Practical Management of Thyroid Cancer: A Multidisciplinary Approach

Preface
Contents
Contributors
1: Advances in Thyroid Cancer Management Beyond the Pandemic
	References
Part I: Multidisciplinary Approach to Management of Thyroid Cancer
	2: Review of NICE Thyroid Cancer Guidelines—UK 2022
		Introduction
		Diagnostic Procedures
		Surgical Management
		Post-Operative Management
		Need for RAI
			Preparation for RAI
		Radionuclide Therapy
		External Beam Radiotherapy (EBRT)
		Thyroid Hormone Replacement
		Dynamic Risk Stratification (DRS)
		Follow Up
		Limitations of Thyroglobulin
		Follow-Up
		Relapse
		Other Topics
		Recommendations for Future Research
		References
3: African Head and Neck Society Clinical Practice Guidelines for Thyroid Nodules and Cancer in Developing Countries and Limited Resource Settings
	Introduction
	Development of AfHNS Clinical Practice Guidelines for Thyroid Nodules and Cancer in Developing Countries and Limited Resource Settings
	Assessing a Thyroid Nodule
	Surgical Management of Thyroid Tumours in Low-Resource Settings
	Papillary Thyroid Cancer (PTC) in Low-Resource Settings
	Follicular (FTC) and Hürthle Cell (HCT) or Oncocytic (OCA) carcinoma in Low-Resource Settings
	Medullary Thyroid Cancer (MTC) in Low-Resource Settings
	Conclusions
	References
Part II: The Diagnosis of Thyroid Cancer
	4: Ultrasonography in Diagnosis and Management of Thyroid Cancer: Current International Recommendations
		US Lexicon and US Features Predictive of Malignancy
		US Risk Stratification System, Thyroid Imaging Reporting and Data System
		Recommendations for Biopsy of Thyroid Nodules
		US Risk Stratification System in Children
		Role of US in the Management of Thyroid Nodules after FNA
			Nondiagnostic
			Benign, Nonmalignant, Nonneoplastic
			Atypia of Undetermined Significance, Low-Risk Indeterminate Lesion, Neoplasm Possible (Atypia)
			Follicular Neoplasm, High-Risk Indeterminate Lesion, Neoplasm Possible (Follicular Neoplasm)
			Suspicious for Malignancy or Malignant
		Role of US in Preoperative Staging of Thyroid Cancer
			US Evaluation of Extrathyroidal Tumor Extension
			US Diagnosis of Cervical Lymph Node Metastasis
			Fine-Needle Aspiration cytology and Washout Thyroglobulin (Tg) Measurement for Cervical Lymph Node
		Role of US in Postoperative Surveillance
		Future Investigation
		References
5: The Molecular Pathology of Thyroid Cancer
	Introduction
	Classification of Thyroid Carcinoma
	Genotypes in Thyroid Cancer
		BRAF V600E Like Thyroid Cancer
		RAS Like Thyroid Cancer
	Mutational Landscapes in Thyroid Cancer
		Papillary Carcinoma
			Molecular Features in High Risk Variants of PTC
		Follicular Carcinoma
		Differentiated High Grade Thyroid Carcinoma
		Poorly Differentiated Thyroid Carcinoma
		Anaplastic Thyroid Carcinoma
		Oncocytic (Hurthle Cell) Carcinoma
		Cribriform Morular Thyroid Carcinoma
		Paediatric Follicular Tumours
			DICER1 Syndrome
		Carcinoma of the Thyroid with Ewing Family Tumour Elements (CEFTE)
		Mammary Analogue Secretory Carcinoma
		Medullary Carcinoma
	Genotype Progression in Thyroid Carcinoma: ‘From Differentiated to Anaplastic Carcinoma’
		Drivers of Poor Outcome in Differentiated Thyroid Cancer (DTC)
			TERT Promoter Mutations
			Genetic Changes Associated with Aggressive or Fatal DTC/PDTC
		Drivers of Poor Outcome in HGDTC/ PDTC
		Drivers of Poor Outcome in ATC
	Conclusion
	References
Part III: Initial Thyroid Surgery
	6: Management of Papillary Thyroid Microcarcinoma: A Japanese Experience
		Introduction
			Background
			Initiation of Active Surveillance (AS) for PTMC
			Major Intercountry Differences in Thyroid Cancer Incidence and Mortality
			Implementation of AS for PTMC
				Exclusion Criteria of AS
				Practice of AS
			Data Accumulation of AS
				Outcomes of Prospective Studies
				Real-World Evaluation of Tumor Enlargement
				Representative Factors Related to PTMC Progression on AS
					Patient Age
					Thyroid-Stimulating Hormone (TSH) Levels
					Ultrasound Findings of Tumors
					Pregnancy
			Lack of Pathological and Molecular Markers Predicting PTMC Progression
			How Long Should AS Be Continued?
			Surgery for PTMC
				Postoperative Prognosis
				Unfavorable Surgical Events
				CS After AS for PTMC Patients
				Medical Costs
				Comparison of Quality of Life (QoL) Between Patients Treated with AS and IS
		Conclusion
		References
	7: Advances in Thyroid Surgery
		Introduction
		Surgical Extent
			Pre-operative Workup
			Molecular Genetic Testing and Implications for Surgery
			De-escalation of Treatment from Routine Total Thyroidectomy to Hemithyroidectomy
			Intraoperative Evaluation
			Locally Advanced Disease
			Lymph Node Management
		Revision Surgery
		Innovations in Thyroid Surgery
			Intraoperative Neuromonitoring
			Intermittent vs Continuous IONM
			Near Infrared Autofluorescence (NIRAF) Detection of Parathyroid Glands
			Remote Access Approaches to Thyroid Surgery
			Radiofrequency Ablation
		Conclusion
		References
	8: Remote Access and Robotic Thyroidectomy: Current Status
		Introduction
		Development of Remote Access Thyroid Surgery
		Selection Criteria
		Surgical Techniques
			MIVAT
			Lateral Remote-Access
			Midline Remote-Access
		Morbidity
		Oncologic Outcomes
			MIVAT
			Robot-Assisted Remote-Access Surgery (BABA, GAA)
			TOETVA
		Discussion
		References
9: Contentious Issues in the Management of the Neck in Well-Differentiated Thyroid Cancers
	Introduction
	The Subjects of Controversy
	Central Compartment
	Lateral Neck Management
	Prognostic Factors in Neck Node Metastasis in Well-Differentiated Thyroid Cancer
	Recurrent Nodal Disease
	The Central Compartment Recurrence
	Recurrent Lateral Neck Disease
	Summary
	References
Part IV: Post Surgical Management of Differentiated Thyroid Cancer
	10: Radioiodine Dosimetric Approaches: Current Concepts and Future Directions
		Introduction
		Potential Benefits of Dosimetry
		Approaches to Dosimetry
			Maximum Tolerated Activity
			Lesional Dosimetry
		Current Evidence for a Dosimetric Approach
		Developments in Dosimetry Methodology
			Dosimetry Requirements
			Quantitative Imaging and Time-Integrated Activity
			Organ-Based S-Values and Voxel-Based Dosimetry
			Summary of Dosimetry Methodologies Advances
		Ongoing Initiatives
			Low Risk Thyroid Cancer
			High Risk/Advanced Thyroid Cancer
			Iodine Refractory Thyroid Cancer
		Future Directions
		References
	11: External Beam Radiation in Differentiated Thyroid Cancer in the Era of IMRT and Modern Radiation Planning Techniques
		Introduction
		EBRT in Differentiated Thyroid Cancer
			Post-operative EBRT to Reduce the Risk of Local-Regional Recurrence
			Definitive EBRT for Unresectable Differentiated Thyroid Cancer
			Chemoradiotherapy for DTC
		EBRT in Medullary Thyroid Cancer
		EBRT in Anaplastic Thyroid Cancer
		Radiotherapy in Symptom Palliation and Oligometastases
			Lung Metastases
			Bone Metastases
			Brain Metastases
		Integrating Radiotherapy with Systemic Therapy
		Techniques and Toxicity
			Technique
			Volumes and Dose Selection
			Acute and Late Complications of EBRT
		Conclusions
		References
	12: Management of Post-operative Hypocalcemia
		Introduction
		Post-operative Hypocalcemia
			Prevention
			Prediction
			Management
				Mild Hypocalcemia
				Moderate to Severe Hypocalcemia
		Chronic Post-operative Hypocalcemia
			Goals of Management
		Conventional Therapy
			Calcium
			Vitamin D and Its Activated Forms
			Optimization of Therapy
			Monitoring
			Long-Term Outcomes and Complications
		Parathyroid Hormone
			Synthetic PTH1–34
			rhPTH1–84
			TransCon PTH
		Pregnancy and Lactation
		References
13: On ART, and ART (Ablative Radioiodine Therapy)!
Part V: Follow Up and Longterm Management of Differentiated Thyroid Cancer
14: Radioiodine Refractory Thyroid Cancer
	Introduction
		Definition of Refractory Thyroid Cancer
		The Molecular Landscape of DTC and Altered Signaling Pathways
		Focal Treatment Modalities
			Locally Advanced Disease
			Bone Metastasis
			Brain Metastasis
			Pulmonary and Liver Metastasis
	Systemic Treatment
		Initiation and Clinical Follow-Up
		Multikinase Inhibitors (Sorafenib and Lenvatinib)
			Sorafenib
			Lenvatinib
			Cabozantinib
		Selective Kinase Inhibitors
			NTRK Inhibitors (Larotrectinib and Entrectinib)
			Resistance to Larotrectinib and Entrectinib
		Selective RET Inhibitors (Selpercatinib and Pralsetinib)
			Resistance to Selpercatinib and Pralsetinib
		Selective BRAF Inhibitors
			Combination of Dabrafenib-Trametinib (D-T)
			Off-Label Drugs for Differentiated Thyroid Carcinoma
			Vemurafenib in RAIR-DTC
			Apatinib
		Selective mTOR Inhibitors (Everolimus, Temsirolimus)
			Redifferentiation Agents
	Immunotherapy
		Pembrolizumab
	Conclusions
	References
Part VI: Medullary Thyroid Carcinoma and Familial Non Medullary Thyroid Cancer
	15: Surgery for Medullary Thyroid Cancer
		Introduction
		The Patient Population and Cancer Genetics
		Investigations
		Treatment
		Prophylactic Thyroid Surgery in Hereditary Cancer Syndromes
		Follow-Up
		Conclusion
		References
	16: Medullary Thyroid Cancer: Diagnosis and Non-surgical Management
		Introduction
		Diagnosis of Medullary Thyroid Cancer
			Clinical Presentation
			Diagnostic Work-Up
				Evaluation of Thyroid Nodule
				Cytopathological Diagnosis on FNA
				Serum Markers
					Calcitonin
					Carcinoembryonic Antigen
					Other Markers
				Pre-operative Imaging
				Histopathology
				Molecular Testing and RET
					Genotyping in Hereditary MTC
		Non-surgical Management
			Locally-Directed Therapies
			Systemic Therapy
				Multikinase Inhibitors
					Special Considerations
				Selective RET-Inhibitors
				Cytotoxic Chemotherapy
				Peptide Receptor Radionuclide Therapy (PRRT)
		Conclusions
		References
17: Familial Non-medullary Thyroid Cancer
	Introduction
	Syndromic FNMTC
		PTEN Hamartoma Tumor Syndrome (PHTS)
			Genetics of PTEN Hamartoma Tumor Syndrome
			Clinical Features of PTEN Hamartoma Tumor Syndrome
				Cowden Syndrome
				Bannayan-Riley-Ruvalcaba Syndrome (BRRS)
			Management of Thyroid Cancer Associated with PTEN Hamartoma Tumor Syndrome
		Peutz-Jeghers Syndrome
			Genetics of Peutz-Jeghers Syndrome
			Clinical Features of Peutz-Jeghers Syndrome
			Management of Thyroid Cancer Associated with Peutz-Jeghers Syndrome
		Familial Adenomatous Polyposis (FAP)
			Genetics of FAP
			Clinical Presentation of FAP
			Management of Thyroid Cancer Associated with FAP
		Carney Complex
			Genetics of Carney Complex
			Clinical Presentation of Carney Complex
			Management of Thyroid Cancer Associated with Carney Complex
		Pendred Syndrome
			Genetics of Pendred Syndrome
			Clinical Features of Pendred Syndrome
			Management of Thyroid Cancer Associated with Pendred Syndrome
		DICER1 Syndrome
			Genetics of DICER1 Syndrome
			Clinical Features of DICER1 Syndrome
			Management of Thyroid Cancer Associated with DICER1 Syndrome
		Ataxia-Telangiectasia
			Genetics of Ataxia-Telangiectasia
			Clinical Features of Ataxia-Telangiectasia
			Management of Thyroid Cancer Associated with Ataxia-Telangiectasia
		Papillary Renal Neoplasia (PRN)
			Genetic Background of PRN
			Clinical Features of PRN
			Management of Thyroid Cancer Associated with PRN
		Werner Syndrome
			Genetics of Werner Syndrome
			Clinical Features of Werner Syndrome
			Management of Thyroid Cancer Associated with Werner Syndrome
		Clinical Uncertainties in Syndromic FNMTC
	Nonsyndromic FNMTC
		Genetics of Nonsyndromic FNMTC
			FOXE1
			HABP2
			Tumor Cell Oxyphilia 1 (TCO1)
			Telomere-Telomerase Complex
			Locus 4q32
			Multinodular Goiter 1 (MNG1)
			Familial PTC/PRN Locus
			NMTC1 Locus
			8p22–23.1 Locus
			6q22 Locus
			SRGAP1
			TTF-1/NKX2.1
			WDR77 (WD Repeat Domain 77)
			SPRY4
			C14orf93 (RTFC)
		Clinical Features of Nonsyndromic FNMTC
		Diagnosis
		Management of FNMTC
	References
Part VII: Thyroid Cancer in Children
18: Childhood Papillary Thyroid Carcinoma
	Introduction and Mayo Clinic Contributions to PTC Management
	Comparisons of PTC in Children and Adults Treated at Mayo Clinic
	Drawing on Guidelines and ‘Golden Rules’ to Propose an Approach to CPTC
	Management Step 1: Diagnosis and Preoperative Evaluation
	Management Step 2: Primary Surgical Treatment
	Management Step 3: Staging and Risk-Group Assignment
	Management Step 4: Adjuvant Therapy and Role of Radioiodine Remnant Ablation
	Management Step 5: Long-Term Surveillance
	Management Step 6: Persistent/Recurrent Neck Disease
	Management Step 7: Distant Metastases and Targeted Therapy
	Conclusions
	References
Part VIII: Aggressive Thyroid Cancers
	19: Anaplastic Thyroid Cancer
		Background
		Approach to ATC Evaluation and Diagnosis
			Clinical Presentation
			Imaging
			Histopathology
			Staging
		Management
			Role of Surgery
				Neoadjuvant Therapy
			Radiotherapy
			Systemic Therapy
				BRAF-Mutated
				BRAF-Wild Type
				Immunotherapy
			Other Supportive Therapies and Symptom Management
		Conclusion
		References
20: Primary Mesenchymal Tumors of the Thyroid
	Introduction
	Classification of Mesenchymal Tumors
	Types of Primary Mesenchymal Tumors of the Thyroid
		Tumors of Vascular Origin
			Hemangioma
			Angiosarcoma
		Primary Nerve Sheath Tumors of the Thyroid
		Paraganglioma
		Granular Cell Tumor
		Smooth Muscle Tumors
		Solitary Fibrous Tumor
	Pathobiology of Primary Mesenchymal Tumors of the Thyroid
		Primary Mesenchymal Tumors of the Thyroid of Vascular Origin
		Primary Thyroid Nerve Sheath Tumor (Schwannomas, Neurofibroma, and Malignant Primary Nerve Sheath Tumors)
		Paraganglioma
		Granular Cell Tumor
		Smooth Muscle Tumor
		Solitary Fibrous Tumor
	Diagnosis of Primary Mesenchymal Tumors of the Thyroid
	Clinical Presentations and Biochemical Evaluation
	Imaging
	Fine Needle Aspiration and Cytology and Histopathology
	Screening in Patients with Primary Mesenchymal Tumors of the Thyroid
	Treatment for Primary Mesenchymal Tumors of the Thyroid
	Prognosis of Primary Mesenchymal Tumors of the Thyroid
	Summary
	References
Part IX: Future Developments and Directions for Research in Thyroid Cancer
	21: Current Trends in Treatment and New Generation of Trials in Thyroid Cancer
		Introduction
		Emerging Strategies with Approved, Commercially Available Drugs
			Redifferentiation Therapies in DTC
			Neoadjuvant Approach in ATC
		Pathway Inhibitors
			MAPK Pathway
			mTOR Pathway
		Targeting the Tumor Microenvironment
			Immune Checkpoint Therapy in Cancer
			Immune Microenvironment and Experience with Immunotherapy in Thyroid Cancer
			Adoptive Cell Therapy
			ACT Clinical Trials, TILs and TCR
			ACT Clinical Trials, CAR T-Cell Therapy
		Resistance Mechanisms
			Overcoming Resistance to Targeted Therapies
		Circulating Tumor DNA as a Potential Thyroid Cancer Biomarker
		Conclusions/Summary
		References
	22: Thyroid Cancer Clinical Trials
		Introduction
		Types of Clinical Trials and Main Design Features
		Early Phase Trials
			Phase I
			Single Arm Phase II
			Phase II Basket Trials: Biomarker Driven (Directed) Treatment Trials
			Randomised Phase II
		Late Phase Trials
			Superiority Phase III Studies (Suitable for Advanced Disease)
			Non-inferiority Phase III Studies (Suitable for Low Risk Disease)
		Immunotherapy Trials
		Surgical Trials
		Future Trials
		Summary
		References
	23: Thyroid Cancer Survivorship: Contemporary Themes
		The Nature of Thyroid Cancer
		The Thyroid Cancer Multidisciplinary Team
			Survivorship
		Health-Related Quality of Life
			Psychological Distress in Patients with Cancer
		Psychological Distress in Thyroid Cancer
		Effectiveness of Interventions
		A Psychological Model of Adjustment to Cancer
		Model of Professional Psychological Assessment and Support
			The Role of the Clinical Nurse Specialist
		Holistic Needs Assessment
			Social Concerns
			Physical/Appearance Concerns
			Emotional Concerns
			An Example of Service Delivery
			Discussion and Contemporary Themes
		Case Examples
		References
	24: Differentiated Thyroid Cancer: A Health Economic Review
		Introduction
		Epidemiology of DTC
		Overdiagnosis and Overtreatment
			Indeterminate Thyroid Nodules
			Extent of Surgery
			Increasing Cost of Thyroid Surgery
			Active Surveillance
			Follow-Up
			Financial Burden
		Conclusion
		References
Part X: Covid-Sars-2 Pandemic: The Impact on Management of Thyroid Cancer—Key Lessons Learnt for the Future
25: Thyroid Cancer Surgery During the Pandemic—UK Perspective
	Introduction
	Referrals for Suspected Thyroid Cancer
	Prioritisation and Resource Allocation
	Surgical Planning
	Potential Impact of Surgical Prioritisation
	Clinic and Telemedicine
	Training in Thyroid Cancer Surgery
	Conclusion and Lessons for the Future
	References
26: Impact on Non Surgical Management and Trials of Thyroid Cancer
	Introduction
	Radioiodine Therapy
	Systemic Anti-cancer Therapy
	Clinical Trials
	Patient Follow Up and Support
	References
Index