Differences in the Recurrence and Survival of Patients with Symptomatic and Asymptomatic Papillary Thyroid Carcinoma: An Observational Study of 11,265 Person-Years of Follow-Up

Abstract

Background:

Papillary thyroid carcinoma (PTC) generally has an indolent course and favorable prognosis. However, an optimal treatment strategy for asymptomatic PTC is not clear. We compared the recurrence and survival outcomes of patients with asymptomatic and symptomatic PTC and identified the associated risk factors.

Materials and Methods:

Patients with previously untreated PTC of size ≤2 cm and who underwent curative surgery were included in this analysis. Asymptomatic PTC was defined as a tumor detected only by ultrasonography, computed tomography (CT), magnetic resonance imaging, and/or ¹⁸F-fluorodeoxyglucose positron emission tomography/CT. Clinical factors, operative and pathologic findings, and posttreatment outcomes were compared between the aforementioned two groups. Univariate and multivariate analyses were performed to identify the factors associated with recurrence-free survival (RFS) and overall survival (OS).

Results:

Out of 1419 patients, 1259 patients (88.7%) were asymptomatic. Patients with symptomatic PTC had significantly larger tumor size, palpability, extrathyroidal extension, high tumor and node stages, and were more likely to undergo treatment with radioactive iodine therapy compared with patients with asymptomatic PTC (p < 0.05 each). Recurrence was significantly higher in the symptomatic PTC group than in the asymptomatic group (p < 0.001). Asymptomatic PTC was an independent predictor of RFS and OS and had higher five-year rates than those associated with symptomatic tumors: 97.3% and 90.6% for RFS (p < 0.001) and 99.4% and 96.9% for OS (p < 0.001), respectively.

Conclusion:

Symptomatic PTC is associated with higher recurrence and lower overall survival rates than asymptomatic PTC. Symptomatic PTC may require total thyroidectomy and close posttreatment surveillance.

Introduction

Papillary thyroid carcinoma (PTC) is the most common histological subtype of thyroid cancer. PTC is generally an indolent tumor that is associated with a low rate of cancer-specific mortality (1,2). Five-year relative survival rates of PTC are overall excellent but differ according to the clinical stage (size of lesion, local invasion, and metastasis) and age of the patient (3,4). The last few decades have seen a rapid increase in new cases of thyroid cancer, which places it among the cancers with the most rapid increase in prevalence in most areas of the world; however, a steady decline in the associated mortality has also been observed in most countries reported from a global overview (5). Most of the increase in incidence is attributable to the increase in tumor detection (6,7).

The increased use of ultrasonography (US) has led to the detection of subclinical thyroid cancer such as small PTC, particularly in women. This overdiagnosis over the last decade has led to massive overtreatment of small asymptomatic thyroid cancer, resulting in a shift in the tumor distribution toward earlier stages and excellent prognosis (7,8). However, identification of a subset of thyroid lesions that are associated with unfavorable prognosis is of immense clinical importance.

A thyroid incidentaloma was originally defined as a postsurgical diagnosis of thyroid lesions that were incidentally detected on the histological examination of surgical specimens (9 –12). Nonincidentaloma is defined as the presence of thyroid lesions identified preoperatively. Along with the increased use of thyroid US, the definition of incidentaloma needs to be expanded in order to include an unsuspected, asymptomatic lesion that is discovered during nonthyroid surgery or preoperative imaging studies such as US, computed tomography (CT), magnetic resonance imaging (MRI), and ¹⁸F-fluorodeoxyglucose (¹⁸F-FDG) positron emission tomography (PET) or PET/CT (13). Incidental PTC, particularly papillary thyroid microcarcinoma (PTMC; tumor maximum diameter of ≤1.0 cm), has different clinical characteristics and a lower recurrence rate than nonincidental PTMC (14).

The clinical differentiation between incidental PTC and nonincidental PTC is subject to debate (9). The conflicting results in the published literature may be attributable to different inclusion criteria for incidental PTC, the use of different definitions of incidentaloma (e.g., asymptomatic PTC detected by US being regarded as nonincidental PTC) (9 –12), and to the small sample sizes of individual studies. Therefore, characterization of the differences in clinical characteristics and disease course between nonincidental and incidental PTC, which is defined as unsuspected, asymptomatic thyroid lesions, are of clinical relevance (13,15). This will aid risk stratification and optimize the treatment approach in cases of asymptomatic or symptomatic PTC.

We hypothesized that symptomatic PTC is associated with a more aggressive clinical phenotype, higher recurrence rate, and lower survival outcomes compared with those associated with asymptomatic PTC. We examined the differences between the two groups in a large cohort of 1419 patients with a lesion size of ≤2 cm and a median duration of follow-up of 95 months. The purpose of this study was to compare the recurrence and survival outcomes between asymptomatic and symptomatic PTC and to identify the risk factors.

Materials and Methods

Study patients

A total of 1693 patients who underwent thyroidectomy for differentiated PTC at the Department of Otolaryngology at Asan Medical Center between January 2006 and December 2009 were retrospectively reviewed. The inclusion criteria were as follows: patients with previously untreated, pathologically proven PTC of size ≤2 cm and those who underwent curative surgery and patients who were followed for at least 2 years after surgery. The exclusion criteria included patients with PTC of size >2 cm (n = 216) and those with a prior history of cancer treatment (n = 32). Patients with incomplete clinical data (n = 26) were also excluded. A total of 1419 patients [274 men and 1145 women; median age 55 years (range 22–86 years)] were included in the final analysis. All patients were diagnosed before surgery by US-guided fine-needle aspiration biopsy (FNAB). Tumor sizes were measured from the surgical specimens. Tumors were staged using the tumor-node-metastasis (TNM) staging system proposed by the American Joint Committee on Cancer (seventh edition). This study was approved by our institutional review board; the requirement for written informed consent from each patient was waived due to the nature of the study.

Definition of asymptomatic and symptomatic PTC

Asymptomatic PTC was defined as an unexpected thyroid tumor detected during clinical investigation of an unrelated condition and incidentally detected by one or more imaging methods (US, CT/MRI, and ¹⁸F-FDG PET/CT) or an US screening program (13). Symptomatic PTC was defined as a tumor detected from symptoms reported by patients (e.g., a palpable thyroid lump, voice change, or difficulty in swallowing, and so on) and confirmed by subsequent imaging studies and FNAB.

Surgery, complications, and posttreatment follow-up

All patients underwent macroscopically complete resection of the tumor. Ipsilateral lobectomy was performed for a tumor restricted to one lobe and with no evidence of malignant nodules in the contralateral lobe. The others underwent total thyroidectomy. Therapeutic lateral lymph node dissection was performed in any patient suspected of having metastatic lymph nodes in the lateral neck compartment. Prophylactic central lymph node dissection was commonly performed at the ipsilateral or bilateral sides of the central compartment according to our institutional protocol. Patients who underwent complete thyroidectomy were considered as having undergone total thyroidectomy. All surgical specimens of thyroids and metastatic lymph nodes were carefully reviewed by surgeons and pathologists. Microscopic and macroscopic invasion to surrounding tissues or organs and lymph node metastasis were documented.

All patients underwent pre- and postoperative laryngoscopic examinations and careful monitoring for any complications. Hypocalcemia was defined as a total calcium concentration of <8.0 mg/dL; permanent hypoparathyroidism was defined as low total calcium concentrations that required calcium supplementation for more than 6 months. Patients with hypocalcemia received oral calcium supplementation and vitamin D replacement therapy.

Most of the patients who underwent total thyroidectomy received postoperative radioactive iodine (RAI) ablation with 30 mCi (n = 535; 37.7%), 80 mCi (n = 222; 15.6%), 150 mCi (n = 531; 37.5%), or 200 mCi (n = 2; 0.1%) depending on a combination of age, tumor size, lymph node status, and individual histological characteristics. RAI remnant ablation was not performed in low-risk patients with unifocal cancer of ≤1 cm and those who underwent lobectomy (n = 129, 9.1%). Most patients also received thyrotropin suppression therapy. All study patients underwent a routine neck US examination and chest radiography; in case of total thyroidectomy, measurements of serum thyroglobulin (Tg) concentrations and whole-body iodine scanning were performed every 0.5–1 year. Any lesions suspected of recurrence in the remnant thyroid, resection bed, or lymph nodes were histologically confirmed by FNAB examination and reoperation.

Variables

Medical records of each patient were carefully reviewed for age at diagnosis, sex, type of surgery, TNM stage, pathological tumor size, MACIS (distant Metastasis, patient Age, Completeness of resection, local Invasion, and tumor Size) score, extrathyroidal extension (ETE), extranodal extension, any complications (e.g., hypocalcemia and vocal fold paralysis), RAI ablation, postoperative serum Tg level, and follow-up data on recurrence and survival. Recurrence of PTC was identified based on a significant rise in thyroglobulin levels from baseline in the absence of thyroglobulin antibodies, detection of disease on follow-up nuclear scans (RAI and PET scans), detection of disease with other imaging modalities including US and contrast-enhanced CT, histological examination of recurrent tumor tissue, or a combination of these methods.

Statistical analysis

Descriptive statistics were used to summarize study data. Data pertaining to continuous variables are expressed as median (range); categorical variables are expressed as frequencies (percentage). Pearson's chi-square test or Fisher's exact test were used to assess differences with respect to clinicopathological characteristics of patients with asymptomatic and symptomatic PTC. Recurrence-free survival (RFS) was defined as the time from surgery until the first evidence of any recurrence, while overall survival (OS) was defined as the time from surgery to death from any cause or to the last follow-up date. The univariate Cox proportional hazard model was used to assess potential relationship between clinicopathological variables and RFS or OS. Variables with statistically significant association were included in the multivariate Cox proportional hazards regression model and analysis performed using backward elimination method. The estimated hazard ratios (HR) and 95% confidence interval [CI] were calculated. Survival curves are prepared using the Kaplan–Meier method and compared with the log-rank test. Two-sided p-value <0.05 was considered statistically significant. All statistical analyses were performed using the IBM SPSS software version 21.0 (IBM Corp., Armonk, NY).

Results

Comparison of characteristics between asymptomatic and symptomatic PTC

The clinicopathological characteristics of the patients with asymptomatic and symptomatic PTC are presented in Table 1. Out of 1419 patients, 1259 (88.7%) had asymptomatic PTC; 1213 (96.3%) patients were detected by US (from part of an US screening program), 37 (2.6%) by CT or MRI, and 9 (0.6%) patients by ¹⁸F-FDG PET/CT. The remaining 160 patients (11.3%) had symptomatic PTC and had presented with clinical symptoms and had palpable thyroid or neck lumps (n = 142, 88.7%); voice changes (n = 11, 6.9%); or difficulty in swallowing (n = 7, 4.4%). Thyroid nodules in the symptomatic PTC group tended to be more readily palpable and larger compared with those in the asymptomatic PTC group (77.5% vs. 11.6%, p < 0.001; mean size: 1.1 vs. 0.9 cm; p < 0.001, respectively). Asymptomatic PTC was more likely to have lower pathological T and N classifications than the symptomatic PTC, and the incidence of ETE tended to be lower than that in the symptomatic PTC (p < 0.01 for both).

Table 1.

Clinical Characteristics of Study Patients (n = 1419)

	Asymptomatic PTC (n = 1259)	Symptomatic PTC (n = 160)	p-Value ^a
Sex, n (%)
Male	251 (19.9)	23 (14.4)	0.093
Female	1008 (80.1)	137 (85.6)
Median age at diagnosis (range), years	55 (24–86)	55 (22–80)	0.889
Thyroid cancer nodule, n (%)
Palpable	146 (11.6)	124 (77.5)	<0.001
Non-palpable	1113 (88.4)	36 (22.5)
Tumor size, mean (range), cm	0.9 (0.2–2.0)	1.1 (0.5–2.0)	<0.001
≤1/1.1–2.0, n (%)	865 (68.7)/394 (31.3)	75 (46.9)/85 (53.1)	<0.001
pTNM stage, n (%)
T1/T2/T3/T4	498 (39.6)/5 (0.4)/729 (57.9)/27 (2.1)	51 (31.9)/1 (0.6)/97 (60.6)/11(6.9)	0.006
N0/N1a/N1b	752 (59.7)/398 (31.6)/109 (8.7)	76 (47.5)/49(30.6)/35 (21.9)	<0.001
Overall I/II/III/IV	527 (41.9)/ 1(0.1)/718 (57)/13 (1)	65(40.6)/0/91 (56.9)/ 4(2.5)	0.435
MACIS score, median (range)	4.74 (3.13–8.28)	4.85 (3.19–7.82)	0.122
<5/≥5	775 (61.6)/484 (38.4)	88 (55.0)/72(45.0)	0.110
Multifocality, n (%)	391(31.1)	48 (30.0)	0.785
Bilaterality, n (%)	282(22.4)	38(23.8)	0.700
Extrathyroidal extension
No	500 (39.7)	52 (32.5)	0.009
Microscopic	511 (40.6)	60 (37.5)
Macroscopic	248 (19.7)	48 (30.0)
Extranodal extension, n (%)	112 (9.0)	25 (18.1)	0.011
Lymph-node ratio, mean (range)	0.14 (0–0.45)	0.21 (0–0.69)	0.001
Surgery, n (%)
Lobectomy	56 (4.4)	3 (1.9)	0.125
Total thyroidectomy	1203 (95.6)	157 (98.1)
Resection margin involved	210 (16.7)	35 (21.9)	0.101
Complications
Hypocalcemia, temporary/permanent	111 (8.8)/44 (3.5)	11 (6.9)/9 (5.6)	0.309
Vocal fold paralysis, temporary/permanent	3 (0.2)/1 (0.1)	5 (3.1) /5 (3.1)	<0.001
Postoperative RAI ablation	1136(90.2)	153(95.6)	0.026
Postoperative serum Tg level,^b ng/mL
smTg at 1 month, median (range)	0.45 (UDR–79.4)	0.71 (UDR–18800)	0.305
smTg at 1 year, median (range)	0.08 (UDR–59.8)	0.08 (UDR–93200)	0.316
unsmTg at 1 year, median (range)	0.08 (UDR–27.4)	0.08 (UDR–25700)	0.317
First relapse,^c n (%)	41 (3.3)	17 (10.6)	<0.001
Thyroid remnants or bed	3 (0.3)	1 (0.6)	0.381
Central compartment LN	5 (0.4)	2 (1.3)	0.182
Lateral compartment LN	33 (3.1)	11 (6.9)	0.012
Distant sites	0	3 (1.9)	0.001
Follow-up data
Median follow-up (range), months	95 (24–119)	96 (24–118)	0.784
Median time to the first relapse (range), months	84 (9–119)	88 (9–118)	0.681
NED/AD/DOD/DOC	1251 (99.3)/0/0/8 (0.6)	152 (95.0)/1 (0.6)/2 (1.3)/5 (3.1)	<0.001

Comparison between two groups using the Fisher's exact test (except age, tumor size, the MACIS score, Tg levels, and follow-up period, which were assessed using the student t test). Bold numbers indicate p < 0.05.

Serum stimulated Tg (smTg) and unstimulated Tg (unsmTg) levels were measured when thyroid-stimulating hormone were elevated up to >30–50 ng/mL or not.

Include mutually overlapping recurrences in part.

AD, alive with disease; DOC, died of other cause; DOD, died of disease; MACIS score, distant metastasis, patient age, completeness of resection, local invasion, and tumor size score; LN, lymph node; LND, lateral compartment neck dissection; NED, no evidence of disease; pTNM, pathologic tumor-node-metastasis stage (seventh edition); RAI, radioactive iodine (I¹³¹) therapy; smTg, serum stimulated thyroglobulin (Tg) level; UDR, undetected range.

Extranodal extension was a more frequent finding in the symptomatic PTC group compared with the asymptomatic PTC group (18.1% vs. 9.0%, respectively; p = 0.011). It significantly correlated with the extent of ETE in both groups (4.3% in no ETE, 8.8% in microscopic ETE, and 21.6% in gross ETE; p < 0.001). Mean lymph node ratio (number of positive lymph nodes divided by number of total harvested lymph nodes) was higher in the symptomatic PTC (0.21 vs. 0.14 in the asymptomatic group; p = 0.001).

Multifocality, bilaterality, and the MACIS score were comparable between the two groups (p > 0.1). Surgical extent, resection margin status, and postoperative serum thyroglobulin levels were also comparable between the two groups (p > 0.1). Moreover, the incidence of temporary and permanent hypocalcemia was comparable between the two groups. Postoperative RAI ablation was more commonly performed in the symptomatic group compared with the asymptomatic group (95.6% vs. 90.2%; p = 0.026). However, permanent vocal fold paralysis was more frequently seen in the symptomatic group (p < 0.001), because of tumor invasion of the recurrent laryngeal nerve.

Over a median follow-up duration of 95 months (range, 24–119 months), 58 patients experienced recurrences; these were more frequent in the symptomatic group than in the asymptomatic group (10.6 vs. 3.3%; p < 0.001). The recurrence rates in the thyroid bed or central compartment were comparable between the two groups (p > 0.1); however, those in the lateral neck and at distant sites were higher in the symptomatic group (p < 0.05). At the time of last follow-up, two patients (0.1%) died of PTC, 13 patients (0.9%) died of other causes, and 1 patient (0.1%) was alive with recurrence. The remaining 1403 patients (98.9%) were alive without evidence of disease. Cause-specific and noncancer death rates were higher in the symptomatic group (p < 0.001 vs. asymptomatic group).

Risk factors for recurrence and OS

On univariate analyses, the significant risk factors for RFS were sex (p = 0.001), pathologic tumor size (p = 0.003), palpability of thyroid nodule (p = 0.004), symptomatic finding (p < 0.001), multifocality (p = 0.001), lateral compartment lymph node metastasis (pN1b, p < 0.001), positive resection margin (p = 0.006), macroscopic ETE (p < 0.001), extranodal extension (p < 0.001), and postoperative stimulated Tg level (>1 ng/mL; p = 0.008) (Table 2).

Table 2.

Relationship Between Clinicopathological Variables and Recurrence-Free Survival

	Univariate		Multivariate
Variable	HR [95% CI] ^a	p-Value	HR [95% CI] ^c	p-Value ^b
Age, years
<45	1
≥45	0.60 [0.34–1.07]	0.084
Sex
Male	1		1
Female	0.35 [0.21–0.60]	0.001	0.53 [0.30–0.94]	0.029
Tumor size, cm
≤1	1		1
>1	2.18 [1.30–3.65]	0.003	1.10 [0.60–2.04]	0.763
Thyroid nodule
Nonpalpable	1		1
Palpable	2.23 [1.30–3.82]	0.004	1.48 [0.77–2.87]	0.241
Finding
Asymptomatic	1		1
Symptomatic	3.36 [1.9–5.92]	<0.001	2.02 [1.02–4.01]	0.043
Bilaterality	1.58 [0.91–2.76]	0.106
Multifocality	2.47 [1.48–4.13]	0.001	1.57 [0.91–2.70]	0.105
T classification
pT1–2	1		1
pT3–4	3.11 [1.57–6.15]	0.605	2.31 [0.1–55.04]	0.125
N classification
pN0	1
pN1a	2.42 [1.18–4.97]	0.016	1.61 [0.73–3.53]	0.236
pN1b	6.87 [3.29–14.37]	<0.001	2.74 [1.05–7.14]	0.039
Overall TNM stage
I–II	1
III–IV	1.47 [0.85–2.55]	0.168
Lobectomy/total thyroidectomy	0.76 [0.24–2.43]	0.642
Positive resection margin	2.18 [1.25–3.81]	0.006	1.01 [0.53–1.91]	0.982
Postoperative RAI ablation	2.74 [0.67–11.24]	0.161
Extrathyroidal extension
No	1		1
Microscopic	2.53 [1.2–5.26]	0.012	1.94 [0.89–4.22]	0.097
Macroscopic	4.14 [1.96–8.75]	<0.001	1.35 [0.56–6.28]	0.507
Extranodal extension	8.91 [5.32–14.92]	<0.001	3.06 [1.76–5.33]	0.001
smTg level, ng/mL
≤1.0	1		1
>1.0	3.47 [1.39–8.70]	0.008	5.10 [2.59–10.08]	<0.001
MACIS score
<5	1
≥5	1.26 [0.75–2.12]	0.381

Bold numbers indicate p < 0.05.

Cox proportional hazards model, p < 0.05.

Cox proportional hazard regression analyses were performed with backward elimination from variables with p-values <0.05 on univariate analyses.

CI, confidence interval; HR, hazard ratio.

On multivariate analyses, sex (HR 0.53 [CI 0.30–0.94], p = 0.029), symptomatic finding (HR 2.02 [CI 1.02–4.01], p = 0.043), lateral compartment lymph node metastasis (HR 2.74 [CI 1.05–7.14], p = 0.039), extranodal extension (HR 3.06 [CI 1.76–5.33], p = 0.001), and postoperative stimulated Tg level (HR 5.10 [CI 2.59–10.08], p < 0.001) were independent predictors of RFS.

On univariate analyses, the significant risk factors for OS were palpability of the thyroid nodule (p = 0.017), symptomatic finding (p < 0.001), bilaterality (p = 0.007), postoperative RAI ablation (p = 0.018), and the MACIS score (p = 0.002) (Table 3). Symptomatic finding (HR 5.84 [CI 2.07–16.44], p = 0.001), bilaterality (HR 3.50 [CI 1.24–9.85], p = 0.018), and the MACIS score (HR 10.14 [CI 2.23–45.98], p = 0.003) were independent correlates of OS.

Table 3.

Relationship Between Clinicopathological Variables and Overall Survival

	Univariate		Multivariate
Variable	HR [95% CI] ^a	p-Value	HR [95% CI] ^b	p-Value ^b
Age, year
<45	1
≥45	27.70 [0.10–7472.82]	0.245
Sex
Male	1
Female	0.642 [0.20–2.02]	0.449
Tumor size, cm
≤1	1
>1	0.298	0.111
Thyroid nodule
Non-palpable	1
Palpable	3.47 [1.25–9.64]	0.017	1.96 [0.55–7.04]	0.303
Finding
Asymptomatic	1		1
Symptomatic	6.43 [2.32–17.83]	<0.001	5.84 [2.07–16.44]	0.001
Bilaterality	4.00 [1.45–11.03]	0.007	3.50 [1.24–9.85]	0.018
Multifocality	2.59 [0.94–7.15]	0.066
T classification
pT1–2	1
pT3–T4	0.55 [0.19–1.51]	0.247
N classification
pN0	1
pN1a	0.82 [0.25–2.66]	0.740
pN1b	1.22 [0.26–5.65]	0.801
Overall TNM stage
I-II	1
III-IV	1.41 [0.48–4.13]	0.529
Positive resection margin	0.33 [0.04–2.49]	0.280
Lobectomy/total thyroidectomy	21.37 [0–2136.59]	0.602
Extrathyroidal extension
No	1
Microscopic	0.60 [0.20–1.83]	0.370
Macroscopic	0.44 [0.09–2.07]	0.298
Extranodal extension	2.32 [0.66–8.22]	0.192
smTg level, ng/mL
≤1.0	1
>1.0	1.85 [0.53–6.40]	0.334
MACIS score
<5	1		1
≥5	10.01 [2.26–44.38]	0.002	10.14 [2.23–45.98]	0.003

Bold numbers indicate p < 0.05.

Cox-proportional hazards model.

Cox-proportional hazard regression analyses were performed with backward elimination from variables with p-values of <0.05 on univariate analyses.

Five-year RFS, cancer-specific survival, and OS rates for the entire study population were 96.8%, 99.9%, and 99.2%, respectively. Patients with asymptomatic PTC had higher 5-year survival rates than those with symptomatic tumors: 97.3% and 90.6% for RFS (p < 0.001) and 99.4% and 96.9% for OS (p < 0.001), respectively (Fig. 1).

FIG. 1.

Kaplan–Meier curves for recurrence-free survival (RFS) (A) and overall survival (OS) (B) in patients with asymptomatic and symptomatic papillary thyroid carcinomas (PTC). Log-rank test, p < 0.001.

Discussion

In this study, symptomatic PTC was associated with more aggressive clinical features, higher recurrence rates, and lower overall survival rates over a median follow-up duration of 95 months in comparison with asymptomatic PTC. We defined asymptomatic PTC as an unsuspicious tumor that was detected primarily by US screening. In most previous studies, incidental PTMC (size ≤1 cm) was classically defined as a tumor diagnosed during the final pathological examination of surgical specimens for disease not related to thyroid malignancy (9 –12). Any thyroid nodules that were preoperatively diagnosed or suspected to be PTMC were considered to be nonincidental tumors (9 –12); however, most such cases in our study were considered as asymptomatic PTC in the absence of overt symptoms (13).

Previous studies that employed the classical definition of incidentaloma reported much lower recurrence rates for incidentalomas compared with those for nonincidentalomas (11,12,14); this suggests the need for additional studies to identify the high-risk subgroups of nonincidentalomas. Our study showed excellent overall RFS and OS in asymptomatic PTC in contrast with those with symptomatic PTC. This suggests the need for more aggressive treatment for PTC with overt symptoms compared with that for asymptomatic PTC detected preoperatively (considered as nonincidentaloma by classical definition).

In the present study, symptomatic PTC exhibited more aggressive clinical characteristics than asymptomatic PTC. Symptomatic PTC were more frequently palpable and larger in size, were associated with higher T, N, and overall TNM stages and were associated with macroscopic ETE with significant local invasion and extranodal extension compared with asymptomatic PTC.

In a recent meta-analysis, the mean tumor size of nonincidental PTMC (n = 2669) cases was larger than that of incidental PTMC (n = 854) cases (6.9 mm vs. 4.6 mm; p < 0.001) (14). The incidence of lymph node metastasis was more commonly found in nonincidental PTMC compared with incidental PTMC (30% vs. 12%); the odds ratio (OR) was 11.1 [CI, 4.2–41.5] (14). Multifocal tumors were also more nonincidental PTMC than incidental PTMC (29.7% vs. 18.5%) with an OR of 2.2 [CI, 1.7–2.8] (p < 0.001) (14).

Our study included patients with PTC of a size between 1.1–2.0 cm, as well as PTMC of size ≤1.0 cm. Multifocality did not differ between asymptomatic and symptomatic tumors; however, most other local and metastatic findings significantly differed between the two groups. Macroscopic ETE representing tumor local invasion was the most differentiating finding between the two groups. Previous studies have shown a correlation between the extent of ETE and oncological outcomes in patients with PTC; gross ETE predicted worsens outcomes (16 –18). Further, extranodal extension is more frequently seen in symptomatic PTC than asymptomatic PTC. Previous studies have shown that extranodal extension of PTC is predicted by the presence of ETE and well correlated with nodal persistence and systemic progression (19 –21). Lymph node ratio, which reportedly indicates locoregional recurrence of PTC, was higher in nonincidental PTC (21,22). All nodal findings as surrogates of tumor aggressiveness were also observed in our study. Therefore, symptomatic PTC appears to be related to more aggressive local and metastatic findings than asymptomatic PTC, as observed in previous studies.

We identified the risk factors for recurrence and poor survival in patients with PTC of size ≤2 cm. Male sex, nodal stage, extranodal extension, and serum-stimulated Tg level after total thyroidectomy were significantly associated with recurrence. Symptomatic findings of PTC were also a significant predictor of recurrence. A recent meta-analysis revealed a significantly higher risk of recurrence in patients with nonincidental PTMC compared with that in patients with incidental PTMC over a mean follow-up duration of 70 months (7.9% vs. 0.5%) with the conditioned OR of 14.7 [CI, 5.6–54.8] (p < 0.001) (14). In a previous study, sites of recurrence in the nonincidental group were lymph nodes (80%) with contralateral recurrence (15%) and distant metastasis (13.7%) (14). A prior study also revealed a higher risk of lymph node recurrence and poor cancer-specific survival associated with symptomatic PTMC as compared with those associated with asymptomatic PTMC (23). In our study, most postsurgical recurrence was found in the lymph nodes of the central or lateral neck compartment (87.9%) in both asymptomatic and symptomatic groups, while distant metastasis developed only from symptomatic PTC (17.6%). Further, symptomatic finding, bilaterality, and the MACIS score (≥5) were significant risk factors of OS. The reported all-cause mortality is as low as 0.1% and tends to be higher in the symptomatic cases (p = 0.02) (14). Our study also showed that the 5-year overall mortality rate was significantly higher in the symptomatic group compared with that in the asymptomatic group (3.1% vs. 0.6%, p < 0.001).

Previously, nonincidental PTMC was detected either by radiological investigation or on the basis of clinically palpable nodules or lymph nodes (14). It has been suggested that radiologically detected asymptomatic PTMC may have more favorable characteristics, being similar to incidental PTMC proven only on histological examination of surgical specimen (14,23). In our study, the radiological incidentalomas, previously considered as nonincidental PTC, were allocated to the asymptomatic group. Thus, the present study presents more reliable data for drawing comparisons between asymptomatic and symptomatic PTC. Further, we included PTC of size 1.1–2.0 cm along with PTMC, since tumors of this size range may be incidentally found.

The retrospective design of our study is a major limitation that may have introduced potential biases and affect the results. Various pathologic subtypes including follicular variant, oxyphilic cell variant, diffuse sclerosing variant, and tall cell variant, among others, were not considered in our analyses because of their very rare occurrence. Furthermore, most cases of asymptomatic PTC in our study were surgically treated without a clinical observational trial. This does not permit to analyze which patients with asymptomatic low-risk PTC should undergo immediate surgery or active surveillance and to determine the extent of surgery for individuals with asymptomatic PTC (15,23,24). In our country, many hospitals have run health promotion and cancer screening programs that include thyroid cancer screening with US and other diagnostic modalities. For this reason, the rates of thyroid cancer diagnoses have increased 15-fold over the past 20 years (25), and most patients with asymptomatic PTC tend to undergo thyroid surgery. However, we may recommend active clinical observation with US follow-up in patients with low-risk PTC of thyroid incidentalomas sized ≤2 cm (26).

In conclusion, our study shows that symptomatic PTC is more likely to exhibit aggressive growth characteristics and metastatic potential than PTC without overt symptoms. Symptomatic PTC is associated with higher recurrence and lower overall survival rates as compared with asymptomatic PTC. These findings call for total thyroidectomy and close posttreatment surveillance in patients with symptomatic PTC.

Footnotes

Acknowledgments

This study was supported by a grant (No. 2015R1A2A1A15054540) from the Basic Science Research Program through the National Research Foundation of Korea, Ministry of Science, ICT, and Future Planning and a grant (No. HI15C2920) from the Korean Health Technology R&D Project through the Korea Health Industry Development Institute, Ministry of Health & Welfare, Seoul, Republic of Korea (J.L.R.).

Author Disclosure Statement

No competing financial interests exist.

References

Grebe

, Hay

. 1996. Thyroid cancer nodal metastases: biologic significance and therapeutic considerations. Surg Oncol Clin N Am, 5:43–63.

Xing

, Alzahrani

, Carson

, Viola

, Elisei

, Bendlova

, Yip

, Mian

, Vianello

, Tuttle

, Robenshtok

, Fagin

, Puxeddu

, Fugazzola

, Czarniecka

, Jarzab

, O'Neill

, Sywak

, Lam

, Riesco-Eizaguirre

, Santisteban

, Nakayama

, Tufano

, Pai

, Zeiger

, Westra

, Clark

, Clifton-Bligh

, Sidransky

, Ladenson

, Sykorova

. 2013. Association between BRAF V600E mutation and mortality in patients with papillary thyroid cancer. JAMA, 309:1493–1501.

American Cancer Society. What are the key statistics about thyroid cancer? Available at www.cancer.org/cancer/thyroidcancer/detailedguide/thyroid-cancer-key-statistics (accessed April 15, 2016 ).

Mazzaferri

, Jhiang

. 1994. Long-term impact of initial surgical and medical therapy on papillary and follicular thyroid cancer. Am J Med, 97:418–428.

La Vecchia

, Malvezzi

, Bosetti

, Garavello

, Bertuccio

, Levi

, Negri

. 2015. Thyroid cancer mortality and incidence: a global overview. Int J Cancer, 136:2187–2195.

Davies

, Welch

. 2006. Increasing incidence of thyroid cancer in the United States, 1973–2002. JAMA, 295:2164–2167.

Welch

, Black

. 2010. Overdiagnosis in cancer. J Natl Cancer Inst, 102:605–613.

Lee

, Shin

. 2014. Overdiagnosis and screening for thyroid cancer in Korea. Lancet, 384:1848.

Roti

, Rossi

, Trasforini

, Bertelli

, Ambrosio

, Busutti

, Pearce

, Braverman

, Degli Uberti

. 2006. Clinical and histological characteristics of papillary thyroid microcarcinoma: results of a retrospective study in 243 patients. J Clin Endocrinol Metab, 91:2171–2178.

10.

Arora

, Turbendian

, Kato

, Moo

, Zarnegar

, Fahey

3rd . 2009. Papillary thyroid carcinoma and microcarcinoma: is there a need to distinguish the two?. Thyroid, 19:473–477.

11.

Lin

, Kuo

, Chao

, Hsueh

. 2008. Incidental and nonincidental papillary thyroid microcarcinoma. Ann Surg Oncol, 15:2287–2292.

12.

Vasileiadis

, Karatzas

, Vasileiadis

, Kapetanakis

, Charitoudis

, Karakostas

, Kouraklis

. 2014. Clinical and pathological characteristics of incidental and nonincidental papillary thyroid microcarcinoma in 339 patients. Head Neck, 36:564–570.

13.

Jin

, McHenry

. 2012. Thyroid incidentaloma. Best Pract Res Clin Endocrinol Metab, 26:83–96.

14.

Mehanna

, Al-Maqbili

, Carter

, Martin

, Campain

, Watkinson

, McCabe

, Boelaert

, Franklyn

. 2014. Differences in the recurrence and mortality outcomes rates of incidental and nonincidental papillary thyroid microcarcinoma: a systematic review and meta-analysis of 21 329 person-years of follow-up. J Clin Endocrinol Metab, 99:2834–2843.

15.

Oda

, Miyauchi

, Ito

, Yoshioka

, Nakayama

, Sasai

, Masuoka

, Yabuta

, Fukushima

, Higashiyama

, Kihara

, Kobayashi

, Miya

. 2016. Incidences of unfavorable events in the management of low-risk papillary microcarcinoma of the thyroid by active surveillance versus immediate surgery. Thyroid, 26:150–155.

16.

Rivera

, Ricarte-Filho

, Tuttle

, Ganly

, Shaha

, Knauf

, Fagin

, Ghossein

. 2010. Molecular, morphologic, and outcome analysis of thyroid carcinomas according to degree of extrathyroid extension. Thyroid, 20:1085–1093.

17.

Radowsky

, Howard

, Burch

, Stojadinovic

. 2014. Impact of degree of extrathyroidal extension of disease on papillary thyroid cancer outcome. Thyroid, 24:241–244.

18.

Jin

, Kim

, Ji

, Song

, Park

, Tae

. 2015. Characteristics and significance of minimal and maximal extrathyroidal extension in papillary thyroid carcinoma. Oral Oncol, 51:759–763.

19.

Lango

, Flieder

, Arrangoiz

, Veloski

, Yu

, Li

, Burtness

, Mehra

, Galloway

, Ridge

. 2013. Extranodal extension of metastatic papillary thyroid carcinoma: correlation with biochemical endpoints, nodal persistence, and systemic disease progression. Thyroid, 23:1099–1105.

20.

Clain

, Scherl

, Dos Reis

, Turk

, Wenig

, Mehra

, Karle

, Urken

. 2014. Extrathyroidal extension predicts extranodal extension in patients with positive lymph nodes: an important association that may affect clinical management. Thyroid, 24:951–957.

21.

Choi

, Cho

, Moon

, Son

. 2016. Metastatic lymph node ratio of central neck compartment has predictive values for locoregional recurrence in papillary thyroid microcarcinoma. Clin Exp Otorhinolaryngol, 9:75–79.

22.

Vas Nunes

, Clark

, Gao

, Chua

, Campbell

, Niles

, Gargya

, Elliott

. 2013. Prognostic implications of lymph node yield and lymph node ratio in papillary thyroid carcinoma. Thyroid, 23:811–816.

23.

Sugitani

, Toda

, Yamada

, Yamamoto

, Ikenaga

, Fujimoto

. 2010. Three distinctly different kinds of papillary thyroid microcarcinoma should be recognized: our treatment strategies and outcomes. World J Surg, 34:1222–1231.

24.

Ito

, Miyauchi

, Inoue

, Fukushima

, Kihara

, Higashiyama

, Tomoda

, Takamura

, Kobayashi

, Miya

. 2010. An observational trial for papillary thyroid microcarcinoma in Japanese patients. World J Surg, 34:28–35.

25.

Ahn

, Kim

, Welch

. 2014. Korea's thyroid-cancer “epidemic”—screening and overdiagnosis. N Engl J Med, 371:1765–1767.

26.

Sugitani

, Fujimoto

. 1999. Symptomatic versus asymptomatic papillary thyroid microcarcinoma: a retrospective analysis of surgical outcome and prognostic factors. Endocr J, 46:209–216.