Pathology of the Thyroid Gland Prof. Dipak Shah Department of Pathology UWI, Mona

Diseases of the Thyroid Gland Congenital diseases Inflammation Functional abnormality Diffuse and Multinodular goiters Neoplasia

Inflammation Thyroiditis Acute illness with pain Infectious Acute Chronic Subacute or granulomatous (De Quervain’s) Little inflammation with dysfunction Subacute lymphocytic thyroiditis Fibrous (Riedel) thyroiditis Autoimmune Hashimoto thyroiditis

HASHIMOTO THYROIDITIS Most common cause of hypothyroidism Autoimmune, non-Mendelian inheritance 45-65 years, F:M = 10-20:1 Painless symmetrical enlargement Risk of developing B-cell non-Hodgkin’s lymphoma Other concomitant autoimmune diseases Endocrine and non-endocrine

Hashimoto Thyroiditis Pathogenesis Immune systems reacts against a variety of thyroid antigens Progressive depletion of thyroid epithelial cells which are gradually replaced by mononuclear cells → fibrosis Immune mechanisms may includes: CD8+ cytotoxic T cell-mediated cell death Cytokine-mediated cell death Binding of antithyroid antibodies → antibody dependent cell-mediated cytotoxicity

Hashimoto Thyroiditis Diffuse enlargement Firm or rubbery Pale, yellow-tan, firm & somewhat nodular cut surface

Hashimoto Thyroiditis Massive lymphoplasmcytic infiltration with lymphoid follicles formation Destruction of thyroid follicles Remaining follicles are small and many are lined by Hurthle cells Increased interstitial connective tissue

Functional Abnormality Hyperfunction  in level of hormone → toxic effects Due to: Diffuse hyperplasia Hyperfunctioning multinodular goiter Hyperfunctioning adenoma Subacute lymphocytic (painless) thyroiditis

Functional Abnormality Hypofunction  in level of hormone → impair development in infants and slowing of physical and mental ability in adults Due to: Postablation Surgery Radiation Autoimmune thyroiditis Drugs Dyshormonogenetic

Graves Disease Most common cause of endogenous hyperthyroidism Characterized by hyperthyroidism, ophthalmopathy with exophthalmos and dermopathy (pretibial myxedema) Autoimmune disease with genetic susceptibility associated with HLA-B8 and DR3 Female:Male = 7:1 3rd to 4th decades Diffuse enlargement with audible bruit Wide,staring gaze,lid lag,exophthalmos,pretibial myxedema ↑ levels of free T4 & T3 and ↓ levels of TSH in blood ↑ uptake of radioactive iodine

Graves’ Disease Autoimmune disease with breakdown of helper-T-cell tolerance Excessive production of TWO thyroid autoantibodies: Thyroid-stimulating antibody (TSAb) & Growth-stimulating antibody (GSAb) Antibodies bind to the TSH receptor of the follicular cell Stimulation of the cell resulting in: Increased levels of thyroid hormones & Hyperplasia of the thyroid gland Hyperthyroidism and Thyroid gland enlargement

Graves Disease Symmetrical enlargement of thyroid gland Cut-surface is homogenous, soft and appear meaty Hyperplasia and hypertrophy of follicular cells

Diffuse & Multinodular goiters Reflects impaired synthesis of thyroid hormone most often caused by iodine deficiency Impairment leads to compensatory ↑ in TSH levels → hypertrophy and hyperplasia of follicular cells → gross enlargement of gland Euthyroid metabolic state Degree of enlargement is proportional to level and duration

Diffuse nontoxic goiter Diffuse non-toxic (simple) goiter colloid goiter Endemic sporadic (dyshormonogenetic)

Endemic Goiter Low iodine content in drinking water & food (Himalayas, Alps, Andes, areas far from the sea) Prevalence decreasing due to prophylactic iodination of salt Iodine deficiency causes decreased hormone levels & consequent elevation in TSH

Sporadic Goiter Commonest type of goiter Euthyroid, but may be hypo- or hyper- Mostly idiopathic, but RARELY, may be caused by: Drugs used in Rx of hyperthyroidism Goitrogens e.g. cauliflower, cabbage, cassava Suboptimal iodine intake Hereditary enzymatic defects

Multinodular goiter Recurrent episodes of hyperplasia and involution leads to irregular enlargement All long standing diffuse endemic and sporadic goiter may eventually convert to multinodular goiter Causes most extreme enlargement and may be mistaken for neoplasm May arise due to variable response of follicular cells to external stimuli such as trophic hormones With uneven follicular hyperplasia, generation of new follicles and uneven accumulation of colloid → rupture of follicle and vessels →hemorrhage, scarring & calcification → nodularity

Multinodular Goiter Asymmetric enlargement Multinodular Haemorrhage Calcification Fibrosis Cystic degeneration

Multinodular Goiter Numerous follicles varying in size Recent haemorrhage Haemosiderin Calcification Cystic degeneration +/- dominant nodule

Thyroid Neoplasms I. Primary Tumours II. Metastatic Tumours Epithelial Malignant Lymphomas Mesenchymal tumours II. Metastatic Tumours

Epithelial Thyroid Neoplasms Tumours of follicular cells Benign (adenomas) Follicular adenoma Malignant (carcinomas) Follicular carcinoma (10-20%) Papillary carcinoma (75-85%) Undifferentiated (anaplastic) carcinoma (<5%) Tumours of C-cells Medullary thyroid carcinoma (MTC - 5%)

Follicular Adenoma Benign, encapsulated tumor showing evidence of follicular differentiation Common Predominantly young to middle women Presents as solitary thyroid nodule Painless nodular mass, cold on isotopic scan

Follicular Adenoma Solitary, Variably sized, encapsulated, well-circumscribed with homogenous gray-white to red-brown cut-surface +/- degenerative changes

Follicular Carcinoma Second most common form, 10-20% Females > Males, average age ~ 45 - 55 yr Rare in children Solitary nodule, painless, cold on isotopic scan Widely invasive Vs minimaly invasive 50% 10 yr survival Vs 90%10 yr survival Haematogenous route is preferred mode of spread

Follicular Carcinoma Solitary round or oval nodule Thick capsule Composed of follicles Capsular invasion or vascular invasion within our outside capsular wall

Papillary Carcinoma Commonest thyroid malignancy, 75-85% Female:Male = 2.5:1 Mean age at onset = 20 - 40 yr May affect children Prior head & neck radiation exposure Indolent, slow-growing painless mass cold on isotopic scan Cervical lymphadenopathy may be presenting feature

Papillary Carcinoma Variable size (microscopic to several cm) Solid or cystic Infiltrative or encapsulated Solitary or multicentric (20%)

Papillary Carcinoma Papillae or follicles Psammoma bodies NUCLEAR FEATURES***

Papillary Carcinoma Nuclear Features Optically clear (ground glass, Orphan Annie) nuclei Nuclear pseudoinclusions or nuclear grooves

Papillary Carcinoma Prognosis Excellent but following factors play important role: Age and sex Size Multicentricity Extra-thyroid extension Distant metastasis Total encapsulation, pushing margin of growth & cystic change

Anaplastic Carcinoma Rare; < 5% of thyroid carcinomas Highly malignant and generally fatal < 1yr. Elderly  65 yrs; females slightly > males Rapidly enlarging bulky neck mass Dysphagia, dyspnoea, hoarseness

Anaplastic Carcinoma Large, firm, necrotic mass Frequently replaces entire thyroid gland Extends into adjacent soft tissue, trachea and oesophagus Highly anaplastic cell on histology with: Giant, spindle,small or mix cell population Foci of papillary or follicular differentiation

Anaplastic Carcinoma Cellular pleomorphism +/- multinucleated giant cells High mitotic activity Necrosis

Medullary Thyroid Carcinoma (MTC) Malignant tumour of thyroid C cells producing cacitonin 5 % of all thyroid malignancies Sporadic (80%) Rest in the setting of MEN IIA or B or as familial without associated MEN syndrome

Medullary Thyroid Carcinoma (MTC) Sporadic MTC Middle-aged adults Female:male = 1.3:1 Unilateral involvement of gland +/- cervical lymph node metastases Indolent course with 60-70% 5-yr survival after thyroidectomy

Multiple Endocrine Neoplasia Types IIA & IIB Germ-line mutation in Ret protooncogene on chromosome 10q11.2 MEN IIA: MTC, phaeochromocytoma, parathyroid adenoma or hyperplasia MEN IIB: MTC, phaeochromocytoma, mucosal ganglioneuromas, Marfanoid habitus, other skeletal abnormalities

Medullary Thyroid Carcinoma (MTC) Associated with MEN IIA Younger patients in twenties Multicentric and bilateral Slow growing Associated with MEN IIB Even younger patients in teens Aggressive with early metastasis Poor prognosis

Medullary Thyroid Carcinoma (MTC) Histology same for sporadic & familial Solid, lobular or insular growth patterns Tumour cells round, polygonal or spindle-shaped Amyloid deposits in many cases

Medullary Thyroid Carcinoma (MTC) Amyloid deposits stain orange-red with Congo Red stain

Prognosis of Thyroid Carcinomas Papillary Best prognosis Follicular Medullary Anaplastic Worst prognosis

Secondary Tumours Direct extensions from: larynx, pharynx, oesophagus etc. Metastasis from: renal cell carcinoma, large intestinal carcinoma, malignant melanoma, lung carcinoma, breast carcinoma etc.

Solitary thyroid nodule Papillary carcinoma Follicular carcinoma Medullary carcinoma Follicular adenoma Hyperplastic (dominant) nodule Metastatic neoplasms FINE NEEDLE ASPIRATION CYTOLOGY

Congenital Thyroid Diseases Agenesis /Aplasia Hypoplasia Accessory or aberrant thyroid glands Thyroglossal duct cyst

Thyroglossal Duct Cyst Children Failure of regression Neck, medial Squamous or columnar lining Complications: inflammation, sinus tracts