Practical Medical Oncology Textbook

Preface
Contents
Contributors
I: From Basic Research to Cancer Diagnosis
	1: Epidemiology and Cancer Prevention
		1.1	 Introduction
		1.2	 Epidemiology of Tumors
			1.2.1	 Incidence
			1.2.2	 Mortality
			1.2.3	 Survival
			1.2.4	 Prevalence
		1.3	 Risk Factors
		1.4	 Primary Prevention
			1.4.1	 Tobacco
			1.4.2	 Physical Inactivity, Dietary Factors, Obesity, and Being Overweight
			1.4.3	 Alcohol Use
			1.4.4	 Infections
			1.4.5	 Environmental Pollution
			1.4.6	 Occupational Carcinogens
			1.4.7	 Radiations
		1.5	 Oncological Screening and Early Diagnosis
			1.5.1	 Breast Cancer
			1.5.2	 Cervix Cancer
			1.5.3	 Colorectal Cancer (CRC)
		1.6	 Cancer Registries
		References
	2: Tumor Biology and Natural History
		2.1	 Introduction
		2.2	 Cancer Clonal Evolution
		2.3	 Intra-tumor Heterogeneity
		2.4	 Natural History of Cancer
			2.4.1	 Carcinogenesis
		2.5	 Conclusions
		References
	3: Histopathology of the Tumors
		3.1	 Definition
		3.2	 Benign Neoplasms
		3.3	 Malignant Neoplasms
		3.4	 Dysplasia
		3.5	 Grading
		3.6	 Staging
		3.7	 Conclusion
		References
	4: Biomarkers
		4.1	 Introduction
		4.2	 Diagnostic Markers
		4.3	 Prognostic Markers
		4.4	 Predictive Markers
		4.5	 Surrogate Markers
		4.6	 Risk Markers
		References
	5: Hereditary Cancers and Genetics
		5.1	 Introduction
		5.2	 Genetic Predisposition to Cancer: Oncogenes and Tumor Suppressor Genes
		5.3	 Linkage Analyses and Association Studies in Families with Genetic Predisposition to Cancer
		5.4	 Sporadic and Heredofamilial Tumors
		5.5	 Genetics of Hereditary Breast and/or Ovarian Cancer
			5.5.1	 BRCA1 and BRCA2 Genes
		5.6	 Genetics of Male Breast Cancer
			5.6.1	 High-Penetrance Genes
			5.6.2	 Moderate-Penetrance Genes
			5.6.3	 Low-Penetrance Genes
			5.6.4	 Oncogenetic Counseling, Screening, and Surveillance
		5.7	 Genetics of Hereditary Colorectal Cancer
			5.7.1	 Polyposis Syndromes
				5.7.1.1	 Familial Adenomatous Polyposis
				5.7.1.2	 MUTYH-Associated Polyposis
				5.7.1.3	 Other Rare Polyposis Syndromes
			5.7.2	 Hereditary Nonpolyposis Colorectal Cancer
				5.7.2.1	 Lynch Syndrome
				5.7.2.2	 Familial Colorectal Cancer Type X
				5.7.2.3	 Other Genes Associated with Increased Colorectal Cancer Risk
		5.8	 Hereditary Melanoma
		References
	6: Liquid Biopsy
		6.1	 Liquid Biopsy
			6.1.1	 Circulating Nucleic Acids (CNAs)
				6.1.1.1	 Circulating Tumor DNA (ctDNA)
					Liquid Biopsy in Clinical Practice: The Paradigm of Non-Small Cell Lung Cancer (NSCLC)
				6.1.1.2	 Circulating microRNA
		6.2	 Circulating Tumor Cells (CTCs)
		6.3	 Exosomes
		6.4	 Liquid Biopsy in the Era of Immunotherapy
		6.5	 Liquid Biopsy for Early Cancer Diagnosis
		6.6	 Remaining Challenges in Liquid Biopsy: False Positive (FP) and False-Negative (FN) Results
			Expert Opinion
				Key Points
				Hints for Deeper Insight
				Suggested Readings
		References
	7: Diagnosis and Staging
		7.1	 Introduction
		7.2	 Clinical Diagnosis of Cancer
		7.3	 Pathological Diagnosis of Cancer
		7.4	 Clinical and Pathological Staging of Cancer
		7.5	 Cancer Restaging and Assessment of Response to Treatment
		7.6	 Conclusions
		References
	8: Molecular Diagnostics: Innovative Technologies for Clinical and Translational Research
		8.1	 From Old to New: Where Did We Start?
			8.1.1	 First-Generation Sequencing
			8.1.2	 Real-Time PCR
			8.1.3	 In Situ Hybridization (ISH) and Fluorescent In Situ Hybridization (FISH)
		8.2	 Innovative Technologies
			8.2.1	 Next-Generation Sequencing (NGS)
			8.2.2	 Nanostring
			8.2.3	 Digital PCR
		8.3	 Conclusion
		References
II: Principles of Cancer Therapeutics
	9: Chemotherapy
		9.1	 Introduction
		9.2	 Biological Basis of Cancer Chemotherapy
		9.3	 Chemotherapeutic Drugs
			9.3.1	 Antimetabolites
				9.3.1.1	 Antifolates
				9.3.1.2	 Pyrimidine Antagonists
				9.3.1.3	 Purine Antagonists
			9.3.2	 DNA Damaging Agents
				9.3.2.1	 Alkylating Agents
				9.3.2.2	 Platinum Complexes
				9.3.2.3	 Intercalators
				9.3.2.4	 Camptothecins
				9.3.2.5	 Epipodophyllotoxins
			9.3.3	 Antimitotics
				9.3.3.1	 Vinca Alkaloids
				9.3.3.2	 Taxanes
				9.3.3.3	 Other Antimitotics
		9.4	 Conclusion
		References
	10: Endocrine Therapy
		10.1 Estrogen Receptor Signaling: A Brief Overview
		10.2 Targeting ER-Dependent Solid Tumors in Clinical Practice
		10.3 SERM [4, 5]
		10.4 Aromatase Inhibitors
		10.5 ER Downregulators
		10.6 Androgen Receptor Signaling: A Brief Overview
		10.7 Targeting AR-Dependent Solid Tumors in Clinical Practice
		10.8 First-Generation AR Inhibitors
		10.9 Second-Generation AR Inhibitors
		10.10 Androgen Synthesis Inhibitors
		10.11 GnRH Agonists and Antagonists
			10.11.1	 The Hypothalamic-Pituitary Axis and the Clinical Use of Analogues/Antagonist of GnRH in Oncology
		10.12 GnRH Agonists
		10.13 GnRH Antagonists
		10.14 Other Hormonal Agents
		10.15 Endocrine Resistance and Newer Endocrine Agents
		References
	11: Targeted Therapy
		11.1	 Introduction
		11.2	 Targeting Receptor Tyrosine Kinases and Related Pathways
			11.2.1	 Agents Targeting EGFR
			11.2.2	 Agents Targeting HER2
			11.2.3	 ALK Inhibitors
			11.2.4	 BRAF/MEK/ERK Inhibitors
			11.2.5	 Inhibitors of the PI3K/AKT/mTOR Pathway
		11.3	 Targeting DNA Damage Response
			11.3.1	 Inhibitors of DNA Repair Mechanisms
				11.3.1.1	 PARP Inhibitors
				11.3.1.2	 Inhibitors of DNA-PK
				11.3.1.3	 ATM Inhibitors
				11.3.1.4	 ATR Inhibitors
			11.3.2	 Cell Cycle Checkpoint Inhibitors
				11.3.2.1	 CHEK1 Inhibitors
				11.3.2.2	 WEE1 Inhibitors
		11.4	 Drugs Targeting CDK4 and CDK6
		11.5	 Drugs Targeting Epigenetic Mechanisms
		11.6	 Drugs Targeting Angiogenesis
		11.7	 Concluding Remarks
		References
	12: Immunotherapy
		12.1	 Introduction
		12.2	 The Immune System
		12.3	 Immunity and Cancer
		12.4	 Theory of Immunoediting
		12.5	 Immune Escape
		12.6	 Immunotherapy
		12.7	 Passive Cancer Therapy
		12.8	 Immune Checkpoint Inhibitor
		12.9	 New Molecular Targets
		12.10	 Car-t
		12.11	 Long Term Survival
		12.12	 No Effect in Surrogate Endpoints and Atypical Patterns of Response
		12.13	 Persistent Responses After Cessation of Therapy
		12.14	 Immunotherapy Targets a Broad Range of Tumour Types
			12.14.1	 Special Populations
		12.15	 Therapeutic Schedule
		12.16	 The Safety Profile
		12.17	 Combination Immuno Checkpoint Strategies
		12.18	 Sequential Therapy
			12.18.1	 Adjuvant Immunotherapies
			12.18.2	 Efficacy in Brain Metastases
			12.18.3	 Duration of Treatment
			12.18.4	 Dose and Schedule
		12.19	 Biomarkers
		12.20	 Microbiota
		References
	13: Integrated Treatments: The Role of Surgery
		13.1 Introduction
		13.2 Multidisciplinary Approaches
		13.3 Tumor Board Assessment
		13.4 Imaging and Diagnostic Tools
			13.4.1	 Multiparametric Evaluation
			13.4.2	 Radiomics
			13.4.3	 Early Diagnosis and Screening
		13.5 Surgical Decision-Making
			13.5.1	 Patient-Related Factors
				13.5.1.1	 The Elderly
				13.5.1.2	 Obesity
				13.5.1.3	 Chronic Lung Disease and Particularly Chronic Obstructive Pulmonary Disease
				13.5.1.4	 Nutritional Status
			13.5.2	 Tumor-Related Factors
				13.5.2.1	 Prophylactic Surgery
				13.5.2.2	 Locally Advanced Tumor and Metastatic Disease
		13.6 Quality of Oncologic Surgery
			13.6.1	 Referral Center
			13.6.2	 Minimally Invasive Surgery
		13.7 Conclusion
		References
	14: Integrated Treatments: The Role of Radiotherapy
		14.1	 Introduction
		14.2	 Effects of Radiotherapy and Chemoradiotherapy
		14.3	 Modern Radiotherapy Techniques
		14.4	 Simulation, Contouring and Imaging Fusion, and Planning
		14.5	 Role of Radiotherapy in Main Tumors
		14.6	 Head and Neck
			14.6.1	 Indication
			14.6.2	 Volumes and Doses
			14.6.3	 Adaptive Radiation Therapy
			14.6.4	 Acute and Late Toxicities
		14.7	 Breast Cancer
			14.7.1	 Indication
			14.7.2	 Timing to Treat After Surgery
			14.7.3	 Volumes and Doses
			14.7.4	 Acute and Late Toxicities
		14.8	 Prostate Cancer
			14.8.1	 Introduction
			14.8.2	 Indication
			14.8.3	 Volumes and Doses
			14.8.4	 Acute and Late Toxicities
		14.9	 Rectal Cancer
			14.9.1	 Introduction
			14.9.2	 Indication
			14.9.3	 Volumes and Doses
			14.9.4	 Acute and Late Toxicities
		References
	15: Response Assessment to Cancer Therapy
		15.1 Diagnostic Criteria
			15.1.1	 RECIST
			15.1.2	 Targeted Therapies and CHOI Criteria
				15.1.2.1	 Choi Response Criteria
			15.1.3	 Immunotherapeutics and iRECIST
		15.2 Conclusion
		References
	16: Clinical Trials and Methodology of Cancer Research
		16.1 Introduction
		Box 16.1 Main Elements of a Clinical Trial Protocol
		16.2 Phase I Trials
		16.3 Phase II Trials
		16.4 Phase III Studies
			16.4.1	 Predictive Factors and Patients’ Selection
			16.4.2	 Non-inferiority Design
		16.5 Interpretation of Study Results and Clinical Relevance
		16.6 Conclusions
		References
	17: Basic Principles of Bioinformatics for Next-Generation Sequencing Molecular Testing in Oncology
		17.1 Introduction
		17.2 A Brief History of Sequencing: From Sanger to Third-Generation Sequencing Platforms
		17.3 From Wet-to-Dry Methods
			17.3.1 NGS Intrinsic Errors
			17.3.2	 Alignment and Coverage Evaluation
			17.3.3	 Variant Calling
			17.3.4	 Variant Annotation
			17.3.5	 CNV Detection
		17.4 Liquid Biopsy
		17.5 Bioinformatic Pipeline Validation
		17.6 Variant Interpretation and Clinical Reporting of Bioinformatic-Related Information
		17.7 Reproducibility in Bioinformatics
		17.8 Conclusions
		References
	18: New Drugs Development
		References
III: Management of Adverse Effects and Post Treatment Considerations
	19: Treatment Toxicity
		19.1 Introduction
		19.2 Haematological Toxicity
		19.3 Skin Toxicity
		19.4 Cardiovascular Toxicity
		19.5 Pulmonary Toxicity
		19.6 Gastrointestinal Toxicity
		19.7 Nephrotoxicity
		19.8 Neurotoxicity and Ocular Toxicity
		19.9 Endocrine and Metabolic Adverse Events
		19.10 Conclusions
		19.11 Summary of Clinical Recommendations
		References
	20: Cardio-Oncology
		20.1 Introduction
		20.2 Chemotherapy and Radiation Therapy-Induced Cardiotoxicity
			20.2.1 Chemotherapy-Induced Cardiotoxicity
				20.2.1.1 Type I
				20.2.1.2 Type II
			20.2.2 Radiation Therapy-Related Cardiotoxicity
		20.3 Cardiovascular Complications of Anticancer Treatment
			20.3.1 Heart Failure/Left Ventricular Dysfunction
				20.3.1.1 Cardiovascular Evaluation of Patients Undergoing Treatment at Risk of HF/ LVD
				20.3.1.2 Management
			20.3.2 Systemic Hypertension
			20.3.3 Pulmonary Hypertension
			20.3.4 Coronary Artery Disease
				20.3.4.1 Cardiovascular Evaluation of Patients Undergoing Treatment at Risk of Coronary Artery Disease
			20.3.5 Peripheral Artery Disease
			20.3.6 Stroke
			20.3.7 Venous Thromboembolism
			20.3.8 Arrhythmias
			20.3.9 Pericardial Disease
			20.3.10 Valvular Disease
		20.4 Cancer Patients Enrolled in Clinical Trials
		Management of Patients Undergoing Treatment with Potentially Cardiotoxic Antineoplastic Drugs
		References
	21: Cancer Cachexia
		21.1 Introduction: Definitions and Epidemiology
		21.2 Clinical Impact
		21.3 Pathophysiology
			21.3.1	 Anorexia
			21.3.2	 Decreased Food Intake
			21.3.3	 Increased Metabolic Rate
			21.3.4	 Adipose Tissue Atrophy
			21.3.5	 Muscle Atrophy
			21.3.6	 Inflammation
		21.4 Diagnosis and Staging: Initial Assessment and Follow-Up
		Case Study 1
		Case Study 2
		Box 21.1 Main pharmacological approaches in cancer cachexia
		Box 21.2 Megestrol acetate. Practical fact sheet
		21.5 Treatment
			21.5.1	 Nutritional Interventions
			21.5.2	 Physical Exercise
			21.5.3	 Pharmacology
				21.5.3.1	 Corticosteroids
				21.5.3.2	 Progestogens
			21.5.4	 Nutraceuticals
			21.5.5	 Recent Advances
				21.5.5.1	 Appetite Enhancers
				21.5.5.2	 Anti-inflammatory Drugs
				21.5.5.3	 Anabolic Drugs
			21.5.6	 Multidrug and Multimodal Approaches
		References
	22: Supportive and Palliative Care
		22.1 Introduction
		22.2 Definition
		22.3 ECOG and Karnofsky Scale (. Table 22.1)
		22.4 Pain and Its Treatment
		22.5 WHO Analgesic Ladder
		22.6 Conversion Rate
		22.7 Adjuvant Drugs
		22.8 Breakthrough Pain
		22.9 Drugs for Breakthrough Pain
		22.10 Conclusion
		References
	23: Patient–Physician Communication
		23.1 Background and Historical Perspective
		23.2 General Outcome of Medical Communication
		23.3 Principles of Patient–Physician Communication
			23.3.1	 Active Listening
			Active Listening Instruments
			23.3.2	 Communication Barriers
			23.3.3	 Emotion and Empathy
		23.4 Classical Communication Model and Techniques into Oncological Setting
		References
	24: Bone Health in Cancer Patients
		24.1 Bone Metastases
		24.2 Bone Metastasis Physiopathology
		24.3 Bone Metastasis Regulator Pathways
			24.3.1	 RANK–RANKL–OPG Axis
			24.3.2	 Endothelin-1 (ET-1)
			24.3.3	 Integrin and Cadherin
			24.3.4	 Wnt and Dkk-1
			24.3.5	 CXCR4/CXCL12
			24.3.6	 TGF-β
			24.3.7	 mTOR
		24.4 Markers of Bone Metastases
		24.5 Treatment of Bone Metastases
		24.6 Bone-Targeted Agents
		24.7 Radiopharmaceutical
		24.8 Anticancer Agents with Bone Effect
			24.8.1	 mTOR Inhibitor
			24.8.2	 Antiandrogen Agents
			24.8.3	 Cabozantinib
		24.9 Osteoimmunology in Bone Metastases
		24.10 Conclusion
		Expert Opinion
			Key points
			Hints for Deeper Insight
			Suggested Reading
		References
	25: Nutrition and Cancer
		25.1 Metabolic Signatures of Cancer Cells
			25.1.1	 Glucose
			25.1.2	 Amino Acids
			25.1.3	 Glutamine
			25.1.4	 Methionine
			25.1.5	 Arginine
			25.1.6	 Serine and Glycine
			25.1.7	 Lipids and Cholesterol
		25.2 Dietary Approach to Enhance Cancer Therapy
			25.2.1	 Ketogenic Diets
			25.2.2	 Fasting and Fasting Mimicking Diet
		25.3 Conclusion
		References
	26: Personalized Medicine
		26.1 Introduction
		26.2 Single Gene Biomarkers for Solid Tumors
			26.2.1	 Positive Predictive Molecular Biomarkers
				26.2.1.1	 Epidermal Growth Factor Receptor (EFGR) Mutations in NSCLC
				26.2.1.2	 ALK in NSCLC
				26.2.1.3	 ROS1 in NSCLC
				26.2.1.4	 HER2 in Breast Cancer
				26.2.1.5	 Her2 in Gastric Cancer
				26.2.1.6	 Tyrosine–Protein Kinase Kit (cKIT) Mutations in Gastrointestinal Stromal Tumors (GIST)
				26.2.1.7	 BRAF Mutations in Malignant Melanoma
				26.2.1.8	 BRCA1/2 Mutations in Breast, Prostate, and Ovarian Cancer
			26.2.2	 Negative Predictive Molecular Biomarkers
				26.2.2.1	 RAS Mutations in Colon Cancer
		26.3 Single Gene Biomarker for Hematologic Malignancies
			26.3.1	 Positive Predictive Molecular Biomarkers
				26.3.1.1	 BCR/ABL Translocations in Chronic Myeloid Leukemia
				26.3.1.2	 JAK-2 in Primary Myelofibrosis and Polycythemia Vera
				26.3.1.3	 BRAF Mutations in Hairy Cell Leukemia
			26.3.2	 Negative Predictive Molecular Biomarkers
				26.3.2.1	 B-cell Lymphomas
		26.4 Liquid Biopsy
		26.5 Immuno-oncology Biomarkers
		26.6 Tissue Agnostic Precision Oncology
		26.7 Precision Medicine Clinical Research
		Name: T.Z.
		Name: G.B.
		References
			Bibliography
	27: Tumor Board and Molecular Tumor Board
		27.1 Tumor Board
		27.2 Molecular Tumor Board
		References
	28: Precision Medicine in Oncology: Glossary of Relevant Scientific Terms
		28.1 Introduction
		28.2 Glossary of Scientific Terminology
			28.2.1	 Pathology, Oncology and Molecular Pharmacology Section
			28.2.2	 Methodology and Clinical Trials Section
		References
	29: Patients Categorization
		29.1 Introduction
		29.2 Cancer Disease
		29.3 Survivorship and Cancer Survivors
		29.4 Contemporary Reality of Cancer
		29.5 Cured
		29.6 Surveillance
		29.7 Patients’ Categorization
		Box 29.1 Cancer survivorship [34]
		Box 29.2 Quality of assistance guidelines
		29.8 Conclusions
		References
IV: Clinical Oncology: Diagnosis and Treatment of Solid Tumors
	30: Locoregional and Locally Advanced Breast Cancer
		30.1 Epidemiology
		30.2 Risk Factors for Breast Cancer
			30.2.1	 Hormonal and Reproductive Factors
			30.2.2	 Dietary and Lifestyle Factors
			30.2.3	 Environmental Factors
			30.2.4	 Family History and Inherited Predisposition to Breast Cancer
			30.2.5	 Personal History of Breast Cancer and Benign Breast Disease
			30.2.6	 Mammary Density
		30.3 Breast Cancer Prevention
			30.3.1	 Breast Cancer Screening for the General Population
			30.3.2	 Management of High-Risk Patients
				30.3.2.1 BC Screening for High-Risk Patients
				30.3.2.2 Chemoprevention
		30.4 Pathological Classification of Breast Cancer
			30.4.1	 Invasive Ductal Carcinoma
			30.4.2	 Invasive Lobular Carcinoma
			30.4.3	 Special Types of Breast Carcinoma
			30.4.4	 Carcinoma In Situ
		30.5 Prognostic and Predictive Pathological Factors in Breast Cancer
			30.5.1	 Grading
			30.5.2	 Hormone Receptors (HR)
			30.5.3	 HER2
			30.5.4	 Proliferation
		30.6 Molecular Classification of Breast Cancer
			30.6.1	 Luminal A
			30.6.2	 Luminal B
			30.6.3	 HER2-Enriched
			30.6.4	 Basal-Like
			30.6.5	 Normal-Like Subtype
			30.6.6	 Gene Expression Prognostic Signatures
		30.7 Clinical Presentation and Diagnosis
			30.7.1	 Clinical Examination of the Breast
			30.7.2	 Imaging Techniques for Breast Cancer Diagnosis and Local Staging
			30.7.3	 Biopsy and Diagnosis
			30.7.4	 Breast Cancer Staging
			30.7.5	 Imaging for Breast Cancer Staging and Other Pre-treatment Evaluations
		30.8 Management of Nonmetastatic Breast Cancer
			30.8.1	 Local Management of Breast Cancer: Surgery
				30.8.1.1 Breast Conservation Treatment: Modalities and Risk of Local Relapse
				30.8.1.2 Breast Reconstruction After Breast Surgery
				30.8.1.3 Advances in Axillary Management
			30.8.2	 Local Management of Breast Cancer: Radiotherapy
				30.8.2.1	 Radiotherapy after Breast-Conserving Treatment
				30.8.2.2 Radiotherapy After Mastectomy
				30.8.2.3 Regional Irradiation After Breast-Conserving Surgery
				30.8.2.4 Radiotherapy for Unresectable Disease
				30.8.2.5 Toxicities of Breast Radiotherapy
			30.8.3	 Adjuvant Systemic Treatment
				30.8.3.1 Endocrine Treatment
				30.8.3.2 Chemotherapy
				30.8.3.3 Bone-Stabilizing Agents
				30.8.3.4 HER2-Targeted Treament
			30.8.4	 Preoperative Systemic Therapy
		30.9 Follow-Up for Breast Cancer Survivors
		30.10 Inflammatory Breast Cancer
		30.11 Management of In Situ Malignancy
			30.11.1	 Surgery for In Situ Malignancy
			30.11.2	 Radiotherapy for In Situ Malignancy
			30.11.3	 Systemic Adjuvant Therapy for In Situ Malignancy
		30.12 Management of Locoregional Recurrence
		References
	31: Metastatic Breast Cancer
		31.1 Introduction
		31.2 Systemic Treatment
			31.2.1 HR+/HER2-Negative Disease
			31.2.2	 HER2+ Disease
			31.2.3	 Triple-Negative Disease
		31.3 Local Therapies for Metastatic BC
			31.3.1	 Management of Oligometastatic Disease
		References
	32: Lung Cancer
		32.1	 Introduction
		32.2	 Epidemiology
		32.3	 Screening
		32.4	 Pathological Features
		32.5	 Molecular Biology
		32.6	 Clinical Features
		32.7	 Diagnosis and Staging
		32.8	 Treatment
			32.8.1	 Localized Disease
			32.8.2	 Locally Advanced Disease
			32.8.3	 Metastatic Disease
		32.9	 Response Evaluation
		32.10	 Follow-Up
		Case Study: Non-oncogene-Addicted Advanced NSCLC
			Question
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			Key Points
		Case Study: Oncogene-Addicted Advanced NSCLC
			Question
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			Key Points
		Expert Opinion
			Key Points
			Hints for Deeper Insight
			Suggested Reading
		References
	33: Malignant Pleural Mesothelioma
		33.1 Introduction
		33.2 Origin and Histologic Subtypes
		33.3 Epidemiology and Risk Factors
		33.4 Genetic Predisposition
		33.5 Clinical Features
		33.6 Diagnosis
		33.7 The Role of Biomarkers
		33.8 Pathology
		33.9 The Role of Immunohistochemistry (IHC) in the Differential Diagnosis
		33.10 Staging
		33.11 Treatment
			33.11.1 Surgery
			33.11.2 Radiation Therapy (RT)
			33.11.3 Chemotherapy
				33.11.3.1	 First-Line Chemotherapy and Targeted Agents
				33.11.3.2	 Second-Line Chemotherapy
				33.11.3.3	 Immunotherapy
			33.11.4 Response Evaluation and Follow-Up
			33.11.5 Screening
			Case Study: A Rare Case of Metastatic MPM
				Question
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			Case Study: A Case of MPM with Aggressive Behaviour
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	34: Cancer of the Esophagus
		34.1	 Introduction and Epidemiology
		34.2	 Risk Factors
			34.2.1	 Squamous Cell Carcinoma
			34.2.2	 Adenocarcinoma
		34.3	 Clinical Features
		34.4	 Pathological Features
			34.4.1	 Macroscopic Aspects
				34.4.1.1	 Squamous Cell Carcinoma
				34.4.1.2	 Adenocarcinoma
			34.4.2	 Microscopic Aspects
				34.4.2.1	 Squamous Cell Carcinoma
				34.4.2.2	 Adenocarcinoma
		34.5	 Molecular Biology
			34.5.1	 Molecular Classifications
		34.6	 Esophageal Cancer Progression
		34.7	 Diagnosis
		34.8	 Differential Diagnosis
		34.9	 Staging
		34.10	 Prognostic Factors
		34.11	 Treatment
			34.11.1	 Limited Disease
			34.11.2	 Locally Advanced Disease
			34.11.3	 Metastatic Disease
				34.11.3.1	 Chemotherapy
				34.11.3.2	 Target and Immune Therapies
			34.11.4	 Supportive and Palliative Care
			34.11.5	 Follow-Up
			Case Study: An Unusual Histotype
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			Case Study: A 35-Year-Old Woman with a Metastatic Esophageal Cancer
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	35: Gastric Cancer: Locoregional Disease
		35.1	 Introduction
		35.2	 Epidemiology
		35.3	 Etiology and Prevention
		35.4	 Carcinogenesis
		35.5	 Clinical Presentation
		35.6	 Histopathology Overview
			35.6.1	 Macroscopic Aspects
			35.6.2	 Microscopic Aspects
		35.7	 Diagnosis and Staging
		35.8	 Staging Systems, Classification, and Prognosis
		35.9	 Molecular Biology
		35.10	 Treatment
			35.10.1	 Endoscopic Therapies
			35.10.2	 Surgery
			35.10.3	 Combined Modality Treatment
		35.11	 Follow-Up
		Case Study: Management of a Patient Affected by Early Gastric Cancer
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		Case Study: Management of Locally Advanced Gastric Cancer Successfully Treated by Combined Modality Treatment
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	36: Gastric Cancer: Advanced/Metastatic Disease
		36.1 Introduction
		36.2 Epidemiology
		36.3 Clinical Features
		36.4 Pathological Features
			36.4.1 Microscopic Aspects and Immunohistochemical
		36.5 Molecular Biology and Main Therapeutic Targets in Advanced Gastric Cancer
			36.5.1 Molecular Classifications
			36.5.2 Human Epidermal Growth Factor Receptor 2 (HER2)-Related Pathways: Therapeutic Targeting and Resistance Mechanisms
			36.5.3 Epidermal Growth Factor Receptor (EGFR)-Related Pathways: Therapeutic Targeting and Resistance Mechanisms
			36.5.4 MET Pathway: Therapeutic Targeting
			36.5.5 VEGF Pathway: Therapeutic Targeting
			36.5.6 Tumor Microenvironment: The Biological Basis of Immune Checkpoint Usage in Metastatic Gastric Cancer
		36.6 Prognostic Factors
		36.7 Treatment
			36.7.1 First Line
				36.7.1.1 Chemotherapy
				36.7.1.2 Chemotherapy for HER2-Positive Disease
			36.7.2 Second Line
			36.7.3 Third-Line Therapy and Beyond
			36.7.4 Immunotherapy
			36.7.5 Particular Conditions
				36.7.5.1 Surgery of Primary Tumor and Metastasectomy
				36.7.5.2 Peritoneal Involvement
		Case Study: An Unusual Clinical Progression
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		Case Study: A 32-Year-Old Man with a Metastatic Gastric Cancer
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	37: Colorectal Cancer: Locoregional Disease
		37.1 Introduction
		37.2 Carcinogenesis
		37.3 Clinical Features
		37.4 Diagnosis
		37.5 Staging
			37.5.1 Staging Procedures
			37.5.2 TNM Classification for Colon and Rectal Cancer
		37.6 Pathological Features
			37.6.1 Histological Features
			37.6.2 Pathological Assessment
		37.7 Treatment
			37.7.1 Colon Cancer
			37.7.2 Rectal Cancer
		37.8 Follow-Up
		References
	38: Colorectal Cancer: Metastatic Disease
		38.1 Introduction
		38.2 Molecular Biology
		38.3 Clinical Presentation and Diagnosis of Metastatic Disease
		38.4 Principles of Management of Metastatic Disease
			38.4.1 Surgical Management of Colorectal Metastases
			38.4.2 “Conversion”: Strategic Treatment Goal for Unresectable Liver Metastases
			38.4.3 Local and Ablative Treatments
				38.4.3.1 Thermal Ablation
				38.4.3.2 Chemoembolization
				38.4.3.3 Radioembolization
				38.4.3.4 HIPEC
			38.4.4 Palliative Treatment
				38.4.4.1 First-Line Treatment
				38.4.4.2 Second-Line Treatment Setting
			38.4.5 Third and Subsequent Lines
			Case Study: Metastatic Colon Cancer, RAS wt
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			Case Study: Metastatic Colon Cancer, RAS Mutated
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	39: Anal Cancer
		39.1 Introduction
		39.2 Epidemiology
		39.3 Anatomy, Histology, and Pathology
		39.4 Staging and Prognostic Factors
		39.5 Clinical Presentation and Evaluation
		39.6 Management
			39.6.1 Primary Treatment of Non Metastatic Anal Carcinoma
		39.7 Metastatic Disease
			39.7.1 Treatment of Recurrent Anal Carcinoma
		39.8 Screening
		39.9 Summary: Conclusion
		Case Study: Locally Advanced Anal Carcinoma
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		Case Study: Metastatic SCCA
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	40: Cancer of Exocrine Pancreas
		40.1 Introduction
		40.2 Epidemiology
		40.3 Risk factors
			40.3.1 Environmental risk factors
			Box 40.1 Protective factors for pancreatic cancer
			40.3.2 Genetic Risk Factors
		40.4 Carcinogenesis of Pancreatic Adenocarcinoma
		40.5 Clinical Features
		40.6 Diagnosis and Staging
			40.6.1 Laboratory Findings
				40.6.1.1 Molecular Biology
				Box 40.2 Laboratory testing in diagnosis of pancreatic cancer
				40.6.1.2 Biomarkers
			40.6.2 Imaging
				40.6.2.1 Transabdominal Ultrasonography
				40.6.2.2 CT, MRI, and PET
				40.6.2.3 ERCP and MRCP
				40.6.2.4 EUS
				40.6.2.5 Pancreatic Incidentalomas
		40.7 Cancer Diffusion and Resectability Evaluation
		Box 40.3 Most common metastatic sites in pancreatic cancer, ordered by frequencies:
		40.8 Treatment
			40.8.1 Resectable cancer
				40.8.1.1 Surgery
				40.8.1.2 Adjuvant and Neoadjuvant Therapies
			40.8.2 Borderline Resectable and Unresectable Cancer
			40.8.3 Metastatic Disease
			40.8.4 BRCA-Mutated Pancreatic Cancer
			40.8.5 Palliative Treatments
		40.9 Surveillance
		Case Study: Pancreatic Cancer Diagnosis and Treatment
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		Case Study: Pancreatic Cancer Diagnosis and Treatment
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	41: Biliary Cancer
		41.1 Epidemiology and Risk Factors
		41.2 Classification and Histological Types
		41.3 Screening and Diagnosis
		41.4 Staging and Prognosis
		41.5 Treatment
		41.6 Surgery
		41.7 Adjuvant and Neoadjuvant Treatment
		41.8 Palliative Therapy
			41.8.1 Chemoradiotherapy in Locally Advanced Disease
			41.8.2 Chemotherapy in Advanced Disease
			41.8.3 Second-Line Chemotherapy
			41.8.4 Locoregional Treatment
		41.9 Key Genomic Alterations and Emerging Therapies
			41.9.1 EGFR Pathway
			41.9.2 MAPK Pathway
			41.9.3 PI3K Pathway
			41.9.4 FGF Pathway
			41.9.5 IDH Pathway
			41.9.6 Chromatin Modifiers
			41.9.7 Other Molecular Pathways
		41.10 Conclusion
		Expert Opinion
			Recommendations
			Hints for a Deeper Insight
		References
	42: Hepatocellular Cancer
		42.1 Introduction
		42.2 Epidemiology
		42.3 Physiopathology
		42.4 Diagnosis
			42.4.1	 Radiological Criteria
			42.4.2	 Role of Alpha-Fetoprotein
			42.4.3	 Histological Criteria and Classification
				42.4.3.1	 Liver Biopsy
				42.4.3.2	 Pathology
					Macroscopic Features
					Microscopic Features
					Different Histological Patterns
					Cell Variants
					Grading
		42.5 Staging
		42.6 Treatment
			42.6.1	 Surgery
				42.6.1.1	 Liver Resection
				42.6.1.2	 Preoperative Assessment of the Patient Plays a Key Role
					Surgical Technique
				42.6.1.3	 Laparoscopic Liver Surgery
				42.6.1.4	 Liver Transplant
			42.6.2	 Locoregional Procedures
				42.6.2.1	 Ablation
				42.6.2.2	 PEI
				42.6.2.3	 RFA and MWA
			42.6.3	 TACE
			42.6.4	 Systemic Treatments
				42.6.4.1	 Sorafenib
				42.6.4.2	 Lenvatinib
				42.6.4.3	 Atezolizumab Plus Bevacizumab
				42.6.4.4	 Regorafenib
				42.6.4.5	 Cabozantinib
				42.6.4.6	 Ramucirumab
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		42.7 Future Perspectives
		42.8 Highlights
			Expert Opinion
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	43: Head and Neck Cancers
		43.1 Introduction
		43.2 Epidemiology and Risk Factors
			43.2.1	 Epidemiology
			43.2.2 Risk Factors
		43.3 Clinical Features
			43.3.1 Clinical Issues According to the Anatomic Subsite
			43.3.2 Oral Cavity
			43.3.3 Oropharynx
			43.3.4 Larynx
			43.3.5 Hypopharynx
			43.3.6 Occult Primary Head and Neck Cancer
		43.4 Natural History
		43.5 Pathological Features
			43.5.1	 Histological Type
		43.6 Diagnostic Work-Up
			43.6.1	 Assessment of HPV Infection
			43.6.2 Imaging
		43.7 Staging
		43.8 General Principles of Curative Treatment
			43.8.1 Surgical Principles
			43.8.2 Radiotherapy Principles
			43.8.3 Systemic Agents as Part of Curative Treatments
				43.8.3.1 Induction Chemotherapy
				43.8.3.2 Concomitant Chemotherapy During Radiation Treatment
				43.8.3.3 Adjuvant Chemotherapy
			43.8.4 Supportive Care During Radiation Treatment
		43.9 Principle for Curative Treatment of Specific Subsite Tumor
			43.9.1	 Oral Cavity
			43.9.2 Larynx
			43.9.3 Oropharynx
			43.9.4 Hypopharynx
		43.10 General Principles for HNC Palliative Treatment
			43.10.1 Radiotherapy: Palliative Treatment
			43.10.2 Systemic Treatment
		Case Study 	Oral Lesion
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		Case Study 	Neck Mass
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	44: Central Nervous System Malignancies
		44.1	 Introduction
		44.2	 Primary Brain Tumors
			44.2.1	 Classification
			44.2.2	 Diagnosis
			44.2.3	 Gliomas
			44.2.4	 Glioblastomas
			44.2.5	 Gliomatosis Cerebri
			44.2.6	 Ependymomas
			44.2.7	 Medulloblastoma
			44.2.8	 Meningiomas
			44.2.9	 Other Tumors
			44.2.10	 Genetic Syndromes
		44.3	 Brain Metastases
			44.3.1	 Epidemiology and Risk Factors
			44.3.2	 Pathophysiology
			44.3.3	 Clinical Manifestations
			44.3.4	 Diagnosis
			44.3.5	 Treatment
			44.3.6	 Conclusion
			Expert Opinion
				Recommendations
				Hints for a Deeper Insight
		References
			Primary Brain Tumors
			Brain Metastases
	45: Renal Cancer
		45.1 Introduction
		45.2 Epidemiology
		45.3 Risk Factors
		45.4 Histological Subtype and Molecular Profile
		45.5 RCC Pathogenesis and Tumor Evolution
			45.5.1	 Role of Genes
			45.5.2	 Role of Angiogenesis and Tumor Microenvironment
				45.5.2.1	 Angiogenesis
				45.5.2.2 Tumor Microenvironment
		45.6 Diagnosis and Staging
		45.7 Management
			45.7.1	 Localized Disease
				45.7.1.1 Risk Assessment in Localized Disease
			45.7.2	 Metastatic Disease
				45.7.2.1 Risk Assessment in Advanced Disease
				45.7.2.2 Integrated Management Strategy
		45.8 Emerging Treatment
		45.9 Follow-Up
		45.10 Conclusion
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	46: Bladder Cancer
		46.1 Introduction
		46.2 Epidemiology
		46.3 Etiology
		46.4 Clinical Features
		46.5 Pathological Features
			46.5.1	 Non-Invasive Bladder Cancer
			46.5.2	 Invasive Bladder Cancer
		46.6 Molecular Biology
		46.7 Diagnosis
		46.8 Staging and Prognosis
		46.9 Treatment
			46.9.1	 Treatment of Non-Muscle-Invasive Bladder Cancer
			46.9.2	 Treatment of Muscle-Invasive Bladder Cancer
				46.9.2.1	 Neoadjuvant and Adjuvant Chemotherapy
				46.9.2.2	 Radiotherapy With or Without Concomitant Chemotherapy
			46.9.3	 Metastatic Disease
				46.9.3.1	 First-Line Therapy
				46.9.3.2	 Second-Line Therapy
				46.9.3.3	 New Agents
		46.10 Follow-Up
			46.10.1	 Non-Muscle Invasive Bladder Cancer
			46.10.2	 Muscle Invasive Bladder Cancer
		Bibliography
	47: Prostate Cancer: Locoregional Disease
		47.1 Epidemiologic Evidence and Risk Factors of Prostate Cancer
			47.1.1	 Epidemiology
			47.1.2	 Risk Factors
		47.2 Initial Prostate Cancer Diagnosis and Disease Staging
			47.2.1	 Prostate Cancer Screening
			47.2.2	 Laboratory Test and Imaging for Diagnosis of Prostate Cancer
			47.2.3	 Histology and Grading Score
			47.2.4	 Staging of Localized Prostate Cancer
		47.3 Treatment Options for Localized Prostate Cancer
			47.3.1	 Observational Strategies: Active Surveillance and Watchful-Waiting
			47.3.2	 Surgical Approaches
				47.3.2.1	 Radical Prostatectomy and Prostate Cancer Risk Groups
				47.3.2.2	 Radical Prostatectomy in Senior Adult Patients (>70 Years of Age)
				47.3.2.3	 After Radical Prostatectomy for Curative Intent
				47.3.2.4	 Oncological Outcomes
				47.3.2.5	 Functional Outcomes
				47.3.2.6	 RP as Second-Line Treatment
			47.3.3	 Radiotherapy
				47.3.3.1	 External Beam Radiation Therapy
				47.3.3.2	 Brachytherapy
				47.3.3.3	 Complications of RT
				47.3.3.4	 Results of RT
			47.3.4	 Neoadjuvant and Adjuvant ADT After RT
		References
	48: Prostate Cancer: Advanced and Metastatic Disease
		48.1 Introduction
		48.2 Metastatic Hormone-Sensitive Prostate Cancer
			48.2.1	 Prognosis
			48.2.2	 Therapy
				48.2.2.1	 Androgen Deprivation Therapy for mHSPC
					Surgical Castration
					Medical Castration
				48.2.2.2	 Chemotherapy for mHSPC
				48.2.2.3	 Second-Generation Hormonal Therapy for mHSPC
		48.3 Metastatic Castration-Resistant Prostate Cancer
			48.3.1	 Introduction
			48.3.2	 Therapy
				48.3.2.1	 Chemotherapy for mCRPC
					Cabazitaxel
				48.3.2.2	 Radiopharmaceutical
					Radium-223
				48.3.2.3	 Novel Androgen-Directed Agents
					Abiraterone Acetate
					Enzalutamide
		References
	49: Testicular Cancer
		49.1 Introduction
		49.2 Epidemiology
		49.3 Clinical Features
		49.4 Diagnosis
			49.4.1	 Clinical Examination
			49.4.2	 Imaging
			49.4.3	 Serum Tumor Markers
			49.4.4	 Screening
		49.5 Differential Diagnosis
			49.5.1	 Pathology
		49.6 Staging
			49.6.1	 Imaging Studies
			49.6.2	 Risk Classification for Advanced Disease
		49.7 Treatment
			49.7.1	 Fertility Issues
			49.7.2	 Management of Testicular Cancer
				49.7.2.1	 Primary Treatment
				49.7.2.2	 Stage I Seminoma
				49.7.2.3	 Stage IS Seminoma
				49.7.2.4	 Stage IIA Seminoma
				49.7.2.5	 Stage IIB Seminoma
				49.7.2.6	 Stage IIC Seminoma
				49.7.2.7	 Stage III Seminoma
				49.7.2.8	 Post-chemotherapy Management of Seminoma Stages II–III
				49.7.2.9	 Stage I Non-seminoma
				49.7.2.10	 Stage IS Non-seminoma
				49.7.2.11	 Stage IIA Non-seminoma
				49.7.2.12	 Management of Non-seminoma Stage IIA After Primary Treatment
				49.7.2.13	 Stage IIB Non-seminoma
				49.7.2.14	 Advanced Metastatic Non-seminoma
		49.8 Follow-Up
		49.9 Survivorship
		References
	50: Cancer of the Penis
		50.1 Epidemiology and Cancer Prevention
		50.2 Genetic Aspects of Hereditary Cancer
		50.3 Differential Diagnosis
		50.4 Typical Signs and Symptoms
		50.5 Diagnostic Strategies and Staging
		50.6 Treatment Options
			50.6.1	 Nodal Anatomy, Drainage, and Treatment
			50.6.2	 Non-surgical Treatments
		50.7 Conclusions
		References
	51: Ovarian Cancer, Early Primary Disease
		51.1 Introduction
		51.2 Epidemiology
		51.3 Ovarian Cancer Staging
		51.4 Risk Factors
			51.4.1 Non-genetic
			51.4.2 Genetic Syndromes
		51.5 Screening
		51.6 Histological Subtypes
		51.7 Patterns of Spread of Epithelial Ovarian Cancer
		51.8 Diagnosis
		51.9 Prognostic Factors
		51.10 Treatment
			51.10.1 Surgery
			51.10.2 Adjuvant Chemotherapy
			51.10.3 Radiotherapy
		References
	52: Ovarian Cancer: Primary Advanced and Recurrent Disease
		52.1 Introduction
		52.2 Epidemiology, Diagnosis, Pathogenesis, and Prognosis
		52.3 Staging of Ovarian Cancer
		52.4 Primary Treatment of Advanced Disease
			52.4.1 Primary Debulking
		52.5 Systemic Treatment
		52.6 Secondary Cytoreductive Surgery
			Case study 1: Management of patient with BRCA germline mutation and recurrent ovarian cancer
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			Case study 2: Management of patient with stage IV ovarian cancer and BRCA germline mutation
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	53: Endometrial and Cervical Cancers
		53.1 Introduction
		53.2 Uterine Corpus Cancers
		53.3 Endometrial Cancer
			53.3.1 Epidemiology
			53.3.2 Etiological, Risk, and Protective Factors
			53.3.3 Prevention and Screening
			53.3.4 Histopathology and Molecular Biology
			53.3.5 Clinical Presentation and Diagnosis
			53.3.6 Pre-operative Work-Up, Staging, and Risk Groups
			53.3.7 Surgical Treatment, Lymphadenectomy, and SLND
			53.3.8 Adjuvant Treatment
			53.3.9 Advanced and Recurrent Disease
			53.3.10 New and Potential Future Therapeutic Perspectives
			53.3.11 Follow-Up
		53.4 Cervical Cancer
			53.4.1 Epidemiology
			53.4.2 Pathogenesis and Molecular Biology
			53.4.3 Primary and Secondary Prevention
			53.4.4 Histopathology
			53.4.5 Clinical Presentation and Diagnosis
			53.4.6 Pre-operative Work-Up, Staging, and Risk Assessment
			53.4.7 Treatment of Pre-invasive Tumors
			53.4.8 Treatment of Early Invasive Tumors (FIGO 2018 - IA1/2, IB1/2, IIA1)
			53.4.9 Adjuvant Treatment
			53.4.10 Treatment of Locally Advanced Disease
			53.4.11 Recurrent and Metastatic Disease
			53.4.12 New and Potential Future Perspectives
			53.4.13 Follow-Up
		53.5 Conclusions
		Case Study: Management of a Patient Affected by Locally Advanced Endometrial Cancer
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		Case Study: Management of a Patient Affected by Metastatic Cervical Cancer
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	54: Vulvar and Vaginal Cancers
		54.1 Vulvar Cancer
			54.1.1	 Overview
			54.1.2	 Clinical Presentation, Diagnosis, and Work-Up
			54.1.3	 Prognostic Factors and Surgical Staging
			54.1.4	 Management
			54.1.5	 Follow-Up
		54.2 Vaginal Cancer
			54.2.1	 Overview
			54.2.2	 Histopathological Approaches
			54.2.3	 Management
			54.2.4	 Follow-Up
		54.3 Summary: Conclusion
		Case Study: 	Vulvar Cancer In Situ
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		Case Study: 	Metastatic Vaginal Cancer
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			Summary of Clinical Recommendations
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	55: Cancer of the Adrenal Gland
		55.1 Introduction
		55.2 Epidemiology
		55.3 Heritability
		55.4 Adrenal Incidentaloma
		55.5 Clinical Features
		55.6 Pathological Features
		55.7 Molecular Biology
		55.8 Diagnosis
			55.8.1	 Hormone and Biochemical Assessment
			55.8.2	 Imaging
		55.9 Differential Diagnosis
		55.10 Prognostic Factors
		55.11 Treatment
		55.12 Follow-up
		References
	56: Cancer of the Thyroid
		56.1 Introduction
		56.2 Epidemiology and Etiology
		56.3 Histopathology Overview
		56.4 Clinical Features
		56.5 Pathological Features
			56.5.1 Macroscopic Aspect
			56.5.2 Microscopic Aspects and Immunohistochemical
		56.6 Diagnosis, Classification, and Staging Systems
		56.7 Molecular Biology
		56.8 Prognostic Factors
		56.9 Treatment
			56.9.1 Localized Disease
			56.9.2 Recurrent or Metastatic Disease
			56.9.3 TKI Resistance: The “Escape Phenomenon”
		56.10 Follow-up
		Case Study: Management of a Patient with a Progressive Metastatic Papillary Thyroid Cancer
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		Case Study Management of MTC in a Patient Affected by MEN2A
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	57: Cutaneous Melanoma and Other Skin Cancers
		57.1 Cutaneous Melanoma
			57.1.1 Introduction
			57.1.2 Epidemiology and Risk factors
			57.1.3 Pathogenesis
				57.1.3.1 Familial Melanoma
				57.1.3.2 Sporadic Melanoma
			57.1.4 Clinical Presentation
			57.1.5 Diagnosis
				57.1.5.1 Histopathology
			57.1.6 Staging
			57.1.7 Treatment of Early-Stage Disease
				57.1.7.1 Surgery
				57.1.7.2 Adjuvant Setting
				57.1.7.3 Interferon Alpha
				57.1.7.4 Ipilimumab
				57.1.7.5 Nivolumab
				57.1.7.6 Pembrolizumab
				57.1.7.7 Dabrafenib Plus Trametinib
			57.1.8 Treatment of Advanced Stage Disease
		57.2 Nonmelanoma Skin Cancer
			57.2.1 Introduction
			57.2.2 Actinic Keratosis
				57.2.2.1 Treatment
			57.2.3 Basal Cell Carcinoma
				57.2.3.1 Clinical Presentation
				57.2.3.2 Treatment
			57.2.4 Squamous Cell Carcinoma
				57.2.4.1 Histology
				57.2.4.2 Low-Risk Invasive cSCC
				57.2.4.3 Intermediate Risk Invasive cSCC
				57.2.4.4 High-Risk Invasive cSCC
				57.2.4.5 Treatment
			57.2.5 Merkel Cell Carcinoma
				57.2.5.1 Epidemiology and Risk Factors
				57.2.5.2 Histopathology
				57.2.5.3 Clinical Presentation
				57.2.5.4 Staging
				57.2.5.5 Treatment
				57.2.5.6 Local Disease
				57.2.5.7 Advanced Disease
				57.2.5.8 Immune Checkpoint Inhibitors
				57.2.5.9 Target Therapies
			57.2.6 Dermatofibrosarcoma Protuberans
				57.2.6.1 Histopathology
				57.2.6.2 Clinical Presentation
				57.2.6.3 Treatment
			57.2.7 Kaposi Sarcoma
				57.2.7.1 Treatment
		References
			Cutaneous Melanoma
			Nonmelanoma Skin Cancer
	58: Soft Tissue Sarcomas (STS)
		58.1 Introduction
			58.1.1 Diagnosis and Pathology
			58.1.2 Staging and Risk Assessment
		58.2 STS Management
			58.2.1 Essential Elements Prior to the Initiation of Therapy
			58.2.2 Principles of Multidisciplinary Therapeutic Approach
				58.2.2.1 Surgery
				58.2.2.2 Radiotherapy
		58.3 Medical Therapy
			58.3.1 Neoadjuvant Chemotherapy
			58.3.2 Adjuvant Chemotherapy
			58.3.3 Palliative Chemotherapy
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	59: Gastrointestinal Stromal Tumors (GISTs)
		59.1 The Role of Medical Treatment in the Management of GIST
			59.1.1 Introduction
			59.1.2 Origin
			59.1.3 Pathological Features
				59.1.3.1 Macroscopic Aspects (. Fig. 59.2)
				59.1.3.2 Microscopic Aspects and Immunohistochemistry (IHC)
			59.1.4 Molecular Biology
				59.1.4.1 KIT and PDGFRA
			59.1.5 Clinical Features
			59.1.6 Diagnosis
			59.1.7 Prognostic Factors
			59.1.8 GIST Management
				59.1.8.1 Focus on Imatinib (. Fig. 59.14)
			59.1.9 The Medical Treatment
				59.1.9.1	 Advanced and Metastatic GIST
				59.1.9.2 Molecular Profile of Primary and Secondary Resistance
				59.1.9.3 Type of Progression
				59.1.9.4 Strategies to Overcome the Resistance
				59.1.9.5 New Therapeutic Targets and Treatments to Overcome Resistance to TKI
				59.1.9.6 Role of Medical Treatment in Localized Disease
			59.1.10 Response Evaluation
		59.2 The Role of Surgery in the Management of GIST
			59.2.1 Introduction
			59.2.2 Localized GIST
			59.2.3 Gastric GIST
			59.2.4 Duodenal GIST
			59.2.5 Small Bowel GIST
			59.2.6 Rectal GIST
			59.2.7 Locally Advanced GIST
			59.2.8 Metastatic GIST
			59.2.9 Conclusion
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			The Role of Medical Treatment in the Management of GIST
			The Role of Surgery in the Management of GIST
	60: Neuroendocrine Neoplasms (NENs)
		60.1 Terminology/Classification
			60.1.1 GEP NENs
			60.1.2 Lung NENs
			60.1.3 Clinical Classification of NENs
		60.2 Epidemiology
			60.2.1	 GEP NENs
			60.2.2 Lung NENs
		60.3 Diagnostic Features of the Functioning and Nonfunctioning GEP NETs
			60.3.1 Clinical Presentation
			60.3.2 Gastrointestinal Neuroendocrine Neoplasms (GI NENs)
			60.3.3 Pancreatic Neuroendocrine Neoplasms (PanNENs)
			60.3.4 Biochemical Markers
			60.3.5 Radiological Techniques and Nuclear Medicine Tests
			60.3.6 Endoscopy
			60.3.7 Histology
		60.4 Diagnostic Features of Lung NETs
			60.4.1 Minimum Requirements of an Anatomopathological Report of Lung Neuroendocrine Neoplasms (NENs)
			60.4.2 Role of Ki67 in Pulmonary NEN
			60.4.3 Immunohistochemistry (IHC) in Lung NENs
			60.4.4 Endoscopic Diagnosis
			60.4.5 Radiological Imaging
		60.5 Molecular Biology Features
			60.5.1	 Gastroenteropancreatic Neuroendocrine Neoplasms (GEP NENs)
			60.5.2 Germline Mutations
				60.5.2.1 MEN1 and Menin
				60.5.2.2 VHL (Von Hippel Lindau)
				60.5.2.3 NF1 (Neurofibromatosis-1)
				60.5.2.4 TSC (Tuberous Sclerosis)1 and 2
			60.5.3 Somatic Mutations
			60.5.4 Role of Chromosomes
			60.5.5 Mechanism of Methylation
			60.5.6 Gene Expression Patterns
		60.6 Molecular Pathways and Biological Drugs
			60.6.1 Bases of Treatment
				60.6.1.1 Gastroenteropancreatic Neuroendocrine Neoplasms (GEP NENs)
				60.6.1.2 Local/Locally Advanced Stage
				60.6.1.3 Advanced Stage
				60.6.1.4 Lung Neuroendocrine Neoplasms (GEP NENs)
					Staging and Characterization (. Fig. 60.5)
						Local or Locally Advanced Stage
						Advanced Stage
		60.7 Theragnostic Role of Nuclear Medicine
			60.7.1 β+ Emitting Radiopharmaceuticals Employed for PET/CT Imaging
			60.7.2 Choice of the Radiopharmaceutical
			60.7.3 Radionuclide Target Therapy (PRRT)
				60.7.3.1 Contraindications to PRRT
		60.8 Chemotherapy
			60.8.1	 Gastroenteropancreatic Neuroendocrine Neoplasms (GEP NENs)
				60.8.1.1 Chemotherapy in Neuroendocrine Carcinomas (NECs)
				60.8.1.2 Chemotherapy in Neuroendocrine Tumors (NETs)
					Lung Neuroendocrine Neoplasms (NENs)
		60.9 Systemic Biological Therapies
			60.9.1	 Gastroenteropancreatic Neuroendocrine Neoplasms (GEP NENs)
			60.9.2 Somatostatin Receptors (SSTRs)
			60.9.3 mTOR Pathway
			60.9.4 Lung NETs
		60.10 Liver-Directed Treatments
			60.10.1 Ablative Treatments
			60.10.2 Vascular Treatments
			Expert Opinion
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				Recommendations
				Hints for a Deeper Insight
			Case Study: A Huge Abdominal Mass
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			Case Study: The Importance of PRRT
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Index