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...... 264 Paraganglioma-Like Variant...... 264 Angiosarcoma-Like Variant...... 265 Encapsulated Variant...... 265 Medullary Microcarcinoma...... 265 Heritable Forms of Medullary Carcinoma...... 266 Mixed Medullary and Follicular Cell Carcinoma...... 266 C-Cell Hyperplasia...... 272 13. Sarcomas of the Thyroid Gland...... 289 General Considerations...... 289 Angiosarcoma...... 291 14. Malignant Lymphoma of the Thyroid Gland and Related Lesions...... 299 Malignant Lymphoma...... 299 Other Lymphoid Tumors and Tumor-Like Conditions...... 305 Hodgkin Lymphoma...... 305 Plasmacytoma...... 307 Plasma Cell Granuloma and Related Lesions...... 307 15. Miscellaneous Thyroid-Related Tumors...... 311 Parathyroid Tumors...... 311 Paraganglioma...... 311 Teratoma...... 313 Solitary Fibrous Tumor...... 314 Other Benign Soft Tissue-Type Tumors...... 314 Tumors with Thymic or Related Branchial Pouch Differentiation...... 315 Ectopic Cervical Thymoma...... 315 Ectopic Hamartomatous Thymoma...... 316 Spindle Epithelial Tumor with Thymus-Like Differentiation...... 316 Carcinoma Showing Thymus-Like Differentiation...... 319 Salivary Gland-Type Tumors...... 320 16. Secondary Tumors of the Thyroid Gland...... 325 17. Tumor-Like Conditions of the Thyroid Gland...... 331 Nodular Hyperplasia...... 331 Diffuse Hyperplasia...... 335 Dyshormonogenetic Goiter...... 336 Thyroiditis...... 339 Hashimoto Thyroiditis...... 339

xiii Tumors of the Thyroid and Parathyroid Glands

Subacute Granulomatous (DeQuervain) Thyroiditis...... 342 Fibrosing (Riedel) Thyroiditis...... 342 Multifocal Fibrosing (Sclerosing) Thyroiditis...... 345 Malakoplakia...... 347 Other Forms of Thyroiditis...... 347 Miscellaneous Lesions...... 347 Langerhans Cell Histiocytosis...... 347 Rosai-Dorfman Disease...... 347 Radiation Changes...... 348 Amyloid Goiter...... 349 18. Benign Thyroid Tissue in Abnormal Locations...... 355 Ectopia...... 355 Mechanical Implantation...... 357 Parasitic Nodule...... 358 Thyroid Inclusions in Lymph Nodes...... 360 Thyroid as a Component of Teratoma (Including Struma Ovarii)...... 361 19. Molecular Genetic Alterations of Specific Thyroid Tumors of Follicular Cells...... 365 Follicular Adenoma and Variants...... 365 Follicular Carcinoma...... 367 Papillary Carcinoma and Variants...... 371 Poorly Differentiated Carcinoma...... 379 Undifferentiated (Anaplastic) Carcinoma...... 380 Other Tumors...... 382 20. Cytopathology of Thyroid Tumors...... 395 The Normal Thyroid Gland...... 397 Cytology of Thyroid Tumors and Tumor-Like Conditions...... 400 Nodular Hyperplasia...... 400 Diffuse Hyperplasia...... 404 Hashimoto Thyroiditis...... 404 Follicular Neoplasms...... 406 Papillary Carcinoma...... 416 Variants of Papillary Thyroid Carcinoma...... 427 Insular Carcinoma...... 431 Undifferentiated (Anaplastic) Carcinoma...... 433 Tumors with Oncocytic Features...... 433 Tumors with Clear Cell Features...... 439 Tumors with Squamous Features...... 440 Medullary Carcinoma...... 441 Malignant Lymphoma...... 445 Secondary/Metastatic Tumors...... 447

xiv Contents

Diagnostic Molecular Genetics of FNAB...... 450 Accuracy of Cytology: What Can be Expected...... 452 Pitfalls of Thyroid FNAB...... 455 Histologic Alterations Following FNAB...... 456 Complications of FNAB...... 456 21. Clinical Aspects of Thyroid Tumors...... 465 Clinical and Laboratory Evaluation of Thyroid Nodules...... 465 Demographics...... 465 Family History...... 465 History of Hashimoto Thyroiditis...... 465 Rate of Growth...... 465 Palpation...... 465 Isotopic Imaging Study...... 465 Ultrasonography (Ultrasound)...... 466 Computerized Tomography (CT) and Magnetic Resonance Imaging (MRI)...... 466 Serum Thyroglobulin Levels...... 466 Serum Calcitonin Levels...... 466 Frozen Section Examination...... 466 Cytologic Evaluation...... 467 Pathologic Evaluation and Reporting...... 467 Handling...... 467 Description...... 467 Sections for Histology...... 467 Example of Gross Description...... 468 Standardized Reporting...... 468 ADASP Recommended Protocol...... 468 CAP Recommended Protocol/Checklist...... 468 Microscopic Grading...... 468 Staging of Thyroid Carcinoma...... 469 Ancillary Testing...... 471 Treatment of Thyroid Tumors...... 472 Prognostic Factors...... 474 22. Immunohistochemical Markers of the Normal and Neoplastic Thyroid Gland...... 481 23. The Normal Parathyroid Gland...... 493 Embryology...... 493 Anatomy...... 494 Gross and Microscopic Findings...... 494 Immunohistochemical Findings...... 499 Ultrastructural Findings...... 501

xv Tumors of the Thyroid and Parathyroid Glands

24. Physiology and Pathophysiology of Parathyroid Glands...... 505 Calcium Homeostasis...... 505 Parathyroid Hormone and Parathyroid Hormone-Related Protein...... 505 Hypercalcemia...... 506 Hyperparathyroidism...... 506 General Considerations...... 506 Primary Hyperparathyroidism...... 506 Bone Manifestations...... 507 Renal and Other Manifestations...... 509 Hypercalcemia of Malignancy...... 509 25. Parathyroid Adenoma and Variants...... 513 Parathyroid Adenoma...... 513 Adenoma Variants...... 531 Oncocytic Adenoma...... 531 Lipoadenoma...... 532 Water Clear Cell Adenoma...... 532 Atypical Adenoma...... 532 Adenoma-Associated Parathyroid Glands...... 537 26. Parathyroid Carcinoma...... 543 General Features...... 543 Clinical Features...... 543 Gross Findings...... 544 Microscopic Findings...... 544 Cytologic Findings...... 552 Immunohistochemical Findings...... 552 Ultrastructural Findings...... 553 Molecular Genetic Findings...... 553 Differential Diagnosis...... 554 Treatment and Prognosis...... 554 Staging of Parathyroid Carcinoma...... 556 27. Primary Chief Cell Hyperplasia, Clear Cell Hyperplasia, and Heritable Hyperparathyroidism Syndromes...... 561 Primary Chief Cell Hyperplasia...... 561 Clear Cell Hyperplasia...... 566 Heritable Hyperparathyroidism Syndromes...... 568 Multiple Endocrine Neoplasia Type 1...... 568 Multiple Endocrine Neoplasia Type 2...... 570 Multiple Endocrine Neoplasia Type 4...... 571 Hyperparathyroidism-Jaw Tumor Syndrome...... 571

xvi Contents

Familial Hypocalciuric Hypercalcemia and Neonatal Severe Primary Hyperparathyroidism...... 571 Familial Isolated Hyperparathyroidism...... 572 28. Secondary and Tertiary Hyperparathyroidism, and Parathyroid Grafts...... 575 Secondary Hyperparathyroidism...... 575 Tertiary Hyperparathyroidism...... 579 Parathyroid Grafts...... 580 29. Miscellaneous Parathyroid Lesions...... 583 Parathyroid Cysts...... 583 Parathyromatosis...... 583 Secondary Tumors...... 585 30. Diagnostic Approaches to Parathyroid Lesions...... 589 Intraoperative Diagnosis...... 589 Fat Stains...... 590 Density Gradients...... 591 DNA Cytometry...... 591 Preoperative Localization and Intraoperative Parathyroid Hormone Assays...... 591 Index ...... 597

xvii