A patient with an anterior neck mass has fine‑needle aspiration cytology consistent with a follicular neoplasm (Bethesda category IV); what is the appropriate next step in evaluation and management?

Management of Follicular Neoplasm (Bethesda IV) on Fine-Needle Aspiration

For a patient with an anterior neck mass and FNA cytology showing follicular neoplasm (Bethesda category IV), proceed directly to surgical excision—either diagnostic lobectomy with isthmusectomy or total thyroidectomy—because cytology cannot distinguish follicular adenoma from carcinoma, and the malignancy rate ranges from 12–47% in this diagnostic category. 1

Why Surgery Is the Definitive Next Step

• Cytologic diagnosis of follicular neoplasm (Bethesda IV) cannot differentiate benign follicular adenoma from follicular carcinoma because FNA samples lack the architectural information needed to assess capsular or vascular invasion, which are the histologic hallmarks that distinguish malignancy. 1, 2

• The malignancy rate in Bethesda IV nodules is substantial, ranging from 12–47% across multiple studies, with some institutions reporting rates as high as 41.9–47.4%. 1, 3, 4 This risk is sufficiently high to warrant surgical intervention rather than observation or repeat biopsy.

• Papillary thyroid carcinoma (PTC), particularly the follicular variant, accounts for 32–65% of malignancies in nodules initially diagnosed as follicular neoplasm on FNA, not just follicular carcinoma. 5, 6, 3 This finding is critical because many of these PTCs have aggressive subtypes (columnar cell variant, diffuse sclerosing variant) that require total thyroidectomy and radioactive iodine ablation. 3

Surgical Approach: Lobectomy vs. Total Thyroidectomy

• Total thyroidectomy should be strongly considered as the initial surgical approach for Bethesda IV nodules, rather than diagnostic lobectomy, because 32–65% of malignancies in this category are papillary carcinomas (not follicular carcinomas), and some PTC subtypes have unfavorable prognosis requiring completion thyroidectomy and radioactive iodine therapy. 3

• Diagnostic lobectomy with isthmusectomy is acceptable only if the patient accepts the possibility of a second operation (completion thyroidectomy) should final histology reveal papillary carcinoma, multifocal disease, or aggressive histologic variants. 1

• For nodules ≥1 cm with confirmed malignancy, metastatic disease, multifocal disease, or familial thyroid cancer, total or near-total thyroidectomy is recommended as the definitive surgical procedure. 1

Pre-Operative Workup Before Surgery

• Obtain comprehensive neck ultrasound to assess cervical lymph node basins (both central and lateral compartments) for suspicious features such as loss of fatty hilum, microcalcifications, cystic change, or abnormal vascularity, because lymph node metastases are present in 15–20% of differentiated thyroid cancers at diagnosis. 1

• Measure serum thyroglobulin (Tg) level before surgery, as Tg ≥75 ng/mL is a significant predictor of malignancy in follicular neoplasm (p < 0.01), with sensitivity for detecting cancer superior to ultrasound features alone. 5

• Measure serum calcitonin to screen for medullary thyroid carcinoma, which has higher sensitivity than FNA alone and is found in approximately 3% of patients with nodular thyroid disease when measured with sensitive immunometric assays. 1

• Document TSH level, because higher TSH levels are associated with increased risk for differentiated thyroid cancer, and suppressed TSH (<0.1 mIU/L) suggests autonomous function (toxic adenoma), which would alter the surgical indication. 1

Role of Molecular Testing (Limited Utility in Bethesda IV)

• Molecular testing for BRAF, RAS, RET/PTC, and PAX8/PPARγ mutations may be considered to refine malignancy risk in Bethesda IV nodules, as 97% of mutation-positive nodules are malignant. 1

• However, molecular testing has minimal impact on management of Bethesda IV nodules because surgery is already indicated regardless of mutation status, and BRAF mutation is positive in only 18% of follicular variant PTC cases (the most common malignancy in this category). 6

• Molecular testing is more useful for Bethesda III (AUS/FLUS) nodules, where it can help decide between observation and surgery, but in Bethesda IV the surgical indication is already established. 1

Why Repeat FNA or Active Surveillance Is Inappropriate

• Repeat FNA does not improve diagnostic accuracy for follicular neoplasm because the cytologic diagnosis will remain indeterminate (Bethesda IV) in 53–59% of cases even after second or third biopsy attempts. 2

• Active surveillance is not appropriate for Bethesda IV nodules because the malignancy rate (12–47%) far exceeds the threshold for surgical intervention, and delayed diagnosis of follicular carcinoma or aggressive PTC variants worsens prognosis. 3, 4

• The positive predictive value of Bethesda IV diagnosis for neoplasm is 73%, meaning nearly three-quarters of these nodules are true neoplasms (either benign adenomas or carcinomas), justifying immediate surgical excision. 2

Clinical Factors That Do NOT Reliably Predict Malignancy

• Male gender, nodule size >4 cm, and patient age >45 years are NOT reliable predictors of malignancy in Bethesda IV nodules, contrary to traditional teaching. 4

• Only extreme ages (below 20 or above 60 years) are associated with increased malignancy risk in follicular neoplasm, but this does not change the surgical recommendation. 4

• Hürthle cell neoplasia on FNA is NOT associated with increased malignancy risk compared to other follicular neoplasms, despite historical beliefs to the contrary. 4

Common Pitfalls to Avoid

• Do not rely on ultrasound features to "rule out" malignancy in Bethesda IV nodules, because follicular carcinomas often present with benign-appearing sonographic features (isoechogenicity, peripheral halo) that overlap with follicular adenomas. 5

• Do not assume that absence of microcalcifications or irregular margins indicates benign disease, because follicular carcinomas and follicular variant PTC frequently lack these classic malignant features. 5, 6

• Do not perform radionuclide thyroid scanning in euthyroid patients with Bethesda IV nodules, as "cold" nodules on scintigraphy do not reliably distinguish benign from malignant follicular lesions, and this test delays definitive surgical management. 1

• Do not override the surgical indication based on a "reassuring" clinical presentation, because up to 16% of Bethesda IV nodules with benign-appearing features on imaging and palpation are ultimately diagnosed as carcinoma on final histology. 6

Post-Surgical Management

• If final histology reveals follicular carcinoma or papillary carcinoma ≥1 cm, radioactive iodine (¹³¹I) ablation should be administered to eliminate remnant thyroid tissue and microscopic residual tumor, which decreases recurrence risk. 1

• If final histology reveals follicular adenoma or benign hyperplastic nodule, no further treatment is required beyond routine surveillance. 1

• Compartment-oriented lymph node dissection should be performed intraoperatively if lymph node metastases are identified during surgery or were suspected preoperatively on ultrasound. 1