Prognostic Impact of Primary Tumor Size in Papillary Thyroid Carcinoma without Lymph Node Metastasis

Article information

Endocrinol Metab. 2025;40(3):405-413

Publication date (electronic) : 2025 February 25

doi : https://doi.org/10.3803/EnM.2024.2199

Chae A Kim ¹^,^*

, Hye In Kim ²^,^*

, Na Hyun Kim ¹

, Tae Yong Kim ¹

, Won Bae Kim ¹

, Jae Hoon Chung ³

, Min Ji Jeon ¹

, Tae Hyuk Kim ³

, Sun Wook Kim^,³

, Won Gu Kim^,¹

¹Division of Endocrinology and Metabolism, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea

²Division of Endocrinology and Metabolism, Department of Internal Medicine, Samsung Changwon Hospital, Sungkyunkwan University School of Medicine, Changwon, Korea

³Division of Endocrinology and Metabolism, Department of Internal Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea

Corresponding authors: Sun Wook Kim. Division of Endocrinology and Metabolism, Department of Internal Medicine, Thyroid Center, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-gu, Seoul 06351, Korea Tel: +82-2-3410-1653, Fax: +82-2-6918-4653, E-mail: swkimmd@skku.edu

Won Gu Kim. Division of Endocrinology and Metabolism, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Songpa-gu, Seoul 05505, Korea Tel: +82-2-3010-5883, Fax: +82-2-3010-6962, E-mail: wongukim@amc.seoul.kr

*These authors contributed equally to this work.

Received 2024 October 2; Revised 2024 December 6; Accepted 2025 January 2.

Abstract

Background

We aimed to investigate the prognostic significance of primary tumor size in patients with pT1–T3a N0 M0 papillary thyroid carcinoma (PTC), minimizing the impact of confounding factors.

Methods

A multicenter retrospective study included 5,759 patients with PTC. Those with lymph node metastasis, gross extrathyroidal extension (ETE), and aggressive variants were excluded. Patients were categorized by primary tumor size (≤1, 1.1–2, 2.1–4, and >4 cm) and subdivided based on the presence of microscopic ETE (mETE).

Results

The median age was 48.0 years, and 87.5% were female. The median primary tumor size was 0.7 cm, with mETE identified in 43.7%. The median follow-up was 8.0 years, with an overall recurrent/persistent disease rate of 2.8%. Multivariate analysis identified male sex, larger tumor size, and the presence of mETE as significant prognostic risk factors. The 10-year recurrent/persistent disease rates for tumors ≤1, 1.1–2, 2.1–4, and >4 cm were 2.5%, 4.7%, 11.1%, and 6.0%, respectively. The 2.1–4 cm group had a significantly higher hazard ratio (HR), with the >4 cm group had the highest HR than the ≤1 cm group. Patients with mETE had a higher recurrent/persistent disease rate (4.5%) than those without, with rates by tumor size being 2.6%, 5.6%, 16.7%, and 8.2%.

Conclusion

Larger tumor size and the presence of mETE significantly increased the risk of recurrent/persistent disease in PTC. Patients with pT2–T3a N0 M0 PTC (>2 cm) had a recurrent/persistent disease risk exceeding 5%, warranting vigilant management.

Keywords: Thyroid cancer, papillary; Tumor size; Microscopic extrathyroidal extension; Lymph node metastasis

GRAPHICAL ABSTRACT

INTRODUCTION

In patients with differentiated thyroid cancer (DTC), an appropriate risk stratification system for predicting recurrence has become essential for guiding treatment decisions, as emphasized in the 2015 American Thyroid Association (ATA) guidelines [1]. These guidelines recommend tailoring the application and extent of treatment, including surgery, radioactive iodine (RAI) therapy, and aggressive thyroid-stimulating hormone suppression therapy, on patient-to-patient basis. The primary objective of this approach is to prevent unnecessary managements in low-risk patients and promptly initiate more aggressive treatment for those who need it.

Age at diagnosis, primary tumor size, the presence of significant extrathyroidal extension (ETE), lymph node (LN) metastasis, and distant metastasis at diagnosis are well-known prognostic factors of DTC [2-7]. Despite tumor size being a pathological characteristic determining tumor-node-metastasis (TNM) staging, the sole impact of tumor size on the risk of recurrence remains unclear [8-12]. While the 2009 ATA guidelines classified intrathyroidal papillary thyroid carcinoma (PTC) of any size as low risk for recurrent/persistent disease, without specifying tumor size criteria, the 2015 ATA guidelines defined intrathyroidal PTCs <4 cm as low risk. This distinction has implications for treatment decisions, as patients in this low-risk category generally do not require completion thyroidectomy or RAI therapy [1,13]. Notably, larger tumor size has been suggested to be closely associated with negative prognostic factors such as ETE, multifocality, and LN metastasis [9,14,15]. Furthermore, the presence of ETE correlates with a higher risk of recurrence with increased LN metastasis in PTC [16]. Consequently, the presence of LN metastasis and gross ETE can be considered confounding variables when evaluating the clinical implications of primary tumor size. Moreover, the prognostic significance of microscopic ETE (mETE) remains controversial [5,10]. This complexity fuels ongoing debate regarding the role of primary tumor size as an independent risk factor, particularly considering the conflicting data that include patients with other risk factors [9,10,17].

Greater knowledge of the clinical and pathological features of PTC may enhance diagnostic frameworks and enable more personalized therapies. Accordingly, this study aimed to elucidate the prognostic significance of primary tumor size in patients with pathologically confirmed T1–T3a N0 M0 PTC, thereby minimizing the impact of other confounding risk factors. Additionally, we analyzed the prognostic significance of mETE in this population.

METHODS

This multicenter, retrospective cohort study was conducted at two tertiary referral centers in Korea: Asan Medical Center (AMC) and Samsung Medical Center (SMC). We initially screened 11,076 consecutive patients with pathologically diagnosed T1–T3a M0 PTC who underwent thyroidectomy with prophylactic central neck dissection at AMC (1995–2012) and SMC (1996–2005), excluding 12 patients with distant metastatic disease identified at the initial assessment or within the first 6 months of follow-up. We excluded 5,068 patients with LN metastasis, 209 with gross ETE, and 40 with aggressive variants of PTC. A total of 5,759 patients with pT1–T3a N0 M0 PTC were included in the study (Fig. 1). The study protocol was approved by the Institutional Review Boards of AMC (IRB No. 2024-0701) and SMC (IRB No.2016-05-053). The need for informed consent was waived due to the retrospective nature of the study.

Fig. 1.

Flow diagram shows the protocol of this cohort study. PTC, papillary thyroid carcinoma; AMC, Asan Medical Center; SMC, Samsung Medical Center.

Baseline demographics data (age at diagnosis and sex) and pathological data (histology, primary tumor size, multifocality, and the presence of mETE) were collected. In addition, the extent of surgical treatment along with adjuvant RAI treatments were recorded. According to the eighth edition of American Joint Committee on Cancer Staging Manual, mETE was defined as tumor extension into the perithyroidal soft tissue [18]. Patients were divided into four groups based on primary tumor size (≤1 cm/T1a, 1.1–2 cm/T1b, 2.1–4 cm/T2, and >4 cm/T3a). Each group was further subdivided according to the presence of mETE.

The primary outcome was structural recurrent/persistent disease, which was defined as the appearance of metastatic lesions after initial treatment, confirmed by cytological or histopathological examination, and/or the appearance of distant metastatic lesions on imaging. Indeterminate or suspicious thyroid nodules and LNs were evaluated using fine-needle aspiration cytology. Additional diagnostic imaging such as neck or chest computed tomography, magnetic resonance imaging, or whole-body fluorodeoxyglucose positron emission tomography, was performed as needed to detect recurrence or distant metastasis.

All statistical analyses were conducted using R version 4.1.1 (R Foundation for Statistical Computing, Vienna, Austria; http://www.R-project.org). Continuous variables are expressed as median values (interquartile ranges [IQRs]) and were compared using the Wilcoxon rank-sum test or unpaired t test, as appropriate. Categorical variables are expressed as numbers (percentages) and were compared using Pearson’s chi-square test or Fisher exact test, as appropriate. Recurrent/persistent disease rates were analyzed using the Kaplan‒Meier method and visualized with GraphPad Prism version 10.2 (GraphPad Software, San Diego, CA, USA; http://www.graphpad.com); these were compared using the log-rank test. The Cox proportional hazard model was used for univariate and multivariate analyses to evaluate relevant risk factors and calculated hazard ratios (HRs) and 95% confidence intervals (CIs). All P values were two-sided, and P<0.05 was considered statistically significant.

RESULTS

Baseline characteristics

The baseline characteristics of patients are delineated in Table 1. The median age at diagnosis was 48.0 years (IQR, 40.7 to 55.0), and 87.5% of patients were female. In terms of pathological subtype, classical PTC was diagnosed in 95.6% of patients, whereas the remaining 4.4% presented with the follicular subtype of PTC. The median primary tumor size was 0.7 cm (IQR, 0.5 to 1.0), and the presence of mETE was identified in 43.7% of patients. During the study period, the earlier ATA guidelines for DTC were followed, which recommended total thyroidectomy even for small tumors [19,20]. In total, 61.0% of patients underwent total thyroidectomy, and 39.0% underwent hemithyroidectomy. Postoperative RAI treatment was administered in 46.0% of patients. The median follow-up period was 8.0 years (IQR, 5.3 to 11.9), and the overall recurrent/persistent disease rate was 2.8% (159/5,759). Among these, locoregional recurrent/persistent disease was observed in 113 patients, including 41 (35.0%) in the thyroid operative bed or central neck LNs, 39 (33.3%) in the lateral neck LNs, and 37 (31.6%) in the contralateral thyroid lobe, with some patients overlapping in recurrent/persistent sites. Distant organ recurrence was identified in eight patients, while location of recurrent/persistent disease in the remaining 38 patients could not be determined. The distribution of patients according to primary tumor size was as follows: ≤1 cm (T1a), 1.1–2 cm (T1b), 2.1–4 cm (T2), and >4 cm (T3a) were found in 4,323 (75.1%), 1,015 (17.6%), 349 (6.1%), and 72 (1.3%) patients, respectively.

Table 1.

Baseline Characteristics of Patients with pT1–T3a N0 M0 Papillary Thyroid Carcinoma

Risk factors predicting structural recurrent/persistent disease

Cox proportional hazard regression analysis was performed to assess variables associated with structural recurrent/persistent disease (Table 2). The univariate analysis identified age, male sex, primary tumor size, the presence of mETE, and RAI therapy as significant prognostic factors of recurrent/persistent disease. In the multivariate analysis, older age (HR, 1.02; 95% CI, 1.0 to 1.03; P=0.017), male sex (HR, 1.42; 95% CI, 1.19 to 2.71; P=0.007), primary tumor size (detail below), and the presence of mETE (HR, 1.53; 95% CI, 1.09 to 2.15; P=0.014) remained significant independent risk factors for predicting structural recurrent/persistent disease.

Table 2.

Clinical and Pathological Characteristics Predicting Structural Recurrent/Persistent Disease

Prognostic impact of primary tumor size on recurrent/persistent disease

Table 3 details clinical and pathological characteristics stratified by primary tumor size. Patients with larger tumors were more likely to be young and male. T3a tumors were more frequently of the follicular subtype and showed a lower incidence of mETE than the other groups (P<0.001). T1b and T2 tumors were more likely to present with mETE than T1a tumors (P<0.001). Additionally, patients with tumors >1 cm (T1b, T2, and T3a) were more likely to have undergone total thyroidectomy and RAI treatment than those in the T1a group (P<0.001).

Table 3.

Clinical and Pathological Characteristics of Patients Based on the Primary Tumor Size

As shown in Fig. 2, the risk of recurrent/persistent disease significantly correlated with primary tumor size (P<0.001). Patients with T1b and T2 tumors exhibited significantly higher recurrent/persistent disease rates than those with T1a tumors (P<0.001). The 10-year recurrent/persistent disease rates, as derived from the Kaplan-Meier survival analysis, were 2.5%, 4.7%, 11.1%, and 6.0% for patients with T1a, T1b, T2, and T3a tumors, respectively. The 15-year recurrent/persistent disease rate for patients with T3a tumors was the highest at 14.1%. The numbers of patients with T1a, T1b, T2, and T3a tumors and structural recurrent/persistent disease were 75 (1.7%), 42 (4.1%), 35 (10.0%), and 7 (9.7%), respectively.

Fig. 2.

The recurrent/persistent disease rates of pT1–T3a N0 M0 papillary thyroid carcinoma based on the primary tumor size. CI, confidence interval.

Table 2 shows the prognostic impact of the primary tumor size on recurrent/persistent disease. Compared with T1a tumors, the crude HRs of recurrent/persistent disease were 4.55 (95% CI, 3.03 to 6.82; P=0.001) for T2 tumors and 4.59 (95% CI, 2.11 to 9.98; P<0.001) for T3a tumors. After adjusting for age, sex, pathological subtype, extent of surgery, RAI therapy, and the presence of mETE, the HRs of recurrent/persistent disease were 4.37 (95% CI, 2.91 to 6.57; P<0.001) for T2 tumors and 4.52 (95% CI, 2.07 to 9.85; P<0.001) for T3a tumors.

Prognostic impact of mETE on recurrent/persistent disease

Patients were divided into two groups based on the presence of mETE (Table 4). Age at diagnosis was higher in patients with mETE than in those without (P<0.001). Tumors with mETE were significantly more likely to be of the follicular subtype, larger, and multifocal compared with those without mETE (all P<0.001). Additionally, patients with mETE were significantly more likely to have undergone total thyroidectomy and RAI treatment than those without (both P<0.001).

Table 4.

Clinical and Pathological Characteristics of Patients Based on the Presence of Microscopic ETE

Fig. 3 illustrates the risk of recurrent/persistent disease based on the presence of mETE. Patients with mETE had significantly higher 10-year recurrent/persistent disease rates than those without (4.5% vs. 2.8%, respectively, P<0.001). We further analyzed the recurrent/persistent disease rate stratified by tumor size and the presence of mETE. In patients without mETE, the 10-year recurrent/persistent disease rates for those with T1a, T1b, T2, and T3a tumors were 2.3%, 3.7%, 5.8%, and 4.7%, respectively (Fig. 4A). In contrast, patients with mETE and T1a, T1b, T2, and T3a tumors had recurrent/persistent disease rates of 2.6%, 5.6%, 16.7%, and 8.2%, respectively (Fig. 4B), with excessive rates in patients with T2 tumors with mETE.

Fig. 3.

The recurrent/persistent disease rates of pT1–T3a N0 M0 papillary thyroid carcinoma based on the presence of microscopic extrathyroidal extension (ETE). CI, confidence interval.

Fig. 4.

The recurrent/persistent disease rates of pT1–T3a N0 M0 papillary thyroid carcinoma (PTC) based on the primary tumor size and presence of microscopic extrathyroidal extension (ETE), where (A) represents PTCs without microscopic ETE and (B) represents PTCs with microscopic ETE. CI, confidence interval.

DISCUSSION

This multicenter retrospective study demonstrated that clinical outcomes in patients with pT1–T3a N0 M0 PTC vary based on the primary tumor size and presence of mETE. Age, sex, primary tumor size, and the presence of mETE were observed to be independent predictors of recurrent/persistent disease in these patients; furthermore, the risk of recurrent/persistent disease significantly increased with increasing tumor sizes, even after adjusting for other variables. The recurrent/persistent disease rates for tumors >2 cm exceeded 5% after 10 years, regardless of mETE status, and when mETE was present, the rates further increased.

Patients with intrathyroidal PTCs <4 cm without gross ETE and LN metastasis are considered to be at low risk for recurrent/persistent disease [1]. Patients with 2.1–4 cm PTCs with the BRAF V600E mutation have been reported to have recurrent/persistent disease rates as high as 12.1% [1,21,22]. Contrary to ATA guidelines, our findings demonstrated that the recurrent/persistent disease rates for patients with 2.1–4 cm tumors without gross ETE and LN metastasis exceeded 10%, which represents an intermediate risk. The rate of recurrent/persistent disease further increased to over 15% when mETE was present. The BRAF V600E mutation rate in Korean patients with PTC has consistently remained high, at approximately 70%, which may have contributed to the higher rates observed in our study [23]. These results indicate that careful disease surveillance with adjuvant treatment is needed for this patient population.

The risk of recurrence is known to be 5%–6% in patients with intrathyroidal PTCs <4 cm and 8%–10% in those with intrathyroidal PTCs >4 cm [1,8,10,24-26]. In line with ATA guidelines, the current study showed a 10-year recurrent/persistent rate of 6.0% for patients with tumors >4 cm, which increased to 14.1% at 15 years, classifying them as intermediate risk. However, patients with tumors >4 cm and without additional risk factors were few, comprising only 1.3% of patients, and many had follicular variants, suggesting that caution is needed in interpreting these results.

The effects of ETE in PTC have been previously investigated, although the prognostic significance of mETE remains controversial [5,10,27,28]. One study observed no significant difference in recurrence-free survival between patients with and without mETE [10]. In contrast, meta-analyses have demonstrated that mETE is associated with a higher probability of recurrence [5,6]. The risk of structural recurrent/persistent disease associated with the presence of mETE ranges from 3% to 9%, with ATA guidelines classifying mETE as an intermediate-risk feature [29,30]. Although we observed the presence of mETE to be an independent risk factor of recurrent/persistent disease, the absolute increase in risk was small; the overall recurrent/persistent disease rate of patients with PTCs with mETE was 4.5%, which is within the low-risk ATA category. Therefore, the current findings suggest that mETE alone may not have a meaningful impact on disease outcomes. However, patients with tumors >2 cm and mETE had a significantly higher recurrent/persistent disease rate than those without mETE, highlighting a substantial effect in this patient population.

The strengths of the current study include its multicenter design and long-term follow-up data, which support the robustness of our findings. Furthermore, this study provides practical information for initial risk stratification based on risk factors specific to Korean patients. Unlike previous studies, this study minimized the influence of confounding risk factors, enhancing the accuracy and reliability of the results. However, the retrospective design, which introduces the possibility of selection bias, was a limitation of the study. In addition, the study was limited by the small number of cases with tumors >4 cm, the large proportion of patients with papillary thyroid microcarcinoma, and the lack of BRAF V600E mutation status data. Moreover, the inclusion of patients who received more aggressive treatment based on earlier guidelines may have led to biased results. Therefore, further large-scale prospective studies are necessary to validate our findings.

In conclusion, primary tumor size and the presence of mETE were identified as significant prognostic factors for recurrent/persistent disease in patients with pT1–T3a N0 M0 PTC. Patients with pT2–T3a N0 M0 PTC, namely those with tumors >2 cm, had a recurrent/persistent disease rate exceeding 5% irrespective of mETE status, placing them in the intermediate-risk category and indicating a need for more vigilant management.

Notes

CONFLICTS OF INTEREST

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

ACKNOWLEDGMENTS

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (RS-2022-NR069128 and RS-2018-NR032917) and by a grant (2024IL0008) from the Asan Institute for Life Sciences, Asan Medical Center, Seoul, Korea. A part of this study was presented as an abstract at a meeting of the Korean Thyroid Association in 2024.

AUTHOR CONTRIBUTIONS

Conception or design: S.W.K., W.G.K. Acquisition, analysis, or interpretation of data: C.A.K., H.I.K., N.H.K., T.Y.K., W.B.K., J.H.C., M.J.J., T.H.K., S.W.K., W.G.K. Drafting the work or revising: C.A.K, H.I.K., W.G.K. Final approval of the manuscript: C.A.K., H.I.K., N.H.K., T.Y.K., W.B.K., J.H.C., M.J.J., T.H.K., S.W.K., W.G.K.

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Characteristic	Total (n=5,759)
Age at diagnosis, yr	48.0 (40.7–55.0)
Male sex	722 (12.5)
Pathological subtype
Classical	5,505 (95.6)
Follicular	254 (4.4)
Primary tumor size, cm	0.7 (0.5–1.0)
≤1 (T1a)	4,323 (75.1)
1.1–2 (T1b)	1,015 (17.6)
2.1–4 (T2)	349 (6.1)
>4 (T3a)	72 (1.3)
Multifocality	1,459 (25.3)
Microscopic extrathyroidal extension	2,517 (43.7)
Surgery
Total thyroidectomy	3,514 (61.0)
Hemithyroidectomy	2,245 (39.0)
Radioactive iodine therapy	2,647 (46.0)

Characteristic	Univariate analysis		Multivariate analysis
Characteristic	HR (95% CI)	P value	HR (95% CI)	P value
Age at diagnosis, yr	1.02 (1.00–1.03)	0.012^a	1.02 (1.00–1.03)	0.017^a
Male sex	1.87 (1.26–2.77)	0.002^a	1.42 (1.19–2.71)	0.007^a
Pathology (follicular subtype)	1.51 (0.84–2.72)	0.172	1.02 (0.78–1.76)	0.802
Primary tumor size, cm
≤1 (T1a)	1.0 (Reference)		1.0 (Reference)
1.1–2 (T1b)	1.93 (1.32–2.82)	0.001^a	1.86 (1.27–2.72)	0.001^a
2.1–4 (T2)	4.55 (3.03–6.82)	0.001^a	4.37 (2.91–6.57)	<0.001^a
>4 (T3a)	4.59 (2.11–9.98)	<0.001^a	4.52 (2.07–9.85)	<0.001^a
Multifocality	0.98 (0.68–1.41)	0.910	0.94 (0.65–1.37)	0.754
Microscopic extrathyroidal extension	1.75 (1.28–2.40)	0.002^a	1.53 (1.09–2.15)	0.014^a
Surgery (total thyroidectomy)	1.27 (0.90–1.79)	0.175	0.62 (0.37–1.05)	0.175
Radioactive iodine therapy	1.73 (1.24–2.41)	0.001^a	1.43 (0.85–2.41)	0.075

Characteristic	≤1 cm (T1a) (n=4,323)	1.1–2 cm (T1b) (n=1,015)	2.1–4 cm (T2) (n=349)	>4 cm (T3a) (n=72)	P value
Age at diagnosis, yr	48.7 (41.3–55.0)	47.0 (38.6–55.4)	46.6 (36.4–57.4)	40.5 (30.3–55.0)	<0.001^a
Male sex	528 (12.2)	125 (12.3)	52 (14.9)	17 (23.6)	0.016^a
Pathological subtype					<0.001^a
Classical	4,257 (98.5)	936 (92.2)	265 (75.9)	47 (65.3)
Follicular	66 (1.5)	79 (7.8)	84 (24.1)	25 (34.7)
Multifocality	1,084 (25.1)	390 (27.6)	76 (21.8)	19 (26.4)	0.154
Microscopic ETE	1,786 (41.3)	529 (52.1)	177 (50.7)	25 (34.7)	<0.001^a
Surgery					<0.001^a
Total thyroidectomy	2,307 (53.4)	838 (82.6)	307 (88.0)	62 (86.1)
Hemithyroidectomy	2,016 (46.6)	177 (17.4)	42 (12.0)	10 (13.9)
Radioactive iodine therapy	1,503 (34.8)	796 (78.4)	288 (82.5)	60 (83.3)	<0.001^a
Follow-up, yr	6.8 (5.2–10.8)	7.8 (5.0–11.8)	7.9 (5.0–12.0)	7.8 (5.1–11.9)	<0.001^a

Characteristic	Without microscopic ETE (n=3,242)	With microscopic ETE (n=2,517)	P value
Age at diagnosis, yr	47.5 (39.7–54.5)	49.0 (41.9–56.7)	<0.001^a
Male sex	397 (12.2)	325 (12.9)	0.006^a
Pathological subtype			<0.001^a
Classical	3,184 (98.2)	2,321 (92.2)
Follicular	58 (1.8)	196 (7.8)
Primary tumor size, cm	0.6 (0.4–1.0)	0.8 (0.6–1.2)	<0.001^a
Multifocality	765 (23.6)	694 (27.6)	<0.001^a
Surgery			<0.001^a
Total thyroidectomy	1,835 (56.6)	1,679 (66.7)
Hemithyroidectomy	1,407 (43.4)	838 (33.2)
Radioactive iodine therapy	1,128 (34.8)	1,519 (60.3)	<0.001^a