Response to Kakudo et al.: “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”

Dear Editor:

We write in reply to a letter to the editor by Kakudo et al., ¹ regarding our recent publication in Thyroid. ² We are glad that our publication has aroused discussion on the topic of molecular tests (MT) for indeterminate thyroid nodules amongst Asian countries. This highlights the need for more research on this important agenda in the region, which is currently lacking.

In line with the practice in Asian countries, our center adopted a more conservative approach than North America (51.3% surgery rate) in managing indeterminate thyroid nodules. We had a lower upfront surgery rate of 36% and a high rate of repeat FNAC (42%) and conservative approach (22%). Knowing the differences in real-world practice between Asia and North America (see supplementary Table 1 of the original article), we conducted the current study to examine the role of MT in an Asian setting. We understand that the results of cost-effectiveness studies vary with different local health policies and are therefore never entirely generalizable. Nevertheless, we hope to take the initiative to explore the role of MT in Asia utilizing real-world data from our center, because evidence on MT in this locality is particularly lacking.

We acknowledge the limitations of MT on classifying non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) as suspicious, hence leading to unnecessary surgery. However, the reported prevalence of NIFTP is lower among Asian countries. ³ In fact, within our cohort, there was only 1 (0.77%) patient with a final pathology of NIFTP amongst the 130 patients who received surgery. While limitations from NIFTP on MT exist, its potential influence is low in our setting. We fully agree with you that validated local data on MT performances would be important, and we call for your support on this matter.

In our practice, nodules <1 cm are seldom biopsied. Therefore, in our study, all the nodules classified as Bethesda III or IV were >1 cm in diameter, and the majority (64.2%) were of TIRADS category 3 or above. In other words, these nodules were not entirely discernible as benign by clinical factors. We agree that currently available MTs are not perfect, and false positive results could still lead to unnecessary surgeries. Knowing the limitations of MT, we find it crucial to assess its effectiveness in an Asian, low surgery rate setting. We found that, despite our lower surgery rate and the known limitations of MT, routine MT could reduce more unnecessary surgeries than our current practice. We further examined the role of routine MT based on limited literature describing clinical practices in Japan, which has an even lower surgery rate and higher cancer rate, with a similar conclusion that more unnecessary surgeries could be avoided by MT. Although routine MT is more effective, it is associated with considerable cost, and therefore it is important to address its cost-effectiveness in Asia.

In regard to high-risk indeterminate nodules (e.g., highly suspicious sonographic features), we prefer to proceed with surgery (rather than avoiding) since we acknowledge the importance of clinical judgment and the limitations of MT.