Evidence has confirmed that there are considerable differences between the Western and Asian series, with a much higher prevalence of BRAF V600E in the latter. The prevalence ranges from 32–49% in the United States of America and Europe[21]. In addition, the heterogeneity of the BRAF rate has been addressed in Asian countries and regions, with the highest prevalence in East Asian countries (> 70%), followed by Southeast Asia (57%), and a region encompassing South Asia, Central Asia, and the Middle East (< 50%)[23]. Moreover, the within-country discrepancy has been discovered in China, ranging from 31–87%[24]. Therefore, it is of necessity to verify the role of BRAF V600E in specific population in an effort to adjust medical strategies appropriately rather than simply followed by contemporary international guidelines, which predominantly reflect western perspectives[25]. To our knowledge, We reported the largest prospective study aimed at investigating the BRAF mutation of PTC in homogenous population of Han Chinese, with detailed analyses on its prevalence, diagnostic performance and prognostic value. In our studied cohort, BRAF V600E was highly and predominantly detected in PTCs, which may result in robust sensitivity of diagnosis and solid connection with prognosis.
It is widely recognized that the most effective approach to curbing unnecessary thyroid surgeries involves improving the sensitivity and specificity of diagnosing thyroid nodules[26, 27]. Nikiforov et al.[28] conducted a large prospective study and illustrated that the BRAF test can enhance the accuracy of FNAC, especially in cases of indeterminate lesions, which account for 10–40% of cytological results. We confirmed the molecular test alone had remarkably high specificity of 100%, which implicates BRAF V600E to be one of the decisive drivers in the process of tumorigenesis. Furthermore, the sensitivity is markedly increased due to the elevated prevalence of the BRAF mutation compared to the result reported by Jinih et al.[29], where only 44.5% of thyroid cancers tested positive for the mutation. Especially, BRAF analysis represents a suitable candidate for cytological indeterminate samples, being a cost effective procedure with a high accuracy for PTC with virtually no false-positive results, which can eliminate the need for repeated aspiration, diagnostic hemithyroidectomy and intraoperative pathology consultation. However, the discrepancy of BRAF mutation prevalence limited its potential to substitute FNAC in clinical practice. As proposed by Xing et al. [30], while the BRAF mutation test alone may not suffice as a highly sensitive diagnostic tool for evaluating thyroid nodules in general, all patients with cytologically diagnosed papillary thyroid carcinoma (PTC) should undergo preoperative BRAF mutation testing on their FNA specimens for prognostic purposes.
The association between patient age and the presence of the BRAF mutation has been a subject of controversy[31]. Although Basolo et al.[32] observed an inverse correlation, most investigators found a higher percentage of BRAF alterations in older patients[33, 34]. Our study supported the reciprocal trend and discovered that age was an independent risk factor for the BRAF V600E mutation. A study performed by Yokoyama et al.[35] demonstrated that remodeling of the normal epithelium by numerous driver-mutated clones was an inevitable consequence of normal aging. Consequently, the plausible explanation for this phenomenon could be that neoplastic transformation initiates more frequently in older individuals.
We found a significant and independent negative association between BRAF V600E and HT in PTC patients, aligning with findings from several prior studies[36]. The molecular associations between HT and PTC remain a subject of ongoing investigation[37]. Guerra et al. [38]proposed that the prevalence of the BRAF mutation in patients with HT has been underestimated by a dilution effect on the mutated alleles of infiltrating lymphocytes, which carried wild-type BRAF. Meanwhile, Pessôa-Pereira et al. [39]believed that the molecular circuits linking HT and PTC mostly did not involve the BRAF V600E mutation, but preferably RET/PTC rearrangements.
Both in vitro studies and transgenic models suggest that the BRAF V600E mutation promotes thyroid cancer progression and is associated with invasive thyroid cancer phenotype[40, 41]. While real-world studies exhibit some variability in their findings, a majority highlight a significant association between the BRAF mutation and one or more conventional adverse pathological features of PTC[42–46]. Whereas the study performed by Guo et al. [42] did not identify a significant association in contrast to the prevailing trend. Our investigation, through multivariate analysis, reveals a positive and independent correlation between the BRAF mutation and key indicators of aggressive thyroid cancer, including larger tumor size, extrathyroidal extension, multifocality. To summarize, the BRAF V600E mutation is implicated in several high-risk clinical variables utilized in prognostic staging systems, indicating a heightened likelihood of disease recurrence and a poorer prognosis. In addition, we found the similar conclusion on micro-PTC that BRAF mutation was associated with negative HT, extrathyroidal extension and multifocality, except for age. Moreover, we demonstrated an unfavorable prognostic role of BRAF V600E based on large-sample follow ups for 6 years. The aggressive role and prognostic value of BRAF V600E mutation in PTC can be explained by several molecular mechanisms, including its aberrant regulation of various signaling pathways, such as the MAP kinase pathway, NFkB pathway, and RASSF1A pathway; upregulation of various pro-oncogenic molecules; and downregulation of various tumor suppressor genes in thyroid cancer[47].
However, we could not confirm an independent prognostic role of BRAF V600E due to the lack of survival data, because the follow-up time was short in view of the natural course of thyroid cancer. In view of our results, it seems to be highly recommended to provide closer scrutiny and more intensive treatment to BRAF + patients of thyroid cancers, even of micro-PTCs which are generally biological indolent.