Thyroid Nodules

Overview

Definition

• A disordered growth of thyroid cells (hyperplastic or neoplastic) that form a lump or a mass
• May occur as:
  • Discrete nodule: single or multiple masses in a normal-sized thyroid gland 
  • Multinodular goiter: Multiple nodules replace the parenchyma and cause thyroid enlargement.

Epidemiology

• In the United States, palpable nodules occur in 4%–7% of all adults.
• Incidence increases with age.
• Affects women more than men
• Nature of thyroid nodules: 
  • Benign > malignant nodules (10:1)
  • Thyroid cancer more common in nodules ≥ 2 cm

Risk factors

• Risk factors for thyroid nodules:
  • Smoking and alcohol drinking
  • Obesity and metabolic syndrome
  • Uterine fibroids
  • Elevated insulin-like growth factor (IGF)-1 levels
• Risk factors for malignant nodules:
  • Male gender
  • Young age (< 30 years old)
  • History of radiation to the head or neck
  • Family history of thyroid cancer
  • Familial adenomatous polyposis (FAP) or other associated syndromes
  • Firm, solid, and/or “cold” nodule

Etiology and Pathogenesis

Etiology

• Benign:
  • Sporadic multinodular goiter
  • Follicular adenoma: 
    • Discrete solitary mass developed from follicle epithelium
    • Can become autonomous secreting thyroid hormone (toxic adenoma)
  • Thyroid cysts: fluid-filled nodules
  • Hurthle cell adenoma
  • Hashimoto’s thyroiditis
• Malignant:
  • Papillary carcinoma
  • Follicular carcinoma
  • Medullary carcinoma
  • Anaplastic carcinoma
  • Primary thyroid lymphoma
  • Metastasis from other sites

Pathogenesis

• Nodular growth affected by: 
  • Underlying condition (e.g., iodine deficiency, Hashimoto’s thyroiditis)
  • Varying growth potentials and response to trophic hormones by follicle cells
  • Acquired mutations (e.g., in thyroid-stimulating hormone (TSH) signaling pathway)
  • Recurrent growth leading to follicle rupture and scarring (predisposition to nodularities)
• Thyroid carcinoma:
  • Majority arise from thyroid follicle epithelium
  • Development affected by:
    • Driver mutations (such as those involving the receptor tyrosine kinase pathway) 
    • Environment (especially ionizing radiation)

Clinical Presentation

Signs and symptoms

• Thyroid nodules can present as a lump and be found by the patient or the clinician on physical exam.
• Suspicious features on history and exam:
  • Fixed hard mass
  • + Cervical lymph nodes
  • Symptoms of obstruction (e.g., dyspnea, wheezing, dysphagia)
  • Vocal cord paralysis
  • Rapid growth

Incidental finding

• Thyroid nodules also present as an incidental finding on radiologic tests obtained for different purposes:
  • Carotid ultrasound
  • Neck or chest CT
  • PET
• No symptoms or observable lesion by exam (but the finding is significant as thyroid cancer needs to be ruled out)

Diagnosis

Initial tests

• TSH: normal, elevated, or low
• Thyroid ultrasound:
  • Determines nodule size and characteristics (including adjacent structures)
  • Benign features: purely cystic, without solid components
  • Suspicious nodule findings:
    • Composition: solid nodule 
    • Echogenicity: hypoechoic
    • Shape: more tall than wide
    • Echogenic foci: microcalcifications or rim calcifications with extrusion of soft tissue
    • Margin: irregular borders and/or extrathyroidal extension
  • Other suspicious ultrasound findings:
    • Subcapsular location adjacent to recurrent laryngeal nerve or trachea
    • Abnormal cervical lymph nodes
    • Central vascularity
    • Documented growth

Subsequent approach

Based on TSH and ultrasound findings:

• Low TSH:
  • Consistent with hyperthyroidism; requires radioactive iodine (RAI) uptake scan or thyroid scan
  • RAI uptake scan reports the following:
    • Functioning nodule (“hot” or iodine uptake more than surrounding tissue)
    • Nonfunctioning nodule (“cold” or iodine uptake less than surrounding tissue)
    • Indeterminate nodule
  • Approach:
    • Hot nodule (likely benign): Evaluate and treat hyperthyroidism.
    • Cold nodule: Consider fine-needle aspiration biopsy (FNAB) depending on ultrasound findings, size, and risk factors.
    • Indeterminate: Consider FNAB depending on ultrasound findings, size, and risk factors.
• Normal/elevated TSH:
  • With benign ultrasound findings: Monitor, evaluate, and treat hypothyroidism.
  • With suspicious ultrasound findings: Consider FNAB depending on size and risk factors.

Biopsy

FNAB indicated in:

• ≥ 1 cm nodule and:
  • Elevated/normal TSH + suspicious ultrasound findings
  • Low TSH + suspicious ultrasound findings + cold or indeterminate nodule(s)
• Large nodule ≥ 1.5 cm
• Thyroid nodule of any size with:
  • Risk factors:
    • Young age
    • Family history of thyroid cancer
    • FAP or other associated syndromes
    • History of radiation

Management

Treatment approach

Based on biopsy results (Bethesda system diagnostic categories for reporting thyroid cytopathology):

• Bethesda I: 
  • Nondiagnostic (inadequate)
  • Management: Repeat FNAB in 4–6 weeks.
• Bethesda II: 
  • Benign
  • Management: periodic ultrasound
• Bethesda III:
  • Atypia of undetermined significance, or follicular lesion of undetermined significance (indeterminate)
  • Management: Repeat biopsy and send for molecular markers.
• Bethesda IV:
  • Follicular neoplasm (indeterminate)
  • Management: Repeat biopsy and send for molecular markers.
• Bethesda V:
  • Suspicious for malignancy
  • > 50% cancer risk
  • Management: surgery
• Bethesda VI:
  • Malignancy
  • Management: surgery

Monitoring and other considerations

• Suspicious nodules < 1 cm: 
  • Ultrasound every 6–12 months (frequency declines depending on stability)
  • Less frequent in low-suspicion nodules
• Simple thyroid cysts (no solid components):
  • Fine-needle cystic aspiration
  • Surgery if cysts are recurrent or if size large enough to be bothersome
• Toxic adenoma:
  • Surgery
  • Radioiodine ablation

Clinical Relevance

• Goiter: the abnormal enlargement of the thyroid gland; occurs in hypothyroidism, hyperthyroidism, or euthyroidism. Presentation can be a diffusely enlarged or multinodular thyroid gland. Diagnostic tests include thyroid function tests and thyroid antibodies. Radiologic imaging helps confirm if concerning features are present. Treatment options include observation, medication, surgery, and radioiodine ablation (depending on findings).
• Thyroid cancer: most common cancer in the endocrine system. Malignancy arises from the cell type of the gland: thyroid follicular cells, calcitonin-producing C cells, lymphocytes, and stromal/vascular elements. Metastasis from other malignancies can also occur in the thyroid gland. Patients can present with a growing thyroid mass, thyroid asymmetry, or gland enlargement/swelling. Diagnosis is by biopsy. Treatment varies by type and stage, but options include surgery, RAI, targeted therapy, and radiation therapy.
• Hypothyroidism: a condition characterized by the deficiency of thyroid hormones. Iodine deficiency and Hashimoto’s thyroiditis are the 2 leading etiologies. Clinical features reflect the effects of slowed organ function and decreased metabolic rate. Lab tests show elevated TSH and a low free thyroxine (T4). Treatment is with levothyroxine.
• Hyperthyroidism: a condition caused by sustained overproduction and release of the thyroid hormone triiodothyronine (T3) and T4. Graves’ disease is the most common cause of hyperthyroidism. Manifestations are mostly due to the increased metabolic rate and overactivity of the sympathetic nervous system. Lab tests show low TSH and elevated free T4. Treatment depends on the underlying condition.
• Hashimoto’s thyroiditis: the most common cause of hypothyroidism in iodine-sufficient regions. Hashimoto’s thyroiditis (also known as chronic lymphocytic thyroiditis) is an autoimmune disorder leading to the destruction of the thyroid cells and to thyroid failure. Presentation may be a painless goiter. In later stages, the gland is atrophic. Lab tests show elevated TSH, low free T4, and positive antibodies against thyroglobulin and thyroid peroxidase. Treatment is lifelong thyroid replacement therapy.