What causes thyroid nodules?

Causes of Thyroid Nodules

Thyroid nodules develop through multiple distinct pathophysiologic mechanisms, with the most common being benign proliferative processes (nodular goiter, follicular adenomas), autoimmune thyroid disease (Hashimoto's thyroiditis), and neoplastic transformation (occurring in approximately 7-15% of nodules). 1, 2

Primary Etiologic Categories

Benign Proliferative Disorders

• Nodular goiter represents abnormal growth and enlargement of the thyroid gland, typically occurring over many years and more commonly in women in their fifth and sixth decades of life 3
• Follicular adenomas are benign encapsulated tumors arising from follicular epithelial cells 4
• Colloid nodules and hyperplastic nodules result from focal areas of thyroid tissue proliferation 3
• Cystic lesions can develop from degeneration of adenomatous nodules or hemorrhage 4

Autoimmune Thyroid Disease

• Hashimoto's thyroiditis (chronic lymphocytic thyroiditis) is the most common cause of hypothyroidism in developed countries and frequently presents with nodular changes 3
• Graves' disease can present with nodular thyroid tissue, though diffuse enlargement is more typical 4
• These autoimmune conditions predispose to nodule development through chronic inflammatory changes 4

Neoplastic Causes (Malignant)

• Papillary thyroid carcinoma accounts for 84% of thyroid malignancies and arises from follicular epithelial cells 3
• Follicular carcinoma represents 11% of thyroid malignancies 3
• Medullary thyroid carcinoma arises from parafollicular C cells and accounts for approximately 5-10% of thyroid cancers, with 80% being sporadic and 20% hereditary (MEN 2A, MEN 2B, familial MTC) 3
• Anaplastic carcinoma is an aggressive undifferentiated tumor typically occurring in elderly patients 3

Environmental and Iatrogenic Factors

• Iodine deficiency remains a significant cause of nodular thyroid disease in iodine-deficient regions 3, 4
• Iodine excess can paradoxically cause thyroid nodules 3
• Radiation exposure, particularly head and neck irradiation, significantly increases risk of thyroid nodule formation and malignancy 3, 4
• Radioactive fallout exposure increases the risk of both benign and malignant nodules 4
• Prior thyroidectomy or radioiodine therapy can lead to nodular changes in remaining thyroid tissue 3

Medication-Related Causes

• Amiodarone-induced thyroid disease can cause nodular changes through both iodine-induced hyperthyroidism (Type I) and destructive thyroiditis (Type II) 3
• Other medications including lithium and certain antithyroid drugs can contribute to nodule formation 3

Genetic and Familial Syndromes

• MEN 2A and MEN 2B syndromes are associated with medullary thyroid carcinoma and require RET proto-oncogene mutation screening 3
• Familial adenomatous polyposis (Gardner's syndrome), Carney complex, and Cowden's syndrome are associated with increased thyroid nodule and cancer risk 3
• Familial non-medullary thyroid cancer accounts for 3-9% of differentiated thyroid cancers 3

Important Clinical Context

Prevalence and Demographics

• Thyroid nodules are detected in up to 50-70% of the general population by age 60 when sensitive imaging is used 1, 2
• Palpable nodules occur in approximately 5% of women and 1% of men in iodine-sufficient areas 2
• The vast majority (85-93%) of thyroid nodules are benign, making risk stratification essential 1, 5

Risk Factors for Malignancy

• Age <15 years or >60 years increases malignancy risk 3
• Male gender confers approximately 2-fold increased risk 3
• Family history of thyroid cancer significantly elevates risk 3
• Rapidly growing nodules, fixation to adjacent structures, vocal cord paralysis, and enlarged regional lymph nodes increase the likelihood of malignancy approximately 7-fold 3

Critical Pitfalls to Avoid

• Do not assume all nodules in the setting of Hashimoto's thyroiditis are benign—these patients have increased risk of thyroid lymphoma and papillary carcinoma 4
• Recognize that some benign-appearing nodules may harbor malignant potential—approximately 2% of malignancies arise within preexisting benign nodules, and molecular markers suggest some follicular adenomas represent premalignant lesions 6
• Do not overlook hereditary syndromes—failure to screen for MEN 2 in medullary thyroid carcinoma patients misses the opportunity for family screening and prophylactic intervention 3
• Avoid attributing all nodules to simple goiter without proper evaluation—this can delay diagnosis of clinically significant malignancy in the 7-15% of nodules that are cancerous 1, 5