H.-J. Biersack F. Griinwald (Eds.) Thyroid Cancer With 51 Figures and 30 Tables Springer
PART 1 Basics 1 The Changing Epidemiology of Thyroid Cancer 3 R. GORGES 1.1 Basic Epidemiological Problems in Thyroid Cancer.. 3 1.2 General Epidemiological Data for Thyroid Cancer... 5 1.3 Prognosis 9 1.4 Thyroid Malignancies with Special Features 11 1.4.1 Papillary Microcarcinoma 11 1.4.2 Hiirthle Cell Carcinoma 12 1.4.3 Tall Cell Variant of Papillary Thyroid Cancer 12 1.4.4 Poorly Differentiated (Insular) Thyroid Carcinoma.. 13 1.4.5 Anaplastic Carcinoma 13 1.4.6 Medullary Thyroid Carcinoma 14 1.4.7 Thyroid Lymphoma 14 1.4.8 Secondary Tumors 15 1.5 Changes in Epidemiology 15 1.6 Summary 20 References 20 2 Histopathology, Immunohistochemistry, and Molecular Biology 27 F. HOFSTADTER 2.1 Introduction 27 2.2 Principles of Histopathological Diagnosis and Classification 27 2.2.1 The Rules and Their Problems 27 2.2.2 Papillary Carcinoma 28 2.2.3 Follicular Carcinoma 29 2.2.4 Anaplastic (Undifferentiated) Carcinoma 31 2.2.5 Medullary (C-cell) Carcinoma 31 2.3 Histopathology and Prognosis 32 2.3.1 Histopathology and Prognostic Scores 32 2.3.2 Histological Subtypes Influencing Prognosis 34
VIII Contents 2.4 Histo/Cytopathology in Preoperative and Intraoperative Diagnosis (Problem of Frozen Section) 36 2.5 Auxiliary Techniques (Cytometry, Immunohistochemistry, Molecular Pathology) 36 2.6 Preoperative Diagnosis (Fine Needle Aspiration Biopsy, FNAB) 37 2.7 Prognosis 38 2.8 Pathogenesis 39 2.8.1 Anatomical Histogenesis 39 2.8.2 Molecular Pathogenesis 40 2.8.2.1 Genetics 40 2.8.2.2 Malignant Transformation 41 2.8.2.3 Mechanisms of Invasion and Metastasis 42 2.8.2.4 Cell Cycle Regulation 43 2.8.2.5 Cytogenetics and Clonality 44 2.8.2.6 Receptor Activation 45 2.8.2.7 Telomerase 45 References 45 3 Familial Differentiated Carcinoma of the Thyroid 55 M.R. CARLISLE and I.R. MCDOUGALL 3.1 Introduction 55 3.2 Etiology of Non-Medullary Thyroid Cancers 55 3.3 Could "Familial" Thyroid Cancers Be a Chance Finding? 57 3.4 Association Between Thyroid Cancer and Familial Cancer Syndromes 58 3.5 Molecular Genetics of Familial Thyroid Cancer 58 3.6 Mode of Inheritance 60 3.7 Natural History of Familial Thyroid Cancer 62 3.8 Clinical Implications of Familial Differentiated Thyroid Cancer 63 3.8.1 Primary Treatment 63 3.8.2 Screening of Families 63 References 63 4 The Diagnosis of Thyroid Cancer 69 C. REINERS 4.1 Prevalence/Risk Assessment 69 4.2 Findings/Symptoms 69 4.3 Ultrasonography 70 4.4 Scintigraphy 71 4.5 Fine-Needle Aspiration Biopsy 74 4.6 Additional Diagnostic Procedures 77 References 78
IX 5 The Current Surgical Approach to Non-Medullary Thyroid Cancer 81 O. GIMM and H. DRALLE 5.1 Introduction 81 5.2 Prognostic Factors 82 5.3 Surgical Treatment 83 5.3.1 Technique 83 5.3.2 Primary Therapy 83 5.3.2.1 Thyroid Gland 83 5.3.2.2 Extrathyroidal Tumor Extension 85 5.3.2.3 Lymph Nodes 85 5.3.2.4 Distant Metastases 86 5.3.3 Completion Thyroidectomy 87 5.3.4 Recurrent Disease 87 References 87 PART 2 Differentiated Thyroid Cancer 6 Radioiodine Therapy for Thyroid Cancer 93 M. DIETLEIN, D. MOKA, and H. SCHICHA 6.1 Introduction 93 6.2 Radioiodine Ablation and Radioiodine Therapy 94 6.2.1 Ablation of Residual Thyroid Tissue 94 6.2.2 Ablative Dose 95 6.2.3 In Which Patients Is Ablation Unnecessary? 98 6.2.4 Radioiodine Therapy for Thyroid Cancer 99 6.2.5 Radioiodine Therapy with Negative Radioiodine Scan 99 6.2.6 Radioiodine Therapy in Patients on Maintenance Hemodialysis 100 6.3 Prognostic Factors and Therapeutic Strategies in Metastatic Thyroid Cancer 101 6.3.1 Lymph Node Metastases 101 6.3.2 Pulmonary Metastases 102 6.3.3 Bone Metastases 104 6.3.4 Brain Metastases 106 6.3.5 Locally Invasive Thyroid Cancer 107 6.4 Optimizing the Therapeutic and Diagnostic Capabilities of 131 I 108 6.4.1 Thyroid-Stimulating Hormone Stimulation 108 6.4.2 Administration of Recombinant Human Thyrotropin 108 6.4.3 Low-Iodine Diet 109 6.4.4 Optimal Diagnostic Scan Dose 110
6.4.5 Redifferentiation Therapy and Future Therapeutic Options Ill 6.4.6 Lithium Ill 6.4.7 Further Optimization of 131 I Imaging Ill 6.4.8 Diuretic-Enhanced 131 I Clearance 112 6.5 Side Effects of 131 I Therapy 112 6.5.1 Radiation Thyroiditis 112 6.5.2 Painless Neck Edema 112 6.5.3 Sialadenitis 113 6.5.4 Taste Dysfunction 113 6.5.5 Gastrointestinal Symptoms 114 6.5.6 Testicular Function and Male Fertility 114 6.5.7 Ovarian Function and Female Fertility 114 6.5.8 Pregnancy Outcome 115 6.5.9 Bone Marrow Suppression 115 6.5.10 Leukemia 116 6.5.11 Solid Tumors 116 6.5.12 Pulmonary Fibrosis 116 6.5.13 Neurologic Complications 116 6.5.14 Parathyroid Dysfunction 117 6.6 Radiation Considerations in the Treatment of Thyroid Cancer 117 References 117 7 Percutaneous Radiation Therapy 121 C. PUSKAS, M. BlERMANN, N. WlLLICH, and O. SCHOBER 7.1 Surgical Therapy and Lymph Node Staging 121 7.2 Lymph Node Status and Prognosis 121 7.3 Indications for External Radiotherapy 122 7.3.1 Gross Residual Disease and Local Recurrence 122 7.3.2 Distant Metastases 123 7.3.3 Anaplastic Carcinoma 123 7.3.4 Adjuvant Radiotherapy 123 7.4 Radiation Treatment Protocols 124 7.4.1 Side Effects ;.. 124 7.5 Review 124 7.5.1 Studies Demonstrating No Beneficial Effect of Percutaneous Radiotherapy 125 7.5.2 Studies Demonstrating Beneficial Effects of Percutaneous Radiotherapy 125 7.6 Inauguration of a Prospective Multicenter Trial 128 References 128
XI 8 Thyroid Cancer: Treatment with Thyroid Hormone 131 P.-M. SCHUMM-DRAEGER 8.1 Introduction 131 8.2 Rationale of Thyroid Hormone Therapy 131 8.3 Effects on Thyroid Growth 132 8.4 Effects on Differentiation of Thyroid Cells 132 8.5 Optimal Level of TSH Suppression in Patients with Differentiated Thyroid Cancer 132 8.6 Treatment with Thyroid Hormones 133 8.7 Pharmacology of Thyroid Hormones (Levothyroxine, L-T4) 133 8.8 Optimal Dosage and Adjustment of L-T4 in Thyroid Cancer Patients According to Disease Status 134 8.9 Important Side Effects of L-T4 Suppressive Therapy 135 8.9.1 Side Effects of L-T4 Therapy: Bone 135 8.9.2 Side Effects of L-T4 Therapy: Heart 136 8.10 Conclusion 136 References 136 9 Treatment with Cytotoxic Drugs 139 B.SALLER 9.1 Introduction 139 9.2 Results of Chemotherapy in Differentiated Thyroid Carcinoma 139 9.2.1 Monotherapy 139 9.2.2 Combination Chemotherapy 140 9.3 Results of Chemotherapy in Poorly Differentiated and Anaplastic Thyroid Carcinoma 142 9.3.1 Chemotherapy 142 9.3.2 Combined Modality Treatment 143 9.3.2.1 Treatment Protocols Including Chemotherapy with Single Cytotoxic Drugs 143 9.3.2.2 Treatment Protocols Including Combination Chemotherapy 144 9.4 Drugs with In Vitro Anti-Tumor Effects 145 9.5 Mechanisms of Resistance Against Cytotoxic Drugs.. 145 9.6 Future Directions in Chemotherapy of Thyroid Cancer, 147 9.7 Current Suggestions for Management 148 References 149
XII Contents 10 Redifferentiation Therapy of Thyroid Carcinomas with Retinoic Acid 153 D. SIMON 10.1 Introduction 153 10.2 Biological Effects of Retinoic Acids 154 10.3 Retinoids in Cancer Treatment 154 10.4 Thyroid-Specific Effects of Retinoids 155 10.4.1 Thyroid-Specific Functions 155 10.4.2 Differentiation 156 10.4.3 Proliferation 156 10.5 Basis for Therapeutic Approach 156 10.6 Results of a Clinical Pilot Study 157 10.7 Conclusion and Perspectives 159 References 160 11 Follow-up of Patients with Well-Differentiated Thyroid Cancer 165 B. SHAPIRO and M.D. GROSS 11.1 Introduction 165 11.2 The Follow-up of Patients with Thyroid Cancer 165 11.2.1 Assessing the Risk of Morbidity and Mortality 165 11.2.2 Postoperative Evaluation of Thyroid Cancer 166 11.2.3 Postoperative Laboratory Evaluation and Imaging... 167 11.2.3.1 Radioiodine 167 11.2.3.2 Other Agents Used to Image Thyroid Cancer 170 11.2.3.3 Thyroglobulin 171 11.2.4 Follow-up Therapy After Thyroidectomy 172 11.2.4.1 Ablation of Thyroid Remnants 172 11.2.4.2 Follow-up Intervals After Successful Ablation 174 11.2.4.3 Thyroid Hormone Replacement in the Thyroid Cancer Patient 175 11.2.4.4 Radioiodine Therapy for Recurrent/ Metastatic Thyroid Cancer 175 11.2.4.5 Radioiodine-Negative Thyroid Cancer 176 11.3 Summary 177 References 178 12 Functional Imaging of Thyroid Cancer 181 F. GRUNWALD 12.1 Introduction 181 12.2 Tracers 181 12.2.1 Thallium Chloride 181 12.2.2 MIBI and Other 99m Tc-Labeled Tracers 182 12.2.3 18 F-Fluorodeoxyglucose 182 12.2.4 nl In-Octreotide 185
XIII 12.3 Clinical Use of Functional Imaging 185 12.3.1 Presurgical Evaluation 185 12.3.2 Postsurgical Treatment and Follow-up 186 References 190 13 Magnetic Resonance Imaging 193 J.H. RISSE 13.1 Introduction 193 13.2 Principles of MRI 193 13.2.1 Physical and Technical Basis 194 13.2.1.1 The Magnetic Signal 194 13.2.1.2 Image Generation: What Are TR and TE, and Tl and T2? 194 13.2.1.3 Further Contrast Modifications: Fat Saturation and Contrast Media 196 13.2.2 Safety 198 13.2.2.1 Safety in the Magnetic Field 198 13.2.2.2 Safety of Contrast Media 199 13.2.2.3 Contraindications 200 13.2.3 Protocol Recommendations for Thyroid Cancer Follow-up 200 13.2.3.1 Hardware 200 13.2.3.2 Sequences 201 13.2.3.3 Planes 201 13.2.3.4 Covered Anatomic Regions 201 13.2.3.5 Our Protocol 202 13.3 Normal MR Anatomy of the Neck, Thyroid, and Upper Mediastinum 203 13.3.1 Normal Anatomy 203 13.3.1.1 Neck Compartments 203 13.3.1.2 Thyroid and Parathyroid Glands 203 13.3.1.3 Salivary Glands 205 13.3.1.4 Lymphatic Drainage 205 13.3.1.5 Upper Anterior Mediastinum 208 13.3.2 Inconspicuous Anatomy After Thyroidectomy 208 13.4 Pathologic Changes 209 13.4.1 Primary Thyroid Cancer 210 13.4.2 Thyroid Remnants 212 13.4.3 Recurrent Thyroid Cancer 214 13.4.4 Pathologic Lymph Nodes 214 13.4.5 Distant Metastases 220 13.4.6 Accidental Pathologic Findings 220 References 222
XIV Contents 14 Thyroid Cancer in Chernobyl Children 225 C. REINERS, J. BIKO, E.P. DEMIDCHIK, and V. DROZD 14.1 Experiences from the Past 225 14.2 The Chernobyl Accident 226 14.3 Thyroid Cancer in Belarus After Chernobyl 226 14.4 Treatment of Thyroid Cancer in Children from Belarus 228 14.4.1 Patients 229 14.4.2 Protocol 230 14.4.3 Results of Treatment 230 14.5 Discussion and Conclusions 231 References 233 PART 3 Medullary Thyroid Cancer 15 Diagnosis of Medullary Thyroid Cancer 239 F. RAUE 15.1 Introduction 239 15.2 Classification and Epidemiology 239 15.3 Pathology and Biochemical Markers 240 15.4 Genetic Abnormalities 241 15.5 Clinical Syndrome and Diagnostic Procedure 243 15.5.1 Sporadic Medullary Thyroid Carcinoma 243 15.5.2 Hereditary Medullary Thyroid Carcinoma 245 15.5.2.1 Pheochromocytoma 245 15.5.2.2 Primary Hyperparathyroidism 246 15.5.2.3 Multiple Endocrine Neoplasia Type 2B 247 15.6 Natural History and Prognostic Factors 247 References 247 16 Imaging in Medullary Thyroid Cancer 251 T.M. BEHR and W. BECKER 16.1 Introduction 251 16.2 Diagnosis and Localization of the Medullary Thyroid Primary Tumor; Presurgical Staging 252 16.3 Imaging and Disease Localization in the Follow-up of Patients with MTC 256 16.3.1 Conventional Radiological Techniques (Ultrasonography, X-ray, Computed Tomography, Magnetic Resonance Imaging, Bone Scanning) 256 16.3.2 Traditional Scintigraphic Techniques [ 201 Tl Chloride, 99m Tc.( V )-DMSA, 123 ' 131 I-MIBG, etc.] 258
XV 16.3.3 Modern Nuclear Medical Techniques (Anti-CEA Immunoscintigraphy, Somatostatin Receptor Scintigraphy, Positron Emission Tomography) 261 16.4 Future Developments: Will Cholecystokinin-B/ Gastrin Receptor Scintigraphy Allow for More Sensitive Staging of MTC? 266 16.5 Conclusion 270 References 270 17 Therapy for Medullary Thyroid Cancer 275 O. GIMM and H. DRALLE 17.1 Introduction 275 17.2 Sporadic Versus Familial Medullary Thyroid Carcinoma 275 17.3 Therapy 276 17.3.1 Surgical Treatment 277 17.3.1.1 Thyroid Gland 277 17.3.1.2 Lymph Node Metastases 277 17.3.1.3 Distant Metastases 279 17.3.1.4 Reoperation 279 17.3.2 Special Therapeutic Considerations in Familial MTC 280 17.3.2.1 Thyroid Gland 280 17.3.2.2 Lymph Node Metastases 280 17.3.3 Nonsurgical Treatment Modalities 281 17.3.3.1 Octreotide 281 17.3.3.2 Radioactive Iodine 281 17.3.3.3 External Radiation 281 17.3.3.4 Chemotherapy 282 17.3.3.5 Psychological Support 282 References 282 18 Follow-up of Medullary Thyroid Cancer 285 T. SCHILLING and R. ZIEGLER 18.1 Distinction Between Sporadic and Familial Form of Medullary Thyroid Cancer 285 18.2 Survival in Patients Suffering from Medullary Thyroid Cancer 286 18.3 Sporadic Form of Medullary Thyroid Cancer 286 18.3.1 Calcitonin as a Tumor Marker During Follow-up... 287 18.3.2 Testing the Result of the Primary Operation 287 18.3.3 Follow-up in General 290 18.3.4 Follow-up in Patients with No Detectable Calcitonin Postoperatively 290 18.3.5 Follow-up in Patients with Detectable Calcitonin Postoperatively 290
XVI Contents 18.3.6 Adjuvant Therapy 290 18.4 Familial Form of Medullary Thyroid Cancer (Multiple Endocrine Neoplasia Type 2) 291 18.4.1 Screening for Pheochromocytoma and Timing of Surgery 291 18.4.2 Screening for Primary Hyperparathyroidism 292 References 293 Subject Index 295