Abstract
Background:
In the 2015 American Thyroid Association guidelines, either lobectomy or total thyroidectomy was recommended for thyroid cancer <4 cm without extrathyroidal extension (ETE) and lymph node (LN) metastasis. Therefore, the purpose of this study was to investigate factors predictive of bilaterality in papillary thyroid carcinoma (PTC) patients with tumor size <4 cm.
Methods:
This study retrospectively reviewed 3296 conventional PTC patients who underwent total thyroidectomy with central neck dissection and/or lateral neck dissection between January 2008 and June 2015.
Results:
In overall conventional PTC patients, per 10-year age increment (adjusted odds ratio [OR] = 1.153, p < 0.001), BRAF mutation positivity (adjusted OR = 1.447, p = 0.002) and multifocality (adjusted OR = 3.895, p < 0.001) were independent predictors for bilaterality. In conventional PTC patients with tumor size 1–4 cm, per 10-year age increment (adjusted OR = 1.289, p < 0.001), BRAF mutation positivity (adjusted OR = 1.560, p = 0.012), multifocality (adjusted OR = 4.220, p < 0.001), and N1b (adjusted OR = 1.570, p = 0.007) were independent predictors for bilaterality. In conventional PTC patients with tumor size <1 cm, BRAF mutation positivity (adjusted OR = 1.327, p = 0.042) and multifocality (adjusted OR = 3.530, p < 0.001) were found to be independent predictors for bilaterality.
Conclusions:
When multifocality and BRAF mutation positivity are observed in PTC patients with tumor size <4 cm, total thyroidectomy may be considered. If lobectomy is performed in PTC patients with multifocality and BRAF mutation positivity, meticulous follow-up is needed to detect hidden malignancies in the contralateral lobe.
Introduction
T
In the 2009 American Thyroid Association (ATA) guidelines (6), lobectomy was only recommended for thyroid cancer <1 cm without extrathyroidal extension (ETE) and clinical evidence of lymph node (LN) metastasis. For thyroid cancer >1 cm, total thyroidectomy was recommended as the initial surgical procedure, unless there were contraindications to this surgery. However, according to the revised 2015 ATA guidelines (7), either lobectomy or total thyroidectomy is recommended for thyroid cancer between 1 and 4 cm without ETE and clinical evidence of LN metastasis.
Upon lobectomy, however, there is the possibility of contralateral lobe remnant carcinoma, which is reported in up to 50% of PTC patients (8,9). Therefore, previous studies have suggested predictive factors for bilaterality in PTC patients (10 –16). However, the results of these studies were inconsistent, and their sample sizes were fewer than 500 cases. Moreover, since the 2009 ATA guidelines recommended lobectomy in patients with tumor size <1 cm, most of the above studies focused on papillary thyroid microcarcinomas.
Therefore, the purpose of this study was to investigate the predictors for bilaterality in a large group of PTC patients with tumor size <4 cm. Since histologic variants of PTC show variable behavior and prognosis (17), only conventional PTC, which is the predominant subtype, was included, and other variants of PTC were excluded to make the results more homogeneous. Following the 2015 ATA guidelines, two subgroup analyses were conducted according to tumor size: <1 cm and 1–4 cm.
Materials and Methods
Patient selection
The medical records of 3296 pathologically proven conventional PTC patients who underwent total thyroidectomy with central neck dissection and/or lateral neck dissection at the Thyroid Cancer Center of Samsung Medical Center between January 2008 and June 2015 were retrospectively reviewed. Patients with the following conditions were excluded from this study: younger than 20 years of age or older than 80 years of age, a previous history of thyroidectomy, non-PTC carcinomas (follicular/medullary/anaplastic), mixed type PTC, PTC variants other than conventional type, lobectomy cases, tumor size >4 cm, absence of BRAF mutation results, and presence of distant metastasis. In particular, because the 2015 ATA guidelines recommended lobectomy in patients with tumor size <4 cm (7), two subgroup analyses were conducted—<1 cm versus 1–4 cm—to examine the predictors for bilaterality.
Surgical methods
Total thyroidectomy was performed when multifocality, tumor bilaterality, ETE, or abnormal lymphadenopathy was detected during the pre- or intraoperative examination. Central neck dissection was defined as a level VI dissection including pre- and paratracheal nodes, precricoid (Delphian) nodes, perithyroidal nodes, and LN along recurrent laryngeal nerves. Therapeutic central neck dissection was performed when central LN metastasis was detected during the preoperative or intraoperative examination. Prophylactic central neck dissection was performed on PTC patients in whom clinically uninvolved lymphadenopathy was observed, especially based on the surgeon's personal preference at the time of the operation or in the case of advanced primary tumors (tumor size >4 cm or ETE) (6). Lateral neck dissection was defined as the excision of the lateral neck LNs, including modified radical neck dissection and selective neck dissection. Modified radical neck dissection referred to the excision of lateral neck LNs, including levels II–V, with preservation of one or more non-lymphatic structures such as the spinal accessory nerve, internal jugular vein, and sternocleidomastoid muscle. Selective neck dissection referred to cervical lymphadenectomy in which there is preservation of one or more of the LN groups that are routinely removed in the radical neck dissection. Lateral neck dissection was performed in cases where lateral LN metastasis was confirmed preoperatively.
Histopathological examination with surgical specimens
Surgical specimens were microscopically examined by two or more experienced pathologists, and the following histopathological factors were assessed: the cell type of the main lesion, the primary tumor size (measured as the longest diameter of the largest lesion), location, multifocality, bilaterality, ETE, lymphovascular invasion, margin involvement, regional LN metastasis, and underlying conditions of the thyroid such as chronic lymphocytic thyroiditis (CLT). To distinguish tumor bilaterality from multifocality, multifocality was defined as having two or more lesions of PTC in a single lobe, regardless of the presence of tumor bilaterality. The staging of thyroid cancer was determined in accordance with the American Joint Committee on Cancer (18).
BRAF mutation analysis
BRAF mutation analysis was performed at the Molecular Diagnostics Laboratory of Samsung Medical Center. DNA samples for molecular analysis were extracted from preoperative FNA biopsy specimens or postoperative surgical specimens using QIAamp DNA minikits (Qiagen, Chatsworth, CA). Generally, BRAF mutation analysis was performed for the largest and the most suspicious nodule. Three distinct molecular methods were used for molecular analysis of the BRAF mutation. Direct sequencing after conventional polymerase chain reaction (PCR) was performed in an ABI PRISM 3100 sequencer using BigDye Terminator cycle sequencing ready reaction kits (Applied Biosystems, Foster City, CA). Dual priming oligonucleotide–based allele-specific PCR using the Seeplex BRAF ACE detection system (Seegene, Seoul, Korea) with amplified products was performed using the ScreenTape system (Lab901 Ltd., Edinburgh, United Kingdom). Mutant enrichment with 3′-modified oligonucleotides-based real-time PCR using Real-Q BRAF detection kits (BioSewoom, Seoul, Korea) with amplified products was analyzed by BigDye Terminator Cycle Sequencing Kits v.3.1 (Applied Biosystems). DNA sequences from all three methods were compared with the normal BRAF gene exon 15 in the GenBank Database using sequence assembly software (Gene Codes Corp, Ann Arbor, MI). When a thyroid nodule was evaluated using two or more molecular methods and yielded discordant results, the positive result was chosen for analysis.
Statistical analysis
Statistical analysis was performed using SPSS Statistics for Windows v22.0 (IBM Corp, Armonk, NY), and statistically significant differences were defined as those with p-values of <0.05. Continuous variables are presented as mean ± standard deviation (SD), and categorical variables are presented as the number of cases with percentage (%) and odds ratio (OR). The chi-square test and linear-by-linear association were used for categorical variables, and Student's t-test was used for continuous variables. Multivariate analysis was carried out on the variables that achieved p-values of <0.05 in the univariate analysis. For multivariate analysis, multiple logistic regression was employed to determine whether the clinicopathologic characteristics were independent predictors for bilaterality in PTC patients.
Results
Baseline clinicopathologic characteristics of 3296 conventional PTC patients with tumor size <4 cm
The baseline clinicopathologic characteristics of 3296 conventional PTC patients with tumor size <4 cm are shown in Table 1. Of the 3296 PTC patients, 716 (21.7%) were men and 2580 (78.3%) were women. The mean age was 47.2 years, and 1850 (56.1%) were >45 years of age. Conventional open surgery was performed in 3018 (91.6%) patients, and oncoplastic (endoscopic or robotic) surgery was performed in 278 (8.4%) patients. All enrolled patients underwent central neck dissection, and 591 (17.9%) patients underwent lateral neck dissection. BRAF mutation positivity was observed in 2764 (83.9%) patients. The mean tumor size was 1.24 cm, and multifocality, bilaterality, ETE, and CLT were observed in 985 (29.9%), 983 (29.8%), 2133 (64.7%), and 995 (30.2%) patients, respectively. Nodal stages were N0 in 1308 (39.7%), N1a in 1446 (43.9%), and N1b in 542 (16.4%) patients.
PTC, papillary thyroid microcarcinoma; SD, standard deviation; ETE, extrathyroidal extension; CLT, chronic lymphocytic thyroiditis.
Associations between clinicopathologic characteristics and bilaterality in 3296 conventional PTC patients with tumor size <4 cm
The associations between clinicopathologic characteristics and bilaterality in 3296 conventional PTC patients with tumor size <4 cm are shown in Table 2. Bilaterality was found in 983 (29.8%) patients. In univariate analysis, per 10-year age increment (p < 0.001), BRAF mutation positivity (p < 0.001), multifocality (p < 0.001), and ETE (p < 0.001) were significantly associated with a high prevalence of bilaterality. In multivariate analysis, per 10-year age increment (adjusted OR = 1.153, p < 0.001), BRAF mutation positivity (adjusted OR = 1.447, p = 0.002) and multifocality (adjusted OR = 3.895, p < 0.001) were shown to be independent predictors for a high prevalence of bilaterality.
Variables that reached p < 0.05 in univariate analysis were included.
Per 10-year age increment.
OR, odds ratio; CI, confidence interval; NA, not available; LN, lymph node.
Associations between clinicopathologic characteristics and bilaterality in 1556 conventional PTC patients with tumor size 1–4 cm
The associations between clinicopathologic characteristics and bilaterality in 1556 conventional PTC patients with tumor size 1–4 cm are shown in Table 3. Bilaterality was found in 458 (29.4%) patients. In univariate analysis, per 10-year age increment (p < 0.001), BRAF mutation positivity (p = 0.013), multifocality (p < 0.001), ETE (p = 0.020), and nodal stage (p = 0.001) were significantly associated with a high prevalence of bilaterality. In multivariate analysis, per 10-year age increment (adjusted OR = 1.289, p < 0.001), BRAF mutation positivity (adjusted OR = 1.560, p = 0.012), multifocality (adjusted OR = 4.220, p < 0.001), and nodal stage, only N1b (adjusted OR = 1.570, p = 0.007) were shown to be independent predictors for a high prevalence of bilaterality.
Variables that reached p < 0.05 in univariate analysis were included.
Per 10-year age increment.
Associations between clinicopathologic characteristics and bilaterality in 1740 conventional PTC patients with tumor size <1 cm
The associations between clinicopathologic characteristics and bilaterality in 1740 conventional PTC patients with tumor size <1 cm are shown in Table 4. Bilaterality was found in 525 (30.2%) patients. In univariate analysis, BRAF mutation positivity (p = 0.004), large tumor size (p = 0.019), multifocality (p < 0.001), and ETE (p = 0.001) were significantly associated with a high prevalence of bilaterality. In multivariate analysis, BRAF mutation positivity (adjusted OR = 1.327, p = 0.042) and multifocality (adjusted OR = 3.530, p < 0.001) were shown to be independent predictors for a high prevalence of bilaterality.
Variables that reached p < 0.05 in univariate analysis were included.
Discussion
In contrast to the 2009 ATA guidelines (6), the 2015 ATA guidelines recommend either lobectomy or total thyroidectomy for thyroid cancer 1–4 cm without ETE and clinical evidence of LN metastasis (7). When lobectomy is performed, the possibility of contralateral lobe remnant carcinoma is of concern. The incidence of bilaterality in PTC patients was reported to be up to 50% in previous studies (8,9). Therefore, the 3296 surgically proven PTC patients were analyzed to investigate factors predictive of bilaterality, and two subgroup analyses were also conducted according to tumor size. Better knowledge regarding the factors predictive of bilaterality from this study could be useful for determining a management strategy in PTC patients.
Presence of a BRAF mutation, the most potent activator of the mitogen-activated protein kinase pathway, plays a central role in the regulation of cell growth, division, and proliferation (19,20). BRAF mutations are found predominantly in PTC, particularly in the conventional and tall-cell variants (21 –23). The reported prevalence of BRAF mutations in PTC ranges from 29% to 83%, depending on the study (23). In particular, numerous studies have demonstrated an association of the BRAF mutation with aggressive clinicopathologic characteristics of PTC, such as advanced stage, ETE, LN metastasis, and tumor recurrence (24,25). A high prevalence of BRAF mutation positivity (83.9% in Table 1) was found in this study population. Similar results were observed in previous studies in the Korean population (26,27). However, a lower incidence of BRAF mutation positivity was seen in previous studies in other populations (23,28).
In the revised 2015 ATA guidelines, lobectomy alone is recommended for the treatment of papillary thyroid microcarcinoma (tumor size <1 cm) without multifocality, ETE, and regional LN metastasis (6). This study only included total thyroidectomy cases, and >50% of cases had microcarcinomas (tumor size <1 cm), as shown in Table 1. The incidence rates of ETE and regional LN metastasis in this study were 64.7% and 60.3%, respectively, which are higher than those seen in previous studies in other populations (29,30). Moreover, as is well known, the incidence of BRAF mutation positivity in the Korean population is higher than that of other populations (23,28). The incidence of ETE, regional LN metastasis, and BRAF mutation positivity found in this study could potentially indicate a geographic bias.
This study found that up to 30% of PTC patients showed bilaterality in thyroidectomy specimens (Table 1). This result was similar to the results of previous studies (10 –16). Among the results of previous studies regarding bilaterality in PTC, tumor size (12,14,15), multifocality (10 –15), and BRAF mutation positivity (13,16) were proven to be independent predictors for bilaterality in PTC patients. To the best of the authors’ knowledge, this study is the largest with regard to identifying factors predicting bilaterality in PTC patients. From the multivariate analysis in this study (Tables 2 –4), multifocality and BRAF mutation positivity were proven to be independent predictors for bilaterality in conventional PTC patients with tumor size <4 cm, regardless of whether these were micro- (tumor size ≤1 cm) or macrocarcinomas (tumor size >1 cm). Although age, tumor size, and regional LN metastasis also showed a predictive power for bilaterality in a certain tumor size group, the results were inconsistent.
If bilaterality can be predicted preoperatively, delayed removal of the contralateral thyroid lobe can be avoided. Therefore, total thyroidectomy may be considered in PTC patients who show multifocality or BRAF mutation positivity preoperatively. However, since the prevalence of BRAF mutation positivity is variable among different countries (23,28), the results of this study may not justify routine preoperative BRAF mutation analysis. Preoperative BRAF mutation analysis may be beneficial if clinicians encounter difficulties in determining the extent of thyroidectomy, especially for PTC patients with relatively large tumors (e.g., T2 cancer) or multifocality. However, it may be difficult to detect multifocality and BRAF mutation positivity preoperatively. A previous study showed that 88.4% of indeterminate nodules and 98.7% of high risk nodules, as characterized by ultrasound, were finally proven to be PTC (31). Therefore, when multiple nodules with intermediate- to high-risk features are observed in preoperative ultrasound, this may be suggestive for multifocality. In addition, numerous studies have demonstrated that BRAF mutation analysis can be performed readily and reliably using solely preoperative FNA specimens (32,33).
If lobectomy has already been performed and PTC patients show multifocality or BRAF mutation positivity postoperatively, meticulous postoperative follow-up might be needed to detect hidden malignancy in the contralateral remnant lobe. Furthermore, since bilaterality itself has been proven to be an indicator for unfavorable outcomes in PTC patients (30), meticulous postoperative follow-up might be required even after total thyroidectomy, especially when combined with multifocality or BRAF mutation positivity.
This study has several limitations. First, there are the inherent features of a non-randomized retrospective cohort study. Therefore, the patient information was not always complete. The possibility of residual confounding variables involving measured or unmeasured factors cannot be ruled out. Second, since only conventional PTC patients were enrolled, the results of this study cannot be applied to other types of thyroid cancers or other variants of PTC. Third, the results may not be applicable to patients from other ethnicities or countries because of the high prevalence of the BRAF mutation in the study population (83.9%), which could be explained by geographic bias (26,27). To overcome this limitation, multicenter or multination studies will be required. Fourth, three distinct types of molecular methods and two distinct types of specimens were used for BRAF mutation analysis. BRAF mutation analysis was not performed as a routine preoperative examination, and molecular methods have been evolving since March 2008. This variability may have introduced inconsistencies in the results from the BRAF mutation testing. Although BRAF mutation analysis was performed with both FNA specimens and surgical specimens, numerous studies have demonstrated that BRAF mutation analysis can be performed readily and reliably using solely preoperative FNA specimens (32,33). Nevertheless, this study has several significant strengths. First, a large group of >3000 patients from a single institution was analyzed. Second, only surgically proven data were used, which included only total thyroidectomy cases. Third, two subgroup analyses according to tumor size were conducted.
In conclusion, this study demonstrates that multifocality and BRAF mutation positivity are strong indicators for bilaterality in PTC patients with tumor size <4 cm. Therefore, when multifocality and BRAF mutation positivity are observed in PTC patients with tumor size <4 cm, total thyroidectomy may be considered. If lobectomy is performed in PTC patients with multifocality and BRAF mutation positivity, meticulous postoperative follow-up is necessary to detect malignancy in the contralateral remnant lobe.
Footnotes
Author Disclosure Statement
No competing financial interests exist.