Clinical Ophthalmic Oncology: Basic Principles

Preface
Acknowledgments
Contents
Contributors
1: Principles of Cancer Epidemiology
	Introduction
	Research Question
	Outcome Measures
		Prevalence
		Incidence
		Mortality
		Time to Event
		Surrogate Endpoints
		Quality of Life
	Measures of Association
		Relative Risk
		Hazard Ratio
		Odds Ratio
		Differences in Risk
		Differences in Mean Score
	Precision of the Estimate
	Bias
		Confounding
		Selection Bias
		Information Bias
	Study Designs
		Case Series
		Cross-Sectional Study
		Cohort Study
		Randomized Controlled Trial
		Case-Control Study
		Pilot Study
		Systematic Review
	Conclusions
	References
		Further Readings
2: Etiology of Cancer
	Introduction
	Carcinogenic Agents
	Chemical Carcinogens
		Environmental Exposure
		Behavioral Exposure
			Tobacco
			Alcohol
	Electromagnetic Radiation
		Ultraviolet Light
		Ionizing Radiation (X-Rays and Gamma Rays)
	Infections Agents
		Viruses
			Human Papillomavirus (HPV)
			Epstein-Barr Virus
			Kaposi Sarcoma Herpes Virus
			Human T-Cell Lymphotropic Virus-1
			Hepatitis B and C Virus
		Bacteria
			Helicobacter pylori
			Chlamydia psittaci
		Fungus
		Parasites
	Immune Evasion
	Dietary Factors
	Genetic Susceptibility
	Iatrogenic Cancers
		Immunosuppression
		Chemotherapy
		Radiation Therapy
	Summary
	References
3: Cancer Pathology
	Introduction
	Classification of Neoplasia
		Benign Tumors
		Malignant Tumors
	Tumorigenesis
		Genomic Instability and Mutations
		Evading Immune Destruction
		Proliferative Signaling and Reprogramming Energy Metabolism
		Resisting Growth Suppressors
		Escaping Cell Death
		Replicative Immortality
		Angiogenesis
		Invasion and Metastasis
		Box 3.1 Steps in Metastatic Process
		The Tumor Microenvironment
	Microscopic Features of Neoplasia
		Cellular Proliferation
		Cellular Pleomorphism
		Cellular Differentiation
		Nuclear Cytoplasmic Ratio
		Invasion of Surrounding Tissues
		Tumor Infiltration by Normal Cells
	Tissue Sampling and Processing
		Cytological Sampling
			Exfoliative Cytology
			Aspiration Cytology
			Histopathologic Sampling and Processing
	Diagnostic Techniques
		Light Microscopy
		Immunohistochemistry
		Additional Techniques
	References
4: Pathology Specimen: Handling Techniques
	Introduction
	Pathological Specimen Handling in Theatre Before Fixation
		Multiple Biopsies from a Surgical Procedure
		Orientation of Specimens
		Conjunctival Mapping Biopsies
		Tissue Handling for Frozen Sections
		Sampling Fresh Tissue Prior to Fixation
	Fixation of Ocular Pathology Specimens [1–7]
		Surgical Tumour Specimens
		Fine-Needle Aspiration (FNA) Specimens [8–13]
		Vitrectomy Specimens [8–13]
		Impression Cytology Samples
		Specimens Requiring Electron Microscopy
	The Ophthalmic Pathology Request Form [14]
	Transporting Specimens to the Pathology Laboratory
	Handling Ophthalmic Surgical Specimens in the Pathology Laboratory [1–7]
		Eyelid Skin Tumour Resections
		Mapping Biopsies
		Frozen Tissue Handling
		Local Resection of Intraocular Tumours
		Enucleation Specimens for Intraocular Tumours
		Exenteration Specimens for Tumours
		Cytology Handling [8–13]
			Impression Cytology
			FNAs
			Vitreous Samples
	References
5: Cancer Angiogenesis
	Introduction
	Tumor Angiogenesis
		Cooption
		Angiogenic Switch
	Steps in Angiogenesis
	Tumor Vessels
	Metastatic Cascade
	Promotors of Angiogenesis
		Vascular Endothelial Growth Factor
			Functions
			Subtypes (VEGF A)
			VEGF Receptors
			Regulation of VEGF
				Hypoxia
				Other Factors
		Fibroblast Growth Factor
		Angiopoietins
		Matrix Metalloproteinases (MMPs)
	Inhibitors of Angiogenesis
		Endogenous
			Thrombospondin
			Angiostatin
			Endostatin
		Pharmaceutical
			Anti-VEGF Agents
				Bevacizumab (Avastin®)
				Ranibizumab (Lucentis®)
				Pegabtanib (Macugen®)
				Aflibercept (Eylea®)
				SU5416, Semaxanib
				Cox-2 Inhibitors (Celecoxib, Nepafenac/Amfenac)
				Trastuzumab (Herceptin®)
				Interferon-α2a
	Antiangiogenic Therapy in Clinical Practice
	Angiogenic Aspects of Specific Ophthalmic Tumors
		Retinoblastoma
			Treatment
		Uveal Melanoma
			Pseudovascular Channels (Vasculogenic Mimicry)
			Microvessel Density
			Tumor Ingrowth into Blood Vessels
			Indocyanine Green Angiographic Patterns
			VEGF Expression
				Metastatic Uveal Melanoma
			Treatment
				Radiation Retinopathy
				Metastatic Uveal Melanoma
		Von Hippel-Lindau Disease
			Treatment
			Hemangioma of the Eyelid
				Treatment
		Conjunctival Squamous Cell Carcinoma (SSC)
			Treatment
	Conclusions
	References
6: Immunology of Ocular Tumors
	Introduction
	Innate and Specific Immune Responses
	Immunological Escape
	Immunological Aspects of Uveal Melanoma
		Immune Responses Against UM in Humans
		HLA Antigen Expression
		Leukocyte Infiltrate
		Previously Irradiated Tumors
		Immunotherapy
			Ipilimumab
			Programmed Death-Ligand 1
			Interferon Alpha-2b
			Dendritic Cell Therapy
		Immune-Related Response to Therapy
	Conclusions
	References
7: Cancer Genetics
	Introduction
	Proliferation and the Cell Cycle
		Growth Factor Signaling Pathways
		Rb-p16Ink4a-Cyclin D Pathway
		MYC Family of Oncogenes
	Apoptosis and Senescence
		p53 and MDM2
		Bcl-2
		Telomere Maintenance
		BRCA and BAP1
	Splicing Factor Mutations
	Angiogenesis
		VEGF
		HIF/VHL
	Epigenetics
	Conclusions
	References
8: Cancer Staging
	Introduction
	History
	Purposes of Staging
		Prognostic Relevance
		Therapeutic Relevance
		Research Relevance
	Summary
	References
9: Principles of Cryotherapy
	Introduction
	Mechanism of Tissue Injury
		Direct Effects
		Indirect Effects
	Technical Aspects
		Tissue Temperature
		Cooling Rate
		Freeze-Thaw Cycle
		Number of Repetitions
	Indications
		Eyelid Tumors
		Conjunctival Tumors
		Intraocular Tumors
		Orbital Tumors
	Techniques of Cryotherapy
		Eyelid Tumors
		Conjunctival Tumors
		Intraocular Tumors
	Complications
	Conclusions
	References
10: Principles of Laser Therapy
	Introduction
	Laser Effects on Tissues
		Photothermal Effects
		Photochemical Effects
		Photomechanical Effects
	Types of Ophthalmic Lasers
	Treatment Variables
	Laser Delivery Systems
	Techniques of Ophthalmic Laser Therapy
	Summary
	References
11: Principles of Radiation Therapy
	Introduction
	Basic Principles
		Dual Nature of Radiation
			Electromagnetic Radiation
			Particle Radiation
		Radioactive Decay
		Ionizing and Nonionizing Radiation
	Teletherapy Sources
		Cobalt-60 Unit
		Linear Accelerator
		Cyclotron
	Radiation Parameters
		Radiation Dose
		Relative Biological Effectiveness
		Cobalt Gray Equivalents
	Treatment Parameters
		Target Volume
		Total Dose
		Fractionation
		Tissue Tolerance
	Teletherapy Techniques
		External Beam Therapy
		Conformal Radiation Therapy
		Three-Dimensional Conformal Therapy
		Intensity-Modulated Radiation Therapy
		Stereotactic Radiosurgery
			Linac-Based Stereotactic Radiosurgery
			Treatment Delivery
			Gamma Knife Radiosurgery
	Charged Particle Therapy
	Brachytherapy
	Summary
	References
12: Ocular Complications of Radiotherapy
	Introduction
	Periorbital Skin
	Conjunctiva
		Cornea
			Radiation-Induced Dry Eye and Keratitis
			Treatment
			Scleral Necrosis
			Extraocular Muscles
			Dose Relationship
			Treatment
		Iris
			Radiation-Induced Iris Neovascularization and Neovascular Glaucoma
			Treatment
		Lens
			Clinical Features
			Dose Relationship
			Treatment
		Radiation Retinopathy
			Clinical Features
			Dose Relationship
			Treatment
			Preventive Strategies
		Radiation Optic Neuropathy
			Clinical Features
			Dose Relationship
			Treatment
			Toxic Tumor Syndrome
	Conclusions
		Box 12.1. Salient Features of Radiation Retinopathy
	References
13: Principles and Complications of Chemotherapy
	Introduction
	Basic Principles of Chemotherapy
		The Cell Cycle
		Mechanisms of Action
		Dose Intensification of Chemotherapy
	Clinical Pharmacology of Chemotherapeutic Agents
		Pharmacokinetics
		Drug-Drug Interactions
		Chemotherapy Resistance
	Multimodal Therapy
		Adjuvant Chemotherapy
		Neoadjuvant Chemotherapy
	Commonly Used Chemotherapeutic Agents in Ophthalmologic Cancers
		Systemic Treatment of Orbital Lymphoma
		Systemic Treatment of Orbital Melanoma
		Systemic Treatment of Retinoblastoma
		Systemic Treatment of Orbital Rhabdomyosarcoma
	Toxicities of Cytotoxic Chemotherapy
	Summary
	References
14: Ocular Complications of Targeted Therapy
	Introduction
	Specific Agents
		Tyrosine Kinase Inhibitors
		Epidermal Growth Factor Receptor Inhibitors
		Inhibitors of Angiogenesis
		mTOR Pathway Inhibitors
		Anaplastic Lymphoma Kinase (ALK) Inhibitors
		Mitogen-Activated Protein Kinase RAS-RAF Signaling Pathway
		Immunotherapy
	Conclusions
	References
15: Counseling Patients with Cancer
	Introduction
	Challenges Faced by Patients with Eye Cancer
	Emotions and Fears
		Box 15.1 Patients’ Emotions and Fears When Informed of Their Diagnosis and Treatment
	Coping Mechanisms
	Patients’ Needs
		Box 15.2 Patients’ Emotional Needs
	Eliciting and Addressing Patients’ Emotional Needs
	Communication
		Box 15.3 Requirements for Effective Communication
	Decision-Making
	Psychological Support
	Patient-Reported Outcome Measures (PROMs)
	Self-Help
	Family Support
	Support from Patient Organisations
	Children with Cancer: What Should They Be Told?
	Conclusion
	References
16: Tumor-Associated Cataract
	Introduction
	Surgical Treatment-Induced Cataract
	Radiation-Induced Cataract
	Chemotherapy- and Hormonal Therapy-Induced Cataract
	Specific Entities
		Medulloepithelioma
		Retinal Lymphoma
		Retinoblastoma
		Uveal Melanoma
		Uveal Metastases
	Perioperative and Intraoperative Considerations
	Summary
	References
17: Tumor-Associated Glaucoma
	Introduction
	Pathogenesis
		Open-Angle Glaucoma
		Angle-Closure Glaucoma
	Clinical Features
	Diagnostic Evaluation
	Specific Entities
		Childhood Glaucoma
			Sturge-Weber Syndrome
			Neurofibromatosis Type 1
			Von Hippel-Lindau Disease
			Juvenile Xanthogranuloma
			Medulloepithelioma
		Adult Glaucoma
			Iris Stromal Cysts
			Melanocytoma
			Fuchs Adenoma
			Uveal Melanoma
			Metastatic Tumors
			Leukemia/Lymphoma
			Myelodysplastic Syndrome/Multiple Myeloma
	Treatment
	Summary
	References
18: Graft-Versus-Host Disease
	Introduction
	Etiology
	Pathogenesis
	Classification of GVHD
		Acute GVHD
		Chronic GVHD
	Clinical Ophthalmic Features
		Ocular Surface Manifestations
		Symptoms and Signs
		Target Tissues
			Lacrimal Glands
			Meibomian Glands
			Conjunctiva
			Cornea
	Diagnostic Evaluation
	Differential Diagnosis
	Treatment of Systemic GVHD
		Biomarkers in Serum and Tears
		Prevention of Systemic GVHD
		Treatment of Established Systemic GVHD
	Treatment of Ocular GVHD
		Topical Lubricants
		Topical Corticosteroids
		Topical Cyclosporine A
		Tacrolimus
		Autologous Serum Eye Drops
		Contact Lenses
	Cataract Surgery in cGVHD
	Follow-Up
	Prognosis of GVHD
		Systemic GVHD
		Ocular GVHD
	References
19: Diagnostic Techniques: Angiography
	Introduction
	Basic Principles
	Anterior Segment Tumors
		Iris Tumors
		Iris Hemangioma
	Retinal Tumors
		Retinoblastoma
		Retinal Vascular Tumors
			Retinal Hemangioblastoma (Retinal Capillary Hemangioma)
			Retinal Vasoproliferative Tumor
			Cavernous Hemangioma
			Racemose Hemangioma (Retinal Arteriovenous Malformation)
		Retinal Astrocytic Hamartoma
		Retinal Pigment Epithelial Tumors
	Choroidal Tumors
		Choroidal Nevus
		Choroidal Melanoma
		Melanocytoma
		Choroidal Hemangioma
		Choroidal Osteoma
		Choroidal Granuloma
		Choroidal Metastatic Tumors
		Choroidal Lymphoma and Vitreoretinal Lymphoma
	Simulating Conditions
		Coats’ Disease
		Persistent Hyperplastic Primary Vitreous/Persistent Fetal Vasculature
		Scleritis
		Central Serous Chorioretinopathy (CSCR)
		Polypoidal Choroidal Vasculopathy (PCV)
		Uveal Effusion Syndrome
		Paraneoplastic Disorders
		Radiation Retinopathy
	References
20: Diagnostic Techniques: OCT
	Introduction
		Enhanced Depth Imaging
		Swept-Source OCT (SS-OCT)
		Optical Coherence Tomography Angiography
	Conjunctival and Corneal Tumors
	Scleral Lesions
	Anterior Uveal Tumors
	Intraocular Tumors
		Retinal Pigment Epithelial Tumors
		Retinal Tumors
			Retinal Astrocytic Hamartoma
			Retinoblastoma
			Primary Vitreoretinal Lymphoma
			Retinal Cavernous Hemangioma
			Retinal Capillary Hemangioma
			Retinal Vasoproliferative Tumor
			Wyburn-Mason Syndrome
			Optic Disc Melanocytoma
		Choroidal Tumors
			Choroidal Nevus
			Choroidal Melanoma
			Choroidal Osteoma
			Choroidal Metastasis
			Choroidal Hemangioma
	Conclusions
	References
21: Diagnostic Techniques: Autofluorescence
	Introduction
	The Origin of Autofluorescence
	Types of Autofluorescence
		Short-Wavelength AF
		Near-Infrared AF
	Choroidal Melanocytic Tumors
		Choroidal Nevus
		Indeterminate Choroidal Melanocytic Tumor (Small Choroidal Melanoma)
		Choroidal Melanoma
	Choroidal Hemangioma
	Choroidal Metastasis
	Congenital Hypertrophy of the Retinal Pigment Epithelium
	Neurofibromatosis Type 1 (NF1)
	Vitreoretinal Lymphoma
	Conclusions
	References
22: Diagnostic Techniques: Ultrasonography
	Introduction
	Basic Physics
	Instrumentation
		Diagnostic A-Scan
		B-Scan
		Ultrasound Biomicroscopy (UBM)
	Methods for Differentiation of Intraocular Tumors
		Topographic Ultrasonography
		Quantitative Ultrasonography
			Reflectivity
			Internal Structure
			Sound Attenuation
		Kinetic Ultrasonography
			Mobility
			Vascularity
			Convection
	Differentiation of Anterior Segment Tumors
		Iridociliary Pigment Epithelial Cyst (IPE Cyst)
		Iris and Ciliary Body Melanoma
		Ciliary Body Melanocytoma
	Differentiation of Retinal Tumors
		Retinoblastoma
			Topographic
			Quantitative and Kinetic
		Persistent Fetal Vasculature (PFV)
		Retinopathy of Prematurity (ROP)
		Coats’ Disease
	Differentiation of Choroidal Tumors
		Choroidal Nevus
		Choroidal Melanoma
			Topographic
			Quantitative and Kinetic
			Special Cases
				Associated Hemorrhage
				Extraocular Extension
				Episcleral Brachytherapy
		Choroidal Hemangioma
			Topographic
			Quantitative and Kinetic
		Choroidal Metastasis
			Topographic
			Quantitative and Kinetic
		Hemorrhagic Disciform Lesion
	References
23: Diagnostic Techniques: FNAB
	Introduction
		Box 23.1 Intraocular biopsy
	Surgical Technique
		Iris Tumors
		Ciliary Body and Pre-equatorial Tumors
		Post-equatorial Tumors
		Vitrectomy-Assisted Aspiration Biopsy
	Sample Handling
	Indications
		Melanoma: Prognostic
		Amelanotic Uveal Tumor (Primary Versus Metastasis)
		Nevus Versus Melanoma (Indeterminate Melanocytic Lesions)
		Melanoma: Diagnostic
		Intraocular Lymphoma
		Retinoblastoma and  Other Retinal Tumors
		Orbital Tumors
	Complications
		False-Negative Biopsy
		False-Positive Biopsy
		Needle Tract Seeding
		Hemorrhage
		Retinal Detachment
		Endophthalmitis
	Conclusions
	References
24: Diagnostic Techniques: Other Biopsy Techniques
	Introduction
		Box 24.1 Other Biopsy Techniques
	Vitreous Cutter Aspiration Biopsy
		Indications and Contraindications
		Surgical Technique
		Results and Complications
	Incisional Biopsy
		Indications and Contraindications
		Surgical Technique
		Results and Complications
	Excisional Biopsy
		Indications and Contraindications
		Surgical Technique
		Results and Complications
	Laboratory Techniques
		Transport
		Laboratory Investigations
	Discussion
	References
Index