Cutaneous Melanoma

Preface to the Sixth Edition
Acknowledgments
Contents
Editorial Board
Contributors
Part I: Biology and Immunology of Melanoma
	Biology of Melanocytes and Primary Melanoma
		Introduction
		Development of Melanoblasts
			Regulation of Specification
			Regulation of Migration
			Regulation of Survival and Proliferation
		Differentiation of Melanocytes
			Regulation of Differentiation
			Regulation of Survival
		Melanomagenesis
			From Melanocyte to Melanoma: A Multistep Process
			Molecular Genetics: Early Lessons from Familial and Sporadic Melanoma
			Melanoma: A Consequence of Homeostatic Disruption
			Melanoma: Cell of Origin
		Melanoma and the Environment
			Sun Exposure and Epidemiology
			Photobiology and Melanoma
		Conclusion
		References
	Immunology of Melanoma
		Innate Immunity
		Adaptive Immunity
		Immune Regulation and Tolerance
			Co-stimulatory/Co-inhibitory Receptors
				B7-CD28 Family
				TNFR Family
				TIM Family
			Regulatory T Cells
			Cytokines
		Animal Tumor Models
		Antigens Recognized by Tumor-Reactive T Cells
			Identification of Tumor Antigens Recognized by T Cells: General Principles
				Cancer Germline Antigens
				Tissue-Specific Differentiation Antigens
				Overexpressed Gene Products
			Melanoma Neoantigens
		Conclusions: Implications for Immunotherapy
		Cross-References
		References
	Biomarkers for Melanoma
		Biomarker Definition and Use
			Definition of Cancer Biomarkers
			Differential Utilization of Cancer Biomarkers
			Biomarker Use in Melanoma
		Biomarker Discovery and Validation
			Biomarker Discovery
			Biomarker Validation
		Tumor Tissue-Based Markers
			Diagnostic Markers for Primary Melanoma
				FISH-Based Diagnostic Assays for Melanoma
				Gene Expression Profiling of Melanocytic Neoplasms
				Immunohistochemical Analysis in the Diagnosis of Melanocytic Neoplasms
			Prognostic Markers for Primary Melanoma
				Gene Expression Profiling of Melanoma Prognostic Markers
			IHC Analysis of Melanoma Prognostic Markers
		Tumor Environment-Based Non-soluble Biomarkers
			Tumor-Initiating Cells
			Epithelial-Mesenchymal Transition
			Epigenetic Changes
			Immune Escape Mechanisms
		Soluble Biomarkers
			Lactate Dehydrogenase (LDH)
		S100B
			Other Serum Biomarkers (CRP, FGF, IL-8, MIA, SAA, VEGF, YKL-40)
			Circulating Tumor Cells (CTCs)
			Circulating Tumor DNA (ctDNA)
			Circulating MicroRNA (miRNA)
			Circulating Immune Cells
		Treatment-Associated Biomarkers
			Serum Lactate Dehydrogenase (LDH)
			Burden of Metastatic Disease
			Body Mass Index (BMI)
			Molecular Features Associated with Outcome on BRAF Inhibitor-Based Therapy
		References
Part II: Diagnosis and Staging
	Clinical Presentations of Melanoma
		Introduction
		Patterns of Presentation
		Clinical Assessment
			Patient History
			Personal History of Skin Cancer
			Family History
			Phototype and Sun Exposure
			Signs and Symptoms
			Physical Examination
			Clinical Features
				Growth Patterns
		Aids to Diagnosis
			Clinical Photography
			Dermoscopy
			Reflectance Confocal Scanning Laser Microscopy (RCM)
			Image Analysis for Diagnosis
			Other Techniques: Multispectral Imaging, Electrical Impedance Spectroscopy, Adhesive Patch Molecular Assays, Optical Coherence...
				Multispectral Imaging
				Electrical Impedance Spectroscopy
				Adhesive Patch Molecular Assays
				Optical Coherence Tomography
				Ultrasound Imaging
			Evolving Paradigms in the Visual Assessment of Skin Lesions
		Cross-References
		References
	Dermoscopy/Confocal Microscopy for Melanoma Diagnosis
		Introduction
			Dermoscopy
				Basics of Dermoscopy
				Diagnostic Accuracy of Dermoscopy
			Reflectance Confocal Microscopy
				Basics of Reflectance Confocal Microscopy
				Diagnostic Accuracy of Reflectance Confocal Microscopy
				Clinical Scenarios for the Use of Reflectance Confocal Microscopy
			Total Body Photography and Digital Dermoscopy
			Other Noninvasive Detection Methods
		Dermoscopic Features of Melanoma and Melanoma Simulants
			Local Dermoscopic Features
			Common Global Dermoscopic Patterns
			Anatomical Site Considerations
			Featureless Melanomas
		Diagnostic Algorithms for Dermoscopy
			Two-Step Algorithm
			Three-Point Checklist
			Revised Seven-Point Checklist
			ABCD Rule of Dermoscopy and Clinical EFG Rule
			Menzies Method
			CASH Acronym
			Chaos and Clues
			TADA
			Pattern Analysis
		Reflectance Confocal Microscopy Features of Melanoma
			Common Confocal Features of Melanoma
		Diagnostic Algorithms for Reflectance Confocal Microscopy
			Modena Algorithm
			Barcelona Algorithm
		Dermoscopic and Confocal Features of Non-superficial Spreading Melanoma Subtypes
			Nodular Melanoma
				Dermoscopic Features of Nodular Melanoma
				Reflectance Confocal Microscopy Features of Nodular Melanoma
			Lentigo Maligna and Lentigo Maligna Melanoma
				Dermoscopic Features of Lentigo Maligna and Lentigo Maligna Melanoma
				Reflectance Confocal Microscopy Features of Lentigo Maligna and Lentigo Maligna Melanoma
			Spitzoid Melanomas
				Dermoscopic Features of Spitzoid Melanomas
				Reflectance Confocal Microscopy Features of Spitzoid Melanomas
			Desmoplastic Melanomas
				Dermoscopic Features of Desmoplastic Melanomas
				Reflectance Confocal Microscopy Features of Desmoplastic Melanomas
		Conclusion
		Cross-References
		References
	Biopsy of Suspected Melanoma
		Prebiopsy Lesion Assessment
		Biopsy Techniques
			Excisional Biopsy
			Incisional Biopsy
			Fine-Needle Aspiration and Core Biopsy
			Frozen Sections
			Biopsy of the Nail Unit
			Biopsy of Mucosa
		Conclusion
		References
	Lymphoscintigraphy in Patients with Melanoma
		Introduction
			The Definition of a Sentinel Node
		Lymphatic Mapping of the Skin: Early Studies
		Lymphoscintigraphy
			The First Radiocolloid, and Early Experience with Lymphoscintigraphy
		Radiopharmaceuticals
			99m-Technetium Labeled Colloids
			99mTc-Antimony Sulfide Colloid
			99mTc-Rhenium Sulfide Colloid and 99mTc-Nanocolloid of Albumin
			99mTc-Sulfur Colloid
			99mTc-Human Serum Albumin
			99mTc-Tilmanocept
			What Is the Ideal Radiocolloid?
			Lymphoscintigraphy for Sentinel Lymph Node Biopsy Procedures
		The Technique of Lymphoscintigraphy
			Injecting the Tracer
			Immediate Dynamic Imaging
			Delayed Static Imaging
				Unexpected Lymphatic Drainage Pathways
			SPECT/CT Imaging of the Sentinel Nodes
			Marking the Surface Location of the Sentinel Node
			Radiation Dosimetry: Risks to the Patient
			Radiation Dosimetry: Risks to a Pregnant Patient
			Radiation Dosimetry: Risks to Attending Staff
		Patterns of Lymphatic Drainage From the Skin
			Trunk (n = 4604 patients)
			Posterior Trunk (Including Posterior Chest) (n = 3803 patients)
			Anterior Trunk (Including Anterior Chest) (n = 801 patients)
			Head and Neck (n = 2995 patients)
			The Limbs
				Upper Limb (n = 2738 patients)
				Lower Limb (n = 2981 patients)
			Interval Nodes (n = 1285 patients)
			Drainage to Multiple Node Fields
			Complex Lymphatic Drainage Patterns
			Lymphoscintigraphy in Patients with Clinically Involved Node Fields
		The Future
			New Tracers for Lymphatic Mapping
			Gamma Probes for Intraoperative Detection of Radioactivity
			Gamma Cameras for Intraoperative Imaging
			Alternative Methods of Lymphatic Mapping
		Conclusions
		References
	Biopsy of the Sentinel Lymph Node
		History and Conceptual Basis of Sentinel Lymph Node Biopsy
		Rationales for SLN Biopsy
			Rationale: Staging
				Staging Value of SLN Biopsy: Relationship to Primary Tumor Thickness
			Rationale: Regional Disease Control
			Rationale: Survival Improvement
		Selection for SLN Biopsy
		Technical Details of Mapping
			Special Situations: Difficult Sites
			Special Situations: Patients Presenting After Wide Excision
			Special Situations: Nonclassical Nodal Sites
		Pathology of the SLN
		False-Negative SLNs
		Complications
		Lymphatic Mapping and SLN Biopsy from Melanoma Metastases
		Completion Lymph Node Dissection
		SLN as an Experimental Model for Tumor-Host Interface
		Considerations for the Future
		Cross-References
		References
	Melanoma Prognosis and Staging
		Overview of the Eighth Edition AJCC Melanoma Staging System
		Prognostic Factors and Staging of Primary Melanoma (AJCC Stages I and II)
			Primary (Breslow) Tumor Thickness
			Primary Tumor Ulceration
			Clark Level of Invasion
			Primary Tumor Mitotic Rate
			Patient Age
			Tumor-Infiltrating Lymphocytes
			Lymphovascular Invasion
			Neurotropism
			Regression
			Other Variables
		Staging Value of the Sentinel Lymph Node
		Prognostic Factors and Staging in Regionally Metastatic Melanoma (Stage III): Lymph Node, In-Transit, Satellite, and Microsate...
			Number of Involved Regional Lymph Nodes
			Clinically Occult Versus Clinically Detected Regional Lymph Node Metastases
			Sentinel Lymph Node Tumor Burden
			Extranodal Extension
			Non-Nodal Locoregional Metastases (Microsatellite, Satellite, and In-Transit Metastases)
		Metastatic Melanoma to Lymph Node(s) from an Unknown Primary Site
		Prognostic Factors and Staging of Patients with Distant Metastatic Melanoma (Stage IV)
			Site of Distant Metastasis
			LDH Level
			Other Factors
		Additional Staging Recommendations
			Patients with Multiple Primary Melanomas
			Staging Patients After Systemic or Radiation Therapy
			Staging Patients at Recurrence
		Conclusions
		References
	Models for Predicting Melanoma Outcome
		Introduction
			Prediction Tools and Statistical Models
			Personalized Prognosis
			Clinical Applications
			The Link Between Prediction Tools and Staging Systems
			The Relevance of Prediction Tools for Clinical Trials
			Brief History of Melanoma Prediction Tools
			Prediction Tools Developed from AJCC Databases
			Other Prediction Tools
		Planning to Build a Prediction Model
			Reporting Prediction Models
			Criteria for Building Prediction Models
			Selection of a Patient Population
			Selection of an Outcome to Predict
				Time to Relapse After Initial Disease Management
			Conditional Survival
			Probability of Binary Outcome
			Considering the Treatment Landscape
			Selection of Relevant and Clearly Defined Predictors
		Model Development
			Cox Proportional Hazards Model
			Hazard Function
			Relative Risk
			The Proportional Hazards Assumption
			When the Proportional Hazards Assumption Is Violated
		Model Validation and Performance
			Internal Validation
			External Validation
			Putting Contemporary Models to the Test
		Challenges and Opportunities
			Sample Size
			Selection Bias
			Missing Data
			Survival from Metastatic Melanoma
		The Future
		Cross-References
		References
Part III: Pathology
	Classification and Histopathology of Melanoma
		Introduction
		The Role and Challenges of Pathologic Assessment of Melanocytic Tumors
		Biopsying Clinically Suspicious Pigmented Tumors
		Pathologic Assessment of Primary Melanomas
		Accuracy of Pathologic Assessment Is Enhanced by Clinical Correlation
			The Role of Specimen Orientation
		Melanoma Tumor Progression: The Concept of Radial and Vertical Growth Phases
		Pathways of Melanoma Pathogenesis and Clinicopathologic Classification of Melanoma
		Low Cumulative Sun Damage Melanoma/Superficial Spreading Melanoma
			Pitfalls
		High-Cumulative Sun Damage Melanoma/Lentigo Maligna Melanoma
			Pitfalls
				Assessment of Excision Margins in Lentigo Maligna
		Acral Melanoma
		Nodular Melanoma
		Histologic Features of the Vertical Growth Phase of Melanoma
			Predominantly Epithelioid Cell Vertical Growth Phase
			Predominantly Spindle Cell Vertical Growth Phase
			Pitfalls
			Mixed Spindle Cell and Epithelioid Cell Vertical Growth Phase
			Nevoid Vertical Growth Phase (``Nevoid Melanoma´´)
		Other Melanoma Subtypes and Variants
			Desmoplastic Melanoma
				Differential Diagnosis
					Desmoplastic Melanoma Versus Sclerosing Nevus (ScN)
					Desmoplastic Melanoma Versus Scar or Fibroma
					Desmoplastic Melanoma Versus Non-melanocytic Desmoplastic Malignant Spindle Cell Neoplasms
			Nevoid Melanoma
			Pigmented Epithelioid Melanocytoma
			Melanoma Arising From a Blue Nevus
			Mucosal Melanoma
			Vulvar and Penile Melanoma
			Conjunctival Melanoma
				Prognosis
				Management
		Atypical Spitz Nevi/Atypical Spitzoid Tumors and Spitz Melanoma (Malignant Spitz Tumor)
		Melanocytic Tumors of Uncertain Malignant Potential (MELTUMP), Intermediate Melanocytic Proliferations and Melanocytomas
			Management
		Spitz Melanoma/Malignant Spitz Tumor
		Histopathologic Features of Prognostic Importance
			Breslow Thickness
			Clark Level of Invasion
			Ulceration
			Mitotic Rate
			Inflammatory Host Response (Including TILs)
			Regression
			Microscopic Satellites
			Blood Vessel and Lymphatic Invasion
			Angiotropism
			Neurotropism
			Desmoplasia
			Anatomic Site
			Sex
			Age
			Lymph Node Metastasis
		The Melanoma Pathology Report Including a Synoptic Format
			The Synoptic Pathology Report
		Melanoma in Children and Adolescents
			Histopathology
		Cutaneous Metastases of Melanoma
		Regional Lymph Node Metastases of Melanoma
			Laboratory Assessment of Regional Lymphadenectomy Specimens
			Lymphatic Mapping and Sentinel Lymph Node Biopsy
			Laboratory Assessment of Sentinel Lymph Nodes
			Laboratory Confirmation That a Submitted Node Is Truly Sentinel
			Intraoperative Evaluation of Sentinel Nodes
			The Need to Evaluate Multiple Levels of the Sentinel Lymph Node
			The Role of Immunohistochemistry in Evaluation of Sentinel Lymph Nodes
			Identification of Nodal Nevi and Their Separation from Metastatic Melanoma
			Sentinel Lymph Node Evaluation in Assessment of the Malignant Potential of Ambiguous (Nevoid) Melanocytic Lesions
			Molecular Biology as a Supplement to Histological Evaluation of Sentinel Nodes
			Measurement of the Amount of Tumor Present and Its Distribution in Sentinel Lymph Nodes
		Melanoma Metastatic to Visceral Organs and Other Sites
		Fine Needle Biopsy in Melanoma Patients
		Clear Cell Sarcoma (Melanoma of Soft Parts)
		Molecular Pathology of Melanoma
			Therapeutic Targets
		The Concept of the Cancer Stem Cell
		The Metastatic Niche Concept
		Closing Remarks
		Cross-References
		References
	Molecular Pathology and Genomics of Melanoma
		Introduction
			The Beginnings of Cancer Genetics
			Basic Principles and Terms in Cancer Genetics
			Types of Genetic Aberrations
			Recent Advances in Cancer Genetics
		Pathogenesis: Acquisition of Mutations
			Ultraviolet radiation (UV) Pathogenesis
			Stepwise Progression of Melanocytic Tumors
				Nevi
				Intermediate Melanocytic Tumors
				Melanoma
		Genetic Aberrations in Melanocytic Tumors
			MAPK-Activating Aberrations
				BRAF
				NRAS
				NF1
				MAP2K1/MAP2K2(MEK1/MEK2)
				KIT
				GNAQ/GNA11/CYSLTR2/PLCB4
				Translocations
			Loss-of-Function Mutations
				CDKN2A
				PTEN
			Noncoding Genetic Aberrations
				TERT Promoter Mutations
				Mutations in Other Noncoding Regions of the DNA
				Noncoding RNAs
			Genes Associated with Increased Melanoma Susceptibility
				Cell Cycle Genes: CDKN2A and CDK4
				Telomere-Associated Mutations: TERT, POT1, ACH, and TERF2IP
				BAP1
				MITF
				MC1R
				Cancer Syndromes Associated with Increased Risk of Melanoma
		Genetic Tests in the Diagnosis of Melanoma
			Polymerase Chain Reaction-Based Methods
				PCR
				Quantitative PCR and Gene Expression-Based Assays
			DNA Sequencing Methods
				Sanger Sequencing
				Next-Generation Sequencing
			Methods to Detect DNA Copy Number Aberrations
				Array Comparative Genomic Hybridization
			SNP Arrays and Molecular Inversion Probes
				Fluorescence In Situ Hybridization
		Genetic Testing for Therapeutic Decision-Making
			BRAF and MAPK Inhibitors
			Immunotherapy
		Outlook
		References
Part IV: Epidemiology and Prevention of Melanoma
	Clinical Epidemiology of Melanoma
		Introduction
		Worldwide Incidence and Mortality Patterns
			Global Distribution
			Highest Rates
			Temporal Trends in Incidence
			Mortality
		Melanoma Risk Factors
			Demographic
				Age
				Sex and Age by Sex
				Socioeconomic Status
				Ethnicity
			Constitutional
				Phenotypic
				Anthropometric Measures
			Environmental
				Ambient UVR and Exposure to Sun
				Other Environmental Exposures
					Ionizing Radiation
					Artificial Sources of UVR
					Occupational
					Reproductive Factors and Exogenous Hormone Use
					Health History
					Diet
					Smoking
					Alcohol
					Trauma
					Immunosuppression
		Screening
		Risk Prediction
		Summary and Conclusions
		Cross-References
		References
	Molecular Epidemiology of Melanoma
		Molecular Characterization of Melanoma
			Overview of Genomic Features
			Cutaneous Melanoma (Non-desmoplastic and Non-acral Types)
			Cutaneous Melanoma (Desmoplastic Type)
			Acral and Mucosal Melanomas
			Uveal Melanoma
		Genomic Factors and Melanoma Risk
			Genetic Susceptibility to Melanoma
		Gene-Environment, Gene-Phenotype, and Gene-Gene Interactions
			Gene-Gene Interactions and Melanoma Risk
			Interactions Between Genes, Phenotype, and the Environment
			Clinical and Public Health Applications
		Future Studies
		Cross-References
		References
	Clinical Genetics and Risk Assessment of Melanoma
		Introduction
		Risk Factors
			All Types of UV Radiation Classified as ``Carcinogenic to Humans´´
			Sun Exposure
			Sunbed Use
		Phenotypical Factors
			Common Melanocytic and Atypical Nevi
			Phenotypical Factors: Skin, Hair, and Eye Color and Freckles
			Second Primary Malignancies Among Melanoma Patients and Risk of Second Primary Melanoma Among Other Primary Cancer Patients
			Actinic Damage Indicators
			Personal and Family History of Other Cancers in Melanoma Families
			Melanoma and Neurological Disorders
			Genetics
				Rare High-Penetrance Melanoma Genes
				Melanocortin 1 Receptor
				GWAS Analyses for Melanoma and Nevi
				Telomere Biology and Aging
				Epigenetic and DNA Methylation
				Gut Microbiome and Melanoma
				Vitamin D
		Integrating Risk Factors in the Clinical Setting
			Historical Features
				Personal History
				Genetic Counseling
		Childhood and Adolescent Melanoma
			Risk Factors for Childhood Melanoma
			Genetic Susceptibility of Childhood Melanoma
		References
	Acquired Precursor Lesions and Phenotypic Markers of Increased Risk for Cutaneous Melanoma
		Introduction
		Phenotypic Markers
			Melanocytic Nevi as Risk Factors
				Total Nevus Count
				Clark Nevi (Synonym ``Large Acquired Nevi,´´ ``Atypical Nevi,´´ ``Dysplastic Nevi´´)
				Congenital Melanocytic Nevi
				Spitz Nevi
				BAP1-Inactivated Melanocytic Tumors (``Bapomas´´)
			Classic Genotype/Phenotype Risk Correlates
				MC1R Polymorphisms (Variants), Skin Color, and Hair Color
				Eye Color
				Freckles and Lentigines
		Precursor Lesions
			Clark Nevus (Syn. Large Acquired Nevi, Atypical, Dysplastic Nevi)
			Congenital Melanocytic Nevi
			Solar Lentigo as Precursor in Xeroderma Pigmentosum Patients
			Other Yet-to-Be-Defined Potential Intermediate Lesions
		Management of High-Risk Patients
			Individuals with Specific Subtypes of Nevi
				Congenital Melanocytic Nevi
				Spitz Nevi
				Patients with BAP1-Inactivated Melanocytic Tumors
			Individuals with Many Nevi and Clark Nevi
				Patients with Single to a Few Clark Nevi
				Patients with Many Nevi and Many Clark Nevi (So-Called Atypical Mole Syndrome)
		Conclusion
		References
	Melanoma Prevention and Screening
		Prevention of Melanoma
			Trends in Melanoma Incidence and Mortality
		Primary Prevention
			Reducing Personal Exposure: Shade, Clothing, and Sunscreens
				Shade and Clothing
				Use of Sunscreens
				Sunscreen Types and Controversies
			Behavioral Change Programs for Reducing Personal Exposure
			Multicomponent Community-Wide Interventions
			Youth Education and Counseling Programs
				US Preventive Services Task Force (USPSTF): Behavioral Counseling
				The SunSmart Program
			Intervention Trials of the Prevention of Nevi
				Prevention of Nevi in Children
			Controlling Exposure to Indoor Tanning Beds
		Therapeutic Prevention of Melanoma and Populations to Target for Interventional Trials
			Therapeutic Prevention of Melanoma
			Candidate Agents
				Pigmentation Enhancers
				DNA Repair Enzymes
				Vitamins and Minerals
				Repurposed Therapeutic Agents
				Aspirin and Nonsteroidal Anti-inflammatory Drugs (NSAIDs)
				Statins
				N-Acetylcysteine
				Difluoromethylornithine
				Phytochemicals (Plant-Derived Biologically Active Compounds)
		Secondary Prevention
			Early Detection and Screening
			Potential Benefits of Screening
			Uncertainties and Conflicts in Melanoma Screening
			Screening-Related Harms
			Prevalence of Screening
			Evidence Relating to the Effectiveness of Screening
				Randomized Trials
				Case-Control Studies
			Economic Assessments of Screening
			Programs of Screening
				Population Screening Programs
					Germany
					University of Pittsburgh Medical Center
				Educational Campaigns to Promote Early Detection
				Opportunistic Screening in Normal Medical Practice
				Skin Self-Examination
				Open-Access Skin Checks
					American Academy of Dermatology (AAD)
					Euromelanoma
				Screening for Occupational Groups
				Screening for Selected High-Risk Groups
			Adjuncts to Clinical Examination
			Challenges in the Detection of More Lethal Melanoma Subtypes
			Advances in Screening Technologies and Community Outreach to Improve Early Detection
		Conclusion
		References
Part V: Management of Primary Melanoma and Locoregional Metastases
	Treatment of Primary Melanomas
		Historical Perspective and the Emergence of a Contemporary Paradigm
		Wide Excision of Primary Melanomas: Fundamental Concepts
			T0: Melanoma In Situ/Lentigo Maligna
				Current Excision Margin Recommendations for T0 Melanomas
			T1: Invasive Melanomas 1 mm in Thickness
				Randomized Trials of Excision Margins for T1 Melanomas
				Nonrandomized Studies of Excision Margins for T1 Melanomas
				Current Excision Margin Recommendations for T1 Melanomas
			T2: Invasive Melanomas >1-2 mm Thick
				Randomized Trials of Excision Margins for T2 Melanomas
				Nonrandomized Studies of Excision Margins for T2 Melanomas
				Current Excision Margin Recommendations for T2 Melanomas
			T3: Invasive Melanomas >2-4 mm in Thickness
				Randomized Trials of Excision Margins for T3 Melanomas
				Nonrandomized Studies of Excision Margins for T3 Melanomas (>2-4 mm)
				Current Excision Margin Recommendations for T3 Melanomas
			T4: Melanomas >4 mm in Thickness
				Randomized Trials of Excision Margins for T4 Melanomas (>4 mm)
				Nonrandomized Studies of Excision Margins for T4 Melanomas
				Current Excision Margin Recommendations for T4 Melanomas
		Excision Margins Summary
		Techniques for Routine Wound Closure
		Excisions for Melanomas in Unusual or Restrictive Locations
		References
	Reconstructive Options Following Surgery of Primary Melanoma
		Introduction
		Principles of Reconstructive Surgery
			Assessment of the Acquired Defect
				Patient Factors
				Disease Factors
				Local Tissue Factors
		Reconstructive Options for Complex Wounds
			Definitions
				Grafts
					Flaps
					Undermining with Primary Closure
					Skin Grafts
					Composite Grafts
					Local Flaps
					Regional Flaps
					Free Tissue Transfer
		Head and Neck Reconstruction
			Scalp
			Forehead
			External Ear
			Nose
			Cheek
			Lip
			Eyelid
		Extremities
			Volar Skin of Foot and Hand
			Distal Phalanx
			Digits
			Dorsal Skin
			Joints
			Reconstruction of Large Wide Local Excision Limb Defects
		Reconstruction of Defects of the Groin and Axilla
			Approaches to Reconstruction of the Groin
			Regional Flaps to the Groin
				Anterolateral Thigh Flap
				Rectus Abdominis Flap
				Gracilis Flap and Perforator Flap Variations
			Reconstruction of Defects of the Axilla
				Skin Graft
				Local Flaps
				Latissimus Dorsi Flap
				Pectoralis Major Flap
			Reconstruction of Mucosal Melanoma Defects
		References
	Axillary and Epitrochlear Lymph Node Dissection for Melanoma
		Introduction
		Axillary Dissection
			Anatomy
			Surgical Technique
				Preoperative and Perioperative Preparation
				Incision
				Skin Flaps
					Dissection of Nodal Tissue
					Closure
			Operative Considerations for Recurrent or Bulky Axillary Metastases in the Upper Axilla
			Postoperative Management
			Complications
		Epitrochlear Dissection
			Rationale
			Anatomy and Surgical Technique
		References
	Inguinofemoral, Iliac/Obturator, and Popliteal Lymphadenectomy for Melanoma
		Inguinofemoral Dissection
			Indications
			Technique
			Modifications of the Classic Technique of Inguinofemoral Lymphadenectomy
		Iliac/Obtuartor (Deep Pelvic) Lymph Node Dissection
			Benefits
			Indications
			Operative Technique
			Modifications of the Classic Technique of Iliac/Obturator Lymphadenectomy
		Robotic-Assisted Transperitoneal Pelvic Lymphadenectomy
		Postoperative Complications: Incidence and Risk Factors
			Complications of Lymph Node Dissection
			Management of Postoperative Complications
		Popliteal Dissection
			Indications
			Operative Technique
		Cross-References
		References
	Neck Dissection and Parotidectomy for Melanoma
		Head and Neck Lymphatics and Their Impact on Melanoma Outcomes
		Neck Dissection and Parotidectomy for Melanoma
		Technique for Neck Dissection and Parotidectomy
		Completion Lymph Node Dissection Utility in Head and Neck Melanoma
		Conclusion
		References
	Local and Recurrent Regional Metastases of Melanoma
		Introduction
		Local and Regional Recurrence of Melanoma
			Local Recurrence
			In-transit Recurrence
			Regional Nodal Recurrence
		Hyperthermic Isolated Limb Perfusion
			History and Early Clinical Studies
			Patient Selection
			Preoperative Evaluation
			Equipment
			Operation
			Leak Monitoring
			Agents
			Hyperthermia
			Results
			Specific Toxicities and Management
		Isolated Limb Infusion
			Background
			Patient Selection and Indications
			Technique
			Response to Therapy
			Survival After ILI
			Burden of Disease
			Toxicity
		Intralesional Therapies for Cutaneous Melanoma
			Introduction
			Bacille Calmette-Guerin (BCG)
			Interleukin-2 (IL-2)
			Granulocyte Macrophage-Colony Stimulating Factor (GM-CSF)
			Velimogene Aliplasmid (Allovectin)
			Talimogene Laherparepvec (T-VEC)
			Rose Bengal (PV-10)
			Daromun (L19IL2 + L19TNF)
			Coxackievirus A21
			Combination with Systemic Immune Therapies
			Electrochemotherapy (ECT)
			Conclusion
		Neoadjuvant Therapy for Borderline Resectable Nodal Metastasis
		References
	Radiotherapy for Primary and Regional Melanoma
		Introduction
		Lentigo Maligna
		Primary Melanoma
		Adjuvant RT After Wide Local Excision of a Primary Melanoma
		Adjuvant RT for Resected Stage III Melanoma
		RT for Inoperable Regional Node Metastases and In-Transit Metastases
		References
	Adjuvant Systemic Therapy for High-Risk Melanoma Patients
		Introduction
		Who Should Be Considered for Adjuvant Therapy?
		Prior Adjuvant Therapeutic Approaches (Interferon and Vaccines)
		Interferons
		Role of Dose and Duration of IFN-α Therapy in Melanoma
		Ulcerated Primary Melanoma: A Potentially More IFN-Sensitive Population
		Immune Checkpoint Blockade
			Anti-CTLA-4
			Ipilimumab
			Anti-PD1
			Nivolumab
			Pembrolizumab
		Targeted Therapy
		Choice of Adjuvant Therapy in the BRAF V600E/K Mutation-Positive Patient
		Contraindications to Immunotherapy
		Conclusions
		References
	Neoadjuvant Systemic Therapy for High-Risk Melanoma Patients
		The Current Landscape of Systemic Therapy for Stage III and IV Melanoma
		Patients with Clinical Stage III Melanoma Are Ideal Candidates for Neoadjuvant Treatment
		Rationale for Neoadjuvant Therapy
		The History of Neoadjuvant Therapy Use in Melanoma
			Neoadjuvant Biochemotherapy
			Neoadjuvant High Dose Interferon
		The Current State of Neoadjuvant Therapy
			Neoadjuvant Targeted Therapies
				Dabrafenib Plus Trametinib
			Neoadjuvant Immune Checkpoint Inhibitors
				Pembrolizumab
				Ipilimumab Plus Nivolumab
			Neoadjuvant Checkpoint Inhibitor Therapy in Combination with Other Therapies
			Neoadjuvant Local Therapies
				Talimogene Laherparepvec
				L19IL2 plus L19TNF
		Neoadjuvant Therapy for Borderline Resectable or Unresectable Melanoma
			Targeted Therapies for Borderline Resectable/Unresectable Melanoma
			Immune Checkpoint Blockade for Borderline Resectable/Unresectable Melanoma
		Predicting Response to Neoadjuvant Therapy
			Prognostic Biomarkers
			Predictive Biomarkers
		Unmet Needs in Neoadjuvant Therapy for Melanoma
		Therapeutic Goals and Considerations
		Conclusion
		References
	Hyperthermic Regional Perfusion for Melanoma of the Limbs
		Introduction
		Epidemiology and Natural History of Extremity In-Transit Disease
		Treatment of Recurrent Extremity Melanoma
		Historical Perspective and Early Clinical Series
		Technical Aspects of Isolated Limb Perfusion
			Melphalan
			Pharmacokinetics of Melphalan in Isolated Limb Perfusion
			Other Chemotherapeutics
			Hyperthermia
			Tumor Necrosis Factor
		Toxicity of Isolated Limb Perfusion
		Adjuvant Isolated Limb Perfusion
		Therapeutic Limb Perfusion
			Melphalan Alone
			Melphalan and TNF
		Future Role of Limb Perfusion in Current Era of More Effective Systemic Therapy
		Conclusions
		References
	Isolated Limb Infusion for Melanoma
		Introduction and Historical Perspective
		Patient Selection for Isolated Limb Infusion
		Technical Details of the Isolated Limb Infusion Procedure
			Preoperative Assessment and Management
			Insertion and Positioning of Arterial and Venous Catheters
			Procedure in the Operating Room
			Postoperative Course and Care
		Similarities and Differences Between Isolated Limb Infusion and Hyperthermic Isolated Limb Perfusion
		Drugs Used in Isolated Limb Infusion
			Pharmacokinetics of Melphalan During Isolated Limb Infusion
			Melphalan Dosage and Ideal Body Weight
			Use of Microdialysis During Isolated Limb Infusion
		Toxicity and Side Effects Following Isolated Limb Infusion
			Locoregional Side Effects of Isolated Limb Infusion
			Limb Toxicity Following Isolated Limb Infusion
			Systemic Toxicity and Complications of Isolated Limb Infusion
		Clinical Results of Isolated Limb Infusion
			Response Rates Following Isolated Limb Infusion
			Limb Recurrence-Free Interval and Overall Survival Following Isolated Limb Infusion
			Prognostic Factors for Outcome Following Isolated Limb Infusion
		Special Isolated Limb Infusion Regimens and Indications
		Novel Isolated Limb Infusion Regimens
		Future of Isolated Limb Infusion
		Conclusions
		Cross-References
		References
	Surveillance and Follow-Up of Melanoma Patients
		Goals of Surveillance
		Patterns of Melanoma Recurrence
			Risk of Local and Regional Recurrence
			Regional Relapse
			Time to Recurrence
		Strategies for Active Follow-Up of Melanoma Patients
		Detection of Recurrences
			Role of Physical Examination
			Patient Education
			Patient Well-Being and Follow-Up
			Follow-Up Schedules
			Radiologic Studies and Laboratory Tests
		Screening for Risk of New Primary Melanomas
		Screening for Other Primary Cancers
		Current Recommendations for Surveillance
		References
	Local Melanoma Recurrence, Satellitosis, and In-transit Metastasis: Incidence, Outcomes, and Selection of Treatment Options
		Introduction
		Etiology of Local and In-transit Metastases
		Incidence of Locoregional Metastasis and Survival
		Treatment Options for Local and In-transit Metastases: Overview
			Surgical Excision
		Cryotherapy
		Topical Treatments
			Diphencyprone Cream
			Imiquimod Cream
		Intralesional Therapies
			BCG
			DNCB
			Interferon Alpha
			Allovectin
			Coxsackie Virus A-21
			Interleukin-2 (IL-2)
			Rose Bengal (PV-10)
			Talimogene Laherparepvec (T-VEC)
			Daromun (Combined IL-2 and TNF)
			Intralesional Oncolytic Immunotherapy and the Abscopal Effect
		Laser and Light-Based Therapies
			Ablative Laser Therapy
			Non-ablative Laser Therapy
			Radio-Frequency Ablation
		Photodynamic Therapy
		Electrochemotherapy
			Reported Results of ECT
			ECT in Perspective
		Regional Therapies
			Isolated Limb Perfusion and Infusion
		Radiation Therapy for Locally Recurrent Melanoma and In-transit Metastases
		Amputation
		Systemic Therapy
		Adjuvant and Neoadjuvant Therapies
			Adjuvant Therapies
			Neoadjuvant Therapies
		Conclusions
		References
Part VI: Uncommon Presentations of Melanoma
	Acral Lentiginous Melanoma
		Epidemiology
		Pathogenesis
		Clinical Features
			Dermoscopic Findings
		Pathological Features
			Immunohistochemistry of ALM
		Molecular Feature
			BRAF
			NRAS
			KIT
			TERT
			NF1
			Mutation Burden
		Diagnosis
		Prognosis
			Compared with Other Subtypes of CM
			Comparison in the Localization of ALM
			Compared in Racial Groups
		Treatment
			Surgery
			Immunotherapy
			Targeted Therapy
		Conclusion
		References
	Lentigo Maligna Melanoma
		Introduction
		Epidemiology and Risk Factors
		Natural Course
		Clinical Features
			Dermoscopic Features of Lentigo Maligna
			Reflectance Confocal Microscopy Diagnostic Features of Lentigo Maligna
		Diagnostic Biopsy Techniques
		Histopathologic Diagnostic Challenges
		Treatment
		Surgical Modalities
		Standard Wide Excision
		Surgical Techniques with Complete Peripheral Margin Assessment
			Staged Excision Techniques
				Staged Excision with Radial Vertical Sections
				Square Technique
			Mohs Surgery
		Histopathological Challenges Associated with Lentigo Maligna Surgical Margins
		Nonsurgical Techniques
		Topical Imiquimod
			Neoadjuvant Use of Imiquimod Prior to Surgery
			Use of Imiquimod as Primary Therapy for LM
			Use of Imiquimod as Adjuvant Therapy for LM
			Monitoring for Response and Recurrence During Imiquimod Treatment
			Radiation Therapy (Radiotherapy) for LM/LMM
		Long-Term Follow-Up
		Potential Role of Reflectance Confocal Microscopy for LM Management
		Quality of Life Considerations
		Conclusion
		References
	Mucosal Melanoma
		Introduction
			Epidemiology
			Pathological Features and Diagnosis
			Staging and Prognosis
		Mucosal Melanoma of the Head and Neck
			Differential Diagnosis
			Staging and Prognosis
			Treatment
			Treatment Overview
		Female Genital Tract Mucosal Melanomas
			Vulvar Melanoma
			Vulvar Melanoma Summary
			Vaginal Melanoma
			Vaginal Melanoma Treatment Overview
			Cervix and Urethra Melanoma
		Mucosal Melanoma of the Penis and Scrotum
		Anorectal Mucosal Melanoma
			Anorectal Melanoma Treatment Overview
		Gastrointestinal Tract Melanoma
			Mucosal Melanoma Adjuvant Therapy
		Mucosal Melanoma Systemic Therapy
		References
	Melanoma in Children and Teenagers
		Introduction
			Epidemiology
			Pathology, Molecular Characteristics, and Differential Diagnosis
				Congenital Melanoma
				Giant Congenital Nevi
				Neurocutaneous Melanosis
				Small- and Medium-Sized Congenital Nevi
			Etiology
			Clinical Presentation and Risk Factors
			Surgical Management
			Medical Management
				Interferon
				Chemotherapy
				Targeted Therapy
				Immunotherapy
			Outcome
			Follow-Up and Surveillance
		Conclusion
		Cross-References
		References
	Pregnancy and the Use of Hormones in Melanoma Patients
		Aspects of Female Reproduction Physiology Including Lactation Relevant to Melanoma
		Do Melanomas Have Functional Estrogen Receptors?
		Do Exogenous Hormones Impact the Risk of Developing Melanoma?
		Does Pregnancy Impact the Risk of Developing Melanoma?
		Does Pregnancy Impact the Prognosis of Melanoma?
		Should a Patient with a Prior History of Melanoma Become Pregnant?
		Should Exogenous Hormones Including Infertility Drugs Be Used in a Patient with History of Melanoma?
			Should Hormonal Contraceptives Be Used in a Patient with History of Melanoma?
			Should Hormonal Infertility Drugs Be Used in a Patient with History of Melanoma?
			Should Postmenopausal Hormone Replacement Therapy Be Used in a Patient with History of Melanoma?
		How Does Management of Melanoma Differ in the Pregnant Woman?
		Surgery Including Sentinel Node Biopsy in the Pregnant or Lactating Patient
		How Does Follow-Up of Melanoma Differ in the Pregnant Woman?
		Transplacental Transmission and Neonatal Melanoma: Should Termination Ever Be Considered?
		Which Antimelanoma Drugs Can Be Used During Pregnancy?
		Does Puberty Influence the Outcome of Pediatric Melanoma?
		Conclusions
		References
	Diagnosis of Stage IV Melanoma
		Introduction
		Timing of Distant Metastasis
		Pattern of Metastasis
		Prognosis and Prognostic Factors
			Sites of Distant Metastases
			Number of Metastatic Sites
			Elevated Serum Lactate Dehydrogenase
			Duration of Remission
			Performance Status
			Other Prognostic Factors
		Clinical Evaluation of Metastasis
			History and Physical Examination
			Laboratory Tests/Biomarkers
				Detection of Cells in Messenger RNA Using PCR
			Radiologic Tests
				CT Scans
				PET Scans
				The Impact of PET/CT Imaging on Clinical Management
				Ultrasound
				Brain MRI/Spinal MRI
				Radionuclide Scans
				Radiolabeled Monoclonal Antibodies
			Pathologic Tests
			Molecular Tests
		Sites of Distant Metastases
			Skin, Subcutaneous Tissues, and Distant Lymph Nodes
			Lung, Pleura, and Mediastinum
			Brain and Spinal Cord
			Gastrointestinal Tract
			Liver, Biliary Tract, and Spleen
			Bone
			Kidneys and Urinary Tract
			Heart and Pericardium
			Pancreas
			Peritoneum and Mesentery
			Endocrine Organs
			Breast
			Ovaries, Uterus, and Placenta
			Testes and Penis
			Oral Cavity, Pharynx, and Larynx
			Eye and Orbit
			Cutaneous Melanosis
		Surveillance in Patients Who Have Localized Melanoma
		Cross-References
		References
Part VII: Management of Distant Metastases
	Evolving Role of Chemotherapy-Based Treatment of Metastatic Melanoma
		Introduction
		Single-Agent Chemotherapy
			Dacarbazine and Temozolomide
			Nitrosoureas
			Platinums
			Microtubule Toxins
		Combination Cytotoxic Chemotherapy
			Nitrosourea Combinations
			Taxane-Based Combination Therapy
			Cisplatin-Based Combination Therapy
		Biochemotherapy
			Interferon Alfa-Based Biochemotherapy Regimens
			Interleukin-2 and Dacarbazine or Temozolomide Combinations
			Cisplatin and Interleukin-2-Based Biochemotherapy Regimens
			Checkpoint Inhibitor-Based Biochemotherapy
			Other Biochemotherapy Combinations
		Chemotherapy and Antiangiogenic Therapy
			Antiangiogenic Agents
		Chemotherapy and Map-Kinase-Targeted Therapy
		Conclusion
		References
	Targeted Therapies for BRAF-Mutant Metastatic Melanoma
		Introduction
		Overview of the MAPK Pathway
		MAPK Pathway in Cancer
		BRAF Inhibitors
		BRAF Inhibition in Other Cancers
		Toxicity of BRAF Inhibitors
		MEK Inhibitors
		Combined BRAF and MEK Inhibition
		Resistance to MAPK Inhibition
			Transcriptional Mediators of Resistance
			Genetic Drivers of Resistance
		Experimental Approaches and Future Directions
			ERK Inhibitors
			Dimer-Disrupting RAF Inhibitors
			Targeted/Immune Combinations
		Conclusions
		Cross-References
		References
	Molecularly Targeted Therapy for Patients with BRAF Wild-Type Melanoma
		Background
		KIT Mutations and Genetic Alterations
		NRAS Mutant Melanoma
		Preclinical Strategies Targeting NRAS Melanoma
		Aurora Kinase A and PPP6c
		Polo-Like Kinase 1 (PLK1) and MEK Inhibition
		Targeting SHP2 (PTPN11)
		Autophagy
		Epigenetic Approaches
			IDH1
			ARID 2
			EZH2
		BH3 Mimetics
		Non-V600 BRAF Mutations (Alternate BRAF Mutations)
		Fusion Receptor Kinases
		NF1
		RAC1
		TP53
		CDKN2A
		Signal Inhibitors Can Modulate the Tumor Immune Microenvironment
		CDK4/6 Inhibitors (Palbociclib, Ribociclib, and Abemaciclib)
		MEK Inhibitors (Trametinib, Cobimetinib, and Binimetinib)
		MEK Inhibition and Cancer Immunity in Melanoma
		Discussion
		References
	Cytokines (IL-2, IFN, GM-CSF, etc.) Melanoma
		Interleukin-2
		Pharmacology of IL-2
		Immunologic Activity of IL-2
		Systemic Effects of IL-2
		Clinical Efficacy of High-Dose IL-2 Alone
		Clinical Efficacy of Alternate Doses, Routes and Schedules of IL-2 Alone
		Clinical Efficacy of IL-2 Combined with Interferon Alpha
		Clinical Efficacy of IL-2 Combined with Other Cytokines, Immune Modulators, Antibodies or Vaccines
		Clinical Efficacy of IL-2 Combined with Targeted Therapy
		Agents to Reduce the Toxicity of IL-2
		Predictors of Clinical Response
		Other Cytokines for Therapy of Metastatic Melanoma
		Summary
		References
	Checkpoint Inhibitors in the Treatment of Metastatic Melanoma
		Background
			Immune Checkpoints
			CTLA-4 Inhibitors
			PD-1 Inhibitors
			Other Immune Checkpoint Inhibitors
			Combination Immune Checkpoint Therapy
				CTLA-4 and PD-1
				Other Immune Checkpoint Combinations
		Primary Resistance to Immune Checkpoint Inhibitors
			Antigen Presentation and T-Cell Activation
				Tumor Immunogenicity
				Antigen Presentation
				Costimulatory Signals
			T-Cell Migration and Tumor Infiltration
				Tumor Infiltration by Activated Cytotoxic T-Cells
			The Tumor Microenvironment
				Indoleamine 2,3-Dioxygenase
				Vascular Endothelial Growth Factor
				Tumor Cell Intrinsic Mechanisms of Creating a Resistant Microenvironment
				Regulatory T-Cells
				Myeloid-Derived Suppressor Cells
				Adenosine
				IPRES Signature Expression
				Gut Microbiome
		Secondary Resistance to Immunotherapy
			Immunoediting
			Antigen Presentation
			Alternative Checkpoint Proteins
		The Future of Checkpoint Inhibition in Melanoma
		Cross-References
		References
	Novel Immunotherapies and Novel Combinations of Immunotherapy for Metastatic Melanoma
		Introduction
		Immune Checkpoint History
		The T-Cell-Inflamed Tumor Microenvironment
		Novel Therapeutics to Enhance a T-Cell-Inflamed Tumor Microenvironment
		The Non-T-Cell-Inflamed Tumor Microenvironment
		Oncogene Pathways of Immune Exclusion
		Direct Activation in the Non-T-Cell-Inflamed Tumor Microenvironment
		Novel Checkpoint Therapies
		4-1BB
		GITR/GITRL
		LAG3
		TIGIT
		Intra-tumoral Therapy
			Oncolytic Virus Therapy
			Non-oncolytic Virus Therapy
				Toll-Like Receptor (TLR) Agonists
				Stimulator of Interferon Gene (STING) Agonists
				PV-10 (Rose Bengal)
		Cytokine
			IL-2
			IL-15
			IL-10
		Tumor Antigens
		Tumor Vaccines
		Antibody Drug Conjugates
		Bispecific Antibodies and Bifunctional Fusion Proteins
		Adoptive Cell Therapy (ACT)
		Chimeric Antigen Receptor (CAR) T-Cell Therapy
		Conclusion
		References
	Managing Checkpoint Inhibitor Symptoms and Toxicity for Metastatic Melanoma
		Introduction
		Meta Analyses: Gastrointestinal irAEs
			Colitis
			Enteritis
			Esophagitis/Gastritis
			Pancreatitis
		Meta-analyses: Neurologic irAEs
			Encephalitis
			Peripheral Neuropathies
			Cranial Neuropathies
			Guillain-Barré Syndrome
			Myasthenia Gravis
			Cerebellar Ataxia
			Transverse Myelitis
				Management and Work-Up of Neurologic irAEs
			Pneumonitis
			Sarcoidosis
		Meta-analysis of Hematologic irAEs
			Thrombocytopenia
			Leukopenia
			Anemia
			Pan-cytopenia
		Meta-analysis of Dermatologic Adverse Effects
			Dermatitis
			Toxic Epidermal Necrolysis (TEN)
				Management and Work-Up of Dermatologic Adverse Events
		Meta-analysis of Autoimmune Hepatitis
			Hepatitis
				Management and Work-Up of Autoimmune Hepatitis
		Meta-analysis of Endocrinopathies
			Thyroid Dysfunction
			Hypophysitis/Adrenal Insufficiency
			Type I Diabetes
				Management and Work-Up of Endocrinopathies
			Nephritis
				Management and Work-Up of Nephritis
			Myocarditis
				Management and Work-Up of Myocarditis
			Arthropathies
				Management and Work-Up of Arthropathies
		Conclusions
		References
	Sequencing and Combinations of Molecularly Targeted and Immunotherapy for BRAF-Mutant Melanoma
		Introduction
		Targeted Therapy
			Vemurafenib and Cobimetinib
			Dabrafenib Plus Trametinib
			Encorafenib with Binimetinib
			Activity Profiles for BRAF/MEK Inhibitor Combinations
		Immunotherapy: Checkpoint Inhibitors
			Ipilimumab
			Anti-PD-1/PD-L1 Agents
			Combined CTLA-4 and PD-1 Blockade
			Characterization of Response Patterns to Immunotherapy
			Differential Activity of Immunotherapy in Patients with BRAF-Mutant Versus BRAF Wild-Type Melanoma
		Sequencing of BRAF/MEK Inhibition and Checkpoint Blockade
		Combined Targeted Therapy and Immunotherapy
		Combined BRAF/MEK Inhibition and Checkpoint Blockade
		Conclusion
		References
	Melanoma Vaccines
		Introduction
		Melanoma Vaccine Studies Prior to Immune Checkpoint Blockade Treatments
		Vaccines with Tumor-Associated Melanoma Antigens
			Melanin Pathway Antigens
			Cancer-Testis Antigens
			Ganglioside Antigen Vaccines
		Melanoma Vaccines in Development
			Neoantigens from Mutated Proteins: The Basis for New Personalized Vaccines in Melanoma
			Clinical Studies with Neoantigen Melanoma Vaccines
		Basic Principles Involved in Melanoma Vaccine Design
			Basics of Antigen Presentation
			Getting the Right Effector Cells Against Melanoma
			Properties of Vaccines Required for Effective Responses Against Melanoma?
				The Size of the Inoculum and the Vaccine Platform Used
				Broad Antigen and Cytokine Responses Are Better than Narrow Specific Responses
				Boosting Responses with Co-stimulators
				Overcoming T Cell Exhaustion
		Vaccine Platforms and Adjuvants
		Combining Cancer Vaccines with Immune Checkpoint Blockade
			Cancer Vaccines Combined with Immune Checkpoint Blockade in Patients
		Where Next for Melanoma Vaccines?
			Selecting Patients Who May Benefit from Vaccine Treatment
			Is the Type of Vaccine Important to Synergize with ICB Treatment?
		Conclusion
		References
	Cellular Therapy for Melanoma
		T Cells Mediate Recognition of Melanoma
		Identifying Tumor-Associated Antigens and Stress Ligands Recognized by T Cells
		Adoptive Cell Therapy Using Tumor Infiltrating Lymphocytes
		ACT Using T Cells Transduced to Express Antitumor Receptors
		The T-Cell Repertoire in TIL
		The Future of ACT
		References
	Systemic Therapy for Mucosal, Acral, and Uveal Melanoma
		Clinical Characteristics
			Epidemiology
			Natural History and Prognosis
		Molecularly Targeted Therapy
			Molecular Biology
			Therapeutic Implications
		Immunotherapy
			Immunobiology
			Therapeutic Implications
		Other Therapeutic Options for Advanced Disease
			Chemotherapy, Biotherapy, and Biochemotherapy
			Other Management Strategies for Advanced Disease
		Systemic Therapy in the Adjuvant Setting
		Conclusions
		References
	Dermatological Complications of Systemic Therapies for Melanoma
		Targeted Therapy with Kinase Inhibitors
			BRAF Inhibitor Monotherapy (Vemurafenib, Dabrafenib, Encorafenib)
				Photosensitivity
				Keratinocytic Lesions
					Verrucal Keratoses
					Keratoacanthomas and Cutaneous Squamous Cell Carcinomas
					Palmar-Plantar Erythrodysesthesia and Plantar Hyperkeratosis
				Maculopapular Rash
				Atypical Melanocytic Proliferations and New Primary Melanomas
				Other Cutaneous AEs
			Monotherapy with MEK Inhibitors (Cobimetinib, Trametinib, Binimetinib)
				Papulopustular Eruption (``Acneiform Rash´´)
				Xerosis Cutis and Pruritus
				Other Cutaneous AEs
			BRAF and MEK Combination Therapy (Vemurafenib and Cobimetinib, Dabrafenib and Trametinib, Encorafenib and Binimetinib)
		Immunotherapy with Checkpoint Inhibitors
			Anti-CTLA-4 Monotherapy
				Rash
				Pruritus
			Anti-PD-1 Monotherapy
				Rash
				Pruritus
				Lichenoid Reactions
				Psoriasis
				Vitiligo
				Other Adverse Events
			Combination of Anti-CTLA-4 and PD-1 Antibodies
				Rash
				Other Adverse Events
		Conclusions
		References
	Surgical Management of Distant Melanoma Metastases
		Introduction
		Historical Perspective of the Role of Surgery in Patients with Stage IV Melanoma
		Surgery with Curative Intent for Patients with Stage IV Melanoma
		Indications for Surgical Resection of Distant Melanoma Metastases
		Relationship Between Tumor Burden, Immune Function, and Surgical Treatment
		Selection of Patients for Surgery and Prognostic Factors
		Palliative Surgery for Distant Melanoma Metastases
		Surgery for Localized Residual Disease After Systemic Therapy
		The Value of Local Disease Control
		Outcomes After Surgical Resection of Melanoma Metastases at Specific Sites
			Skin, Subcutaneous Tissue, and Lymph Nodes
			Lung, Trachea, and Bronchi
			Brain and Spinal Cord
			Gastrointestinal Tract
			Liver
			Biliary Tract
			Pancreas
			Spleen
			Bone
			Kidney and Urinary Tract
			Heart and Pericardium
			Endocrine Organs
			Breast
			Reproductive Organs
			Oral Cavity and Pharynx
			Eye and Orbit
		Surgery in the Era of Effective Systemic Therapies
		The Changing Role of Surgery in Patients with Stage IV Melanoma
		Role of Imaging in Predicting Surgical Benefits
		Conclusions
		Cross-References
		References
	Radiotherapy for Distant Melanoma Metastases
		Introduction
		Soft Tissue Metastases
		Bone Metastases
		Brain Metastases
		Single and Oligo-Brain Metastases
		Adjuvant Whole Brain Radiation Therapy After Local Treatment of Single or Oligo Brain Metastases
		The Role of Whole Brain Radiation Therapy in Multiple Metastases and Leptomeningeal Disease
		Stereotactic Body Radiation Therapy for Extracranial Metastases
		Combination of Systemic Drug Therapy with Radiation Therapy
		References
	Melanoma Brain Metastases: Unique Biology and Implications for Systemic Therapy
		Introduction
		Biology and Immunology of MBM
			The Structure and Function of the Blood-Brain Barrier
			Molecular Biology of Melanoma Brain Metastases
			Immunity of the Central Nervous System
			The Immune Microenvironment in the Setting of Brain Metastasis
		Systemic Therapy for MBM
			Targeted Therapy
			Immunotherapy
		Radiation Therapy for MBM
			Whole Brain Radiation Therapy (WBRT)
			Stereotactic Radiotherapies/Radiosurgery
		Combinatorial Approaches
			Combining Immunotherapy and Targeted Therapy
			Targeted Therapy in Combination with Stereotactic Radiosurgery
			Immunotherapy in Combination with Stereotactic Radiosurgery
		Key Challenges and Opportunities
			Assessment of Clinical Responses in MBM Patients
			Pseudoprogression and Radiation Necrosis
			Corticosteroids
			Considerations for Future Clinical Trial Design
			Leptomeningeal Disease (LMD)
		Multidisciplinary Approaches to Management of CNS Metastases
		Conclusion
		References
Part VIII: History of Melanoma
	A History of Melanoma: From Hunter to Morton
		Introduction
		John Hunter (1728-1793)
		Rene Laennec (1781-1826)
		William Norris (1792-1877)
		Other Early Nineteenth Century Descriptions
		Contemporary Histories of Melanoma
			Excision of Lymph Node Metastases
		Oliver Pemberton (1825-1897)
		James Paget (1814-1899)
		Sir Jonathan Hutchinson (1828-1913)
		Other Late Nineteenth Century Descriptions of Melanoma
		Early Twentieth Century Reports
		William Sampson Handley (1872-1962)
		Alexander Breslow (1928-1980)
		Vincent J. McGovern (1915-1983)
		Sophie Spitz (1910-1956) And Arthur Allen (1910-1994)
		Wallace H. Clark, Jr. (1924-1997)
		Thomas B. Fitzpatrick, Jr. (1919-2003)
		Gerald W. Milton (1924-2007)
		Seng-Jaw Soong (1943-2012)
		Donald L. Morton (1934-2012)
		References
Index