What are the possible causes of bilateral thyroid multiple nodules in a patient with a normal Thyroid-Stimulating Hormone (TSH) level and nodule sizes ranging from 1.36 to 2.25 cm?

Causes of Bilateral Multiple Thyroid Nodules with Normal TSH

Bilateral multiple thyroid nodules with normal TSH levels most commonly represent multinodular goiter (colloid nodular hyperplasia), though other etiologies including Hashimoto's thyroiditis, follicular adenomas, and less commonly malignancy must be considered through systematic evaluation.

Primary Etiologies

Multinodular Goiter (Most Common)

• Colloid nodular hyperplasia represents the most frequent cause of bilateral multiple thyroid nodules in euthyroid patients, resulting from chronic stimulation and involution cycles leading to heterogeneous nodular transformation 1, 2
• Thyroid nodules increase in frequency throughout life, with palpable nodules occurring approximately 4 times more commonly in women than men, and up to 50% of the general population having at least one nodule by age 60 1, 3
• The reported prevalence reaches up to 70% when imaging studies are performed for other indications 3

Hashimoto's Thyroiditis

• Chronic lymphocytic thyroiditis commonly presents with multiple nodules that are typically solid, isoechoic nodules representing hyperplastic/adenomatoid nodules rather than true neoplasms 2
• These nodules in the setting of Hashimoto's thyroiditis are typically benign with very low malignancy risk (1-3%) 2

Follicular Adenomas

• Multiple follicular adenomas can present as bilateral nodules, though this is less common than multinodular goiter 4, 3
• These require fine-needle aspiration for differentiation from follicular carcinoma, as cytology alone cannot distinguish adenoma from carcinoma 2, 5

Malignancy Considerations

• Papillary thyroid carcinoma can present with bilateral disease or multifocal involvement, occurring in approximately 5-15% of thyroid nodules overall 4, 5, 3
• Medullary thyroid carcinoma should be considered, particularly if there is family history of thyroid cancer or multiple endocrine neoplasia syndromes, as sporadic MTC accounts for 80% of cases while inherited forms (MEN 2A, MEN 2B, familial MTC) comprise the remaining 20% 1
• The presence of multiple nodules (41.1% vs. 26.4%, p=0.0014) is paradoxically associated with higher malignancy risk compared to solitary nodules 6

Critical Diagnostic Algorithm

Initial Risk Stratification

• Measure TSH levels to exclude autonomous function, though normal TSH does not exclude malignancy as most thyroid cancers present with normal thyroid function 2, 5, 3
• Perform high-resolution ultrasound of thyroid and cervical lymph nodes to characterize nodule features and identify suspicious characteristics 1, 2, 7
• Higher TSH levels within the normal range are associated with increased risk for differentiated thyroid cancer, with mean TSH values of 2.24 mIU/L for papillary carcinoma versus 1.90 mIU/L for colloid goiter 8

Ultrasound Feature Assessment

• Suspicious features warranting FNA include microcalcifications (highly specific for papillary carcinoma), marked hypoechogenicity, irregular or microlobulated margins, absence of peripheral halo, solid composition, and central hypervascularity 2, 7, 5
• Size thresholds for FNA: Nodules 1.36-2.25 cm all exceed the 1 cm threshold requiring fine-needle aspiration if any suspicious ultrasound features are present 2, 5
• Nodules >4 cm require FNA regardless of ultrasound appearance due to increased false-negative rates 2

Mandatory Workup for Your Patient

• Ultrasound-guided FNA of the largest nodule (2.25 cm) is mandatory, as larger nodules should be prioritized and this size significantly exceeds the 1 cm threshold 2, 5
• Consider FNA of additional nodules if they demonstrate suspicious ultrasound features independent of the dominant nodule 1, 2
• Measure serum calcitonin as part of initial workup to screen for medullary thyroid carcinoma, which has higher sensitivity (5-7% detection rate) than FNA alone 2, 7
• Evaluate cervical lymph nodes with ultrasound, performing FNA of any clinically suspicious nodes 1, 2

High-Risk Clinical Factors That Modify Management

Patient History Red Flags

• History of head and neck irradiation increases malignancy risk approximately 7-fold and lowers the threshold for FNA even in nodules <1 cm 2, 7
• Family history of thyroid cancer, particularly medullary carcinoma or familial syndromes (MEN 2A, MEN 2B), warrants genetic counseling and RET proto-oncogene mutation screening 1, 2
• Age <15 years or male gender increases baseline malignancy probability 2, 7
• Rapidly growing nodules, firm/fixed nodules on palpation, vocal cord paralysis, or compressive symptoms suggest invasive disease 2, 7

Genetic Considerations

• Screen for RET proto-oncogene mutations (exons 10,11,13-16) if medullary thyroid carcinoma is suspected or if there is family history of MEN syndromes 1
• Germline RET mutations should prompt family testing of first-degree relatives and genetic counseling 1

Management Based on FNA Results

Bethesda Classification System

• Bethesda II (Benign): Surveillance with repeat ultrasound at 12-24 months, as malignancy risk is only 1-3% 2, 5
• Bethesda III/IV (Indeterminate): Consider molecular testing for BRAF, RAS, RET/PTC, and PAX8/PPARγ mutations, as 97% of mutation-positive nodules are malignant 2, 5
• Bethesda V/VI (Suspicious/Malignant): Immediate referral for total or near-total thyroidectomy with bilateral central neck dissection (level VI) 1, 2

Surgical Indications

• Total thyroidectomy with bilateral central neck dissection is recommended for confirmed malignancy ≥1 cm, bilateral thyroid disease, multifocal disease, or familial thyroid cancer 1, 2
• Therapeutic modified neck dissection (levels II-V) for clinically or radiologically identifiable lymph node disease 1
• Consider prophylactic ipsilateral modified neck dissection if high volume or gross disease in adjacent central neck 1

Critical Pitfalls to Avoid

• Do not rely solely on TSH levels to exclude malignancy—most thyroid cancers occur in euthyroid patients 2, 5, 3
• Do not perform radionuclide scanning in euthyroid patients to determine malignancy risk, as ultrasound features are far more predictive 2, 7
• Do not delay FNA for nodules >1 cm with any suspicious features, as the false-negative rate increases with nodule size 2, 5
• Do not override reassuring FNA results when worrisome clinical findings persist, as false-negative results occur in up to 11-33% of cases 2
• Avoid performing FNA on nodules <1 cm without high-risk features or suspicious ultrasound characteristics, as this leads to overdiagnosis of clinically insignificant papillary microcarcinomas 2