Bilateral Multifocality, a Marker for Aggressive Disease, Is Not an Independent Prognostic Factor for Papillary Thyroid Microcarcinoma

A Propensity Score Matching Analysis

Ting Yan; Wangwang Qiu; Jianlu Song; Tao Ying; Youben Fan; Zhili Yang


Clin Endocrinol. 2021;95(1):209-216. 

In This Article

Abstract and Introduction


Context: Multifocality and bilaterality are common in patients with papillary thyroid microcarcinoma (PTMC). However, their clinical behaviours and prognostic implications remain controversial.

Objective: To investigate the relationship between multifocality and classically aggressive characteristics and outcomes in patients with PTMC.

Methods: Clinical data of 3005 patients with PTMC were retrospectively reviewed at a tertiary medical centre. The role of unilateral and bilateral multifocality in aggressive characteristics and clinical outcomes of PTMC was evaluated using propensity score matching (PSM).

Results: A total of 573 patients had bilateral multifocal disease (B-MFD), 272 had unilateral multifocal disease (U-MFD), and 2160 had unifocal disease (UFD). Univariate analysis showed that patients in the multifocal disease (MFD) groups showed significantly different characteristics compared to patients in the UFD group in terms of age, chronic lymphocytic thyroiditis (CLT), follicular variant PTMC, tumour diameter, aggressive growth, including extrathyroidal extension (ETE), central lymph node metastasis (CLNM) and lateral lymph node metastasis (LLNM), and TNM stage, and underwent radioactive iodine (RAI) therapy. Further stratified analysis revealed that patients in the B-MFD group reflected the differences between the MFD and UFD groups. However, those in the U-MFD group showed slight differences only in sex, CLT and cell subtypes, compared to the UFD group. In addition, PSM indicated differences in ETE, CLNM and LLNM between the B-MFD and UFD groups (p < .001), while only ETE differed between the U-MFD and UFD groups (p < .001). After a median follow-up period of 60 months, no difference was observed in recurrence-free survival between the UFD and B-MFD (p = .294) or U-MFD (p = .603) groups using PSM.

Conclusion: This propensity score matching analysis provides strong evidence that bilateral multifocality, rather than unilateral multifocality, should be considered as an aggressive marker at presentation, and neither is an independent prognostic factor for clinical outcome in PTMC.


The incidence of thyroid cancer, the most common endocrine malignancy, continues to increase worldwide.[1] This increase is mainly due to better techniques for the detection of papillary thyroid microcarcinomas (PTMCs), which are defined as tumours with a maximum diameter of 1.0 cm or less.[2,3] Although most PTMCs have excellent prognoses and are often considered indolent diseases, some PTMCs show aggressive behaviours such as extrathyroidal extension (ETE), central lymph node metastasis (CLNM), lateral lymph node metastasis (LLNM), distant metastasis and postoperative recurrence.[4–6]

Multifocality, in which there are two or more anatomically separate foci within the gland, is one of the common clinicopathologic features in PTMC, and its prevalence was reported to be 24.0%–31.8% in a large series.[6–9] Japanese scholars classified multifocality as a clinically low-risk factor for aggressive progression of PTMC and recommended active surveillance as the first-line management.[10] The American Thyroid Association (ATA) guideline included multifocal PTMC without ETE in the low-risk category, while ETE was included in the intermediate-risk category.[11] However, recent studies have shown that multifocality is associated with aggressive progression of the disease (ETE and/or LNM) and impacts the prognosis.[7,8,12,13] Several studies on PTMC and papillary thyroid carcinoma (PTC) have shown that bilateral multifocality accounted for the majority of multifocal cases,[8,9,14,15] and it was an independent predictor for LNM and should be treated aggressively.[16,17] In addition, one study suggested that patients with bilateral multifocality had more aggressive features and shorter disease-free survival than patients with PTC and unilateral multifocality.[14] Another study showed that aggressive features were more likely in bilateral multifocality than in unilateral PTCs, but bilaterality itself was not associated with poor clinical outcomes.[15] Thus, whether multifocality or its bilaterality is related to aggressive progression of PTMC and its impact on the clinical outcome are not clear.

Propensity score matching (PSM) is a popular analytic method for estimating the effects of treatments in observational studies.[18] By obtaining the propensity scores from a logistic regression model and matching patients with similar propensity scores, PSM achieves a comparison with reduced selection bias due to confounding factors.[19] The controversial results regarding the significance of multifocality and/or bilaterality in PTMC probably arise from biases and confounding effects of the baseline characteristics; therefore, using PSM might increase the level of evidence of the related research and increase the strength and generalizability of its results.

In this study, we retrospectively reviewed the clinical data of 3005 patients with PTMC and investigated the impact of unilateral and bilateral multifocality on its aggressive characteristics and clinical outcomes using PSM.