BACKGROUND: Benign thyroid tumors account for most nodular thyroid disease. Determination of whether a thyroid nodule is benign or malignant is a major clinical dilemma and underlies the decision to proceed to surgery in many patients. Although the accuracy of thyroid nodule fine-needle aspiration (FNA) has reduced the need for surgery over the years, questions regarding how to follow FNA-designated benign nodules remain unresolved. This is true at least in part because of uncertainty over whether some benign nodules harbor malignant potential. METHODS: An evidence-based review of recent clinical, pathologic, and molecular data is presented. A summary of data and observations from our own experience is also provided. RESULTS: Review of our recent 10-year experience indicates that 2% of thyroid malignancies arise within a preexisting benign thyroid nodule. In addition, both cytologic and molecular tumor markers, including Gal-3, CITED1, HBME-1, Ras, RET/PTC, and PAX8/PPAR gamma, have been identified in some histopathologically classified benign nodules. Gene expression profiling suggests that follicular adenomas and Hurthle cell adenomas have similarities to both benign and malignant tumors, suggesting that some of these tumors are premalignant. In addition, 10% of surgically excised follicular tumors are encapsulated follicular lesions with nuclear atypia, which have been termed "well-differentiated tumors of uncertain malignant potential." The data available suggest that these tumors could be precursors to carcinoma. CONCLUSION: Some benign thyroid nodules have malignant potential. Further molecular testing of these tumors can shed light on the pathogenesis of early malignant transformation.
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