospective study on methods of cranial reconstruction. J Oral Maxillofac Surg. 2015; 73(12):2375–2378

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46 The Future of Robotics in Skull Base Surgery S. Harrison Farber, James J. Zhou, Arnau Benet, Andrew S. Little, and Michael A. Mooney Abstract The future of robotics in skull base surgery will be built upon the endoscopic endonasal approaches. Although endoscopic endonasal approaches offer numerous advantages over traditional microscopic transsphenoidal techniques, these approaches have several limitations, including the ergonomic difficulties of operating with both hands in small operative corridors. Robotic systems are being tested in the field of skull base surgery to address these limitations. In cadaver feasibility studies and in some small patient trials, several groups have tested the da Vinci Surgical System (Intuitive Surgical, Inc., Sunnyvale, CA) and the Flex Robotic System (Medrobotics Corp., Raynham, MA). These approaches include transoral, transnasal–transantral, and transnasal–transoral approaches to reach different regions of the skull base, including the infratemporal fossa, sella turcica, clivus and paraclival region, and craniocervical junction. These studies have demonstrated several areas requiring additional development to enhance the use of robotics in skull base surgery, including the need for additional instrumentation (e.g., a high-speed drill), tools with smaller diameters, the incorporation of neuronavigation, and haptic feedback for the neurosurgeon. Multiple new robotic prototypes are also being developed to address these needs. As research and technological advances continue, robotics will play an increasing role in the field of skull base surgery. Keywords: endoscope, nasopharynx, skull base, transnasal, transoral, transoral robotic surgery

46.1 Introduction The application of robotics in surgery has rapidly expanded over the past several years. The greatest advancements have occurred in the fields of general surgery, urology, and gynecology.1,2,3 With the advent of the CyberKnife System (Accuray, Inc., Sunnyvale, CA) came the first application of robotic techniques to neurosurgery, with stereotactic radiosurgery procedures performed by a surgeon working not on the patient directly but rather by remotely manipulating the robotic system.4 The field of neurosurgery is aptly positioned to evolve using robotic systems for several reasons, including the abundant history of advancements in stereotactic surgery, a culture of innovation within the field, and the inherent need to perform microsurgical procedures through less invasive approaches.5,6 The subspecialty of skull base surgery is primed for the application of surgical robotics. The historic trend has been toward the use of minimally invasive techniques to access and treat pathology of the skull base. Notably, endoscopic endonasal approaches (EEAs) have gained increasing popularity for the treatment of pathology of the anterior and central skull base, and their applications continue to expand. These techniques have been used to gain access to lesions within the sinonasal tract and the sella turcica and to suprasellar, petroclival, and infratemporal lesions.7 The use of robotics portends several

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advantages for skull base surgeons treating pathology in these regions. However, the exact role of robotics in this specialty remains to be defined, and several controversies exist. In this chapter, we discuss the current state of robotics in skull base surgery and define issues yet to be resolved.

46.2 Review 46.2.1 Existing Robotic Systems Most surgical robotic systems are still in the early developmental prototype phase. Two surgical robotic systems have been approved by the U.S. Food and Drug Administration (FDA) that allow for both visualization and instrumentation within the sinonasal cavity. These are the da Vinci Surgical System (Intuitive Surgical, Inc., Sunnyvale, CA) and the Flex Robotic System (Medrobotics Corp., Raynham, MA; ▶ Fig. 46.1). The da Vinci robotic Surgical System, which was approved in 2000, is the most widely used robotic system in the United States.5,8 It has been used in head and neck surgery for more than 10 years.9 A new version of the technology, the da Vinci Xi, which was released in 2014, has several improvements such as threedimensional (3D) vision and enhanced ergonomics. The second FDA-approved robotic system, the Flex Robotic System, was approved in 2015 for otolaryngology procedures. This flexible endoscopic system offers the advantage of increased maneuverability for visualization of anatomical landmarks.8

46.2.2 Existing Robotic Approaches to the Skull Base The application of robotic systems to the treatment of diseases of the skull base is still in its infancy. Most studies have been demonstrations of feasibility in cadavers and other skull base models, such as 3D-printed models. Few robotic systems for skull base treatment have reached the stage of clinical testing in human subjects. Multiple approaches to the skull base have been described to provide access for the robotic systems (▶ Table 46.1).10,11,12,13,14,15,16,17,18,19,20,21

Transnasal–Transantral Approach A cadaver study of a combined transnasal and transantral approach to the skull base using the da Vinci Surgical System was reported in 2007 by Hanna et al.10 In four cadavers, surgical access was obtained through bilateral sublabial incisions with anterior maxillotomies and middle meatal antrostomies (bilateral Caldwell-Luc approaches). A posterior nasal septectomy was then performed to allow for bilateral access. The camera port was inserted in the right nostril, and both the right and left surgical arm ports were placed through the anterior and middle antrostomies. Hanna et al10 thus demonstrated that anterior and posterior ethmoidectomies and resection of the superior or middle turbinates were possible with the da Vinci Surgical System. They also performed a wide sphenoidotomy to expose the

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Fig. 46.1 Two approved robotic systems: (a) the da Vinci Surgical System (Intuitive Surgical, Inc., Sunnyvale, CA) and (b) the Flex Robotic System (Medrobotics Corp., Raynham, MA). (a is used with permission from Intuitive Surgical, Inc. b is used with permission from Medrobotics Corp.)

planum sphenoidale, sella turcica, and parasellar regions. Lastly, they resected the cribriform plate and incised the dura mater of the anterior cranial fossa to expose the intradural space. These authors noted distinct advantages of this approach, including 3D visualization afforded by the dual-channel endoscope and the ability to operate two-handed and tremor free. A disadvantage of this technique was the bilateral sublabial incisions necessary to accommodate the comparatively large ports: The da Vinci cameras are 8.8 mm, whereas the typical endonasal endoscope is 4 mm in diameter.

Transoral Approach Multiple groups have also been working to develop and study a solely transoral approach for reaching pathology of the skull

base using the da Vinci Surgical System. These approaches have been used to target the sella and parasellar regions, the parapharyngeal space, the clivus, and the infratemporal fossa. In 2007, O’Malley and Weinstein11 reported their use of transoral robotic surgery (TORS) to reach the skull base. They performed this approach on two cadavers and on one live dog, reaching the parapharyngeal space and the infratemporal fossa in each case. They then applied their technique to the treatment of a patient with a benign cystic neoplasm in the same area. They achieved complete resection of the tumor without complications. In 2010, Lee et al12 used the TORS approach to access the middle or lower clivus, the sella, and the infratemporal fossa in seven cadavers. This group used a retractor and a rubber catheter to elevate the soft palate while the surgeon created a midline incision in the posterior pharyngeal mucosa. A surgical

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Table 46.1 Studies of robotic skull base surgery using existing robotic systems Approach

Access

Study type

Level of evidence

Sella, anterior cranial fossa

Cadaver feasibility

IV

O’Malley and Weinstein (2007)11

Parapharyngeal space, infratemporal fossa

Cadaver, live dog, clinical (1 patient)

IV

Lee et al (2010)12

Clivus, sella, infratemporal fossa

Cadaver feasibility

IV

McCool et al (2010)13

Infratemporal fossa (suprahyoid port)

Cadaver feasibility

IV

Kim and Zanation (2012)14

Parapharyngeal space, infratemporal fossa, retropharyngeal node basin

Clinical (4 patients)

IV

Chauvet et al (2014)15

Sella

Cadaver feasibility

IV

Schuler et al (2015)16

Nasopharynxa

Cadaver feasibility

IV

Chauvet et al (2017)17

Sella

Clinical (4 patients)

IV

Combined transnasal and transantral Hanna et al (2007)10 Transoral

Combined transnasal and transoral Yin Tsang et al (2012)18

Nasopharynx

Clinical (1 patient)

IV

Dallan et al (2012)19

Nasopharynx (transcervical ports)

Cadaver feasibility

IV

Carrau et al (2013)20

Infratemporal fossa, nasopharynx, posterior skull base, craniovertebral junction

Cadaver feasibility, clinical (2 patients)

IV

Sreenath et al (2014)21

Parapharyngeal space, nasopharynx

Clinical (3 patients)

IV

aStudy

using the Flex Robotic System (Medrobotics Corp., Raynham, MA). All other studies used the da Vinci Surgical System (Intuitive Surgical, Inc., Sunnyvale, CA).

assistant was required to perform all drilling at bedside, as drilling equipment is not yet available for the robotic system. Another approach to the infratemporal fossa was demonstrated by McCool et al13 in a study of four cadavers in which they described the placement of a novel midline suprahyoid port. One robotic arm was placed through the suprahyoid port to reach the vallecula, whereas the second robotic arm and camera were placed transorally. McCool et al showed that this combined transoral suprahyoid approach can be used to dissect the central and lateral skull base with minimal risk to neurovascular structures. In 2012, Kim and Zanation14 reported on their clinical use of TORS to resect tumors of the skull base in four patients. These patients presented with tumors located within the parapharyngeal space, the infratemporal fossa, and the retropharyngeal node basin. The tumors (three cases of pleomorphic adenoma and one case of papillary thyroid cancer) were accessed either by a transpalatal approach or by lateral pharyngotomies. In all four cases, good resection was achieved without major complications. The authors were able to achieve access without the need for a separate port (suprahyoid or cervical). A solely transoral approach to gain access to the sella turcica has also been described in both a cadaver feasibility study and a clinical study. In 2014, Chauvet et al15 reported their results in performing TORS to reach the sella in four cadavers. All three robotic arms, consisting of an endoscope and two working instrument arms, were inserted into the oral cavity. Again, all bone drilling was performed by a surgical assistant at the bedside under endoscopic guidance. The authors were able to successfully reach the sella in all four cadaveric procedures. In 2017, this group published their subsequent clinical results with the use of this approach in four patients with sellar tumors.17 All four patients had presented with pituitary adenomas causing compression of the optic chiasm. The sella

290

was accessed in all four cases without the need for a repeat operation, and complete resection was achieved in three of the four cases. TORS-specific side effects included minor sore throat, transient hypernasal speech, and one case of delayed otitis media. All the tumors in this small series were almost entirely cystic, and the authors noted that they plan to perform this procedure for solid tumors of the sella in the future. In both of these studies, Chauvet et al15,17 discussed the potential benefits of the inferosuperior approach to the sella, particularly for tumors with significant suprasellar extension, as the working corridor is more in line with the tumor axis than with the traditional transnasal–transsphenoidal approach. Finally, investigations are beginning to be conducted on the performance of TORS with the use of the Flex Robotic System. This system has been shown to be able to access pathology in the oropharynx and larynx.22,23 In a 2016 cadaver study, Schuler et al16 demonstrated the feasibility of using the Flex Robotic System to gain transoral access to the nasopharynx in eight cadavers. As of this writing, specific clinical applications of this system in skull base surgery have not yet been performed.

Transnasal–Transoral Approach Several studies have examined the use of a combined transnasal and transoral approach to the nasopharynx and skull base using the da Vinci Surgical System. In 2012, Yin Tsang et al18 reported using this combined approach in a patient with a recurrent nasopharyngeal carcinoma in the roof of the nasopharynx. The inferior margin of the tumor was resected transorally after splitting the soft palate, and the superior portion was resected using the endoscopic endonasal technique. The tumor was excised, with negative margins and no complications. In 2012, the use of this combined approach for nasopharyngectomy was compared to the use of the purely transoral approach in a

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The Future of Robotics in Skull Base Surgery cadaver study conducted by Dallan et al19 using two cadavers. Although working times were comparable between the two approaches, the authors found that the combined approach enabled them to avoid the palatal splitting required by the transoral route. The combined approach also provided them with a better surgical view and facilitated dissection. Of note, in this study and others, a transcervical approach was used to facilitate transoral access. A small paramandibular incision is made close to the angle of the mandible through which the trocars are inserted. The floor of the mouth is reached by a subperiosteal dissection, and the mucosa is opened to gain access to the oral cavity.19,24,25 In 2013, Carrau and colleagues20 reported their initial experience with a combination of the EEA and the TORS, first in two cadavers and then in two patients. Their work supported the feasibility of combining these two approaches to perform adequate dissections of the infratemporal fossa, nasopharynx, posterior skull base, and craniovertebral junction. They were able to use these approaches to resect two complex lesions in these regions that extended into the infratemporal fossa and the craniocervical junction. Finally, in 2014, Sreenath et al21 presented their experience with three patients who underwent the combined endonasal–transoral approach for the treatment of nasopharyngeal and skull base pathologies. These three patients had distinct lesions in the parapharyngeal space and the nasopharynx. All three patients who were treated with the combined EEA–TORS technique tolerated the procedures well and had good clinical outcomes.

46.2.3 Advantages with Robotic Systems As demonstrated earlier, the past decade has seen an increase in the number of studies using robotic systems to treat pathology of the skull base. Most of this research has been in the form of feasibility studies using cadavers to demonstrate novel techniques. However, these approaches are being tested in patients, as evidenced by a few small case series and reports on these techniques. These preliminary reports have resulted in the identification of several common themes regarding the relative advantages afforded by these approaches. A key advantage is the ergonomic access provided to the surgeon by robotic access. Likewise, tremor-free manipulation of tissue with the robotic arms is advantageous and has been documented in multiple studies. Combined with increased angles of manipulation, tremor-free manipulation makes possible the opening and closing of the dura, which is a limitation of existing endoscopic techniques.10,12 Moreover, in normal endoscopic approaches, two-hand surgery is possible only when an assistant or a mechanical holder is used to hold the camera. Two surgeons must work around each other to accommodate their instruments in the small corridor provided by the sinonasal cavity. Robotic systems are equipped with three or four available arms that can be utilized during surgery by one surgeon working from a console, thus largely addressing these issues of ergonomics and improved tissue manipulation. The trend toward the ultimate use of minimally invasive robotic techniques has gained momentum with the increased popularity of approaches such as the EEA. This approach allows for direct access to the anterior and central skull base while

obviating the need for extensive open surgical approaches.7 This minimally invasive characteristic may hold true for robotic approaches as they are further refined.

46.2.4 Remaining Areas of Need Despite their numerous theoretical advantages, existing robotic systems have several significant limitations. The first limitation is the instrumentation that is available for skull base surgery. Most notable is the lack of a drill or bur, which is frequently used by neurosurgeons for skull base operations. As noted earlier, all drilling with existing robotic systems must be done by a co-surgeon at the bedside. A second limitation is that the robotic tools that are available were not developed to work in corridors as small as the sinonasal cavity. The smallest tools that are available for the da Vinci systems are 5 mm in diameter, and the robotic endoscope is 8.8 mm in diameter. Thus, both are considerably larger than the tools used in traditional EEAs. The development of smaller diameter tools will be necessary for the continued application of robotic surgery to skull base pathology. A third limitation is the lack of haptic feedback in robotic surgery. The term haptic refers to the sense of touch, which has been lacking in robotic surgical systems. One goal of robotics engineering as it relates to surgery is to replicate the realistic tactile interactions that the surgeon experiences with the instrument as it comes into contact with bone and tissue. With existing robotic surgical systems that cannot provide tactile feedback, surgeons are forced to rely on vision alone. The issues to be addressed in this area include how to appropriately incorporate sensors of the occurring forces and how to design an interface to convey this information to the operator.26 This area of research has been reviewed elsewhere.27 A fourth limitation of the existing robotic systems is their inability to incorporate stereotactic navigation. The development of this technology will enhance surgical techniques. Finally, a fifth limitation is the high cost of existing robotic surgical systems. Since the cost of this technology, which is in the million-dollar range, exceeds the cost of the endoscopic systems that are in widespread use, budgetary constraints may slow down its implementation. Thus, the adoption of robotic technology by neurosurgeons and institutions may occur incrementally.28

46.2.5 Future Prototypes To overcome the shortcomings of existing robotic systems as outlined earlier, multiple groups are working to develop novel systems to improve upon the existing technology. A robotic prototype under development at Vanderbilt University utilizes concentric tube technology. These flexible tubes, with diameters ranging from 0.2 to 4.0 mm, are nested within each other. The tubes are able to undergo “tentacle-like motion” in that they can be bent and elongated into complex shapes. Existing instruments for endoscopic skull base surgery can be mounted to the tips of the tubes, and up to four instruments can be inserted simultaneously and maneuvered through one nostril. Moreover, this prototype incorporates image guidance.26 This group has shown their system to be effective for removal of a phantom pituitary tumor from a model skull using a curette.29

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Surgical Approaches and Techniques A “one degree-of-freedom” wrist has also been incorporated onto the tip of the robotic arm to allow for rotation of the instrument. Experiments testing this technology are under way.30 In 2017, Bolzoni Villaret et al31 reported on the use of their hybrid robotic prototype, the Brescia Endoscope Assistant Robotic Holder, for endoscopic skull base surgery. This system consists of a robotic endoscope holder that is controlled by the surgeon. The surgeon moves the camera by wearing a pair of glasses with a light source that can be detected by a sensor; the lights are directed at prespecified points on the sensor. This device is also equipped with a source sensor that limits the degrees of freedom around a fulcrum (at the nostril) to prevent any damage. This same group of researchers also conducted a systematic review of the surgical literature to catalog the reported prototypes for robotic transnasal endoscopic skull base surgery. They identified a total of 11 robotic prototypes used for endoscopic skull base surgery, and they noted several common areas for improvement that were the targets of these prototypes. These areas of potential improvement include advancements in the interface between the surgeon and the machine, the capability of the machine to generate force feedback to the surgeon, and various thresholds and safety features. These authors also documented the continued limitations of such systems, including the lack of ability to handle medical emergencies using the systems.

46.3 Conclusions The trend in skull base surgery has increasingly been toward less invasive procedures such as the endoscopic endonasal techniques. Robotic surgical systems have the potential to build on these minimally invasive approaches while enhancing the technical skills of the surgeon and improving surgical ergonomics. Various researchers have demonstrated the potential use of robotic surgical systems in the treatment of patients with skull base pathology. Moreover, new prototypes are being developed to overcome the shortcomings of the existing systems. The future of robotic surgery for the treatment of skull base pathology is promising, but it will depend largely on the development of improved, skull-base–specific instrumentation and improvements in haptic feedback for the operator. As these needs are increasingly met by additional technological advances, robotic surgery will enlarge its footprint in this field.

References [1] Trastulli S, Farinella E, Cirocchi R, et al. Robotic resection compared with laparoscopic rectal resection for cancer: systematic review and meta-analysis of short-term outcome. Colorectal Dis. 2012; 14(4):e134–e156 [2] Sammon J, Trinh QD, Menon M. Robotic radical prostatectomy: a critical analysis of surgical quality. Curr Opin Urol. 2011; 21(3):195–199 [3] Lowery WJ, Leath CA, III, Robinson RD. Robotic surgery applications in the management of gynecologic malignancies. J Surg Oncol. 2012; 105(5):481– 487 [4] Adler JR, Jr. Surgical guidance now and in the future: the next generation of instrumentation. Clin Neurosurg. 2002; 49:105–114 [5] Wang MY, Goto T, Tessitore E, Veeravagu A. Introduction. Robotics in neurosurgery. Neurosurg Focus. 2017; 42(5):E1 [6] Attenello FJ, Lee B, Yu C, Liu CY, Apuzzo ML. Supplementing the neurosurgical virtuoso: evolution of automation from mythology to operating room adjunct. World Neurosurg. 2014; 81(5–6):719–729 [7] Kupferman ME, Hanna E. Robotic surgery of the skull base. Otolaryngol Clin North Am. 2014; 47(3):415–423

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[8] Rangarajan S, Hachem RA, Ozer E, Beer-Furlan A, Prevedello D, Carrau RL. Robotics in sinus and skull base surgery. Otolaryngol Clin North Am. 2017; 50 (3):633–641 [9] McLeod IK, Melder PC. Da Vinci robot-assisted excision of a vallecular cyst: a case report. Ear Nose Throat J. 2005; 84(3):170–172 [10] Hanna EY, Holsinger C, DeMonte F, Kupferman M. Robotic endoscopic surgery of the skull base: a novel surgical approach. Arch Otolaryngol Head Neck Surg. 2007; 133(12):1209–1214 [11] O’Malley BW, Jr, Weinstein GS. Robotic skull base surgery: preclinical investigations to human clinical application. Arch Otolaryngol Head Neck Surg. 2007; 133(12):1215–1219 [12] Lee JY, O’Malley BW, Jr, Newman JG, et al. Transoral robotic surgery of the skull base: a cadaver and feasibility study. ORL J Otorhinolaryngol Relat Spec. 2010; 72(4):181–187 [13] McCool RR, Warren FM, Wiggins RH, III, Hunt JP. Robotic surgery of the infratemporal fossa utilizing novel suprahyoid port. Laryngoscope. 2010; 120(9): 1738–1743 [14] Kim GG, Zanation AM. Transoral robotic surgery to resect skull base tumors via transpalatal and lateral pharyngeal approaches. Laryngoscope. 2012; 122 (7):1575–1578 [15] Chauvet D, Missistrano A, Hivelin M, Carpentier A, Cornu P, Hans S. Transoral robotic-assisted skull base surgery to approach the sella turcica: cadaveric study. Neurosurg Rev. 2014; 37(4):609–617 [16] Schuler PJ, Hoffmann TK, Duvvuri U, Rotter N, Greve J, Scheithauer MO. Demonstration of nasopharyngeal surgery with a single port operator-controlled flexible endoscope system. Head Neck. 2016; 38(3):370–374 [17] Chauvet D, Hans S, Missistrano A, Rebours C, Bakkouri WE, Lot G. Transoral robotic surgery for sellar tumors: first clinical study. J Neurosurg. 2017; 127 (4):941–948 [18] Yin Tsang RK, Ho WK, Wei WI. Combined transnasal endoscopic and transoral robotic resection of recurrent nasopharyngeal carcinoma. Head Neck. 2012; 34(8):1190–1193 [19] Dallan I, Castelnuovo P, Montevecchi F, et al. Combined transoral transnasal robotic-assisted nasopharyngectomy: a cadaveric feasibility study. Eur Arch Otorhinolaryngol. 2012; 269(1):235–239 [20] Carrau RL, Prevedello DM, de Lara D, Durmus K, Ozer E. Combined transoral robotic surgery and endoscopic endonasal approach for the resection of extensive malignancies of the skull base. Head Neck. 2013; 35(11):E351– E358 [21] Sreenath SB, Rawal RB, Zanation AM. The combined endonasal and transoral approach for the management of skull base and nasopharyngeal pathology: a case series. Neurosurg Focus. 2014; 37(4):E2 [22] Mandapathil M, Duvvuri U, Güldner C, Teymoortash A, Lawson G, Werner JA. Transoral surgery for oropharyngeal tumors using the Medrobotics(®) Flex (®) System - a case report. Int J Surg Case Rep. 2015; 10:173–175 [23] Remacle M, M N Prasad V, Lawson G, Plisson L, Bachy V, Van der Vorst S. Transoral robotic surgery (TORS) with the Medrobotics Flex™ System: first surgical application on humans. Eur Arch Otorhinolaryngol. 2015; 272(6): 1451–1455 [24] Dallan I, Castelnuovo P, Seccia V, et al. Combined transnasal transcervical robotic dissection of posterior skull base: feasibility in a cadaveric model. Rhinology. 2012; 50(2):165–170 [25] Ozer E, Durmus K, Carrau RL, et al. Applications of transoral, transcervical, transnasal, and transpalatal corridors for robotic surgery of the skull base. Laryngoscope. 2013; 123(9):2176–2179 [26] Schneider JS, Burgner J, Webster RJ, III, Russell PT, III. Robotic surgery for the sinuses and skull base: what are the possibilities and what are the obstacles? Curr Opin Otolaryngol Head Neck Surg. 2013; 21(1):11–16 [27] L’Orsa R, Macnab CJ, Tavakoli M. Introduction to haptics for neurosurgeons. Neurosurgery. 2013; 72 Suppl 1:139–153 [28] Dallan I, Castelnuovo P, Vicini C, Tschabitscher M. The natural evolution of endoscopic approaches in skull base surgery: robotic-assisted surgery? Acta Otorhinolaryngol Ital. 2011; 31(6):390–394 [29] Swaney PJ, Gilbert HB, Webster RJ, III, Russell PT, III, Weaver KD. Endonasal skull base tumor removal using concentric tube continuum robots: a phantom study. J Neurol Surg B Skull Base. 2015; 76(2):145–149 [30] Gilbert H, Hendrick R, Remirez A, Webster R, III. A robot for transnasal surgery featuring needle-sized tentacle-like arms. Expert Rev Med Devices. 2014; 11(1):5–7 [31] Bolzoni Villaret A, Doglietto F, Carobbio A, et al. Robotic transnasal endoscopic skull base surgery: systematic review of the literature and report of a novel prototype for a hybrid system (Brescia Endoscope Assistant Robotic Holder). World Neurosurg. 2017; 105:875–883

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Index Note: Page numbers set bold or italic indicate headings or figures, respectively.

2 2PP2BC, in chordoma 169

A Abdel Kerim, A. 44 Abdel-Aziz, K. M. 37, 38, 39 abducens nerve schwannoma – anatomic consideration 206 – case studies 207, 207 – radiosurgery vs. surgery studies 205, 207 – treatment selection 205, 206, 207 Abolfotoh, M. 199 Aboud, E. 189 Accuracy, see CyberKnife radiosurgery Ackerman, P. D. 246 acoustic neuroma, see vestibular schwannoma acromegaly – characterization 78 – combination therapy 83 – primary medical treatment algorithm 83 – radiosurgery 89, 89–90 – remission, factors affecting 94 – salvage radiotherapy 105 – SRLs for, see somatostatin receptor ligands (SRLs) – whole-sellar targeting 91 ACROSTUDY 82 ACTH secretion inhibitors 73 actin, in chordoma 167, 169 Adeberg, S. 51 adenoid cystic carcinoma – case studies 227, 227, 228 – characterization 225 – combined photon/proton therapy 232 – literature review 225, 225 – overall survival 226–228 – radiation, adjuvant 226 – recurrence rate 226 – sinonasal 227 – survival, factors affecting 226, 228 adrenal steroidogenesis inhibitors 73 aggrecan, in chordoma 170 Aghi, M. K. 50, 51, 53 Aho, C. J. 132, 134, 145 Aizer, A. A. 51 Ajlan, A. 95 Akagami, R. 261 Akar, Z. 189 Akhavan-Sigari, R. 171 Al-Bar, M. H. 252 Al-Mefty, O. 155, 189, 209–210 Al-Nashar, I. S. 276, 278 Alalade, A. F. 120 Albu, S. 250, 252 Alexander, N. S. 276, 278 ALG11, in chordoma 169 Ali, Z. S. 112–113, 113, 199 alkylator 58, 59 Almefty, R. 39, 39, 45 altered fractionation, sinonasal malignancies 231 Alvernia, J. E. 267

Amhaz, H. H. 138 amikacin 251 Amit, M. 155, 225, 226 Annamalai, A. K. 80 Annys, E. 250, 252 Anterior Skull Base Questionnaire (ASBQ) 260 anti-VEGF antibody 59–60, 60 antibiotic prophylaxis in reconstruction 241 AR-42 60 Arbolay, O. L. 155 Arita, K. 98 Attia, A. 51, 54 Augmentin 250 autografts in skull base reconstruction 237 autologous bone 283, 284, 285 avelumab 60 Aylwin, S. J. 127 Ayuk, J. 101

B Bachmann-Harildstad, G. 276, 278 Bagshaw, H. P. 52, 53 Bailo, M. 10, 11 Bakhsheshian, J. 245 Baldelli, R. 80 Bander, E. D. 26, 26, 29, 30 Barbot, M. 76 Baschnagel, A. M. 8 Baudry, C. 76 Benet, A. 39 Bengtsson, D. 106 Benveniste, R. J. 134, 138, 145 Berger, M. S. 189 Besser, M. 138 beta-catenin signaling as targeted therapy 129 bevacizumab 59, 60, 60, 61 bevacizumab + everolimus 59–60 Bevan, J. S. 80 Bhattacharyya, N. 251 Bien, A. G. 246 Bikmaz, K. 277 Biller, H. F. 221, 221 Bir, S. C. 88 Bloch, D. C. 10 Bloch, O. 186 Bolger, W. E. 276, 278 Bolzoni Villaret, A. 292 bone autografts in skull base reconstruction 237 Bonicki, W. 101 Bonnet bypass 267 Borba, L. A. B. 155, 177 Borovich, B. 51 Boskos, C. 51, 54 Bozorg, A. 15 brachyury transcription factor, in chordoma 167, 169 Brackmann, D. E. 17, 183, 184 BRAF inhibitors 128, 129 BRAF mutations 128 BRAF-MEK inhibition 128 BRAF-V600E mutation 149 Brastianos, P. K. 127, 128

Bratzler, D. W. 252 Breivik, C. N. 261 Brescia Endoscope Assistant Robotic Holder 292 Briceno, V. 95 Briet, C. 98 Brisman, M. H. 265 Brown, S. M. 251, 252 Bruno, O. D. 106 Bujawansa, S. 99–100, 101 Bush, Z. M. 106

C cabergoline – acromegaly 78 – as primary medical therapy 82 – Cushing syndrome 74–75 – pegvisomant with 83 – SRLs with 83 Calcaterra, T. C. 221 Carlsen, S. M. 84 Carlson, M. L. 176–177, 184 carmustine 107 Caron, P. J. 80 Carrabba, G. 155 Carrau, R. L. 290, 291 case studies – A3-A3 bypass, case study 269, 272 – abducens nerve schwannoma 207, 207 – adenoid cystic carcinoma 227, 227, 228 – cavernous sinus tumor 268, 271 – cavernous sinus/pituitary adenoma 94, 96 – chordoma 162 – craniopharyngioma 113, 114, 114, 115, 121, 121, 122 – Cushing syndrome/disease 66–67, 74 – embolization 45 – endoscopic endonasal approach 31 – endoscopy 201 – esthesioneuroblastoma 216, 217– 219 – giant complex craniopharyngioma, EAA 123, 124 – hydrocephalus/cyst drainage 114, 115 – Langerhans cell histiocytosis 150 – LSR encephaloceles 274, 277, 279 – lumbar drains 247, 247, 248 – olfactory groove meningioma 32, 34–35 – orbital schwannomas 202, 203 – paraganglioma observation 175, 175, 176 – paraganglioma radiation 178, 178, 179–180 – paraganglioma surgery 176, 177 – PCA-to-SCA bypass 270–271, 272 – petroclival meningioma 40, 41, 46, 46 – posterior fossa epidermoids 190, 190, 191 – Rathke cleft cyst 134, 135 – residual AN management 12

– revascularization 271 – sphenoid wing meningioma 45, 45 – trigeminal/jugular foramen schwannomas 201, 202, 202, 203 – tuberculum sella meningioma 31, 32, 32 Castelnuovo, P. 276, 278 Castinetti, F. 88–89 Castro, D. G. 88 cavernous sinus tumor, high-flow bypass 266, 268 cavernous sinus/pituitary adenoma – case studies 94, 96 – remission, factors affecting 94 – surgical treatment of 94, 95 Caye-Thomasen, P. 15 CDK4/6 inhibitor 60 CDKN2A/CDKN2B loss, in chordoma 168, 171 Ceccato, F. 106 cefazolin 251 ceftazidime 251 ceftriaxone 251 cefuroxime 250 Ceylan, S. 95 Chan, J. Y. 265 Chang, S. D. 5, 8 Chang, S. W. 39 Charabi, S. 3 Chauvet, D. 290, 290 Chazono, H. 265 Chen, A. M. 229 Chen, K. 171 Chen, L. F. 209–210 Chen, P. G. 179 Chen, Z. 10 Chibbaro, S. 155 Cho, Y. H. 155 Choi, C. Y. 51 chondroitin sulfate proteoglycan-1, in chordoma 170 chondrosarcomas 183, 185 chordoma – case studies 162 – characterization 167, 171 – clival 171 – cohesive cluster phenotype 169 – copy number variation 168 – craniocervical junction, case studies 162, 163 – DNA damage response in 167, 169, 170 – etiology 167, 171 – gene products in 169, 170 – genetic markers in 168, 168 – histology 167, 167 – panclival, case studies 162, 164 – sacral 171 – skull base, management, see skull base chordoma – surgical approach to 154, 154, 155 – tumor phenotypes 170, 172 – upper clival, case studies 162, 162, 163 Chotai, S. 138 Chovanec, M. 199 Chowdhury, F. H. 29, 189 Choy, E. 171

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Index chronic rhinosinusitis 255 cisplatin 231 clarithromycin 251 Clark, A. J. 112, 113 Cleveland Clinic 54 clindamycin 251 Cohen, S. 246 Cohen-Inbar, O. 89, 90 cohesive cluster phenotype 169 Colao, A. 76, 80, 82 Colli, B. 155 Combs, S. E. 51 Coskun, M. 51 Cote, D. J. 138, 139, 145 Coughlan, C. A. 251, 252 Couldwell, W. T. 155 Cozzi, R. 79, 80 craniopharyngioma – adamantinomatous 127–128, 129 – anterolateral approaches 118 – approach selection 117 – case studies 113, 114, 114, 115, 121, 121, 122 – characterization 112, 117 – clinical studies 119, 120 – complication avoidance 119 – endoscopic endonasal approaches 119, 119, 120, 121, 121, 122, 123, 124 – gene mutations in 128 – giant complex, EAA 123, 124 – histological subtypes 127 – hypothalamic-sparing surgery 113 – intraventricular approaches 118 – lateral approaches 118 – midline approaches 118 – molecular pathogenesis 127, 128 – molecular therapy studies 127, 127 – MRI findings, in children 113 – papillary 127–128, 128 – radical vs. subtotal resection 112, 113, 115 – skull base reconstruction, CSF leakage in 240 – subtemporal approach 118 – targeted therapy 128, 129, 129 – transpetrosal approach 118 cranioplasty – clinical studies 286 – complications 282, 285 – implant placement 283, 284 – materials 283, 284, 285, 285 – timing of 282, 283 – wound healing phases 282 Crockard, H. A. 183, 184, 186 Crooke's cell adenoma 104 CSPCP, in chordoma 170 CTNNB1 mutations 128 Cunha, M. 205, 206 Cushing syndrome/disease – antibiotic prophylaxis 251 – antisecreting medications cessation 91 – bilateral adrenalectomy 70, 75 – case studies 66–67, 74 – characterization 66, 70 – evaluation of 66, 67, 67 – inferior petrosal sinus sampling 66, 68, 68, 69 – MRI-negative, whole-sellar radiation 91 – patients, medical needs of 72 – pharmacotherapy, combination 74

294

– pharmacotherapy, post-surgical 71, 71–72, 73, 75, 76 –– See also specific agents by name or class – radiosurgery 88, 88, 90 – radiotherapy 70 – treatment options 70 – treatment, outcome 67–68 CyberKnife radiosurgery – background 288 – outcomes 7, 8 – outcomes vs. Gamma Knife 8, 8 – patient demographics 6, 7 – radiation dosing 8, 8 – small intracanalicular VS 17 – treatment plan 5, 6

D da Vinci Surgical System 288, 289, 290 dabrafenib 128, 129 Dagan, R. 231, 231 Dallan, I. 290 Daly, M. E. 230 Dana Farber Cancer Institute 50 Davidson, L. 149, 149 Day, J. D. 194, 209–210 de Almeida, J. R. 29, 29 de Divitiis, E. 28, 29 de Notaris, M. 39 Dehdashti, A. R. 155 deSouza, C. E. 189 Dewaele, B. 171 Di Maio, S. 155, 261 diabetes insipidus – histiocytosis-induced, management of 150 – postoperative 133, 145 Dirix, P. 230 Dizziness Handicap Inventory 261 Dobberpuhl, M. R. 179 dopamine agonists (DAs) – acromegaly 78 – as primary medical therapy 82 – lactotroph adenomas 104 – prolactinomas 91 Dubuisson, A. S. 101 Dulguerov, P. 221 Dziuk, T. W. 51, 54

E Ebner, F. H. 189 EGFR inhibitor 59, 60 EGFR, in chordoma 169, 171 Eid, A. S. 155 Eke, I. 169 El Tarabishi, M. N. 276, 278 El-Khatib, M. 51, 55 El-Shehaby, A. M. N. 88 Elekta, see Gamma Knife radiosurgery Elmalem, V. I. 205, 206 Elowe-Gruau, E. 113, 113 Eloy, J. A. 245, 246 Elsharkawy, M. 205, 206 embolization – case studies 45 – complications 44 – embolysates 43 – outcomes 44, 44 – preoperative, for meningioma 43 – vascular pedicles 44

endoscopic endonasal surgery – antibiotics, postoperative 250–252, 252 – background 288 – case studies 31 – collaboration/teamwork in 254, 255, 255, 256, 256 – early experiences 28, 254 – infectious complications rate 251 – literature review 28, 29 – lumbar drains, clinical studies 246 – overview 28 – petroclival meningioma 38 – QALY outcome 30, 31 – skull base reconstruction 239, 251 – TORS combined with 291 – transcranial vs. 29, 31 endoscopy – case studies 201 – endoscope design 201 – of cranial nerve schwannoma 199, 199 – technique, maneuverability 201 Engenheart-Cabillic, R. 51 Erdheim-Chester disease 150 erlotinib 59, 60 escape phenomena 73 esthesioneuroblastoma – case studies 216, 217–219 – characterization 214, 221 – chemoradiation, outcomes 216 – chemotherapy 215, 223 – classification of 214 – craniofacial resection 214 – endoscopic approach 215 – induction chemotherapy 216 – induction therapy 215 – Kadish staging 221, 221 – management 214 – neck irradiation 215 – radiotherapy, adjuvant 215 – radiotherapy, neoadjuvant 216, 223 – radiotherapy, principles/ dosages 222 – salvage therapy 223 – surgical management 221–222 – treatment algorithm 221, 222 – treatment, postoperative adjuvant 216 estrogen receptor alpha, in chordoma 170 etomidate 73 everolimus 59–60, 61 extranasal rotational flaps in reconstruction 238

F facial nerve injury 18 Fahlbusch, R. 80, 120 FAK inhibitor 60, 61 Fatemi, N. 155 Fayad, J. N. 3, 3, 177 Feelders, R. A. 74, 76 Feng, M. 68 Fisch classification, paragangliomas 174 Fisher, L. M. 194 Fitzek, M. M. 232 Flannery, T. J. 39, 40 Fleseriu, M. 76, 145 Flex Robotic System 288, 289, 290 Flickinger, J. C. 8

Forer, B. 276, 278 Fougner, S. L. 84 Frank, S. J. 231 Franzin, A. 89 Fraser, J. F. 155 free tissue grafts in skull base reconstruction 237 Freeman, S. R. 10, 11 Fu, K. J. 286 Fu, T. S/ 223 Fucci, M. J. 3 Fukaya, R. 209 Fukuda, M. 194 Fukui, I. 133, 137, 138 Fukumitsu, N. 231 Fukushima, T. 209 Furtado, S. V. 205, 205

G Galland-Girodet, S. 179, 179 Gamma Knife radiosurgery – Cushing syndrome/disease 88 – outcomes 7, 8, 91 – outcomes vs. CyberKnife 8, 8 – patient demographics 6, 7 – petroclival meningioma 40 – pituitary adenomas 91 – radiation dosing 8, 8 – small intracanalicular VS 17 – treatment plan 5, 6 – trigeminal/jugular foramen schwannomas 194 Garcia-Navarro, V. 246 Gardner, P. A. 28, 29, 120 Garzaro, M. 155 gastroomental free flap in reconstruction 239 Göksu, N. 199 gefitinib 59, 60 gelatinase-B, in chordoma 170 Genc, A. 179 Gerganov, V. M. 11, 199 GH adenoma, sparsely granulated 104 Gil, Z. 260 Gilbo, P. 179 Gioacchini, F. M. 252 Glasgow Balance Inventory 261 Glasgow Outcome Scale (GOS) 259 glioma, temozolomide dosage regimen 106 glucocorticoid receptor antagonist 74 Gluth, M. B. 18 Goel, A. 194, 209–210 Goldsmith, B. J. 51, 54 Golfinos, J. G. 15 Gondim, J. A. 98 Gopalakrishnan, C. V. 189 Goyal, L. K. 51 Graffeo, C. S. 53 Grant, P. 68 Grant, R. A. 88–89 growth hormone receptor antagonist, see pegvisomant growth hormone secreting adenomas, see acromegaly Gruber, A. 101 Gui, S. 155 Gurgel, R. K. 18 Gürkanlar, D. 277 Guss, Z. D. 180

Controversies in Skull Base Surgery | 04.06.19 - 14:54

Index

H Hafez, R. F. A. 179 Haines, S. J. 17 Halani, S. H. 286 Hammouche, S. 53 Han, M. S. 267 Hanna, E. Y. 288, 290 Hansasuta, A. 8 Haque, M. R. 189 Har-El, G. 199 Hardesty, D. A. 53 Harris, A. E. 51, 55 Harvey, R. J. 223 Hasegawa, H. 185, 185, 186, 195 Hasegawa, M. 189 Hasegawa, T. 88, 195, 195–196 Hayashi, M. 88–89 HDAC inhibitor 60 Health Status Questionnaire 261 health-related quality of life (HRQOL) 259 Hearing Handicap Inventory 261 hedgehog signaling pathway 60, 61 Hegde, A. S. 205 Higgins, D. M. 132, 134 Hirohata, M. 44 Hirohata, T. 106 histiocytoses – characterization 148 – Erdheim-Chester disease 150 – juvenile xanthogranuloma 151 – Langerhans cell 148 – surgical considerations 151 Hofstetter, C. P. 276, 278 Holliday, E. B. 231 Holzmann, D. 155 Hong Jiang, W. 155 Horgan, M. A. 38 Hori, T. 199 Horiba, A. 8 Horiguchi, K. 245 hormonal therapy 61 Hoybye, C. 88 Huang, M. J. 10 Huffmann, B. C. 51 Hug, E. B. 51, 54, 186 hydroxyurea 58, 59, 60 hydroxyurea + imatinib 59 hyperglycemia, pasireotide-induced 73 hypopituitarism 87

I Iaccarino, C. 286 Iacoangel, M. 199 ICA injury, surgical 94 IL-1β, in chordoma 170 imatinib 59, 60, 60 immune checkpoint inhibitors 60, 61 immunomodulation 58, 59–60, 61 implants – autologous bone 284, 285 – PEEK 283, 285, 285 – placement 283, 284 – titanium mesh 282, 283 IMRT, sinonasal malignancies 229, 230 interferon-α 59, 61 intracanalicular VS – hearing preservation factors 18 – middle fossa craniotomy 17–18, 19– 21 – natural history 15, 15, 16

– overview 15 – radiation therapy 17 – radiosurgery 17 – retrosigmoid approaches 18 – treatment recommendations 18 – tumor growth 16 – watchful waiting 16 – WRS 100% 16, 16 Ito, E. 155 Ivan, M. E. 180 Iwai, Y. 89 Iwata, H. 88 α6 integrin, in chordoma 167, 169, 170

J Jackson, C. G. 177 Jacquesson, T. 39, 39 Jahangiri, A. 155 Jannetta, P. J. 11 Jansen, J. C. 176 Jenkinson, M. D. 51 Jervis-Bardy, J. 251 Jeswani, S. 119, 120 Jezkova, J. 89 Jho, D. H. 99–100 Jiang, R. S. 250, 252 Jinguji, S. 149 Johnson, G. 3 jugular foramen schwannomas, see trigeminal/jugular foramen schwannomas juvenile xanthogranuloma 151

K Kalani, M. Y. 265 Kamenicky, P. 74, 76 Kano, H. 51, 155, 186, 195–196, 209–210 Kanter, A. S. 132 Kanzaki, J. 3 Karaca, Z. 80, 82 Karam, S. D. 5 Karnofsky performance score (KPS) 259–260 Kelleher, M. O. 261 Kelly, P. J. 51 Keric, N. 277 ketoconazole 73, 74–75, 91 Khrais, T. 2 Kim, G. G. 290, 290 Kim, J. E. 132, 134, 138, 145 Kim, Y. H. 155, 184 King, W. A. 199 Kinjo, T. 51 Kirchmann, M. 3, 3, 15 Kirkman, M. A. 260 Klinger, D. R. 53 Kobata, H. 189 Kobayashi, T. 88–89 Komatsuzaki, A. 2 Komotar, R. J. 25–26, 51, 53, 119, 120, 155, 223 Kondziolka, D. 51 Korlym, see mifepristone Koutourousiou, M. 29, 39, 39, 95, 154, 155 Kumon, Y. 199

L Labidi, M. 155

lactotroph adenomas 104 Lai, S. Y. 276, 278 Langerhans cell histiocytosis – case studies 150 – characterization 148 – diagnosis 149 – imaging 148, 150 – management 149 – presentation 149, 149 – staging 149 – surgical considerations 151 Langerman, A. 176 Langlois, A. M. 205, 206 lanreotide/lanreotide SR – acromegaly 78 –– biochemical control 79, 80 –– tumor shrinkage 79 – Cushing syndrome 73 – preoperative use of 84, 84 Lasolle, H. 106 lateral sphenoid recess, see LSR encephaloceles latissimus dorsi flaps in reconstruction 238–239 Laurencikas, E. 149 Lauretti, L. 120 Laws, E. R. 132, 134 Lawton, M. T. 265 Lee, C.-C. 89, 91 Lee, D.-H. 171 Lee, J. D. 3 Lee, J. Y. 199, 289, 290 Lefournier, V. 68 Levine, S. C. 17 Leyer, C. 101 Li, D. 177 Li, Z. Q. 84, 84 Lillehei, K. O. 134 LINAC radiosurgery – acromegaly 89 – Cushing disease 88 – pituitary adenomas 88 Link, M. J. 189, 189 liquid embolic agents, in embolization 43 liraglutide 73 Liscák, R. 88 Little, A. S. 251, 252 Liu, X. 89 Lo, A. C. 113 Lombardi, G. 80 Losa, M. 87, 88, 106 Louis, D. N. 51 lower trapezius flap in reconstruction 238 LSR encephaloceles – background 274, 274 – case studies 274, 277, 279 – endoscopic transpterygoid repairs –– characterization 275, 276, 278 –– complications 278 –– failures 274, 277 – etiology of 275 – large 277, 277, 278 – open transcranial approaches 275, 277 – seizures 275 Lubgan, D. 51 Lucaciu, R. 250 lumbar drains – benefits/limitations of 245 – case studies 247, 247, 248 – clinical studies 245, 246

– complication management 246 – in reconstruction 241 Lupinetti, A. D. 225, 226 Luque-Ramirez, M. 80

M Maccagnan, P. 98, 101 macroadenomas 82, 84 macroprolactinoma 99 Madani, I. 230 Magnan, J. 199 Mahboubi, H. 15 Mair, R. 51, 53 Maiza, J. C. 80 Makarenko, S. 26 Malcolm, J. G. 286 Malhotra, P. S. 3 Mallucci, C. L. 189 Maniakas, A. 15, 17 Mao, Z. G. 84, 84 Marchetti, M. 179 Marek, J. 88 Martínez Arias, A. 276, 278 Martin, J. J. 195, 196 Martin, T. P. 10 Mason, E. 39, 39 matrix metalloproteinases, in chordoma 170 McCool, R. R. 290, 290 McCormick, P. C. 209–210 Medina, M. D. 261 MEK inhibitor 60 Mendelson, Z. S. 138 meningioma – A3-A3 bypass, case study 269, 272 – background 24, 48, 58 – brain lesion surgical impression 49 – chemotherapy –– background 58 –– clinical trials 60 –– studies 59 – consortium trials 49 – embolization 43 – high-grade, published reports 51 – high-grade, recurrence 49 – olfactory groove –– case studies 32, 34–35 –– characterization 24, 25 –– endoscopic techniques 25, 25 –– QALY outcome 30 –– transcranial resection 24–25, 25 – petroclival 37 – radiosurgery –– clinical target volume 53 –– Grade II 52–53 –– Grade III 54 – radiotherapy, adjuvant –– Grade II 50, 52 –– Grade II, radiation dose 52 –– Grade III 54 –– Grade III, radiation dose 54 –– radiation-induced complications 50 –– radiation-induced transformation 50 –– recurrence, clinical consequences 49 –– survival rates 49–50, 52, 53, 54 –– tuberculum sella, see case studies, characterization, endoscopic endonasal approach, endoscopic techniques, QALY outcome, transcranial resection

295

Controversies in Skull Base Surgery | 04.06.19 - 14:54

Index –– vascular pedicles 44 –– WHO grading criteria 48, 49 – safe maximal resection 49 – skull base reconstruction, CSF leakage in 240 – sphenoid wing, case studies 45, 45 – surgical sampling 49 – targeted therapy, see specific agents by name or class –– background 58 –– clinical trials 58 –– survival rates 61 – venous sinus repair/bypass studies 267 – WHO grading criteria, prognostic/ interobserver reproducibility 48 meningitis, perioperative 251 Mercado, M. 79, 80 Mesquita Filho, P. M. 183, 185, 185 metyrapone 73, 74–75 Micko, A. S. 95 mifepristone – Cushing syndrome 71, 74, 75 – meningioma 59, 61 Milker-Zabel, S. 49, 51 mitotane 73, 74 modified Rankin score (mRS) 259 moneybox slot technique 238 Morera, V. A. 39 Moriyama, T. 18 Moussazadeh, N. 119, 120, 183, 185 mTORC inhibitor 59–60, 61 Muscatello, L. 276, 278

N Nagasawa, D. 190 nasal wall/nasoseptal flap in reconstruction 238 nasopharyngeal carcinoma, robotic surgery 290 nasoseptal flap in reconstruction 237, 240–241 NBCA, in embolization 43 NCT03224767 128 Netterville classification, paragangliomas 174 Netterville, J. L. 177, 178 Newman, C. B. 80 Nicoli, T. K. 176, 177 Nishioka, H. 95, 137, 138, 139 nivolumab 60 nonacoustic neuroma, see trigeminal/ jugular foramen schwannomas nonvestibular schwannoma, see trigeminal/jugular foramen schwannomas NRG/RTOG 0539 48, 50, 52, 55

O O'Malley, B. W., Jr. 289, 290 O'Reilly, B. F. 194 octreotide/octreotide LAR – acromegaly 78 –– biochemical control 79, 80 –– tumor shrinkage 79 – Cushing syndrome 73 – meningioma 59 – pasireotide vs. 79 – preoperative use of 84, 84 – transsphenoidal surgery vs. 82

296

oculomotor nerve schwannoma – radiosurgery vs. surgery studies 205, 205 – surgical indications 205 – treatment selection 205 Odia, Y. 127 Oghalai, J. S. 183 Oka, H. 44 Okano, S. 231, 231 Onyx, in embolization 43–44 orbital schwannomas – case studies 202, 203 – endoscopic resection of 199, 200 Orlando, R. 251, 252 ORYX initiative 258 Ottenhausen, M. 29 outcome measures – anterior/mediolateral skull base surgery 260 – definitions 258 – history of 258 – in acoustic neuroma 260–261 – overview 258 – patient-centered care 259 – quality of life 259, 261 – traditional 259 Ouyang, T. 155 Oyama, N. 138

P PA grading system 99, 100, 102 PA scale 99, 99, 102 Padhye, V. 29 paragangliomas – background 174 – carotid body 178 – case studies –– observation 175, 175, 176 –– radiation 178, 178, 179–180 –– surgery 176, 177 – classification 174, 174 – diagnosis, workup 174 – jugular 176 – management 175 – tympanomastoid 176 – vagal 178 paranasal schwannomas 199, 200 Paredes, I. 286 Park, H. J. 51, 53 Park, H. R. 120 Parsa, A.T. 186 pasireotide-induced hyperglycemia 73 pasireotide/pasireotide LAR – acromegaly 79 – Cushing syndrome 71, 73, 74 – meningioma 59, 60 – octreotide vs. 79 Pasquini, E. 276, 278 Patel, M. R. 246 Patel, N. S. 179, 179 Patel, S. H. 232 Patel, V. S. 120 patient report outcome measurement (PROM) 259 patient-centered care 259 patient-specific implants 284 PD-1 inhibitor 60, 61 PD-L1 inhibitor 60, 61 PDGFR inhibitor 59, 60 PDGFR-α, in chordoma 171 PDGFR-positive cytotoxic 59

pectoralis major flaps in reconstruction 239 PEEK implant 283, 285, 285 pegvisomant – acromegaly 78 – as primary medical therapy 82 – cabergoline with 83 – SRLs with 83 Peker, S. 196, 209–210 pembrolizumab 60 Peng, Y. 189, 190 Penn Acoustic Neuroma Quality of Life (PANQOL) scale 261 peptide receptor radionuclide therapy (PRRT) 107 performance measurement, see outcome measures pericranial flaps in reconstruction 238 Perry, A. 49 Petit, J. H. 88 petroclival meningioma – case studies 40, 41, 46, 46 – characterization 37, 38 – endoscopic endonasal approaches 38 – Gamma Knife radiosurgery 40 – Kawase approach 37 – literature review 39, 39 – petrosectomy 37, 38 – retrosigmoid craniotomy 38 – surgical approach, choice of 37, 38 – Tufts Medical Center protocol 40 Phi, J. H. 195, 209–210 photon/proton therapy – altered fractionation 231 – chemotherapy, neoadjuvant 231 – combined therapy 232, 232 – comparative studies 232 – photon therapy review 229, 230 – proton therapy review 230, 230, 231 – sinonasal malignancies 229 PI3K-AKT-mTOR pathway, in chordoma 171 Piitulainen, J. M. 286 PIT-1 adenoma 104 Pitman, K. T. 225, 226 pituitary adenomas, see cavernous sinus/pituitary adenoma, vestibular schwannoma – aggressive, alternative treatment strategies 104 – aggressiveness, identification/ management 103, 104, 107, 108 – carmustine 107 – characterization 87, 103 – chemotherapy, for aggressive 106, 106 – classification 103 – p53 immunoreactivity 103 – PCA-to-SCA bypass 270–271, 272 – PRRT 107 – radiosurgery –– adverse effects 87 –– aggressive 104, 105 –– dosage 105 –– early 105 –– functioning, outcomes 88, 88, 89 –– nonfunctioning, outcomes 87, 88 –– outcomes 87 –– salvage 105 – RCC-induced headaches 139 – robotic surgery 290 pituitary apoplexy

– characterization 98 – conservative management 98, 102 – conservative vs. surgical management 100, 101 – corticosteroid management 102 – grading scales 99, 102 – surgical management 98, 99, 102 Pivonello, R. 76 Pollock, B. E. 10, 51, 88–89, 195 polyvinyl alcohol (PVA) particles, in embolization 43 Pommier, P. 232 Poon, T. L. 89 posterior fossa epidermoids – case studies 190, 190, 191 – characterization 188 – endoscopic visualization 190 – minimally invasive approaches 190 – natural history of 188 – radiosurgery 190 – remission rates 188–189 – review 188, 189 POTA study 84 Prabhu, K. 277 Prasad, S. C. 176, 176–177 Press, R. H. 51, 54 Prevedello, D. M. 29 PrL adenoma, densely granulated 104 progesterone receptor beta, in chordoma 170 progesterone receptor inhibitor 59 prolactinomas – dopamine agonists 91 – radiosurgery 89, 90 – whole-sellar targeting 91 proton-beam radiotherapy, skull base chordoma 185 PTEN loss, in chordoma 168, 169, 171 Puget, S. 113

Q Quah, B. L. 286 quality of life measures 259, 261

R Rachinger, W. 155 radial artery flaps in reconstruction 239 radiation resistance, β1 integrin in 169 radiosurgery – acromegaly 89, 89–90 – adverse effects 87 – antisecreting medications cessation 91 – characterization 87 – cochlear nerve injury 179 – Cushing syndrome/disease 70, 88, 88, 90 – CyberKnife, see CyberKnife radiosurgery – early vs. late 91 – Gamma Knife, see Gamma Knife radiosurgery – meningioma, see under meningioma – paragangliomas case studies 178, 178, 179–180 – petroclival meningioma 40 – pituitary adenomas, aggressive 105, 105 – posterior fossa epidermoids 190

Controversies in Skull Base Surgery | 04.06.19 - 14:54

Index – prolactinomas 89, 90 – residual vestibular schwannoma 11–12, 13 – silent corticotroph adenomas 90 – upfront 91 Raghunath, A. 189 Rahme, R. J. 155 Ramakrishna, R. 225, 226, 228 Ramm-Pettersen, J. 155 Rangel-Castilla, L. 267 Rao, Y. J. 113 rapamycin 61 Raper, D. M. 138 Rathke cleft cyst, see pituitary apoplexy – alcohol instillation 133 – case studies 134, 135 – characterization 132, 133, 137, 137, 142 – clinical studies 132, 134 – complications 146 – differential diagnosis 143 – embryology of 142 – endocrinologic workup 144 – headaches in 137, 138 – headaches, pathophysiology 139 – location differences 139 – marsupialization 133 – MRI findings 139, 143, 143, 144 – ophthalmologic workup 144 – pathogenesis 137 – pathology 142 – recurrence 140 – sellar floor packing 133 – size differences 139 – surgery vs. natural history 146 – surgical management 144 – surgical outcomes 145, 145 – symptoms 137, 143 – treatment 139 Raverot, G. 106 Raza, S. M. 199 receptor tyrosine kinases (RTKs), in chordoma 170 reconstruction, see skull base reconstruction rectus abdominis flap in reconstruction 239 Reddy, S. 286 Regis, J. 8 rescue flaps in reconstruction 238 residual vestibular schwannoma – case studies 12 – literature studies 10 – microsurgical resection 11–12, 13 – observation 10, 12, 12 – overview 10 – stereotactic radiosurgery 11–12, 13 Resto, V. A. 232, 232 revascularization – bypass approaches, summary 272 – bypass, planned 264, 264 – case series 265, 267 – case studies 271 – emergent bypass/vessel injury 266– 267, 267, 269–271 – high-flow bypass 266, 268 – planned resection/vessel sacrifice 264, 265 revascularized free flaps in reconstruction 239 rhinosinusitis, chronic 255 ribociclib 60

ribonucleotide reductase inhibitor 59 Roberson, J. B. Jr. 10 Roberts, B. K. 89 Robinett, Z. N. 261 robotics – advantages of 291 – background 288 – limitations of 291 – prototypes 291 – skull base approaches 288, 290 – systems, existing 288, 289 – transnasal/transantral approach 288 – transnasal/transoral approach 290 – transoral approach 289 Roche, P. H. 11 Rogers, C. L. 51 Rogers, L. 51, 53 Ronchi, C. L. 89 Roque, A. 127 Rosen, C. L. 44, 44 Rosenberg, L. A. 51 Rosenberg, S. I. 3 Runge, M. J. R. 88 Russo, A. L. 231, 231

S Safavi-Abbasi, S. 189 Saito, K. 155 Saleh, A. M. 252 Saliba, I. 17 Samadian, M. 277 Samii, A. 155, 184, 188, 189, 199, 209 Samii, M. 10, 11, 38 Sandooram, D. 261 sandostatin 60 Sanna, M. 10, 11 Sare, G. M. 277 scapular free flaps in reconstruction 239 Schiefer, T. K. 189, 189 Schmidt, R. F. 276, 278 Schroeder, H. W. S. 189, 190 Schuler, P. J. 290, 290 Schwab, J. H. 170 SEISMIC trial 74 seizures, LSR encephaloceles 275 Sekhar, L. N. 155, 183, 186, 265 Sekine, S. 127 Selesnick, S. H. 3 selumetinib 60 Semple, P. L. 98 Sen, C. 155 Sethi, D. S. 276 SF-36 measure 260–261 Shakir, S. I. 53 Shalaby, A. 171 Shamblin's classification, paragangliomas 174 Sheehan, J. P. 87, 88, 195, 209–210 Shelton, C. 17 Shen, M. 84, 84 Sheptak, P. E. 11 Sherlock, M. 82 Sheth, S. A. 68 Shetty, S. R. 25 Shi, X. 120 Shidoh, S. 155 Shin, J. L. 138 Sibal, L. 101, 101 Signifor, see pasireotide silent corticotroph adenomas 90, 104 Sindou, M. P. 267

Sinonasal Outcome Test (SNOT22) 260 sinonasal SCC, proton therapy 231 skull base chordoma – characterization 182 – chondrosarcomas 183, 185 – endoscopic endonasal treatment 183, 185 – histopathologic subtypes 182 – management 182 – open microsurgical resection 182, 183–184 – radiosurgery 185 skull base reconstruction – antibiotic prophylaxis 241 – approach selection rationale 236, 240 – background 236 – closure technique 241 – CSF leakage in 239–241, 251 – endoscopic endonasal approach 239 – extranasal rotational flaps 238 – free tissue grafts/autografts 237 – lumbar drains 241 – materials 237 – nasal wall/nasoseptal flap 238 – nasoseptal flap 237, 240–241 – pericranial flaps 238 – rescue flaps 238 – revascularized free flaps 239 – temporoparietal fascia flap 238 – turbinate flaps 238 – vascularized flaps 237, 237, 240– 241 SMARCB1, in chordoma 171 SMO inhibitor 60, 61 Solares, C. A. 155 somatostatin analogues – Cushing syndrome 73 – meningioma 59 somatostatin receptor ligands (SRLs), see specific agents by name – as primary medical therapy 79, 80 – cabergoline with 83 – characterization 78 – pegvisomant with 83 – preoperative use of 84, 84 – transsphenoidal surgery vs. 82 somatostatin receptors 61 Somma, T. 251, 252 Spetzler, R. F. 265 Src (c-Src), in chordoma 170 Src family kinases (SFKs), in chordoma 170 Sreenath, S. B. 290, 291 Stammberger, H. 276 Stangerup, S. E. 3, 15 Staphylococcus aureus 251 STAT3, in chordoma 169, 170 stereotactic radiosurgery, see radiosurgery Sternberg's canal 275 Steward, T. J. 2 Stippler, M. 155 Stoker, M. A. 246 Suárez, C. 180 Sughrue, M. E. 51 Sun, H. 207 Sun, J. 195, 209–210 sunitinib 59, 60 Suzuki, K. 44 Swedish National Registry 50

T Tabaee, A. 276, 278 Takahashi, S. 155 Talacchi, A. 189 Tami, T. A. 276, 278 Tamura, T. 155 Tan, N. C. W. 155 Tanaka, S. 89 Tancredi, A. 189 Tang, S. 3 Taniguchi, M. 155, 199 temozolomide – dosage regimen 106 – efficacy of 106, 106 – meningioma 58, 59 – pituitary adenomas, aggressive 106, 106 – radiotherapy concurrent with 106 temporal lobe epilepsy 275 temporoparietal fascia flap in reconstruction 238 temsirolimus 61 Teufert, K. B. 183, 184 TGF-α, in chordoma 170 Tinnel, B. A. 88–89 titanium mesh implants 282, 283 Tomazic, P. V. 276, 278 trabectedin 58, 60 trametinib 128 transoral robotic surgery (TORS) 289, 291 trapezius flap in reconstruction 238 trigeminal neuralgia – characterization 210 – medication-refractory 210 – persistent 211 trigeminal neuropathic pain 211 trigeminal/jugular foramen schwannomas – case studies 201, 202, 202, 203 – characterization 194 – endoscopic resection of 199, 200 – facial pain in 209, 209 – microsurgical resection, facial pain outcomes 209, 210 – radiosurgery 194, 195, 195, 196– 197, 209, 210 – treatment options summary 210 – trigeminal neuralgia, medicationrefractory 210 – trigeminal neuralgia, persistent 211 Trivelatto, F. 44, 44 trochlear nerve schwannoma – radiosurgery vs. surgery studies 205 – treatment selection 205, 206 Truong, M. T. 231 Tsai, J.-T. 8 Tsunoda, A. 2 Tuchman, A. 189 turbinate flaps in reconstruction 238 Tzortzidis, F. 155, 184, 185–186

U UCHL3, in chordoma 169 University of Pittsburgh 246 Unsal, A. A. 225, 226

V Valassi, E. 74–75, 76

297

Controversies in Skull Base Surgery | 04.06.19 - 14:54

Index van der Mey, A. G. 176 Van Gompel, J. J. 29 vancomycin 251 Varan, A. 149 vascularized flaps in reconstruction 237, 237, 240–241 vatalanib 59, 60 VEGFR inhibitor 59, 60 Vellutini, E. A. 155 vemurafenib 128 Vergoni, G. 277 vestibular schwannoma, see pituitary adenomas – age at diagnosis 3 – background 2 – conservative management outcomes 3 – endoscopic resection of 199, 199, 200 – growth pattern 3 – growth rate 3 – hypofractionated therapy 5, 8 – incidence 2 – multifractionated therapy 5, 8 – natural history 2

298

– – – –

nerve of origin 2 outcome measures in 260 quality of life measures 261 residual, postresection management 10, 10 – small intracanalicular 15 Vik-Mo, E. O. 89 Vilar, L. 74, 76 vildagliptin 73 vismodegib + GSK2256098 60, 61 vistusertib 60 Vivas, E. X. 8 Voelker, J. L. 138 Voges, J. 88–89 VS, see vestibular schwannoma

W Wackym, P. A. 199 Wait, S. D. 132–133, 134, 145 Waldron, J. S. 44, 44 Wan, H. 88–89, 90 Wanebo, J. E. 184 Wang, C. 52

Wang, L. 155 Wang, Q. 29 Wang, Z. Y. 199 Wannemuehler, T. J. 120 Weber, D. C. 232 Wein, L. 88 Weinstein, G. S. 289, 290 White, W. L. 251 Wiegner, E. A. 230 Wijnen, M. 113 Wilson, C. B. 189 Wilson, P. J. 88–89 Winford, T. W. 179 Woodworth, G. F. 95 Wu, Z. 155

X xanthogranulomas – juvenile 151 – presentation 149 Xenellis, J. E. 2 Xu, Z. 87

Y Yan, J.-L. 89 Yang, C. 170 Yang, I. 5, 8 Yang, S. Y. 10 Yang, T. 264, 265 Yasargil, M. G. 120 Yasuda, M. 155 Yawn, R. J. 189 Yianni, J. 195, 195 Yin Tsang, R. K. 290, 290 Yoneoka, Y. 155 Yoshimoto, Y. 3 Yuen, K. C. 76

Z Zanation, A. M. 290 Zenda, S. 231 Zeng, X. J. 194 Zhang, Q. 155, 209–210 Zoli, M. 155, 276, 278 Zwagerman, N. T. 246

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