1. Dr.Bharathi Sengodan M.D.,

2. Thyroiditis Acute thyroiditis Bacterial infection (e.g., Staphylococcus aureus) Clinical findings (1) Fever (2) Tender gland with painful cervical adenopathy Acute thyroiditis: thyrotoxicosis; ↓ 131I uptake –Treatment Penicillin or ampicillin if abscess are present it has to be drained surgically

3. Dr.Bharathi Sengodan M.D., HASHIMOTO THYROIDITIS F> M - Incidence increases with age (HLA)-Dr3 and -Dr5 associations Increased incidence in: Turner's,Down & Klinefelter's syndrome & other autoimmune diseases (pernicious anemia) Risk - B-cell non-Hodgkin lymphomas. Characterized by (1)diffuse enlargement of the thyroid (2)lymphocytic infiltration of the thyroid gland and (3)gradual thyroid failure because of autoimmune destruction (Autoimmune thyroiditis-presence of auto Ab’s) Most common cause of primary hypothyroidism Initial thyrotoxicosis from gland destruction - Known as hashitoxicosis Hypothyroidism

4. Dr.Bharathi Sengodan M.D., Pathogenesis (1) Cytotoxic T cells destroy parenchyma (type IV hypersensitivity). (2) Binding of antithyroid antibodies followed by antibody- dependent cell-mediated cytotoxicity (ADCC) ] Decrease hormone synthesis; type II hypersensitivity (3) Antimicrosomal and thyroglobulin antibodies

5. Dr.Bharathi Sengodan M.D., Morphology Gross :Diffusely enlarged,gray, firm and rubbery Micro: Lymphocytic infiltrate with prominent germinal follicles The thyroid follicles are atrophic and are lined by epithelial cells with abundant eosinophilic, granular cytoplasm, termed Hurthle cells

6. Dr.Bharathi Sengodan M.D., Clinical findings (1) Most common cause of primary hypothyroidism (2) Initial thyrotoxicosis from gland destruction - Known as hashitoxicosis (3) Risk factor for primary B-cell malignant lymphoma of the thyroid

7. Dr.Bharathi Sengodan M.D., SUBACUTE (GRANULOMATOUS) THYROIDITIS Also referred to as De Quervain thyroiditis 30 and 50 age group /F>M (3:1 to 5:1) Associated with HLA B 35 haplotype Pathogenesis Caused by a viral infection [Coxsackievirus, mumps, measles, adenovirus, and other viral] Gross: Asymmetric, unilateral or bilateral enlarged and firm,with intact capsule Micro: Early inflammatory phase Multinucleate giant cells enclose colloid hence the designation granulomatous thyroiditis

8. Dr.Bharathi Sengodan M.D., Clinical Course It is characterized by pain in the neck, which may radiate to the upper neck, jaw, throat, or ears, particularly when swallowing. Fever, fatigue, malaise, anorexia, and myalgia accompany a variable enlargement of the thyroid. Elevated levels of T4/T3 regresses within 2 to 6 weeks, even if the patient is not treated. Immunoreactivity for CA19-9 AND CEA is seen

9. Dr.Bharathi Sengodan M.D., SUBACUTE LYMPHOCYTIC (PAINLESS) THYROIDITIS Middle-aged adults More common in women, especially during the postpartum period (postpartum thyroiditis) Morphology Gross: Mild symmetric enlargement Micro :Lymphocytic infiltration with hyperplastic germinal centers Clinical Presentation : Mild hyperthyroidism, goitrous enlargement of the gland, or both The principal clinical manifestation of painless thyroiditis is hyperthyroidism. Laboratory findings during periods of thyrotoxicosis include elevated levels of T4 and T3 and depressed levels of TSH

10. Dr.Bharathi Sengodan M.D., Other, less common forms of thyroiditis Riedel thyroiditis, a rare disorder of unknown etiology characterized by extensive fibrosis involving the thyroid and contiguous neck structures. Palpation thyroiditis, caused by vigorous clinical palpation of the thyroid gland, results in multifocal follicular disruption associated with chronic inflammatory cells Other inflammatory conditions – Tuberculosis/ sarcoidosis / mycoses Post-operative necrotizing granulomas

11. Dr.Bharathi Sengodan M.D., Graves Disease characterized by "violent and long continued palpitations in females" associated with enlargement of the thyroid gland. (Basedow’s disease) Graves disease is the most common cause of endogenous hyperthyroidism. F>M It is characterized by a triad of clinical findings: Hyperthyroidism owing to hyper functional, diffuse enlargement of the thyroid Infiltrative ophthalmopathy with resultant exophthalmos Localized, infiltrative dermopathy, sometimes called pretibial myxedema, which is present in a minority of patients

12. Dr.Bharathi Sengodan M.D., Ages of 20 and 40 – 7:1 -F:M High prevalence in smokers and emotion stress Genetic factors Associated with HLA-B8 and -DR3 and Polymorphisms CTLA-4 gene Pathogenesis Auto antibodies to the TSH receptor are central to disease pathogenesis Thyroid-stimulating immunoglobulin (TSI) Thyroid growth-stimulating immunoglobulins (TGI) TSH-binding inhibitor immunoglobulins (TBII)

13. Dr.Bharathi Sengodan M.D., Morphology Gross: Symmetrically enlarged The gland is usually smooth and soft, and its capsule is intact On cut section, the parenchyma has a soft, meaty appearance resembling normal muscle. Micro; The dominant feature is too many cells This crowding results in the formation of papillae, which project into the follicular lumen and encroach on the colloid, sometimes filling the follicles (Scalloping) Colloid is less

14. Dr.Bharathi Sengodan M.D., Diffuse and multinodular goiters Pathogenesis Impaired synthesis of thyroid hormone (dietary iodine def) Leads to a compensatory rise in the serum TSH level Which causes hypertrophy and hyperplasia of thyroid follicular cells Ultimately, gross enlargement of the thyroid gland. The compensatory increase in functional mass of the gland is able to overcome the hormone deficiency, ensuring an euthyroid metabolic state If disorder is severe, the compensatory responses may be inadequate, resulting in goitrous hypothyroidism.

15. Dr.Bharathi Sengodan M.D., Etiology Genetic Hereditary defect on thyroid hormone synthesis and transport Inborn errors of iodine metabolism Suboptimal iodine intake Occurs in areas where the soil, water, and food supply contain only low levels of iodine. (mountainous areas ) Goitrogens; substances that interfere with thyroid hormone synthesis such as excessive calcium and vegetables (e.g., cabbage, cauliflower, Brussels sprouts, turnips, and cassava) The lack of iodine-- leads to decreased synthesis of thyroid hormone and a--- compensatory increase in TSH -- leading to follicular cell hypertrophy- and hyperplasia and goitrous enlargement

16. Dr.Bharathi Sengodan M.D., Diffuse nontoxic (simple) goiter Goiter that diffusely involves the entire gland without producing nodularity Because the enlarged follicles are filled with colloid, the term colloid goiter Both endemic and sporadic forms seen MULTINODULAR GOITER Recurrent episodes of hyperplasia and involution combine to produce a more irregular enlargement of the thyroid, termed multinodular goiter They may be nontoxic or may induce thyrotoxicosis (toxic multinodular goiter)

17. Dr.Bharathi Sengodan M.D., Morphology Multilobulated, asymmetrically enlarged glands ( weigh > 2000 gm) grows behind the sternum and clavicles to produce the so-called intrathoracic or plunging goiter c/s irregular nodules containing variable amounts of brown, gelatinous colloid are present. Microscopic features Colloid-rich follicles lined by flattened, inactive epithelium Areas of follicular epithelial hypertrophy and hyperplasia Accompanied by cyst formation, scarring, areas of heamorrhage, calcification and presence of hemosiderin laden macrophages

18. Dr.Bharathi Sengodan M.D., Clinical Course Mass effects Cosmetic effects, airway obstruction, dysphagia, and compression of large vessels in the neck and upper thorax. Most patients are euthyroid OR hyperthyroidism (toxic multinodular goiter). Radioiodine uptake is uneven, reflecting varied levels of activity in different regions. Hyperfunctioning nodules concentrate radioiodine and appear "hot.“

19. Dr.Bharathi Sengodan M.D., Thyroid Tumours The solitary thyroid nodule is a palpably discrete swelling Benign neoplasms outnumber thyroid carcinomas by a ratio of nearly 10:1 Carcinomas of the thyroid are thus uncommon Clinical criteria provides a clue to the nature of a given thyroid nodule: Solitary nodules, in general, are more likely to be neoplastic than are multiple nodules Nodules in younger patients are more likely to be neoplastic than are those in older patients. Nodules in males are more likely to be neoplastic than are those in females. A history of radiation treatment to the head and neck region is associated with an increased incidence of thyroid malignancy. Nodules that take up radioactive iodine in imaging studies (hot nodules) are more likely to be benign than malignant

20. Dr.Bharathi Sengodan M.D., PRIMARY TUMORS EPITHELIAL TUMORS Tumors of Follicular cells Benign: Follicular adenoma (conventional and variants) Malignant: Carcinoma Differentiated Follicular carcinoma Papillary carcinoma Poorly differentiated Insular carcinoma Undifferentiated (Anaplastic) Tumors of C cells ( and related neuroendocrine cells ) Medullary Carcinoma Others Tumors of Follicular and C cells SARCOMAS MALIGNANT LYMPHOMA (AND RELATED HAEMATOPOIETIC NEOPLASMS) MISCELLANEOUS NEOPLASMS SECONDARY TUMORS Classification of Tumours of the Thyroid Gland

21. Dr.Bharathi Sengodan M.D., Solitary thyroid nodule –Majority are cold nodules (95%). –Solitary nodule in a woman: majority are benign; 15% malignant –Approximately 85% to 90% of solitary nodules are euthyroid. –Solitary nodule in man/child: more likely to be malignant –Solitary nodule with history of radiation exposure: more likely to be malignant (40%) Diagnosis –First step in management of solitary thyroid nodule: fine needle aspiration –Thyroid hormone studies

22. Dr.Bharathi Sengodan M.D., Adenomas Are typically discrete, solitary masses derived from follicular epithelium Vast majority of adenomas are nonfunctional, Small proportion produce thyroid hormones called functional adenomas ("toxic adenomas") Morphology Gross: Solitary, spherical, encapsulated lesion Areas of hemorrhage, fibrosis, calcification,& cystic change seen The hallmark of all follicular adenomas is the presence of an intact, well-formed capsule encircling the tumor.

23. Dr.Bharathi Sengodan M.D., Microscopically Shows encapsulation Tumour Cells are benign follicular epithelial cells which form follicles Growth patterns that are seen are: Microfollicular (foetal) adenoma Normofollicular (simple) adenoma Macrofollicular (colloid) adenoma Trabecular (embryonal) adenoma Hurtle cell (oxyphil) adenoma Atypical adenoma Clinical unilateral painless mass Larger masses may symptoms, such as difficulty in swallowing. On radionuclide scanning, usually appear as cold nodules In a minority of cases, adenomas may be hyperfunctional, producing signs and symptoms of hyperthyroidism (toxic adenomas

24. Dr.Bharathi Sengodan M.D., CARCINOMAS Most cases occur in adults, although some forms, particularly papillary carcinomas, may present in childhood. A female predominance Most thyroid carcinomas are well-differentiated lesions. Subtypes : Papillary carcinoma (75% to 85% of cases) Follicular carcinoma (10% to 20% of cases) Medullary carcinoma (5% of cases) Anaplastic carcinoma (<5% of cases)

25. Dr.Bharathi Sengodan M.D., Genetic Factors Important in both familial and nonfamilial ("sporadic") Mutations Follicular Thyroid Carcinomas -mutations in the RAS Papillary Thyroid Carcinomas -Rearrangements RET (RET/PTC1) or NTRK1 Anaplastic Carcinomas- point mutations in the p53 Medullary Thyroid Carcinomas Familial medullary thyroid carcinomas occur in multiple endocrine neoplasia type 2 (MEN-2) are also associated with germ-line RET protooncogene mutations RET mutations are also seen in nonfamilial (sporadic) medullary thyroid cancer 2. Environmental Factors

26. Dr.Bharathi Sengodan M.D., Papillary Carcinoma Most common endocrine cancer Papillary carcinomas are the most common form of thyroid cancer(>75%) Usually occur in second and third decades F>M (3:1) Increase incidence of papillary ca in Hashimotos is evident Associated with radiation exposure Foci of lymphatic invasion by tumor are often present, but involvement of blood vessels is relatively uncommon, particularly in smaller lesions. Metastases to adjacent cervical lymph nodes are estimated to occur in up to half the cases.

27. Dr.Bharathi Sengodan M.D., Morphology- Macro solitary well-circumscribed and even encapsulated (10%) Others may infiltrate cut surface they appear granular and can contain papillary structures Micro Branching papillae having a fibrovascular stalk Occasionally inflammatory infiltrate & Psammoma bodies are present

28. Dr.Bharathi Sengodan M.D., Nuclear features 1. The nuclei are optically clear or empty appearance - ground glass or Orphan Annie eye nuclei. 2. Invaginations of the cytoplasm give the appearance of intranuclear inclusions ("pseudo- inclusions") 3.Nuclear grooves –infoldings of a redundant nuclear membrane

29. Dr.Bharathi Sengodan M.D., Diagnostic tests. Most papillary lesions are cold masses on scintiscans. Improvements in cytologic analysis have made fine-needle aspiration cytology a reliable test for distinguishing between benign and malignant nodules. Prognosis Papillary thyroid cancers have an excellent prognosis, with a 10-year survival rate in excess of 95%.

30. Dr.Bharathi Sengodan M.D., Follicular Carcinoma Follicular carcinomas are the second most common form of thyroid cancer, accounting for 10% to 20% of all thyroid cancers. They tend to present in women, and at an older age-forties and fifties. The incidence of follicular carcinoma is increased in areas of dietary iodine deficiency

31. Dr.Bharathi Sengodan M.D., Morphology Single nodules that may be well circumscribed or widely infiltrative They are gray to tan to pink on cut section Degenerative changes present.

32. Dr.Bharathi Sengodan M.D., Microscopically  composed of fairly uniform cells forming small follicles containing colloid,  the nuclei lack the features typical of papillary carcinoma,  capsular and/or vascular invasion Minimally invasive follicular carcinoma micro-follicular or trabecular pattern Widely invasive follicular carcinoma Not encapsulated, widespread infiltration of blood vessels, and often extends into neighboring tissue

33. Dr.Bharathi Sengodan M.D., Clinical Course Follicular carcinomas present as slowly enlarging painless nodules. Most frequently, they are cold nodules on scintigrams Follicular carcinomas have little propensity for invading lymphatics But vascular invasion is common, with spread to bone, lungs, liver, and elsewhere. The prognosis is largely dependent on the extent of invasion and stage at presentation.

34. Dr.Bharathi Sengodan M.D., Medullary Carcinoma 5% of thyroid carcinomas neuroendocrine neoplasms derived from the parafollicular cells, or C cells, of the thyroid secrete calcitonin, the measurement of which plays an important role in the diagnosis and postoperative follow-up of patients M = F,middle or old age group solitary slow growing nodule Sporadic / Familial occurrence occurs in the setting of MEN syndrome 2A or 2B (Younger age group)

35. Dr.Bharathi Sengodan M.D., Morphology Medullary carcinomas can arise as a solitary nodule In contrast, bilaterality and multicentricity are common in familial cases. The tumor tissue is firm, pale gray to tan, and infiltrative. There may be foci of hemorrhage and necrosis in the larger lesions.

36. Dr.Bharathi Sengodan M.D., Microscopically  Composed of polygonal to spindle- shaped cells, which may form nests, trabeculae, and even follicles.  Stroma : Acellular amyloid deposits, derived from altered calcitonin molecules, are present and stain positive for congo red

37. Dr.Bharathi Sengodan M.D., Clinical Course Sporadic cases of medullary carcinoma come to medical attention most often as a mass in the neck, sometimes associated with local effects such as dysphagia or hoarseness. In some instances, the initial manifestations are those of a paraneoplastic syndrome, caused by the secretion of a peptide hormone (e.g., diarrhea owing to the secretion of VIP). Notably, hypocalcemia is not a prominent feature, despite the presence of raised calcitonin levels Screening of relatives for elevated calcitonin levels or RET mutations permits early detection of tumors in familial cases.

38. Dr.Bharathi Sengodan M.D., Anaplastic Carcinoma Are undifferentiated tumors of the thyroid follicular epithelium. Are aggressive tumors, with a mortality rate approaching 100%. These tumors account for fewer than 5% of all thyroid cancers. with a mean age of 65 years. About half of the patients have a history of multinodular goiter The malignancy typically arises in a pre- existing tumour

39. Dr.Bharathi Sengodan M.D., Morphology Microscopically, these neoplasms are composed of highly anaplastic cells, which may take one of several histologic patterns: (1) Large, pleomorphic giant cells, including occasional osteoclast - like multinucleate giant cells (2) Spindle cells with a sarcomatous appearance (3) Mixed spindle and giant cells and (4) Small cells resembling those seen in small cell carcinomas arising at other sites.

40. Dr.Bharathi Sengodan M.D., Clinical Course Anaplastic carcinomas usually present as a rapidly enlarging bulky neck mass. In most cases, the disease has already spread beyond the thyroid capsule into adjacent neck structures or has metastasized to the lungs at the time of presentation. Compression and invasion symptoms, such as dyspnea, dysphagia, hoarseness, and cough, are common. There is no effective therapy for anaplastic thyroid carcinoma, and the disease is almost uniformly fatal.

41. Dr.Bharathi Sengodan M.D., Follicular adenoma is commonFollicular adenoma is common Papillary Adenoma and Medullary Adenoma does not exist !Papillary Adenoma and Medullary Adenoma does not exist ! Follicular and Hurthle Cell Neoplasm have both Benign and Malignant [Adenoma and Carcinoma] counterparts!Follicular and Hurthle Cell Neoplasm have both Benign and Malignant [Adenoma and Carcinoma] counterparts! Papillary Carcinoma and Medullary Carcinoma do not have benign counterpartsPapillary Carcinoma and Medullary Carcinoma do not have benign counterparts

42. Dr.Bharathi Sengodan M.D., Tumour Markers Thyroglobulin Marker for follicular differentiation positive in follicular neoplasm, papillary ca & poorly differentiated Calcitonin Marker for Para-follicular cells Positive in medullary ca CEA Sensitive marker in medullary ca Chromogranin Specific neuroendocrine marker Positive in medullary ca & paraglioma Cytokeratin Epithelial marker for follicular cells, positive in c-cell tumours, thymic tumours