Thyroid

Historical Background

• Goiters (Latin guttur, throat): Enlargement of the thyroid recognized since 2700 B.C.
• Thyroid gland not documented until the Renaissance period.
• 1619: Hieronymus Fabricius ab Aquapendente recognized goiters arose from the thyroid gland.
• Term "thyroid gland" (Greek thyreoeides, shield-shaped) attributed to Thomas Wharton in Adenographia (1656).
• 1776: Albrecht von Haller classified thyroid as a ductless gland.
  • Thought to have functions such as:
    • Lubrication of the larynx.
    • Acting as a reservoir for blood to provide continuous flow to the brain.
    • Beautifying women's necks.
• Burnt seaweed considered effective treatment for goiters.

Thyroid Surgery

• 1170: Roger Frugardi's accounts of thyroid surgery for goiters.
  • Used setons inserted into the goiter, tightened twice daily until separation.
• High mortality rates (>40%) until the latter half of the 19th century.
• Advances in general anesthesia, antisepsis, and hemostasis reduced mortality and morbidity.
• Notable thyroid surgeons:
  • Emil Theodor Kocher (1841–1917).
  • C.A. Theodor Billroth (1829–1894).
  • Performed thousands of operations with increasing success.
• Postoperative myxedema observed, especially in children after total thyroidectomy.
• 1891: George Murray treated myxedema with subcutaneous injection of sheep's thyroid extract.
• Edward Fox demonstrated oral therapy was equally effective.
• 1909: Kocher awarded Nobel Prize for medicine for work on thyroid physiology, pathology, and surgery.

---

Embryology

• Thyroid gland arises as an outpouching of the primitive foregut (~3rd week of gestation).
• Originates at the base of the tongue at the foramen cecum.
• Median thyroid anlage:
  • Endoderm cells in floor of pharyngeal anlage thicken.
  • Descends anterior to structures forming hyoid bone and larynx.
  • Remains connected to foramen cecum via the thyroglossal duct.
  • Gives rise to thyroid follicular cells.
• Paired lateral anlages:
  • Originate from the fourth branchial pouch.
  • Fuse with median anlage (~5th week of gestation).
  • Neuroectodermal origin (ultimobranchial bodies).
  • Provide calcitonin-producing parafollicular (C) cells.

• Thyroid follicles apparent by 8 weeks.
• Colloid formation begins by the 11th week of gestation.

---

Developmental Abnormalities

1. Thyroglossal Duct Cyst and Sinus

• Most common congenital cervical anomalies.
• Thyroglossal duct:
  • Lumen starts to obliterate during the 5th week.
  • Duct disappears by the 8th week of gestation.
  • Persistence may lead to cysts anywhere along migratory path (80% near hyoid bone).
• Clinical features:
  • Usually asymptomatic.
  • May become infected by oral bacteria.
  • Sinuses result from infection and spontaneous or surgical drainage.
• Histology:
  • Lined by pseudostratified ciliated columnar and squamous epithelium.
  • Heterotopic thyroid tissue present in 20% of cases.
• Diagnosis:
  • 1–2 cm smooth, well-defined midline neck mass.
  • Moves upward with tongue protrusion.
  • Routine thyroid imaging not necessary.
• Treatment:
  • Sistrunk operation: En bloc cystectomy and excision of central hyoid bone to minimize recurrence.
• Cancer in thyroglossal duct cysts:
  • Approximately 1% contain cancer, usually papillary carcinoma (85%).
  • Total thyroidectomy debated; advised in large tumors, additional thyroid nodules, cyst wall invasion, or lymph node metastases.
  • Medullary thyroid cancers (MTCs) not found in thyroglossal duct cysts.

2. Lingual Thyroid

• Failure of median thyroid anlage to descend normally.
• May be the only thyroid tissue present.
• Symptoms:
  • Obstructive symptoms: choking, dysphagia, airway obstruction, hemorrhage.
  • Many develop hypothyroidism.
• Treatment options:
  • Exogenous thyroid hormone to suppress TSH.
  • Radioactive iodine (RAI) ablation followed by hormone replacement.
  • Surgical excision rarely needed.
  • Preoperative evaluation to confirm presence of normal thyroid tissue in neck.

3. Ectopic Thyroid

• Normal thyroid tissue may be found in central neck compartment:
  • Esophagus.
  • Trachea.
  • Anterior mediastinum.
• Tongues of thyroid tissue may extend off inferior poles, especially in large goiters.
• Lateral aberrant thyroid:
  • Thyroid tissue lateral to carotid sheath and jugular vein.
  • Almost always represents metastatic thyroid cancer in lymph nodes, not remnants of lateral anlage.
  • Ipsilateral thyroid lobe contains focus of papillary thyroid cancer (PTC), may be microscopic.

4. Pyramidal Lobe

• Persistent distal end of thyroglossal duct.
• Present in about 50% of individuals.
• Projects upward from isthmus, just left or right of midline.
• Not palpable in normal individuals.
• Enlarged and palpable in thyroid hypertrophy disorders:
  • Graves’ disease.
  • Diffuse nodular goiter.
  • Lymphocytic thyroiditis.

---

Thyroid Anatomy

Anatomic Relations

• Located posterior to strap muscles:
  • Sternohyoid.
  • Sternothyroid.
  • Superior belly of omohyoid.
  • Innervated by ansa cervicalis (ansa hypoglossi).
• Normal thyroid weight ~20 g (varies with body weight and iodine intake).
• Thyroid lobes adjacent to thyroid cartilage.
• Connected by an isthmus located just inferior to cricoid cartilage.
• Pyramidal lobe present in about 50% of patients.
• Lobes extend to mid-thyroid cartilage superiorly.
• True capsule:
  • Thin, densely adherent fibrous layer.
  • Sends septa forming pseudolobules.

• Berry's ligament:

  • Posterior suspensory ligament near cricoid cartilage and upper tracheal rings.
  • Capsule condensed into Berry's ligament.

  

Surgical Triangles Related to Thyroid Surgery

1. Beahr's Triangle (Riddle's Triangle):
   • Nerve Involved: Recurrent Laryngeal Nerve (RLN).
   • Borders:
     • Lateral: Common Carotid Artery.
     • Inferior: Inferior Thyroid Artery.
     • Medial: Recurrent Laryngeal Nerve (in the tracheo-oesophageal groove).
2. Joll's Triangle (Sternothyrolaryngeal Triangle):
   • Nerve Involved: External Branch of the Superior Laryngeal Nerve (EBSLN).
   • Borders:
     • Lateral: Upper pole of the thyroid gland and superior thyroid vessels.
     • Superior: Attachment of the strap muscles.
     • Medial: Midline.
     • Floor: Cricothyroid muscle.

3. Simon's Triangle:

   • Nerve Involved: Recurrent Laryngeal Nerve (RLN).

   • Borders:

     • Anterior: Recurrent Laryngeal Nerve.
     • Posterior: Common Carotid Artery.
     • Base: Inferior Thyroid Artery.

     

4. Lore's Triangle:

   • Nerve Involved: Recurrent Laryngeal Nerve (RLN).
   • Borders:
     • Medial: Trachea/Esophagus.
     • Lateral: Carotid Artery.
     • Superior: Surface of the inferior pole of the thyroid.
5. Triangle of Concern:
   • Significance: This area has a high potential for bleeding due to the presence of:
     • Middle Thyroid Veins.
     • Inferior Thyroid Veins.
     • Branches of the Inferior Thyroid Artery.
   • Vicinity: Close to the Recurrent Laryngeal Nerve (RLN), making it a critical area to manage carefully during surgery to avoid bleeding and nerve injury.

6. Cricothyroid Space of Reeves:

   • Significance: An avascular space between the upper pole of the thyroid and the cricothyroid muscle.
   • Utility: Useful during dissection to avoid injury to surrounding structures, particularly the Superior Laryngeal Nerve.

   

Blood Supply

• Superior thyroid arteries:
  • Arise from ipsilateral external carotid arteries.
  • Divide into anterior and posterior branches at thyroid apices.
• Inferior thyroid arteries:
  • Arise from thyrocervical trunk of subclavian arteries.
  • Travel posterior to carotid sheath.
  • Enter lobes at midpoint.
• Thyroidea ima artery:
  • Arises from aorta or innominate artery in 1–4% of individuals.
  • Enters isthmus or replaces missing inferior thyroid artery.
• Venous drainage:

  • Multiple small surface veins coalesce into:

    • Superior thyroid veins (drain into internal jugular veins).
    • Middle thyroid veins (least consistent; drain into internal jugular veins).
    • Inferior thyroid veins (form plexus, drain into brachiocephalic veins).

    

Nerves

• Recurrent Laryngeal Nerves (RLNs):

  • Left RLN:
    • Arises from vagus nerve at aortic arch.
    • Loops around ligamentum arteriosum.
    • Ascends medially in tracheoesophageal groove.
  • Right RLN:
    • Arises from vagus nerve at crossing with right subclavian artery.
    • Passes posterior to artery.
    • More oblique course than left RLN.
    • May branch and pass anterior, posterior, or interdigitate with branches of inferior thyroid artery.
  • Nonrecurrent RLN:
    • Right RLN may be nonrecurrent in 0.5–1% (associated with vascular anomaly = Aberrant RSCA).
    • Nonrecurrent left RLN is rare.
  • Terminate by entering larynx posterior to cricothyroid muscle.
  • Function:
    • Innervate all intrinsic muscles of larynx except cricothyroid muscles.
    • Sensory supply to larynx below vocal cords.
  • Injury:
    • Unilateral injury:
      • Ipsilateral vocal cord paralysis (paramedian or abducted position).
      • Paramedian position: Normal but weak voice.
      • Abducted position: Hoarse voice, ineffective cough.

    • Bilateral injury:

      • Airway obstruction requiring emergency tracheostomy.
      • Loss of voice.

      

• Superior Laryngeal Nerves:

  • Arise from vagus nerves.
  • Divide into:
    • Internal branch: Sensory to supraglottic larynx.
    • External branch:
      • Lies on inferior pharyngeal constrictor muscle.
      • Descends alongside superior thyroid vessels.
      • Innervates cricothyroid muscle.
  • Cernea classification:
    • Describes relationship to superior thyroid vessels.
    • Type 2a variant (nerve crosses below tip of thyroid superior pole) in up to 20%.
      • Risk of injury higher; superior pole vessels should be individually divided low on thyroid gland.

  • Injury to external branch:

    • Inability to tense ipsilateral vocal cord.
    • Difficulty hitting high notes.
    • Difficulty projecting voice.
    • Voice fatigue during prolonged speech.

    

• Sympathetic innervation:
  • From superior and middle cervical sympathetic ganglia.
  • Vasomotor in action.

• Parasympathetic fibers:

  • From vagus nerve via branches of laryngeal nerves.

  

Parathyroid Glands

• Usually four glands (85% of individuals).
• Located within 1 cm of junction of inferior thyroid artery and RLN.
• Superior glands: Dorsal to RLN.
• Inferior glands: Ventral to RLN.

Lymphatic System

• Extensive network of lymphatics.
• Intraglandular lymphatic vessels connect both thyroid lobes through the isthmus.
• Regional lymph nodes:
  • Pretracheal.
  • Paratracheal.
  • Perithyroidal.
  • RLN nodes.
  • Superior mediastinal.
  • Retropharyngeal.
  • Esophageal.
  • Upper, middle, and lower jugular chain nodes.
• Classified into seven levels.
  • Level I: Submaxillary nodes (rarely involved).
  • Central compartment: Nodes between carotid sheaths.
  • Lateral compartment: Nodes lateral to vessels.
• Thyroid cancers may metastasize to any of these regions.
• "Skip" metastases: Metastases to lateral ipsilateral neck nodes without central neck nodes.

---

Thyroid Histology

• Microscopically divided into lobules containing 20 to 40 follicles.
• Approximately 3 × 10⁶ follicles in the adult male thyroid gland.
• Follicles:
  • Spherical, average 30 μm in diameter.
  • Lined by cuboidal epithelial cells.
  • Contain central store of colloid.
  • Colloid secretion influenced by TSH (thyroid-stimulating hormone).
• C cells (parafollicular cells):
  • Second group of thyroid secretory cells.
  • Contain and secrete calcitonin.
  • Found individually or in small groups in interfollicular stroma.
  • Located in upper poles of thyroid lobes.

---

Thyroid Physiology

Iodine Metabolism

• Average daily iodine requirement: 0.1 mg.
• Sources: Fish, milk, eggs, additives in bread or salt.
• In stomach and jejunum:
  • Iodine converted to iodide.
  • Rapid absorption into bloodstream.
• Iodide distribution: Uniform throughout extracellular space.
• Active transport into thyroid follicular cells via an ATP-dependent process.
• Thyroid stores >90% of body's iodine.
• Accounts for one-third of plasma iodine loss.
• Remaining plasma iodine cleared via renal excretion.
• PENDRED's syndrome:
  • Partial organification defect, goitre with sensorineural deafness is seen.
  • Mutation in putative sulfate transporter gene associated

Thyroid Hormone Synthesis, Secretion, and Transport

• Synthesis Steps:
  1. Iodide Trapping:
     • Active transport of iodide across thyrocyte basement membrane.
     • Via sodium/iodide (Na⁺/I⁻) symporter.
  2. Oxidation and Iodination:
     • Oxidation of iodide to iodine.
     • Iodination of tyrosine residues on thyroglobulin (Tg).
     • Forms monoiodotyrosines (MIT) and diiodotyrosines (DIT).
     • Catalyzed by thyroid peroxidase (TPO).
     • Pendrin mediates iodine efflux at apical membrane.
  3. Coupling:
     • Two DIT molecules form thyroxine (T₄).
     • One DIT and one MIT form triiodothyronine (T₃) or reverse T₃ (rT₃).
  4. Endocytosis and Hydrolysis:
     • Under TSH stimulation, thyrocytes form pseudopodia.
     • Tg hydrolyzed to release free T₃ and T₄, and MIT/DIT.
  5. Deiodination:
     • MIT and DIT deiodinated to yield iodide for reuse.
• Hormone Production:
  • T₄:
    • Produced entirely by the thyroid gland.
    • Half-life: Approximately 7 days.
  • T₃:
    • Only 20% produced by the thyroid.
    • 80% produced by peripheral deiodination of T₄.
    • Catalyzed by 5′-monodeiodinase.
    • More potent than T₄.
    • Enters tissues more readily.
    • Half-life: About 1 day. [8-12 hrs]
  • rT₃:
    • Metabolically inactive.
    • Formed by deiodination of inner ring of T₄.
  • Type I Deiodinase:
    • Liver, Kidney and Thyroid
  • Type II Deiodinase:
    • CNS Pituitary
    • Placenta brown adipose tissue
    • Cardiac skeletal muscle and thyroid
• Transport:
  • Bound to carrier proteins:
    • T₄-binding globulin.
    • T₄-binding prealbumin.
    • Albumin.
  • Only 0.02% is free (unbound) and physiologically active.
• Regulation:
  • Controlled by hypothalamic-pituitary-thyroid axis.
  • Hypothalamus:
    • Produces thyrotropin-releasing hormone (TRH).
    • TRH stimulates pituitary to release TSH.
  • Pituitary Gland:
    • TSH stimulates iodide trapping, hormone secretion.
    • TSH receptor (TSH-R): G-protein–coupled receptor.
  • Negative Feedback:
    • T₄ and T₃ inhibit TSH secretion.
    • T₃ inhibits release of TRH.
• Autoregulation:
  • Low iodide intake:
    • Gland synthesizes more T₃ to increase efficiency.
  • Iodine excess:
    • Inhibits iodide transport, hormone synthesis/secretion.
    • Wolff-Chaikoff effect: Initial increase followed by suppression.
  • Stimulated by epinephrine and human chorionic gonadotropin (hCG).
  • Inhibited by glucocorticoids.
  • Euthyroid sick syndrome:
    • Reduced peripheral thyroid hormones without increased TSH.

Thyroid Hormone Function

• Cellular Mechanism:
  • Free thyroid hormone enters cells by diffusion or specific carriers.
  • T₄ deiodinated to T₃ inside the cell.
  • T₃ binds to nuclear thyroid hormone receptors.
  • Receptors:
    • Two types: α and β genes on chromosomes 3 and 17.
    • Tissue-specific expression:
      • α form: Abundant in CNS.
      • β form: Predominates in liver.
  • Binding leads to transcription and translation of specific genes.
• Physiological Effects:
  • Fetal Development:
    • Critical for brain development and skeletal maturation.
  • Metabolism:
    • Increases oxygen consumption, basal metabolic rate, heat production.
    • Stimulates Na⁺/K⁺ ATPase activity.
  • Cardiac Effects:
    • Positive inotropic and chronotropic effects.
    • Increases transcription of Ca²⁺ ATPase.
    • Increases β-adrenergic receptors and G proteins.
    • Decreases myocardial α receptors.
    • Amplifies catecholamine actions.
  • Respiratory System:
    • Maintains normal hypoxic and hypercapnic drive.
  • Gastrointestinal:
    • Increases GI motility.
    • Hyperthyroidism: Diarrhea.
    • Hypothyroidism: Constipation.
  • Musculoskeletal:
    • Increases bone and protein turnover.
    • Enhances muscle contraction and relaxation speed.
  • Metabolic Pathways:
    • Increases glycogenolysis, gluconeogenesis.
    • Enhances glucose absorption.
    • Affects cholesterol synthesis and degradation.

---

Evaluation of Patients With Thyroid Disease

---

Tests of Thyroid Function

• Multiple tests available; must interpret results in clinical context.
• TSH is sufficient for most euthyroid patients with thyroid nodules.

Serum Thyroid-Stimulating Hormone (TSH) (Normal 0.5–5 μU/mL)

• Immunometric Assay:
  • Monoclonal TSH antibodies bind serum TSH.
  • Secondary labeled antibody detects bound TSH.
• Reflects anterior pituitary's detection of free T₄ levels.
• Inverse relationship between free T₄ and logarithm of TSH.
• Ultrasensitive TSH assay:
  • Most sensitive and specific for diagnosing hyper-/hypothyroidism.
  • Used for optimizing T₄ therapy.

Total T₄ (Reference Range 55–150 nmol/L) and T₃ (Reference Range 1.5–3.5 nmol/L)

• Measured by radioimmunoassay.
• Include both free and bound hormone.
• Total T₄ Levels:
  • Reflect thyroid gland output.
  • Increased in hyperthyroidism, pregnancy, estrogen/progesterone use.
  • Decreased in hypothyroidism, anabolic steroid use, nephrotic syndrome.
  • Euthyroid individuals may have normal free T₄ despite altered total T₄.
• Total T₃ Levels:
  • Important in hyperthyroid patients with normal T₄ (T₃ thyrotoxicosis).
  • Increased in early hypothyroidism.

Free T₄ (Reference Range 12–28 pmol/L) and Free T₃ (3–9 pmol/L)

• Sensitive measurement of biologically active hormone.
• Not routine screening tests.
• Useful in early hyperthyroidism:
  • Total T₄ may be normal; free T₄ elevated.
• Refetoff’s Syndrome:
  • End Organ resistance to T₄
  • Increased T₄ levels; normal TSH.
• Free T₃ confirms early hyperthyroidism.
• T₃-Resin Uptake Test:
  • Indirectly measures free T₄.
  • Increased uptake indicates elevated free T₄.

Thyrotropin-Releasing Hormone (TRH) Test

• Evaluates pituitary TSH function.
• Procedure:
  • Administer 500 μg TRH intravenously.
  • Measure TSH after 30 and 60 minutes.
• Normal response: TSH increase ≥ 6 μIU/mL from baseline.
• Largely replaced by sensitive TSH assays.

Thyroid Antibodies

• Include anti-Tg, anti-microsomal, anti-TPO, and TSI.
• Anti-Tg and anti-TPO indicate underlying disorders (e.g., autoimmune thyroiditis).
• Elevated in:
  • Hashimoto’s thyroiditis (~80% of patients).
  • Graves’ disease.
  • Multinodular goiter.
  • Occasionally in thyroid neoplasms.

Serum Thyroglobulin (Tg)

• Produced only by thyroid tissue.
• Levels increase in:
  • Destructive processes (thyroiditis).
  • Overactive states (Graves’ disease, toxic multinodular goiter).
• Primary use: Monitor differentiated thyroid cancer recurrence post-thyroidectomy and RAI ablation.
• Anti-Tg antibodies can interfere with Tg measurement.

Serum Calcitonin (Normal 0–4 pg/mL Basal)

• Secreted by C cells.
• Lowers serum calcium (minimal effect in humans).
• Sensitive marker for medullary thyroid carcinoma (MTC).

---

Thyroid Imaging

Radionuclide Imaging

• Iodine-123 (¹²³I):
  • Low-dose radiation.
  • Half-life: 12–14 hours.
  • Used for imaging lingual thyroids or goiters.
• Iodine-131 (¹³¹I):
  • Higher radiation exposure.
  • Half-life: 8–10 days.
  • Used to screen and treat differentiated thyroid cancers.
• Lesion Classification:
  • Cold areas:
    • Trap less radioactivity.
    • Higher malignancy risk (20%).
  • Hot areas:
    • Increased activity.
    • Lower malignancy risk (<5%).
• Technetium Tc 99m Pertechnetate (⁹⁹ᵐTc):
  • Uptaken by thyroid.
  • Shorter half-life; less radiation.
  • Sensitive for nodal metastases.
• FDG PET-CT:
  • Detects metastases in thyroid cancer patients with negative other imaging.
  • Not routine for thyroid nodule evaluation.
  • Incidental findings:
    • Malignancy rates 14–63%.
    • Requires evaluation with ultrasound and FNAB.

Ultrasound

• Noninvasive, portable, no radiation.
• Evaluates thyroid nodules:
  • Distinguishes solid vs. cystic.
  • Assesses size, multicentricity.
• Provides information on:
  • Echotexture.
  • Shape.
  • Borders.
  • Calcifications.
  • Vascularity.
• Assesses cervical lymphadenopathy.
• Guides fine-needle aspiration biopsy (FNAB).
• Best performed by experienced ultrasonographer.

Computed Tomography (CT)/Magnetic Resonance Imaging (MRI) Scan

• Excellent imaging of thyroid and adjacent nodes.
• Useful for:
  • Large, fixed, or substernal goiters not evaluated by ultrasound.
  • Determining relationship to airway and vascular structures.
• Noncontrast CT scans:
  • Recommended for patients needing RAI therapy.
  • Contrast use delays RAI therapy by months.
• Combined PET-CT scans:
  • Used for Tg-positive, RAI-negative tumors.

---

Benign Thyroid Disorders

---

Hyperthyroidism

• Clinical manifestations result from an excess of circulating thyroid hormone.

• May arise from various conditions (see Table 38-1).

  

• Important distinctions:

  • Disorders resulting from increased production of thyroid hormone (e.g., Graves’ disease, toxic nodular goiters).
    • Characterized by increased RAI uptake (RAIU).
  • Disorders leading to release of stored hormone due to thyroid injury (e.g., thyroiditis).
    • Characterized by low RAIU.
• Relevant conditions for surgeons:
  • Graves’ disease
  • Toxic multinodular goiter
  • Solitary toxic nodule

---

Diffuse Toxic Goiter (Graves’ Disease)

• First described by Caleb Parry (1825); named after Robert Graves (1835).
• Most common cause of hyperthyroidism in North America (60–80% of cases).
• Autoimmune disease with:
  • Strong familial predisposition
  • Female preponderance (5:1)
  • Peak incidence between 40–60 years.
• Characterized by:
  • Thyrotoxicosis
  • Diffuse goiter
  • Extrathyroidal manifestations:
    • Ophthalmopathy
    • Dermopathy (pretibial myxedema)
    • Thyroid acropachy
    • Gynecomastia

Etiology, Pathogenesis, and Pathology

• Possible triggers:
  • Postpartum state
  • Iodine excess
  • Lithium therapy
  • Bacterial and viral infections
• Genetic factors:
  • Associated with HLA haplotypes:
    • HLA-B8
    • HLA-DR3
    • HLA-DQA1*0501 (Caucasians)
    • HLA-DRB1*0701 (protective)
  • CTLA-4 gene polymorphisms
  • CD40 gene upregulation:
    • Lowers threshold for B-cell activation
    • Enhances IL-6 secretion and T-cell activation
  • Other genes:
    • PTPN22
    • CD25 (encodes IL-2 receptor α-chain)
• Pathogenesis:
  • Sensitized T-helper lymphocytes stimulate B lymphocytes
  • Production of antibodies against TSH receptor (TSIs)
  • Stimulate thyrocytes to grow and synthesize excess hormone
• Associated autoimmune conditions:
  • Type 1 diabetes mellitus
  • Addison’s disease
  • Pernicious anemia
  • Myasthenia gravis
• Pathology:
  • Macroscopically:
    • Diffusely and smoothly enlarged thyroid gland
    • Increased vascularity
  • Microscopically:
    • Hyperplastic gland with columnar epithelium
    • Minimal colloid
    • Nuclear mitosis
    • Papillary projections
    • Lymphoid aggregates
    • Markedly increased vascularity

Clinical Features

• Hyperthyroid symptoms:

  • Heat intolerance
  • Increased sweating and thirst
  • Weight loss despite adequate intake
  • Adrenergic symptoms:
    • Palpitations
    • Nervousness
    • Fatigue
    • Emotional lability
    • Hyperkinesis
    • Tremors
  • Gastrointestinal:
    • Increased bowel movements
    • Diarrhea
  • Females:
    • Amenorrhea
    • Decreased fertility
    • Increased miscarriages
  • Children:
    • Rapid growth
    • Early bone maturation
  • Older patients:
    • Atrial fibrillation
    • Congestive heart failure

• Physical examination:

  • Weight loss
  • Facial flushing
  • Warm, moist skin
  • Skin darkening (in African American patients)
  • Tachycardia or atrial fibrillation
  • Cutaneous vasodilation:
    • Widened pulse pressure
    • Rapid falloff in pulse wave (collapsing pulse)
  • Fine tremor
  • Muscle wasting
  • Proximal muscle weakness
  • Hyperactive tendon reflexes

• Ophthalmopathy (in ~50% of patients):

  • Eye signs:
    • Lid lag (von Graefe’s sign)
    • Upper eyelid spasm revealing sclera (Dalrymple’s sign)
    • Prominent stare
    • Periorbital edema
    • Chemosis (conjunctival swelling)
    • Proptosis
    • Limited gaze
    • Keratitis
    • Optic nerve involvement leading to blindness
• Dermopathy:
  • Pretibial myxedema:
    • Thickened skin in pretibial region and dorsum of foot
• Other manifestations:
  • Gynecomastia (in young men)
  • Thyroid acropachy
  • Onycholysis (fingernail separation)
  • Thyroid gland:
    • Diffusely and symmetrically enlarged
    • Possible pyramidal lobe enlargement
    • Overlying bruit or thrill
    • Venous hum in supraclavicular space

Diagnostic Tests

• Laboratory findings:
  • Suppressed TSH
  • Elevated free T₄ or T₃ levels
• Radioactive iodine uptake (¹²³I RAIU):
  • Elevated uptake with diffusely enlarged gland confirms Graves’ disease
• Technetium scintigraphy:
  • Uses pertechnetate
  • Determines etiology
• Antibodies:
  • Anti-Tg and anti-TPO elevated in up to 75%
  • TSH-R antibodies (TSAb) increased in 90%
• Imaging:
  • CT or MRI of orbits for ophthalmopathy evaluation

Treatment:

1. Antithyroid drugs
2. Radioactive iodine therapy (¹³¹I)
3. Thyroidectomy

1. Antithyroid Drugs

• Used to prepare for RAI ablation or surgery
• Medications:
  • Propylthiouracil (PTU): 100–300 mg three times daily
  • Methimazole: 10–30 mg three times daily, then once daily
    • Longer half-life; allows once-daily dosing
• Mechanism:
  • Inhibit iodine binding and coupling of iodotyrosines (TPO-mediated)
  • PTU also inhibits peripheral conversion of T₄ to T₃
• Pregnancy considerations:
  • Both cross placenta and are excreted in breast milk
  • PTU preferred (lower transplacental transfer)
  • Methimazole linked to congenital aplasia

• Side effects:

  • Reversible granulocytopenia
  • Skin rashes
  • Fever
  • Peripheral neuritis
  • Polyarteritis
  • Vasculitis
  • Hepatitis
  • Rarely, agranulocytosis and aplastic anemia

• Monitoring:

  • Warn patients to discontinue if they develop sore throat or fever
  • Agranulocytosis treatment: Hospitalization, drug discontinuation, antibiotics
• Dosage adjustment:
  • Based on TSH and T₄ levels
  • Symptoms improve in 2 weeks
  • Euthyroid state achieved in 6 weeks
• Block-replace regimen:
  • Adding T₄ (0.05–0.10 mg) to prevent hypothyroidism
• Relapse rates:
  • High (40–80%) after 1–2 years
• Ideal candidates:
  • Small, nontoxic goiters (<40 g)
  • Mild hormone elevation
  • Negative or low TSH-R antibody titers
  • Rapid gland size decrease with medication
• β-Blockers:
  • Alleviate catecholamine symptoms
  • Recommended for:
    • Symptomatic patients
    • Elderly
    • Cardiac disease
    • Resting HR >90 bpm
  • Propranolol: 20–40 mg four times daily
  • Caution in asthma patients
  • Calcium channel blockers as alternatives

2. Radioactive Iodine Therapy (¹³¹I)

• Primary treatment in North America
• Advantages:
  • Avoids surgery
  • Lower cost
  • Ease of administration
• Preparation:
  • Antithyroid drugs until euthyroid
  • Discontinue drugs to maximize uptake
• Dosage:
  • 8–12 mCi orally
• Outcomes:
  • Euthyroid in 2 months for most
  • 50% euthyroid at 6 months
  • Gradual hypothyroidism development
• Risks:
  • Ophthalmopathy progression (more common in smokers)
  • Small increased risk of:
    • Nodular goiter
    • Thyroid cancer
    • Hyperparathyroidism
  • Increased overall and cardiovascular mortality
• Indications:
  • Older patients with small/moderate goiters
  • Relapse after other therapies
  • Contraindications to drugs or surgery
• Contraindications:
  • Pregnancy or planning within 6 months
  • Breastfeeding
  • Relative in young patients and those with ophthalmopathy

3. Surgical Treatment

• Indications:
  • Confirmed cancer or suspicious nodules
  • Young patients
  • Desire to conceive soon (<6 months)
  • Severe reactions to medications
  • Large goiters (>80 g) causing compression
  • Reluctance to undergo RAI therapy
• Relative indications:
  • Moderate to severe ophthalmopathy
  • Rapid control desired
  • Poor medication compliance
• Pregnancy:
  • Surgery in second trimester if necessary
• Preoperative preparation:
  • Antithyroid drugs until day of surgery
  • Lugol’s iodide solution or potassium iodide:
    • Begin 7–10 days pre-op
    • Three drops twice daily
    • Reduces vascularity and hormone release
• Extent of surgery:
  • Total or near-total thyroidectomy recommended
• Outcomes:
  • Permanent disease control with minimal morbidity
  • Ophthalmopathy stabilizes or improves post-surgery
• Recurrent thyrotoxicosis:
  • Managed with radioiodine therapy

---

Toxic Multinodular Goiter

• Occurs in older individuals
• History of nontoxic multinodular goiter
• Gradual development of hyperthyroidism over years
• Presentation:
  • May be subtle
  • Hyperthyroidism evident upon thyroid hormone suppression therapy
  • Possible T₃ toxicosis
  • Atrial fibrillation or congestive heart failure
• Precipitating factors:
  • Iodide-containing drugs:
    • Contrast media
    • Amiodarone (Jod-Basedow hyperthyroidism)
• Symptoms similar to Graves’ disease but without extrathyroidal signs

Diagnostic Studies

• Blood tests:
  • Suppressed TSH
  • Elevated free T₄ or T₃
• RAI uptake scan:
  • Increased uptake in multiple nodules
  • Suppression of remaining gland

Treatment

• Control hyperthyroidism first
• Surgery:
  • Near-total or total thyroidectomy recommended
  • Careful RLN identification due to anatomical variations
• RAI therapy:
  • Option for elderly with high surgical risk
  • Requires larger doses
  • Risk of RAI-induced thyroiditis and airway compromise
  • Goiter remains intact, potential for recurrence

---

Toxic Adenoma

• Single hyperfunctioning nodule
• Typically in younger patients
• Presentation:
  • Growth of long-standing nodule
  • Hyperthyroid symptoms
• Genetics:
  • Somatic mutations in TSH-R gene
  • Possible gsp mutations
• Nodule size:
  • Usually ≥3 cm before symptoms
• Physical exam:
  • Solitary nodule
  • No contralateral thyroid tissue palpable
• RAI scan:
  • Hot nodule
  • Suppression of surrounding thyroid
• Malignancy:
  • Rare in these nodules

Treatment

• Small nodules:
  • Antithyroid medications
  • RAI therapy
• Large nodules:
  • Higher RAI doses risk hypothyroidism
  • Surgery (lobectomy and isthmusectomy) preferred
• Percutaneous ethanol injection (PEI):
  • Reported success
  • Not directly compared to surgery

---

Thyroid Storm

• Severe hyperthyroidism with:
  • Fever
  • CNS agitation or depression
  • Cardiovascular dysfunction
  • Gastrointestinal dysfunction (including hepatic failure)
• Precipitating factors:
  • Abrupt cessation of medications
  • Infection
  • Surgery
  • Trauma
  • Amiodarone or iodinated contrast agents
  • Post-RAI therapy
• Management:
  • Intensive care unit admission
  • β-Blockers:
    • Reduce T₄ to T₃ conversion
    • Decrease symptoms
  • Oxygen supplementation
  • Hemodynamic support
  • Non-aspirin antipyretics for fever
  • Lugol’s iodine or sodium ipodate IV:
    • Decrease iodine uptake
    • Inhibit hormone secretion
  • PTU therapy:
    • Blocks new hormone formation
    • Reduces peripheral conversion
  • Corticosteroids:
    • Prevent adrenal exhaustion
    • Inhibit hepatic T₄ to T₃ conversion

---

Amiodarone-Induced Thyrotoxicosis (AIT)

Overview:

Amiodarone, an antiarrhythmic medication commonly used for atrial or ventricular tachyarrhythmias, contains a high iodine content (37% by molecular weight), delivering over 100 times the normal daily dietary iodine requirement. Up to 6% of patients on amiodarone may develop Amiodarone-Induced Thyrotoxicosis (AIT).

Mechanisms of AIT:

1. Type 1 AIT:
   • Caused by the Jod-Basedow phenomenon.
   • Excess iodine leads to increased thyroid hormone synthesis and release.
   • More common in patients with preexisting hyperthyroid disease.
2. Type 2 AIT:
   • Occurs in patients with normal thyroid function.
   • Results from destructive thyroiditis due to direct toxic effects of amiodarone on follicular cells.
   • Leads to the release of preformed thyroid hormone.
3. Mixed Forms:
   • A combination of both Type 1 and Type 2 mechanisms may occur in some patients.

Medical Management:

• Type 1 AIT: Treated with methimazole to inhibit thyroid hormone synthesis.
• Type 2 AIT: Treated with corticosteroids to address thyroiditis.
• A decision to discontinue amiodarone requires careful consideration with the cardiologist, as it is critical for managing the underlying arrhythmia in high-risk patients.

Surgical Management:

• Total thyroidectomy is recommended for patients who do not respond to aggressive medical therapy.
• Surgery carries a perioperative mortality risk of 9%-10% for AIT, higher than for other thyroid conditions.
• However, delaying surgery increases the risk of mortality even further.

---

Hypothyroidism

Deficiency in circulating levels of thyroid hormone leads to hypothyroidism and, in neonates, to cretinism, which is characterized by neurologic impairment and mental retardation. Hypothyroidism also may occur in Pendred’s syndrome (associated with deafness) and Turner’s syndrome. Conditions that cause hypothyroidism are listed in Table 38-2.

Clinical Features

• Neonatal Hypothyroidism (Cretinism):

  • Failure of thyroid gland development or function in utero.
  • Characteristics:
    • Neurologic impairment.
    • Mental retardation.
    • Characteristic facies similar to Down syndrome.
    • Dwarfism.
    • Failure to thrive.
  • Treatment:
    • Immediate testing at birth.
    • Early thyroid hormone therapy lessens deficits.

• Childhood or Adolescence:

  • Delayed development.
  • May lead to:
    • Abdominal distention.
    • Umbilical hernia.
    • Rectal prolapse.
• Adults:
  • Symptoms (often nonspecific):
    • Tiredness.
    • Weight gain.
    • Cold intolerance.
    • Constipation.
    • Menorrhagia.
  • Myxedema (severe hypothyroidism):
    • Deposition of glycosaminoglycans in subcutaneous tissues.
    • Facial and periorbital puffiness.
    • Skin:
      • Rough, dry.
      • Yellowish hue (reduced carotene conversion).
    • Hair:
      • Dry, brittle.
      • Severe hair loss.
      • Loss of outer two-thirds of eyebrows.
    • Enlarged tongue affecting speech.
    • Mental processes slowed.
    • Gastrointestinal:
      • Nonspecific abdominal pain.
      • Distention.
      • Constipation.
    • Reproductive:
      • Impaired libido and fertility in both sexes.
    • Cardiovascular:
      • Bradycardia.
      • Cardiomegaly.
      • Pericardial effusion.
      • Reduced cardiac output.
      • Pulmonary effusions.
  • Hypopituitarism features (if pituitary failure):
    • Pale, waxy skin.
    • Loss of body hair.
    • Atrophic genitalia.

Laboratory Findings

• Thyroid Hormone Levels:
  • Low T₄ and T₃.
• TSH Levels:
  • Primary thyroid failure: Elevated TSH.
  • Secondary hypothyroidism: Low TSH that doesn't increase after TRH stimulation.
• Thyroid Autoantibodies:
  • Highest in autoimmune diseases (Hashimoto’s thyroiditis, Graves’ disease).
  • May be elevated in nodular goiter and thyroid neoplasms.
• Electrocardiogram:
  • Decreased voltage.
  • Flattening or inversion of T waves.

Treatment

• Thyroxine (T₄) is the treatment of choice.
• Dosage:
  • Varies from 50–200 μg per day.
  • Starting doses:
    • 100 μg daily for general patients.
    • 25–50 μg daily for elderly or those with heart disease.
• Monitoring:
  • Baseline electrocardiogram for severe hypothyroidism.
  • TSH levels guide dosage adjustments.
• Subclinical Hypothyroidism:
  • Controversial management.
  • Treatment considered if:
    • Increased antithyroid antibody levels.
    • TSH levels >10 μIU/mL.
    • Presence of goiter or anti-TPO antibodies.
    • Cardiovascular risk factors.
    • Pregnant patients.
• Myxedema Coma:
  • Requires emergency treatment.
  • Large doses of IV T₄ (300–400 μg).
  • Intensive care monitoring.

---

Thyroiditis

1. Acute (Suppurative) Thyroiditis

• Etiology:
  • Infection via:
    • Hematogenous or lymphatic routes.
    • Direct spread from pyriform sinus fistulae or thyroglossal duct cysts.
    • Penetrating trauma.
    • Immunosuppression.
  • Common pathogens:
    • Streptococcus species.
    • Anaerobes.
• Clinical Features:
  • Severe neck pain radiating to jaws or ear.
  • Fever, chills.
  • Odynophagia (painful swallowing).
  • Dysphonia (voice changes).
  • Possible complications:
    • Systemic sepsis.
    • Tracheal or esophageal rupture.
    • Jugular vein thrombosis.
    • Laryngeal chondritis or perichondritis.
    • Sympathetic trunk paralysis.
• Diagnosis:
  • Leukocytosis on blood tests.
  • FNAB for Gram's stain, culture, and cytology.
  • CT scans to delineate infection extent and identify abscesses.
  • Persistent pyriform sinus fistula should be suspected in recurrent cases.
• Treatment:
  • Parenteral antibiotics.
  • Drainage of abscesses.
  • Thyroidectomy may be needed for persistent abscesses.
  • Surgical excision of pyriform sinus fistulae when present.

2. Subacute Thyroiditis

A. Painful Thyroiditis

• Etiology:
  • Thought to be viral or postviral inflammatory response.
  • Strong association with HLA-B35 haplotype.
• Clinical Features:
  • Occurs in 30–40-year-old women.
  • Sudden or gradual neck pain radiating to mandible or ear.
  • History of preceding upper respiratory tract infection.
  • Gland is enlarged, tender, and firm.
• Disease Progression:
  1. Hyperthyroid phase (due to hormone release from destroyed follicles).
  2. Euthyroid phase.
  3. Hypothyroid phase (in 20–30% of patients).
  4. Resolution (return to euthyroid state in >90%).
• Laboratory Findings:
  • Decreased TSH.
  • Elevated Tg, T₄, and T₃.
  • Erythrocyte sedimentation rate >100 mm/h.
  • Decreased RAIU (<2% at 24 hours).
• Treatment:
  • Symptomatic:
    • Aspirin and NSAIDs for pain.
    • Steroids for severe cases.
    • Short-term thyroid replacement may be needed.
  • Thyroidectomy reserved for rare prolonged or recurrent cases.

B. Painless Thyroiditis

• Etiology:
  • Considered autoimmune.
  • May occur sporadically or postpartum.
  • Postpartum typically at ~6 weeks after delivery.
• Clinical Features:
  • More common in women aged 30–60 years.
  • Gland is normal-sized or slightly enlarged, firm, and nontender.
• Laboratory Findings:
  • Similar to painful thyroiditis.
  • Normal erythrocyte sedimentation rate.
• Treatment:
  • β-Blockers and thyroid hormone replacement for symptoms.
  • Thyroidectomy or RAI ablation rarely indicated.

3. Chronic Thyroiditis

A. Lymphocytic (Hashimoto’s) Thyroiditis

• Etiology and Pathogenesis:
  • Autoimmune process.
  • Activation of CD4⁺ T helper lymphocytes.
  • Recruitment of cytotoxic CD8⁺ T cells.
  • Hypothyroidism results from:
    • Destruction by cytotoxic T cells.
    • Autoantibodies leading to complement fixation and natural killer cell activity.
    • Blocking of TSH receptor.
  • Antibodies against:
    • Thyroglobulin (Tg) (~60%).
    • Thyroid peroxidase (TPO) (~95%).
    • TSH receptor (~60%).
    • Sodium/iodide symporter (~25%).
  • Apoptosis implicated in pathogenesis.
  • Associated with increased iodine intake and medications (e.g., interferon-α, lithium, amiodarone).
  • Genetic predisposition:
    • Increased incidence in first-degree relatives.
    • Associated with Turner’s syndrome and Down syndrome.
    • HLA associations (HLA-B8, DR3, DR5).
    • Alterations in CTLA4 gene.
• Pathology:
  • Gross:
    • Mildly enlarged gland.
    • Pale, gray-tan, granular, nodular, firm cut surface.
  • Microscopic:
    • Diffuse infiltration by small lymphocytes and plasma cells.
    • Germinal centers may be present.
    • Small follicles with reduced colloid.
    • Lined by Hürthle cells (Askanazy cells).
• Clinical Presentation:
  • More common in women (1:10–20 male-to-female ratio).
  • Age 30–50 years.
  • Presentations:
    • Minimally or moderately enlarged, firm, granular gland.
    • Awareness of painless anterior neck mass.
    • Hypothyroidism (20% of patients).
    • Hyperthyroidism (Hashitoxicosis) (5% of patients).
  • Physical exam:
    • Diffusely enlarged, firm, lobulated gland.
    • Palpable enlarged pyramidal lobe.
• Diagnostic Studies:
  • Elevated TSH.
  • Presence of thyroid autoantibodies.
  • FNAB indicated for solitary suspicious nodules or rapidly enlarging goiter.
  • Thyroid lymphoma is a rare complication.
• Treatment:
  • Thyroid hormone replacement to maintain normal TSH.
  • Subclinical hypothyroidism management:
    • Treatment if TSH >10 μIU/mL.
    • Goiter or anti-TPO antibodies present.
    • Cardiovascular risk factors.
    • Pregnancy.
  • Surgery:
    • Indicated for suspicion of malignancy.
    • Goiters causing compressive symptoms or cosmetic concerns.

B. Riedel’s Thyroiditis

• Etiology and Pathogenesis:
  • Rare variant known as Riedel’s struma or invasive fibrous thyroiditis.
  • Replacement of thyroid parenchyma with fibrous tissue invading adjacent structures.
  • Possible autoimmune etiology.
  • Associated with other focal sclerosing syndromes:
    • Mediastinal fibrosis.
    • Retroperitoneal fibrosis.
    • Periorbital and retro-orbital fibrosis.
    • Sclerosing cholangitis.
  • Considered a manifestation of IgG4-related systemic disease.
• Clinical Features:
  • Predominantly in women aged 30–60 years.
  • Presents as painless, hard anterior neck mass.
  • Progressive compression symptoms:
    • Dysphagia.
    • Dyspnea.
    • Choking.
    • Hoarseness.
  • May have hypothyroidism and hypoparathyroidism.
  • Physical exam:
    • Hard, "woody" thyroid gland.
    • Fixation to surrounding tissues.
• Diagnosis:
  • Requires open thyroid biopsy (FNAB often inadequate).
• Treatment:
  • Surgery:
    • Wedge excision of thyroid isthmus to decompress trachea.
    • Aim is to obtain tissue diagnosis and relieve compression.
    • Extensive resections not advised due to infiltrative nature.
  • Thyroid hormone replacement for hypothyroidism.
  • Medical therapy:
    • Corticosteroids and tamoxifen may improve symptoms.
    • Mycophenolate mofetil and rituximab reported to attenuate inflammation.

---

Goiter

Overview

• Definition: Any enlargement of the thyroid gland.
• Types:
  • Diffuse goiter.
  • Uninodular goiter.
  • Multinodular goiter.

• Etiology:

  • TSH stimulation due to inadequate thyroid hormone synthesis.
  • Paracrine growth factors.
  • Familial goiters from inherited enzyme deficiencies.
  • Endemic goiter:
    • Occurs in regions with iodine deficiency.
    • Dietary goitrogens (e.g., kelp, cassava, cabbage).
  • Sporadic goiters: No obvious cause identified.

  

• In the past, dietary iodine deficiency was the most common cause of endemic goiter.

Clinical Features

• Symptoms:
  • Often asymptomatic.
  • Pressure sensation in the neck.
  • Compressive symptoms (in large goiters):
    • Dyspnea.
    • Dysphagia.
    • Frequent throat clearing (catarrh).
    • Dysphonia (rare, unless malignancy present).
  • Pemberton’s sign:
    • Facial flushing and cervical vein dilation when raising arms above head.
    • Indicates obstruction of venous return from substernal goiter.
  • Acute pain from sudden enlargement due to hemorrhage.
• Physical Examination:
  • Simple goiter: Soft, diffusely enlarged gland.
  • Multinodular goiter: Nodules of various sizes and consistency.
  • May reveal tracheal deviation or compression.

Diagnostic Tests

• Thyroid Function Tests:
  • Usually euthyroid (normal TSH, low-normal or normal free T₄).
  • Suppressed TSH or hyperthyroidism if nodules become autonomous.
• RAI Uptake:
  • Patchy uptake with hot and cold nodules.
• Fine-Needle Aspiration Biopsy (FNAB):
  • Recommended for:
    • Dominant nodules.
    • Painful or enlarging nodules.
  • Carcinoma risk: 5–10% in multinodular goiters.
• Imaging:
  • CT scans to evaluate:
    • Retrosternal extension.
    • Airway compression.

Treatment

• Observation:
  • Small, diffuse goiters in euthyroid patients may not require treatment.
• Thyroid Hormone Suppression Therapy:
  • Exogenous T₄ to reduce TSH stimulation.
  • May decrease or stabilize goiter size.
  • Most effective for small diffuse goiters.
• Iodine Administration:
  • For endemic goiters due to iodine deficiency.
• Surgical Resection:
  • Indications:
    • Goiters increasing despite T₄ suppression.
    • Obstructive symptoms.
    • Substernal extension (relative indication).
    • Malignancy suspected or proven by FNAB.
    • Cosmetic concerns.
  • Procedure:
    • Near-total or total thyroidectomy.
    • Lifelong T₄ therapy required postoperatively.

---

Solitary Thyroid Nodule

Overview

• Prevalence: Present in approximately 4% of individuals in the United States.
• Thyroid cancer incidence: Much lower, with 40 new cases per 1 million people.
• Importance: Critical to determine which patients with a solitary thyroid nodule would benefit from surgery.

---

History

• Key details to elicit:
  • Time of onset of the nodule.
  • Change in size over time.
  • Associated symptoms:
    • Pain (unusual; may indicate intrathyroidal hemorrhage, thyroiditis, or malignancy).
    • Dysphagia (difficulty swallowing).
    • Dyspnea (shortness of breath).
    • Choking.
  • Hoarseness:
    • Worrisome sign.
    • May indicate malignant involvement of the recurrent laryngeal nerves (RLNs).
• Risk factors for malignancy:
  • Exposure to ionizing radiation.
  • Family history of thyroid cancer or associated malignancies.

---

External-Beam Radiation

• Historical uses of low-dose therapeutic radiation:
  • Tinea capitis (6.5 cGy).
  • Thymic enlargement (100–400 cGy).
  • Enlarged tonsils and adenoids (750 cGy).
  • Acne vulgaris (200–1500 cGy).
  • Hemangioma and scrofula.
• High-dose radiation:
  • Approximately 4000 cGy used in Hodgkin’s disease management.
• Risk of thyroid cancer:
  • Increased with history of low-dose radiation exposure to the thyroid.
  • Risk increases linearly from 6.5 to 2000 cGy; declines beyond 2000 cGy due to thyroid tissue destruction.
  • Maximum risk period: 20–30 years after exposure.
  • Lifelong monitoring is required.
• Chernobyl nuclear fallout (1986):
  • Release of ¹³¹I led to increased incidence of benign and malignant thyroid lesions within 4 years, especially in children.
• Thyroid carcinomas post-radiation:
  • Mostly papillary thyroid carcinomas.
  • Some aggressive types with solid histology and RET/PTC translocations.
• Probability:
  • 40% chance of thyroid cancer in patients with a thyroid nodule and radiation history.
  • Cancer location:
    • 60% in the dominant nodule.
    • 40% in other nodules within the thyroid gland.

---

Family History

• Risk factor for both medullary (MTC) and nonmedullary thyroid cancer.
• Familial MTCs:
  • Occur in isolation or with other tumors as part of multiple endocrine neoplasia type 2 (MEN2) syndromes.
• Nonmedullary thyroid cancers:
  • Associated with familial cancer syndromes:
    • Cowden’s syndrome.
    • Werner’s syndrome (adult progeroid syndrome).
    • Familial adenomatous polyposis.
    • DICER1 syndrome.
  • Familial Nonmedullary Thyroid Cancer (FNMTC):
    • Accounts for 95% of nonsyndromic cases.
    • Defined by two or more first-degree relatives with follicular cell–derived cancers.
    • Recognized as a distinct clinical entity.
    • Characteristics:
      • High incidence of multifocal tumors.
      • Presence of benign thyroid nodules.
      • Potential for higher locoregional recurrence rates.
      • Shorter disease-free survival.
    • Candidate chromosomal loci:
      • MNG1 (14q32).
      • TCO (19p13.2).
      • PRN (1q21).
      • NMTC1 (2q21).
      • FTEN (8p23.1-p22).
    • Susceptibility genes:
      • SRGAP1 (12q14).
      • TITF-1/NKX2.1 (14q13).
      • FOXE1 (9q22).
      • Telomere-telomerase complex.

---

Physical Examination

• Technique:
  • Palpate the thyroid gland from behind the patient with the neck in mild extension.
• Landmarks:
  • Cricoid cartilage: The thyroid isthmus is located just below this.
• Signs suggestive of malignancy:
  • Nodules that are hard, gritty, or fixed to surrounding structures (e.g., trachea, strap muscles).
• Lymph node assessment:
  • Evaluate the cervical lymph nodes and nodes in the posterior triangle.

---

Diagnostic Investigations

Fine-Needle Aspiration Biopsy (FNAB)

• Most important test for evaluating thyroid masses.
• Ultrasound guidance recommended for:
  • Nodules difficult to palpate.
  • Cystic or solid-cystic nodules that recur after initial aspiration.
  • Multinodular goiters.
• Procedure:
  • Use a 23-gauge needle.
  • Several passes are made while aspirating.
  • Cells are placed on prelabeled slides:
    • Some immersed in 70% alcohol.
    • Others are air-dried.
  • A sample is placed in 90% alcohol for cytospin or cell pellet.
  • Slides are stained with Papanicolaou’s or Wright’s stains.
• If a bloody aspirate is obtained:
  • Reposition the patient more upright.
  • Repeat biopsy with a finer (25- to 30-gauge) needle.

FNAB Results and Bethesda Criteria

• Bethesda System categorizes FNAB results:
  1. Nondiagnostic or Unsatisfactory:
     • Occurs in 2%–20% of cases.
     • Due to acellular specimen, cyst fluid, blood, or clotting artifacts.
     • Risk of malignancy: 1%–4%.
     • Recommendation: Repeat aspiration under ultrasound guidance.
  2. Benign:
     • 60%–70% of FNAs.
     • Common diagnoses:
       • Follicular nodule (adenomatoid nodule, colloid nodule, follicular adenoma).
       • Lymphocytic (Hashimoto’s) thyroiditis.
       • Granulomatous thyroiditis.
     • False-negative rate: Up to 3%.
     • Follow-up is recommended.
  3. Atypia of Unknown Significance (AUS) or Follicular Lesion of Unknown Significance (FLUS):
     • Found in 3%–6% of biopsies.
     • Risk of malignancy: 5%–15%.
     • Recommendation:
       • Clinical correlation.
       • Repeat FNA.
       • Observation or surgery based on clinical and ultrasound findings.
  4. Follicular Neoplasm or Suspicious for Follicular Neoplasm:
     • Aims to identify potential follicular carcinomas.
     • Includes Hürthle cell neoplasms.
     • Malignancy rate: 15%–35%.
     • Recommendation: Lobectomy is preferred.
  5. Suspicious for Malignancy:
     • Lesions with features suggestive but not diagnostic of cancer.
     • Malignancy rate: 60%–75%.
     • Includes suspicion for medullary carcinoma and lymphoma.
     • Recommendation: Lobectomy or near-total thyroidectomy.
     • Ancillary testing: May include immunohistochemistry, flow cytometry.
  6. Malignant:
     • Risk of malignancy: 97%–99%.
     • Recommendation: Near-total or total thyroidectomy.

Molecular Testing of FNA Specimens

Accuracy of Cytology Diagnoses:

• FNA Cytology: No FNA cytology can fully rule out or confirm malignancy in thyroid nodules.
• Bethesda Category II (Benign) and Bethesda VI (Malignant): Highly accurate, with an error rate of less than 3%.
• Indeterminate Categories (Bethesda III & IV):
  • Bethesda III (Atypia of undetermined significance or follicular lesion of undetermined significance): Cancer risk 6%-30%.
  • Bethesda IV (Follicular neoplasm): Cancer risk 10%-40%.
• Bethesda V (Suspicious for malignancy): Cancer risk 50%-75%; managed similarly to Bethesda VI.

Traditional Management

• Bethesda III & IV nodules: Traditionally led to diagnostic thyroid lobectomy, but most nodules are benign upon final pathology.

Molecular Testing

• Objective: Improve malignancy risk prediction to reduce unnecessary thyroidectomies.

Major Molecular Tests

1. Afirma (Veracyte, San Francisco, CA)
   • First Generation (Gene Expression Classifier):
     • Assessed via machine learning on a 167-gene mRNA microarray.
     • Categorizes gene expression signatures into benign and suspicious.
     • Sensitivity: 90%, Negative Predictive Value (NPV): ~95%.
     • Specificity: Poor, Positive Predictive Value (PPV): ~50% (Bethesda III & IV).
   • Second Generation (Genomic Sequence Classifier, GSC):
     • Evaluates a 10,196-gene array plus genetic mutations.
     • Sensitivity: 91%, Specificity: 68%, NPV: 96%, PPV: 47%.
     • Hürthle Cell Neoplasms: Poor performance—accurate in only 10/17 adenomas and 1/9 carcinomas.
2. ThyroSeq (CBLPath, Rye Brook, NY)
   • ThyroSeq v2:
     • Uses next-generation DNA sequencing to detect 13 mutations and 42 gene fusions.
     • Sensitivity & Specificity: Low 90% range, PPV: 60%-80%, NPV: Over 95%.
   • ThyroSeq v3:
     • Expands gene panel to include mutations, gene copy number changes, and gene expression data.
     • Sensitivity: 94%, Specificity: 82%, NPV: 97%, PPV: 66%.
     • Hürthle Cell Neoplasms: Correctly predicted adenoma in 62% and carcinoma in 100% of cases.

Laboratory Studies

• Thyroid-Stimulating Hormone (TSH):
  • Most patients with nodules are euthyroid.
  • If hyperthyroid, the risk of malignancy is approximately 1%.
• Thyroglobulin (Tg) levels:
  • Cannot differentiate between benign and malignant nodules unless extremely high.
  • Useful for monitoring after total thyroidectomy for thyroid cancer.
• Calcitonin levels:
  • Should be measured in patients with MTC or a family history of MTC or MEN2.
  • Routine testing in all nodules is not recommended.
• RET oncogene testing:
  • Recommended for all patients with MTC.
• Pheochromocytoma screening:
  • 24-hour urine collection for vanillylmandelic acid (VMA), metanephrine, and catecholamines.
  • Necessary as 10% of familial MTC and MEN2A patients have de novo RET mutations, posing a risk to offspring.

Imaging

• Ultrasound:

  • Detects nonpalpable thyroid nodules.
  • Differentiates solid from cystic nodules.
  • Identifies adjacent lymphadenopathy.
  • Can reveal features increasing malignancy risk:
    • Fine stippled calcifications.
    • Enlarged regional lymph nodes.

  • Ultrasound elastography:

    • Evaluates tissue stiffness.
    • Malignant nodules are typically harder.
    • Requires more extensive studies before routine use.

    

    

• CT and MRI:

  • Not necessary for routine evaluation.
  • Useful for large, fixed, or substernal lesions.
• Thyroid Scanning (using ¹²³I or ⁹⁹ᵐTc):
  • Rarely needed.
  • Recommended for:
    • Patients with follicular thyroid nodules on FNAB.
    • Suppressed TSH levels.

• PET Scanning:

  • Not typically used in primary evaluation of thyroid nodules.

  

---

Management

• Malignant tumors:
  • Treated by thyroidectomy as per guidelines.
• Simple thyroid cysts:
  • Resolve with aspiration in about 75% of cases.
  • If persistent after three aspirations:
    • Unilateral thyroid lobectomy is recommended.
• Cysts >4 cm or complex cysts (solid and cystic components):
  • Lobectomy is recommended.
  • Higher malignancy incidence (15%) in complex cysts.
  • FNAB should target the solid portion.
• Colloid nodules diagnosed by FNAB:
  • Observation with serial ultrasound and Tg measurements.
  • Repeat FNAB if the nodule enlarges.
• Levothyroxine therapy:
  • Controversial efficacy.
  • Doses sufficient to maintain TSH between 0.1 and 1.0 μU/mL.
  • May decrease nodule size in iodine-deficient areas.
  • Less effective in iodine-sufficient populations.
• Indications for Thyroidectomy:
  • Nodule enlarges despite TSH suppression.
  • Causes compressive symptoms.
  • For cosmetic reasons.
• Special Considerations:
  • Patients with previous thyroid irradiation.
  • Those with a family history of thyroid cancer.
  • Total or near-total thyroidectomy is recommended due to:
    • High incidence of thyroid cancer.
    • Decreased reliability of FNAB in these patients.

---

Malignant Thyroid Disease

Overview

• Incidence:
  • Thyroid cancer accounts for <1% of all malignancies in the United States.
  • More prevalent in women (2%) than in men (0.5%).
  • It's the most rapidly increasing cancer among women.
• Mortality:
  • Causes approximately six deaths per million people annually.
• Presentation:
  • Patients typically present with a palpable neck mass.
  • Assessment includes history, physical examination, and fine-needle aspiration biopsy (FNAB).

---

Molecular Genetics of Thyroid Tumorigenesis

• RET Proto-Oncogene:
  • Located on chromosome 10.
  • Encodes a receptor tyrosine kinase involved in cell growth and differentiation.
  • Mutations:
    • Germline mutations predispose to:
      • Multiple endocrine neoplasia type 2A (MEN2A).
      • MEN2B.
      • Familial medullary thyroid carcinomas (MTCs).
    • Somatic mutations found in:
      • MTCs (~30%).
      • Pheochromocytomas.
  • RET/PTC Rearrangements:
    • Fusion of RET with other genes leading to constitutive activation.
    • Implicated in the development of papillary thyroid carcinomas (PTCs).
    • Risk Factors:
      • Radiation exposure.
      • Young age.
    • Common types:
      • RET/PTC1.
      • RET/PTC3 (associated with aggressive tumors).
• MAPK Pathway Activation:
  • RET/PTC rearrangements activate the MAPK pathway, promoting tumorigenesis.
  • Ras Mutations:
    • Found in 20%–40% of:
      • Thyroid follicular adenomas and carcinomas.
      • Multinodular goiters.
      • Papillary and anaplastic carcinomas.
  • BRAF Mutations:
    • V600E mutation is most common.
    • Occurs in:
      • Papillary thyroid cancers (~44% prevalence).
      • Anaplastic thyroid cancers (~22% prevalence).
    • Associated with:
      • Larger tumor size.
      • Invasion.
      • Lymph node metastasis.
      • Poor prognosis.
• Other Genetic Alterations:
  • p53 Tumor Suppressor Gene:
    • Rarely mutated in PTCs.
    • Commonly mutated in undifferentiated thyroid cancers.
  • PAX8-PPARγ1 Fusion Gene:
    • Involved in follicular neoplasms development.
  • TERT Promoter Mutations:
    • Linked to poor prognosis in well-differentiated thyroid cancers.
  • Thyroid Cancer Stem Cells:
    • Identified but their exact role is yet to be clarified.

  • PIK3CA and AKT1 Mutations:

    • Rare and occur late in tumor progression.

    

---

SPECIFIC TUMOR TYPES:

Papillary Carcinoma

Epidemiology

• Accounts for 80% of all thyroid malignancies in iodine-sufficient areas.
• Predominant thyroid cancer in children and individuals exposed to external radiation.
• Occurs more often in women (2:1 female-to-male ratio).
• Mean age at presentation: 30 to 40 years.

Clinical Presentation

• Most patients are euthyroid.
• Present with a slow-growing painless neck mass.
• Dysphagia, dyspnea, and dysphonia are associated with locally advanced invasive disease.
• Lymph node metastases are common, especially in children and young adults.
  • May be the presenting complaint.
• "Lateral aberrant thyroid" usually denotes a cervical lymph node invaded by metastatic cancer.
• Diagnosis established by Fine-Needle Aspiration Biopsy (FNAB) of the thyroid mass or lymph node.
• Complete neck ultrasound is strongly recommended after diagnosis to evaluate:
  • Contralateral lobe.
  • Lymph node metastases in central and lateral neck compartments.
• Distant metastases are uncommon at initial presentation but may develop in up to 20% of patients.
  • Most common sites: lungs, followed by bone, liver, and brain.

Pathology

• Gross Examination:
  • Tumors are hard and whitish.
  • Remain flat on sectioning.
  • May show macroscopic calcification, necrosis, or cystic change.

• Histology:

  • May exhibit papillary projections, mixed papillary and follicular structures, or pure follicular pattern (follicular variant).
  • Characteristic nuclear features:
    • Cuboidal cells with pale, abundant cytoplasm.
    • Crowded nuclei with possible "grooving".
    • Intranuclear cytoplasmic inclusions (Orphan Annie nuclei).
  • Presence of psammoma bodies.

  

Variants of Papillary Thyroid Carcinoma (PTC)

• Follicular Variant of Papillary Thyroid Carcinoma (FVPTC)
  • Subtypes:
    • Encapsulated FVPTC:
      • Challenging to diagnose due to lack of invasion.
      • Diagnosis relies on finding characteristic nuclei, which can be subjective.
      • Tumors have an indolent behavior.
      • Genetically distinct from infiltrative counterparts.
      • Now designated as Noninvasive Follicular Thyroid Neoplasm with Papillary-like Nuclear Features (NIFTP).
    • Nonencapsulated (Infiltrative) FVPTC:
      • Exhibits invasion into surrounding thyroid tissue.
• Multifocality:
  • Present in up to 85% of cases.
  • Associated with increased risk of cervical nodal metastases.
  • May invade adjacent structures: trachea, esophagus, RLNs.
• Other variants (~1% of cases) with worse prognosis:
  • Tall cell, insular, columnar, diffuse sclerosing, clear cell, trabecular, poorly differentiated types.

Minimal or Occult/Microcarcinoma

• Tumors ≤1 cm in size.
• No evidence of local invasiveness or angioinvasion.
• Not associated with lymph node metastases.
• Nonpalpable; often incidental findings.
• Found in 2% to 36% of autopsied thyroid glands.
• Increasingly identified due to ultrasound use.
• Generally have a better prognosis but may be more aggressive than previously thought.
• ~25% have associated occult lymph node metastases.

Prognostic Indicators

• Excellent prognosis: >95% 10-year survival rate.
• Prognostic staging systems (data not available preoperatively):

Staging Systems

• AGES Score:
  • Age.
  • Histologic Grade.
  • Extrathyroidal invasion.
  • Metastases.
  • Tumor Size.
  • Low-risk: young, well-differentiated, no metastases, small tumors.
  • High-risk: older, poorly differentiated, invasive, metastatic, large tumors.
• MACIS Scale:
  • Metastases (distant).
  • Age at presentation (<40 or >40 years).
  • Completeness of surgical resection.
  • Invasion (extrathyroidal).
  • Size of lesion (cm).
  • Classifies patients into four risk groups.
• AMES System:
  • Age (men <40, women <50).
  • Metastases.
  • Extrathyroidal spread.
  • Size (< or >5 cm).
  • Categorizes into low- and high-risk groups.
• DeGroot Classification:
  • Class I: Intrathyroidal.
  • Class II: Cervical nodal metastases.
  • Class III: Extrathyroidal invasion.
  • Class IV: Distant metastases.

• TNM System:

  • Tumor size and extent.
  • Nodal status.
  • Metastases.
  • Recently updated; minimal extrathyroidal extension is no longer T3a.

  

Other Prognostic Markers

• Thyroglobulin doubling time (TSH <0.1 mIU/L): independent marker for metastatic disease and recurrence.
• Molecular and Genetic Markers associated with worse prognosis:
  • Tumor DNA aneuploidy.
  • Decreased cAMP response to TSH.
  • Increased epidermal growth factor binding.
  • N-ras and gsp mutations.
  • Overexpression of c-myc.
  • p53 mutations.
• BRAF V600E Mutation:
  • Associated with aggressive features:
    • Extrathyroidal extension.
    • Older age at presentation.
    • Lymph node and distant metastases.
  • Independent predictor of recurrence and mortality.
• TERT Promoter Mutations:
  • Associated with poor disease-specific and disease-free survival.

Surgical Treatment

• High-risk tumors or bilateral tumors: recommend total or near-total thyroidectomy.
• Low-risk (small, unilateral) cancers:
  • Historically controversial; recent guidelines provide clarity.
  • Total thyroidectomy proponents highlight:
    • Facilitates RAI therapy for residual tissue or metastases.
    • Makes serum thyroglobulin a sensitive marker for recurrence.
    • Associated with lowered recurrence rates and improved survival.
• ATA Guidelines:
  • 2009: Recommended total thyroidectomy for tumors >1 cm.
  • 2015: Either total thyroidectomy or lobectomy is appropriate for tumors >1 cm and <4 cm without extrathyroidal extension or lymph node involvement (cN0).
    • Treatment choice may consider RAI therapy facilitation, follow-up enhancement, or patient preference.
• Papillary Microcarcinomas (<1 cm):
  • Active surveillance is viable for very-low-risk tumors without extrathyroidal extension or lymph node metastases.
  • If surgery is chosen, thyroid lobectomy is sufficient.
• PTC Diagnosed by FNAB:
  • Definitive surgery without intraoperative frozen-section confirmation.
  • Thyroid lobectomy and isthmusectomy performed if suspicion remains.
  • Completion thyroidectomy considered based on risk stratification.
• Central Neck Nodes Management:
  • Therapeutic central-compartment neck dissection (level VI) for enlarged or involved nodes.
  • Routine prophylactic central neck dissection is debated due to:
    • High incidence of microscopic metastases.
    • Increased risk of hypoparathyroidism.
    • Unclear impact on recurrence rates.
  • ATA 2015 Guidelines:
    • Prophylactic dissection may be performed in advanced cases (T3/T4) or when lateral neck nodes are involved (N1b).
• Lateral Neck Nodes Management:
  • Modified radical or functional neck dissection for biopsy-proven metastases.
  • Posterior triangle and suprahyoid dissection not usually necessary unless extensive disease in levels II-IV.
  • Prophylactic lateral neck dissection is not recommended.

---

Follicular Carcinoma

Epidemiology

• Accounts for 10% of thyroid cancers.
• Occurs more commonly in iodine-deficient areas.
• Incidence is declining in the United States due to:
  • Iodine supplementation.
  • Improved histologic classification.
• Higher incidence in women (female-to-male ratio of 3:1).
• Mean age at presentation: 50 years.

Clinical Presentation

• Usually present as solitary thyroid nodules.
• May have a history of rapid size increase.
• Possible long-standing goiter.
• Pain is uncommon unless hemorrhage into the nodule occurs.
• Cervical lymphadenopathy is uncommon at initial presentation (~5%).
• Distant metastases may be present.
• In <1% of cases, tumors may be hyperfunctioning, leading to thyrotoxicosis.

Diagnosis Challenges

• FNAB cannot distinguish benign follicular lesions from follicular carcinomas.
• Preoperative clinical diagnosis of cancer is difficult unless distant metastases are present.
• Large follicular tumors (>4 cm) in older men are more likely to be malignant.

Molecular Markers

• Studies focus on identifying molecular markers using tissue from FNAB.
• Seven-gene panel to "rule in" malignancy detects mutations in:
  • BRAF, Ras, RET/PTC, PAX8/PPARγ.
  • Sensitivity: 57–75%.
  • Specificity: 97–100%.
  • PPV: 87–100%.
  • NPV: 79–86%.
• Afirma Gene Expression Classifier (GEC) uses a "rule out" strategy:
  • Analyzes a 167-gene panel from additional FNA passes.
  • Reports as benign or suspicious.
  • PPV: 37%.
  • NPV: 94% for follicular/Hürthle cell neoplasms.
• ThyroSeqV2 (next-generation sequencing):
  • Sensitivity: 90%.
  • Specificity: 93%.
  • PPV: 83%.
  • NPV: 96%.
  • Useful as both "rule in" and "rule out" test.
• Performance varies with prevalence of malignancy in the tested population.
• ATA Guidelines:
  • Do not advise molecular testing in "suspicious for malignancy" nodules.
  • Molecular testing may supplement cytology in:
    • AUS/FLUS nodules.
    • Follicular/Hürthle cell neoplasm/suspicious nodules.

MicroRNAs

• MicroRNAs (miRNAs) implicated in carcinogenesis.
• miR-197 and miR-346 are upregulated in follicular thyroid cancers.
  • Potential diagnostic markers.
• ThyGenX/ThyraMIR:
  • Uses a mutation panel with 10 miRNA markers.
• Rosetta GX Reveal:
  • Exclusively based on miRNA markers.
• Both require further validation.

Pathology

• Usually solitary lesions.
• Majority are encapsulated.

• Histology:

  • Presence of follicles, possibly lacking colloid.
  • Malignancy defined by capsular and vascular invasion.

  

Tumor Invasion Types

• Minimally Invasive Tumors:
  • Grossly encapsulated.
  • Microscopic invasion through the tumor capsule.
  • No extension into parenchyma.
  • Invasion into small to medium-sized vessels in or immediately outside the capsule.
• Widely Invasive Tumors:
  • Evidence of large vessel invasion.
  • Broad areas of tumor invasion through the capsule.
  • May be unencapsulated.
• Tumor infiltration and invasion may involve:
  • Tumor thrombus within middle thyroid or jugular veins.

Surgical Treatment and Prognosis

• Thyroid lobectomy recommended for patients diagnosed by FNAB with a follicular lesion:
  • 70–80% will have benign adenomas.
• Total thyroidectomy recommended for:
  • Older patients with lesions >4 cm (cancer risk ~50%).
  • Patients with atypia on FNA.
  • Family history of thyroid cancer.
  • Radiation exposure history.
• Intraoperative frozen-section examination:
  • Usually not helpful.
  • Performed if evidence of capsular/vascular invasion or adjacent lymphadenopathy.
• Total thyroidectomy when thyroid cancer is diagnosed.
• Debate on completion thyroidectomy for minimally invasive cancers due to good prognosis.
• Frankly invasive carcinoma or angioinvasive follicular carcinoma:
  • Completion total thyroidectomy necessary.
  • Enables use of ¹³¹I for detecting and ablating metastatic disease.
• Prophylactic nodal dissection:
  • Not needed due to infrequent nodal involvement.
  • Therapeutic neck dissection recommended for nodal metastases.
  • Prophylactic central neck dissection may be considered for large tumors.

Prognosis

• Cumulative mortality:
  • 15% at 10 years.
  • 30% at 20 years.
• Poor prognosis indicators:
  • Age >50 years at presentation.
  • Tumor size >4 cm.
  • Higher tumor grade.
  • Marked vascular invasion.
  • Extrathyroidal invasion.
  • Distant metastases at diagnosis.

---

Hürthle Cell Carcinoma

Epidemiology

• Accounts for ~3% of all thyroid malignancies.
• Classified as a subtype of follicular thyroid cancer (WHO classification).
• Considered a separate class by some due to distinct features.

Pathology

• Cannot be diagnosed by FNAB.
• Characterized by vascular or capsular invasion.
• Tumor composition:
  • Sheets of eosinophilic cells packed with mitochondria.
  • Derived from oxyphilic cells of the thyroid gland.

Clinical Features

• More often multifocal and bilateral (~30%).
• Usually do not take up RAI (~5%).
• Higher likelihood of metastasis to:
  • Local nodes (25%).
  • Distant sites.
• Associated with higher mortality rate (~20% at 10 years).

Management

• Similar to follicular neoplasms.
• Lobectomy and isthmusectomy sufficient for unilateral Hürthle cell adenomas.
• Total thyroidectomy when invasive on definitive histology.
• Patients should undergo:
  • Routine central neck node removal (similar to MTC patients).
  • Modified radical neck dissection if lateral neck nodes are palpable or identified via ultrasound.
• RAI scanning and ablation:
  • Usually ineffective.
  • Considered to ablate residual normal thyroid tissue.
  • May occasionally ablate tumors due to lack of better therapies.

---

Postoperative Management of Differentiated Thyroid Cancer

Radioiodine Therapy

• Benefit of RAI therapy is controversial due to lack of prospective, randomized controlled trials.
• Long-term cohort studies suggest:
  • Postoperative RAI therapy reduces recurrence.
  • Provides a small improvement in survival, even in low-risk patients.
• RAI screening is:
  • More sensitive than chest X-ray or CT for detecting metastases.
  • Less sensitive than thyroglobulin (Tg) measurements for detecting metastatic disease (except in Hürthle cell tumors).
• Removal of all normal thyroid tissue enhances screening and treatment efficacy.
• Metastatic differentiated thyroid carcinoma can be detected and treated by ¹³¹I in about 75% of patients.
• RAI effectiveness:
  • Treats >70% of lung micrometastases detected by RAI scan with normal chest X-ray.
  • Success rates drop to <10% with pulmonary macrometastases.
• Early detection is crucial for improving prognosis.

Risk Stratification (2015 ATA Guidelines)

• Low-Risk Papillary Thyroid Cancer:

  • No local tumor invasion.
  • All macroscopic tumor resected.
  • Absence of aggressive histology (e.g., tall cell, columnar cell carcinoma).
  • No known distant metastases.
  • No vascular invasion.
  • Clinical N0 or ≤5 pathologic N1 micrometastases (<0.2 cm).
  • Intrathyroidal, encapsulated follicular variant of papillary thyroid cancer.
  • Intrathyroidal, well-differentiated follicular thyroid cancer with capsular invasion and minimal (<4 foci) vascular invasion.
  • Intrathyroidal papillary microcarcinoma (unifocal or multifocal, including BRAFV600E mutated).

• Intermediate-Risk Tumors:

  • Microscopic invasion into perithyroidal soft tissues.
  • RAI-avid metastatic foci in the neck on first posttreatment whole-body RAI scan.
  • Aggressive histology.
  • Papillary thyroid cancer with vascular invasion.
  • Clinical N1 or >5 pathologic N1 with lymph nodes <3 cm.
  • Multifocal papillary microcarcinoma with extrathyroidal extension (ETE) and BRAFV600E mutated.

• High-Risk Tumors:

  • Macroscopic invasion into perithyroidal soft tissues (gross ETE).
  • Incomplete tumor resection.
  • Presence of distant metastases or postoperative serum Tg suggestive of distant metastases.
  • Pathologic N1 with any metastatic lymph node ≥3 cm.
  • Follicular thyroid cancers with extensive vascular invasion (>4 foci).
• Recurrence Rates:
  • 1–2% for low-risk cancers.
  • Over 50% for high-risk cancers.

ATA Guidelines for RAI Therapy

• High-Risk Disease:
  • RAI therapy recommended after surgical treatment.
• Papillary Microcarcinomas:
  • RAI therapy not recommended, whether unifocal or multifocal.
• Low-Risk DTC Patients:
  • RAI remnant ablation not routinely recommended after thyroidectomy.
  • May be considered for patients with aggressive histology or vascular invasion.
• Intermediate-Risk Disease:
  • Consideration of RAI is recommended.
  • Generally favored for:
    • Microscopic ETE due to risk of recurrent disease.
    • Large (>2–3 cm) or clinically evident lymph nodes (central, mediastinal, lateral neck).
    • Presence of extranodal extension.
    • Advancing age may favor RAI use.
  • Not needed for patients with few (<5) microscopic nodal metastases in central compartment without other adverse features.
  • Generally favored for patients with lateral neck disease.
• Molecular Testing:
  • Currently, no established role in determining RAI therapy.

Remnant Ablation Methods

• Can be performed with either:
  • Thyroid hormone withdrawal.
  • Recombinant TSH (rTSH) stimulation.
• Effectiveness:
  • Both methods are equally effective for preparing patients.
  • rTSH associated with improved quality of life.
• High-Risk Disease:
  • Hormone withdrawal preferred due to insufficient data on thyrogen-mediated ablation.
• Patients with Comorbidities:
  • Consider thyrogen-mediated RAI if severe hypothyroidism may exacerbate conditions (cardiac or psychiatric).

Hormone Withdrawal Protocol

• Discontinue T4 therapy for ~6 weeks before scanning with ¹³¹I.
• Administer T3 during this period to reduce hypothyroidism duration.
  • T3 has a half-life of 1 day (vs. T4's 1 week).
  • Discontinue T3 2 weeks before treatment to allow TSH levels to rise (>30 mU/L optimal).
• Low-Iodine Diet recommended during the last 2 weeks.
• Screening Dose:
  • Administer 1–3 mCi of RAI.
  • Measure uptake after 24 hours.
  • Post-total thyroidectomy uptake should be <1%.
• Residual Tissue:
  • A "hot" spot may indicate residual normal thyroid tissue.
• Scanning Dose Considerations:
  • Some recommend omitting to minimize thyrocyte "stunning".
  • Others recommend scanning if remnant size is uncertain or results may alter treatment.
• Current Guidelines:
  • Recommend using ¹²³I or low-activity ¹³¹I (1–3 mCi).
  • Deliver therapeutic dose within 72 hours.

Recommended RAI Doses

• 30 mCi:
  • For remnant ablation after total thyroidectomy in ATA low-risk or intermediate-risk cancer with lower risk features.
• 30–150 mCi:
  • For adjuvant treatment of suspected microscopic disease without metastases.
  • No solid evidence that higher doses reduce recurrence rates in T3 and N1 disease.

Elevated Tg but Negative RAI Scan

• Some physicians recommend:
  • Treating with 100 mCi of ¹³¹I.
  • Repeat imaging after 1–2 weeks.
• Approximately one-third demonstrate uptake on posttreatment imaging.
• Tg levels usually decrease, indicating therapeutic benefit.

Maximum RAI Doses

• 200 mCi maximum without dosimetry at one time.
• Cumulative dose of 1000–1500 mCi.
• Up to 500 mCi can be given with proper pretreatment dosimetry.
• Recent studies show increased risk of second cancers in patients treated with RAI.

Complications of RAI Therapy

• Early and Delayed Complications are detailed in Table 38-7.

Thyroid Hormone Therapy

• T₄ replacement therapy is necessary after total or near-total thyroidectomy.
• Suppresses TSH, reducing growth stimulus for residual cancer cells.
• TSH Suppression reduces tumor recurrence rates.

TSH Level Recommendations

• High-Risk Thyroid Cancer:
  • Maintain TSH <0.1 mU/mL.
• Intermediate-Risk Disease:
  • Maintain TSH 0.1–0.5 mU/mL.
• Low-Risk Patients with undetectable serum Tg levels:
  • Maintain TSH at lower end of reference range (0.5–2 mU/L).
• Low-Risk Patients with low measurable Tg levels:
  • Maintain TSH at 0.1–0.5 mU/L while monitoring for recurrence.
• Low-Risk Patients treated with lobectomy alone:
  • Keep TSH in mid to lower reference range (0.5–2 mU/L).
  • Hormone therapy may be needed.
• TSH Suppression Levels are adjusted based on response to therapy.
• Side Effects of Prolonged TSH Suppression:
  • Osteopenia.
  • Cardiac problems, especially in older patients.
• Balance risk of tumor recurrence with potential side effects.

Follow-Up of Patients with Differentiated Thyroid Cancer

Thyroglobulin Measurement

• Tg and anti-Tg antibody levels:
  • Measured initially at 6–12 month intervals.
  • More frequent in patients with high-risk tumors.
• Further Measurements guided by response to therapy.
• Excellent Response to Treatment:
  • Suppressed Tg <0.2 ng/mL.
  • Stimulated Tg <1 ng/mL.
  • Negative imaging.
  • Follow Tg levels every 12–24 months.
  • Low risk of recurrence (1–4%).
• Incomplete or Indeterminate Responses:
  • Require additional investigations.
  • Criteria include:
    • Negative imaging but suppressed Tg ≥1 ng/mL or stimulated Tg ≥10 ng/mL.
    • Rising anti-Tg levels.
• Tg Measurements in FNAB Aspirates:
  • Useful for detecting nodal metastatic disease.

Imaging

• After First Posttreatment Scan:
  • Low- and some intermediate-risk patients with negative TSH-stimulated Tg and cervical ultrasound do not require routine diagnostic whole-body RAI scans.
• Diagnostic Whole-Body Scans (6–12 months after remnant ablation):
  • May benefit high- or intermediate-risk patients with higher risk features.
• Other Scenarios for Follow-Up Scans:
  • Abnormal uptake outside thyroid bed on posttherapy scan.
  • Poorly informative postablation scans (e.g., high thyroid bed uptake).
  • Patients with Tg antibodies.
• Cervical Ultrasound:
  • Performed at 6 and 12 months post-thyroidectomy.
  • Then annually for at least 3–5 years.
  • Evaluates thyroid bed and central/lateral cervical nodal compartments.
• Suspicious Nodes (≥8–10 mm):
  • Should be biopsied for:
    • Cytology.
    • Tg measurement in aspirate washout.
• Smaller Nodes:
  • Can be monitored and biopsied if growth continues.
• FDG-PET and PET-CT Scans:
  • Useful for:
    • Localizing recurrent or persistent cancer in Tg-positive, RAI scan–negative patients.
    • Initial staging of poorly differentiated thyroid carcinomas or Hürthle cell tumors.
    • Prognostic tool in metastatic disease.
    • Evaluating response to treatment in metastatic or locally advanced disease.

Additional Treatment Modalities

Radiotherapy, Thermal Ablation, and Chemotherapy

• External-Beam Radiotherapy:
  • Used for:
    • Unresectable, locally invasive, or recurrent disease.
    • Treating metastases in bones to reduce fracture risk.
    • Controlling pain from bony metastases with minimal or no RAI uptake.
• Stereotactic Brain Radiotherapy and Intensity-Modulated Radiation Therapy:
  • Successfully used for metastatic lesions.
• Percutaneous Thermal Ablation:
  • Radiofrequency ablation (heating) or cryoablation (cooling).
  • Induces irreversible cellular damage.
  • Shows promise for lung, bone, and liver lesions.
• Chemotherapy:
  • Single-drug and multidrug regimens have limited success.
  • No role for routine chemotherapy in disseminated thyroid cancer.
  • Doxorubicin (Adriamycin) and Paclitaxel (Taxol) previously used.
    • Doxorubicin acts as a radiation sensitizer.

Novel Therapies

• Target Molecular Pathways involved in thyroid cancers.
• Sorafenib and Lenvatinib:
  • Approved by FDA and EMA for advanced differentiated thyroid cancer non-responsive to RAI.
  • Multikinase inhibitors targeting:
    • RET kinase.
    • Vascular endothelial growth factor (VEGF) receptor.
  • Lenvatinib also inhibits:
    • Fibroblast growth factor receptor.
    • Platelet-derived growth factor receptor.
• Clinical Trial Results:
  • Sorafenib (DECISION study):
    • Improved progression-free survival (PFS) by 5 months.
    • About 12% partial response rates.
  • Lenvatinib (SELECT study):
    • Prolonged median PFS by 15.7 months compared to placebo.
    • Response rates of 65%, including some complete responses.
• Vandetanib:
  • Mainly a RET-kinase inhibitor.
  • Also affects VEGF receptor and epidermal growth factor receptor.
  • Improved PFS in a phase 2 trial.
• Limitations:
  • No improvements in overall survival.
  • Associated with significant side effects:
    • Diarrhea.
    • Fatigue.
    • Hypertension.
    • Hepatotoxicity.
    • Bleeding.
    • Thrombosis.
  • Affect quality of life.
• Usage:
  • Considered for patients with:
    • Metastatic, rapidly progressive, symptomatic disease.
    • Disease unresponsive to other local treatments.
    • Generally in the context of clinical trials.
• Oncogenic Kinase Inhibitors:
  • Dabrafenib selectively inhibits mutant V600E BRAF kinase.
  • Shows promise in treating a subset of patients with advanced differentiated thyroid cancer.

---

Medullary Carcinoma

Epidemiology

• Accounts for ~5% of thyroid malignancies.
• Arises from the parafollicular or C cells of the thyroid.
  • Derived from the ultimobranchial bodies.
• C cells are concentrated superolaterally in thyroid lobes.
  • MTC usually develops in these areas.
• Calcitonin secretion:
  • A 32-amino-acid polypeptide.
  • Functions to lower serum calcium levels (minimal effect in humans).
• Most MTCs are sporadic.
• Approximately 25% occur within inherited syndromes:
  • Familial MTC.
  • MEN2A.
  • MEN2B.
• Result from germline mutations in the RET proto-oncogene.
  • Genotype-phenotype correlations with specific mutations.
• Female-to-male ratio: 1.5:1.

• Most patients present between 50 and 60 years old.

  • Familial cases present at a younger age.

  

Clinical Presentation

• Patients often present with a neck mass.
  • May be associated with palpable cervical lymphadenopathy (15–20%).
• Pain or aching is more common.
• Local invasion may cause:
  • Dysphagia.
  • Dyspnea.
  • Dysphonia.
• Distant metastases occur later:
  • Liver.
  • Bone (frequently osteoblastic).
  • Lung.
• Tumors secrete:
  • Calcitonin.
  • Carcinoembryonic antigen (CEA).
  • Other peptides:
    • Calcitonin gene–related peptide.
    • Histaminases.
    • Prostaglandins E₂ and F₂α.
    • Serotonin.
• Diarrhea may develop in patients with extensive metastatic disease.
  • Due to increased intestinal motility and impaired water and electrolyte flux.
• Cushing's syndrome occurs in 2–4% due to ectopic ACTH production.

Pathology

• Unilateral tumors in 80% of sporadic cases.
• Multicentric and bilateral tumors in up to 90% of familial cases.
• Associated with C-cell hyperplasia (premalignant lesion).
• Microscopic features:
  • Sheets of infiltrating neoplastic cells separated by collagen and amyloid.
  • Marked heterogeneity; cells may be polygonal or spindle-shaped.
• Amyloid presence is diagnostic.
  • Immunohistochemistry for calcitonin is commonly used.
• Tumors also stain positively for:
  • CEA.
  • Calcitonin gene–related peptide.

Diagnosis

• Established by:
  • History and physical examination.
  • Raised serum calcitonin and CEA levels.
  • FNAB cytology of the thyroid mass.
• Family history is important.
  • ~25% have familial disease.
• Screening:
  • All new patients should be screened for:
    • RET point mutations.
    • Pheochromocytoma.
    • Hyperparathyroidism (HPT).
  • Screening of patients with familial MTC for RET point mutations has largely replaced using provocative testing with pentagastrin or calcium-stimulated calcitonin levels to make the diagnosis.
• Calcitonin and CEA used to identify persistent or recurrent MTC.
  • Calcitonin: more sensitive tumor marker.
  • CEA: better predictor of prognosis.

Treatment

• Neck ultrasound recommended to evaluate:
  • Central and lateral neck compartments.
  • Superior mediastinum.
• Measure serum:
  • Calcitonin.
  • CEA.
  • Calcium levels.
• Perform RET proto-oncogene mutation testing.
• Exclude pheochromocytoma.
  • If present, operate on pheochromocytoma first.
• Primary hyperparathyroidism, if present, is treated during thyroidectomy.
• Total thyroidectomy is the treatment of choice.
  • High incidence of multicentricity.
  • More aggressive course.
  • ¹³¹I therapy usually ineffective.
• Central neck node dissection:
  • Bilateral prophylactic central neck dissection routinely performed.
• Additional imaging if:
  • Palpable or imaging-detected cervical nodes.
  • Symptoms or signs of distant disease.
  • Calcitonin levels >500 pg/mL.
  • Imaging includes:
    • Neck and chest CT.
    • Triple-phase liver CT or contrast-enhanced MRI.
    • Axial MRI/bone scan.
• If nodal involvement without distant disease:
  • Perform ipsilateral or bilateral lateral neck dissection (levels IIa, III, IV, V).
• Less aggressive neck surgery considered to preserve speech and swallowing in limited metastatic disease.
• Prophylactic lateral neck dissection is controversial.
  • May be considered based on calcitonin levels.
  • Some groups favor if:
    • Central neck lymph nodes are involved.
    • Primary tumor is ≥1.5 cm.
• Locally recurrent or widely metastatic disease:
  • Tumor debulking advised to:
    • Ameliorate symptoms (pain, flushing, diarrhea).
    • Decrease risk of death from recurrent disease.
• External-beam radiotherapy:
  • Controversial but can be considered for:
    • Resected T4 disease.
    • Unresectable residual or recurrent tumor.
    • Symptomatic bony metastases.
• Liver metastases:
  • Tend to be multiple.
  • Typically not amenable to:
    • Resection.
    • Percutaneous ethanol ablation.
    • Radiofrequency ablation.
  • Chemoembolization may be helpful.
• No effective chemotherapy regimen.

Targeted Therapies

• Multikinase inhibitors:
  • Sorafenib, sunitinib, lenvatinib, cabozantinib.
  • Target RET kinase and VEGF receptor.
• Vandetanib:
  • Inhibits RET kinase, VEGF receptor, and EGF receptor.
• Cabozantinib:
  • Also targets c-MET.
• FDA and EMA approved:
  • Vandetanib and cabozantinib for advanced and progressive MTC.
  • Prolong progression-free survival.
  • Reduce secretion of calcitonin and CEA.
• Recommended as first-line systemic therapy in symptomatic patients with advanced MTC.
• Anti-CEA monoclonal antibody (labetuzumab):
  • Shown antitumor response in a small group of patients.
• Patients with recurrent/metastatic disease:
  • Should be enrolled in well-designed clinical trials.

Management of Associated Conditions

• Hyperparathyroidism (HPT):
  • Remove only obviously enlarged parathyroid glands.
  • Preserve and mark other glands in patients with normocalcemia.
    • ~20% of MEN2A patients develop HPT.
  • If a normal parathyroid cannot be maintained:
    • Remove, biopsy to confirm, and autotransplant to:
      • Forearm of nondominant arm (especially in MEN2A).
      • Sternocleidomastoid muscle (acceptable for MEN2B and familial MTC).
• Prophylactic total thyroidectomy in RET mutation carriers:
  • Indicated once the mutation is confirmed.
• ATA guidelines stratify mutations to:
  • Recommend age for prophylactic thyroidectomy.
  • Predict phenotypes, including pheochromocytomas.
• Moderate-risk mutations:
  • Thyroidectomy may be delayed beyond 5 years if:
    • Normal annual serum calcitonin.
    • Normal neck ultrasound.
    • Less aggressive family history.
    • Family preference.
• High-risk mutations (MEN2A, codon 634):
  • Thyroidectomy at <5 years of age.
• Highest-risk mutations (MEN2B-related, codon 918):
  • Thyroidectomy before age 1.
• Central neck dissection can be avoided in:
  • RET-positive, calcitonin-negative children with normal ultrasound.

• Prophylactic central neck dissection indicated if:

  • Calcitonin increased.
  • Ultrasound suggests thyroid cancer.

  

Postoperative Follow-Up and Prognosis

• Annual measurements of:
  • Calcitonin.
  • CEA levels.
• Use history and physical examination.
• Localization of recurrent disease with:
  • Ultrasound.
  • CT.
  • MRI.
  • FDG-PET/CT scans.
• Prognosis related to disease stage.
  • 10-year survival rate: approximately 80%.
  • Decreases to 45% with lymph node involvement.
• Survival influenced by disease type:
  • Best in non-MEN familial MTC.
  • Followed by MEN2A.
  • Then sporadic disease.
  • Worst in MEN2B (35% survival at 10 years).
• Prophylactic surgery in RET mutation carriers:
  • Improves survival rates.
  • Renders most patients calcitonin-free.

---

Anaplastic Carcinoma

Epidemiology

• Accounts for ~1% of all thyroid malignancies in the United States.
• More commonly affects women.
• Majority present in the seventh and eighth decades of life.

Clinical Presentation

• Long-standing neck mass that rapidly enlarges and may be painful.
• Associated symptoms:
  • Dysphonia
  • Dysphagia
  • Dyspnea
• Tumor characteristics:
  • Large and may be fixed to surrounding structures.
  • May be ulcerated with areas of necrosis.
• Lymph nodes usually palpable at presentation.
• Evidence of metastatic spread may be present.

Diagnosis

• Confirmed by Fine-Needle Aspiration Biopsy (FNAB) revealing characteristic giant and multinucleated cells.
• Differential diagnoses on FNA include:
  • Lymphomas
  • Medullary carcinomas
  • Direct extension from a laryngeal carcinoma
  • Other metastatic carcinomas or melanoma
  • Presence of spindle cell elements may suggest primary or metastatic sarcomas.
• Immunohistochemical markers aid in excluding other diagnoses.
• Core or incisional biopsy may be needed, especially if FNA yields necrotic material.

Pathology

• Gross appearance: Firm and whitish tumors.
• Microscopic features:
  • Sheets of cells with marked heterogeneity.
  • Three main histologic growth patterns:
    • Spindle cell
    • Squamoid
    • Pleomorphic giant cell
  • Tumors may show one pattern or a mixture.
• Foci of more differentiated thyroid tumors (follicular or papillary) may be present.
  • Suggests anaplastic tumors may arise from well-differentiated tumors.

Treatment and Prognosis

• One of the most aggressive thyroid malignancies.
• Few patients survive beyond 6 months after diagnosis.
• Treatment options have been disappointing.
• ATA Guidelines recommend:
  • Obtain imaging (ultrasound, CT, MRI, PET-CT) to assess resectability.
  • Perform preoperative laryngoscopy to assess vocal cord status.
  • Total or near-total thyroidectomy with therapeutic lymph node dissection for intrathyroidal mass.
    • Lobectomy may be appropriate if concern for vocal cord paralysis.
  • If extrathyroidal extension is present, consider en bloc resection if all gross disease can be removed (R1).
  • Avoid tracheostomy unless there is impending airway loss.
• Adjuvant radiation:
  • Offered to patients with good performance status and no metastatic disease.
• Cytotoxic chemotherapy:
  • Combination of taxane, anthracycline, and platinum agents.
  • Given concurrently with radiation.
  • Associated with prolonged survival.
  • Used neoadjuvantly in unresectable disease.

---

Lymphoma

Epidemiology

• Accounts for <1% of thyroid malignancies.
• Most are of the non-Hodgkin’s B-cell type.
• Often develop in patients with chronic lymphocytic thyroiditis.
  • Chronic antigenic lymphocyte stimulation may lead to lymphocyte transformation.

Clinical Presentation

• Symptoms similar to those of anaplastic carcinoma.
• Rapidly enlarging neck mass, often painless.
• May present with acute respiratory distress.
• Ultrasound:
  • Useful for early diagnosis.
  • Appears as a well-defined hypoechoic mass.

Diagnosis

• Suggested by FNAB but can be nondiagnostic in low-grade lymphomas.
• Needle core or open biopsy may be necessary for definitive diagnosis.
• Staging studies should be obtained promptly to assess extrathyroidal spread.

Treatment and Prognosis

• Respond rapidly to chemotherapy (CHOP regimen):
  • Cyclophosphamide
  • Doxorubicin
  • Vincristine
  • Prednisone
• Combined radiotherapy and chemotherapy often recommended.
• Thyroidectomy and nodal resection used to alleviate airway obstruction in patients who:
  • Do not respond quickly to chemotherapy.
  • Have completed the regimen before diagnosis.
• Prognosis depends on:
  • Histologic grade of the tumor.
  • Whether the lymphoma is confined to the thyroid or disseminated.
• Overall 5-year survival rate: About 50%.
  • Patients with extrathyroidal disease have markedly lower survival rates.

---

Metastatic Carcinoma

Overview

• The thyroid gland is a rare site for metastases from other cancers.
• Common primary sources include:
  • Kidney
  • Breast
  • Lung
  • Melanoma

Diagnosis

• Clinical examination and patient history often suggest the source of metastasis.
• FNAB usually provides definitive diagnosis.

Treatment

• Resection of the thyroid (usually lobectomy) may be helpful.
• Depends on the status of the primary tumor.

---