Guidelines for the management of thyroid cancer

Clinical EndocrinologyVolume 81, Issue s1 p. 1-122 British Thyroid Association Guidelines for the Management of Thyroid CancerFree Access Guidelines for the management of thyroid cancer Dr Petros Perros BSc, MBBS, MD, FRCP, Dr Petros Perros BSc, MBBS, MD, FRCP Chair Consultant Endocrinologist British Thyroid Association representative Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle-upon-TyneSearch for more papers by this authorDr Kristien Boelaert MD, PhD, FRCP, Dr Kristien Boelaert MD, PhD, FRCP Senior Lecturer in Endocrinology Society for Endocrinology representative Queen Elizabeth Hospital, BirminghamSearch for more papers by this authorDr Steve Colley MB ChB, FRCR, Dr Steve Colley MB ChB, FRCR Consultant Radiologist The Royal College of Radiologists representative Queen Elizabeth Hospital BirminghamSearch for more papers by this authorDr Carol Evans, Dr Carol Evans Consultant Clinical Scientist Association for Clinical Biochemistry representative University Hospital of Wales, CardiffSearch for more papers by this authorDr Rhodri M Evans MB BCh, FRCR, Dr Rhodri M Evans MB BCh, FRCR Consultant Radiologist The Royal College of Radiologists representative Swansea, WalesSearch for more papers by this authorDr Georgina Gerrard BA BSc, MB, BChir, MRCP, FRCR, Dr Georgina Gerrard BA BSc, MB, BChir, MRCP, FRCR Consultant in Clinical Oncology British Association of Head and Neck Oncologists and The Royal College of Radiologists representative St James Institute of Oncology, LeedsSearch for more papers by this authorDr Jackie Gilbert MBBS, PhD, MRCP, Dr Jackie Gilbert MBBS, PhD, MRCP Consultant Endocrinologist British Thyroid Association representative King's College Hospital, LondonSearch for more papers by this authorDr Barney Harrison MS, FRCS (Eng), Dr Barney Harrison MS, FRCS (Eng) Consultant Endocrine Surgeon British Association of Endocrine and Thyroid Surgeons and Royal College of Surgeons of England representative Royal Hallamshire Hospital, SheffieldSearch for more papers by this authorDr Sarah J Johnson MBBS, PhD, FRCPath, Dr Sarah J Johnson MBBS, PhD, FRCPath Consultant Cyto/Histopathologist Royal College of Pathologists and UK Endocrine Pathology Society and British Association for Cytopathology representative Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle-upon-TyneSearch for more papers by this authorDr Thomas E Giles MB, ChB, FRCPath, Dr Thomas E Giles MB, ChB, FRCPath Consultant Cytopathologist British Association for Cytopathology representative Royal Liverpool University Hospital, LiverpoolSearch for more papers by this authorDr Laura Moss MB BCh, FRCP, FRCR, LLM, Dr Laura Moss MB BCh, FRCP, FRCR, LLM Consultant Clinical Oncologist National Cancer Research Institute-Thyroid Cancer Subgroup and Thyroid Cancer Forum-UK representative Velindre Cancer Centre, CardiffSearch for more papers by this authorProfessor Val Lewington, Professor Val Lewington Consultant Nuclear Medicine Physician British Nuclear Medicine Society, Joint Specialty Committee (Nuclear Medicine) of Royal College of Physicians representative King's College, LondonSearch for more papers by this authorDr Kate Newbold MB ChB MRCP FRCP (Edin) FRCR MD, Dr Kate Newbold MB ChB MRCP FRCP (Edin) FRCR MD British Association of Head and Neck Oncologists and The Royal College of Radiologists representative Consultant Clinical Oncologist Royal Marsden, LondonSearch for more papers by this authorMrs Judith Taylor BA, Mrs Judith Taylor BA (patient representative) Lead Association for Multiple Endocrine Neoplasia Disorders, British Thyroid Foundation, Butterfl y Thyroid Cancer Trust, Hypopara UK, Thyroid Cancer Support Group Wales representative Thyroid cancer patient group, British Thyroid Foundation, Harrogate and Secretary, Thyroid Cancer AllianceSearch for more papers by this authorProfessor Rajesh V Thakker MD, ScD, FRCP, FRCPath, FMedSci, Professor Rajesh V Thakker MD, ScD, FRCP, FRCPath, FMedSci May Professor of Medicine Royal College of Physicians (Diabetes and Endocrinology Committee) representative University of OxfordSearch for more papers by this authorProfessor John Watkinson MSc, MS, FRCS (Eng), DLO, Professor John Watkinson MSc, MS, FRCS (Eng), DLO Consultant Otolaryngologist/Head and Neck Surgeon British Association of Oncology/Head and Neck Surgeons of ENT UK representative Queen Elizabeth Medical Centre, BirminghamSearch for more papers by this authorProfessor Graham R. Williams BSc, MBBS, PhD, FRCP, FRCP (Edin), Professor Graham R. Williams BSc, MBBS, PhD, FRCP, FRCP (Edin) Professor of Endocrinology British Thyroid Association representative Imperial College LondonSearch for more papers by this author Dr Petros Perros BSc, MBBS, MD, FRCP, Dr Petros Perros BSc, MBBS, MD, FRCP Chair Consultant Endocrinologist British Thyroid Association representative Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle-upon-TyneSearch for more papers by this authorDr Kristien Boelaert MD, PhD, FRCP, Dr Kristien Boelaert MD, PhD, FRCP Senior Lecturer in Endocrinology Society for Endocrinology representative Queen Elizabeth Hospital, BirminghamSearch for more papers by this authorDr Steve Colley MB ChB, FRCR, Dr Steve Colley MB ChB, FRCR Consultant Radiologist The Royal College of Radiologists representative Queen Elizabeth Hospital BirminghamSearch for more papers by this authorDr Carol Evans, Dr Carol Evans Consultant Clinical Scientist Association for Clinical Biochemistry representative University Hospital of Wales, CardiffSearch for more papers by this authorDr Rhodri M Evans MB BCh, FRCR, Dr Rhodri M Evans MB BCh, FRCR Consultant Radiologist The Royal College of Radiologists representative Swansea, WalesSearch for more papers by this authorDr Georgina Gerrard BA BSc, MB, BChir, MRCP, FRCR, Dr Georgina Gerrard BA BSc, MB, BChir, MRCP, FRCR Consultant in Clinical Oncology British Association of Head and Neck Oncologists and The Royal College of Radiologists representative St James Institute of Oncology, LeedsSearch for more papers by this authorDr Jackie Gilbert MBBS, PhD, MRCP, Dr Jackie Gilbert MBBS, PhD, MRCP Consultant Endocrinologist British Thyroid Association representative King's College Hospital, LondonSearch for more papers by this authorDr Barney Harrison MS, FRCS (Eng), Dr Barney Harrison MS, FRCS (Eng) Consultant Endocrine Surgeon British Association of Endocrine and Thyroid Surgeons and Royal College of Surgeons of England representative Royal Hallamshire Hospital, SheffieldSearch for more papers by this authorDr Sarah J Johnson MBBS, PhD, FRCPath, Dr Sarah J Johnson MBBS, PhD, FRCPath Consultant Cyto/Histopathologist Royal College of Pathologists and UK Endocrine Pathology Society and British Association for Cytopathology representative Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle-upon-TyneSearch for more papers by this authorDr Thomas E Giles MB, ChB, FRCPath, Dr Thomas E Giles MB, ChB, FRCPath Consultant Cytopathologist British Association for Cytopathology representative Royal Liverpool University Hospital, LiverpoolSearch for more papers by this authorDr Laura Moss MB BCh, FRCP, FRCR, LLM, Dr Laura Moss MB BCh, FRCP, FRCR, LLM Consultant Clinical Oncologist National Cancer Research Institute-Thyroid Cancer Subgroup and Thyroid Cancer Forum-UK representative Velindre Cancer Centre, CardiffSearch for more papers by this authorProfessor Val Lewington, Professor Val Lewington Consultant Nuclear Medicine Physician British Nuclear Medicine Society, Joint Specialty Committee (Nuclear Medicine) of Royal College of Physicians representative King's College, LondonSearch for more papers by this authorDr Kate Newbold MB ChB MRCP FRCP (Edin) FRCR MD, Dr Kate Newbold MB ChB MRCP FRCP (Edin) FRCR MD British Association of Head and Neck Oncologists and The Royal College of Radiologists representative Consultant Clinical Oncologist Royal Marsden, LondonSearch for more papers by this authorMrs Judith Taylor BA, Mrs Judith Taylor BA (patient representative) Lead Association for Multiple Endocrine Neoplasia Disorders, British Thyroid Foundation, Butterfl y Thyroid Cancer Trust, Hypopara UK, Thyroid Cancer Support Group Wales representative Thyroid cancer patient group, British Thyroid Foundation, Harrogate and Secretary, Thyroid Cancer AllianceSearch for more papers by this authorProfessor Rajesh V Thakker MD, ScD, FRCP, FRCPath, FMedSci, Professor Rajesh V Thakker MD, ScD, FRCP, FRCPath, FMedSci May Professor of Medicine Royal College of Physicians (Diabetes and Endocrinology Committee) representative University of OxfordSearch for more papers by this authorProfessor John Watkinson MSc, MS, FRCS (Eng), DLO, Professor John Watkinson MSc, MS, FRCS (Eng), DLO Consultant Otolaryngologist/Head and Neck Surgeon British Association of Oncology/Head and Neck Surgeons of ENT UK representative Queen Elizabeth Medical Centre, BirminghamSearch for more papers by this authorProfessor Graham R. Williams BSc, MBBS, PhD, FRCP, FRCP (Edin), Professor Graham R. Williams BSc, MBBS, PhD, FRCP, FRCP (Edin) Professor of Endocrinology British Thyroid Association representative Imperial College LondonSearch for more papers by this author First published: 03 July 2014 https://doi.org/10.1111/cen.12515Citations: 742AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinkedInRedditWechat Thyroid Cancer Guidelines Update Group v Notes on the development and use of the guidelines vii Types of evidence and grading of recommendations viii Abbreviations ix Key recommendations and overview of management of thyroid cancer 1. Access to a multidisciplinary thyroid cancer team x 2. Patient focus x 3. Prognostic factors, staging, risk stratification and management of uncertainty in differentiated thyroid cancer x 4. Presentation, diagnosis and referral x 5. Ultrasound assessment of thyroid nodules x 6. Fine-needle aspiration cytology xi 7. Surgery for differentiated thyroid cancer xi 8. Management of papillary microcarcinoma xi 9. Radioiodine remnant ablation and therapy for differentiated thyroid cancer xi 10. External beam radiotherapy for differentiated thyroid cancer xii 11. Post-treatment follow-up of patients with differentiated thyroid cancer xii 12. Recurrent / persistent differentiated thyroid cancer xii 13. Long-term follow-up of differentiated thyroid cancer xii 14. Thyroid nodules and thyroid cancer in pregnancy xii 15. Pathology reporting, grading and staging of thyroid cancers xiii 16. Medullary thyroid cancer xiii 17. Anaplastic thyroid cancer xiii 18. Thyroid cancer: a guide for general practitioners xiii 19. Research and audit xiii 1 Introduction 1.1 The need for guidelines 1 1.2 Aim of the guidelines 1 1.3 Incidence 1 1.4 Public health and prevention 1 1.5 Screening 1 1.6 Research 2 2 Prognostic factors, staging, risk stratification and management of uncertainty in differentiated thyroid cancer 2.1 Prognostic factors 4 2.2 Staging systems 4 2.3 Use of prognostic systems in DTC for stratified management 4 2.4 Managing uncertainty and Personalised Decision Making 7 3 Presentation, diagnosis and referral 3.1 Cancer waiting times 10 3.2 Symptoms or signs that warrant investigation 10 3.3 Physical examination 10 3.4 Appropriate investigations pending hospital appointment 10 3.5 Who to refer to? 11 3.6 The role of the multidisciplinary team 11 3.7 Hospital investigations 11 3.8 Communication and patient information prior to investigations 12 3.9 Communicating the diagnosis of thyroid cancer 12 4 Ultrasound assessment of thyroid nodules 4.1 Role of US in the investigation of thyroid nodules 14 4.2 Benign and malignant US features of thyroid nodules 14 4.3 Selection of nodules for FNAC 14 4.4 Radiology reporting 15 4.5 Follow up of thyroid nodules 15 4.6 Incidental nodules 17 4.7 US Assessment by non-radiologists 17 5 Fine-needle aspiration cytology 5.1 Aspiration cytology of thyroid 19 5.2 Diagnostic categories 19 6 Primary treatment of differentiated thyroid cancer 6.1 Timescale 24 6.2 Staging and risk assignment 24 6.3 Documentation 24 7 Surgery for differentiated thyroid cancer 7.1 Terminology 25 7.2 Pre-operative imaging 25 7.3 Preparation for surgery 25 7.4 Surgical approach to laryngeal nerves and parathyroid glands 25 7.5 Diagnostic thyroid surgery 26 7.6 Therapeutic surgery for thyroid cancer 26 7.7 Emergency surgery 29 7.8 Surgery for locally advanced disease 29 7.9 Early post-surgical management 29 7.10 Management of other rare malignancies of the thyroid 29 8 Management of papillary microcarcinoma 8.1 Disease extent at diagnosis 33 8.2 Clinical outcome 33 8.3 Management 33 9 Radioiodine remnant ablation and therapy for differentiated thyroid cancer 9.1 Post-operative RRA 37 9.2 Preparation for RRA or 131I therapy 39 9.3 Activity of 131I 40 9.4 131I-refractory disease 41 9.5 Short-term and long-term side effects of RRA and 131I therapy 41 9.6 Outpatient administration of 131I for RRA or therapy 42 9.7 Aftercare following RRA and 131I therapy 42 9.8 Assessment of RRA success 42 10 External beam radiotherapy for differentiated thyroid cancer 10.1 Adjuvant treatment 47 10.2 EBRT dose, fractionation and target volume 47 10.3 EBRT in the palliative setting 47 11 Post-treatment follow-up of patients with differentiated thyroid cancer 11.1 Voice dysfunction 49 11.2 Management of acute post-thyroidectomy hypocalcaemia 49 11.3 Long-term management of hypoparathyroidism 49 11.4 Management of iatrogenic hypercalcaemia 50 11.5 Suppression of serum thyroid stimulating hormone (TSH) 50 11.6 Measurement of serum thyroglobulin (Tg) in long-term follow-up (see also Appendix 1) 51 12 Recurrent/persistent differentiated thyroid cancer 12.1 Recurrence in the thyroid bed or cervical lymph nodes 56 12.2 Metastatic disease involving lung and other soft tissue areas 56 12.3 Bone metastases 56 12.4 Cerebral metastases 56 12.5 Other metastatic sites 57 12.6 Management of patients with an elevated serum thyroglobulin 57 12.7 Palliative care 58 13 Long-term follow-up of differentiated thyroid cancer 60 14 Thyroid nodules and thyroid cancer in pregnancy 14.1 Thyroid nodules in pregnancy 61 14.2 Diagnosis of thyroid cancer in pregnancy 61 14.3 Pregnancy in the treated patient with thyroid cancer 61 15 Thyroid cancer in childhood 64 16 Pathology reporting, grading and staging of thyroid cancers 16.1 General principles 65 16.2 Pathology report 65 16.3 Pathological staging 65 16.4 Staging protocol 65 16.5 Summary of thyroid cancer types 65 17 Medullary thyroid cancer 17.1 Presentation 69 17.2 Initial investigations of patients with suspected or confirmed MTC 70 17.3 Treatment 70 17.4 Adjuvant therapies 71 17.5 Pathology 72 17.6 Follow-up for MTC 73 17.7 Investigation of persistent or increasing hypercalcitoninaemia in treated patients 73 17.8 Treatment of persistent or recurrent disease 74 17.9 Molecular genetics 74 17.10 Multiple Endocrine Neoplasia Type 3/2B (MEN3/2B) 76 18 Anaplastic thyroid cancer 18.1 Background 79 18.2 Presentation 79 18.3 Investigation 79 18.4 Staging 80 18.5 Prognosis 80 18.6 Treatment 80 19 Long-term survivorship 84 20 Registration, core dataset and audit 85 21 Thyroid cancer: a guide for general practitioners 21.1 Raising awareness 86 21.2 Prevention 86 21.3 Screening 86 21.4 Diagnosis and referral 86 21.5 Summary of treatment of thyroid cancer 87 21.6 Follow-up 88 Appendices 1. Assay methodology 89 2. Recognition of MEN3 (MEN2B) 94 3. Search methodology 95 4. Patient information 97 Patient support groups 97 Websites with useful information for patients 97 Leaflets for patients 1. The thyroid gland and thyroid cancer – tests and treatment 99 2. Information for patients being investigated for thyroid lumps 102 3. Surgery for thyroid Cancer 104 4. Radioactive iodine ablation and therapy 109 5. Medullary thyroid cancer 113 6. Advanced or higher risk differentiated (papillary and follicular) thyroid cancer 117 7. Anaplastic thyroid cancer 121 Chapter 1 1 Introduction 1.1 The need for guidelines In spite of advances in diagnostic methods, surgical techniques and clinical care, there are differences in survival of patients with thyroid cancer in different countries, and the outcome in the UK prior to 1989 appeared to be worse than in other western European nations.1 The reasons for this are unclear and may be multifactorial. There is a sense that outcomes in the UK are improving, but only long term national registry data can confirm or refute this in future. However, it may not be unreasonable to speculate that the impact of previous editions of these guidelines, and recent changes in cancer services within the National Health Service may have contributed. These include mandatory specialist multidisciplinary team management of all cancers (http://www.mycancertreatment.nhs.uk/wp-content/themes/mct/uploads/2012/09/resources_measures_HeadNeck_Measures_April2011.pdf), regular mandatory national peer review, equity of access to specialist care, the cancer drug fund, national cancer research groups supporting trials, patient support groups, national audits by professional organisations, the cancer reform strategy and survivorship programme. It is hoped that the third edition of the national guidelines for thyroid cancer, and their implementation through local protocols of the NHS networks, will continue to facilitate this process and improve care and outcomes in the UK. 1.2 Aim of the guidelines The intention is to provide guidance for all those involved in the management of patients with differentiated thyroid cancer (DTC) and some of the rarer thyroid cancers. This document is not intended as guidelines for management of thyroid nodules, though the role of ultrasound (US) in assessing thyroid nodules is included. A summary of the key recommendations for the management of adult differentiated thyroid cancer, medullary thyroid cancer (MTC) and anaplastic thyroid cancer is provided (see previous section). Randomised trials are often not available in this setting. Therefore, evidence is based on large retrospective studies and the level of evidence is ascribed according to the Scottish Intercollegiate Guidelines Network 50 (A guideline developer's handbook (http://www.sign.ac.uk/pdf/sign50.pdf). The three main aims of the guidelines are: to improve the referral pattern and management of patients with thyroid cancer; to improve the long-term overall and disease-free survival of patients with thyroid cancer; to enhance the health-related quality of life of patients with thyroid cancer. These guidelines do not address thyroid lymphomas or metastases to the thyroid. 1.3 Incidence In the period 1971–1995, the annual UK incidence was reported at 2.3 per 100 000 women and 0.9 per 100 000 men, with approximately 900 new cases and 250 deaths recorded in England and Wales due to thyroid cancer every year.2 In 2010, data from Cancer Research UK indicate 2654 new cases in the UK and 346 deaths. (http://www.cancerresearchuk.org/cancer-info/cancerstats/types/thyroid/uk-thyroid-cancer-statistics). Annual incidence data for the UK from 2008 show 5.1 per 100 000 women and 1.9 per 100 000 men (http://www.cancerresearchuk.org/cancer-info/cancerstats/types/thyroid/uk-thyroid-cancer-statistics). Thyroid cancer is the most common malignant endocrine tumour, but represents only about 1% of all malignancies.2 The incidence of thyroid cancer is increasing globally, mostly due to PTC,3 including in the paediatric population.4 The bulk of the increase is lower stage cancers and/or incidental micro-papillary thyroid cancers found when surgery is performed for thyroid diseases other than cancer.5, 6 Overall mortality from thyroid cancer has remained stable over many years.7 It has been suggested that the increase in incidence of thyroid cancer is due to better detection of incidental microcarcinomas.7, 8 This view has been challenged by studies which found that the incidence of thyroid cancers of all sizes has been increasing over time.3, 9 It seems plausible that factors other than increased detection, may underlie the rising incidence of thyroid cancer, and may include changing iodine status and exposure to radiation,10 but in most cases the cause is unknown. 1.4 Public health and prevention Nuclear fallout is a well recognised cause of an increase in the risk of thyroid cancer in children. Following the Chernobyl accident, the incidence of thyroid cancer rose several hundred times in children in the region. Therapeutic and diagnostic X-rays in childhood are also possible causes of thyroid cancer in adults; exposure to these sources should be limited whenever possible. In cases of populations or individuals being contaminated with 131I the thyroid can be protected by administering potassium iodide.11-13 1.5 Screening At present there is no screening programme to detect thyroid cancer for the general population. Screening is possible for familial MTCs associated with specific oncogene mutations. The genetic basis of papillary, follicular and anaplastic thyroid cancer has been investigated and the roles and potential prognostic value of several genes, e.g. RET, TRK, RAS, BRAF, PPARG and p53, have been identified. Testing for these genes is not routinely available in clinical practice.14 The following are considered to be risk factors for thyroid cancer15-26: neck irradiation in childhood; endemic goitre; Hashimoto's thyroiditis (risk of lymphoma); family or personal history of thyroid adenoma; Cowden's syndrome (macrocephaly, mild learning difficulties, carpet-pile tongue, with benign or malignant breast disease); familial adenomatous polyposis; familial thyroid cancer; obesity. While screening generally is not indicated, a family history for thyroid cancer should be taken in each case and if there is a strong familial incidence of thyroid cancer or association with other cancers, genetic advice should be considered in appropriate cases from the regional genetics service (4, D). 1.6 Research In the past, randomised trials were very rare, and robust evidence for or against a treatment were not frequently available for early and advanced thyroid cancers. Although this is slowly improving, clinicians still have to deal with management of uncertainty or clinical equipoise frequently. In such cases participation in clinical trials in pursuit of level 1 evidence is important. Patients should be informed about and given the opportunity to consider participation in ongoing randomized clinical trials in cases where there is genuine clinical equipoise or lack of level 1 evidence (4, D). Key recommendation References 1Teppo, L. & Hakulinen, T. (1998) Variation in survival of adult patients with thyroid cancer in Europe. European Journal of Cancer, 34, 2248– 2252. 2Coleman, P.M., Babb, P., Damiecki, P. et al. (1999) Cancer Survival Trends in England and Wales 1971–1995: Deprivation and NHS Region. Series SMPS No. 61. Stationery Office, London, 471– 478. 3Sipos, J.A. & Mazzaferri, E.L. (2010) Thyroid cancer epidemiology and prognostic variables. Clinical Oncology (Royal College of Radiologist), 22, 395– 404. 4Hogan, A.R., Zhuge, Y., Perez, E.A. et al. (2009) Pediatric thyroid carcinoma: incidence and outcomes in 1753 patients. Journal of Surgical Research, 156, 167– 172. 5Griniatsos, J., Tsigris, C., Kanakis, M. et al. (2009) Increased incidence of papillary thyroid cancer detection among thyroidectomies in Greece between 1991 and 2006. Anticancer Research, 29, 5163– 5169. 6Hoang, J.K., Raduazo, P., Yousem, D.M. et al. (2012) What to do with incidental thyroid nodules on imaging? An approach for the radiologist. Seminars in Ultrasound, CT and MR, 33, 150– 157. 7Davies, L. & Welch, H.G. (2006) Increasing incidence of thyroid cancer in the United States, 1973–2002. JAMA, 295, 2164– 2167. 8Harach, H.R., Franssila, K.O. & Wasenius, V.M. (1985) Occult papillary carcinoma of the thyroid: a “normal” finding in Finland: a systematic autopsy study. Cancer, 56, 531– 538. 9Chen, A.Y., Jemal, A. & Ward, E.M. (2009) Increasing incidence of differentiated thyroid cancer in the United States, 1988–2005. Cancer, 115, 3801– 3807. 10Wartofsky, L. (2010) Increasing world incidence of thyroid cancer: increased detection or higher radiation exposure? Hormones, 9, 103– 108. 11 Administration of Radioactive Substances Advisory Committee (2006) Notes for Guidance on the Clinical Administration of Radiopharmaceuticals and Use of Sealed Radioactive Sources. ARSAC, Didoct, Oxon. www.arsac.org.uk/notes_for_guidence/index.htm. 12 International Atomic Energy Agency (1991) Intervention Criteria in a Nuclear or Nuclear Radiation Emergency. Safety series number 109. IAEA, Vienna. 13 International Commission on Radiological Protection (1991) ICRP Publication 63: Principles for Intervention for Protection of the Public in Radiological Emergency. Pergamon Press, Oxford. 14Giordano, T.J., Kuick, R., Thomas, D.G. et al. (2005) Molecular classification of papillary thyroid carcinoma: distinct BRAF, RAS, and RET/PTC mutation-specific gene expression profiles discovered by DNA microarray analysis. Oncogene, 24, 6646– 6656. 15Schlumberger, M., De Vathaire, F., Travagli, J.P. et al. (1987) Differentiated thyroid carcinoma in childhood: long term follow-up of 72 patients. Journal of Clinical Endocrinology and Metabolism, 65, 1088– 1094. 16Hancock, S.L., Cox, R.S. & McDougall, I.R. (1991) Thyroid disease after treatment of Hodgkin's disease. New England Journal of Medicine, 325, 599– 605. 17Ron, E., Lubin, J.H., Shore, R.E. et al. (1995) Thyroid cancer after exposure of external radiation: a pooled analysis of seven studies. Radiation Research, 141, 259– 277. 18Thompson, D.E., Mabuchi, K., Ron, E. et al. (1994) Cancer incidence in atomic bomb survivors. Part II: solid tumors, 1958–1987. Radiation Research, 137(Suppl 2), S17– S67. 19Winship, T. & Rosvoll, R.V. (1970) Thyroid carcinoma in childhood: final report on a 20 year study. Clinical Proceedings – Children's Hospital of the District of Columbia, 26, 327– 348. 20Franceschi, S., Boyle, P., Maisonneuve, P. et al. (1993) The epidemiology of thyroid carcinoma. Critical Reviews in Oncogenesis, 4, 25– 52. 21Levi, F., Franceschi, S., la Vecchia, C. et al. (1991) Prior thyroid disease and risk of thyroid cancer in Switzerland. European Journal of Cancer, 27, 85– 88. 22Preston-Martin, S., Berenstein, L., Pike, M.C. et al. (1987) Thyroid cancer among young women related to prior thyroid disease and pregnancy history. British Journal of Cancer, 55, 191– 195. 23Mack, W.J. & Preston-Martin, S. (1998) Epidemiology of thyroid cancer. In: J.A. Fagin ed. Thyroid cancer, Vol. 2. Kluwer Academic Publishers, Boston, 1– 25. 24Holm, L.E., Blomgren, H. & Lowhagen, T. (1985) Cancer risks in patients with chronic lymphocytic thyroiditis. New England Journal of Medicine, 312, 601– 604. 25Kitahara, C.M., Platz, E.A., Freeman, L.E. et al. (2011) Obesity and thyroid cancer risk among U.S. men and women: a pooled analysis of five prospective studies. Cancer Epidemiology, Biomarkers & Prevention, 20, 464– 472. 26Dal Maso, L., La Vecchia, C., Franceschi, S. et al. (2000) A pooled analysis of thyroid cancer studies. V. Anthropometric factors. Cancer Causes and Control, 11, 137– 144. Chapter 2 1 Prognostic factors, staging, risk stratification and management of uncertainty in differentiated thyroid cancer The long-term outcome of patients treated effectively for differentiated thyroid cancer (DTC) is usually favourable. The overall 10-year survival rate for middle-aged adults with DTC is 80–90%. However, 5–20% of patients develop local or regional recurrences and 10–15% distant metastases.1-3 Nine per cent of patients with a diagnosis of thyroid cancer die of their disease.4, 5 It is important to assess both risk of death from the disease and risk of recurrence in patients with DTC using a prognostic scoring system. This enables a more accurate prognosis to be given and the appropriate treatment decisions to be made. 1.1 Prognostic factors Several factors have been shown consistently to be important for predicting death and recurrence in multivariate analyses of large patient cohorts: Age Age at the time of diagnosis is one of the most consistent prognostic factors in patients with DTC. The risk of recurrence and death increases with age, particularly after the age of 40 years.6-11 Young children, under the age of 10 years, are at higher risk of recurrence than old