Letter: “High Rates of Unnecessary Surgery for Indeterminate Thyroid Nodules in the Absence of Molecular Test and the Cost-Effectiveness of Utilizing Molecular Test in an Asian Population: A Decision Analysis” by Fung et al

Dear Editor:

We read with great interest the recent study by Fung et al. published in Thyroid. ¹ The authors highlighted the high rate of unnecessary surgeries for cytologically indeterminate thyroid nodules in Hong Kong and proposed that introducing molecular testing (MT) could reduce these surgeries and improve cost-effectiveness. While we agree that diagnostic lobectomies contribute to unnecessary healthcare costs, potential complications, and decreased quality of life, we have concerns regarding the authors’ conclusions about the role of MT in resolving this issue.

The authors estimated that routine MT could reduce unnecessary surgeries by more than 26% compared to current practices. However, their model assumes that MT results will consistently change management decisions, which may not accurately reflect real-world practice. For example, many hospitals in Asia prioritize conservative approaches, such as repeat fine-needle aspiration (FNA) and ultrasound-based risk stratification, and typically reserve surgery for cases with high-risk clinical or imaging features.

An important limitation of the analysis by Fung et al. is the classification of surgical outcomes into strictly benign or malignant categories, defining unnecessary surgery based solely on final benign histopathology. However, thyroid tumors consist not only of benign and malignant categories but also include low-risk neoplasms that do not fit neatly into either category. MT often identifies indolent lesions with RAS-like mutations, such as non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) and other low-risk neoplasms, as molecularly suspicious. Most MT studies have traditionally classified low-risk neoplasms like NIFTP as part of the malignant group. Surgeries resulting in a diagnosis of low-risk neoplasms have therefore been categorized as necessary, but we challenge this classification. These lesions are unlikely to progress to clinically significant cancer but are frequently subjected to surgery when MT results are positive, which raises concerns about potential overdiagnosis and overtreatment, even with selective application of MT. Fung et al. did not account for the presence of low-risk neoplasms in their analysis, potentially leading to an inaccurate estimation of unnecessary surgeries.

The study does not fully address regional variability in thyroid cancer risk profiles and healthcare practices. In many Asian populations, the prevalence of clinically significant thyroid cancer differs from that observed in North America, where most MT validation studies were conducted. Applying North American-based performance characteristics to Asian populations without appropriate local validation could result in inaccurate risk stratification and unnecessary interventions. ^2,3

Furthermore, the authors conclude that MT may become cost-effective if test prices decrease. While cost considerations are important, the utility of MT should primarily be assessed based on clinical outcomes. The high sensitivity of MT for low-risk mutations often leads to unnecessary surgeries, particularly for patients with benign or borderline lesions, where active surveillance may suffice. ⁴

Similar to other strategies to reduce overdiagnosis and overtreatment of thyroid carcinoma, such as (i) not performing FNA for small (<1 cm) thyroid nodules, (ii) avoiding routine ultrasound screening for thyroid cancer in asymptomatic adults, and (iii) implementing active surveillance for low-risk small papillary thyroid carcinomas, molecular testing can be avoided with minimal consequences for low-risk thyroid nodules. These nodules are more efficiently excluded from surgical treatment through conservative approaches, which are widely practiced globally for managing indolent or low-risk thyroid tumors. ⁵

In conclusion, we acknowledge the potential utility of MT in certain high-risk cases but emphasize the need for more region-specific validation and a cautious, selective application of these tests. We recommend that MT be reserved for cases where the results are likely to alter clinical management significantly rather than being applied routinely to all indeterminate nodules.