Thyroid carcinoma is the most frequent endocrine malignancy, accounting for approximately 2.9% of all newly diagnosed cancer (1). Its incidence has increased from 5.7 to 14.7 per 100,000 people over the past two decades (2). Papillary thyroid carcinoma (PTC), medullary thyroid carcinoma, follicular thyroid carcinoma, and anaplastic thyroid carcinoma are the four main types of thyroid carcinoma. PTC is the most common thyroid cancer type, accounting for approximately 80.0% of malignant thyroid tumors (3). In addition, papillary thyroid microcarcinoma (PTMC) is classified to PTC. According to the histological classification of thyroid tumors by the World Health Organization, PTMC is defined as tumors with a maximum size of 10 mm or smaller. PTC has an excellent prognosis, with the main treatment being surgical resection. The overall survival rate has remained between 90% and 96% in recent decades (4, 5).

Despite advances in the understanding of the underlying biological characteristics of PTC and the development of evidence-based guidelines for its treatment, the adequate extent of surgical management (lobectomy vs. total thyroidectomy) of PTC is still a matter of debate. Neck ultrasound (US) and US-guided fine-needle aspiration (FNA) are currently used in decision making for the surgical management of PTC. However, despite that high-resolution US can detect foci as small as 2 mm (6), smaller tumors remain undetected. Occult carcinoma is defined as a tumor that is not detected preoperatively but pathologically after surgery. As reported, PTC frequently occurs as multifocal or bilateral lesions, with the prevalence of multifocality ranging from 20.0% to 36.1% (7–9). The 2015 American Thyroid Association Guidelines (10) endorse thyroid lobectomy (TL) as an initial surgical approach for low risk, small- to medium-sized (T1-T2), N0 PTC in the absence of an extrathyroidal extension (ETE). For PTCs detected preoperatively in bilateral lobes, there is no controversy in performing total thyroidectomy (TT). Contralateral occult PTC is a specific subtype of bilateral multifocal PTC. It has been reported that the rate of occult PTC in the contralateral lobe ranges from 12% to 40% (11–13). For contralateral occult PTC, TL may be insufficient and could cause relapse and even lead to re-operation, which brings higher risks. Therefore, identifying risk factors of contralateral occult PTC could help surgeons to determine the optimal scope of surgery, but there is a limited number of studies focusing on risk factors of contralateral occult PTC. In this study, we used our retrospective research data and reviewed all related literature on the website that conducted this meta-analysis, aiming to estimate the risk factors for contralateral occult carcinoma in patients with unilateral PTC.

We collected the clinical data of patients with PTC treated in the First Hospital of China Medical University (Shenyang, China) from January 2016 to January 2021. Data collected included age, sex, thyroid ultrasound report, operation record, diagnosis, and pathology report. The inclusion criteria were as follows: PTC confined to the only unilateral lobe by preoperative image examinations or fine-needle aspiration cytology; patients who underwent initially total or near-total thyroidectomy; and postoperative pathological examination confirming the unilateral lesion was PTC. Also, the exclusion criteria were as follows: the patients had a suspicious lesion on the contralateral lobe; PTC located in the isthmus. Finally, 204 patients were included in our study, in which 27 patients were with contralateral occult PTC (confirmed by pathological examination). These clinical data were included in the meta-analysis.

Our meta-analysis was conducted according to the guidelines proposed by the preferred reporting items for systematic review and meta-analyses statement (14).

Each eligible study was extracted by two independent reviewers. Disagreements were resolved by consensus or adjudication of the senior authors. We extracted the following data from the included studies: (1) study characteristics: first author, publication year, country of study, study design, study population (PTC or PTMC), number of patients, and surgical extent; (2) clinicopathologic factors for contralateral occult carcinoma: sex, age, tumor size, ipsilateral multifocality, ETE, capsular invasion, BRAF mutation, Hashimoto thyroiditis (HT), presence of contralateral benign nodule, central lymph node metastasis (CLNM), and lateral lymph node metastasis (LLNM).

The included studies were estimated using the Newcastle-Ottawa scale (15), which allows evaluation of cohort studies by a total of eight items of three major parts, including the study population selection, comparability, and the result. A score of 0 to 9 stars was used to assess each study. A study achieving more than six stars was considered a high-quality study. All quality assessments were performed by two independent reviewers.

The retrospective research data statistical analyses were performed using the SPSS v 26.0 software (Chicago, USA). The continuous variables are expressed as a mean ± standard deviation (SD). Univariate analysis for comparisons between patient groups was performed using Pearson’s chi-square test or Fisher’s exact test. Variables with a p < 0.05 in the univariate analysis were included in the multivariable analysis. Logistic regression analysis was performed to assess the risk factors of contralateral occult carcinoma.

We performed the meta-analysis by Revman Manager 5.0 (Cochrane Collaboration, Oxford, UK). The OR was used to compare dichotomous variables. All results were estimated with 95% confidence intervals (CIs). A P-value < 0.05 was considered statistically significant. Heterogeneity was examined by using the Q-test and I² statistic. When p > 0.1 and I² < 50%, a fixed-effect model was used; otherwise, a random-effects model was applied. Possible publication bias was tested using Begg’s funnel plot.

Thyroid cancer has been the most rapidly increasing cancer over the past few decades in many countries. PTC comprises 90% of all thyroid malignancies and has an excellent prognosis with conventional therapies, such as surgery and radioactive iodine therapy. According to the latest ATA guidelines, TT is recommended for patients with a tumor > 4 cm, gross maximal ETE (T4), cervical lymph node metastasis, or distant metastasis. In addition, TL is endorsed as an initial surgical approach for low-risk, small- to medium-sized (T1-T2), N0 PTC in the absence of ETE (10). Considering that TT is associated with an increased risk of complications, such as vocal cord palsy and hypoparathyroidism (3, 21), TL may be sufficient for unilateral PTC with tumors < 4 cm and without ETE or clinical evidence of lymph node metastasis. There is no disagreement to performing TT for tumors detected preoperatively in bilateral lobes. However, when unilateral lobectomy is performed for patients with contralateral occult PTC, occult foci would lead to local recurrence and cervical lymph node metastasis and even re-operation, which is related to higher surgical risks compared with primary surgery (22, 23). Hence, we attempted to identify the risk factors for contralateral occult carcinoma to help select high-risk patients with occult carcinoma who would benefit from more extensive treatment.

Among patients with PTC, male patients have higher rates of ETE, regional lymph node, and distant metastasis, and mortality than female patients, regardless of age (24). Liu et al. reported that the male gender is an independent poor prognostic factor for all PTCs, and more aggressive treatment options should be considered for men (25). However, our pooled data showed that sex is not associated with the occurrence of contralateral occult PTC. Thus, there is no need to consider expanding the scope of lymph node dissection due to sex differences.

The biology of PTC is highly dependent on age, with young patients outperforming older patients in terms of survival (26). The previous guideline for thyroid cancer used 45 years as the cutoff age, and 55 years was the cutoff age used since 2017 (27). Thus, inclusion of a few of the literatures that used the previous guideline standard was inevitable. We set up two forest figures to suit two different cutoff values. Considering the effect of age on PTC’s biological activity, older patients whose PTC might more malignant, contralateral occult PTC might more likely to happen. However, the results of meta-analysis showed that regardless of whether the age cutoff value is 45 or 55 years, it did not affect the occurrence of the contralateral occult PTC. However, there were only two studies (included in our new data) that regarded 55 years as the cutoff age, and the OR value was higher than the 45 years cutoff age. Therefore, after expanding the sample size, this difference may become more significant.

Tumor size is the first factor evaluated for the biological characteristics of PTC because it is easily measured by preoperative US. The relationship between the size of the tumor and the presence of contralateral occult carcinoma remains controversial. It was concluded that tumor size is an independent predictor of bilaterality in PTC patients (28, 29). This is consistent with our new results. However, Pitt et al. examined a cohort of 228 patients and reported a rate of contralateral PTC for patients with primary tumors ≥1, <1, and <0.5 cm (30%, 26%, and 27%, respectively; nonsignificant p-value for all) (30). Combining the results of our meta-analysis, we suspected that Pitt’s results are limited by sample size. We suggest that researchers should perform a larger cohort study to clarify this problem.

Multifocality is a unique feature of PTC, and the rate of multifocality is reported to be 20% to 30% (31, 32). It was reported that increased tumor number is associated with higher rates of capsular invasion, ETE, and lymph node metastasis (33). A recent meta-analysis showed that multifocality in thyroid cancer increases the risk of disease recurrence (hazard ratio = 2.81; 95% CI = 1.07–7.36; p < 0.001) (34). What is more, Yoon et al. identified that multifocal tumors in the unilateral lobe have a high risk of bilateral carcinoma (9). Therefore, aggressive treatment, such as total thyroidectomy, central neck dissection, or postoperative radioactive iodine ablation, is suggested as the adequate treatment for multifocal PTCs. Our meta-analysis showed that patients with ipsilateral multifocal tumors have a 5.6-fold more contralateral occult PTC than patients with single-tumor foci. Thus, we strongly recommend patients with multifocality to pay attention to the presence of contralateral occult PTC.

An ETE is defined as an extension of the primary tumor beyond the thyroid capsule into the perithyroidal soft tissues, strap muscles, and adjacent structures (35). ETE is a well-known and significant factor for poor prognosis. It was reported that patients with ETE have a lower 10-year survival rate (75.2%) and a lower 10-year disease-specific survival rate (84.2%) (36). Also, Feng et al. reported that ETE is more commonly found in bilateral PTC than unilateral PTC (20.2% vs. 11.4%, p = 0.016) (37). Therefore, it is conjectured that ETE would be a risk factor for contralateral concealed PTC, and our retrospective research also got the same results. However, this was not the case. The meta-analysis results showed that there was no association between ETE and contralateral occult PTC. We considered that the reason is that the ETE (+) patients’ number was insufficient, ETE (+) patients accounted for about 7% to 37% of the total number in every study. This led to greater heterogeneity. What is more, the two studies with OR value <1 (from Gu et al. and Wang et al. respectively) had a percentage <10%. Less ETE (+) patients included, greater heterogeneity was important factor for the effect of ETE to contralateral occult PTC. Therefore, we suggest that researchers should perform a more perfect cohort study to get more credible conclusions.

In encapsulated thyroid neoplasms, the presence of capsular invasion is the most important criterion for separating benign neoplasms from malignancy. Currently, capsular invasion is defined in major guidelines as complete penetration of tumor capsules by neoplastic cells (38). Capsular invasion is not rare and has been reported from 9.9% to 26.8% of PTC (39). It was reported that capsular invasion is more common in patients with multifocal PTC and is related to tumor recurrence (33, 40). In our meta-analysis results, there is no connection between capsular invasion and contralateral occult PTC.

BRAF is a cytoplasmic protein kinase, and it is the main subtype of RAF kinase that could trigger tumorigenesis through the activation of the MAPK pathway. PTC patients with a BRAF mutation are associated with a higher risk of unfavorable clinicopathological characteristics (41). A study of 2,048 patients showed that a BRAF mutation is an independent risk factor for bilateral multifocal PTC (OR = 1.233, 95% CI = 1.063–1.431, p = 0.006) (42). However, we found no association between BRAF mutation and contralateral occult PTC. This may be because of the coexistent benign nodules in the contralateral lobe that could have affected the observed rate of contralateral occult carcinoma. The more useful reason may be the limited sample size; we considered that if there is an expanded sample size, the results would be reversed.

HT is the most common autoimmune thyroid disease. It causes the immune system to attack and destroy the thyroid gland and is the most common cause of primary hypothyroidism and nonendemic goiter. Liang et al. reported that PTC patients with HT have a higher rate of multifocality (p = 0.024) than patients without HT (42). This meta-analysis results showed no relation between HT and contralateral occult PTC.

Among the patients with unilateral PTC, a portion of them had contralateral thyroid nodules. A study of 1,442 patients reported that 667 (46.95%) patients with contralateral benign nodules were ultimately confirmed to be PTC (19). The therapeutic strategy for patients in this situation is controversial and challenging. Our data demonstrate that patients with contralateral benign nodules have increased contralateral occult PTC. This result may be because some small foci masked by a benign nodule in the contralateral lobe could lead to incorrect assessment during preoperative US or FNA. Therefore, we suggest that surgeons should evaluate the huge possibility of the presence of contralateral occult carcinoma in PTC patients with contralateral thyroid nodules and to deal with it more actively.

Multifocality might occur through the spread of an original tumor via intraglandular lymphatics. Cancer cells can cause metastasis to the contralateral gland through lymphatic dissemination, as well as lymph node metastasis. It is well established that PTC has a strong propensity for lymph node metastasis. Lymph node metastasis in PTC follows a predictable pattern. Most commonly, tumor cells metastasize to the central lymph node, followed by those of the lateral lymph node. Rarely, some patients develop LLNM in PTC without CLNM (43). It was reported that multifocality increases the risk of CLNM (44). However, the role of multifocality in LLNM remains a topic of debate (43, 45). Our results showed that patients with CLNM have more contralateral occult PTC but no significant relationship between LLNM and contralateral occult PTC. This might be because only three studies evaluated LLNM, and we considered that the result would be reversed by bringing in a large sample size research.

There are some limitations to this study. First, all of the studies were conducted in Asian countries. Second, most of the pooled studies were not prospective or randomized case-control trials. Third, the number of included studies was limited, which might have affected the results of our study, especially the risk factor analysis.

The meta-analysis demonstrates the following risk factors for contralateral occult PTC: tumor size > 1 cm, ipsilateral multifocality, contralateral benign nodule, and CLNM. Sex, age, ETE, capsular invasion, BRAF mutation, HT, and LLNM do not affect contralateral occult PTC. Overall, although TT presents complications, the operation should be evaluated and implemented more actively when ≥ 1 risk factor is found in patients with PTC.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

The studies involving human participants were reviewed and approved by Medical Science Research Ethics Committee of the First Hospital of China Medical University. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

FZ is the first author of this study. WT is the corresponding author supervising this work. FZ, BZ, and XW collected the clinical medical records. FZ and BZ conceived and designed the meta-analysis. BZ and XY performed the meta-analysis. FZ performed the statistical analyses of all the data and wrote the manuscript. XW and SW contributed material/analysis tools. FZ and BZ collected reference and managed the data. FZ and WT designed the study. All authors contributed to the article and approved the submitted version.

This study was supported by The Research Fund for Public Welfare, National Health and Family Planning Commission of China (grant 201402005). The funder had no role in study design, data collection or analysis, or in the presentation or publication of the results.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.