Can a benign follicular thyroid nodule in an adult with low‑risk ultrasound features and size <1 cm become malignant?

Can a Benign Follicular Thyroid Nodule Become Malignant?

A cytologically "benign" follicular nodule carries a residual 1–3% malignancy risk at initial diagnosis, but a truly benign follicular adenoma does not transform into cancer over time. The critical issue is that fine-needle aspiration (FNA) cannot definitively distinguish benign follicular adenoma from follicular carcinoma or the follicular variant of papillary carcinoma, because the diagnosis of malignancy requires histologic evidence of capsular or vascular invasion that is invisible on cytology. 1

Understanding the Diagnostic Limitation

The term "benign follicular nodule" on FNA (Bethesda II) reflects cytologic appearance, not definitive histologic diagnosis. When FNA shows a follicular-patterned lesion classified as Bethesda II (benign), the false-negative rate ranges from 1–3% in most series, but can reach 11–33% when clinical or ultrasound features are highly suspicious. 1, 2 This means:

• A small percentage of nodules called "benign" are actually malignant at the time of FNA—they were never benign and did not "become" malignant; they were simply misclassified due to sampling error or overlapping cytologic features. 2, 3

• Follicular neoplasms (Bethesda IV) carry a 15–40% malignancy risk, and even nodules with atypia of undetermined significance (Bethesda III) harbor 5–15% malignancy risk, demonstrating that cytology alone cannot exclude cancer in follicular-patterned lesions. 1

The NIFTP Reclassification and Its Impact

The introduction of noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) has further complicated risk assessment:

• NIFTP was previously classified as the encapsulated follicular variant of papillary thyroid carcinoma but is now considered a neoplasm with low malignant potential, effectively reducing the "malignancy" rate for many follicular-patterned lesions. 3

• NIFTP cases span the entire Bethesda spectrum: 10% are called benign (Bethesda II), 30% are atypia of undetermined significance (Bethesda III), 21% are follicular neoplasm (Bethesda IV), 24% are suspicious for malignancy (Bethesda V), and 8% are malignant (Bethesda VI). 3 This wide distribution underscores that cytology cannot reliably predict the final histologic diagnosis in follicular lesions.

Malignant Transformation vs. Misdiagnosis

True benign follicular adenomas do not undergo malignant transformation. The literature contains no evidence that a histologically confirmed benign follicular adenoma later becomes follicular carcinoma. What appears as "transformation" is actually:

1. Initial misclassification: A nodule called benign on FNA was malignant from the outset but lacked diagnostic features on the aspirate. 2, 4

2. Sampling error: FNA may miss the malignant component in heterogeneous nodules or fail to sample areas with capsular/vascular invasion. 4, 5

3. Cytologic overlap: Follicular adenomas, follicular carcinomas, and the follicular variant of papillary carcinoma share cytomorphologic features—high cellularity, microfollicles, and nuclear atypia—that cannot be reliably distinguished without histology. 4, 5

Clinical Implications and Management

For nodules with low-risk ultrasound features and size <1 cm classified as Bethesda II, active surveillance is appropriate, with repeat ultrasound at 12–24 months to monitor for growth or development of suspicious features. 1, 2 However:

• Growth ≥3 mm in any dimension during surveillance warrants repeat FNA, as rapid enlargement is an independent predictor of malignancy. 2

• High-risk clinical factors override reassuring cytology: history of head/neck irradiation (7-fold increased risk), family history of thyroid cancer, age <15 years or >60 years, male gender, firm/fixed nodule, vocal cord paralysis, or suspicious cervical lymphadenopathy all lower the threshold for surgical excision despite benign FNA. 1, 2, 6

• Molecular testing (BRAF, RAS, RET/PTC, PAX8/PPARγ) may refine risk in indeterminate cases (Bethesda III/IV), with 97% of mutation-positive nodules proving malignant at surgery. 1, 2

Key Pitfalls to Avoid

• Do not assume a benign FNA result excludes malignancy when clinical suspicion is high. False-negative rates of 11–33% have been reported in high-risk populations. 2

• Do not rely on nodule size alone to determine malignancy risk in follicular lesions. Studies show that male gender, nodule size ≥3 cm, and age extremes (<20 or >60 years) increase malignancy probability in follicular neoplasms, but these factors are not absolute predictors. 7, 6

• Do not perform FNA on nodules <1 cm without high-risk features, as this leads to overdiagnosis of clinically insignificant papillary microcarcinomas. 2

• Recognize that follicular carcinoma and Hürthle cell carcinoma require histologic evidence of capsular or vascular invasion, which cannot be determined by FNA; therefore, surgical excision is the only definitive diagnostic method for Bethesda IV lesions. 1, 7

Evidence-Based Algorithm for Follicular-Patterned Nodules

For nodules ≥1 cm with follicular cytology (Bethesda II–IV):

1. Bethesda II (benign) with low-risk ultrasound features: Surveillance with ultrasound at 12–24 months; consider surgery only if compressive symptoms, cosmetic concerns, or suspicious features develop. 1, 2

2. Bethesda III (AUS/FLUS) or IV (follicular neoplasm): Consider molecular testing; if molecular markers suggest malignancy or if clinical/ultrasound features are high-risk, proceed to lobectomy or total thyroidectomy for definitive diagnosis. 1

3. Bethesda V (suspicious) or VI (malignant): Immediate referral for total or near-total thyroidectomy with pre-operative lymph node assessment. 1, 2

For nodules <1 cm with follicular cytology:

• Do not perform FNA unless high-risk clinical factors are present (subcapsular location, history of radiation, family history, suspicious lymph nodes). 2

• If FNA is performed and shows Bethesda II, active surveillance is safe, with progression rates manageable through regular imaging. 2