Front Cover 1
Thyroid Cancer and Other 
2 
copyright 
3 
Contributors 4
Contents 8
Endocrinology And 
 
 
13 
Foreword 
14 
Preface 
18 
How to Manage Patients with Differentiated Thyroid Cancer and a Rising Serum Thyroglobulin Level 20
Key points 20
Introduction 20
Differentiated Thyroid Cancer 20
LT4 Therapy in Patients with DTC 21
The Ability to Trap Iodine 21
Serum Tg 21
Biochemistry and Physiology of Tg 21
Serum Tg: A Sensitive and Specific DTC Tumor Marker 22
Tg in the management of patients with thyroid cancer 23
Disease-Free Patients with DTC 23
Unexpected Detectable Levels of Serum Tg: Disease Recurrence 23
Increasing of Already Detectable Serum Tg: Persistent Disease 25
Increasing Serum Tg Levels and Imaging Procedures 26
Neck Ultrasound 26
CT Scan, MRI, and Bone Scintigraphy 28
Nuclear Medicine Imaging 28
Summary 29
References 30
Molecular Diagnostics for Thyroid Nodules 34
Key points 34
Introduction 34
Immunohistochemical testing for thyroid cancer 35
Galectin-3 35
HBME-1 35
CK-19 36
CXCR-4 36
Fibronecin-1, CITED-1, CXCL-12 36
Combined Immunohistochemical Panels 36
Genetic testing for the identification of thyroid cancer 36
BRAF 36
RAS 37
RET/PTC 38
PAX8/PPARG 38
Combined Genetic Analysis 39
Commercially Available Multigene Mutation Panels from Quest Diagnostics and Asuragen 40
Next-Generation Sequencing Expanded Multigene Panel 40
The Veracyte Afirma Gene Expression Classifier 41
Microarray analysis 44
MicroRNA Expression 44
The Cleveland Clinic TSHR mRNA Assay (in Serum) 45
Summary and recommendations 45
Nodules with AUS/FLUS Cytology 45
Nodules with FN/SFN Cytology 46
Nodules with SMC Cytology 47
References 49
Thyrotropin in the Development and Management of Differentiated Thyroid Cancer 56
Key points 56
Introduction 57
TSH biology 57
History 57
Physiology of TSH 57
TSH and thyroid cancer development 57
Animal Model Evidence 57
Clinical Evidence 59
Future Research Needs and Opportunities 60
Thyroid cancer management 60
TSH and Radioactive Iodine 60
TSH and Monitoring of Thyroid Cancer 63
TSH Targets in Long-Term Levothyroxine Treatment 64
Summary 65
References 65
Initial Radioiodine Administration 74
Key points 74
Introduction and historical facts 74
Definition and overview of radioactive iodine treatment 75
Remnant Ablation 76
Adjuvant Therapy 76
Therapy for Known Residual or Metastatic Disease 78
Risk assessment of well-differentiated thyroid cancer: initial staging and implications for radioiodine treatment 78
The Use of Radioiodine Scans for Initial Staging 79
Factors affecting delivery of radioactive iodine 80
Patient Preparation 80
rTSH-rhTSH 80
Low-Iodine Diet 81
Minimization of side effects 81
Use of empiric or dosimetric methods 82
Summary and selection of 131-I activity 83
Very-Low-Risk Patients 83
Low-Risk Patients 83
Intermediate-Risk Patients: Adjuvant Treatment 84
High-Risk Patients: Treatment of Residual or Metastatic Disease 84
References 85
Update on Differentiated Thyroid Cancer Staging 90
Key points 90
Introduction 90
Initial Risk Stratification 91
Initial Estimates of Disease-Specific Mortality 91
Initial Staging System Used to Predict Risk of Persistent/Recurrent Disease 94
Restratification over time: response to therapy assessment 96
Response to Therapy Definitions 96
Using the response-to-therapy reclassification system to predict subsequent outcomes and guide long-term follow-up after to ... 99
Excellent Response to Therapy 99
Biochemical Incomplete Response to Therapy 99
Structural Incomplete Response to Therapy 100
Indeterminate Response to Therapy 100
Modification of the response-to-therapy reclassification system definitions for use in patients who did not receive RAI abl ... 101
Total Thyroidectomy Without RAI Ablation 101
Thyroid Lobectomy Alone 103
Summary 104
References 104
Update on Medullary Thyroid Cancer 112
Key points 112
Introduction 112
TK receptors and pathways involved in MTC development 113
The RET Receptor 113
Vascular Endothelial Growth Factor Receptors 113
Epidermal Growth Factor Receptor 113
Hepatocyte Growth Factor Receptor 114
Fibroblast Growth Factor Receptor 4 114
RAS 114
Syndromes 115
Sporadic MTC 115
Hereditary MTC 115
Initial diagnostic evaluation 116
Radiologic Surveillance 116
18F-FDG PET 117
18F-DOPA and 68Ga-DOTA PET 117
18F-NaF PET 117
Somatostatin Receptor Scintigraphy 117
Prognosis 118
Treatment 118
Prophylactic Surgical Management in Germline RET-Positive Patients 118
Surgical Management of MTC Presenting with Clinically Apparent Disease 119
Persistent Elevation of Serum Calcitonin and Carcinoembryonic Antigen After Surgery 120
Active Surveillance for Progression of Metastatic MTC 120
Locoregional Targeted Treatments of Metastases or Paraneoplastic Syndromes 121
Systemic Chemotherapy—Tyrosine Kinase Inhibitors 121
Summary 124
References 125
Surgery for Thyroid Cancer 132
Key points 132
Introduction 132
Indications 133
Preoperative surgical evaluation 134
Surgery for differentiated thyroid cancer 135
Surgery for MTC 139
Surgery for ATC 139
Reoperative thyroid surgery 140
Minimally invasive thyroid surgery 140
Pediatric thyroid surgery 141
Summary 142
References 142
Alternative Approaches to the Thyroid Gland 148
Key points 148
Introduction 148
Background and history 149
Defining alternative approaches 149
Advantages and disadvantages of alternative approaches 150
Approaches 151
Minimally Invasive Anterior Cervical 151
MIVAT 151
MINET 153
Remote Access Endoscopic 154
Chest/breast approaches 154
Axillary approaches 154
Transoral approaches 155
Remote Access Robotic Procedures 156
Robotic axillary thyroidectomy 156
Robotic facelift thyroidectomy 157
Summary 160
References 160
Persistent Posttreatment Fatigue in Thyroid Cancer Survivors 164
Key points 165
Introduction 165
Methods 165
Research Questions 165
Inclusion and Exclusion Criteria for Studies 165
Search for Relevant Studies 166
Study Selection 166
Data Abstraction and Reporting of Results 166
Consultation Phase 167
Results 168
Studies Included in the Scoping Review 168
Description of Studies According to Thematic Content 169
Epidemiologic studies 169
Descriptive fatigue-related data without non-TC control group comparisons 169
Case-control comparisons of fatigue-related outcomes at 1 time point 170
Explanatory studies 175
RCTs of interventions 176
Summary 177
Acknowledgments 178
References 178
Management of Graves' Disease 184
Key points 184
Introduction 185
Pathogenesis 185
Clinical manifestations 186
Cardiovascular 186
Pulmonary 186
Gastrointestinal 186
Neuropsychiatric 188
Reproductive 188
Musculoskeletal 189
Ophthalmopathy 189
Dermopathy and Acropachy 190
Apathetic Thyrotoxicosis 190
Treatment 190
Antithyroid Drugs 190
Radioactive Iodine 191
Thyroid Surgery 192
Adjuvant Treatment 193
Management of Thyrotoxicosis During Pregnancy 193
CPGs versus current clinical practice 194
Comparison of Guidelines with Current Practice Trends 194
Diagnosis 195
Primary treatment modality 195
Preferred ATD 196
Monitoring for adverse effects of ATD therapy 196
Management of hyperthyroidism in patients with Graves' ophthalmopathy 197
Management of GD during pregnancy 197
Summary 199
References 199
Thyroid Disease and the Cardiovascular System 206
Key points 206
Introduction 206
Thyroid hormone regulation and metabolism 206
Thyroid hormone action at the cellular level 207
Thyroid hormone action on the heart and cardiovascular system 208
Hyperthyroidism 209
Hypothyroidism 211
Subclinical thyroid disease 212
Subclinical hypothyroidism 212
Diagnosis and treatment 213
Alterations in thyroid hormone metabolism that accompany heart disease 213
Amiodarone-induced thyroid dysfunction 214
References 215
Thyroid Disease and Cognition 218
Key points 218
Introduction 218
Mechanisms of psychiatric and cognitive effects of hypothyroidism 220
Psychiatric and cognitive effects of overt hypothyroidism 220
Mood Effects 220
Cognitive Effects 220
Psychiatric and cognitive effects of subclinical hypothyroidism 221
Mood Effects 221
Cognitive Effects 221
Psychiatric and cognitive effects of overt thyrotoxicosis 222
Mood Effects 222
Cognitive Effects 223
Psychiatric and cognitive effects of subclinical thyrotoxicosis 223
Mood Effects 223
Cognitive Effects 223
Effect of thyroid function variations within the normal range on mood and cognition 224
Impact of T4/T3 combination therapy on mood and cognition in hypothyroidism 225
Possible associations between altered thyroid function and the development of dementia 225
Hashimoto encephalopathy 226
Summary 226
References 227
Ethical Issues in the Management of Thyroid Disease 234
Key points 234
Introduction 234
Core ethical principles 235
Origins of the 4 Principles 237
Informed Consent 238
Privacy and Confidentiality 238
Professional Virtues and Integrity 238
Ethical issues in autoimmune thyroid diseases 239
Unique Ethical Issues in Graves' Disease 239
Informed consent for radioablation 240
Ethical Challenges with Hypothyroidism 240
When hypothyroid patients refuse thyroid hormone replacement therapy 241
Unique issues with diagnostic challenges 241
Ethical issues in thyroid cancer 242
Ethical Issues in Adjuvant RAI Therapy 242
Radioidine dosimetry 243
Unique Ethical Issues in Iodine Non-avid Thyroid Cancer 243
The ethical use of tyrosine kinase inhibitors 244
Confidentiality, Genomics, and MTC 244
Ethical frameworks for vulnerable populations 245
Prenatal Ethics Frameworks 245
Preventative screening for maternal hypothyroidism 246
Pediatric Ethics Frameworks 246
When to involve child protective services 246
Geriatric Ethics Frameworks 247
Resource allocation and priority setting 247
Summary 248
References 249
Management of Recurrent Cervical Papillary Thyroid Cancer 254
Key points 254
Introduction 254
Background 255
Surgery 257
Radioactive iodine therapy 258
Observation 258
Ethanol injection 259
Summary 259
References 260
Thyroid Disorders During Pregnancy 262
Key points 262
Thyroid gland physiology in pregnancy 262
Universal screening versus targeted high-risk case finding of thyroid disorders in pregnancy 264
Hypothyroidism during pregnancy 265
Diagnosis 265
Pregnancy Complications 266
Adverse Outcomes in Neonates and Offspring 266
Isolated Hypothyroxinemia 267
Treatment 267
Euthyroidism with autoimmune thyroid disease 268
Hyperthyroidism in pregnancy 269
Gestational Transient Thyrotoxicosis 269
Graves' Disease in Pregnancy 270
Diagnosis 270
Outcomes 270
Treatment of Maternal Hyperthyroidism in Pregnancy 271
Preconception counseling 271
Antithyroid drugs 271
Surgery 272
ß-blockers 272
Cold iodine 273
Radioactive iodine therapy 273
Fetal monitoring 273
Postpartum care 274
Postpartum thyroiditis 274
Prevalence 275
Diagnosis 275
Maternal Outcomes 275
Treatment of Postpartum Thyroiditis 275
Evaluation of thyroid nodules and thyroid cancer in pregnancy 276
Summary 278
References 279
Index 288