CONTENTS 1. Normal Thyroid Gland .................................................................................................... 1 Embryology .................................................................................................................. 1 Anatomy ...................................................................................................................... 3 Histology ...................................................................................................................... 4 The Follicular Cell ........................................................................................................ 8 Thyroid Hormones ................................................................................................... 10 The C-Cell .................................................................................................................... 11 Calcitonin and Calcitonin Gene-Related Peptide .................................................... 14 Solid Cell Nests ............................................................................................................ 15 2. Genes Involved in Thyroid Tumorigenesis ..................................................................... 23 TSH Receptor/cAMP Pathway ...................................................................................... 25 MAPK Pathway ............................................................................................................ 31 Tyrosine Kinase Receptors (RET, NTK1, MET) .......................................................... 31 RAS............................................................................................................................ 36 BRAF ......................................................................................................................... 37 P13K/PTEN/AKT Pathway ............................................................................................ 39 PPARg Rearrangement .................................................................................................. 41 ß-Catenin/APC/Wnt Signaling ................................................................................... 42 TERT ............................................................................................................................. 43 Tumor Protein p53 ....................................................................................................... 45 3. General Features of Thyroid Tumors ............................................................................... 57 Incidence of Thyroid Carcinoma ................................................................................ 57 Thyroid Tumors and Iodine Deficiency....................................................................... 57 Thyroid Tumors and Radiation Exposure .................................................................... 57 Thyroid Tumors in Childhood .................................................................................... 58 4. Classification of Thyroid Tumors .................................................................................... 61 Primary Tumors ........................................................................................................... 62 Secondary Tumors and Tumor-Like Lesions ................................................................ 62 5. Follicular Thyroid Adenoma and Variants ...................................................................... 65 Follicular Adenoma ...................................................................................................... 65 Adenoma Variants ....................................................................................................... 73 Adenoma with Bizarre Nuclei .................................................................................. 73 Hyalinizing Trabecular Adenoma............................................................................. 73 Adenolipoma and Adenochondroma ...................................................................... 78 Atypical Adenoma (Including Spindle Cell Adenoma) ........................................... 78 Adenoma with Papillary Features ............................................................................ 79 “Toxic” Adenoma ..................................................................................................... 81 xi Tumors of the Thyroid and Parathyroid Glands 6. Follicular Thyroid Carcinoma ......................................................................................... 85 Minimally Invasive (Encapsulated) Type .................................................................... 86 Widely Invasive Type ................................................................................................... 97 7. Papillary Thyroid Carcinoma and Variants ..................................................................... 103 Papillary Carcinoma .................................................................................................... 103 Papillary Carcinoma Variants ...................................................................................... 127 Papillary Microcarcinoma ........................................................................................ 127 Encapsulated Variant ................................................................................................ 130 Follicular Variant ...................................................................................................... 131 Encapsulated Follicular Variant of PTC and the “Uncertain Malignant Potential (UMP)” Concept .................................................................................... 135 Solid/Trabecular Variant ........................................................................................... 139 Diffuse Sclerosing Variant ........................................................................................ 141 Oncocytic and Warthin-Like Variants ..................................................................... 143 Tall and Columnar Cell Variants .............................................................................. 146 Cribriform/Morular Variant ..................................................................................... 149 8. Poorly Differentiated Thyroid Carcinoma ...................................................................... 165 Insular Carcinoma ....................................................................................................... 165 Other Poorly Differentiated Carcinomas..................................................................... 172 9. Undifferentiated (Anaplastic) Thyroid Carcinoma ......................................................... 177 10. Thyroid Tumors with Oncocytic (Hürthle Cell) Features ............................................... 199 General Considerations ............................................................................................... 199 Oncocytic Adenoma (Hürthle Cell Adenoma) ............................................................ 203 Oncocytic Carcinoma (Hürthle Cell Carcinoma) ........................................................ 209 Papillary Oncocytic Neoplasms ................................................................................... 215 11. Thyroid Tumors with Clear Cell, Squamous, and Mucinous Features ........................... 221 Tumors with Clear Cell Features .................................................................................. 221 General Considerations ............................................................................................ 221 Tumor Types ............................................................................................................. 222 Other Conditions ..................................................................................................... 227 Tumors with Squamous Features ................................................................................. 228 Tumors with Mucinous Features ................................................................................. 233 12. Medullary Thyroid Carcinoma and C-Cell Hyperplasia ................................................. 241 Medullary Thyroid Carcinoma .................................................................................... 241 Medullary Carcinoma Variants .................................................................................... 261 Papillary Variant ....................................................................................................... 261 Follicular (Tubular) Variant ...................................................................................... 261 Small Cell Variant ..................................................................................................... 261 Giant Cell Variant .................................................................................................... 261 xii Contents Clear Cell Variant ..................................................................................................... 262 Melanotic Variant ..................................................................................................... 262 Oncocytic Variant .................................................................................................... 262 Squamous Cell Variant ............................................................................................. 264 Amphicrine Cell Variant .........................................................................................