Key PointsQuestion
Does multifocality increase the risk of tumor recurrence in patients with papillary thyroid carcinoma?
Findings
In this systematic review and meta-analysis of 26 studies comprising 33 976 patients, multifocality was significantly associated with an increased risk of tumor recurrence.
Meaning
These findings suggest that papillary thyroid carcinoma with multifocality may require careful treatment and follow-up approaches.
Importance
Multifocality is common in papillary thyroid carcinoma (PTC), but it is unclear whether multifocal tumors are associated with tumor recurrence or cancer-specific survival.
Objective
To compare tumor recurrence rates in patients with multifocal vs unifocal PTCs.
Data Sources
We searched PubMed, SCOPUS, Web of Science Core Collection, and Cochrane Database of Systematic Reviews for pertinent studies published in English from inception to June 30, 2020.
Study Selection
The search strategy yielded 26 studies that compared tumor recurrence in patients with multifocal vs unifocal PTC.
Data Extraction and Synthesis
Data was extracted in accordance with the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline. Characteristics of study populations and hazard ratio (HR) of multifocality were independently extracted by 2 investigators.
Main Outcomes and Measures
The primary outcome was tumor recurrence and the secondary outcome was cancer-specific survival. Subgroup analysis of the primary outcome was based on primary tumor size, number of tumor foci, and patient age.
Results
Among 26 studies with a total of 33 976 patients, recurrence rates were significantly higher in patients with multifocal PTC than in those with unifocal PTC (pooled HR, 1.81; 95% CI, 1.52–2.14). Cancer-specific survival was comparable between the groups (HR, 1.19; 95% CI, 0.85–1.68). In subgroup analyses, the HRs of multifocality for recurrence were associated with primary tumor size (HRs for PTC ≤1 cm and >1 cm were 1.81 and 1.90, respectively), number of tumor foci (HRs for 2 foci and ≥3 foci were 1.45 and 1.95, respectively), and patient age (HRs for pediatric and adult patients were 3.19 and 1.89, respectively).
Conclusions and Relevance
This systematic review with meta-analysis found that multifocality was significantly associated with an increased risk of recurrence in patients with PTC, while cancer-specific survival showed no difference. Differences in tumor size, number of tumor foci, and patient age should be considered when interpreting the multifocality and the risk of recurrence.
Thyroid cancer is the ninth most frequent cancer worldwide, and its incidence has risen dramatically.1,2 There were 567 233 patients with newly diagnosed thyroid cancer in 2018, representing 3.1% of all cancer cases worldwide. Papillary thyroid carcinoma (PTC) comprises more than 80% of all thyroid cancers, and is usually associated with an excellent prognosis;3 however, up to 30% of patients experience significant disease progression, including regional recurrences and distant metastases.4-6 Researchers have tried to identify the patients at high-risk from among the population with favorable outcomes;7-9 clinicopathological factors, including tumor size, extrathyroidal extension, lymph node metastasis, and multifocality, have been thoroughly evaluated in an effort to predict recurrence and mortality.
Multifocality in thyroid cancer is defined as the simultaneous presence of more than 1 tumor focus within the thyroid gland.10 Multifocality in PTC occurred in 18% to 87% of the cases in the literature.10,11 Several studies have demonstrated that multifocality is associated with high-risk features of PTC, including aggressive histologic subtype, extrathyroidal extension, lymph node involvement, distant metastasis, and recurrences.12-14 Some researchers have further demonstrated that multifocal PTCs could decrease overall and cancer-specific survival.11,15 Other researchers have indicated that patients with multifocal diseases showed a similar clinical course or comparable recurrence rates as those with unifocal disease.16-18 These conflicting results indicate a need for more comprehensive studies, including meta-analysis. Therefore, we conducted a systematic review with meta-analysis to identify a possible association between multifocality and the prognosis of PTC.
A comprehensive search was performed of PubMed, SCOPUS, Web of Science Core Collection, and Cochrane Database of Systematic Reviews, from inception to June 30, 2020. The search strategy included a combination of the following search terms using the Boolean “and/or” operator: thyroid cancer, PTC, recurrence, prognosis, and multifocal. In addition, references in review articles and editorials were carefully examined for possible inclusion of studies. This meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline.19 Ethics committee review was not required for a meta-analysis.
Inclusion criteria were observational cohort studies of patients with PTC that reported comparative data associating multifocality and an outcome of interest (recurrence or cancer-specific survival). Exclusion criteria were: (1) overlapping data from another study; (2) studies without original data, such as case series, commentaries, and editorials; (3) studies involving nonhuman subjects; and (4) articles not written in English.
Data Collection and Quality Assessment
Two investigators (H. Kim and H. Kwan) independently evaluated studies on the basis of the eligibility criteria. Disagreements in selection were resolved by discussion with a third investigator (B.-I. M). If multiple studies used the same data source, the most informative study was selected for inclusion. Each reviewer carefully extracted the relevant information using a structured data collection form. Extracted data included country of publication, study period, number of patients, multifocality rates, and hazard ratio (HR) for recurrences. The quality of the included studies was rated using the Newcastle-Ottawa Scale.20
All statistical analyses were performed using Review Manager, version 5.3 (Cochrane Collaboration). We extracted or estimated HRs for multifocality with 95% CIs to calculate pooled estimates of HRs and 95% CIs. When HRs were not reported and unable to be calculated from raw individual data, HRs and 95% CIs were estimated using the number of observed events, the number of patients in each group, and P values from log-rank tests using published methodology.21 Heterogeneity across studies was quantified by the I2 statistic and interpreted qualitatively as low (25%-49%), moderate (50%-74%), and high (≥75%). A random-effect model was applied when significant heterogeneity was found across studies (I2 ≥50%); otherwise, a fixed-effect model was used. P values were 2-tailed and statistical significance was defined as P < .05. Publication bias was evaluated by both Begg and Egger regression tests using funnel plots.
A total of 2712 studies were identified by the initial literature search. After removal of 918 duplicates, 1794 publications were screened for further review. We eliminated 1682 of these publications for meeting exclusion criteria or not being relevant. Of the remaining 112 reviewed for eligibility, 26 unique studies were finally selected for inclusion in this meta-analysis.11,15,17,18,22-43 The flow diagram for study selection is available as eFigure in the Supplement).
Characteristics of Included Studies
The main characteristics of the included studies are described in the Table. Among 33 976 patients in 26 studies, the median rate of multifocality was 28.1% (range, 6.4%-60.1%). The recurrence rate of PTC in the included studies ranged from 2.7% to 46.4%, with an average rate of 8.0%. The median follow-up duration was 6.6 years (range, 2.4-27.0 y).
Multifocality and Tumor Recurrence
Figure 1 presents the meta-analysis findings.11,15,17,18,22-43 As moderate heterogeneity was found across the studies (I2 = 67%; P < .001), we used random-effect models. Patients with multifocal diseases had a higher risk of recurrence (pooled HR, 1.81; 95% CI, 1.52–2.14) compared with those with unifocal PTC.
Subgroup analysis was performed to evaluate potential sources of heterogeneity that might influence the recurrence of PTC. We evaluated 3 factors that could affect the HR for recurrences: primary tumor size (≤1 cm or >1 cm), number of tumor foci (2 or ≥3), and patient age (pediatric [<20 y] or adult).
Six studies comprising 7550 patients were eligible for evaluating the association of multifocality with recurrence, according to the primary tumor size (Figure 2A).18,23,28,32,36,42 The pooled HR of multifocality for recurrence in patients with papillary thyroid microcarcinoma (PTMC; defined as PTC ≤1 cm) was 1.81 (95% CI, 1.18–2.77), while that in patients with PTC larger than 1 cm was 1.90 (95% CI, 1.11–3.25). High heterogeneity (I2 = 79%; P = .002) was found in subgroup with PTC larger than 1 cm, while the PTMC subgroup showed low heterogeneity (I2 = 46%; P = .11).
Two studies39,40 of 1758 patients were analyzed to evaluate the association between the number of tumor foci and recurrences (Figure 2B). The subgroup of patients with 3 or more foci was associated with a higher risk of recurrence (pooled HR, 1.95; 95% CI, 1.33–2.85; P < .001), while the subgroup with 2 foci was associated with a nonsignificant increased risk (pooled HR, 1.45; 95% CI, 0.97–2.17; P = .07). Moderate heterogeneity (I2 = 59%; P = .12) was found in the 3 or more foci subgroup, although the 2 foci subgroup showed low heterogeneity (I2 = 40%; P = .20).
The recurrence rate among pediatric patients with thyroid cancer was reported in 4 studies with a total of 1139 patients,27,29,37,38 while recurrence among adults was described in 5 studies with 1705 patients22,23,30,32,35 (Figure 2C). Multifocality of thyroid cancer was associated with a significant increased risk of recurrence in both pediatric (pooled HR, 3.19; 95% CI, 1.29–7.90; P = .01) and adult subgroups (pooled HR, 1.89; 95% CI, 1.06–3.38; P = .03), respectively. Moderate heterogeneity (I2 = 62%; P = .03) was found in the adult subgroup, while the pediatric subgroup showed low heterogeneity (I2 = 45%; P = .14).
Effect of the Multifocality on Cancer-Specific Survival
Four studies of 3895 patients reported the HR of patients with multifocal disease for cancer-specific survival11,15,34,41 (Figure 3). The cancer-specific mortality rates of the included studies ranged from 2.2% to 8.9%, with an average rate of 5.8%. The median follow-up duration was 16.6 years (range, 7.0 years-27.0 years). Patients with multifocal disease showed cancer-specific survival comparable to that of those with unifocal PTC (pooled HR, 1.19; 95% CI, 0.85–1.68; P = .31). Low heterogeneity (I2 = 30%; P = .12) was found across these studies.
A funnel plot was generated to assess publication bias in the studies that evaluated recurrence rates. Results of both Begg and Egger statistical tests were nonsignificant (P = .39 and P = .14, respectively; Figure 4), suggesting no publication bias.
This meta-analysis demonstrated that multifocal PTCs were associated with a higher risk of recurrence, while cancer-specific survival was not associated with multifocal PTCs. Multifocality has been considered to be a risk factor for the progression of PTC.44-49 More aggressive treatments, including total thyroidectomy and higher-dose radioiodine, have been commonly applied to treat patients with multifocal diseases.36,44,50 Current risk stratification systems also include multifocality as a predictive factor for recurrence, although they classify multifocality alone (without other risk factors) as a low-risk category.47,48 However, a recent large multi-institutional study suggested that multifocality has no independent prognostic value for clinical outcomes.18 We attempted to address this controversy with this systematic review and meta-analysis.
A few other meta-analyses have evaluated the association between multifocality and the recurrence rates of PTC.12-14,16 Guo and colleagues demonstrated that multifocality had no association with recurrence;16 however, the other meta-analyses12-14 found an association between multifocality and the risk of recurrence. In part these controversial are owed to the different statistical methods used for analyzing outcomes. Because time-to-event outcomes, such as recurrence and survival, can be more accurately evaluated using HRs,21 we used HRs for this statistical analysis. In this updated and comprehensive meta-analysis, we concluded that multifocality was associated with an increased risk of recurrence (pooled HR, 1.81; 95% CI, 1.52–2.14). Interpretation of the overall effect size, however, should be done with caution because moderate heterogeneity was found across the studies (I2 = 67%; P < .001).
Subgroup analyses were conducted to understand the potential sources of heterogeneity across the studies. The influence of multifocality can vary according to the primary tumor size.36,51 A consensus report by the European Society of Endocrine Surgeons suggested that multifocality may be a prognostic tool in overt PTC, but would not be useful for PTMC.44 On the contrary, Feng and colleagues reported that the HR for recurrence could be higher in patients with PTMC than for those with PTC >1 cm.23 The subgroup analysis that we performed by tumor size demonstrated that multifocality was associated with an increased risk of recurrences in patients with PTMC (HR, 1.81; 95% CI, 1.18–2.77) as well as those with PTC > -cm (HR, 1.90; 95% CI, 1.11–3.25). These findings imply that multifocality should be considered a risk factor for tumor recurrence even in patients with small PTCs, such as PTMC.
Multifocal PTCs may have different characteristics according to the number of tumor foci52 in part because they may be the consequence of intrathyroidal spread from a single tumor, which represents the tumor burden.52,53 Patients with 3 or more tumor foci experienced higher rates of recurrence than those with 2 foci.23 Lin and colleagues reported that recurrence rates could increase proportionately (up to 45.8%) with a rising number of tumor foci.54 The subgroup analysis in this study found that having 3 or more tumor foci was associated with a higher risk of recurrence, while having only 2 tumor foci did not increase the risk.
PTC in pediatric patients has been found to be more aggressive and to have a higher risk of recurrence than PTC in adulthood.37 Nevertheless, the role of multifocality in recurrence according to age groups is controversial. A meta-analysis conducted in 2016 concluded that multifocality was associated with higher rates of recurrence in pediatric patients;14 however, that study had some limitations, such as the inaccurate estimation of HRs and the inclusion of both PTC and follicular thyroid carcinoma. Because recent studies have been reporting controversial findings,27,29 we conducted a subgroup analysis by patient age and found that multifocality was associated with recurrence in pediatric patients (HR, 3.19; 95% CI, 1.29–7.90) at a higher rate than in adults (HR, 1.89; 95% CI, 1.06–3.38). The findings of the present study support the claim that pediatric patients with multifocal PTCs require careful treatment and follow-up approaches.37
This meta-analysis had some limitations. First, methodological approaches can affect reports of multifocality and tumor foci numbers.44 Mazeh and colleagues55 have indicated that the number of tumor foci may increase when entire thyroid glands are serially sectioned and examined. Different methods used by the studies may have resulted in certain types of biases. Second, although we concluded that multifocality was associated with an increased risk of recurrence, it is still unclear whether multifocality justifies aggressive surgery or adjuvant therapy. Additional comparative studies are warranted to address these issues. Third, some studies have suggested that total tumor diameter could be useful for the prediction of aggressiveness.56 However, because of insufficient data, we did not conduct meta-regression nor subgroup analysis for total tumor diameter.
This updated systematic review with meta-analysis confirmed that multifocality is associated with an increased risk of tumor recurrence in patients with PTC. Tumor size, number of tumor foci, and patient age should be considered when determining treatment and follow-up approaches.
Accepted for Publication: June 30, 2021.
Published Online: August 19, 2021. doi:10.1001/jamaoto.2021.1976
Corresponding Author: Hyungju Kwon, MD, PhD, Department of Surgery, Ewha Womans University Medical Center, 1071 Anyangcheon-ro, Yangcheon-Gu, Seoul 07985, Republic of Korea (hkwon@ewha.ac.kr).
Author Contributions: Dr Kwon had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Concept and design: Kwon, Moon.
Acquisition, analysis, or interpretation of data: Kim, Kwon.
Drafting of the manuscript: All authors.
Critical revision of the manuscript for important intellectual content: Kwon.
Statistical analysis: Kim, Kwon.
Administrative, technical, or material support: Kwon.
Supervision: Moon.
Conflict of Interest Disclosures: None reported.
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