Journal List > Endocrinol Metab > v.38(1) > 1516081381

Moon, Song, Jung, Lee, and Park: Lower Thyroid Cancer Mortality in Patients Detected by Screening: A Meta-Analysis

Abstract

Background

Thyroid cancer screening has contributed to the skyrocketing prevalence of thyroid cancer. However, the true benefit of thyroid cancer screening is not fully understood. This study aimed to evaluate the impact of screening on the clinical outcomes of thyroid cancer by comparing incidental thyroid cancer (ITC) with non-incidental thyroid cancer (NITC) through a meta-analysis.

Methods

PubMed and Embase were searched from inception to September 2022. We estimated and compared the prevalence of high-risk features (aggressive histology of thyroid cancer, extrathyroidal extension, metastasis to regional lymph nodes or distant organs, and advanced tumor-node-metastasis [TNM] stage), thyroid cancer-specific death, and recurrence in the ITC and NITC groups. We also calculated pooled risks and 95% confidence intervals (CIs) of the outcomes derived from these two groups.

Results

From 1,078 studies screened, 14 were included. In comparison to NITC, the ITC group had a lower incidence of aggressive histology (odds ratio [OR], 0.46; 95% CI, 0.31 to 0.7), smaller tumors (mean difference, −7.9 mm; 95% CI, −10.2 to −5.6), lymph node metastasis (OR, 0.64; 95% CI, 0.48 to 0.86), and distant metastasis (OR, 0.42; 95% CI, 0.23 to 0.77). The risks of recurrence and thyroid cancer-specific mortality were also lower in the ITC group (OR, 0.42; 95% CI, 0.25 to 0.71 and OR, 0.46; 95% CI, 0.28 to 0.74) than in the NITC group.

Conclusion

Our findings provide important evidence of a survival benefit from the early detection of thyroid cancer compared to symptomatic thyroid cancer.

INTRODUCTION

The incidence of thyroid cancer has risen worldwide during the last three decades [1]. The observed increase in thyroid cancer may be attributable to the increase in incidentally detected subclinical microcarcinomas, rather than a real change in incidence [2,3]. The rapid increase in the incidence of thyroid cancer in the Korean population has been substantial, and a previous study argued that 90% of thyroid cancer cases in South Korean women between 2008 and 2012 were attributable to overdiagnosis, despite the non-inclusion of thyroid cancer screening in the national screening program [4]. In recent years, there has been intensified debate regarding the role of thyroid ultrasound screening in detecting thyroid cancer.
The importance of a cancer screening program relies on its proven net benefit. According to the United States Preventive Services Task Force (USPSTF), the benefit is assessed in terms of five aspects: the screening effectiveness or accuracy, the benefits or harms of screening, and the benefits and harms of treatment [5]. To evaluate the benefits of thyroid cancer screening, associated experts reviewed references in the literature and assessed the evidence; however, few studies dealing with the benefits and harms of thyroid cancer screening were found [6]. Furthermore, the most important question—whether screening leads to a reduced risk of thyroid cancer-specific mortality— could not be answered yet [7].
The necessity or uselessness of thyroid cancer screening has been investigated using outcomes derived from retrospective observational studies, but the extraordinarily good prognosis of thyroid cancer, the wide spectrum of definitions of thyroid incidentalomas, and the diverse sociomedical circumstances of the studied populations have yielded inconsistent results. This study aimed to evaluate the impact of screening on the outcomes of thyroid cancer through a comparison between the outcomes of incidental thyroid cancer (ITC) and non-incidental thyroid cancer (NITC). First, we estimated the prevalence of aggressive histologic features in ITC and NITC. Second, we compared the thyroid cancer-specific mortality and recurrence rates between ITC and NITC.

METHODS

For the purposes of this study, ITC was defined as an unexpected thyroid cancer incidentally detected by imaging methods (ultrasound, computed tomography [CT]/magnetic resonance imaging [MRI], and 18F-fludeoxyglucose [FDG] positron emission tomography [PET]/CT) or an analysis of a surgical pathology specimen. NITC was defined as thyroid cancer that had been detected due to clinical signs or symptoms (palpable thyroid lump, voice change or difficulty in swallowing, abnormality on a physical examination by a physician, and so on). This meta-analysis was performed following the Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines (Supplemental Tables S1, S2) [8]. The flow diagram is shown in Fig. 1. The study protocol was registered in the Prospective Register of Systematic Reviews (number CRD42022365478).

Search strategy and selection criteria

We performed a systematic literature search through Ovid-MEDLINE, Embase, and the Cochrane Library for studies published since 2012. Studies prior to 2012 that were included in the 2012 National Evidence-based Healthcare Collaborating Agency (NECA) report [9] (n=3) and studies included in a recent systematic review [10] but not included in our search results (n=3) were manually added. The search started on August 29, 2022 and finished on September 7, 2022. Previous reviews were evaluated, and individual articles included therein were eligible for the present review. Search terms were created using the PICO structure as follows. The patients (P) were all individuals diagnosed with thyroid cancer. The intervention (I) was a thyroid imaging test with the intention of screening or another purpose. The comparator (C) was palpation of the thyroid gland or thyroid imaging test due to thyroid disease-related symptoms. The outcomes (O) comprised findings on clinicopathologic reports, including histology, tumor size, extrathyroidal extension (ETE), lymph node metastasis, distant metastasis, and tumornode-metastasis (TNM) stage, as well as the recurrence and thyroid cancer-specific mortality rates. The study design was a case-control design. The search terms and electronic search strategy are summarized in Supplemental Table S3.
Duplicates were filtered through an automated function of the Endnote X9 citation manager and then manually searched. After removing duplicates, the titles and abstracts of the initial search results were screened, and non-English language publications were excluded. The full texts of the remaining articles were independently assessed by four investigators (S.M., Y.S.S., K.Y.J., and E.K.L.). Any discrepancies were resolved by discussion and consensus between the two researchers.

Data extraction and management

Data sets were extracted from each eligible study by four independent reviewers (S.M., Y.S.S., K.Y.J., and E.K.L.). The required information included author name, publication year, study design, country, the total number of patients and controls, the mean age of subjects, the sex ratio, histology, clinicopathologic characteristics, recurrence, and thyroid cancer-specific mortality for both groups. Discrepancies between the reviewers regarding study eligibility were resolved by discussion.

Quality assessment and risk of bias

The quality of the included studies and the risk of bias were assessed using the Cochrane risk of bias criteria (Risk of Bias Assessment of Non-randomized Studies [RoBANS] version 2.0), which included: (1) selection of participants, (2) confounding variables, (3) measurement of intervention, (4) blinding for outcome assessment, (5) incomplete outcome data, and (6) selective outcome reporting; these parameters were independently assessed by four reviewers (S.M., Y.S.S., K.Y.J., and E.K.L.). Any discrepancies were resolved by discussion. The quality of the 14 included studies was evaluated using RoBANS version 2.0 (Fig. 2).

Statistical methods

Comparisons of pathologic staging, recurrence rate, and thyroid cancer mortality were expressed as risk ratios and 95% confidence intervals (CIs). The heterogeneity of the studies was tested using the Higgins I2 statistic. I2 values of 25%, 50%, and 75% represented low, moderate, and high heterogeneity, respectively. If the I2 value was ≥50%, a random-effect model was used; if I2 was <50%, a fixed-effect model was used. Publication bias was investigated with the Egger test and by a visual evaluation of the funnel plot (Supplemental Fig. S1). A sensitivity analysis was conducted to determine the robustness of outcomes through repeated meta-analyses after excluding each study (Supplemental Fig. S2). Statistical analyses were performed with Comprehensive Meta-Analysis software version 3 (Biostat Inc., Englewood, NJ, USA) and R version 3.1.0 (R Foundation for Statistical Computing, Vienna, Austria; www.rproject.org). P values <0.05 were considered statistically significant.

RESULTS

Study characteristics

The literature search yielded 1,078 studies. After the exclusion of 19 duplicate studies and 1,032 studies that did not meet the inclusion criteria, 14 studies [11-24] were finally included in the meta-analysis (Fig. 1). The characteristics of each study are summarized in Table 1. A total of 9,432 participants with thyroid cancer were enrolled, of whom 5,091 (53.9%) were incidentally diagnosed with thyroid cancer. Among them, 13 studies reported clinicopathologic results and six studies provided longitudinal data for recurrence or thyroid cancer-specific mortality in ITC and NITC. Five studies were conducted in Korea, six in America, and three in Europe.

Risk of bias assessment

The results of the risk of bias assessment using RoBANS are summarized in Fig. 2. (1) Regarding participant selection, four of the 14 case-control studies had a low risk in selection of participants, while three studies had a high-risk of bias due to an inadequate control group. The remaining seven studies were unclear. (2) Eight studies had a low-risk of bias due to confounders, while four had high-risk. Two studies were unclear. (3) All studies had a low-risk of bias due to measurement of intervention. (4) All studies showed a low-risk of bias due to blinding for outcome assessment or inadequate outcome assessment. (5) Thirteen studies had a low-risk of bias due to incomplete outcome data, and one was unclear. (6) For selective outcome reporting, seven studies were at a low-risk of bias, one at high-risk, and six at unclear risk.

Comparison of pathologic characteristics between ITC and NITC

To compare the distribution of aggressive histology between ITC and NITC, 10 studies were analyzed. The incidence of aggressive histology of thyroid cancer (medullary thyroid cancer or anaplastic thyroid cancer) was significantly lower in ITC than in NITC (odds ratio [OR], 0.46; 95% CI, 0.31 to 0.7) (Fig. 3A). Heterogeneity was not significant among these studies (I2=21%).
Nine studies were included in the meta-analysis of tumor size in ITC and NITC. The mean difference between ITC and NITC was −7.9 mm (95% CI, −10.2 to −5.6), and I2 was 94%, indicating significant heterogeneity (Fig. 3B). The funnel plot was symmetrical, and publication bias was not detected (Egger test, P=0.315) (Supplemental Fig. S1). In the sensitivity analysis, the significance of the results did not change even after each study was removed, and no outliers were observed (Supplemental Fig. S2).
To compare the proportion of ETE in ITC and NITC, seven studies were included. The ITC group had a lower risk of ETE (OR, 0.88; 95% CI, 0.79 to 0.98) (Fig. 3C). Heterogeneity was not significant among these studies (I2=0%); however, the funnel plot was asymmetrical and significant publication bias was detected (Egger test, P=0.019). The trim-and-fill method was conducted to adjust for publication bias and showed that statistical significance disappeared after adding three estimated missing studies (OR, 0.91; 95 % CI, 0.82 to 1.01) (Supplemental Fig. S1). The sensitivity analysis showed robust results from repeated analyses after excluding each study (Supplemental Fig. S2).
Twelve studies were included in the meta-analysis of lymph node metastasis. The ITC group had a lower risk of lymph node metastasis (OR, 0.64; 95% CI, 0.48 to 0.86) compared to the NITC group, and I2 was 74%, indicating significant heterogeneity (Fig. 3D). The funnel plot was symmetrical, and publication bias was not significant (Egger test, P=0.134) (Supplemental Fig. S1). In the sensitivity analysis, the significance of the results did not change even after each study was removed, and no outliers were observed (Supplemental Fig. S2). In addition, lymph node metastasis was divided into central and lateral metastasis, and a meta-analysis was performed of the four studies that contained this information. The risk of central lymph node metastasis was not significantly different between the two groups (OR, 0.69; 95% CI, 0.38 to 1.24), but that of lateral lymph node metastasis was lower in the ITC group (OR, 0.31; 95% CI, 0.21 to 0.44) (Supplemental Fig. S3).
Five studies were included in the meta-analysis of distant metastasis. The ITC group had a lower risk of distant metastasis (OR, 0.42; 95% CI, 0.23 to 0.77) than the NITC group, without significant heterogeneity (I2=43%) (Fig. 3E).
Seven studies were included in the meta-analysis of TNM stage. The OR for advanced TNM stage (III to IV) was not significantly higher in the ITC group than in the NITC group, and there was significant heterogeneity (OR, 0.99; 95% CI, 0.73 to 1.33; I2=59%) (Fig. 3F).

Mortality and recurrence rate in ITC and NITC

Four studies were included in the meta-analysis of the recurrence rate in the ITC and NITC groups. The overall recurrence rate was 3.4% in the ITC group, versus 11.4% in the NITC group. In comparison with the NITC group, the ITC group had a significantly lower risk of recurrence (OR, 0.42; 95% CI, 0.25 to 0.71) (Fig. 4). Although no significant heterogeneity was found among these studies (I2=0%), the funnel plot was asymmetrical, and significant publication bias was detected (Egger’s test, P=0.01). The trim-and-fill method was conducted to adjust for publication bias and showed that statistical significance remained after adding two estimated missing studies (OR, 0.46; 95% CI, 0.28 to 0.74) (Supplemental Fig. S1). The sensitivity analysis showed robust results from repeated analyses after excluding each study (Supplemental Fig. S2).
Five studies with eight datasets were included in the meta-analysis of thyroid cancer-specific mortality. In comparison with the NITC group, the ITC group had a lower risk of thyroid cancer-specific mortality (OR, 0.28; 95% CI, 0.18 to 0.43) (Fig. 5). Heterogeneity was not significant among these studies (I2=0%). The funnel plot analysis and the Egger test revealed no significant publication bias (P=0.503) (Supplemental Fig. S1). The sensitivity analysis showed robust results from repeated analyses after excluding each study (Supplemental Fig. 2).
Regarding postoperative complications, only two articles were included, which was insufficient to perform a meta-analysis. A summary derived from systematic reviews is presented in Supplemental Table S4, revealing no significant differences in the prevalence of postoperative complications between ITC and NITC.

DISCUSSION

This meta-analysis demonstrated that ITC patients had lower risks of unfavorable clinicopathologic characteristics, such as aggressive histology, large tumor size, ETE, lymph node metastasis, distant metastasis, and advanced TNM stage, than NITC patients. Furthermore, in ITC patients, the risks of recurrence and mortality were significantly lower than in NITC patients, confirming the effectiveness and benefits of thyroid cancer screening.
In the 2017 USPSTF report [5], there was insufficient evidence to conclude whether thyroid cancer screening for adults leads to a reduced risk of thyroid cancer-specific morbidity, mortality, and/or all-cause mortality. Recently, Chooi et al. [10] reported a systematic review on the prognosis of thyroid incidentalomas. Although a meta-analysis could not be performed for the prognosis due to heterogeneity in the inclusion criteria, prognosis marker assessments, and follow-up duration, they reviewed 14 studies on the prognosis or various prognostic markers, such as histological characteristics and cancer staging in ITC and NITC. Four studies on recurrence—not mortality—were included to compare the thyroid cancer prognosis of ITC and NITC. All included studies showed a lower risk of recurrence in ITC than in NITC [11,12,22,25], although some studies did not reach statistical significance. Meanwhile, in our study, we added more studies through a thorough systematic review and performed a meta-analysis with recent studies, including the National Epidemiological Survey of Thyroid cancer (NEST) [21].
We analyzed the NEST study [21] as three separate populations according to the time period, because the study randomly sampled Korean thyroid cancer patients at three time points (1999, 2005, and 2008) [26]. As Kim et al. [18] described previously, the early detection of thyroid cancer by ultrasound in Korea started in earnest in 2004 [27]. Moreover, the incidence of thyroid cancer increased dramatically in 2009 [28]. Therefore, to reflect heterogeneity in the clinicopathological features of thyroid cancer over time, each population from these three time points was analyzed as an independent group in this study.
The increased incidence of thyroid cancer coincided with the introduction and widespread use of imaging modalities such as ultrasound, and the improved sensitivity of diagnostic tools since the 2000s [4,29]. Despite the rising incidence of thyroid cancer, mortality from thyroid cancer remained stable, which has been interpreted as reflecting overdiagnosis [30,31]. However, according to a recent study of Surveillance, Epidemiology, and End Results (SEER) data, thyroid cancer incidence decreased during 2014 to 2018, but incidence-based mortality continued to increase [32]. Given the results of our study, which showed that thyroid cancer screening can reduce mortality, overdiagnosis alone might not be sufficient to explain the increased incidence of thyroid cancer.
The current meta-analysis revealed that patients with ITC had more indolent tumor behaviors and better prognoses, suggesting that early detection improves the clinical outcomes of thyroid cancer. For patients with locally advanced or high-risk thyroid cancer, early diagnosis and treatment can prevent serious disease progression [33]. Therefore, to solve the issues of overdiagnosis and overtreatment caused by thyroid cancer screening, it is necessary to minimize the harms of screening and treatment while maintaining the benefits of screening. Moreover, it is critical to develop appropriate diagnosis and management guidelines for incidentally detected thyroid nodules. In this context, the Korean Society of Thyroid Radiology revised the indications for fine-needle aspiration to be stricter [34,35] to reduce unnecessary diagnostic tests. In addition, active surveillance for low-risk thyroid cancers has been introduced [36] and large-scale multicenter prospective clinical studies are currently being conducted in Korea, thereby minimizing the risk of unnecessary surgery [37,38].
Our study has several strengths. First, this is the first meta-analysis to comprehensively compare the clinicopathological characteristics and prognosis of ITC and NITC. Second, we demonstrated that ITC had better thyroid cancer-specific survival. The ultimate goal of cancer screening, which generally aims to detect cancer at an early stage rather than to prevent cancer occurrence, is to reduce cancer-related mortality [39,40]. Thus, it is meaningful that this study revealed a survival benefit, reflecting the purpose of cancer screening. However, this study has certain limitations. First, the spectrum of ITC was wide, including incidentalomas detected by various imaging modalities (ultrasound, carotid Doppler, neck CT/MRI, and 18F-FDG PET/CT) or occult tumors found in the surgical pathology specimens of benign tumors. Furthermore, NITC covered various symptoms or signs, mostly neck symptoms, but one study [18] included patients with systemic symptoms due to distant metastasis in the NITC category. Second, no prospective randomized clinical trials were included in the meta-analysis, and retrospective cohort studies harbor a high probability of bias, as is widely recognized [41,42]. Nevertheless, the included studies were assessed as having a low-risk of bias, considering the large number of participants and well-controlled design.
In conclusion, our findings provide important evidence for a survival benefit from the early detection of thyroid cancer compared to symptomatic thyroid cancer.

Supplementary Material

Supplemental Table S1.

PRISMA Checklists for Risk Study
EnM-2023-1667-suppl1.pdf

Supplementary Table S2.

PRISMA Checklists for Prognosis Study
EnM-2023-1667-suppl2.pdf

Supplementary Table S3.

Electronic Search Strategy
EnM-2023-1667-suppl3.pdf

Supplementary Table S4.

Systematic Review Comparing the Prevalence of Postoperative Complication between ITC and NITC Groups
EnM-2023-1667-suppl4.pdf

Supplementary Fig. S1.

Funnel plots for visual assessment of publication bias. (A) medullary thyroid cancer (MTC) or anaplasatic thyroid cancer (ATC), (B) size, (C) extrathyroidal extension (ETE), (D) lymph node metastasis (LNM), (E) distant metastasis, (F) advanced stage III to IV, (G) recurrence, and (H) thyroid cancer specific mortality. OR, odds ratio; CI, confidence interval; RR, risk ratio.
EnM-2023-1667-suppl5.pdf

Supplementary Fig. S2.

Results of sensitivity analysis. (A) medullary thyroid cancer (MTC) or anaplasatic thyroid cancer (ATC), (B) size, (C) extrathyroidal extension (ETE), (D) lymph node metastasis (LNM), (E) distant metastasis, (F) advanced stage III to IV, (G) recurrence, and (H) thyroid cancer specific mortality. OR, odds ratio; CI, confidence interval; MD, mean difference; RR, risk ratio.
EnM-2023-1667-suppl6.pdf

Supplementary Fig. S3.

Results of meta-analysis for central and lateral lymph node metastasis between the incidental thyroid cancer (ITC) and non-incidental thyroid cancer (NITC) groups. OR, odds ratio; CI, confidence interval.
EnM-2023-1667-suppl7.pdf

Notes

CONFLICTS OF INTEREST

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

AUTHOR CONTRIBUTIONS

Conception or design: E.K.L., Y.J.P. Acquisition, analysis, or interpretation of data: S.M., Y.S.S., K.Y.J., E.K.L. Drafting the work or revising: S.M., Y.S.S., K.Y.J., E.K.L. Final approval of the manuscript: S.M., Y.S.S., K.Y.J., E.K.L., Y.J.P.

ACKNOWLEDGMENTS

This study was supported by the Korean Thyroid Association, research funding from the National Cancer Center (Grant Number 2210521-2 and 2112570-3), and a grant from the National Research Foundation (NRF) of Korea (NRF-2020R1C1-C1003924).
We acknowledge and thank Miyoung Choi (National Evidence-based Healthcare Collaborating Agency, Division of Health Technology Assessment Research) and Chang Hee Cho (The Korean Society of Radiology), who contributed to searching and interpreting the evidence.

REFERENCES

1. Kim J, Gosnell JE, Roman SA. Geographic influences in the global rise of thyroid cancer. Nat Rev Endocrinol. 2020; 16:17–29.
crossref
2. Davies L, Welch HG. Increasing incidence of thyroid cancer in the United States, 1973-2002. JAMA. 2006; 295:2164–7.
crossref
3. Pizzato M, Li M, Vignat J, Laversanne M, Singh D, La Vecchia C, et al. The epidemiological landscape of thyroid cancer worldwide: GLOBOCAN estimates for incidence and mortality rates in 2020. Lancet Diabetes Endocrinol. 2022; 10:264–72.
crossref
4. Li M, Dal Maso L, Vaccarella S. Global trends in thyroid cancer incidence and the impact of overdiagnosis. Lancet Diabetes Endocrinol. 2020; 8:468–70.
crossref
5. Lin JS, Bowles EJ, Williams SB, Morrison CC. Screening for thyroid cancer: updated evidence report and systematic review for the US Preventive Services Task Force. JAMA. 2017; 317:1888–903.
6. Yi KH, Kim SY, Kim DH, Kim SW, Na DG, Lee YJ, et al. The Korean guideline for thyroid cancer screening. J Korean Med Assoc. 2015; 58:302–12.
crossref
7. US Preventive Services Task Force, Bibbins-Domingo K, Grossman DC, Curry SJ, Barry MJ, Davidson KW, et al. Screening for thyroid cancer: US Preventive Services Task Force recommendation statement. JAMA. 2017; 317:1882–7.
8. Moher D, Liberati A, Tetzlaff J, Altman DG; PRISMA Group. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ. 2009; 339:b2535.
crossref
9. National Evidence-based Healthcare Collaborating Agency. Effectiveness of ultrasonographic screening for thyroid cancer 2012 [Internet]. Seoul: NECA;2023. [cited 2023 Feb 17]. Available from: https://neca.re.kr.
10. Chooi JE, Ravindiran A, Balasubramanian SP. The influence of incidental detection of thyroid nodule on thyroid cancer risk and prognosis: a systematic review. Clin Endocrinol (Oxf). 2022; 96:246–54.
11. Shakil J, Ansari MZ, Brady J, Xu J, Robbins RJ. Lower rates of residual/recurrent disease in patients with incidentally discovered thyroid carcinoma. Endocr Pract. 2017; 23:163–9.
crossref
12. Kim SH, Roh JL, Gong G, Cho KJ, Choi SH, Nam SY, et al. 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. Thyroid. 2016; 26:1472–9.
crossref
13. Marina M, Ceda GP, Aldigeri R, Ceresini G. Causes of referral to the first endocrine visit of patients with thyroid carcinoma in a mildly iodine-deficient area. Endocrine. 2017; 57:247–55.
crossref
14. Pisanu A, Reccia I, Nardello O, Uccheddu A. Risk factors for nodal metastasis and recurrence among patients with papillary thyroid microcarcinoma: differences in clinical relevance between nonincidental and incidental tumors. World J Surg. 2009; 33:460–8.
crossref
15. Malone MK, Zagzag J, Ogilvie JB, Patel KN, Heller KS. Thyroid cancers detected by imaging are not necessarily small or early stage. Thyroid. 2014; 24:314–8.
crossref
16. Bahl M, Sosa JA, Nelson RC, Esclamado RM, Choudhury KR, Hoang JK. Trends in incidentally identified thyroid cancers over a decade: a retrospective analysis of 2,090 surgical patients. World J Surg. 2014; 38:1312–7.
crossref
17. Brito JP, Al Nofal A, Montori VM, Hay ID, Morris JC. The impact of subclinical disease and mechanism of detection on the rise in thyroid cancer incidence: a population-based study in Olmsted County, Minnesota during 1935 through 2012. Thyroid. 2015; 25:999–1007.
crossref
18. Kim H, Park SY, Jung J, Kim JH, Hahn SY, Shin JH, et al. Improved survival after early detection of asymptomatic distant metastasis in patients with thyroid cancer. Sci Rep. 2019; 9:18745.
crossref
19. Chung WY, Chang HS, Kim EK, Park CS. Ultrasonographic mass screening for thyroid carcinoma: a study in women scheduled to undergo a breast examination. Surg Today. 2001; 31:763–7.
crossref
20. Choi YJ, Park YL, Koh JH. Prevalence of thyroid cancer at a medical screening center: pathological features of screen-detected thyroid carcinomas. Yonsei Med J. 2008; 49:748–56.
crossref
21. Moon S, Lee EK, Choi H, Park SK, Park YJ. Survival comparison of incidentally found versus clinically detected thyroid cancers: an analysis of a nationwide cohort study. Endocrinol Metab (Seoul). 2023; 38:81–92.
crossref
22. Solis-Pazmino P, Salazar-Vega J, Lincango-Naranjo E, Garcia C, Koupermann GJ, Ortiz-Prado E, et al. Thyroid cancer overdiagnosis and overtreatment: a cross-sectional study at a thyroid cancer referral center in Ecuador. BMC Cancer. 2021; 21:42.
23. Farra JC, Picado O, Liu S, Ouyang W, Teo R, Franco AM, et al. Clinically significant cancer rates in incidentally discovered thyroid nodules by routine imaging. J Surg Res. 2017; 219:341–6.
crossref
24. Yoo F, Chaikhoutdinov I, Mitzner R, Liao J, Goldenberg D. Characteristics of incidentally discovered thyroid cancer. JAMA Otolaryngol Head Neck Surg. 2013; 139:1181–6.
crossref
25. Marina M, Serra MF, Aldigeri R, Ceresini G. Incidental versus clinically diagnosed differentiated thyroid cancer in both adult and elderly subjects: histological characteristics and follow-up in a retrospective analysis from a single institution. Endocrine. 2020; 68:584–91.
crossref
26. Oh CM, Kong HJ, Kim E, Kim H, Jung KW, Park S, et al. National epidemiologic survey of thyroid cancer (NEST) in Korea. Epidemiol Health. 2018; 40:e2018052.
crossref
27. Park S, Oh CM, Cho H, Lee JY, Jung KW, Jun JK, et al. Association between screening and the thyroid cancer “epidemic” in South Korea: evidence from a nationwide study. BMJ. 2016; 355:i5745.
crossref
28. Jung KW, Won YJ, Kong HJ, Oh CM, Cho H, Lee DH, et al. Cancer statistics in Korea: incidence, mortality, survival, and prevalence in 2012. Cancer Res Treat. 2015; 47:127–41.
crossref
29. Ahn HS, Kim HJ, Welch HG. Korea’s thyroid-cancer “epidemic”: screening and overdiagnosis. N Engl J Med. 2014; 371:1765–7.
crossref
30. Vaccarella S, Franceschi S, Bray F, Wild CP, Plummer M, Dal Maso L. Worldwide thyroid-cancer epidemic?: the increasing impact of overdiagnosis. N Engl J Med. 2016; 375:614–7.
crossref
31. Franceschi S, Vaccarella S. Thyroid cancer: an epidemic of disease or an epidemic of diagnosis? Int J Cancer. 2015; 136:2738–9.
crossref
32. Megwalu UC, Moon PK. Thyroid cancer incidence and mortality trends in the United States: 2000-2018. Thyroid. 2022; 32:560–70.
crossref
33. Nguyen QT, Lee EJ, Huang MG, Park YI, Khullar A, Plodkowski RA. Diagnosis and treatment of patients with thyroid cancer. Am Health Drug Benefits. 2015; 8:30–40.
34. Shin JH, Baek JH, Chung J, Ha EJ, Kim JH, Lee YH, et al. Ultrasonography diagnosis and imaging-based management of thyroid nodules: revised Korean Society of Thyroid Radiology consensus statement and recommendations. Korean J Radiol. 2016; 17:370–95.
crossref
35. Ha EJ, Chung SR, Na DG, Ahn HS, Chung J, Lee JY, et al. 2021 Korean thyroid imaging reporting and data system and imaging-based management of thyroid nodules: Korean Society of Thyroid Radiology consensus statement and recommendations. Korean J Radiol. 2021; 22:2094–123.
crossref
36. Yi KH, Lee EK, Kang HC, Koh Y, Kim SW, Kim IJ, et al. 2016 Revised Korean Thyroid Association management guidelines for patients with thyroid nodules and thyroid cancer. Int J Thyroidol. 2016; 9:59–126.
crossref
37. Moon JH, Kim JH, Lee EK, Lee KE, Kong SH, Kim YK, et al. Study protocol of multicenter prospective cohort study of active surveillance on papillary thyroid microcarcinoma (MAeSTro). Endocrinol Metab (Seoul). 2018; 33:278–86.
crossref
38. Jeon MJ, Kang YE, Moon JH, Lim DJ, Lee CY, Lee YS, et al. Protocol for a Korean multicenter prospective cohort study of active surveillance or surgery (KoMPASS) in papillary thyroid microcarcinoma. Endocrinol Metab (Seoul). 2021; 36:359–64.
crossref
39. Prorok PC. Epidemiologic approach for cancer screening: problems in design and analysis of trials. Am J Pediatr Hematol Oncol. 1992; 14:117–28.
40. Kramer BS, Brawley OW. Cancer screening. Hematol Oncol Clin North Am. 2000; 14:831–48.
crossref
41. Carlson MD, Morrison RS. Study design, precision, and validity in observational studies. J Palliat Med. 2009; 12:77–82.
crossref
42. Boyko EJ. Observational research: opportunities and limitations. J Diabetes Complications. 2013; 27:642–8.

Figure 1.
Flow diagram of study selection. aStudies that did not report the mortality/recurrence or pathologic characteristics of incidental thyroid cancer were excluded. Additionally, studies of patients with thyroid cancer risk factors, such as nuclear accidents and radiation exposure, were excluded.
EnM-2023-1667f1.tif
Figure 2.
Risk of bias assessment within studies using Risk of Bias Assessment of Non-randomized Studies (RoBANS).
EnM-2023-1667f2.tif
Figure 3.
Results of the meta-analysis for pathologic characteristics between the incidental thyroid cancer (ITC) and non-incidental thyroid cancer (NITC) groups. (A) Medullary thyroid cancer (MTC) or anaplastic thyroid cancer (ATC), (B) size, (C) extrathyroidal extension (ETE), (D) lymph node metastasis (LNM), (E) distant metastasis, and (F) advanced stage III to IV. OR, odds ratio; CI, confidence interval; SD, standard deviation; MD, mean difference.
EnM-2023-1667f3.tif
Figure 4.
Results of the meta-analysis for recurrence between the incidental thyroid cancer (ITC) and non-incidental thyroid cancer (NITC) groups. CI, confidence interval. aRecurrence and residual cancer.
EnM-2023-1667f4.tif
Figure 5.
Results of the meta-analysis for mortality between the incidental thyroid cancer (ITC) and non-incidental thyroid cancer (NITC) groups. CI, confidence interval. aThyroid cancer with distant metastasis.
EnM-2023-1667f5.tif
Table 1.
Summary of Studies Included in the Meta-Analysis
Study Country, recruitment years Groupa Method of incidental detection No. of patients Mean age, yr PTC, % Mean tumor size, cm Lymph node metastasis at diagnosis % Distant metastasis at diagnosis % No. of recurrence (%) No. of thyroid cancerspecific death (%) Overall follow-up, mo (range)
Moon et al. (2023) [21] Korea, 1999, 2005, 2008 ITC Imaging 2,655 46.8 95.3 1.0 42 0.6 NR 23 (0.9) 164
NITC 1,784 47.0 92.7 1.7 46.8 1 NR 74 (4.1) 179
Solis-Pazmino et al. (2021) [22] Ecuador, 2014–2017 ITC Imaging, pathology 246 46.3 NR 2.23 43.8 NR NR NR NR
NITC 206 43 NR 3.57 53.7 NR NR NR NR
Kim et al. (2019) [18] Korea, 1994–2013 Before 2004 Imaging, pathology 33 44.2 54.5 3.5 51.5 100 NR 16 (48.5) 72 (0–276)
ITC 13 100 NR 6 (46.2)
NITCb 20 100 NR 10 (50.0)
After 2004 94 50.7 52.1 3.7 64.5 100 NR 29 (30.9) 72 (0–276)
ITC 64 100 NR 11 (17.2)
NITCb 30 100 NR 18 (60.0)
Shakil et al. (2017) [11] USA, 2005–2014 ITC Imaging, pathology 46 53.0 95.5 NR 13 NR 3 (6.7)d NR 27.0 (6–55)
NITC 126 45.3 94.4 NR 29.4 NR 25 (20.8)d NR 26.5 (6–58)
Marina et al. (2017) [13] Italy, 1998–2015 ITC Imaging 99 50.0 92.9 1.3 13.3 1.0 4 (4) 1 (1.0) 67.2 (32.4–114)
NITC 62 44.0 87.1 2.5 23.3 6.5 7 (11) 1 (1.6) 67.2 (32.4–114)
Farra et al. (2017) [23] USA, 2010–2016 ITC Imaging 65 54 91 NR 47 NR NR NR NR
NITC 401 50 92 NR 33 NR NR NR NR
Kim et al. (2016) [12] Korea, 2006–2009 ITC Imaging 1,259 55.0 100 0.9 40.2 0 41 (3.3) 0 95.0 (24–119)
NITC 160 55.0 100 1.1 52.5 1.9 17 (10.6) 2 (1.3) 96.0 (24–118)
Brito et al. (2015) [17] USA, 2000–2012 1935–1999 Imaging, pathology
ITC 59 52.3 89.8 0.98 NR NR NR NR NR
NITC 203 44.2 79.8 2.3 NR NR NR NR NR
2000–2012
ITC 113 49.6 95.6 1.3 NR NR NR NR NR
NITC 100 42.7 91 2.3 NR NR NR NR NR
Malone et al. (2014) [15] USA, 2007–2010 ITC Imaging 184 51 NR 1.6 39 NR NR NR NR
NITC 218 46 NR 2.1 58 NR NR NR NR
Bahl et al. (2014) [16] USA, 2003–2012 ITC Imaging 101 57 84.2 1.8 24.7 0 NR NR NR
NITC 485 46 82.7 2.2 32.4 1.0 NR NR NR
Yoo et al. (2013) [24] USA, 2008–2009 ITC Imaging 31 56.4 83.9 2.15 22.6 0 NR NR NR
NITC 207 41.8 87.9 2.11 20.8 0.5 NR NR NR
Pisanu et al. (2009) [14] Italy, 1998–2007 ITC Pathology 73 52.5 100 0.4 1.4 NR 0 0 65.2
NITC 76 49.5 100 0.7 34.1 NR 3 (3.9) 0 65.2
Choi et al. (2008) [20] Korea, 2006–2008 ITC Imaging 46 51.1 93.5 0.6 28.3 NR NR NR NR
NITC 157 48.1 97.5 1.6 29.9 NR NR NR NR
Chung et al. (2001) [19] Korea, 1997–1998 ITCc Imaging 37 46.5 97.3 1.0 40.5 NR NR NR NR
NITC 106 45.3 92.5 1.9 78.3 NR NR NR NR

PTC, papillary thyroid carcinoma; ITC, incidental thyroid cancer; NR, not reported; NITC, non-incidental thyroid cancer.

a Incidental thyroid cancer was defined as an unexpected thyroid cancer incidentally detected by imaging methods (ultrasound, computed tomography/magnetic resonance imaging, and 18-fludeoxyglucose positron emission tomography/computed tomography) or analysis of a surgical pathology specimen. Non-incidental thyroid cancer was defined as thyroid cancer that had been detected due to clinical signs or symptoms (palpable thyroid lump, voice change or difficulty in swallowing, abnormality on physical examination by a physician, and so on);

b The enrolled patients had thyroid cancer with initial distant metastasis. The NITC group included both patients with local symptoms and patients with systemic symptoms;

c Women who were scheduled to undergo either a breast cancer screening or a follow-up examination for breast cancer were screened for thyroid cancer;

d Recurrence or residual.

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