Clinical Outcomes of Follicular Thyroid Carcinoma Did Not Significantly Differ according to Tumor Size in an Iodine-Excessive Country
Article information
Abstract
Background
Follicular thyroid carcinoma (FTC) measuring <2 cm is generally associated with good prognosis, while tumor size ≥4 cm is regarded as being associated with a poor prognosis. This study aimed to evaluate FTC prognosis by tumor size to investigate whether the 2- and 4-cm criteria are appropriate for assessing prognosis.
Methods
Data of 248 patients with FTC diagnosed between August 1995 and June 2021 were retrospectively analyzed. The population was divided into four groups according to tumor size: <2.0, 2.0–3.9, 4.0–5.9, and ≥6.0 cm. Distant metastasis (DM), recurrence and/or structural persistence (R/SP), cancer-specific death (CSD), and frequency of telomerase reverse transcriptase (TERT) promoter mutations based on tumor size were evaluated.
Results
While the rates of DM, R/SP, and CSD and the frequency of TERT promoter mutations did not differ among the size groups <6 cm, they increase sharply in tumor size ≥6 cm, although statistically insignificant (P=0.608, P=0.248, P=0.089, and P=0.165 respectively). Widely invasive subtypes, and TERT promoter mutations were significantly associated with DM (P=0.009 and P<0.001, respectively). Age ≥55 years, gross extrathyroidal extension, synchronous DM, and TERT promoter mutation were independent risk factors for CSD (P=0.005, P=0.003, P<0.001, and P=0.002, respectively).
Conclusion
DM, R/SP, CSD, and TERT promoter mutations were not uncommon in FTCs <2 cm compared to those in larger FTCs, whereas FTCs ≥6 cm showed a sharp decline in prognosis, although this was statistically insignificant.
INTRODUCTION
Follicular thyroid carcinoma (FTC) is the second most common subtype of thyroid cancer after papillary thyroid carcinoma (PTC), accounting for 10% to 15% of all thyroid cancers in Western countries [1]. In Korea, an iodine-excessive country, FTC accounts for 1.7% of all thyroid cancers [2].
FTC has a lower frequency of lymph node metastasis but higher rates of distant metastasis (DM) and cancer-specific death (CSD) than does PTC [3-5]. Nevertheless, several guidelines have emphasized the good prognosis of FTCs <2 cm. According to the 2015 American Thyroid Association (ATA) guidelines for thyroid nodules and differentiated thyroid cancer, fine-needle aspiration cytology (FNAC) for tumors suspected as follicular neoplasms is recommended for nodules ≥2 cm because DM is rare in tumors <2 cm [6]. Additionally, the recommendations and guidelines of the 2021 Korean Thyroid Imaging Reporting and Data System suggest an increased risk of DM for tumors >2 cm and state that the risk of local invasion, lymph node metastasis, and DM increases with tumor size [7].
The 2023 Korean Thyroid Association guidelines for patients with thyroid nodules recommend surgical excision for tumors ≥2 cm suspected as follicular neoplasms, as these tumors have a higher risk of malignancy, with malignancy rates of 35.2% in tumors ≥2 cm and 24.5% in tumors <2 cm [8]. Given that the malignancy risk is not low in tumors <2 cm, the criteria for surgical excision should be based not only on the malignancy rate but also on the prognosis of small-sized FTCs.
Compared with PTC, FTC often lacks distinguishable suspicious ultrasonographic features, making it difficult to diagnose with ultrasonography. Furthermore, the cytological and pathological samples acquired via fine-needle aspiration or core-needle biopsy cannot distinguish follicular adenoma from FTC, unless surgical resection is performed. Owing to these difficulties, the diagnosis and treatment of small-sized FTCs are often delayed [9,10]. Therefore, a more cautious approach for small-sized FTC is required.
On the other hand, several guidelines have suggested a tumor size of 4 cm as the threshold for poor prognosis. In the American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) 8th edition staging, tumors larger than 4 cm are classified as pT3a and clinical stage group II in patients ≥55 years [11]. Furthermore, the ATA management guidelines for differentiated thyroid cancer recommend near-total or total thyroidectomy for differentiated thyroid carcinoma (DTC) patient with a tumor size >4 cm [6].
In this study, we analyzed prognosis of FTC by tumor size to investigate whether tumor size criteria of 2 cm for good prognosis and 4 cm for poor prognosis are appropriate. Only few previous studies have investigated DM in small-sized FTCs, and research on prognosis other than DM remains lacking. Moreover, most studies on size factors predicting poor prognosis have suggested 4 cm as the threshold, and there are no studies based on different tumor size criteria associated with poor prognosis.
Therefore, the current study aimed (1) to analyze the prognosis of FTC by tumor size to investigate whether the 2- and 4-cm cutoff values are an appropriate for assessing prognosis, including DM, recurrence and/or structural persistence (R/SP), and CSD, and (2) to examine the frequency and clinical outcomes of patients with FTC with telomerase reverse transcriptase (TERT) promoter mutations, which are associated with poor survival.
METHODS
Patients
Data of 248 patients diagnosed with FTC based on pathology after surgery between August 1995 and June 2021 at Samsung Medical Center (Seoul, Korea) were retrospectively analyzed. All surgical specimens were classified according to the fifth edition of the World Health Organization (WHO) histologic classification of thyroid neoplasms released in 2022 [12], and oncocytic thyroid carcinoma and differentiated high-grade thyroid carcinoma were excluded from this study. Patients with a follow-up period of less than 2 years from the time of diagnosis were excluded, as a minimum follow-up period of 2 years was deemed necessary to assess the prognosis of FTC. However, patients who died from FTC within 2 years of diagnosis were included, as their early mortality itself serves as a prognostic indicator reflecting the aggressive nature of the disease. Among all FTC patients diagnosed between August 1995 and June 2021 at our center, there was only one patient who died from FTC within the 2-year follow-up period, specifically at 18 months. This patient was included in the study. The study protocol was approved by the Institutional Review Board of Samsung Medical Center (IRB no. 2023-11-043-001). Requirement for obtaining informed consent was waived due to the retrospective nature of this study.
Additional analysis was performed to investigate the association between FTC prognosis and TERT promoter mutation status in 160 patients with information on their TERT promoter mutation status. Since 2019, TERT promoter mutation testing has been performed at our center for all patients diagnosed with FTC, regardless of their risk of recurrence. For patients diagnosed with FTC before 2019, TERT promoter mutation testing was performed retrospectively if their DNA samples were available. TERT promoter mutations were assessed using semi-nested polymerase chain reaction and direct Sanger sequencing (chr5:1,295,228C>T and chr5:1,295,250C>T, commonly termed C228T and C250T, respectively).
Management and follow-up
The extent of surgery followed the guideline recommendations, and radioactive iodine (RAI) therapy was administered based on the risk of recurrence. Generally, diagnostic surgery is not recommended for FTCs <2 cm. However, surgical resection was performed in 53 patients with tumors <2 cm under the following circumstances: (1) 25 (47.2%) patients had tumors that measured nearly 2 cm or larger on ultrasonography and were confirmed as follicular neoplasms via FNAC; (2) 12 (22.6%) patients had FTCs that were discovered incidentally after surgery for a different accompanying thyroid mass, such as a PTC or huge benign nodule; (3) eight (15.1%) patients underwent surgery because PTC could not be excluded based on ultrasonography and FNAC; (4) five (9.4%) patients had bone and/or lung metastases identified before surgery; and (5) three (5.7%) patients underwent surgery because of an abrupt increase in tumor size or the patients’ preference. Notably, nine out of 12 patients with coexisting masses were identified as having PTC; however, none of them experienced DM, R/SP, or CSD, indicating that the presence of coexisting PTC did not affect their prognosis.
Patients were followed up at the outpatient clinic every 3 to 6 months. Serum thyroglobulin (Tg) test, anti-Tg antibody test, and thyroid sonography were conducted during follow-up. Chest computed tomography, diagnostic I-131, 99mtechnetium whole-body bone scintigraphy, and 18F-fluorodeoxyglucose positron emission tomography were performed in patients with evidence of recurrence. 88 (35.5%) patients underwent lobectomy, while 160 (64.5%) patients underwent total thyroidectomy, followed by thyroid-stimulating hormone (TSH) suppression therapy. The target TSH level was determined according to dynamic risk stratification. Localized bone metastases were treated surgically, whereas multifocal distant metastases were treated with RAI therapy. In cases of continuous disease progression, tyrosine kinase inhibitors, such as sorafenib or lenvatinib, were administered.
Clinical data were obtained by reviewing the electronic medical record system, and survival status and cause of death were determined from electronic medical records or the Korean Statistical Information Service (KOSIS).
Statistical analysis
Continuous and categorical variables are presented as mean±standard deviation and numbers with percentages, respectively. Linear-by-linear association was used to analyze the P for trend for categorical variables, and Spearman’s correlation analysis was performed for continuous variables. A Cox regression analysis was conducted to analyze the factors associated with CSD. Binary logistic regression was used to assess the factors associated with DM. Two-sided P values <0.05 were considered statistically significant. Statistical analysis was performed using SPSS version 28.0 for Windows (IBM Corp., Armonk, NY, USA).
RESULTS
Baseline characteristics
The baseline clinicopathological characteristics of the 248 patients are summarized in Table 1. The mean patient age was 46.1±15.2 years, with women accounting for 78.2% (n=194) of patients. The mean tumor size was 3.4±1.9 cm (range, 0.4 to 12.0), with the tumors measuring <2 cm in 53 patients (21.4%). Distant metastases (synchronous or metachronous) were observed in 40 patients (16.1%). Total thyroidectomies and lobectomies were performed in 160 (64.5%) and 88 (35.5%) patients, respectively. RAI therapy was administered to 153 (61.7%) patients. According to the WHO classification, 121 patients (48.8%) had the minimally invasive subtype, whereas 81 (32.7%) and 46 (18.5%) patients had the encapsulated angioinvasive and widely invasive subtypes, respectively. According to the AJCC/tumor node metastasis (TNM) staging manual, 8th edition, 221 patients (89.1%) had stage I and II disease, whereas 27 patients (10.9%) had stage III and IV disease. The median follow-up period after the initial surgery was 107 months (range, 18 to 339).
Baseline Clinicopathological Characteristics of 248 Patients with Follicular Thyroid Carcinoma
Clinicopathological features of patients according to tumor size
The clinicopathological features of patients according to tumor size are shown in Table 2. The study population was divided into four groups based on tumor size: <2.0, 2.0–3.9, 4.0–5.9, and ≥6.0 cm. No significant difference in age was observed according to the tumor size. The proportion of males and widely invasive subtypes significantly increased with an increase in tumor size, whereas that of the minimally invasive subtype decreased (P<0.001). Additionally, as the tumor size increases, the proportion of tumors with vascular invasion also increases (P<0.001). As tumor size increased, the frequency of total thyroidectomy and RAI therapy increased, indicating a more aggressive treatment approach (P=0.002).
Clinicopathological Characteristics of 248 Patients with Follicular Thyroid Carcinoma according to Tumor Size
However, no significant difference in prognosis was observed according to tumor size. DM began to occur when the tumor size was 1 cm, which remained similar till the tumor size was <6 cm (13.2% for <2.0 cm vs. 17.9% for 2.0–3.9 cm vs. 13.1% for 4.0–5.9 cm); however, their detection sharply increased when the tumor size exceeded 6.0 cm (22.7%) (P for trend=0.608). R/SP increased slightly as the tumor size increased, and a sharp increase was observed with tumors ≥6.0 cm (11.3% for <2.0 cm vs. 16.1% for 2.0–3.9 cm vs. 16.4% for 4.0–5.9 cm vs. 22.7% for ≥6.0 cm, P for trend=0.248). CSD began to occur when the tumor size was 1.4 cm, and it tended to increase as tumor size increased, although this trend was not statistically significant (3.8% for <2.0 cm vs. 13.4% for 2.0–3.9 cm vs. 8.2% for 4.0–5.9 cm vs. 22.7% for ≥6.0 cm, P for trend=0.089). Two patients with tumors <2 cm died from thyroid cancer.
We conducted TERT promoter mutation testing in 160 of 248 patients whose DNA samples were available. In patients with tumors ≥6 cm, the frequency of TERT promoter mutation significantly increased (42.9%), whereas its detection rates were similar in patients with tumors <6 cm (19.0% for <2.0 cm vs. 16.4% for 2.0–3.9 cm vs. 18.9% for 4.0–5.9 cm, P for trend=0.165).
Clinicopathological factors associated with distant metastasis and cancer-specific death
Among the 248 patients, 40 (16.1%) had DM. Older age (≥55 years), widely invasive subtype, vascular invasion, and TERT promoter mutations were risk factors for DM in all FTCs based on the univariate analysis (all P<0.001) (Table 3). However, only widely invasive subtype and TERT promoter mutations were independent risk factors for DM on the multivariate analysis (P=0.009, and P<0.001, respectively). All patients with gross extrathyroidal extensions had DM. Tumor size was not associated with DM.
Clinicopathological Factors Associated with Distant Metastasis in 248 Patients with Follicular Thyroid Carcinoma
Of the 248 patients, 27 (10.9%) experienced CSD. Older age (≥55 years), widely invasive subtype, vascular invasion, tumor size ≥6 cm, gross extrathyroidal extension, synchronous DM, and TERT promoter mutation were significantly associated with CSD based on the univariate analysis (P<0.001, P=0.005, P=0.018, P=0.018, P<0.001, P<0.001, and P<0.001, respectively) (Table 4). However, only older age (≥55 years), gross extrathyroidal extension, and synchronous DM, and TERT promoter mutations were independent risk factors for CSD in based on the multivariate analysis (P=0.005, P=0.003, P<0.001 and P=0.002, respectively).
Clinicopathological Factors Associated with Cancer-Specific Death in 248 Patients with Follicular Thyroid Carcinoma
DISCUSSION
In this study, the frequencies of DM, R/SP, and CSD in FTC tended to increase, but they did not significantly differ according to tumor size. FTCs <2 cm showed a prognosis not significantly different from that of FTCs ≥2 cm in terms of DM, R/SP, and CSD. Furthermore, tumors <6 cm showed similar prognosis between the size groups, whereas those larger than 6 cm exhibited a sharp decline in prognosis, although statistically insignificant.
The finding that increasing tumor size does not influence the occurrence of DM in FTC has been demonstrated in a few previous studies. O’Neil et al. [13] observed DM in 15.2% (5/33) patients with tumors ≤2.0 cm, in 7.7% (4/52) with tumors measuring 2.1–4.0 cm, and in 15.4% (4/26) with tumors >4.0 cm, and there was no association between tumor diameter and the occurrence of DM in patients with FTC. Similarly, Passler et al. [14] reported DM in 28.6% (2/7) patients with tumors ≤1.0 cm, in 24.0% (6/25) with tumors measuring 1.1–2.0 cm, and in 13.5% (7/52) with tumors measuring 2.1–4.0 cm, with no significant difference across the three groups. In our study, the rates of DM were also found to be similar when the tumor size was <6 cm, whereas they increased when the tumor size exceeded 6.0 cm (22.7%) (P for trend=0.608). This finding contrasts with other studies that regarded FTCs <2 cm as indolent tumors [15,16].
Most studies suggesting tumor size as a prognostic factor compared the prognosis of patients with tumors ≤4 cm with those of patients with tumors >4 cm. Wang et al. [17] and Ito et al. [18] presented tumor size >4 cm as a risk factor for CSD. Su et al. [19] showed that tumors >4 cm have a harmful effect on overall survival, and Sugino et al. [20] presented tumor size ≥4 cm as a significant risk factor for postoperative distant metastases. Yamazaki et al. [21] showed that tumor size >4 cm was associated with poor disease-free survival in minimally invasive FTC. In contrast with these studies, we assessed the prognosis by subdividing the cases into four groups based on tumor size (<2.0, 2.0–3.9, 4.0–5.9, and ≥6.0 cm). The worst outcomes, such as frequent DM, high R/SP, and high CSD rates, as well as frequent TERT promoter mutations, were found in patients with tumors ≥6 cm than in those with tumors <6 cm, although no statistically significant difference was observed between the groups with tumors <6 and ≥6 cm, except for the frequency of TERT promoter mutation (P=0.026) (Table 5). These results raised doubts regarding whether it is reasonable to set a tumor size of 2 or 4 cm as the cutoff value when determining prognosis. Whether the size criteria presented in the TNM staging of DTC, most of which account for PTC, are appropriate for FTC must be considered.
Comparison of the Rates of Distant Metastasis, Recurrence and/or Structural Persistence, Cancer-Specific Death, and TERT Promoter Mutations between Each Pair of Groups
In previous studies, TERT promoter mutation had been shown to be associated with poor prognosis, not only in PTC but also in FTC [22]. However, its frequency did not correlate with tumor size [22-25]. In our study, the frequency of TERT promoter mutation significantly increased in patients with tumors ≥6 cm, whereas it remained unchanged even when tumor size increased in patients with tumors <6 cm. This finding suggests that FTC presents a different frequency pattern from that of PTC, where its frequency increases with an increase in tumor size [26].
This study has some limitations. First, this was a retrospective study conducted at a single center, and the number of patients available for analysis was restricted owing to the low incidence of FTC in Korea. Further research with larger sample sizes would be required. Second, TERT promoter mutation testing could be performed for only 64.5% (160/248) of the patients with FTC; thus, there remained a possibility of selection bias. Third, while the presence of vascular invasion was analyzed as one factor in this study, the extent of vascular invasion was not addressed in the present study.
In conclusion, the clinical significance of this study lies in proposing a new size criterion for assessing prognosis by comparing patient outcomes according to tumor size, and in providing the outcome with a relatively long follow-up period in an iodine-excessive area. Although the clinical outcomes were worst in patients with tumors ≥6 cm, the rates of DM, R/SP, and CSD, as well as TERT promoter mutation status, in patients with FTCs <2 cm were not uncommon compared to those in patients with a tumor size of 2–5.9 cm.
Notes
CONFLICTS OF INTEREST
No potential conflict of interest relevant to this article was reported.
AUTHOR CONTRIBUTIONS
Conception or design: D.E.L., J.H.C. Acquisition, analysis, or interpretation of data: D.E.L., J.H.Y., B.R.K., J.S.K., T.H.K., S.W.K., Y.J.C., J.H.C., Y.L.O. Drafting the work or revising: D.E.L., J.H.C., Y.L.O. Final approval of the manuscript: D.E.L., J.H.Y., B.R.K., J.S.K., T.H.K., S.W.K., Y.J.C., J.H.C., Y.L.O.