Lecture 15: Thyroid

Thyroid Ectopic Gland

Thyroid gland develops from outpouching of pharyngeal epithelium at base of tongue (Foramen Cecum) which descends along midline forming the temporary Thyroglossal duct

Ectopic thyroid at base of the tongue (Lingual Thyroid) & midline anterior neck (Thyroglossal Duct Cyst)

Hypothalamic-Pituitary-Thyroid Axis

Hypothalamus releases Thyrotropin-Releasing Hormone (TRH) → release of Anterior Pituitary Thyroid-Stimulating Hormone (TSH) → TSH binds TSH receptor on Thyrocytes ↑ Synthesis + ↑ Release of Thyroid Hormones (T4 & T3) → Negative feedback by T3 & T4 to Pituitary Thyrotrophs that ↓ TSH & to the Hypothalamus that ↓TRH

Thyroid Hormone Synthesis and Transport

Thyroid Peroxidase

Thyroid-Binding Globulin/Thyroxine-Binding Globulin (TBG)

free hormone is the biologically active form of the hormone

T3 has most biologic activity

Most of the plasma T3 is derived by peripheral conversion of T4 by tissue Deiodinase

Effects of thyroid hormone

↑ Metabolic rate

↑ thermogenesis

↑ β-Sympathetic activity

Lab tests

primary screening test for thyroid dysfunction is serum TSH

High TSH: Hypothyroidism, follow with a Free T4

Low TSH: Hyperthyroidism, follow with a Free T4 + Total T3

Estrogens → ↑ Total T4 & T3 because Estrogens ↑ carrier proteins

Biotin → ↓ TSH & ↑ T3 & T4

Drugs, Glucocorticoids, Dopamine also ↓ TSH

Hyperthyroidism

Thyrotoxicosis: Hypermetabolic state caused by ↑ Free T3 & T4

Hyperthyroidism: ↑ T3, T4

Primary hyperthyroidism: Pathology in the thyroid tissue

Secondary Hyperthyroidism: pathology not of the thyroid gland itself

2 mechanisms → 24-hour radioiodine uptake scan:

↑ de novo hormone synthesis in thyroid gland: Normal or high radioiodine uptake

↑ release of pre-formed hormone (without synthesis) or extra-thyroidal source: Near absent radioiodine uptake

Thyrotoxicosis

Tachycardia, Arrhythmias (palpitations)

Exophthalmos

Graves → Pretibial myxedema

More common in older people:

Apathetic type (symptoms blunted)

Depression

CHF, Cardiomegaly

Irregular heartbeat (A-Fib common)

unexplained weight loss

Graves Disease

Hyperthyroidism with diffuse thyroid gland enlargement

Infiltrative Ophthalmopathy → Exophthalmos

Localized infiltrative dermopathy (Pretibial Myxedema)

Autoimmune disorder with anti-thyroid antibodies to the TSH Receptor

Binding of autoantibodies to the TSH receptor → stimulate TSH receptor (Thyroid-stimulating Immunoglobulin / TSI)

Female , peak incidence 30-40 years

Graves Disease: Exophthalmos/Proptosis/Graves Orbitopathy

Fibroblasts in retro-orbital space (& some dermal fibroblasts) have TSH Receptors & IGF-1 Receptors

TSH Receptor Antibodies (TSI) bind & stimulate fibroblasts to proliferate & differentiate into myofibroblasts & secrete Hyaluronic acid

↑ volume of the retro-orbital tissues & extraocular muscles → eyes to progressively bulge out (Exophthalmos), diplopia, blurred vision, light sensitivity

Fibroblasts in dermis of shins → Infiltrative Dermopathy (Pretibial Myxedema)

Skin Changes of Graves Disease

Infiltrative Dermopathy (formerly: Pretibial Myxedema)

skin over shins scaly, orange peel-like thickening

pigmented papules or nodules

Acropachy: clubbed fingers & swollen hands → Associated with Ophthalmopathy

Infiltrative Dermopathy

Infiltrative Dermopathy

Acropachy

Infiltrative Dermopathy

Infiltrative Dermopathy

Skin: separation of collagen fibers by mucin in reticular dermis

Neonatal Thyrotoxicosis

if Mom has Graves Disease

→ TSI crosses placenta (are IgG)

→ Maternal thyroid hormones cross placenta

Thyroid Storm

Severe clinical manifestations of Thyrotoxicosis:

Tachycardia > 140 or Heart Failure

Fever (104-106 °F)

Altered mentation (Agitation, anxiety, delirium, psychosis, stupor, or coma)

Labs: ↓ TSH and ↑ free T4 and/or total T3

Precipitated by acute ↑ in catecholamines from a medical event or other stressor

Graves Disease

diffusely enlarged, hyperplastic gland

bruit from increased arterial blood flow

may cause difficulty in swallowing

Gland smooth & soft; capsule smooth

Graves Disease

Dilated follicles lined by increased numbers of tall follicular cells with papillary infoldings

Scalloped colloid (↑ pinocytosis of colloid)

Granulomatous (De Quervain) Thyroiditis

Females predominate; peaks age 30-50

Pathogenesis: Triggered by Viral infection; “Viral thyroiditis”; usually after URI; peaks in the summer

tissue damage from activation of cross-reactive cytotoxic T-cells by virus

Thyroid is Painful or tender; worse on swallowing; radiates to jaw, ears

Constitutional symptoms often absent

Transient Thyrotoxicosis, followed by transient hypothyroidism with complete symptomatic & metabolic recovery in ≈2 months (Self-limited)

Radioactive nuclide uptake is not increased

Sometimes called "Subacute Painful Thyroiditis"

Granulomatous (De Quervain) Thyroiditis

Gland enlarged; firm

Most common cause of thyroid pain

Histology: Multinucleated giant cells = Granulomatous

Chronic inflammation with multinucleated Giant Cells surrounding pools of colloid

Hypothyroidism Types

Primary: Thyroid gland problem; majority; Labs ↑ TSH, ↓ Free T4

Secondary: Pituitary destruction/insufficiency; Labs: ↓ TSH; ↓ Free T4

Tertiary: Hypothalamic: ↓ TRH, ↓ TSH, ↓ Free T4

Hypothyroidism in the Fetus & Infant

Maternal thyroid hormones cross the placenta

Maternal deficiency in early pregnancy affects fetus most, impairing brain development

Fetal Hypothyroidism (Congenital Hypothyroidism): maternal thyroid hormones protects the fetus until birth; born relatively normal

Maternal + Fetal Hypothyroidism (Congenital Iodine Deficiency/Cretinism)

Cretinism

Weak muscle tone (Floppy baby); puffy face

Coarse facial features & hair

Large, protruding tongue

Protruding abdomen, Umbilical hernia

Hoarse cry

Constipation

Cool, pale skin

Slow skeletal growth, short stature

Impaired CNS development

Myxedema

Hypothyroidism in older children/adult

Puffiness of face, eyelids, hands (“non-pitting edema”) due to accumulation of extracellular matrix (ECM) substances

Hypothyroidism

Cold intolerance

Weight gain

Slow pulse (Bradycardia)

puffy face, hands, feet (Generalized Myxedema)

Hair loss; brittle fingernails

Constipation

Carpal tunnel syndrome

More common in older people:

High cholesterol

Heart failure

Bowel movement changes, usually constipation

Joint pain or general muscular pain

Depression or psychosis

Dementia

Unsteadiness while walking

Chronic Lymphocytic Thyroiditis (Hashimoto Thyroiditis)

Autoimmune thyroiditis with progressive gland destruction & eventual Hypothyroidism

Women

peak incidence 45-65 years

Caused by breakdown in self-tolerance to thyroid autoantigens

Infiltrates of Lymphocytic cells, progressive depletion of Thyrocytes, intra-glandular fibrosis

Chronic Lymphocytic Thyroiditis (Hashimoto Thyroiditis) Clinical

Painless symmetric diffuse thyroid enlargement (eventual fibrosis may shrink)

Hypothyroidism

Increased risk for B-cell MALT lymphoma

Screen with TSH + Free T4 (↑ TSH, ↓ Free T4)

Anti-Thyroid Peroxidase antibody (anti-TPO)

Anti-Thyroglobulin antibody (anti-TG)

TSH receptor blocking immunoglobin

Thyroid Moderately enlarged thyroid

Rubbery, nodular fleshy cut surface

Chronic Lymphocytic Thyroiditis (Hashimoto Thyroiditis)

Chronic Lymphocytic Thyroiditis (Hashimoto Thyroiditis)

Chronic Lymphocytic Thyroiditis (Hashimoto Thyroiditis)

Infiltrate of Lymphocytes with germinal centers (Struma Lymphomatosa)

Chronic Lymphocytic Thyroiditis (Hashimoto Thyroiditis)

Hurthle cells

Chronic Lymphocytic Thyroiditis (Hashimoto Thyroiditis)

Subacute Lymphocytic (painless) Thyroiditis

Autoimmune (anti-TPO & anti-TG Ab)

3 phases: Initial Transient Hyperthyroidism, later as Transient Hypothyroidism, then recovery

mild transient Hyperthyroidism +/- thyroid enlargement with ↓ RAIU & negative TSI

Sporadic form usually seen in middle aged women; Post Partum form is most common

Morphology: Lymphoid infiltration with germinal centers, but fewer Hurthle cells

about 1/3 become permanently hypothyroid with Chronic Lymphocytic Thyroiditis (Hashimoto)

Reidel Thyroiditis (Reidel struma)

middle aged Adults

firm (“rock hard”), fixed, painless enlargement (mass) due to chronic inflammation with dense fibrosis of the thyroid & contiguous neck structures

Micro: collagenized tissue with lymphs, plasma cells & eosinophils within & outside of thyroid capsule

Hypothyroidism, tracheal compression, & recurrent laryngeal nerve impingement (vocal cord paralysis)

Manifestation of IgG4-related disease; associated with fibrosis of retroperitoneum, salivary glands, mediastinum, pancreas

Goiter

Impaired synthesis of thyroid hormone due to Iodine deficiency or enzyme defect → compensatory ↑ TSH

TSH causes ↑ in thyroid mass (hyperplasia) & usually maintains Euthyroid state (but if unable to compensate → hypothyroidism)

Enlargement is proportional to level & duration of hormone deficiency

Multinodular goiter develops in most longstanding simple goiters due to recurrent episodes of hyperplasia & involution

Hyperplasia gives opportunity for clonal nodules to arise

Low iodine in soil/food

Goitrogens

Multinodular goiter

Mass effects - compress neck structures, thoracic vessels

Intrathoracic extension = plunging goiter

Airway obstruction; deviation of trachea

Development of Clonal nodules:

With activating mutations in TSH receptor gene → Clonal, Autonomous Hyperfunctioning nodules may cause Thyrotoxicosis (Toxic Multinodular Goiter, aka, Plummer Disease)

Risk of Follicular Carcinoma is low

Nodular, asymmetrically enlarged

Regressive changes: hemorrhage, fibrosis, calcification, cysts

Multinodular goiter

Euthyroid Sick Syndrome (Nonthyroidal illness syndrome)

Laboratory changes in thyroid function tests in patients in the medical ICU, starvation (anorexia nervosa) or with other critical illness

Clinically Euthyroid

Thyroid function should not be assessed in seriously ill patients unless there is a strong suspicion of dysfunction

↓ total & free T3

reverse T3 (rT3) is increased

Follicular Adenoma

Most common neoplasm of thyroid

follicular epithelium derived

NOT precursor of carcinomas

Solitary, well circumscribed, painless

Vast majority are non-functioning & Cold on Scan

A few are functional & hot on scan (“Toxic Adenomas”)

Histology: Uniformly sized follicles with colloid (microfollicles); Hurthle/oxyphil cell change

Hallmark is the presence of an intact collagenous capsule encircling the tumor

Follicular Carcinoma

Capsular invasion and/or vascular invasion

Follicular Adenoma

circumscription, collagenous capsule, & central hemorrhage/cystic change

Follicular Adenoma

circumscription, collagenous capsule

Follicular Adenoma
circumscription, collagenous capsule

Follicular Adenoma

Larger follicles, thinner capsule

Follicular Adenoma

Hurthle Cell

Papillary Thyroid Carcinoma (PTC)

RET or Translocation (fusion gene)

BRAF V600E

Risk factors: Ionizing radiation, Female

Gross: solitary or multifocal; Microcarcinoma

Micro: Papillae with fibrovascular stalks; neoplastic epithelium covering stalks shows variable atypia

Nuclei: Optically clear or ground glass nuclei; nuclear pseudo-inclusions, grooves

Concentric calcifications (Psammoma bodies)

Behavior: early spread via Lymphatics; metastases to cervical nodes; neck node mass frequent; Excellent px

Follicular Thyroid Carcinoma (FTC)

RAS

Familial: Loss of PTEN (Cowden)

Peak age 40-60; more common in women

Risk: Iodine deficient areas

circumscribed or grossly infiltrative

Micro: most Microfollicles with intraluminal colloid

some show abundant eosinophilic cytoplasm (Oncocytic/Hurthle cell variant)

Behavior: most often a cold nodule; Hematogenous spread preferentially (mets to bone, lungs, liver)

Good px

Medullary Thyroid Carcinoma (MTC)

RET receptor GOF mutation

In germline defines Familial MEN-2

Neuroendocrine neoplasm derived from the parafollicular Calcitonin secreting cells (C-cells)

Gross: In MEN-2, younger, Bilateral/Multicentric; sporadic single nodule

Lack capsules (are infiltrative)

Micro: Neoplastic cells in nests/ribbons with background deposition of Amyloid (derived from Calcitonin)

EM: Neurosecretory granules

Associated C-cell hyperplasia

Mass; destructive infiltration or pressure locally (hoarseness, dysphagia)

Paraneoplastic syndrome (diarrhea due to VIP, Cushing due to ACTH)

Raised serum Calcitonin & CEA

Anaplastic Thyroid Carcinoma

Highly aggressive thyroid carcinoma of undifferentiated follicular cells

evidence of epithelial differentiation but are devoid of morphologic & immunophenotypic markers of thyroid origin

most succumb within a year

Risk factors: Older age, Goiter (chronic Iodine deficiency), past thyroid cancer

Rapidly enlarging (days/weeks), bulky, fixed neck mass

Hoarseness, dyspnea, dysphagia as neck compressive symptoms

Extrathyroidal extension

Regional nodal metastases & vocal cord paralysis

Majority have distant metastases

spindle cell sarcoma-like appearance

Most + PAX8 (Nuclear marker for epithelial neoplasms), +/- Cytokeratin

Follicular Thyroid Carcinoma

Capsular invasion in Minimally Invasive FTC

Follicular Thyroid Carcinoma

FTC involving most of a lobe

Follicular Thyroid Carcinoma

abortive microfollicles making recognizable colloid

Papillary Thyroid Carcinoma

Papillary folds

Papillary Thyroid Carcinoma

Papillary folds

Psammoma Body

Papillary Thyroid Carcinoma

Papillary Thyroid Carcinoma

Gross specimen with papillae

Medullary Thyroid Carcinoma

Medullary Thyroid Carcinoma

Congo Red stain For Amyloid

Medullary Thyroid Carcinoma

Endocrine neurosecretory granules

Medullary Thyroid Carcinoma

Medullary Thyroid Carcinoma

Anaplastic Thyroid Carcinoma