Practical Management of Thyroid Cancer: A Multidisciplinary Approach [3rd ed. 2023] 3031386043, 9783031386046

Table of contents :
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

Citation preview

Practical Management of Thyroid Cancer A Multidisciplinary Approach Ujjal K. Mallick Clive Harmer Editors Third Edition

123

Practical Management of Thyroid Cancer

Ujjal K. Mallick  •  Clive Harmer Editors

Practical Management of Thyroid Cancer A Multidisciplinary Approach Third Edition

Editors Ujjal K. Mallick MS FRCPE(Hon) FRCP(Hon) FRCR Consultant Clinical Oncologist (Hon) Northern Centre for Cancer Care Freeman Hospital Newcastle Upon Tyne Hospitals NHS Foundation Trust Newcastle upon Tyne, UK

Clive Harmer St. George’s Healthcare NHS Trust and The Royal Marsden NHS Trust London, UK

Chief Investigator, “Hilo” (NEJM 2012) & “IoN” Thyroid Cancer Trials UK National Cancer Research Institute Cancer Research (UK) Funded Member IDMC, NIHR “HoT” TriaL Member Oncology Council Royal Society of Medicine London, UK

ISBN 978-3-031-38604-6    ISBN 978-3-031-38605-3 (eBook) https://doi.org/10.1007/978-3-031-38605-3 © The Editor(s) (if applicable) and The Author(s), under exclusive license to Springer Nature Switzerland AG 2023. Springer-Verlag London Limited, 2006, 2018 This work is subject to copyright. All rights are solely and exclusively licensed by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors, and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, expressed or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. This Springer imprint is published by the registered company Springer Nature Switzerland AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland Paper in this product is recyclable.

This Book is dedicated to All who happened to have had Thyroid Cancer, hoping it might be of some Help and Support.

Preface

The second edition of this international reference book was published in 2018. Major and transformative advances have taken place in the research and management of thyroid cancer over the last 5 years. New studies and ­trials have been designed, many based on the explosion of knowledge about the molecular landscape of Thyroid Cancer and there has been on-going significant international collaboration towards uniform evidence-based ­ guidelines and their implementation. The fervent hope is that every patient would have access to a current guideline-based effective, cost-effective, ­efficient, patient-focused, timely management wherever the patient is being treated. This book, in a tiny way, attempts to embody this view. We are most grateful for the kindness and hard work of leading world authorities and of the excellent team at Springer, which made this third ­edition possible, despite the unforeseen pandemic and its unfortunate devastating global impact. We sincerely hope it will be of some help to our patients and our professional colleagues. Ujjal Mallick Clive Harmer

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Contents

1 Advances  in Thyroid Cancer Management Beyond the Pandemic������������������������������������������������������������������������������������   1 Ujjal K. Mallick and Clive Harmer Part I Multidisciplinary Approach to Management of Thyroid Cancer 2 Review  of NICE Thyroid Cancer Guidelines—UK 2022 ������������  11 Nick Reed 3 African  Head and Neck Society Clinical Practice Guidelines for Thyroid Nodules and Cancer in Developing Countries and Limited Resource Settings ������������������������������������������������������  19 Johannes J. Fagan, Mark Zafereo, Kathryn Marcus, Marika D. Russell, and Gregory Randolph Part II The Diagnosis of Thyroid Cancer 4 Ultrasonography  in Diagnosis and Management of Thyroid Cancer: Current International Recommendations����������������������  31 Dong Gyu Na, Ji-hoon Kim, and Eun Ju Ha 5 The  Molecular Pathology of Thyroid Cancer��������������������������������  59 Mufaddal T. Moonim Part III Initial Thyroid Surgery 6 Management  of Papillary Thyroid Microcarcinoma: A Japanese Experience��������������������������������������������������������������������  77 Yasuhiro Ito, Akira Miyauchi, and Makoto Fujishima 7 Advances in Thyroid Surgery ��������������������������������������������������������  87 Erin Buczek, Teresa Kroeker, Cristian Slough, Damilola R. Fakunle, Amr H. Abdelhamid Ahmed, and Gregory W. Randolph 8 R  emote Access and Robotic Thyroidectomy: Current Status���������������������������������������������������������������������������������� 101 Klaas Van Den Heede, Matilda Annebäck, and Neil Tolley ix

x

9 Contentious  Issues in the Management of the Neck in WellDifferentiated Thyroid Cancers������������������������������������������������������ 111 Ashok R. Shaha and R. Michael Tuttle Part IV Post Surgical Management of Differentiated Thyroid Cancer 10 R  adioiodine Dosimetric Approaches: Current Concepts and Future Directions ���������������������������������������������������� 123 Jan Taprogge, Glenn Flux, Kate Garcez, Matthew Beasley, and Jonathan Wadsley 11 External  Beam Radiation in Differentiated Thyroid Cancer in the Era of IMRT and Modern Radiation Planning Techniques������������������������������������������������������������������������ 133 Jelena Lukovic, James D. Brierley, and Aruz Mesci 12 Management  of Post-operative Hypocalcemia������������������������������ 143 Claudio Marcocci 13 On  ART, and ART (Ablative Radioiodine Therapy)! ������������������ 161 Furio Pacini and Ujjal K. Mallick Part V Follow Up and Longterm Management of Differentiated Thyroid Cancer 14 Radioiodine Refractory Thyroid Cancer �������������������������������������� 165 Fabian Pitoia, Anabella Smulever, and Fernando Jerkovich Part VI Medullary Thyroid Carcinoma and Familial Non Medullary Thyroid Cancer 15 Surgery  for Medullary Thyroid Cancer���������������������������������������� 191 E. Gréant, A. R. Shaha, and I. J. Nixon 16 Medullary  Thyroid Cancer: Diagnosis and Non-surgical Management ������������������������������������������������������������������������������������ 201 Leslie Cheng and Kate Newbold 17 Familial Non-medullary Thyroid Cancer�������������������������������������� 215 Joanna Klubo-Gwiezdzinska, Yevgenia Kushchayeva, Sudheer Kumar Gara, and Electron Kebebew Part VII Thyroid Cancer in Children 18 Childhood Papillary Thyroid Carcinoma�������������������������������������� 249 Ian D. Hay Part VIII Aggressive Thyroid Cancers 19 Anaplastic Thyroid Cancer ������������������������������������������������������������ 281 Leslie Cheng and Kate Newbold

Contents

Contents

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20 Primary  Mesenchymal Tumors of the Thyroid ���������������������������� 291 Jiangnan Hu, Rodas Kassu, and Electron Kebebew Part IX Future Developments and Directions for Research in Thyroid Cancer 21 Current  Trends in Treatment and New Generation of Trials in Thyroid Cancer������������������������������������������������������������ 307 Priyanka C. Iyer, Samer A. Srour, Marie Claude Hofmann, and Maria E. Cabanillas 22 Thyroid Cancer Clinical Trials ������������������������������������������������������ 325 Allan Hackshaw 23 Thyroid  Cancer Survivorship: Contemporary Themes �������������� 343 Katherine Kendell and Nicola Jane Armstrong 24 D  ifferentiated Thyroid Cancer: A Health Economic Review ���������������������������������������������������������������������������� 369 Matilda Annebäck, Klaas Van Den Heede, and Neil Tolley 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������������������������������������������������������������ 381 Sumrit Bola and Vinidh Paleri 26 Impact  on Non Surgical Management and Trials of Thyroid Cancer���������������������������������������������������������������������������� 387 Kathleen A. Farnell and Jon Wadsley Index���������������������������������������������������������������������������������������������������������� 391

Contributors

Amr  H.  Abdelhamid  Ahmed Division of Thyroid and Parathyroid Endocrine Surgery, Department of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA Matilda  Annebäck  Department of Surgical Sciences, Uppsala University, Uppsala, Sweden Department of Surgery, Uppsala University Hospital, Uppsala, Sweden Nicola Jane Armstrong  Thyroid Multidisciplinaty Team, Newcastle upon tyne Hospitals NHS trust, Newcastle upon Tyne, UK Matthew  Beasley Department of Clinical Oncology, Bristol Cancer Institute, Bristol, UK Sumrit Bola  Deapartment of Head and Neck Surgery, The Royal Marsden NHS Foundation Trust, London, UK James  D.  Brierley  Department of Radiation Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada Erin  Buczek Department of Otolaryngology-Head and Neck Surgery, University of Kansas Medical Center, Kansas City, KS, USA Maria  E.  Cabanillas Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Leslie  Cheng Thyroid Unit, The Royal Marsden NHS Foundation Trust, London, UK Johannes  J.  Fagan Division of Otorhinolaryngology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa Damilola  R.  Fakunle University of Cincinnati College of Medicine, Cincinnati, OH, USA Kathleen A. Farnell  Butterfly Thyroid Cancer Trust, Tyne and Wear, UK Glenn Flux  Department of Physics Institute of Cancer Research, Institute of Cancer Research, London, UK Makoto Fujishima  Department of Surgery, Kuma Hospital, Kobe, Japan xiii

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Sudheer Kumar Gara  Thoracic Surgery Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA Kate  Garcez Department of Clinical Oncology, Christie Hospital, Manchester, UK E. Gréant  Department of Head and Neck Surgery, NHS Lothian, Edinburgh, UK Eun Ju Ha  Department of Radiology, Ajou University School of Medicine, Suwon, Republic of Korea Allan  Hackshaw Cancer Research UK & UCL Cancer Trials Centre, University College London, London, UK Clive Harmer  Thyroid Unit, Royal Marsden Hospital, London, UK Medical Society of London, London, UK Ian D. Hay  Division of Endocrinology and Internal Medicine, Mayo Clinic College of Medicine and Science, Rochester, MN, USA Marie Claude Hofmann  Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Jiangnan  Hu Department of Surgery, Stanford University, Stanford, CA, USA Yasuhiro Ito  Department of Surgery, Kuma Hospital, Kobe, Japan Priyanka  C.  Iyer Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Fernando  Jerkovich Division of Endocrinology, Hospital de Clínicas, University of Buenos Aires, Buenos Aires, Argentina Rodas  Kassu Department of Surgery, Stanford University, Stanford, CA, USA Electron Kebebew  Department of Surgery, Stanford University School of Medicine, Stanford, CA, USA Department of Surgery, Stanford University, Stanford, CA, USA Stanford Cancer Institute, Stanford University, Stanford, CA, USA Katherine  Kendell Department of Clinical Psychology, The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK Ji-hoon Kim  Department of Radiology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Republic of Korea Joanna Klubo-Gwiezdzinska  Metabolic Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA

Contributors

Contributors

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Teresa  Kroeker The Texas Thyroid and Parathyroid Center, Austin, TX, USA Yevgenia  Kushchayeva Division of Endocrinology, University of South Florida, Tampa, FL, USA Jelena  Lukovic Department of Radiation Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada Ujjal  K.  Mallick Northern Centre for Cancer Care, Freeman Hospital Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK Claudio  Marcocci Department of Clinical and Experimental Medicine, Endocrine Unit 2, University Hospital of Pisa, University of Pisa, Pisa, Italy Kathryn Marcus  Department of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA Aruz Mesci  Department of Radiation Oncology, Princess Margaret Cancer Centre, University of Toronto, Toronto, ON, Canada Akira Miyauchi  Department of Surgery, Kuma Hospital, Kobe, Japan Mufaddal  T.  Moonim  Department of Pathology, Charing Cross Hospital, Imperial College Healthcare Trust, London, UK Dong  Gyu  Na Department of Radiology, GangNeung Asan Hospital, University of Ulsan College of Medicine, Gangneung, Gangwon, Republic of Korea Kate Newbold  Thyroid Unit, The Royal Marsden NHS Foundation Trust, London, UK I. J. Nixon  Department of Head and Neck Surgery, NHS Lothian, Edinburgh, UK Furio  Pacini  Endocrinology and Metabolism, University of Siena, Siena, Italy Vinidh Paleri  Department of Head and Neck Surgery, The Royal Marsden Hospital, London, UK Fabian Pitoia  Division of Endocrinology, Hospital de Clínicas, University of Buenos Aires, Buenos Aires, Argentina Gregory W. Randolph  Otolaryngology-Head and Neck Surgery, Division of Thyroid and Parathyroid Endocrine Surgery, Department of Otolaryngology-­ Head and Neck Surgery, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

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Nick  Reed Department of Clinical Oncology, NHS Glasgow and Clyde, Glasgow, Scotland, UK Marika D. Russell  Division of Thyroid and Parathyroid Endocrine Surgery, Department of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA Ashok R. Shaha  Head and Neck Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA Weill-Cornell Medical College, New York, NY, USA Cristian  Slough Department of Otolaryngology-Head and Neck Surgery, Hawke’s Bay Fallen Soldiers’ Memorial Hospital, Hawke’s Bay District Health Board, Hastings, New Zealand Anabella  Smulever Division of Endocrinology, Hospital de Clínicas, University of Buenos Aires, Buenos Aires, Argentina Samer A. Srour  Department of Stem Cell Transplantation, The University of Texas MD Anderson Cancer Center, Houston, TX, USA Jan Taprogge  Department of Physics Institute of Cancer Research, Institute of Cancer Research, London, UK Neil  Tolley  Department of Endocrine and Thyroid Surgery, Hammersmith Hospital, London, UK Department of Otorhinolaryngology and Head and Neck Surgery, St Mary’s Hospital, London, UK Department of Surgery and Cancer, Imperial College, London, UK R.  Michael  Tuttle Endocrinology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA Klaas  Van Den Heede Department of General and Endocrine Surgery, Onze-Lieve-Vrouw (OLV) Hospital Aalst-Asse-Ninove, Aalst, Belgium Jonathan Wadsley  Department of Clinical Oncology, Weston Park Hospital, Sheffield, UK Mark  Zafereo Head and Neck Surgery, MD Anderson Cancer Center, Houston, TX, USA

Contributors

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Advances in Thyroid Cancer Management Beyond the Pandemic Ujjal K. Mallick and Clive Harmer

Abbreviations ATA American Thyroid Association ATC Anaplastic thyroid cancer BRAF B-Raf proto-oncogene CPTC Childhood papillary thyroid carcinoma CSM Cause-specific mortality DTC Differentiated thyroid cancer DTC Differentiated thyroid carcinoma ERK Extracellular signal-regulated kinase FDA US Food and Drug Administration FNA Fine needle aspiration FTC Follicular thyroid cancer

U. K. Mallick (*) Consultant Clinical Oncologist (Hon), Northern Centre for Cancer Care, Freeman Hospital Newcastle Upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK e-mail: [email protected] C. Harmer Thyroid Unit, Royal Marsden Hospital, London, UK Medical Society of London, London, UK

GBq Gigabecquerel ITH Intratumour heterogeneity LRDTC Low-risk Differentiated Thyroid Cancer LRPTC Low-risk papillary thyroid cancer MAPK Mitogen-activated protein kinase MDT Multidisciplinary team MEK Mitogen-activated extracellular signal-­regulated kinase NRAS Neuroblastoma RAS viral oncogene homolog NTRK Neurotrophic tyrosine receptor kinase ORR Objective response rate OS Overall survival PDTC Poorly differentiated thyroid cancer PFS Progression-free survival PR Partial response PTC Papillary thyroid cancer RAI Radioactive iodine RET Rearranged during transfection rhTSH Recombinant human TSH RRA Radioiodine remnant ablation TC Thyroid cancer Tg Thyroglobulin TIME Tumour immune microenvironment TNM Tumour-node-metastasis TRK Tropomyosin receptor kinase TT Total thyroidectomy US Ultrasound VEGFR Vascular endothelial growth factor receptor

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 U. K. Mallick, C. Harmer (eds.), Practical Management of Thyroid Cancer, https://doi.org/10.1007/978-3-031-38605-3_1

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2 A physician is obligated to consider more than a diseased organ, more even than the whole person, the physician must view the person in his or her own world

U. K. Mallick and C. Harmer

declined since 2014 by about 2% per year because of changes in clinical practice guidelines restricting over-detection by unnecessary ultrasound and needle biopsies, recommendations against thy—Harvey Cushing roid cancer screening by the USPSTF, and possibly in a small way some coding changes for Key Points follicular variant of papillary thyroid carcinoma Changing incidence, “Less is More”— during 2015–2017 . However, disease-specific Minimalistic management options for low-risk mortality had not increased [2–4]. DTC, adapting, adopting, and implementing curIn the past, vast majority of LRDTC were rent guidelines, intersocietal consensus (e.g. treated by Total Thyroidectomy (TT) and Martinique Principles) and global health approach Radioiodine Ablation (RAIAB). One of the reafor uniform equitable treatment, Next Generation sons was to ablate the remaining normal thyroid Sequencing (NGS), Single cell Sequencing remnant—Radioiodine Remnant Ablation (RRA) (Sc-Seq), molecular landscape of Thyroid Cancer to make Thyroglobulin (TG) and subsequent (TC) with high frequency of druggable mutations Radioiodine Scan (RS) more sensitive in detectand kinase fusions , basket trials and tumour ing residual and recurrent disease early. However, agnostic drug approvals, dual kinase inhibition in since the availability of serial-sensitive TG and BRAF V 600 E mutated ATC with significant high-resolution ultrasound (US) of the neck (the impact, quality of life, survivorship issues, commonest site of recurrence in LRDTC), this patient’s view, lessons of the pandemic, and pos- was not essential and detecting residual and prosible emerging role of AI in the future. gressive disease usually within 3–6 years or so became possible. Other reasons for postoperative According to GLOBOCAN cancer incidence and RAI is Adjuvant RAI (ARAI) for presumed mortality figures, an estimated 19.3 million new microscopic disease in intermediate risk and cancer cases (18.1  million excluding non-­ some low-risk cases and therapeutic RAI (TRAI) melanoma skin cancer) and almost 10.0 million in high-risk cases with known metastatic disease cancer deaths (9.9 million excluding non-­ to improve disease-specific survival and recurmelanoma skin cancer) occurred in 2020. The rence rates [5, 6]. global cancer burden is expected to be 28.4 milThe overall outcome of LRDTC is excellent. lion cases in 2040, a 47% rise from 2020 [1]. Because of this in recent years, the therapeutic In 2023, 1,958,310 new cancer cases and philosophy has taken a minimalistic and “Primum 609,820 cancer deaths are projected to occur in Non Nocere” (First do no Harm) and “Less is the United States. Against this background, the More” approach. The paradigm of almost routine estimated incidence of new cases of thyroid can- TT +RAIAB is shifting. cer, the commonest endocrine cancer, in the Two large multicentre randomised controlled United States in 2023 is likely to be 43,720 of trials (RCT) provided level 1 evidence that after 3 which 12,540 are males and 31,180 are females. years of follow-up in selected cases of LRDTC The total number of cases of death from thyroid total thyroidectomy only by a specialist surgeon cancer in 2023 is likely to be 2120 of which 970 is non-inferior to TT + RAI 1.1GBq in terms of are males, and 1150 are females [2]. event rates or recurrence rates ([7], Allan The commonest type of thyroid cancer, Hackshaw-Personal Communication). However, Differentiated Thyroid Cancer (DTC) ranks high- specialist multidisciplinary team management, est (98%) amongst the other cancers with high proper case selection, and preoperative risk stratsurvival rates prostate (97%), testis (95%), and ification, surgery by a high-volume surgeon with for melanoma (94%). careful intraoperative assessment, and postoperaAfter decades of increase due to overdiagnosis tive risk stratification are critical. The criteria for of LRDTC, thyroid cancer incidence rates have postoperative decision to use RAI based on US

1  Advances in Thyroid Cancer Management Beyond the Pandemic

and thyroglobulin level need further clarification at this time as the detailed findings of another trial is awaited (Allan Hackshaw-personal communication). Also perhaps slightly longer ­ period of follow-up would be helpful. Now for selected LRDTC—Active Surveillance (AS) without immediate surgery, Thyroid Lobectomy (TL) not TT, Thermal RFA , TT without RAIAB, and TT+RAIAB are all possible options depending on proper risk stratification using the ATA risk category. These are based on few level 1 evidence from RCT and more on well-designed prospective non-randomised studies, retrospective studies, analysis of registry data, etc. Because of this paucity of level 1 evidence at present, the controversy continues although time and cost-intensive RCTs continue to be designed and published [8–17]. Because of this doctor-patient shared decision-­ making for an individualised treatment plan is of paramount importance, making sure that the right risk stratified thyroid cancer in the right patient (with full understanding) is treated by the right specialist multidisciplinary team with the right evidence-based guidance in right time, every time, everywhere to echo the dictum of the National Academy of Medicine. Also because of this controversy, the team needs to carefully assess which option suits the patient best given the patient’s age, sex, general health, job, family and societal commitments, psychological make­up to cope with protracted treatment, follow-up and its financial pressures in certain health care settings, etc. Dr. Cushing’s adage is so appropriate in the setting of LRDTC! This personalised and nuanced minimalistic approach for the treatment of LRDTC remains one of the central issues in the Thyroid Cancer Management. Leading world authorities will give their latest views on this very important topic in this edition to help the readers with their practical day-to-day clinical activities, detailing the advantages and disadvantages of each approach. However, according to some authorities there has been slightly increased incidence of advanced thyroid cancers in recent years as well, possibly

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related to obesity and environmental factors. This is also supposed to be associated with slightly increased incidence-based mortality [18–22]. DTC is stratified for recurrence by ATA classification and overall outcome by the AJCC TNM 8th edition. Recent advances in surgical approaches, Intraoperative Neural Monitoring (IONM), radioiodine treatment, theranostics, radioiodine dosimetry, advances in radiotherapy, and other forms of local treatment as required will be discussed by world leaders. In recent years, major efforts have been taken to develop international and intersocietal consensus such as the Martinique Principles for a uniform approach to radioiodine therapy and its concepts. While LRDTC is highly curable, advanced DTC has a poor prognosis specially if it is radioiodine refractory. In addition, Medullary Thyroid Cancer (MTC), Poorly Differentiated Thyroid Cancer (PDTC), and ATC have worse prognosis and until recently ATC was untreatable and incurable. Major international guidelines and scholarly articles have been produced to facilitate and improve outcome. Thyroid cancer is a tumour type with one of the highest proportion of actionable mutations after gastrointestinal stromal tumour (76%) and thyroid cancer (60%). TCGA analysis also showed that thyroid cancers harbour the highest frequency of oncogenic driver kinase fusions of all solid tumours [23, 24]. But major advances in the methodologies over the last few years such as NGS have provided detailed knowledge of the molecular underpinnings of thyroid cancer allowing specific gene-­ directed systemic treatments with better outcomes. In addition, advances in the field of Sc-Seq have enabled transcriptomic and other information at a single-cell resolution rather than bulk sequencing providing averaged data. This provides valuable information regarding ITH, TIME, Circulating Tumour Cells (CTC), etc. helping our understanding of the tumour dynamics and biology and planning of precision targeted therapy with better outcomes.

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Some of the actionable or druggable targets in thyroid cancer are BRAF V600E and KRAS, NRAS, and HRAS mutations. In addition, kinase fusions involving NTRK, RET, ALK, and other fusions are oncogenic drivers and have been identified as actionable targets in thyroid cancer. They are being treated with selective MKIs with progression-free survival benefit though overtime acquired resistance does develop after initial response when new treatments are required. In recent years, new forms of trials with master protocols or basket trials have shown that some drugs are effective in treating a range of tumours with a specific gene alteration or bio-­ marker regardless of their histology or anatomical site of origin and are called tumour agnostic drugs. Such drugs have been approved by FDA and also are being used in thyroid cancer with better outcomes and acceptable side effects. For example, following the phase II Basket Trial, the ROAR study, FDA, and regulatory bodies in other countries have authorised the dual treatment by dabrafenib (BRAFV600E MAPK inhibitor) and trametinib (MEK inhibitor) for the treatment of BRAFV600E-mutated ATC.  This has been a major advancement in ATC with durable responses which previously was untreatable and incurable with an Objective Response Rate of about 55% including three complete responses; the 12-month Overall Survival (OS) was just over 50% with reasonable tolerance and manageable toxicity. In recent years, many non-selective multi-­ kinase inhibitors (MKI), including sorafenib, lenvatinib, and cabozantinib, have been used for the therapy of aggressive radioiodine (RAI)-resistant DTC and cabozantinib and vandetanib for MTC. Selpercatinib and pralsetinib selectively inhibit mutant RET in MTC, but they can also block the RET fusion proteins-mediated signalling found in PTC and are being used. Selective inhibitors, entrectinib and larotrectinib, have been approved for use in patients with progressive RAI-resistant TC harbouring NTRK fusion proteins. Some of these new gene-specific treatments are also being used in the neoadjuvant setting for advanced diseases. Some also have been used for

U. K. Mallick and C. Harmer

redifferentiation of radioiodine-resistant DTC for retreatment with RAI again. In addition to druggable gene alterations, tumour mutational burden, microsatellite instability status, and PD-L 1 status are being evaluated for the appropriateness of use of immunotherapy for some of these tumours [25–33]. Progress in liquid biopsy such as (CTC) and circulating free tumour DNA (ct-DNA) are emerging as additional bio-markers. It can help early detection, monitoring, and early treatment of recurrent disease by a blood test to improve outcomes without the need for multiple tissue biopsies particularly from metastases in inaccessible areas. Serial assessment can provide information about tumour heterogeneity, clonal evolutional trajectory of progressive tumours, and detection of resistant clones. But further developments are necessary before routine clinical use is possible though is being used in trial settings in some tumours. Many tumours will become resistant after initial period of response to non-selective and selective kinase inhibitors. Instead of further multiple tissue biopsies, liquid biopsy with CTC or ct-­ DNA by a simple blood test can detect the resistant cell clone and help design subsequent treatment [34–37]. World experts discuss these in detail in this edition informing us about the current state of the art and the future directions of research. The world faced the unforeseen pandemic in 2020 and millions of lives were unfortunately lost. But an unprecedented spirit of international collaboration was unlocked and professionals, scientists, and people crossing all boundaries devoted themselves to making major innovative, transformative scientific advances in a global effort to combat the pandemic. Diagnostic tests, innovative viral m-RNA-based vaccines, new drugs and therapeutics, new reliable large trial designs, etc. were all developed with unimaginable speed to tackle the pandemic first. Major positive systemic changes and adaptations in health care delivery also affected all types of cancer management including thyroid cancer

1  Advances in Thyroid Cancer Management Beyond the Pandemic

management. Safe and timely diagnosis and treatment were planned if necessary with the help of digital technology such as telemedicine, remote technical and quality assurance ­mitigating workforce and equipment shortages, while many were busy treating covid-19 patients on the frontline not only taking appropriate care but also taking considerable personal risk. Highly successful trials such as the Recovery Trial during the pandemic also showed that reliable trials with newer design and newer methods of conducting can be done efficiently and in a time-efficient manner. Remote randomisation, treatment, monitoring, (decentralising the processes), integrating research data with patient-­ reported outcomes and routine data and other developments in trials is discussed by world expert statisticians and clinicians and professionals. Written by world authorities from several countries like the previous editions, this third edition hopes to embrace and embody this philosophy of international and intersocietal collaboration and disseminate the recent advances in the field of thyroid cancer with a truly global health perspective. There is variation in thyroid cancer treatment between country to country and not infrequently between different parts of the same country. This is due to multiple factors surrounding the implementation of guidelines. Although the situation is improving, currently guidelines cannot give strong recommendations in every clinical scenario due to paucity of randomised trials and therefore can be interpreted differently by different clinicians; limited availability of health care resources and limited access to specialist care provided by multidisciplinary teams with high-­volume professionals are also likely caused in some areas. This is being addressed by best possible adaptation of international guidelines to the specific country’s health care infrastructure as detailed in the guidelines section. Also international and intersocietal collaboration and consensus statements are facilitating implementation of uniform guidance as far as practicable for equitable delivery of evidencedbased care reducing such variations within a global health perspective [13, 38, 39]. Although most LRDTC are curable, thyroid cancer patients are well known to have poor quality of

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life comparable to some of the major cancers, high anxiety level, and financial burden of protracted treatment and follow-up. Global dissemination of information and guidelines, optimal communication with patients, survivorship and psychosocial support, patient education, and co-­ operation between specialists are therefore essential [40–42]. Artificial Intelligence (AI) or the ability of computer machines to apply almost human-like reasoning to solving problems usually involves two techniques. Machine learning, in which computers learn by observing data provided by humans, and Deep Learning, which uses Artificial Neural Networks (ANN) similar to the functional structure of the brain to analyse data. The latter has a nontransparent black-box pattern of working which is not fully “Explainable” and is a cause for concern in direct patient care according to some [43]. Explosion of medical data and revolution in data-driven medicine have necessitated embedding data analytics, Artificial Intelligence-­ Machine Learning operations in many aspects of health care, and it is no surprise that its role is increasingly being assessed in the field of thyroid cancer. AI-driven algorithms are being used for accurate, objective and fast radiology, and pathological diagnosis and in risk stratification of thyroid nodules (already four AI platforms have been approved by the FDA), assessment of cytopathology, involvement of lymph nodes and in genomics for prediction of gene mutation, storage and analysis of -omics data helping precision oncology, etc. It is also a great help in quality control, managing workflow, training, managing staff shortages, and remote guidance even in limited resource settings [43]. Like many new advances, its use is likely to evolve in the thyroid cancer field but cost-­ effective, user friendly, reliable, validated AI platforms are required. More importantly, clinicians need to be trained and reassured about the reliability of AI black box algorithms as used in direct patient care. Many guidelines such as EU guidelines, US Food and Drug Administration (FDA) whitepaper, guidelines from the National Institute for Health and Care Excellence (NICE), etc. recommend AI should be robust, ethical, and lawful.

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And many authorities feel it should augment the actions of humans through explainable transparent decision pathways rather than black box opaque decision-making which is the usual way ANNs work [43–50]. As before, this book is aimed at experts of all disciplines who are members of a specialist multidisciplinary team involved in the day-to-day management of thyroid cancer including trainees and students. In addition, in the new post-­ pandemic world this might be a helpful resource book for information technologists involved in telemedicine and AI in health care, health policy makers, hospital managers, geneticists, researchers, scientists, and statisticians. Like the previous editions, its focus is providing a practical, person-centred approach that also informs and empowers patients for shared decision-­making during their treatment journey with a chapter written by an expert patient and patient adviser. The publication of this third edition would not have been possible without the collaborative leadership, profound kindness, hard work, commitment, and enthusiasm of respected international experts in thyroid cancer from several countries and the world leading Springer editorial team led by Melissa Morton who ignored the many major problems facing the post-pandemic world and sacrificed their precious time to offer their expertise and valuable contributions. We extend our thanks and heartfelt gratitude to all of them. We thank our wives and family for their tolerance and kind support during the preparation of the book.

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1  Advances in Thyroid Cancer Management Beyond the Pandemic developing countries and limited resource settings. Head Neck. 2020;42(8):1746–56. (3rd edition) 14. Tuttle RM, Li D, Ridouani F.  Percutaneous ablation of low-risk papillary thyroid cancer. Endocr Relat Cancer. 2023:ERC-22-0244. doi: https://doi. org/10.1530/ERC-­22-­0244. Online ahead of print. 15. Orloff LA, Noel JE, Stack BC Jr, et al. Radiofrequency ablation and related ultrasound-guided ablation technologies for treatment of benign and malignant thyroid disease: an international multidisciplinary consensus statement. Head Neck. 2022;44(3):633–60. https://doi.org/10.1002/hed.26960. 16. Chou R, Dana T, Haymart M, Leung AM, Tufano RP, Sosa JA, Ringel MD. Active surveillance versus thyroid surgery for differentiated thyroid cancer: a systematic review. Thyroid. 2022;32(4):351–67. https:// doi.org/10.1089/thy.2021.0539. Epub 2022 Mar 17 17. Jasim S, Patel KN, Randolph G, Adams S, Cesareo R, Condon E. American association of clinical endocrinology disease state clinical review: the clinical utility of minimally invasive interventional procedures in the management of benign and malignant thyroid lesions. Endocr Pract. 2022;28(4):433–48. https://doi. org/10.1016/j.eprac.2022.02.011. 18. Lim H, Devesa SS, Sosa JA, Check D, Kitahara CM.  Trends in thyroid cancer incidence and mortality in the United States, 1974–2013. JAMA. 2017;317(13):1338–48. https://doi.org/10.1001/ jama.2017.2719. 19. Yan KL, Li S, Tseng CH, Kim J, Nguyen DT, Dawood NB, Livhits MJ, Yeh MW, Leung AM.  Rising incidence and incidence-based mortality of thyroid cancer in California, 2000–2017. J Clin Endocrinol Metab. 2020;105(6):dgaa121. https://doi.org/10.1210/ clinem/dgaa121. 20. Wilhelm A, Conroy PC, Calthorpe L, Shui AM, Kitahara CM, Roman SA, Sosa JA. Disease-specific survival trends for patients presenting with differentiated thyroid cancer and distant metastases in the United States, 1992–2018. Thyroid. 2023;33(1):63– 73. https://doi.org/10.1089/thy.2022.0353. Published Online:13 Jan 2023 21. Kim J, Gosnell JE, Roman SA.  Geographic influences in the global rise of thyroid cancer. Nat Rev Endocrinol. 2020;16:17–29. https://doi.org/10.1038/ s41574-­019-­0263-­x. 22. Karzai S, Zhang Z, Sutton W, Prescott J, Segev DL, McAdams-DeMarco M, Biswal SS, Ramanathan M Jr, Mathur A.  Ambient particulate matter air pollution is associated with increased risk of papillary thyroid cancer. Surgery. 2022;171(1):212–9. https://doi. org/10.1016/j.surg.2021.05.002. Epub 2021 Jun 29 23. Stransky N, Cerami E, Schalm S, Kim JL, Lengauer C.  The landscape of kinase fusions in cancer. Nat Commun. 2014;5:4846. 24. Zehir A, Benayed R, Shah RH, Syed A, Middha S, Kim HR, Srinivasan P, Gao J, Chakravarty D, Devlin SM, Hellmann MD, Barron DA, Schram AM, Hameed M, Dogan S, et al. Mutational landscape of metastatic cancer revealed from prospective clinical sequenc-

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ing of 10,000 patients. Nat Med. 2017;23(6):703–13. https://doi.org/10.1038/nm.4333. Epub 2017 May 8 25. Lubitz CC, Sadow PM, Daniels GH, Wirth LJ. Progress in treating advanced thyroid cancers in the era of targeted therapy. Thyroid. 2021;31(10):1451–62. https:// doi.org/10.1089/thy.2020.0962. Epub 2021 Jun 22 26. Shonka DC Jr, Ho A, Chintakuntlawar AV, Geiger JL, Park JC, Seetharamu N.  American Head and Neck Society Endocrine Surgery Section and International Thyroid Oncology Group consensus statement on mutational testing in thyroid cancer: defining advanced thyroid cancer and its targeted treatment. Head Neck. 2022;44(6):1277–300. https://doi. org/10.1002/hed.27025. Epub 2022 Mar 11 27. Fugazzola L, Elisei R, Fuhrer D, Jarzab B, Leboulleux S, Newbold K, et  al. European Thyroid association guidelines for the treatment and follow-up of advanced radioiodine-refractory thyroid cancer. Eur Thyroid J. 2019;8:227–45. https://doi.org/10.1159/000502229. 28. Subbiah V, Kreitman RJ, Wainberg ZA, et  al. Dabrafenib plus trametinib in patients with BRAF V600E-mutant anaplastic thyroid cancer: updated analysis from the phase II ROAR basket study. Ann Oncol. 2022;33:406–15. 29. Shaha AR.  Anaplastic thyroid cancer: shifting paradigms—a ray of hope. Thyroid. 2023;33(4):402– 3. https://doi.org/10.1089/thy.2023.29150.sha. Published Online: 28 February 2023 30. Gild ML, Bullock M, Tsang V, Clifton-Bligh RJ, Robinson BG, Wirth LJ.  Challenges and strategies to combat resistance mechanisms in thyroid cancer therapeutics. Thyroid. 2023;33(6):682–90. https:// doi.org/10.1089/thy.2022.0704. 31. Chmielik E, Rusinek D, Oczko-Wojciechowska M, Jarzab M, Krajewska J, Czarniecka A, et  al. Heterogeneity of thyroid cancer. Pathobiology. 2018;85(1–2):117–29. https://doi. org/10.1159/000486422. 32. Baslan T, Hicks J.  Unravelling biology and shifting paradigms in cancer with single-cell sequencing. Nat Rev Cancer. 2017;17(9):557–69. https://doi. org/10.1038/nrc.2017.58. 33. Boufraqech M, Nilubol N.  Multi-omics signatures and translational potential to improve thyroid cancer patient outcome. Cancers. 2019;11(12):1988. https:// doi.org/10.3390/cancers11121988. Published online 2019 Dec 10 34. Romano C, Martorana F, Pennisi MS, Stella S, Massimino M, Tirrò E, Vitale SR, Di Gregorio S, Puma A, Tomarchio C, Manzella L.  Opportunities and challenges of liquid biopsy in thyroid cancer. Int J Mol Sci. 2021;22(14):7707. https://doi.org/10.3390/ ijms22147707. 35. Dent BM, Ogle LF, O'Donnell RL, Hayes N, Malik U, Curtin NJ, Boddy AV, Plummer ER, Edmondson RJ, Reeves HL, May FE, Jamieson D.  High-resolution imaging for the detection and characterisation of circulating tumour cells from patients with oesophageal, hepatocellular, thyroid and ovarian cancers. Int J Cancer. 2016;138(1):206–16.

8 36. Xu JY, Handy B, Michaelis CL, Waguespack SG, Hu MI, Busaidy N, Jimenez C, Cabanillas ME, Fritsche HA Jr, Cote GJ, Sherman SI. Detection and prognostic significance of circulating tumor cells in patients with metastatic thyroid cancer. J Clin Endocrinol Metab. 2016;101(11):4461–7. 37. Allin DM, Shaikh R, Carter P, Thway K, Sharabiani MTA, Gonzales-de-Castro D, O’Leary B, Garcia-­ Murillas I, Bhide S, Hubank M, Harrington K, Kim D, Newbold K. Circulating tumour DNA is a potential biomarker for disease progression and response to targeted therapy in advanced thyroid cancer. Eur J Cancer. 2018;103:165–75. https://doi.org/10.1016/j. ejca.2018.08.013. Epub 2018 Sep 22 38. Davis S, Ullmann TM, Roman S.  Disparities in treatment for differentiated thyroid cancer. Thyroid. 2023;33(3):287–93. https://doi.org/10.1089/ thy.2022.0432. Published Online: 3 Nov 2022 39. Mallick UK, Pitoia F. The barriers to uniform implementation of Clinical Practice Guidelines (CPG) for thyroid cancer. In: Practical management of thyroid cancer: a multidisciplinary approach. Switzerland: Springer Verlag AG; 2018. p. 357–68. 40. Karcioglu AS, Dhillon VK, Davies L, Stack BC Jr, Bloom G, Randolph G, Lango MN.  Analysis of unmet information needs among patients with thyroid cancer. JAMA Otolaryngol Head Neck Surg. 2023;149(2):110–9. https://doi.org/10.1001/ jamaoto.2022.4108. 41. Pace-Asciak P, Russell JO, Tufano RP.  Review: improving quality of life in patients with differentiated thyroid cancer. Front Oncol. 2023;13:1032581. https://doi.org/10.3389/fonc.2023.1032581. eCollection 2023 42. Lubitz CC, Sosa JA.  The changing landscape of papillary thyroid cancer: epidemiology, management, and the implications for patients. Cancer.

U. K. Mallick and C. Harmer 2016;122(24):3754–9. https://doi.org/10.1002/ cncr.30201. Epub 2016 Aug 12 43. Tessler FN, Thomas J.  Artificial intelligence for evaluation of thyroid nodules: a primer. Thyroid. 2023;33(2):150–8. https://doi.org/10.1089/ thy.2022.0560. Epub 2023 Jan 25 44. Tarabichi M, Demetter P, Craciun L, Maenhaut C, Detours V.  Thyroid cancer under the scope of emerging technologies. Mol Cell Endocrinol. 2022;541:111491. https://doi.org/10.1016/j. mce.2021.111491. Epub 2021 Nov 2 45. Topol EJ.  High-performance medicine: the convergence of human and artificial intelligence. Nat Med. 2019;25:44–56. 46. Abazeed ME. Walking the tightrope of artificial intelligence guidelines in clinical practice. Lancet Digit Health. 2019;1(3):e100. https://doi.org/10.1016/ S2589-­7500(19)30063-­9. Epub 2019 Jun 27 47. Peng S, Liu Y, Lv W, Liu L, Zhou Q, Yang H. Deep learning-based artificial intelligence model to assist thyroid nodule diagnosis and management: a multicentre diagnostic study. Lancet Digit Health. 2021;3(4):e250–9. https://doi.org/10.1016/ S2589-­7500(21)00041-­8. 48. Li LR, Du B, Liu HQ, Chen C.  Artificial intelligence for personalized medicine in thyroid cancer: current status and future perspectives. Front Oncol. 2021;10:604051. https://doi.org/10.3389/ fonc.2020.604051. eCollection 2020 49. Matheny M, Israni Thadaney S, Ahmed M, Whicher D.  Artificial intelligence in health care: the hope, the hype, the promise, the peril. Washington, DC: National Academy of Medicine; 2022. Accessed March 15, 2023. https://nam.edu/ artificial-­intelligence-­special-­publication/ 50. Haug CJ, Drazen JM.  Artificial intelligence and machine learning in clinical medicine, 2023. N Engl J Med. 2023;388:1201–8.

Part I Multidisciplinary Approach to Management of Thyroid Cancer

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Review of NICE Thyroid Cancer Guidelines—UK 2022 Nick Reed

Introduction The purpose of this document is to review the recent publication by the National Institute for Health and Care Excellence (NICE) regarding the management of differentiated thyroid cancer (DTC) in the NHS England. The following reference will provide the reader with a background to NICE processes [1]. It maybe helpful to start to explain what are guidelines and what is the rationale for producing guidelines and try to explain the difference between guidance, guidelines and protocols and these terms are sometimes used interchangeably. Guidelines are usually evolutionary and often form a series of publications over a number of years reflecting changes in clinical practice. The key point is that they are evidence based and make recommendations for delivery of care. They are useful reference documents for clinical decision-making and also audit and benchmarking. They also help to establish minimal standards of care. This is helpful for both large and small units and helps to ensure similar standards are applied in both. They provide good practice guidance and recommendations rather than mandating the level of care. It is hoped that the consequence is an improvement in overall standard of N. Reed (*) Department of Clinical Oncology, NHS Glasgow and Clyde, Glasgow, Scotland, UK

care. This guideline presents a new review of the topic in differentiated thyroid cancer. Guidance tends to be a more informal process, as it implies guiding clinical care. Protocols more usually apply to the details of clinical trials. It covers both those with thyroid nodules suspicious of malignancy and confirmed thyroid cancer. Thyroid cancer itself is relatively uncommon although its incidence has been rising but thyroid lumps, nodules and swellings are frequent and usually innocent. The target audience is generally medical staff, nurses, allied health professionals, medical physics and nuclear medicine staff, charities, heath care providers/commissioners and patients and their families. This is a broad remit and the challenge is to make it readable for all groups. This is of course not a textbook. In this new NICE guideline we will indicate how this changes clinical practice, what has been added as a new recommendation for care and what has been replaced or updated [2]. It is broken up into a number of component sections including diagnostic techniques, surgery, the role of radio iodine, medical treatment, external beam radiotherapy and follow up. The diagnostic sections include imaging, biochemistry, cytology and histopathology. Molecular profiling is still establishing its role as technology changes so rapidly. The composition of the members of the NICE guideline reflects the multidisciplinary management of thyroid cancer and includes ENT and

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 U. K. Mallick, C. Harmer (eds.), Practical Management of Thyroid Cancer, https://doi.org/10.1007/978-3-031-38605-3_2

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N. Reed

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thyroid/endocrine surgeons, pathologists, imaging specialists, endocrinologists, clinical oncologists, nuclear medicine specialists, general practitioners and nurses. Other papers have described in detail the processes used to determine NICE guidelines but this short paper will focus on the changes and challenges and highlight some of the controversies. Modern medicine is rarely black and white and there are frequently grey areas where even experts may disagree but generally we are able to achieve a consensus and it is hoped that this document has fulfilled that aspiration. The document specifically covers differentiated thyroid cancer, namely papillary, follicular and oncocytic (Hurthle cell) variants. It does not include medullary thyroid cancer (MTC) nor anaplastic thyroid cancer (ATC). It also excludes paediatric thyroid cancer and recurrent thyroid cancer. The topics covered include the following: 1. Management of suspected thyroid cancer, diagnostic procedures 2. Patients planned for surgery 3. Confirmed diagnosis of DTC 4. Information about Radio-iodine 5. Biochemical monitoring and tumour markers 6. Follow up of DTC The cancer journey starts with symptoms suggestive of an underlying thyroid cancer although recent practice has seen a rising incidence of incidentally detected tumours on imaging. This is followed by the diagnostic procedures to establish a diagnosis. These include Ultrasound and cytology with Rapid On Site Evaluation (ROSE). Tumour markers play a limited role, they have no place in diagnosis but are valuable in post therapy management. Other imaging will be discussed including CT scans, MRI and nuclear medicine scans. Some aspects of these topics are covered by other NICE guidelines [3]. Molecular pathology is an emerging topic in DTC. The patient may present with symptoms, most commonly a lump in the neck or goitre but an

increasing number have thyroid nodules incidentally picked up on scans done for other purposes. In recent times with the increasing role of FDG PET scans for staging cancers, avid uptake is seen in the thyroid gland. Most patients with a lump are now referred to dedicated neck lump clinics run by ENT surgeons or specialist thyroid or endocrine surgeons. Rarely patients will present with metastatic disease in bones or lungs. The next step is to discuss the management at the Multi-Disciplinary Team (MDT) meeting, also known as the Tumour Board.

Diagnostic Procedures Ultrasound (US) and Fine Needle Aspiration Cytology (FNAC) are the mainstay of testing. There are different US techniques which are discussed. This generated much difficulty as there are many techniques but grey scale US was considered to be the best initial procedure. Grading systems are used to “score” the findings which can be combined with the results of FNAC as discussed. Both lobes should be checked as well as the regional nodes. FNAC is well established and easily carried out as a day case procedure. It maybe liquid based cytology, direct smear or both, and this is usually determined by local practice and experience. Within the UK the Royal College of Pathologists (RCPath) reporting system is used and given that this is a UK based guideline it is anticipated this will be used [4]. Rapid OnSite Evaluation (ROSE) has been shown to significantly reduce the number of non-­ diagnostic tests. This will require a change of practice where this is non standardly used. It is again expected that this will be cost effective but local audits are its introduction are recommended. When to carry out Core biopsy? This is proposed when the FNAC is inadequate or indeterminate, however after one inadequate sample it is proposed to repeat the FNAC and if still indeterminate, proceed to a core needle biopsy (CNB). When a Thy3a is seen, repeat sampling with

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FNAC or CNB is recommended which is a change from previous practice. Active surveillance may also be considered. For Thy3f lesions, recommendation to proceed to a diagnostic lobectomy is more usually advised. For Thy4 or Thy5 immediate referral to surgery is usual with the debate only being whether to offer lobectomy or total. This reflects current practice. Blood sampling and tumour markers: There is no value from the use of Thyroglobulin (Tg) screening, it is only of value after total thyroidectomy and even then there may be limitations which are discussed later in document. Thyroid peroxidase antibody testing (TPO) may have a role in supporting FNAC interpretation especially if thyroiditis is suspected. It is only recommended where there is indeterminate pathology. Calcitonin is only measured if there is a strong Family History or strong suspicion of MTC. There is no justification for doing this routinely in suspected thyroid cancers, it should be targeted at patients with known risk factors such as family history. Many of these will already be attending endocrine genetics clinics. When is CT or MRI required? What is the place of staging CT? The committee felt that staging scans were no longer routinely recommended for T1 and T2 tumours unless some clinical suspicion of more advanced disease or concern for metastasis. For more advanced tumours (T3 and T4) CT scanning is needed to stage and help plan surgery. It is anticipated this will have little impact on current practice in the UK. Impact of contrast scans on subsequent RAI scheduling? Following use of contrast scans there needs to be delay before RAI can be used. This must be borne in mind when scheduling RAI.  Most authorities recommend waiting at least 8 weeks otherwise treatment with RAI may be compromised. Is there any continuing role of radio-isotope scans? This is now considered unnecessary as a routine and arguably may offer potential harm from unnecessary radiation exposure. Scanning may be of more value in looking for recurrent disease which is outwith the remit of the guideline.

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Molecular profiling may have an important supplementary role especially in borderline cases and will be discussed later. It will also feature strongly in recommendations for research.

Surgical Management Who should operate? The committee did not address this issue but it should be a team experienced in managing thyroid cancer and will usually be from ENT/Head and Neck Oncology, thyroid and endocrine surgical background. Which procedure? Hemi vs total thyroidectomy? The surgical management of thyroid cancer has changed enormously in the past 15–20 years. Traditionally a total thyroidectomy was offered as standard except in small lesions. However with many incidentally identified small tumours there has been a re-assessment of what surgical procedure is required, and this has extended to include some larger tumours with lower risk factors. The decision will also be affected by the likely indication of whether to give (or withhold) RAI. Given the lower relapse rate after Total thyroidectomy, this is still considered standard for higher risk cases, eg large tumours or bilateral disease, significant capsular and/or vascular invasion. For lower risk cases a diagnostic hemithyroidectomy maybe offered which allows the option of active surveillance or completion after review of pathology and other factors. An Italian trial did show a significant proportion of patients on active surveillance choosing delayed intervention with subsequent completion. HOT study. This trial is investigating whether total thyroidectomy is still required in low risk cases. It opened only relatively recently but will help to address if a lobectomy is a safe alternative in low risk cases. This question will be highlighted in future research. This trial compares a total thyroidectomy vs hemi-thyroidectomy [5]. When there is uncertainty, a diagnostic lobectomy should be offered and then discussed at the MDT.

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Management of Nodal disease. The committee used existing clinical experience as there was no evidence to support other recommendations. It is recommended that the nodes are dealt with at time of primary surgery rather than as delayed or two step procedure. When nodal disease seems confined to lateral neck, a compartment orientated lateral neck dissection is standardly ­recommended, and similarly if central nodes then a compartment orientated central neck dissection is offered. There may be considerations of ipsilateral central dissection if considered appropriate. Prophylactic neck surgery is more controversial. Whilst it may reduce risk of relapse, this may be counterbalanced by higher risk of hypo-­ parathyroidism and to a lesser extent recurrent laryngeal nerve damage. On balance the committee favoured NOT performing prophylactic neck dissections. Impact of pregnancy. Thyroid cancer found in pregnancy or in the year after pregnancy is not uncommon. The issues are most challenging in early pregnancy. Given that most thyroid cancer is relatively slow growing, it is generally recommended to delay any surgery until second or third trimesters. Imaging should try and avoid ionising radiation so US tends to be favoured, however if there is evidence of rapid growth discussion should occur at the MDT and individual decisions made about timing of surgery. Pathology: The WHO Blue book revision 2022 has made some significant changes to pathology classification but came too late for the NICE guideline publication [6].

Post-Operative Management Following surgery the case should be taken back to the MDT for further discussion of management. The first discussion is to decide whether further surgery is required or active surveillance or even discharge if a low risk tumour. Low risk patients will not need anything other than surveillance although for how long and how to monitor is debatable. Low risk will be determined by age,

pathology grade and subtype, and the degree of capsular and vascular invasion. For higher risk patients, completion will be recommended and the patient sent back to surgical team. Following this it is back to the MDT for further discussion as to the need to offer adjuvant RAI vs surveillance.

Need for RAI The MDT or tumour board will discuss the role of adjuvant RAI. This should be in concordance with National guidelines. We have seen a marked change in guidance from high usage of radio-­ iodine usage to far greater selectivity and discussion about high versus low activities. Traditionally many patients were given a standard of high dose usually in range of 80–100  mCi (3700– 4000  MBq) but recent trials such as HiLo and ESTIMABL have shown higher activity is only needed for higher risk cases and low activity (1100 MBq) is safe option in lower risk patients [7–10]. Now the focus is on whether RAI can be withheld in low risk cases again from the ESTIMABL2 and ION trials. Results are still awaited but represent a significant change in approach avoiding the use of RAI in truly low risk cases. When indicated low dose (1100 MBq) is now the standard of care in these lower risk cases [11, 12]. This essentially leaves three risk groups. Those where RAI is strongly indicated, secondly those where the risk of relapse is low so that RAI can be avoided. Finally there is the “uncertain group” where its role is unclear and the specialist will discuss with the individual the pros and cons of administering RAI.  Within the group where RAI is clearly indicated the discussion will involve whether to give high or low activities. Nowadays the majority will fall into the intermediate risk group were 1.1GBq is recommended whereas the high risk group receive upto 3.7 GBq. Within the UK, patients are referred for RAI, depending on local practice to clinical oncolo-

2  Review of NICE Thyroid Cancer Guidelines—UK 2022

gists, endocrinologists or nuclear medicine physicians. All practitioners must have an ARSAC certificate and work within the multi-disciplinary team. Once again the impact on current management is minimally affected as most practitioners have already adopted the guidance.

Preparation for RAI A number of steps are required prior to booking treatment. These include checking ­appropriateness for a radionuclide. These include discussing Fertility issues and contraception. Pregnancy is an absolute contra-indication. Pregnancy should be avoided for at least 6 months post RAI and contraception used. Males must abstain from fathering children for at least 6  months. Patients need to be counselled about radiation protection issues, in hospital and post discharge. This is not within the scope of this document. Thyrogen stimulation vs Thyroid Hormone withdrawal (THW). Historically in preparation for RAI, patients were switched from levothyroxine to liothyronine and then hormone treatment was withdrawn to achieve a stimulated TSH. This is now achieved with use of recombinant TSH (thyrogen). It avoids hormone withdrawal and all the misery associated with this. It is used in nearly all situations nowadays and its use has become standard practice. Quality of life is maintained and patients can return to normal lifestyle and work more quickly.

Radionuclide Therapy What activity is recommended? This is discussed above. Low activity −1100 MBq is used for most cases which are low or intermediate risk. The higher activity of 3700 Mq is reserved for higher risk cases. There is no strong evidence to support even higher activities which were used in the past. The majority of patients require a single administration. Generally a maximum of 4–6

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activities may be given. Beyond this this there is little evidence to suggest any further benefit and risk of myelodysplasia and leukaemias start to rise to concerning levels. There are now effective alternative medical therapies for iodine refractory disease. Diet. It is recommended to use a low iodine diet for 1–2 weeks pre treatment, generally avoiding seafood, excess dairy and a few other foods. Most departments have their own sheets that are handed out. Timing. The use of adjuvant RAI is usually advised within 3 months of surgery. It is usually recommended to withhold a repeat dose format least 4–6  months to allow recovery from myelosuppression. Post discharge care. Each department will produce its own leaflet or handout for post treatment care. Generally the main cautions involve minimising risk of radiation exposure to young persons or pregnant women. These comply with the national guidelines.

External Beam Radiotherapy (EBRT) Adjuvant neck/nodal irradiation is rarely used. Similarly it is very infrequent to use sequential RAI and EBRT.  There will be occasional cases where radio-iodine maybe contra-indicated and EBRT considered as an option. Usually EBRT is reserved for locally recurrent or persistent disease which is outwith the scope of this document. Similarly EBRT maybe used for treatment of symptomatic bone metastases or spinal cord compression. Rare follicular thyroid cancer cases will actually present with bone metastases and EBRT may be used for initial symptom control whilst awaiting planned elective surgery and RAI. In the case of patients presenting with solitary or oligometastatic bone disease, high dose palliative is usually recommended as these patients can live for many years or even be cured. Symptomatic management for acute bleeding may very rarely be indicated. These are all really uncommon situations.

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Thyroid Hormone Replacement What hormone replacement is required? Initially it is not just replacement but suppressive doses of levothyroxine that are required to keep the TSH level in range 0.5–1 IU/L, at least for the first 2  years. For low/intermediate risk patients the doses may then be modified to allow the TSH to rise to range 1 to 3. This is to reduce risks of atrial fibrillation and osteoporosis. For high risk patients or those with metastases, continued suppression is advised. Levothyroxine is the preferred hormonal replacement, usual starting doses are 2  mg/kg but the doses are titrated against the TSH levels. Patients should be monitored for symptoms and biochemical evidence of over or under-replacement. This is required lifelong but usually only annually after 10  years. Liothyronine or even combinations are occasionally used. It should not be recommended as a standard but maybe useful in individual patients.

bodies should raise suspicions of relapse and these tests must be interpreted with caution.

Follow Up

Follow up visits are carried out to monitor for recurrence and to be able to offer intervention treatments. Follow up is a combination of clinical examination, biochemical monitoring of thyroid function to include TSH levels and the Thyroglobulin as a tumour marker. There is a limited role for US and no place for regular imaging with CT or MRI unless indicated by clinical findings or Tg levels. The frequency of visits tends to be more often for first 2  years and for low risk patients the frequency can be relaxed. Following the COVID pandemic there has been increasing use of telephone or video-­conferencing for follow up with “remote” blood sampling. The use of the new generation thyroglobulin assays has made remote consultations more secure. Blood tests monitoring—As mentioned above Dynamic Risk Stratification (DRS) the routine testing will include thyroid function, (free thyroxine, TSH and T3) together with thyLow/intermediate risk vs High risk/metastatic. roglobulin and Tg anti-bodies. Calcium should Recent experience has shown that follow up strat- also be checked and as appropriate Parathyroid egies may be decided by determining if patients Hormone and vitamin D levels. fall into lower or high risk groups. The measureThe target levels of TSH have changed in past ment of thyroglobulin at 9–12 months may help 5  years. Historically super suppression of TSH to predict the likely risk of relapse. This can be was the aim but recognition that the risks of supported by neck ultrasound. Previously stimu- osteoporosis and atrial fibrillation out weigh the lated Tg was used either using THW or thyrogen perceived benefits of suppression. Suppressive stimulation but the sensitivity and reliability of doses of levothyroxine are still required for high modern Tg assays has made this less necessary. risk cases and those with metastatic disease. DRS may be less useful or reliable in the pres- Modern practice now shows that for low/intermeence of Tg antibodies. Assignment to a low DRS diate risk cases suppression no longer required group means risk of relapse is very low and less after 2 years and target levels can be allowed to intense follow up is needed. Furthermore super-­ rise to 1–3  IU/L.  Lifelong monitoring of TSH suppression of the TSH is not needed. Generally levels are required even when patients are disTg levels 1 may indicate a higher risk and term. Thyroglobulin is now established as a reliable consideration of Thyrogen stimulation and other imaging and the need for further intervention. post-operative tumour marker except where there The presence of rising or emergence of Tg anti- are antibodies where results need to be inter-

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preted with caution. Ironically TgAb may have a role in monitoring. The emergence of new rising levels of antibodies strongly suggests recurrence and should trigger scanning to look for disease hence its role as a surrogate marker. US and follow up iodine scans have a limited and more controversial role. It has been practice to do a thyroid US along with stimulated thyrogen at 9–12  months post surgery as part of dynamic risk stratification (DRS).

with agreed protocols. The recommendations generally reflect current practice.

Limitations of Thyroglobulin

Other Topics

The monitoring of Tg is only reliable after total thyroidectomy but may have a limited if uncertain role after lobectomy. After lobectomy US has a more secure role is monitoring recurrence. Interference from Tg antibodies has already been discussed above leading to cautions about rising Tg Abs as surrogate marker for relapse.

Molecular profiling is still establishing its role differentiated thyroid cancer. It can be important in confirming diagnosis (eg braf mutation) as well as having some predictive behaviour. Most recently other markers including ras, tert, ret. and NTRK are more important in helping to select targeted agents for relapsed disease but new data is likely to show that combining molecular testing may have prognostic qualities. At present there are limited criteria for referral to Clinical genetics for DTC.  There are some families with patterns of associated malignancies and these should be discussed with local genetics clinics. There are already clear pathways for medullary thyroid cancer/MEN syndrome patients.

Follow-Up Who should carry out follow up? This will depend on local practice and experience. The important issue is that the specialist should have experience and expertise in managing thyroid cancer. It may be endocrinology, surgery, ENT, oncology or nuclear medicine based or a combined clinic. This usually reflects local experience and expertise. The use of nurse-led clinics or remote telephone/video consulting has become more common especially since the COVID pandemic. Given the relative rarity in primary care, general practitioners cannot be expected to to have sufficient expertise to carry out post-­ operative care outwith the shared care setting which be required for those living in remote and rural locations. However for lower risk cases after 5 years care can be transferred back to primary care with recommendations from the specialist clinics. Higher risk cases or metastatic patients need long term specialist clinic follow up. For patients who live a long way from the specialist centre, shared care may be considered

Relapse The management of recurrent disease is outwith the remit of the guideline. Patients should be discussed at the MDT to determine whether management is surgical or oncological or combined.

Recommendations for Future Research The main issues that are topical are those likely to affect decision making about surgical procedures required, for example where total thyroidectomy can be replaced by hemi-thyroidectomy. This is covered by the HOT trial. Further work will clarify optimal doses of RAI and the use of personalised dosing is likely to become standard. Molecular profiling will continue to evolve both for diagnosis and prognostic/predictive testing and selection of treatment for relapse. Other measures will be looked at to reduce long term morbidities.

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References

N. Reed

9. Schlumberger M, Leboulleux S, Catargi B, et  al. Outcome after ablation in patients with low-risk thyroid cancer (ESTIMABL1): 5-year follow-up results 1. https://www.nice.org.uk/process/pmg20/chapter/ of a randomised, phase 3, equivalence trial. Lancet introduction#nice-­guidelines. Diabetes Endocrinol. 2018;6:618–26. 2. https://www.nice.org.uk/guidance/NG230. 10. Dehbi HM, Mallick U, Wadsley J, et al. Recurrence 3. https://www.nice.org.uk/guidance/NG145. after low-dose radioiodine ablation and recombinant 4. https://www.rcpath.org/resourceLibrary/g089-­ human thyroid-stimulating hormone for differentiated guidance-­reporting-­thyroid-­cytology.html. thyroid cancer (HiLo): long-term results of an open-­ 5. h t t p s : / / w w w. b t f -­t h y r o i d . o rg / h e m i -­o r-­t o t a l -­ label, non-inferiority randomised controlled trial. thyroidectomy-­hot-­trial-­in-­low-­risk-­thyroid-­cancer. Lancet Diabetes Endocrinol. 2019;7:44–51. 6. Baloch ZW, Asa SL, Barletta JA, Ghossein RA, Juhlin 11. Leboulleux S, Bournaud C, Chougnet CN, Zerdoud S, CC, Jung CK, LiVolsi VA, Papotti MG, Sobrinho-­ Al Ghuzlan A, Catargi B, Do Cao C, Kelly A, Barge Simões M, Tallini G, Mete O. Overview of the 2022 M-L, Lacroix L, Dygai I, Vera P.  Thyroidectomy WHO classification of thyroid neoplasms. Endocr without radioiodine in patients with low-risk thyroid Pathol. 2022;33(1):27–63. cancer. N Engl J Med. 2022;386:923–32. 7. Schlumberger M, Catargi B, Borget I, et al. Strategies 12. Mallick U, Harmer C, et  al. Iodine or not (IoN) for of radioiodine ablation in patients with low-risk thylow-risk differentiated thyroid cancer: the next UK roid cancer. N Engl J Med. 2012;366:1663–73. National Cancer Research Network randomised 8. Mallick U, Harmer C, Yap B, et al. Ablation with low-­ trial following HiLo. Clin Oncol (R Coll Radiol). dose radioiodine and thyrotropin alfa in thyroid can2012;24(3):159–61. cer. N Engl J Med. 2012;366:1674–85.

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African Head and Neck Society Clinical Practice Guidelines for Thyroid Nodules and Cancer in Developing Countries and Limited Resource Settings Johannes J. Fagan, Mark Zafereo, Kathryn Marcus, Marika D. Russell, and Gregory Randolph

Introduction International guidelines for managing thyroid nodules and cancers such as that of the American Thyroid Association (ATA) and National Comprehensive Cancer Network (NCCN) assume the availability of thyroid stimulating hormone (TSH) assays, ultrasound (U/S), fine needle aspiration cytology (FNAC), radioactive iodine (RAI) scans and therapy, thyroid and calcium monitoring and replacement, and reliable follow-up [1, 2]. Yet 80% of the world’s people live in lowerand middle-income countries (LMICs), and many patients in high-income countries (HICs) live in remote or less developed regions where

J. J. Fagan (*) Division of Otorhinolaryngology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa e-mail: [email protected] M. Zafereo Head and Neck Surgery, MD Anderson Cancer Center, Houston, TX, USA e-mail: [email protected] K. Marcus Department of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA e-mail: [email protected]

thyroid function tests, U/S, FNAC, and RAI imaging are unaffordable, unavailable or of poor quality. About 25% of patients become hypothyroid following thyroid lobectomy, and 1–5% of patients become hypocalcaemic following total thyroidectomy [3, 4]; yet many patients in LMICs or in rural settings do not have access to monitoring and treatment of hypothyroidism or hypocalcaemia. RAI therapy is also frequently unavailable, obviating the need for total thyroidectomy to facilitate RAI therapy. Failure to take such resource limitations into account may lead to inappropriate surgery with life-altering or fatal consequences from sequelae such as hypothyroidism and hypocalcaemia.

M. D. Russell Division of Thyroid and Parathyroid Endocrine Surgery, Department of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA e-mail: [email protected] G. Randolph Otolaryngology-Head and Neck Surgery, Division of Thyroid and Parathyroid Endocrine Surgery, Department of Otolaryngology-Head and Neck Surgery, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, MA, USA Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA e-mail: [email protected]

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2023 U. K. Mallick, C. Harmer (eds.), Practical Management of Thyroid Cancer, https://doi.org/10.1007/978-3-031-38605-3_3

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Given such diagnostic and therapeutic limitations in limited resource settings, international guidelines written for well-resourced settings [1, 2] cannot simply be applied in lower-resourced settings but must be personalised depending on the availability or affordability of special investigations, access to RAI therapy and access to surveillance and treatment of hypocalcaemia and hypothyroidism. It is for this reason that the African Head and Neck Society (AfHNS) promulgated the African Head and Neck Society Clinical Practice Guidelines for Thyroid Nodules and Cancer in Developing Countries and Limited Resource Settings (https://developingworldheadandneckcancerguidelines.com/) that customise management of thyroid nodules and cancers according the availability and affordability of diagnostic tests, RAI therapy, and surveillance and treatment of hypothyroidism and hypocalcaemia [5].

 evelopment of AfHNS Clinical D Practice Guidelines for Thyroid Nodules and Cancer in Developing Countries and Limited Resource Settings A group of African head and neck and thyroid surgeons, surgeons from the American Head & Neck Society  - Endocrine Section and European head and neck surgeons met in Cape Town in December 2018 to develop guidelines for diagnosis and management of thyroid nodules and cancers in low resource settings. The diagnostic and treatment algorithms are available on the open access African Head and Neck Society Clinical Practice Guidelines for Cancer in Developing Countries and Limited Resource Settings website (https:// developingworldheadandneckcancerguidelines. com/), and were published in Head and Neck [5]. Recommendations are based on literature reviews and expert opinion. Diagnostic and treatment algorithms were adapted from the National Comprehensive Cancer Network (NCCN) guidelines [2]. Low resource settings were simulated

by systematically excluding elements from the NCCN guidelines such as availability of laboratory tests, diagnostic U/S, FNAC, RAI scans and treatment, and hormone and calcium monitoring and replacement.

Assessing a Thyroid Nodule Thyroid function should be routinely checked in patients presenting with a thyroid nodule. To rule out thyroid cancer, the standard diagnostic workup includes thyroid U/S with FNAC [1, 2]. U/S is the most sensitive and specific initial imaging modality for thyroid nodules; however, it is often unavailable in LMIC settings, and even when available, the quality and interpretation may be poor. When hyperthyroidism is diagnosed, a RAI uptake test may be indicated to assess the function of a thyroid nodule. Indeterminate thyroid nodules can be further evaluated with molecular genetics to assist with risk stratification [1]; however, this is resource-­ intensive and expensive technology and is rarely available in low resource settings. Any combination of the above investigations may not be available in low resource settings, and clinicians must often rely on clinical evaluation and alternative diagnostic pathways. The AfHNS guidelines tailor best practice according to availability of thyroid function tests, good quality U/S and cytology, and RAI scans. When serum TSH is unavailable or unaffordable to assess thyroid function, clinical signs and symptoms can accurately determine the probability of hyperthyroid vs. euthyroid/hypothyroid states using a clinically validated method called Wayne’s Index with sensitivity 87%, specificity 96%, PPV 95% and NPV of 90% [6, 7] (Table 3.1). When U/S is unavailable or of poor quality, a detailed history and physical examination of the thyroid and neck may suggest malignancy. High-­ risk clinical features such as rapid growth, a firm mass, thyroid asymmetry, cervical lymphadenopathy, voice change, and vocal cord paralysis are

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3  African Head and Neck Society Clinical Practice Guidelines for Thyroid Nodules and Cancer… Table 3.1  Wayne’s Index: Scores of 19 = Hyperthyroid [6] Symptoms Dyspnoea on effort Palpitations Tiredness Preference for heat Preference for cold Excessive sweating Nervousness Appetite increased Appetite decreased Weight increased Weight decreased

Score +1 +2 +2 −5 +5 +3 +2 +3 −3 −3 +3

Signs Palpable thyroid Bruit over thyroid Exophthalmos Lid retraction Lid lag Hyperkinesis Hands hot Hands moist Casual pulse rate  • >80/min  • >90/min  • Atrial fibrillation

Present +3 +2 +2 +2 +1 +4 +2 +1

Absent −3 −2 – – – −2 −2 −1

– +3 +4

−3 – –

Fig. 3.1  Management algorithm in absence of U/S, FNAC

indications for FNAC. Other than with a rapidly growing thyroid mass, biopsy of a thyroid nodule is generally not urgent, and such patients should ideally be referred to a center that offers FNAC. If such a referral is not possible, then clinical features should be used to determine the need for surgery vs. observation with clinical follow-up. Only when U/S is not available, and only in selected cases may CT or MRI be considered to assess a thyroid nodule, as they have poorer sensitivity and specificity for malignancy and are expensive. When available, U/S findings should

be used to risk-stratify thyroid nodules using the Thyroid Imaging Reporting and Data System (TI-RADS) (http://tiradscalculator.com/) [8]. In the absence of FNAC, patients with high-risk clinical and U/S features may be recommended to proceed directly to surgery with histopathologic review of the thyroid specimen. Figures 3.1 and 3.2 illustrate how the AfHNS guidelines customise management of a thyroid nodule when patients do not have access to U/S and FNAC (Fig. 3.1), or U/S, TSH, RAI scan and FNAC (Fig. 3.2) [5].

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Fig. 3.2  Management algorithms in absence of U/S, TSH, RAI scan and FNAC [5]

 urgical Management of Thyroid S Tumours in Low-Resource Settings Surgery may be done with diagnostic and/or therapeutic intent. In a patient with high suspicion for malignancy, a diagnostic thyroid lobectomy with identification and preservation of the recurrent laryngeal nerve (RLN) may be done to determine the histopathology when FNAC is unavailable. When surgery is required for a suspicious thyroid nodule located in the isthmus, a thyroid isthmusectomy may be performed, preserving both thyroid lobes. Because approximately 25% of thyroid lobectomy patients ultimately develop hypothyroidism [3] with quality-of-life implications if not adequately supplemented with thyroid hormone, consideration should be given to performing a nodulectomy for those that do not have access to thyroid hormone monitoring and replacement. When considering nodulectomy, a surgeon must carefully weigh the risk of lifelong hypothyroidism with the risk of RLN injury by considering

the size and location of the nodule; superficially located anterior, superior, and inferior thyroid nodules pose a much lesser risk of nerve injury than posterior nodules. Surgical resection is generally recommended as primary treatment for thyroid carcinoma. However, when patients cannot be monitored and supplemented for hypothyroidism and hypocalcaemia, the extent of thyroid resection should be carefully considered, and total thyroidectomy must be avoided. Subtotal thyroidectomy is an option for patients with benign thyroid goitres, and for patients with thyroid cancers who require bilateral thyroid surgery but cannot undergo total thyroidectomy due to lack of access to thyroid or calcium monitoring and replacement. A Dunhill procedure is an example of subtotal thyroidectomy that preserves only the superior and posterior thyroid tissue contralateral to the tumour to avoid injury to the RLN and to preserve the superior parathyroid gland, which is generally located along the posterosuperior aspect of the gland.

3  African Head and Neck Society Clinical Practice Guidelines for Thyroid Nodules and Cancer…

 apillary Thyroid Cancer (PTC) P in Low-Resource Settings PTC is a well-differentiated thyroid cancer and is generally characterised by slow growth and a good prognosis. High-risk features include large size (>4  cm), significant extrathyroidal or extranodal extension, bulky cervical lymph node metastases, and distant metastases. In appropriately resourced settings, younger patients with small (4  cm) generally require total thyroidectomy with possible central neck dissection, whereas smaller tumours (4  cm) papillary thyroid cancers, although this is not universally recommended. Postoperative RAI requires total thyroidectomy. When thyroid and calcium replacement are unavailable, management of PTC may be stratified based on the extent of disease to avoid placing all four parathyroid glands at risk with life-threatening hypoparathyroidism and hypocalcaemia. For a tumour