INTRODUCTION

Active surveillance is a treatment option for slow-growing malignancies that involves avoiding or delaying conventional treatment, such as surgery, chemotherapy, or radiation therapy, that may cause other side effects [1]. Regarding thyroid cancer, Miyauchi and colleagues initially implemented active surveillance in 1993 [2]. Subsequently, this alternative option has been supported by numerous studies and incorporated into clinical guidelines since 2011 [3].

The definition of low-risk thyroid cancer for which active surveillance can be considered varies across studies; however, active surveillance could be selectively recommended for papillary thyroid cancer (PTC) measuring less than 1 cm, without significant extra-thyroidal extension or clinical lymph node metastasis [4]. Although surgical risk, patient comorbidities, and limited life expectancy are potential reasons for choosing active surveillance, most patients require a thorough assessment of additional clinical factors associated with cancer progression [5].

The BRAF V600E mutation (BRAF mutation) is known to occur early in the progression of PTC, and it is the most common genetic alteration in thyroid cancer, occurring in approximately half of patients with PTC [6]. In previous studies in which surgical outcome was examined, BRAF mutation was associated with aggressive characteristics [7], the risk of recurrence [8], and higher death rates [9]. However, evidence indicating the clinical impact of BRAF mutation in active surveillance remains limited.

This study investigated tumor volume doubling time (TVDT) during active surveillance of PTC and presents the novel finding that BRAF mutation predicts rapid tumor growth during active surveillance.

METHODS

Study setting

This cohort study included patients with PTC who were managed with active surveillance at a tertiary referral center in Korea. Clinical and imaging data were obtained through retrospective review of medical records. Patients who postponed surgery for more than 1 year after being diagnosed with PTC by fine needle aspiration cytology (Bethesda category V and VI) were screened. Among a total of 130 patients, those with a maximal tumor diameter of 1 cm or more at first diagnosis (n=3) and subjects in which BRAF mutation testing was not performed (n=42) were excluded. The study cohort (n=85) was enrolled from 2014 to 2021, and followed until 2023. The median observation time was 4.4 years.

Patients were informed of the option of active surveillance at the time of diagnosis and voluntarily agreed to defer surgical treatment. Throughout the study period, all counseling and discussions regarding active surveillance were conducted by a single endocrinologist (K.H.B.), ensuring consistency in patient education and clinical decision-making. This approach minimized inter-physician variability, although it may limit the generalizability of the findings. The study protocol was approved by the Institutional Review Board of Yeouido St. Mary’s Hospital (Study number SC23RISI0217). Written informed consent by the patients was waived due to a retrospective nature of our study.

Measurements

TVDT was calculated using tumor size measurements obtained from three or more serial ultrasound examinations, entered into a calculator developed at Kuma Hospital in Japan [10]. All ultrasound imaging characteristics, including tumor size measurements and serial changes of PTC were reviewed by a board-certified radiologist (M.K.L.).

BRAF mutation was detected using real-time polymerase chain reaction with a commercial kit (Cobas 4800 BRAF V600 Mutation Test, Roche Diagnostics, Basel, Switzerland). The assay was performed using fine needle aspiration cytology (n=69), core needle biopsy (n=9), or surgical specimen (n=7).

Statistical analysis

For descriptive statistics, continuous variables were described using median and interquartile range, and categorical variables were described using numbers and percentages. For comparisons between groups, continuous variables were analyzed using the Mann–Whitney U test or the Kruskal–Wallis test, as appropriate, while categorical variables were compared using Fisher’s exact test. A multivariable Cox proportional hazards model was used to analyze time to delayed surgery and to identify clinical factors associated with delayed surgery. Based on the calculated TVDT, patients were classified into rapid-growing disease if less than 5 years, slow-growing disease if between 5 and 10 years, and stable disease if more than 10 years. To analyze predictive factors for tumor progression, multinomial logistic regression analysis was performed for the three TVDT groups. Statistical analysis was performed using R software version 4.4.1 (The R project for statistical computing, Vienna, Austria).

RESULTS

Baseline characteristics

A total of 85 patients were analyzed, the median age was 49 years, and 74% were female (Table 1). The positivity rate for BRAF mutation was 51% in the study cohort. Patients were followed for a median of 4.4 years, and 23 patients (27%) underwent surgery after a median time of 3.2 years. Lymph node metastasis was identified in six patients (26%) who underwent surgery.

Doubling rate in the study cohort

Patients with rapid-growing disease accounted for 19% of the study subjects (Table 2). The waterfall plot illustrated the doubling rate percentage (per year) of each patient based on the TVDT calculation. In more than half of the patients, tumor size decreased or remained stable (Fig. 1).

Clinical outcomes

At baseline, patients who subsequently underwent surgery were younger and had a larger tumor diameter compared with those who remained under active surveillance (Supplemental Table S1). When time to surgery was taken into account, multivariable Cox-regression analysis demonstrated that rapid tumor growth and larger baseline tumor size were independently associated with an increased risk of surgery (Fig. 2).

Clinical variables associated with tumor volume doubling time

To evaluate factors associated with tumor progression, multinomial logistic regression was performed across the three TVDT groups (Table 3). BRAF mutation was significantly associated with the rapid-growing TVDT group. In complementary binary logistic regression analyses, the presence of microcalcifications on ultrasound was associated with tumor growth.

No significant interaction was observed between BRAF mutation and age (stratified at the median) with respect to rapid-growing disease, indicating that the association between BRAF mutation and tumor progression was consistent across age groups. This association remained robust in sensitivity analyses using alternative cut-offs for age and baseline tumor size (Supplemental Table S2).

DISCUSSION

In the present study, we analyzed 85 patients with papillary thyroid microcarcinoma (PTMC) who were managed with active surveillance for several years rather than undergoing immediate surgery; the median age was 49 years, and 63 patients (74%) were female. The patients were followed for a median time of 4.4 years; 23 (27%) patients underwent surgery after a median time of 3.2 years. Lymph node metastasis was identified in six patients (26%) among the patient group who underwent delayed surgery. When TVDT groups were analyzed using multivariable logistic regression, BRAF mutation was associated with rapid-growing disease (P<0.05).

Active surveillance is being considered as a safe option for PTMC; however, ongoing discussions are needed regarding the selection of target patients and long-term safety [11]. Primary tumor size may be the first characteristic considered. In most studies, the maximum tumor diameter was limited to 1 cm, although studies including larger tumors have also been conducted [12]. Due to the possibility of invasion into surrounding structures, tumor location must also be considered. Locations close to the trachea or the dorsal surface of the thyroid near the recurrent laryngeal nerve may be inappropriate for delaying surgery [13]. In addition, when selecting candidates for active surveillance, tumor size and location should be considered as interrelated factors [14]. In a large cohort of low-risk PTMC patients who underwent immediate surgery, tumors measuring ≥7 mm were reported to have a higher risk of invasion into the trachea or the recurrent laryngeal nerve [15]. Accordingly, a tumor size of 7 mm was adopted as a dichotomous cut-off for statistical analysis in the present study to facilitate clinical interpretation.

In fact, patients with a baseline tumor diameter of 0.7 cm or greater, as well as those with rapidly growing disease, were more likely to undergo surgery during follow-up in this cohort. Although patient counseling and management decisions were conducted by a single physician, potentially limiting generalizability, the factors associated with delayed surgery and tumor progression identified may reflect commonly applied clinical considerations in the active surveillance of PTC.

Given the retrospective design and the resulting variability in sonographic follow-up intervals, TVDT was introduced as a quantitative measure of tumor growth. TVDT is calculated using regression analysis as the time required for tumor volume to double, and this metric has been proposed as a quantitative measure of tumor growth [16]. TVDT is considered to more sensitively assess the increase in tumor size than measurement of the longest diameter, and researchers have previously validated TVDT for evaluating tumor progression in active surveillance of PTC [17]. In particular, TVDT of less than 5 years is significantly associated with lymph node metastasis, and this is considered a useful prognostic value for active surveillance [18].

BRAF mutation is the most commonly identified genetic marker for PTC, with a prevalence of 70% to 80% reported in previous Korean studies that primarily analyzed surgical specimens [19,20]. In the present cohort, the overall prevalence of BRAF mutation was approximately 50%. This difference may be attributable, at least in part, to differences in testing approaches, as BRAF mutation analysis in this study was performed predominantly using fine needle aspiration cytology, whereas surgical specimen-based analysis was available in only a subset of patients. Consistent with this, a previous study using fine needle aspiration cytology reported a BRAF positivity rate of 43% [21,22]. Moreover, given the invasive nature of surgical treatment for thyroid nodules, patients who ultimately underwent surgery may have represented a subgroup with more rapidly growing or clinically concerning tumors. In this context, a higher prevalence of BRAF mutation (78%) was observed in the surgery group (Supplemental Table S1).

Prior studies have yielded conflicting results regarding the prognostic significance of BRAF mutation in PTMC. Several studies focusing on tumors measuring 1 cm or less in maximum diameter reported no significant association between BRAF mutation and disease progression [23,24], whereas a recent meta-analysis demonstrated a significant association between BRAF mutation and aggressive clinicopathological features in PTMC [23]. Taken together, these findings indicate that the prognostic role of BRAF mutation in PTMC remains controversial.

Evidence addressing the prognostic relevance of genetic mutations is even more limited in the setting of active surveillance. Previous studies have suggested that genetic factors, including BRAF mutation, were not significantly associated with disease progression; however, these analyses were frequently constrained by small sample sizes [20], restriction to surgical cohorts [25], or a low number of progression events [26]. Consequently, the clinical significance of genetic mutations during active surveillance for PTMC has not been clearly established.

In this context, the present study addresses this gap by applying TVDT as a quantitative measure of tumor growth kinetics, demonstrating an association between BRAF mutation status and rapid tumor growth during active surveillance. In our study cohort, BRAF mutation was significantly associated with tumor growth in PTMC. Given the established association between BRAF mutation and advanced anatomical stages in surgically treated patients [19], it is plausible that tumors harboring BRAF mutations exhibit faster growth during active surveillance. Although BRAF mutation alone is insufficient to predict tumor progression [27], it may represent an important clinical factor to consider in the risk stratification of patients undergoing active surveillance for thyroid cancer.

In the present study as well, four patients without BRAF mutation showed rapid tumor growth during active surveillance, underscoring that BRAF mutation status alone does not fully explain the heterogeneous growth patterns observed in PTC. A substantial proportion of BRAF-negative papillary thyroid carcinomas are driven by RAS-related pathways and have traditionally been considered indolent; however, accumulating evidence indicates that a subset of these tumors—particularly those with a follicular growth pattern—may exhibit invasive behavior and unexpected tumor growth during active surveillance. Moreover, other genetic alterations, including telomerase reverse transcriptase (TERT) promoter mutations and gene fusions involving rearranged during transfection (RET), neurotrophic tyrosine receptor kinase (NTRK), or anaplastic lymphoma kinase (ALK), have been implicated in rapid tumor growth or invasive features in thyroid cancer [28–30]. Genomic instability and copy number alterations may further contribute to tumor progression independent of BRAF mutation status [31].

Previous studies have reported an association between younger age and rapid tumor growth in active surveillance cohorts [32,33]. Moreover, immediate surgery has been suggested to be more cost-effective in younger patients, given the longer duration of surveillance required after diagnosis [34]. However, in the present study, patient age was not significantly correlated with TVDT. At the time this study was conducted, it was already recognized that younger individuals tended to show more rapid disease progression during active surveillance of PTC; consequently, younger patients were less likely to be selected for active surveillance. Notably, the median age of our study cohort was 49 years, which is older than the reported average age at diagnosis of thyroid cancer in Korea (approximately 40 years) [35]. In addition, the BRAF mutation-positive group was significantly younger at baseline, raising the possibility of age-related confounding. Accordingly, interaction analyses between age and BRAF mutation status were performed, but no statistically significant interaction was observed, indicating that the association between BRAF mutation and tumor growth was not modified by patient age.

In addition to genetic factors, sonographic features have been explored as phenotypic markers of tumor aggressiveness. Various sonographic features have been investigated as predictors of rapid tumor growth in PTC. Calcifications and increased vascularity have been suggested to be associated with tumor growth [36,37]. In cancer tissues, calcification may arise from dystrophic changes or necrosis related to cellular proliferation [38]. Based on the classification system for the diagnosis of thyroid cancer, calcification is divided into macrocalcification and microcalcification, and the red flag for the diagnosis of PTC is microcalcification [39]. Therefore, we attempted to analyze these patterns separately. Based on the results of the present study, microcalcification found on ultrasound images of PTC may indicate an aggressive nature.

This study has several limitations. First, as this was a retrospective, single-center study, the generalizability of the findings is limited, and the possibility of selection bias cannot be completely excluded. In particular, the relatively small number of patients may have limited the statistical power of the analyses and constrained the interpretation of the results. Second, BRAF mutation testing was not uniformly performed at baseline, and in a subset of patients, mutation status was determined only after delayed surgery using surgical specimens. Third, the regression model used to calculate TVDT was based on the assumption of exponential tumor growth over time. However, the natural course of thyroid cancer may not follow a strictly linear or exponential pattern and may remain stable or even decrease in some cases [40,41]. Finally, only BRAF mutation status was evaluated in this study, and other potentially relevant genetic alterations were not systematically assessed. Several studies have suggested that the coexistence of BRAF mutation with additional genetic alterations, particularly TERT promoter mutations, may confer a higher risk of aggressive behavior and unfavorable outcomes in PTC [42,43]. Accordingly, the absence of comprehensive molecular profiling represents a limitation in understanding the genetic determinants of PTC [44].

In conclusion, BRAF mutation is presumed to be associated with tumor progression and may help predict growth of PTMC. Although the routine application of genetic analysis in low-risk thyroid cancer remains controversial because of cost and feasibility considerations, we suggest that genetic profiling, including BRAF mutation testing, may help identify thyroid cancers at increased risk of rapid growth.

Supplementary Material

Article information

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

ACKNOWLEDGMENTS

This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education (RS-2023-00245534). A part of this study was presented at the 12th Seoul International Congress of Endocrinology and Metabolism in Seoul, Korea, and the 46th annual meeting of the European Thyroid Association in Athens, Greece.

AUTHOR CONTRIBUTIONS

Conception or design: J.K., K.H.B. Acquisition, analysis, or interpretation of data: J.K., M.K.L., T.J.K., K.H.B. Drafting the work or revising: J.K., D.J.L. Final approval of the manuscript: J.K., M.K.L., T.J.K., D.J.L., K.H.B.

Fig. 1

Waterfall plot for tumor volume doubling rate (%) per year. The change in tumor volume for each patient was expressed as doubling rate per year (percentage). Tumor volume doubling rates were sorted in ascending order, and patients indicated on the right were considered to have shown tumor progression. The bar graph was colored differently depending on BRAF mutation status.

Fig. 2

Multivariable Cox-regression for the delayed surgery as clinical outcomes. Hazard ratios (HRs) were estimated using multivariable Cox proportional hazards regression adjusted for age group, sex, tumor size group, and tumor volume doubling time (TVDT) groups. Reference categories were age ≥50 years, female sex, tumor size <0.7 cm, and the stable disease. CI, confidence interval.

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