Abstract
Objective
Active surveillance (AS) has been suggested as a management option for low-risk papillary thyroid microcarcinoma (PTMC). However, the currently proposed selection criteria for AS application do not consider various clinical factors. The purpose of this study was to analyze clinical factors related to recurrence that could be confirmed preoperatively in patients who underwent surgery for PTMC and to identify factors worth considering when deciding whether to apply AS.
Materials and methods
Data were collected from patients with PTMC who underwent surgical treatment at Chungnam National University Hospital. A retrospective cohort was established according to the presence or absence of recurrence during the follow-up period. In total, 2717 patients were enrolled, of whom 60 experienced recurrence. Various clinical factors that could be identified before surgery were analyzed.
Results
The relationship between various clinical factors that could be confirmed preoperatively and recurrence was confirmed through Cox regression analysis and Kaplan–Meier curve analysis. BRAF mutation and the tall cell variant were significantly more common in patients with recurrence. In patients aged 55 years or older, the risk of recurrence was lower than in younger patients, while the recurrence-free survival (RFS) rate was higher.
Conclusion
When choosing between surgical treatment or AS in PTMC patients, additional consideration of the patient’s clinical factors, such as age and BRAF mutation status, may be required in addition to the existing criteria.
Introduction
Thyroid cancer is the most common cancer among tumors of endocrine origin. According to the Global Cancer Statistics in 2020, approximately 586,202 people are diagnosed with thyroid cancer each year, and it ranks 11th in incidence among all cancers (1). The majority of thyroid cancers are differentiated thyroid carcinoma, the most common form of which is papillary thyroid carcinoma (2, 3). Since the 1980s, thyroid cancer, particularly papillary thyroid cancer, has been characterized by a rapid increase in incidence and a reduced mortality rate, which is thought to have resulted from the increase in diagnostic sensitivity due to advances in diagnostic technology, including ultrasonography (4, 5). This trend has led to an increase in papillary thyroid microcarcinoma (PTMC), defined as papillary thyroid carcinoma less than 1 cm; accordingly, concerns have been raised regarding overdiagnosis (6, 7). Another characteristic of thyroid cancer is indolent progression. According to the eighth edition of the American Joint Committee on Cancer staging manual, 95% of differentiated thyroid carcinoma patients are diagnosed at stage I or II, for which the 10-year disease-specific survival rates are 99.8% and 88.3%, respectively (8).
The increased incidence of thyroid cancer due to excessive diagnosis, along with advances in the pathophysiological understanding of thyroid cancer, prompted a change in the existing treatment paradigm focusing on surgical treatment. As early as 1993, a management protocol using active surveillance (AS) was attempted for PTMC patients, mainly in Japan. The results of approximately 10 years of follow-up were reported (9, 10), and based on those results, AS was accepted as an effective management protocol given the indolent characteristics of PTMC (11, 12).
Patients with the following clinically high-risk characteristics are excluded from AS: (i) cases with lymphatic metastasis or distant metastasis, (ii) cases with symptoms suggestive of recurrent laryngeal nerve involvement, and (iii) cases where the tumor is attached to the trachea or recurrent laryngeal nerve (13). However, despite excluding patients with these conditions from AS, several papers have reported that 6.7-8% of patients who received AS eventually underwent rescue surgery due to an increase in tumor size and 1–3.8% of patients required surgery due to newly appearing lymph node metastases (9, 10, 14, 15).
In this study, based on clinical factors that can be identified before treatment, we analyzed parameters associated with recurrence among patients who were surgically treated for PTMC. The purpose of this study was to identify additional clinical factors that can affect the prognosis of PTMC and should be considered in order to apply AS more precisely.
Materials and methods
Patients
From January 2005 to April 2021, patients who were diagnosed with PTMC through preoperative fine-needle aspiration biopsy and underwent surgical treatment at the Department of Otolaryngology – Head and Neck Surgery, Chungnam National University Hospital were evaluated. This study was approved by the Institutional Review Board of Chungnam National University Hospital (no. CNUH-2020-04-094). Total thyroidectomy or lobectomy was performed for the treatment of PTMC, and central neck dissection was additionally performed when central neck lymph node metastasis was suspected based on preoperative radiologic findings. In total, 2747 patients were evaluated. Of them, patients who received radioiodine ablation therapy were excluded from the study. In addition, since it is difficult to distinguish between recurrent disease and persistent disease in patients with a follow-up period of less than 2 years, only patients with a follow-up period of 2 years or longer were selected (16). The study ultimately included a total of 2717 PTMC patients, of whom 2657 had no evidence of disease (NED) and 60 experienced recurrence. The median follow-up period was 9.92 (range: 2.29–18.22) years in the NED group and 12.11 (range: 5.26–18.27) years in the recurrence group.
Evaluation parameters
The demographic characteristics (age, sex, body mass index (BMI)) of all patients included in the study were recorded, and the following hematological test values that could be measured before surgical treatment were evaluated: free thyroxine (fT4), thyroid stimulating hormone (TSH), thyroglobulin (Tg), anti-Tg antibody (Ab), and anti-thyroid peroxidase (TPO) Ab. Preoperative ultrasonography was performed on 2424 out of 2717 patients, and data on tumor size and location were collected and evaluated. Preoperative BRAF mutational testing was performed on 311 out of 2717 patients, and data was collected and evaluated. The surgical method and pathological results of surgical specimens were used as parameters for postoperative evaluation. For cell variant, only patients who underwent the corresponding test were analyzed.
Statistical analysis
Categorical variables are expressed as numbers with percentages, and continuous variables are given as mean ± s.d. Correlations between parameters were evaluated using the chi-square test, Fisher’s exact test, independent-sample t-test, and Cox regression analysis. The results of Cox regression analysis are expressed as hazard ratios (HRs) with 95% confidence intervals (CIs). Kaplan–Meier analysis was used to compare the recurrence-free survival (RFS) rate according to the parameters. The threshold for statistical significance was set at P < 0.05. Data were collected and analyzed using SPSS version 20.0 (IBM Corp.).
Results
Differences in basic characteristics, including preoperative clinical parameters and ultrasonographic findings, according to recurrence
A comparison of patient characteristics between the NED group and the recurrence group showed no significant difference except for sex (Table 1). The proportion of women in the recurrence group was 93.3%, which was significantly higher than that in the NED group (P = 0.036). The size and location of the tumor were recorded in 2424 patients who underwent ultrasonography before surgery, and all of these results were confirmed by a radiologist (Table 1). The length of the tumor measured based on ultrasonography was longer in the recurrence group on average, but the difference was not statistically significant. Likewise, no significant difference in recurrence was found according to the location of the tumor in the thyroid lobe.
Baseline characteristics, including preoperative evaluation clinical parameters and ultrasonographic findings.
| Characteristics and parameters | NED group | Recurrence group | P |
|---|---|---|---|
| Total n | 2657 | 60 | |
| Age (years), mean ± s.d. | 54.08 ± 11.59 | 53.42 ± 11.08 | 0.662 |
| <55, n (%) | 1339 (50.4) | 31 (51.7) | |
| ≥55, n (%) | 1318 (49.6) | 29 (48.3) | |
| Sex, n (%) | 0.036 | ||
| Male | 448 (20.3) | 4 (6.7) | |
| Female | 2209 (79.7) | 56 (93.3) | |
| BMI, mean ± s.d. | 24.32 ± 3.73 | 24.03 ± 3.30 | 0.562 |
| Follow-up (years) period, median | 9.92 (2.29-18.22) | 12.11 (5.26-18.27) | – |
| fT4 | 1.25 ± 0.36 | 1.02 ± 0.22 | 0.381 |
| TSH | 2.14 ± 1.60 | 2.25 ± 1.44 | 0.530 |
| Tg | 22.84 ± 248.05 | 21.93 ± 62.86 | 0.993 |
| Anti-Tg Ab | 106.21 ± 729.75 | 106.27 ± 283.58 | 0.999 |
| Anti-TPO Ab | 356.83 ± 2216.23 | 446.48 ± 1529.88 | 0.764 |
| Test for BRAF mutation, n | 299 | 12 | |
| BRAF mutation present, n (%) | 193 (64.5) | 8 (66.7) | 1.000 |
| Ultrasonography performed, n | 2369 | 55 | |
| Sonographic tumor size, cma | 0.65 ± 0.28 | 0.70 ± 0.26 | 0.181 |
| Location, n (%) | |||
| Upper lobe | 387 (16.3) | 10 (18.2) | 0.715 |
| Mid-lobe | 1541 (65.0) | 37 (67.3) | 0.731 |
| Lower lobe | 303 (12.8) | 6 (10.9) | 0.679 |
| Isthmus | 138 (5.8) | 2 (3.6) | 0.768 |
aLongest diameter.
Statistically significant (P < 0.05) values are presented in bold.
Ab, antibody; BMI, body mass index; fT4, free T4; NED, no evidence of disease; Tg, thyroglobulin; TPO, anti-thyroid peroxidase; TSH, thyroid-stimulating hormone.
Univariate and multivariate Cox regression analyses were performed for preoperative clinical parameters and ultrasonographic findings (Table 2). The univariate (P < 0.001) and multivariate (P = 0.002) analysis of preoperative variables demonstrated that the risk of recurrence decreased with age (Table 2). The association with BRAF mutational status was analyzed only among 311 patients who were preoperatively tested by fine-needle aspiration biopsy or core needle biopsy sample; nonetheless, univariate (P = 0.003) and multivariate (P = 0.007) Cox regression analysis showed that the presence of a BRAF mutation significantly increased the risk of recurrence (Table 2). The concordance rate of BRAF mutation between primary and recurrence tissues in patients with recurrence group was 83.3% (10/12) (Supplementary Table 1, see section on supplementary materials given at the end of this article). Ultrasonographic findings did not show significant results in Cox regression analysis, although a tendency was observed for a lower risk of recurrence in tumors located in areas other than the upper lobe (Table 2).
Univariate and multivariate Cox regression analysis of preoperative clinical parameters and ultrasonographic findings for recurrence.
| Characteristics and parameters | Univariate | Multivariate | ||
|---|---|---|---|---|
| HR (95% CI) | P | HR (95% CI) | P | |
| Age | ||||
| <55 | Ref. | Ref. | ||
| ≥55 | 0.33 (0.19–0.59) | <0.001 | 0.30 (0.14–0.65) | 0.002 |
| Sex | ||||
| Male | Ref. | Ref. | ||
| Female | 1.83 (0.66–5.07) | 0.246 | 0 (0) | 0.971 |
| BMI, mean ± s.d. | 1.00 (0.93–1.09) | 0.925 | 1.05 (0.95–1.16) | 0.330 |
| fT4 | 0.52 (0.19–1.37) | 0.187 | 0.58 (0.18–1.90) | 0.370 |
| TSH | 1.01 (0.88–1.16) | 0.869 | 1.00 (0.81–1.24) | 0.989 |
| Tg | 1.00 (1.00–1.00) | 0.462 | 1.01 (1.00–1.01) | 0.054 |
| Anti-Tg Ab | 1.00 (1.00–1.00) | 0.994 | 1.00 (1.00–1.00) | 0.967 |
| Anti-TPO Ab | 1.00 (1.00–1.00) | 0.758 | 1.00 (1.00–1.00) | 0.855 |
| BRAF mutation (%) | 8.73 (2.06–36.98) | 0.003 | 7.47 (1.73–32.21) | 0.007 |
| Ultrasonographic findings | ||||
| Sonographic tumor sizea, cm | 1.32 (0.64–2.78) | 0.450 | 1.23 (0.57–2.64) | 0.601 |
| Location | ||||
| Upper lobe | Ref. | Ref. | ||
| Mid-lobe | 0.99 (0.48–2.05) | 0.978 | 0.99 (0.48–2.05) | 0.976 |
| Lower lobe | 0.73 (0.26–2.04) | 0.544 | 0.73 (0.26–2.04) | 0.547 |
| Isthmus | 0.68 (0.15–3.17) | 0.625 | 0.71 (0.15–3.30) | 0.662 |
aLongest diameter. Statistically significant (P < 0.05) values are presented in bold.
Ab, antibody; BMI, body mass index; CI, confidence interval; fT4, free T4; HR, hazard ratio; NED, no evidence of disease; Tg, thyroglobulin; TPO, anti-thyroid peroxidase; TSH, thyroid-stimulating hormone.
Differences in postoperative evaluation parameters according to recurrence
Parameters related to recurrence were identified according to the surgical method and based on the pathological findings confirmed after surgery by a pathologist. In a comparison according to the surgical method and whether central neck dissection was performed, no significant association with recurrence was found in a simple comparison (Supplementary Table 1). However, univariate Cox regression analysis showed that the risk of recurrence increased significantly when thyroid lobectomy (P = 0.027) or central neck dissection (P < 0.001) was performed (Supplementary Table 2). In addition, the prevalence of pathologically confirmed Hashimoto’s thyroiditis was significantly higher in the recurrence group (P = 0.013) (Supplementary Table 2), but statistical significance was not found in the Cox regression analysis (Supplementary Table 3).
Next, the correlation with recurrence according to the variant cell type of PTMC was analyzed. Regression analysis was performed on 1799 patients whose variant cell type was specified in the pathology report. Compared to classical PTMC, the recurrence rate was significantly higher in patients with tall cell-variant PTMC in univariate (P = 0.008) and multivariate (P = 0.015) analyses (Table 3).
Variant cell type (postoperative pathologic findings) and Cox regression analysis for recurrence.
| Cell type | NED group (n = 1765) | Recurrence group (n = 34) | Univariate | Multivariate | ||
|---|---|---|---|---|---|---|
| HR (95% CI) | P | HR (95% CI) | P | |||
| Classical | 1633 (92.5) | 21 (79.4) | Ref. | Ref. | ||
| Follicular | 70 (4.0) | 5 (1.5) | 1.05 (0.38–2.91) | 0.924 | 1.31 (0.45–3.80) | 0.614 |
| Tall cell | 42 (2.4) | 2 (5.9) | 8.64 (1.77–42.31) | 0.008 | 7.33 (1.48–36.25) | 0.015 |
| Poorly differentiated | 6 (0.3) | 0 (0) | 0 (0) | 0.974 | 0 (0) | 0.989 |
| Others | 14 (0.8) | 0 (0) | 0 (0) | 0.989 | 0 (0) | 0.995 |
CI, confidence interval; HR, hazard ratio; NED, no evidence of disease.
Location of recurrence and RFS rate comparison result
Patients who experienced recurrence were classified into three groups according to the location of recurrence. Fifty-six patients (93.3%) had local recurrence (thyroid bed: 5/56, contralateral lobe or remnant isthmus: 52/56), and regional recurrence (peripheral lymph nodes) was identified in 10 patients (16.7%). No patients had distant metastases, while local and regional metastases were simultaneously confirmed in 6 of 60 patients.
RFS rates were compared through a Kaplan–Meier curve analysis for parameters that showed significant results in the previous analysis. The RFS rate was significantly lower in patients younger than 55 years (P < 0.001) (Fig. 1A). In addition, the RFS rate was significantly lower in the presence of a BRAF mutation (P = 0.001) (Fig. 1B).
Kaplan–Meier curves of recurrence-free survival (RFS). (A) Age, (B) BRAF mutation.
Citation: European Thyroid Journal 12, 6; 10.1530/ETJ-23-0195
Discussion
As AS was first presented as a management option for PTMC (9), many studies have confirmed its legitimacy as a new protocol (17). Therefore, the 2011 Japanese guidelines (11) and the 2015 American Thyroid Association (ATA) guidelines (12) suggest AS as an optional recommendation for PTMC patients. Despite the fairly limited patient selection factors for AS application, the first reported study showed an increase in the size of the tumor in 8% of patients who received AS and new lymph node metastasis in 3.8% (18). Rescue surgery was performed in 16% of patients based on clinical features and patient preferences (18). Since then, several follow-up studies have also reported conversion rates from AS to surgery from 3.5% to 24% (5). In other words, there is no doubt that AS is a reasonable protocol for PTMC management, but more detailed AS patient selection requirements are necessary for more efficient management.
In our study, PTMC patients aged 55 years or older had a significantly lower risk of recurrence in the univariate Cox regression analysis (hazard ratio (HR) =0.33; 95% CI: 0.19–0.59; P < 0.001) and multivariate Cox regression analysis (HR = 0.30; 95% CI: 0.14–0.65; P = 0.002) (Table 2), and older patients also showed a significantly higher RFS (P < 0.001) (Fig. 1B). Of course, age is classically an independent poor prognostic factor in patients with differentiated thyroid carcinoma, but that relationship is based on evaluating the prognosis of patients with all stages. According to the results of a 10-year follow-up of PTMC patients who received AS published by Ito et al., tumor size enlargement and novel lymph node appearance were more common in younger patients (18). In addition, a meta-analysis by Koshkina et al. also found that tumor progression decreased with advancing age (19). These data show similar results to our findings. Therefore, age is one of the important prognostic factors for PTMC patients, and age can be considered when deciding whether to apply AS to PTMC patients.
The location of the tumor within the thyroid lobe can be accurately identified using ultrasonography and conveys important clinical information prior to surgical treatment. According to the second set of results reported after the first application of AS, lateral lymph node metastasis was significantly more common when the tumor was located in the upper region than when the tumor was located in other regions, suggesting that more intensive observation is needed in certain cases (14). Our study did not find a significant relationship with recurrence according to the location of the tumor, but the risk of recurrence was generally lower when the tumor was located in a site other than the upper region (Table 2). The location of the tumor may not be a definitive factor for whether AS is applied, but it might suggest the need to observe certain patients more closely during the AS process.
BRAF is a well-known thyroid cancer-related oncogene, and several studies have revealed that it is associated with disease recurrence and disease-specific mortality (20, 21). Therefore, in the 2015 ATA guidelines, BRAF mutation is reported as a factor that increases the risk of structural disease recurrence by 10–40% compared to wild-type tumors, which is a similar increase in risk to that associated with extrathyroidal extension (12). However, it has not yet been studied whether BRAF mutation is a factor influencing disease progression in PTMC patients (13). Studies have even reported that BRAF mutation did not affect the prognosis, except in high-risk patients (22, 23). In our study, BRAF mutation was identified as a factor that significantly increased the risk of PTMC recurrence in the univariate Cox regression analysis (HR = 8.73; 95% CI: 2.06–36.98; P = 0.003) and multivariate Cox regression analysis (HR = 7.47; 95% CI: 1.73–32.21; P = 0.007) (Table 2). BRAF mutation was also significantly decreased RFS (P = 0.001) (Fig. 1B). However, the reliability of this result is somewhat limited because BRAF mutational status was not routinely tested in all PTMC patients, and only a subset of the study subjects was analyzed. In addition, in this study, the BRAF mutation test was analyzed only in the results confirmed in fine-needle aspiration biopsy or core needle biopsy specimens performed before surgery. In cases where ultrasonography findings and pathological findings through fine-needle aspiration did not match, BRAF mutation tests were performed to confirm and support the diagnosis. Therefore, the inability to rule out the possibility that selective bias occurred is also a limitation of this study. However, if it is difficult to determine whether AS should be applied to PTMC patients, BRAF mutation testing through fine-needle aspiration biopsy can be useful as a factor informing the decision.
In this study, the rate of Hashimoto’s thyroiditis in patients with recurrence was significantly higher in a simple comparison (P = 0.028) (Supplementary Table 2), but it did not show significance in other analysis methods (Supplementary Table 3). According to the studies published to date, the relationship between Hashimoto’s thyroiditis and papillary thyroid carcinoma remains unclear (24, 25, 26). Therefore, this issue needs to be elucidated through extensive prospective studies in the future. Furthermore, recurrence was significantly higher in PTMC patients with the tall cell variant (Table 3). Of course, there are limitations in distinguishing the exact cell variant type of papillary thyroid carcinoma through fine-needle aspiration biopsy or core needle biopsy performed before treatment (27). However, if it is possible to identify the variant cell type at the time of diagnosis with PTMC, the conversion rate to rescue surgery might be reduced. Furthermore, in univariate Cox regression analysis, total thyroidectomy significantly lowered the recurrence rate compared to thyroid lobectomy and the RFS was significantly higher than thyroid lobectomy (Supplementary Table 3 and Supplementary Fig. 1). These results are thought to be related to the reason why the rate of local recurrence (occurrence in the operative bed or the opposite lobe in patients who underwent lobectomy) was relatively high in patients with recurrence. Therefore, if tumor progression occurs during the AS process and the management is converted to surgery, the type of thyroid surgery should be carefully selected.
As described earlier, this study was able to identify the relevance of potential clinical factors that affected recurrence in PTMC patients. Considering the characteristics of PTMC, such as multifocality and bilaterally, there is a possibility that it was a preexisting cancer, as the type of recurrence was significantly higher in the lobe on the contralateral side of the surgery. In this study, to overcome these limitations, patients who relapsed within 2 years were excluded from the study (16). Additionally, when comparing the ultrasonography findings before surgery, only 4 out of 60 patients could not completely rule out the possibility that the recurrence site had already existed (Supplementary Table 1). Additionally, of course, preoperative clinical factors related to recurrence in PTMC patients who underwent surgical treatment are not a direct reason for inducing tumor progression in AS applications. However, since recurrence is an important outcome that determines the prognosis of PTMC, clinical factors related to recurrence will affect the aggressiveness of the tumor. Therefore, if the clinical factors that determine the prognosis of PTMC are additionally considered in the context of AS or surgical treatment decisions, a more sensitive selection can be made. However, large-scale prospective studies are needed to fully elucidate the influence of all these clinical factors on the progression of PTMC.
Conclusion
In conclusion, age and BRAF mutational status can be considered as additional clinical factors that predict the prognosis of PTMC before deciding upon a treatment modality. Therefore, these factors might be useful in patient selection for AS application.
Supplementary materials
This is linked to the online version of the paper at https://doi.org/10.1530/ETJ-23-0195.
Declaration of interest
The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the study reported.
Funding
This work was supported by the Korean Thyroid Association Clinical Research Award 2020, Chungnam National University, the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning (grant number 2022R1C1C1008265), the Patient-Centered Clinical Research Coordinating Center funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HC19C0103) and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HR22C1734)
Statement of ethics
This study was approved by the Institutional Review Board of Chungnam National University Hospital (no. CNUH-2020-04-094). This study is an analytical study based on a retrospective chart review. According to the Institutional Review Board policy of Chungnam National University Hospital, this study was exempted from informed consent for the following two reasons: (i) obtaining the consent of the research subject is practically impossible in the course of the research or seriously affects the validity of the research and (ii) there is no reason to presume the refusal of consent by research subjects, and even if seeking consent is waived, the risk to research subjects because of that is extremely low.
Author contribution statement
The study reported in the paper has been carried out by the authors, unless clearly specified otherwise in the text. HRW contributed to conception, design, data acquisition, and interpretation, drafted and critically revised the manuscript; MGK contributed to data acquisition and analysis during the revision process; MSK and JWC contributed to data acquisition; BSK contributed to conception and critically revised the manuscript. All authors gave final approval and agree to be accountable for all aspects of the work.
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