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
-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
CONTENTS
Tumors of the Thyroid and Parathyroid Glands
xii
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
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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
Tumors of the Thyroid and Parathyroid Glands
xiv
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
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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
Tumors of the Thyroid and Parathyroid Glands
xvi
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
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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
P