According to the conventional perspective on the pathogenesis of thyroid carcinoma, these lesions develop owing to the accumulation of mutations, which propel progression through an initial dedifferentiation process that results in the formation of well-differentiated carcinomas, namely papillary and follicular carcinomas [17]. Several genetic alterations contributing to most subtypes of thyroid carcinoma have been identified. These alterations predominantly affect the components of the principal oncogenic pathways, such as the MAPK and PI3K/AKT pathways, which are involved in signal transduction from receptor tyrosine kinases. Thus, these pathways play a crucial role in cell survival and proliferation and are primarily regulated by external growth factors supplied by the surrounding cells. Genetic mutations result in the dysregulated activation of these pathways, leading to tumor formation [18]. Activation of the MAPK pathway plays a key role in the development of PTC and involves BRAF mutations, RET rearrangements, and NTRK fusion genes [19].

The binding of RET to another gene via chromosomal rearrangements leads to RET rearrangements, yielding several types of RET rearrangements depending on the partner gene. Over 30 types have been reported to date. RET/PTC1 (CCDC6-RET) and RET/PCT3 (NCOA4-RET) account for 90% of RET rearrangements in patients with PTC [20,21,22,23,24,25]. Recent clinical data suggest a positivity rate of 10–20% [11, 26], with some recent reports indicating a decline in prevalence [27]. A large cohort study published in 2014 reported a prevalence rate of 6.8% [12]. RET rearrangements were observed in eight of the 80 patients (10%) in the present study, which is consistent with the findings of previous reports. In our study, a significant difference in the clinical characteristics was observed with respect to younger age, an increased number of multifocal lesions distant metastasis and decreased 18F-FDG uptake. Significant differences in age, multifocal lesions, and distant metastasis were consistent with previous reports [14, 28, 29]. On the other hand, no correlations with, lymph node metastasis, or extrathyroidal extension were observed, as reported in previous studies. This may be attributed to the small number of cases. Moreover, the iodine uptake rate could not be evaluated comprehensively owing to insufficient data. No previous study has investigated the association between 18F-FDG uptake and RET rearrangements. A study on the diagnostic efficacy of 18F-FDG-positron emission tomography (PET)/computed tomography (CT) for recurrent medullary carcinoma reported a sensitivity and specificity of 17–95% and 68–100%, respectively, which limited the utility of 18F-FDG-PET/CT [30, 31]. As discussed below, the mechanism of 18F-FDG accumulation is complex and further research is needed to elucidate it.

T1799A transversion mutation in exon 15, which results in the substitution of valine at position 600 with glutamic acid (BRAFV600E), is the most commonly observed BRAF mutation in thyroid carcinoma. This substitution activates BRAF, which subsequently activates the MAPK pathway [32, 33]. BRAF mutations have been detected in 29–83% of cases of PTC [34,35,36]. BRAF mutation is associated with extrathyroidal extension, advanced TNM stage, lymph node metastasis, multifocality, and recurrence [37,38,39,40]. The prevalence of BRAF mutations was 78.6% in the present study, which is consistent with the findings of previous studies [41, 42]. BRAF mutations are associated with an increase in the number of unifocal lesions and elevated 18F-FDG uptake. The findings pertaining to the unifocal lesions contradicted those of previous reports.　Many previous studies focused on cases where total thyroidectomy was performed. In this study, partial thyroidectomy accounted for 70% of the cases, which may have influenced the results [43, 44].

There are studies suggesting that BRAF mutations influence the increase in 18F-FDG uptake. Generally, FDG uptake is correlated with the expression of GLUT1, and the MAPK pathway promotes the expression of GLUT1. Therefore, it has been considered that FDG uptake increases in BRAF mutation-positive PTC. However, there are also reports suggesting that GLUT1 expression does not correlate with FDG accumulation, and other reports indicate an association with GLUT3, GLUT4, HIF1α, and YAP signaling. Additionally, BRAF mutations have been suggested to be associated with increased expression of HIF1α. Thus, the mechanisms of FDG accumulation in tumor tissues are not yet fully understood, and further research is needed [45,46,47,48,49].

The role of genetic testing in thyroid carcinoma is considered complementary. Next-generation sequencing methods can be used to detect gene mutations; however, the prognosis for many patients with PTC is favorable. A consensus regarding when and in which cases genetic testing should be conducted remains to be established. The 2015 ATA Guidelines recommend confirming the presence of genetic mutations (BRAF, RET/PTC, RAS, PAX8/PPARγ) in cases that are difficult to differentiate or assess via cytological examinations [50]. The 2023 NCCN guidelines recommend conducting genetic testing for patients with anaplastic thyroid carcinoma when considering treatment. A combination therapy of a BRAF inhibitor (dabrafenib) and MEK inhibitor (trametinib) or RET inhibitors (selpercatinib or pralsetinib) is recommended based on the mutation detected [51]. Studies are also underway to expand the indications of these molecular-targeted drugs for the treatment of PTC [52, 53].

The present study investigated the prevalence of BRAF mutations and RET rearrangements in PTC, as well as the clinical characteristics contributing to the treatment algorithm. There was an increase in distant metastasis cases in the RET rearrangement group, but this did not affect stage. No significant associations were observed between the presence of genetic mutations and other factors such as TN stage elevation or thyroid gland invasion that could be incorporated into risk classification or treatment algorithms for thyroid carcinoma. Furthermore, specific features that warranted genetic testing could not be identified. Genetic mutations may not be directly associated with malignancy; however, the combined prevalence of BRAF mutations and RET rearrangements was high (87.5%), indicating that cases with genetic mutations targeted by molecular-targeted drugs exist widely, regardless of the clinical stage. Thus, genetic testing should be performed whenever possible, particularly when treating patients with recurrent metastases. The importance of genetic mutations is expected to increase and their application in treatment will further advance as genetic testing becomes more widespread.