Essentials in Ophthalmology Oculoplastics and Orbit

R. F. Guthoff J. A. Katowitz Editors Essentials in Ophthalmology Glaucoma

G. K. Krieglstein R. N. Weinreb Cataract and Refractive Surgery Series Editors Uveitis and Immunological Disorders

Vitreo-retinal Surgery

Medical Retina

Oculoplastics and Orbit

Pediatric Ophthalmology, Neuro-Ophthalmology, Genetics

Cornea and External Eye Disease Editors Rudolf F. Guthoff James A. Katowitz

Oculoplastics and Orbit

Aesthetic and Functional Oculofacial Plastic Problem-Solving in the 21st Century

With 181 Figures, Mostly in Colour and 18 Tables Series Editors Volume Editors Günter K. Krieglstein, MD Rudolf F. Guthoff , MD Professor and Chairman Professor of Ophthalmology Department of Ophthalmology University of Rostock University of Cologne Department of Ophthalmology Joseph-Stelzmann-Straße 9 Doberaner Straße 140 50931 Köln 18055 Rostock Germany Germany

James A. Katowitz, MD Robert N. Weinreb, MD Professor of Ophthalmology Professor and Director Children’s Hospital of Philadelphia Hamilton Glaucoma Center R. D. Wood Ambulatory Care Building Department of Ophthalmology – 0946 Division of Ophthalmology University of California at San Diego 34th Street Civic Center Blvd. 9500 Gilman Drive Philadelphia, PA 19104 La Jolla, CA 92093-0946 USA USA

ISBN: 978-3-540-85541-5 e-ISBN: 978-3-540-85542-2

DOI: 10.1007/978-3-540-85542-2

Library of Congress Control Number: 2009933987

© Springer-Verlag Berlin Heidelberg 2010

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(www.springer.com) Foreword

Th e Essentials in Ophthalmology series represents an ership acceptance of the fi rst two series, each of eight unique updating publication on the progress in all sub- volumes. Th is is a success that was made possible pre- specialties of ophthalmology. dominantly by the numerous opinion-leading authors In a quarterly rhythm, eight issues are published cov- and the outstanding section editors, as well as with the ering clinically relevant achievements in the whole fi eld constructive support of the publisher. Th ere are many of ophthalmology. Th is timely transfer of advancements good reasons to continue andstill improve the dissemina- for the best possible care of our eye patients has proven to tion of this didactic and clinically relevant information. be eff ective. Th e initial working hypothesis of providing new knowledge immediately following publication in the peer-reviewed journal and not waiting for the textbook appears to be highly workable. G.K. Krieglstein We are now in the third cycle of the Essentials in R.N. Weinreb Ophthalmology series, having been encouraged by read- Series Editors Preface

Th is third volume of Oculoplastic and Orbital Surgery Appearance issues are also discussed in relation to promises to challenge the reader with stimulating new managing ophthalmic anomalies in congenital ano- concepts at the cutting edge of this subspecialty. A variety phthalmic and microphthalmic patients. Controversies in of innovative techniques is described in this volume, cov- enucleation techniques, implant selection, and implant ering both cosmetic and functional aspects of oculoplas- preparation are presented, and the role of pegging an tic and orbital surgery. implant to ultimately improve prosthesis motility is criti- Pearls in cosmetic and oculofacialplastic surgery are cally evaluated. presented in great detail, based on extensive experience. It is our hope, as with the previous two volumes, that Rather than presenting merely anecdotal solutions, spe- this presentation of the latest concepts and management cifi c steps are outlined for problem solving in this rapidly techniques for a variety of problem areas in the fi eld of evolving fi eld. oculoplastic surgery will be of value for both comprehen- Th e latest therapies in the management of capillary sive ophthalmologists and subspecialists with a particular hemangiomas, periorbital infections, and orbital and interest in this fi eld. periorbital malignancies using specifi c targeted therapies demonstrate the increasingly important interaction between ophthalmic plastic surgery and the broad fi eld of Rudolf F. Guthoff modern oncology. James A. Katowitz Contents

Chapter 1 2.4.4 Upper Blepharoplasty Surgical Ocular Adnexal Lymphoproliferative Disease Procedure Pearls ...... 30 Timothy J. Sullivan 2.5 Lower Blepharoplasty, Fillers, and Midface Augmentation ...... 33 1.1 Pathogenesis ...... 2 2.5.1 Introduction ...... 33 1.2 Chronic Antigen Stimulation ...... 3 2.5.2 Patient Evaluation...... 33 1.3 Immunosuppression ...... 3 2.5.3 Lower Blepharoplasty 1.4 Pathology...... 4 Anesthesia Pearls ...... 37 1.5 Cytogenetics...... 4 2.5.4 Lower Blepharoplasty Surgical 1.6 Clinical Features...... 7 Procedure Pearls ...... 38 1.7 Imaging Findings ...... 8 References ...... 44 1.8 Staging ...... 9 1.9 Positron Emission Tomography ...... 9 Chapter 3 1.10 Treatment ...... 9 Current Concepts in the Management 1.11 Follicular Lymphoma ...... 11 of Idiopathic Orbital Infl ammation 1.12 Mantle Cell Lymphoma...... 11 Katherine A. Lane and Jurij R. Bilyk 1.13 Radiotherapy ...... 11 1.14 Chemotherapy...... 12 3.1 Introduction ...... 47 1.15 Immunotherapy...... 12 3.2 What Is the Diagnosis? ...... 47 1.16 Radioimmunotherapy ...... 13 3.2.1 Pitfalls of Diagnosis...... 48 1.17 Outcome ...... 13 3.2.2 A Diagnostic Corticosteroid Trial? ...... 54 1.18 The Future ...... 13 3.2.3 The Question of Biopsy ...... 56 References ...... 14 3.3 Treatment ...... 56 3.3.1 Corticosteroids...... 57 Chapter 2 3.3.2 Radiation ...... 58 Pearls in Cosmetic Oculofacial Plastic Surgery 3.3.3 Other Agents ...... 58 Jonathan A. Hoenig 3.4 Special Circumstances...... 60 3.4.1 Pediatric IOIS...... 60 2.1 General Introduction ...... 21 3.4.2 Sclerosing Pseudotumor ...... 60 2.2 The Aging Process and Facial Analysis. . . 22 3.4.3 Tolosa–Hunt Syndrome...... 62 2.3 Endoscopic Brow Lift ...... 23 References ...... 63 2.3.1 Introduction ...... 23 2.3.2 Endoscopic Browlift Anesthesia Pearls . . . . 26 Chapter 4 2.3.3 Endoscopic Browlift Surgical Lacrimal Canalicular Infl ammation and Occlusion: Procedure Pearls ...... 26 Diagnosis and Management 2.3.4 Endoscopic Browlift Postoperative David H. Verity and Geoff rey E. Rose Care Pearls ...... 27 2.4 Upper Blepharoplasty ...... 29 4.1 Introduction ...... 67 2.4.1 Introduction ...... 29 4.2 Embryology, Anatomy, Physiology, 2.4.2 Patient Evaluation...... 29 and Pathophysiology of the Canalicular 2.4.3 Upper Blepharoplasty System...... 67 Anesthesia Pearls ...... 30 4.3 Infective Causes...... 69 x Contents

4.3.1 Periocular Herpes Simplex Infection . . . . 69 5.7.3.1 The Upper Eyelid ...... 85 4.3.2 Bacterial Canaliculitis...... 70 5.7.3.2 The Lower Eyelid and Midface ...... 85 4.4 Systemic Infl ammatory Disease ...... 70 5.7.4 Orbital Involvement ...... 86 4.4.1 Lichen Planus ...... 70 5.7.4.1 Proptosis...... 86 4.4.2 Ocular Cicatricial Pemphigoid ...... 70 5.7.4.2 Proptosis Due to Orbital 4.4.3 Drug Eruptions (Stevens–Johnson Neurofi bromas...... 87 Syndrome) ...... 71 5.7.4.3 Proptosis Due to Optic Nerve Glioma . . . 87 4.5 Iatrogenic Causes ...... 71 5.7.4.4 Orbital Enlargement with Dystopia 4.5.1 Systemic Drugs ...... 71 and Hypoglobus ...... 87 4.5.1.1 5-Fluorouracil (5-FU) ...... 71 5.8 The Natural History of NF1 Tumor 4.5.1.2 Docetaxel (Taxotere) ...... 72 Growth from Birth to Senescence ...... 90 4.5.2 Radiotherapy ...... 72 References ...... 92 4.5.3 Topical Ophthalmic Treatments...... 73 4.5.3.1 Preservative-Related Chronic Chapter 6 Conjunctivitis ...... 73 Clinicopathologic Features of Lesions 4.5.3.2 Mitomycin C Therapy...... 73 Aff ecting the Lacrimal Drainage System in External Dacryocystorhinostomy 4.5.4 Lacrimal Stents and Plugs ...... 73 4.6 The Surgical Approach to Managing Ludwig M. Heindl, Anselm G. M. Jünemann, Canalicular Disease...... 74 and Leonard M. Holbach 4.6.1 Surgical Technique for 6.1 Introduction ...... 95 Dacryocystorhinostomy with 6.2 Surgical Anatomy of the Lacrimal Retrograde Canaliculostomy...... 74 Drainage System ...... 96 4.6.2 Placement of a Jones Canalicular 6.3 Basic Diagnostics for Disorders Bypass Tube...... 75 of the Lacrimal Drainage System...... 97 References ...... 76 6.4 Selective Lacrimal Sac Biopsy in External Dacryocystorhinostomy . . . . . 97 Chapter 5 6.5 Defi nitive Treatment and Prognosis Orbitofacial Neurofi bromatosis 1: Current Medical and Surgical Management of Lesions Aff ecting the Lacrimal Drainage System ...... 99 William R. Katowitz and James A. Katowitz 6.5.1 Case A ...... 99 5.1 Introduction ...... 79 6.5.2 Case B ...... 99 5.2 Nomenclature...... 79 6.5.3 Case C ...... 100 5.3 Clinical Manifestations of NF1 ...... 79 6.5.4 Case D ...... 100 5.4 Orbitofacial Tumors in NF1 ...... 80 6.5.5 Case E ...... 101 5.4.1 Neurofi bromas...... 80 6.5.6 Case F ...... 101 5.4.2 Malignant Peripheral Nerve 6.5.7 Case G ...... 101 Sheath Tumors ...... 81 References ...... 103 5.4.3 Optic Pathway Gliomas...... 81 Chapter 7 5.5 Genetics ...... 83 Systemic and Ophthalmic Anomalies 5.5.1 The NF1 Gene...... 83 in Congenital Anophthalmic 5.5.2 Overlapping NF1-Like Phenotype or Microphthalmic Patients (SPRED1)...... 83 Michael P. Schittkowski and Rudolf F. Guthoff 5.6 Management of Neurofi bromatosis Type 1 ...... 84 7.1 Introduction ...... 105 5.6.1 Introduction ...... 84 7.2 Patients and Methods ...... 106 5.6.2 Medical Management of 7.2.1 Patients...... 106 Neurofi bromas...... 84 7.2.2 Examination ...... 106 5.7 Surgical Management of Orbitofacial 7.3 Results...... 106 Tumors in NF1 ...... 84 7.3.1 Patient Data...... 106 5.7.1 Introduction ...... 84 7.3.2 Age...... 106 5.7.2 Timing of Surgery ...... 84 7.3.3 Family History...... 106 5.7.3 Periorbital Involvement ...... 85 7.3.4 Pregnancy History...... 107 Contents xi

7.3.5 Birth ...... 107 8.4.1.1 Nonautogenous Materials ...... 121 7.3.6 Associated Systemic and 8.4.1.2 Autogenous Fascia Lata ...... 121 Ocular Diseases ...... 107 8.4.2 Our Technique of Harvesting 7.3.7 Developmental Anomaly and Autogenous Fascia Lata ...... 121 Potential Visual Capacity of the 8.4.3 Mechanical Principals of Brow Fellow Eye in Unilateral Disease...... 110 Suspension ...... 122 7.3.8 Neuroradiological Findings (Brain MRI). . 111 8.4.4 Upper Lid Approach...... 122 7.3.9 Nasolacrimal System Findings ...... 111 8.4.5 Fascia Implantation ...... 122 7.4 Discussion ...... 112 References ...... 123 7.4.1 Patients...... 112 7.4.2 Obstetric and Family History...... 112 Chapter 9 Modern Concepts in Orbital Imaging 7.4.3 Associated Pathologies...... 113 7.4.3.1 Ophthalmological Findings Jonathan J. Dutton in Unilateral Disease...... 113 9.1 Computerized Tomography ...... 125 7.4.3.2 Neuroradiological Findings ...... 113 9.2 Three-Dimensional Imaging ...... 129 7.4.3.3 Systemic Diseases ...... 114 9.3 Magnetic Resonance Imaging ...... 129 7.4.3.4 Nasolacrimal Duct Findings...... 114 9.3.1 The T1 Constant...... 130 7.5 Conclusions...... 115 9.3.2 The T2 Constant...... 131 References ...... 116 9.3.3 Creating the MR Image ...... 131 9.4 Imaging of Common Orbital Chapter 8 Lesions ...... 134 Brow Suspension in Complicated Unilateral 9.4.1 Adenoid Cystic Carcinoma...... 134 Ptosis: Frontalis Muscle Stimulation via 9.4.2 Cavernous Hemangioma ...... 134 Contralateral Levator Recession 9.4.3 Dermoid Cyst ...... 134 Markus F. Pfeiff er 9.4.4 Fibrous Dysplasia ...... 135 8.1 Introduction ...... 117 9.4.5 Lymphangioma ...... 136 8.2 Evaluation of Complicated Ptosis ...... 117 9.4.6 Lymphoma ...... 136 8.2.1 Compensatory Eyebrow Elevation ...... 117 9.4.7 Myositis...... 136 8.2.2 Examples of Complicated Unilateral 9.4.8 Optic Nerve Glioma ...... 138 Ptosis with Insuffi cient Compensatory 9.4.9 Pseudotumor ...... 139 Brow Elevation ...... 118 9.4.10 Rhabdomyosarcoma ...... 139 8.2.3 Innervation Patterns of the Frontalis 9.5 Diff usion MRI (Diff usion-Weighted Muscle...... 118 Imaging)...... 140 8.2.4 Checklist of Preoperative Evaluation 9.6 Positron Emission Tomography ...... 141 of Complicated Ptosis ...... 118 9.7 Orbital Ultrasound ...... 142 8.2.5 Planning Partial or Total Levator 9.7.1 Physics and Instrumentation...... 142 Muscle Recession Combined with 9.7.1.1 Topographic Echography...... 143 Unilateral or Bilateral Brow 9.7.1.2 Quantitative Echography ...... 143 Suspension ...... 118 9.7.1.3 Kinetic Echography...... 143 8.3 Surgical Technique of Levator Muscle 9.7.2 Extraocular Muscles ...... 145 Recession ...... 119 9.7.3 Optic Nerves ...... 146 8.3.1 Principle ...... 119 References ...... 146 8.3.2 Approach to the Levator...... 119 Chapter 10 8.3.3 Partial Levator Recession ...... 119 Management of Periorbital Cellulitis 8.3.4 Total Levator Recession...... 119 in the 21st Century 8.3.5 The Lid-Lowering Eff ect and Eyelid Michael P. Rabinowitz and Scott M. Goldstein Symmetry: Evolution of the Eyelid Level After Levator Recession ...... 121 10.1 Introduction ...... 149 8.3.6 Undercorrection and Overcorrection. . . . 121 10.2 The Infection: Stages, Symptoms, 8.4 Surgical Technique of Brow and Eff ects ...... 149 Suspension ...... 121 10.3 Etiology...... 151 8.4.1 Materials for Brow Suspension ...... 121 10.4 Microbiology...... 151 xii Contents

10.5 Changing Pathogens and Resistance. . . . 152 12.5 Localization ...... 174 10.5.1 CA-MRSA Versus Hospital-Acquired 12.6 Clinical Features...... 175 MRSA ...... 152 12.7 Imaging and Patterns of Orbital 10.5.2 Orbital MRSA...... 153 Metastatic Disease ...... 176 10.6 Evaluation of Orbital Cellulitis ...... 154 12.8 Biopsy ...... 177 10.7 Medical Treatment of Orbital Cellulitis . . 155 12.9 Common Types of Orbital Metastases . . . 178 10.8 Surgical Treatment of Orbital Cellulitis . . 156 12.9.1 Breast Carcinoma ...... 178 10.9 Prevention of Orbital Cellulitis 12.9.2 Lung Carcinoma ...... 178 after Orbital Fracture ...... 158 12.9.3 Prostatic Cancer...... 179 References ...... 159 12.9.4 Melanoma ...... 179 12.9.5 Carcinoid Tumor ...... 179 Chapter 11 12.10 Diff erential Diagnosis ...... 180 Current Concepts in the Management 12.11 Treatment ...... 180 of Capillary Hemangiomas: Steroids, 12.11.1 Radiotherapy ...... 180 Beta-Blockers, or Surgery 12.11.2 Chemotherapy...... 180 François Codère and Julie Powell 12.11.3 Hormonal Therapy ...... 180 12.11.4 Surgery ...... 181 11.1 Clinical Picture ...... 161 12.12 Prognosis and Survival ...... 181 11.1.1 Clinical Phases ...... 161 References ...... 181 11.1.2 Etiology, Histology, and Classifi cation . . . 161 11.1.3 Diff erential Diagnosis of Infantile Chapter 13 Hemangioma ...... 162 Targeted Therapy in the Treatment 11.2 Ocular Complications ...... 163 of Orbital and Periorbital Malignancies 11.3 Investigation...... 163 Aaron Savar and Bita Esmaeli 11.3.1 Angiography...... 164 11.4 Management ...... 165 13.1 Introduction ...... 187 11.4.1 Active Nonintervention...... 165 13.2 Rituximab...... 188 11.4.2 Indications for Treatment ...... 165 13.3 Yttrium-90-Labeled Ibritumomab 11.5 Modalities of Treatment ...... 165 Tiuxetan ...... 189 11.5.1 Steroids...... 165 13.4 Imatinib Mesylate ...... 190 11.5.1.1 Topical Steroids ...... 165 13.5 Cetuximab ...... 191 11.5.1.2 Intralesional Corticosteroid Injection. . . . 165 References ...... 192 11.5.1.3 Oral Corticosteroids ...... 166 11.5.2 Interferon-Alfa ...... 166 Chapter 14 11.5.3 Vincristine ...... 167 Controversies in Enucleation Technique 11.5.4 Laser...... 167 and Implant Selection: Whether to Wrap, 11.5.5 Embolization...... 167 Attach Muscles, and Peg? 11.5.6 Surgery ...... 167 David R. Jordan and Stephen R. Klapper 11.5.7 Beta-Blockers: A New Promising 14.1 Introduction ...... 195 Modality of Treatment...... 168 14.2 Porous Orbital Implants ...... 196 References ...... 170 14.3 Orbital Implant Selection in Adults...... 199 Chapter 12 14.4 Orbital Implant Selection Evaluation and Management in Children ...... 200 of Metastatic Orbital Tumors 14.5 Volume Considerations Alejandra A. Valenzuela and Alan A. McNab in Orbital Implant Selection ...... 201 14.6 Orbital Implant Wrapping 12.1 Introduction ...... 173 and Attaching Extraocular Muscles . . . . . 202 12.2 Epidemiology ...... 173 14.7 Which Wrap to Use ...... 203 12.3 Biological Behavior and Timing 14.8 To Peg or Not to Peg Porous Implants . . . 204 of Metastasis...... 174 14.9 Summary ...... 206 12.4 Lateralization ...... 174 References ...... 206 Contents xiii

Chapter 15 15.4 Types of Injectable Soft-Tissue Filler. . . . . 216 Non-surgical Volume Enhancement 15.4.1 Collagen Fillers...... 216 with Fillers in the Orbit and Periorbital Tissues: 15.4.2 Hyaluronic acid Fillers ...... 216 Cosmetic and Functional Considerations 15.4.3 Semipermanent Injectable Ana M. Susana Morley and Raman Malhotra Soft-Tissue Fillers...... 216 15.5 Treatment Areas ...... 217 15.1 Introduction ...... 213 15.5.1 Orbit...... 217 15.2 Etiology and Presentation ...... 213 15.5.2 Upper Eyelid and Brow ...... 220 15.2.1 Etiology of Orbital Volume Loss ...... 213 15.5.3 Tear Trough ...... 220 15.2.2 Etiology of Periorbital Volume Loss . . . . . 213 15.5.4 Temple and Brow ...... 223 15.2.3 Features of Orbital Volume Loss...... 214 15.6 Other Periorbital Uses 15.2.4 Features of PeriOorbital Volume Loss. . . . 215 of Injectable Soft-Tissue Fillers ...... 225 15.3 Background to Injectable 15.6.1 Upper Eyelid Loading ...... 226 Soft-Tissue Fillers...... 215 15.6.2 Lower Eyelid Elevation...... 226 15.3.1 Historical Perspective on Volume 15.6.3 Treatment of Cicatricial Ectropion...... 226 Replacement...... 215 15.7 Future Developments ...... 226 15.3.2 Advantages of Injectable References ...... 227 Soft-Tissue Fillers...... 215 15.3.3 Complications of Injectable Soft-Tissue Fillers...... 215 Index ...... 231 Contributors

Jurij R. Bilyk Anselm G.M. Jünemann Oculoplastic and Orbital Surgery Service, Department of Ophthalmology and Eye Hospital, Wills Eye Institute, 840 Walnut St., University Erlangen-Nürnberg, Schwabachanlage 6, Philadelphia, PA 19107, USA 91054 Erlangen, Germany

François Codère James A. Katowitz Department of Ophthalmology, Hôpital Ste-Justine, Children’s Hospital of Philadelphia, Université de Montréal, 3175 Côte Ste-Catherine, Division of Ophthalmology, Montreal, Quebec, Canada, H3T 1C5 R.D. Wood Ambulatory Care Building 34th Street Civic Center Blvd. Jonathan J. Dutton Philadelphia, PA 19104, Department of Ophthalmology, USA University of North Carolina, Chapel Hill, NC 27599-7040, USA William R. Katowitz Oculoplastic Surgery, Children’s Hospital of Philadelphia Bita Esmaeli Division of Ophthalmology, Section of Ophthalmology, 34th Street Civic Center Blvd. Department of Head and Neck Surgery, Philadelphia, PA 19104, USA Th e University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 1445, Houston, Stephen R. Klapper Texas 77030, USA Klapper Eyelid and Facial Plastic Surgery, 11900 North Pennsylvania Street, Suite 104, Scott M. Goldstein Carmel, IN 46032, USA Oculoplastic Service, Wills Eye Institute, Th omas Jeff erson University, Philadelphia, PA, USA Katherine A. Lane Department of Ophthalmology, Rudolf F. Guthoff Th e Children’s Hospital of Philadelphia, Department of Opthalmology, Rostock University, 34th and Civic Center Blvd., Doberaner Straβe 140, 18055 Rostock, Germany Philadelphia, PA 19104, USA

Ludwig M. Heindl Raman Malhotra Department of Ophthalmology and Eye Hospital, Queen Victoria Hospital, Corneoplastic Unit, University Erlangen-Nürnberg, Schwabachanlage 6, Holtye Road, East Grinstead, RH19 3DZ, 91054 Erlangen, Germany West Sussex, UK

Jonathan A. Hoenig Alan A. McNab 9735 Wilshire Blvd. #308, Beverly Hills, CA 90212, USA Royal Victorian Eye and Ear Hospital, Orbital, Lacrimal and Plastic Clinic, Leonard M. Holbach Suite 216, 100 Victoria Parade, East Melbourne 3002, Department of Ophthalmology and Eye Hospital, Victoria, Australia University Erlangen-Nürnberg, Schwabachanlage 6, 91054 Erlangen, Germany Ana M. Susana Morley Queen Victoria Hospital, Corneoplastic Unit, David R. Jordan East Grinstead, West Sussex, UK University of Ottawa Eye Institute, 301 O’Connor Street, St. Th omas’ Hospital, Department of Ophthalmology, Ottawa, Ontario, Canada, K2P 1V6 Westminster Bridge Rd., London SE1 7EH, UK xvi Contributors

Markus J. Pfeiff er Timothy J. Sullivan Augenklinik Herzog Carl Th eodor, University of Queensland, Eyelid, Nymphenburger Str.43, Lacrimal and Orbital Clinic, 80335 München, Germany Royal Brisbane and Women’s Hospital, Butterfi eld Street, Herston, Brisbane, Julie Powell Queensland, 4029, Australia Division of Pediatric Dermatology, Hôpital Ste-Justine, Université de Montréal, Alejandra A. Valenzuela 3175 Côte Ste-Catherine, Montreal, Quebec, Orbital, Lacrimal and Oculoplastic Clinic, Canada, H3T 1C5 Department of Ophthalmology and Visual Sciences, Division of Neurosurgery, QEII Health Sciences Centre, Michael P. Rabinowitz Dalhousie University, Room 2035, 2W Victoria Building, Wills Eye Institute, Oculoplastic Service, 1276 South Park Street, Halifax, NS, B3H 2Y9, Canada Th omas Jeff erson University, Philadelphia, PA, USA David H. Verity Geoff rey E. Rose Moorfi elds Eye Hospital, City Road, Moorfi elds Eye Hospital, Adnexal Service, City Road, London EC1V 2PD, UK London EC1V 2PD Lacrimal Clinic, Moorfi elds Eye Hospital, City Road, London EC1V 2PD, UK Aaron Savar Department of Head and Neck Surgery, Section of Ophthalmology, Th e University of Texas M.D. Anderson Cancer Center, Houston, Texas, USA

Michael P. Schittkowski Georg-August University, University Medical Center Goettingen, Department of Ophthalmology, Section for Strabismus, Neuroophthalmology and Oculoplastic Surgery R.-Koch-Str. 40 D 37075 Goettingen, Germany Chapter 1 Ocular Adnexal Lymphoproliferative Disease 1 Timothy J. Sullivan

Core Messages ■ Lymphoma is the most common orbital malig- ■ Computed tomographic (CT) images usually nancy, usually presenting clinically with a short show homogeneous, well-circumscribed lesions, history of painless swelling, proptosis, or a salmon molding to the globe, of greater than brain den- patch. Th e incidence of ocular adnexal lymphop- sity with moderate enhancement. Magnetic reso- roliferative disease Ocular adnexal lymphoprolif- nance imaging (MRI) lesions are isointense to erative disease (OALD) is increasing at 6% per extraocular muscles on T1- and T2-weighted year. Th e majority of adnexal lymphomas are images and show moderate enhancement with extranodal marginal zone lymphoma (EMZL) or gadolinium. Positron emission tomography mucosa-associated lymphoid tissue (MALT). (PET) scanning provides improved detection of ■ Chronic antigen stimulation and immunosup- the presence and extent of systemic involvement. pression, including ultraviolet (UV) irradia- ■ While radiotherapy remains the mainstay of tion, contribute to pathogenesis. Improvements treatment, management approaches are undergo- in molecular genetic techniques have led ing major changes. Treatments directed to reduce to more accurate diagnosis. Advances in imag- chronic antigen stimulation or to use immuno- ing mean our ability to stage the presence therapy or radioimmunotherapy result in greater and extent of systemic involvement has response to treatment as well as improved quality increased. of life and survival.

Th e annual incidence for mature B-cell neoplasms, Summary for the Clinician which form the largest subgroup of lymphoma, ranges ■ MALT lymphoma is the most common OALD. from 15/100,000 in the United States, Europe, and ■ MALT arises in response to chronic antigen Australia to only 1.2/100,000 in China [61]. stimulation, and increasing genetic aberrations While the overall incidence of lymphoma has been lead to malignancy. increasing annually by 3–4% per year for many decades ■ Molecular genetic testing with polymerase chain [22, 48], the rate of extranodal disease has been increas- reaction (PCR) and fl uorescent in situ hybridiza- ing at a greater rate [36, 50]. Within the extranodal sub- tion (FISH) is being routinely performed to com- group, OALD has shown the greatest increase in incidence plement morphological fi ndings to allow more at a rate of up to 6.3% per year [106, 116, 137]. OALD rapid accurate diagnosis of OALD. represents a spectrum, ranging from benign reactive lym- phoid hyperplasia (RLH) to malignant ocular adnexal lymphomas (OALs). Almost all OALs are B-cell NHLs. Malignant lymphomas represent neoplastic proliferation OALD disease has provided many challenges for the of cells predominantly located in lymphoid tissues. clinician and pathologist. Because of limitations in patho- Lymphoma can be broadly divided into non-Hodgkin logical techniques and understanding, previous workers lymphoma (NHL; 70%) and Hodgkin disease (30%) were unable to correlate clinical behavior with pathologi- [145]. Th ere are 65,000 new cases of NHL annually as cal diagnosis in between 20% and 50% of cases [77, 114, well as 19,000 deaths each year in the United States [83]. 115]. Th is mismatch applied to both benign-appearing 2 1 Ocular Adnexal Lymphoproliferative Disease

lesions, which followed an aggressive course, and frankly may occur, and T- and NK (natural killer) cell lympho- malignant orbital lesions on histology, which failed to dis- mas also occur rarely [27, 149, 156]. seminate [94, 96]. With the discovery in the early 1970’s [74, 75, 155], that separate B- and T- lymphocyte subsets existed and also through insights gained with electron 1 1.1 Pathogenesis microscopy [78], pathologists began to understand that lymphoma comprised many distinct entities. Unfortunately, Lymphomas represent a malignant, clonal proliferation of however, despite these advances, they were still unable to lymphocytes, although clonality does not always consti- correlate clinical behavior with morphological appear- tute malignancy. Th e various lymphoma subtypes largely ance. Th is only came with an appreciation of immunophe- correspond to clonal proliferations of cells arrested at notype and the use of the cluster of diff erentiation (CD) specifi c stages of lymphocyte development. Th is process nomenclature [37, 54, 74, 77, 94–97]. Th e fi rst CD discov- begins in the marrow with precursor B lymphoblasts, ered was B1, now known as CD20, a pan B-cell marker which undergo immunoglobulin VDJ recombination to and target for monoclonal antibody therapy. Th e applica- become surface immunoglobulin-positive naïve B cells tion of molecular genetics to pathological specimens [76, [99]. Th ese recirculating naïve B cells are found in blood, 80, 98, 108–110] has fi nally given pathologists the ability primary lymphoid follicles, and follicle mantle zones. to precisely defi ne the genetic aberrations underlying these Exposure to antigen leads to transformation to blast cells, lesions. which migrate into the center of the primary follicle, Shortly aft er extranodal lymphomas of MALT were establishing the germinal center by fi lling the follicular described elsewhere in the body [62, 68, 71, 72], similar dendritic cell meshwork, where they are now known as lesions were recognized in the orbit [76, 79] but had prob- centroblasts. BCL-6 is necessary for germinal center for- ably been described in the orbit prior to the systemic rec- mation, and then its downregulation is important for fur- ognition of this entity [78]. Since the early descriptions of ther lymphocyte development [21]. Here, the cells MALT lymphoma, a greater appreciation of the impor- undergo somatic mutations of the immunoglobulin vari- tance of this entity in the ocular adnexa has developed, able region gene and BCL-6 as part of the normal immune where it constitutes the majority of primary OALs [8, 15, response, eventually becoming centrocytes. Centrocytes 26, 84, 104, 113, 117, 153, 154]. Th ere were also problems interact with surface molecules to diff erentiate into mem- of applicability of existing classifi cation schemes to OALD ory B cells or plasma cells. Th e memory B cells are found because of an inability to incorporate extranodal lesions. in the marginal zone of the lymph follicle, whereas plasma Fortunately, the classifi cation in current use, the World cells home to marrow [61]. Health Organization (WHO) modifi cation of the Revised Th ere is site specifi city for the homing of postgerminal European American Lymphoma Classifi cation, recog- center B cells, orchestrated by adhesion molecules and nizes both extranodal disease and marginal zone MALT cytokines [122, 130]. Th us, MALT-derived B cells home lymphomas and is designed to accommodate new entities to their specifi c MALT and nodal B cells to specifi c lymph as further diagnostic progress elucidates additional sub- nodes. Corresponding to these stages of development, types [69, 73]. EMZL and lymphoplasmacytic lymphoma arise from OAL may be a primary process, arising within adnexal memory B cells and FLs and DLBCLs from the germinal structures, but it may also be secondary from primary center, whereas MCL arises from mature naïve B cells, lesions elsewhere in the body. Less commonly, the adnexa found in the mantle region of the lymph node. A range of may be involved by direct extension from primary lesions chromosomal translocations, deletions, and mutations in adjacent structures such as the sinuses. occurs during the diff erent phases of lymphocyte devel- OAL is usually subdivided into orbital, eyelid, con- opment, eventually establishing a clone of malignant cells. junctival, and lacrimal sac lesions. Most large series con- Th e clinical behavior of the tumor usually refl ects the fi rmed that EMZL of MALT comprise one half to two behavior of the normal cell counterpart. Th is corresponds thirds of OALs in Western countries and up to 90% in to the lymphocyte stage at which the abnormal cell has Asian communities, where the incidence of follicular accumulated suffi cient genetic abnormalities to prolifer- lymphoma (FL) is very low. Other common indolent ate without control or avoid programmed cell death, con- lesions include follicular (FL) and lymphoplasmacytic stituting malignancy. Malignant cell clones that have low lymphoma, while the two more common aggressive turnover produce indolent lymphomas such as MALT lesions are the diff use large B-cell lymphoma (DLBCL) and FL, whereas cell stages that are more active will give and Mantle cell lymphoma (MCL). Less commonly, other rise to more aggressive lesions such as MCL or DLBCL. A non-Hodgkin B-cell lesions (e.g., small cell lymphoma) small percentage of the low-grade lymphomas will 1.3 Immunosuppression 3 undergo transformation to a higher-grade lesion, for example, follicular and MALT lesions can transform into DLBCL. Th e most common OAL is the MALT lymphoma. Although the orbit itself has no lymph nodes or true lym- phatic drainage system, studies have confi rmed the pres- ence of small lymphatic channels associated with the optic nerve [55, 56]. Th ere is also a well-established ocu- lar MALT system extending from the lacrimal gland, encompassing the conjunctival tissues, and including the lacrimal drainage apparatus. Th is can be broken down into the conjunctiva-associated lymphoid tissue and lac- rimal drainage-associated lymphoid tissue (CALT and LDALT, respectively) with an overall designation of eye- Fig. 1.1 Clinical image showing conjunctival MALT lymphoma associated lymphoid tissue (EALT) [92, 93]. Lymphoid that had arisen in response to chronic antigen stimulation from chronic conjunctival infl ammation follicles from these tissues participate in the normal immune response to antigens with production of anti- bodies and eff ector plasma cells. While most OAL is with PCR techniques using universal bacterial primers MALT derived, presumably arising from these tissues, failed to detect bacterial DNA [107]. lymphocytes destined to reside in the EALT system pass Chlamydia causes chronic infections with inhibition of through the normal lymphocyte development cycle, and apoptosis and tumorogenic immunomodulatory eff ects this may explain why we see other primary B-cell lym- that predispose to lymphoma formation [14, 112, 138]. phomas in the ocular adnexal region. Lymphomas origi- Th e chronic systemic infection may be present for years, nating in ocular adnexal tissues can have systemic providing long-term chronic antigen stimulation. Th e lymphoid involvement of the marrow and other tissues. pathogen may elaborate antigens that lead to molecular Conversely, systemic lymphomas may involve adnexal mimicry, allowing the organism to be tolerated, while tissue secondarily. other factors contribute to chronic antigen stimulation of Primary ocular adnexal T- and NK cell lymphomas both humoral and cell-mediated responses, creating an may also be seen, but are less common, possibly refl ecting environment suitable for development of ocular adnexal the fewer gene rearrangements that occur in their normal MALT lymphoma. Ocular adnexal Mucosa Associated development compared to B lymphocytes [89]. Lymphoid Tissue (MALT) lymphomas show a limited number of similar VH gene segments, and analysis of the mutations in these VH gene segments also suggests chronic 1.2 Chronic Antigen Stimulation antigen stimulation plays a role in their development [9]. Chronic antigen stimulation and infectious agents have an important role in pathogenesis of lymphomas. Chronic 1.3 Immunosuppression low-grade infection and infl ammation may induce and promote carcinogenesis, altering DNA and providing a Immunosuppression has long had an association with carcinogenic environment bathed in cytokines and lymphoma development, which was underlined by growth factors [131]. Ocular adnexal MALT oft en devel- increased incidence of lymphoma paralleling the AIDS ops in a setting of chronic infl ammation [44] (Fig. 1.1) era [58]. Lymphoma associated with immunosuppression and has been shown to be associated with Chlamydia psit- tends to have a high prevalence of Epstein–Barr virus taci and a number of other pathogens [1, 41, 133]. Th ere (EBV), defects in immunoregulation, as well as abnormal is considerable regional variability with a number of stud- immunoglobulin and T-cell receptor gene rearrangement ies showing no association with Chlamydia [34, 66, 159]. during lymphopoiesis [46] Disorders of immunity such Th ere may be diff erent pathogens in diff erent regional as primary congenital immune defi ciency, ataxia telangi- locations predisposing to the development of ocular adn- ectasia, and Wiscott–Aldridge syndrome all predispose exal MALT lymphoma. For example, the hepatitis C virus to lymphoma development. Immunosuppressive therapy (HCV) has been detected in a small number of patients aft er organ transplantation is associated with a high rate with ocular adnexal MALT [43]. In contrast, analysis of of lymphoma, oft en with reduced latency and aggressive 49 cases of ocular adnexal MALT lymphoma from Florida behavior [23, 91]. Interestingly, environments with high 4 1 Ocular Adnexal Lymphoproliferative Disease

UV light exposure such as Australia and Florida have high rates of both nonmelanoma skin cancer and lym- phoma, suggesting a common role in immunosuppres- sion from UV light in these tumors [7, 106]. Th ere is good 1 epidemiological support for this hypothesis, but mecha- nisms remain unclear [2, 65, 86, 129].

1.4 Pathology Th e MALT-type OAL resembles MALT lymphoma else- where, comprised of morphologically small marginal zone cells, monocytoid cells, with occasional immuno- blasts, centroblasts, and small lymphocytes (Fig. 1.2). Th ere may be some plasmacytic diff erentiation and infi l- tration of epithelial tissues with malignant cells to form Fig. 1.3 MALT lymphoma. Hematoxylin and eosin ×400 show- ing a well-formed lymphoepithelial unit so-called lymphoepithelial units (Fig. 1.3 and 1.4). Dutcher bodies Periodic Acid-Schiff (PAS+ pseduointra- nuclear inclusions) are seen in about 25% of cases. Immunohistochemically, the cells are CD20 and CD79a+ and CD5 (95%), CD10, and CD23– [62, 68, 70–72]. Follicular lymphoma recapitulates the normal follicle formation with tumor cells but with poor defi nition, absence of mantle zone, and eff acement of normal archi- tecture with tumor cells (Fig 1.5). Th ese cells are of two types, small cleaved centrocytes and larger noncleaved centroblasts. Th ey are positive for pan B-cell markers CD19, CD20, CD22, and CD79a; are Bcl2+; and express germinal center markers BCL6, CD38, and CD10, but are CD5 and CD43− [11]. DLBCL diff usely involves tissues with a monotonous proliferation of large neoplastic B cells with large nuclei, which most commonly resemble centroblasts. Again, Fig. 1.4 MALT lymphoma. Cytokeratin stain ×400 highlight- they are usually positive for pan B-cell markers CD19, ing the epithelial component in a lymphoepithelial unit

CD20, and CD79a and may be CD5+, although they do not express cyclin D1, in contrast to MCL. Mantle cell lymphoma can show somewhat nodular patterns but with loss of normal architecture and infi ltra- tion by abnormal centrocyte-like cells, without blast forms (Fig. 1.6). Th ey have a characteristic immunophenotype with CD5+ and CD43+ and BCL6 and CD10– (Fig. 1.7). Th ey are all bcl2 and cyclin D1+ (Fig. 1.8). T-cell lesions include a broad range of subtypes but are typically CD20− and CD3+.

1.5 Cytogenetics Th e acquisition of genetics aberrations in lymphocytes Fig. 1.2 MALT lymphoma. Hematoxylin and Eosin ×400 show- causes clonal cell proliferation and suppression of apop- ing predominantly small marginal zone cells and monocytoid totic mechanisms, immune suppression, and altered cell cells with occasional centroblasts and small lymphocytes signaling functions, which result in tumor initiation, 1.5 Cytogenetics 5

Conventional cytogenetics, usually performed with cell culture of a single-cell suspension from a mechani- cally disrupted lymph node, is not always rewarding due to diffi culty in establishing a culture, low mitotic rates for many of the chronic and indolent lesions, and a poor response to mitogens. Southern blot methods are used but are labor intensive and time consuming, restricting their use in a routine setting. PCR techniques are usually the initial molecular diagnostic test in most pathology laboratories for assessment of lymphoid lesions. Th ey can be performed quickly using DNA or RNA as templates, on small amounts of tissue, which may be fresh, fi xed, or archival [143]. FISH uses labeled DNA probes that hybridize to sequences of interest, allowing detection of structural and numerical chromosomal abnormalities. Fig. 1.5 Follicular lymphoma histology. Hematoxylin and eosin Th ere are a wide variety of commercially available FISH ×400, showing eff acement of normal architecture with tumor cells. Most cells are small cleaved centrocytes, with occasional probes that are routinely used in lymphoma diagnosis in larger noncleaved centroblasts most laboratories [16]. Multiple chromosomal targets can be assessed with multicolor FISH (M-FISH) and spectral promotion, and growth. Th e delicate balance between karyotyping (SKY). Comparative genome hybridization oncogenes and tumor suppressor genes becomes altered, (CGH) permits analysis of DNA sequence copy number leading to lymphoid malignancy. to detect loss or gain across the genome. Complementary Certain cytogenetic abnormalities are characteristi- DNA (cDNA) microarray testing allows gene expression cally seen in diff erent lymphoma types. Th e fi rst abnor- profi ling of lymphomas, which may be useful to correlate mality to be detected was the 8;14 translocation seen in clinical behavior, response to treatment, and prognosis Burkitt’s lymphoma, using standard karyotypic methods. with improved lymphoma diagnosis [143]. Not all of Since that time, there have been many advances in molec- these modalities are currently in routine laboratory use, ular genetics, allowing more refi ned diagnosis of OALDs. but they will have increasing importance as more data are Molecular testing is important to establish clonality and assembled on their application. to establish a diagnosis. Th is is relevant in OALD to dif- Looking at OALD, the most common lesion is the ferentiate between small B-cell lymphomas (such as EMZL of MALT type. Th ese lymphomas show a range of MALT, FL, chronic lymphocytic lymphoma (CLL)/small cytogenetic abnormalities that vary from those seen in lymphocytic lymphoma (SLL) MCL). Certain cytoge- MALT lesions elsewhere in the body. Th ese include netic abnormalities may also point to prognosis or t(11;18)(q21;q21) of the API2 and MALT1 genes (occurs response to particular treatments. in 0–10% ocular adnexal MALT lymphoma); t(14;18)

Fig. 1.6 Mantle cell lymphoma histology. Hematoxylin and eosin ×400, showing loss of normal architecture and infi ltration Fig. 1.7 Mantle cell lymphoma histology ×400 showing strongly by abnormal centrocyte-like cells positive CD5 immunostain 6 1 Ocular Adnexal Lymphoproliferative Disease

(q32;q21) of the IGH and MALT1 genes (occurs in 7–11% morphologically and immunohistochemically diff erent ocular adnexal MALT lymphoma); t(1;14)(p22;q32) of centroblastic and immunoblastic subtypes of DLBCL [51]. the Bcl-10 and IGH genes (not reported to occur in ocu- Th ere are at least three distinct entities grouped together lar adnexal MALT lymphoma); and t(3;14)(p14;q32) of under the DLBCL banner based on distinct chromosomal 1 the FOXP1 and IGH genes (not reported to occur in ocu- imbalances. Th ese are germinal center B-cell-like (best lar adnexal MALT lymphoma) [136]. Th ese diff erent prognosis), activated B-cell-like (intermediate-to-poor abnormalities result in activation of the transcription fac- prognosis), and a poor prognosis non-germinal center tor NF-κB (nuclear factor kappa B), which upregulates B-cell-like (non-GCB-like) non-ABC-like subgroup [32]. various proliferation genes in B cells [87]. Other abnor- Mantle cell lymphoma develops from a combination malities seen include trisomy 3 (occurs in 40–60% of of dysregulation of cell proliferation and survival path- ocular adnexal MALT lymphoma) and trisomy18 (occurs ways with a high level of chromosome instability. Th e in 14–50% of ocular adnexal MALT lymphoma) [146]. genetic hallmark of MCL is the t(11;14)(q13;q32) translo- Th e incidence of these cytogenetic abnormalities varies cation that juxtaposes CCND1, at chromosome 11q13, to greatly, with MALT lymphomas derived from diff erent the immunoglobulin (Ig) heavy chain gene at chromo- tissues (e.g., gastric, lung, skin, and ocular adnexa [101]. some 14q32 [82]. CCND1 is a proto-oncogene that Interestingly, given the low percentage of ocular adnexal encodes cyclin D1, resulting in cyclin D1 overexpression. MALT lymphomas showing the aberrations common in Th is translocation occurs in the bone marrow in an early other MALT lymphomas, there may be other as-yet- B cell at the pre-B stage of diff erentiation when the cell is undiscovered abnormalities associated with this entity. initiating the Ig gene rearrangement with the recombina- Follicular lymphoma develops from centrocytes and tion of the VDJ segments. Th e cell of origin is a mature B centroblasts of the germinal centers that fail to undergo cell found in the mantle region of normal lymphoid fol- apoptosis because BCL2 expression is preserved as a licles. Although the initial translocation occurs in imma- result of the initial t(14;18) chromosomal rearrangement ture B cells in the marrow, the oncogenic advantage is [61]. Additional genetic alterations occur, leading to FL, realized only when additional genetic aberrations occur which may have a better or worse prognosis, depending as the cell matures into a naïve pregerminal center B cell on which secondary alterations take place [11]. [82, 139]. Diagnosis of this small cell lymphoma can be We have already learned that BCL6 plays an important confi rmed by immunohistochemical staining for cyclin role in germinal center formation and subsequent lym- D1 and with FISH techniques (Fig. 1.9) [24]. phocyte development. Failure to downregulate BCL6 aft er T-cell malignancies comprise two main groups: pre- affi nity maturation may be lymphomagenic [21, 81]. cursor T-cell lymphoblastic neoplasms, derived from BCL6 is necessary for survival of human DLBCL cells. maturing thymocytes, and peripheral T-cell lymphomas DLBCL commonly shows alterations of the BCL6 gene at (PTCLs), arising from mature postthymic T cells (Figs. the 3q27 locus, but other complex karyotypes may be 1.10 and 1.11). Physiological T-cell development is regu- seen [51]. Th ese diff erent abnormalities may explain the lated by numerous oncogenes and oncogenic pathways, suggesting a balance between normal diff erentiation and malignant transformation [4]. Th e molecular pathogene- sis of T-cell lymphomas is still poorly understood, but it is recognized that there are oft en complex karyotypic abnormalities present [3].

Summary for the Clinician ■ OAL usually presents with a short history (5–7 months) of painless proptosis or a salmon patch. ■ MRI and CT are both useful, with MRI showing soft tissue involvement better and CT showing bone changes better. ■ PET scanning has an important role in the sys- temic staging of OAL, but CT and MRI show the Fig. 1.8 Mantle cell lymphoma histology ×400 showing strongly orbital disease better. positive cyclin D1immunostain 1.6 Clinical Features 7

1.6 Clinical Features Patients with OALD may present with a range of symp- toms and signs. Proptosis, eyelid swelling, a palpable mass or conjunctival salmon patch, are common [35, 149]. Less frequently, patients may show visual disturbance (e.g., diplopia, visual loss), pain, or infl ammation and occa- sionally dacryocystitis [85, 149] (Figs. 1.12 and 1.13). Pain and infl ammation tend to be associated with more aggressive histologies. Th e typical patient is in the sixth or seventh decade, and there may be a history of autoim- mune disease or thyroid eye disease [45, 85, 120, 149]. Th ere does not appear to be any sex predilection, with some series having almost equal sex distribution [85] and others showing a slight female [45, 149] or male [35] Fig. 1.9 Mantle cell lymphoma diagnosed rapidly by FISH predominance. using an IGH/CCND1 dual-color, dual-fusion translocation probe. Th e IGH probe is labeled with spectrum green, and the CCND1 probe is labeled with spectrum orange. Th e mantle cells can be seen as background shadows containing the t(11;14) (q13;q32) translocation shown by the fused green/orange nuclei (arrows)

Fig. 1.12 Clinical appearance of left orbital MALT lymphoma showing left proptosis Fig. 1.10 NK T-cell lymphoma histology showing tumor invad- ing small vessel. Hematoxylin and eosin ×400

Fig. 1.13 Clinical appearance of mantle cell lymphoma show- Fig. 1.11 NK T-cell lymphoma histology CD56 stain ×400 ing right conjunctival salmon patch 8 1 Ocular Adnexal Lymphoproliferative Disease

1.7 Imaging Findings Th e classic descriptions of early articles on the CT appearance of OALD are still current. Yeo et al. stated 1 that these lesions molded or plastered themselves to pre- existing orbital structures, such as the globe, extraocular muscles, lacrimal gland, or bony orbital walls, without eroding bone or enlarging the orbit (Fig. 1.14). Where lymphoid tumors abutted orbital fat, they adopted a streaky profi le, presumably due to irregular infi ltration refl ecting involvement of microfascial structural ele- ments [158]. Th e molding pattern has also been described as “puttylike” or having a pancake contour, following the fascial planes of the orbit [63, 134]. Other typical CT fea- tures include circumscription, homogeneity, greater than Fig. 1.15 Coronal CT DLBCL arising in the right lacrimal sac brain density, and moderate enhancement. Atypical showing the bone destruction commonly seen in DLBCL appearances that show an infi ltrative pattern, are inho- mogeneous, or have calcifi cation or bone changes may also be seen [147] (Fig. 1.15). Investigators have generally been unable to correlate clinical behavior with imaging appearance [126, 147, 152]. One study showed a statistically signifi cant association between the CT appearance of molding and indolent his- tology [147]. Bone destruction has been associated with DLBCL by a number of authors [84, 134, 147]. Magnetic resonance imaging studies are complemen- tary to CT, possibly showing extraorbital extension and central nervous system (CNS) involvement better than CT but not showing bony changes as well as CT. OALD lesions are usually isointense to extraocular muscle on both T1-and T2-weighted MRI images and show moder- ate enhancement with gadolinium in the majority of cases [35, 134, 147] (Figs. 1.16 –1.18). Th e imaging features of Fig. 1.16 T1-weighted MRI showing follicular lymphoma R lac- PET are considered in the staging section. rimal gland with no response to systemic chemotherapy

Fig. 1.14 Coronal CT MALT lymphoma showing molding of Fig. 1.17 T2-weighted fat saturation MRI follicular lymphoma left lacrimal gland to the globe R lacrimal gland from the same patient as Fig. 1.16 1.10 Treatment 9

1.9 Positron Emission Tomography Th e role of PET in staging, restaging, treatment moni- toring, and follow-up of lymphoma is well accepted but is constantly evolving [6, 67]. Nearly all PET scanners sold currently are combined PET–CT scanners, giving functional and anatomic correlation and a diagnostic advantage over either PET or CT alone [5]. PET utilizes the decay physics of positron-emitting isotopes, with 18F-fl uorodeoxyglucose (18F-FDG) the most common PET tracer [88]. Increased glucose metabolism is a hallmark of malignancy, and this can be quantifi ed by fl uorine-18 labeling of FDG, a glucose analogue, which becomes trapped within tumor cells. Positron emission by 18F is then detected by the PET scanner [6]. Fig. 1.18 T1-weighted fat saturation MRI with gadolinium, fol- Th e application of PET to extranodal disease such as licular lymphoma R lacrimal gland from the same patient as OALD, including EMZL and MALT lymphoma, is still Figs. 1.16 and 1.17. Post rituximab, showing good response to being defi ned [52, 123] (Fig. 1.19). Th ere are a small num- immunotherapy, having failed chemotherapy ber of studies reporting the application of PET to OALD [18, 57, 128, 147, 151]. PET is superior to CT in detecting systemic disease associated with OALD and can result in the upstaging of disease by detecting systemic disease not 1.8 Staging detected by conventional imaging, which may have impli- cations for treatment and outcome (Fig. 1.20). PET does Although a diagnosis of OALD might be suspected on have some limitations in detecting disease in the orbit due the basis of clinical fi ndings and imaging studies, tissue to the small volume of orbital disease as well as background analysis using the techniques described is necessary for physiological uptake of the extraocular muscles and the confi rmation and to allow classifi cation of the lym- frontal lobes [147, 151]. One important role of PET is in phoma. Once a diagnosis of OALD has been estab- the distinction between viable tumor and necrosis or fi bro- lished, the patient should be referred to an oncology sis in residual masses [88]. PET has also been shown to center familiar with the management of hematological have a role as an adjunct to conventional imaging in evalu- malignancy. Systemic investigation and staging, accord- ating the response to treatment in OALD [57]. ing to the Ann Arbor system, should be performed [17]. Th is is also true of reactive lymphoid hyperplasia (RLH) and atypical lymphoid hyperplasia (ALH) as a 1.10 Treatment proportion of these will have systemic involvement with lymphoma. A full medical history, including any Th ere are currently no universally accepted guidelines for prior hematological malignancy, autoimmune disease, the management of OALD. Treatment options for many or history of thyroid eye disease should be taken. decades mainly consisted of external beam radiotherapy Clinical examination should include palpation of lymph nodes, liver, and spleen. Blood tests, including com- plete blood counts with cytologic examination, protein Summary for the Clinician electrophoresis, lactate dehydrogenase, and beta-2-mi- ■ Long-term follow-up showed there is an overall croglobulin levels; evaluation of renal and hepatic func- 25% mortality with OAL. tion; and serology for HCV and HIV infections. Bone ■ Radiotherapy remains the most common treat- marrow analysis is mandatory, and many advocate ment for primary OAL. bilateral iliac crest samples. Chest radiographs and ■ Th e advent of immunotherapy has seen a major imaging of the cervical region, thorax, abdomen, and change in treatment of OAL and is being used alone pelvis should be performed. While this has previously or in combination with systemic chemotherapy. been performed utilizing CT images, increasingly, ■ Radioimmunotherapy off ers even more targeted combined PET–CT scans are being used for initial therapy and is currently under investigation. staging. 10 1 Ocular Adnexal Lymphoproliferative Disease

1

Fig. 1.19 PET CT scan showing right lacrimal gland FDFG avid MALT lymphoma (cursors)

and chemotherapy. Th ere has been a paradigm shift last 5 extraorbital spread and tumor-related death were more years since 2004 with the application of immunotherapy common with bilateral adnexal disease, a fi nding con- and radioimmunotherapy to the management of lym- fi rmed by other authors [35, 149]. Th is is in contrast to phoma. Th ere is no doubt that the management approach earlier studies in which bilateral adnexal disease was not in 5 years will be very diff erent from that in the recent felt to have had an eff ect on extraorbital spread [76]. past. Advanced age, stage at presentation, aggressive histology, General principles of management should be evidence and tumor growth cell fraction are also associated with a based, considered broadly, and then applied to the indi- poorer prognosis [26–28, 84, 85, 149]. vidual case. Th ere are factors that relate to the patient (e.g., Decaudin et al. recommend combined immunother- age, comorbidities, performance) and to the tumor (histo- apy and chemotherapy (rituximab, cyclophosphamide, logical type, stage, and site of involvement) as well as the adriamycin, vincristine, and prednisone, R-CHOP) if impact on the eye from treatment that will infl uence the there are perjorative prognostic factors present, radio- management approach [44, 144]. Ocular adnexal disease therapy if there are no perjorative factors but there is can be broadly divided into more indolent lymphoma visual threat, and a range of treatments can be consid- subtypes (e.g., MALT, follicular, small cell lymphoma) and ered if there are no perjorative factors and no visual aggressive disease processes (DLBCL, MCL, and T- and threat. Th ese treatments include radiotherapy, immuno- NK cell lesions). Th ere are international prognostic indi- therapy with the monoclonal anti-CD20 antibody, ritux- cators for aggressive disease and for FL [135, 141]. imab, chlorambucil, antimicrobial therapy, and a Various clinical, histopatholoical, immunophenotypic, “wait-and-see” approach for the elderly and frail with and other markers have been found to infl uence the prog- comorbidities [33]. nosis and outcome of OALD. Assessing 326 patients with Before looking at individual treatment modalities, OAL, Jenkins et al. found that a greater than 1-year his- some comments are relevant for diff erent lymphoma cat- tory of adnexal involvement was associated with less like- egories. One emerging principle of management in the lihood of disseminated disease [85]. Th ey also found management of MALT lymphoma is to reduce or 1.13 Radiotherapy 11

disease should be treated with involved fi eld radiother- apy (IFRT), and the addition of chemotherapy does not change survival. If disease is widespread, palliation is the aim, and initial management may be conservative. Treatment is initiated when there is bulky disease (>7 cm), more than three nodal groups are involved, or the patient has B symptoms or symptomatic splenom- egaly [140]. Usually, this will be with combined ritux- imab and chemotherapy. Locoregional IFRT may be considered and is appropriate for ocular adnexal involve- ment. Radioimmunotherapy with 90Y-ibritumomab tiuxetan or 131I-tositumomab is also possible and is currently being evaluated. Advanced multiply relapsed disease may be treated with autologous stem cell transplant. Newly diagnosed DLBCL patients are treated with curative intent. While cyclophosphamide, adriamycin, vincristine, and prednisone (CHOP) is the preferred chemotheraputic regime, R-CHOP has been shown to improve survival in a number of randomized controlled trials [25, 47, 60, 124, 125].

1.12 Mantle Cell Lymphoma Th e majority of ocular adnexal cases are secondary. R-CHOP for systemic MCL is associated with a 50% response rate, with duration of eff ect of less than 2 years. Fig. 1.20 PET scan showing systemic involvement with MALT lymphoma Th is lesion usually requires aggressive treatment with alternating or sequential non-cross-reacting chemother- apy regimes, giving a remission rate of 90%. Despite con- eliminate the chronic antigen stimulus and eradicate any solidation treatment with chemotherapy and autologous local infective cause. Th is has been shown to be of benefi t stem cell transplantation, overall 5-year disease-free sur- in gastric MALT lymphoma with elimination of vival is around 50% [40, 84, 90, 100, 102, 149]. One prom- Helicobacter pylori resulting in regression or remission in ising recent report of 21 cases of orbital or adnexal MCL 50–80% of patients [157]. Because the association with found 80% 5-year survival in patients treated with ritux- Chlamydia and other infective agents is not as clear in imab and chemotherapy compared with an 8% 5-year ocular adnexal MALT lymphoma, blind anti-Chlamydia survival in patients not treated with rituximab [127]. therapy is not recommended but could be considered if a T-cell lymphomas are a diverse group of poorly under- chlamydial infection has been proved in geographical stood entities that may rarely behave moderately aggres- areas where associated chlamydial infection has been sively and be curable, but more commonly they are demonstrated [1, 41, 59, 66]. aggressive and associated with a poor outcome. Th e ocu- lar adnexa may be involved secondarily or less frequently as a primary process [27, 84, 149, 156]. 1.11 Follicular Lymphoma Because FL can transform into DLBCL with accumu- 1.13 Radiotherapy lated genetic mutations, staging is critical to identify whether this has occurred. 18F-FDG PET has a special Having said all this, radiotherapy is currently the most role when the most intense focus on PET should be common fi rst-line treatment for primary OALD biopsied to look for any such transformation. If the pro- (Figs. 1.21 and 1.22). Superfi cial conjunctival and anterior cess has not transformed, staging is important. Localized orbital lesions are usually treated with electron beams,