Surgical Extent of Low-to-Intermediate Thyroid Cancer: Molecular Testing and Clinical Decision-Making
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Preoperative molecular testing has emerged as a transformative approach for optimizing surgical management of Bethesda V and VI thyroid nodules. This review examines the evolving role of molecular profiling in guiding the extent of thyroid surgery, particularly for low-to-intermediate risk thyroid cancers. Key genetic alterations, including BRAF V600E, TERT promoter mutations, RAS mutations, RET/PTC rearrangements, and PAX8/PPARγ fusions, demonstrate distinct prognostic implications that can inform surgical decision-making. The coexistence of mutations, particularly BRAF V600E with TERT promoter mutations, significantly correlates with aggressive tumor behavior, higher recurrence rates, and increased risk of distant metastasis despite aggressive treatment. Conversely, isolated RAS-like alterations generally indicate more indolent disease, potentially amenable to lobectomy alone. Contemporary molecular diagnostic platforms, including ThyroSeq, Afirma, and ThyGeNEXT/ ThyraMIR, enable stratification of patients into molecular risk groups that predict oncologic outcomes more accurately than traditional clinicopathologic features alone. Evidence demonstrates that preoperative molecular testing leads to more appropriate initial surgical management, potentially reducing both overtreatment of indolent disease and undertreatment of aggressive variants. While molecular profiling represents a significant advance toward personalized thyroid cancer management, further prospective studies with standardized protocols and long-term follow-up are needed to fully establish the clinical utility and cost-effectiveness of the molecular testing based surgical extent decision.
Abstract
Preoperative molecular testing has emerged as a transformative approach for optimizing surgical management of Bethesda V and VI thyroid nodules. This review examines the evolving role of molecular profiling in guiding the extent of thyroid surgery, particularly for low-to-intermediate risk thyroid cancers. Key genetic alterations, including BRAF V600E, TERT promoter mutations, RAS mutations, RET/PTC rearrangements, and PAX8/PPARγ fusions, demonstrate distinct prognostic implications that can inform surgical decision-making. The coexistence of mutations, particularly BRAF V600E with TERT promoter mutations, significantly correlates with aggressive tumor behavior, higher recurrence rates, and increased risk of distant metastasis despite aggressive treatment. Conversely, isolated RAS-like alterations generally indicate more indolent disease, potentially amenable to lobectomy alone. Contemporary molecular diagnostic platforms, including ThyroSeq, Afirma, and ThyGeNEXT/ ThyraMIR, enable stratification of patients into molecular risk groups that predict oncologic outcomes more accurately than traditional clinicopathologic features alone. Evidence demonstrates that preoperative molecular testing leads to more appropriate initial surgical management, potentially reducing both overtreatment of indolent disease and undertreatment of aggressive variants. While molecular profiling represents a significant advance toward personalized thyroid cancer management, further prospective studies with standardized protocols and long-term follow-up are needed to fully establish the clinical utility and cost-effectiveness of the molecular testing based surgical extent decision.