Bibliometric insights in advances of papillary thyroid microcarcinoma: Research situation, hot points, and global trends

Thyroid cancer is the most common endocrine tumor globally (1). In 2015, 3.2 million people developed thyroid cancer worldwide, resulting in 31,900 deaths (2, 3). Thyroid cancer ranked ninth in incidence in 2020, with 586,000 cases worldwide (4), a slight increase from 567,000 new cases in 2018 (1), rendering it a substantial public health problem universally. Papillary thyroid microcarcinoma (PTMC) is the most common thyroid cancer in clinical practice, defined as PTC involving tumors <1 cm in diameter. As a result, PTMC predominates in the context of diagnosis and treatment of thyroid cancer. An increasing number of people are being diagnosed with PTMC with ultrasound technology advancement. Many patients come to the clinic because of thyroid nodules, which can be detected in the physical examination, which help in their diagnosis (5). Cho et al. summarized the clinicopathological and prognostic changes of thyroid cancer in South Korea over the past 40 years. They found that the proportion of PTMC increased from 6.1% in 1962 to about 9% in 1990, to 54% in 2005, and 43.1% in 2009 (6), but there was no significant rise in mortality (7).

Even though many systematic reviews and meta-analysis have thoroughly and explicitly addressed PTMC research, only a few summarized this topic from the perspective of bibliometric analysis or provided the developing trends in this domain. Some studies performed bibliometric analysis but did not provide future trends for PTMC. Therefore, we aimed to conduct a bibliometric network analysis, which would offer an objective measurement in scientific literature and aggregate the opinions of multiple PTMC researchers.

As there was no comparable bibliometric analysis in the research field of PTMC, we applied related tools to systematically and objectively evaluate the research foundation, frontiers, and focus on PTMC.

This study used bibliometrics and visual analysis methods to discuss the research trends and hot spots in PTMC research field from 2000 to 2021. According to this study, PTMC research has shown an increasing trend over the last 20 years, with 2019 being the year with the most published literature.

During the 20 years, 1,098 papers from 75 countries were published. China published the most publications (329), but its h, g, and m indexes were lower than South Korea and the USA. Japan published 73, which was more than publications from South Korea and the USA. It is worth noting that South Korea accounted for five of the top listed research institutions in the number of publications, indicating that South Korea led PTMC research.

Keywords co-occurrence (Figure 5) obtained by VOSviewer 1.6.17 can be used to understand the primary research directions of a field. In this study, there were 2,380 keywords; 64 of them appeared more than 30 times. Cluster analysis classified the 64 terms into 5 clusters.

Cluster 1 was predominantly concerned with disease recurrence. The inconsistency in the risk of recurrence was primarily due to the heterogeneity of thyroid cancer characteristics, including surgical scope, pathological factors, and clinical factors. Therefore, different studies reported different risk factors for recurrence. Age, sex, tumor size, extrathyroidal extension (ETE), multifocality, and lymph node metastasis were all potential risk factors (16–18). First, for the more controversial unilateral PTMC, a recent study revealed that total thyroidectomy was associated with a lower recurrence rate with no significant difference in survival (19). In addition, prophylactic central neck dissection during surgery may reduce the recurrence rate (20). Second, compared to patients with unifocal PTC, multicentric PTC patients were older, had advanced TNM staging, and had a higher recurrence rate (21). Metastatic lymph node ratio higher than 0.44 was linked with an increased risk of locoregional recurrence, mostly in the lateral neck (22). However, tumors smaller than 5 mm were less likely to recur (23).

Cluster 2 was about the application of ultrasound. Ultrasound is one of the main diagnostic methods for thyroid cancer. The following ultrasonic features of thyroid nodules were significantly associated with PTMC: an irregular shape; an aspect ratio of 1; an unclear boundary; blurred margins; internal heterogeneous hypoechogenicity; and microcalcification (24). An ultrasound can diagnose thyroid cancer by fine-needle aspiration biopsy (FNAB). Lyu Yi-jun’s study presented that the malignancy rate of PTMC diagnosed by FNAB was highly consistent with the histopathological diagnosis (88.2% vs. 89.5%) (25). FNAB had 87% sensitivity to PTMC smaller than 5 mm (26). Third, ultrasound is an important method to predict lymph node metastasis (27). However, in Ito Y’s study, the specificity and sensitivity of ultrasound for central lymph node metastasis diagnosis were 99.1% and only 10.9%, respectively (28). Although ultrasound is now routinely revised after surgery, some studies believe that due to the very low recurrence rate of PTMC, monitoring via ultrasound one to two years after surgery may be unnecessary (29).

Cluster 3 was related to the prevalence of PTMC. The incidence of thyroid cancer in South Korea increased dramatically in 2000 and is now increasing by 25% per year. In 2011, approximately 40,568 people were diagnosed with thyroid cancer, and the incidence of thyroid cancer became15 times higher than in 1993 (30). According to Louise Davies’ research, medical imaging technology and diagnostic skills enabled the discovery of many asymptomatic cases of subclinical thyroid cancer (31). A study in Greece found an increased prevalence of PTMC (63.6% of all thyroid cancers) from 2007 to 2016 due to frequent use of FNAB (32). Positive diagnosis and treatment may also increase the patient’s distress, significantly affecting the patient’s subsequent quality of life.

Cluster 4 mainly correlated with active surveillance (AS). Due to the favorable prognosis of PTMC, it has a mortality rate of 0.3%, even in the presence of distance metastasis (33). Since the 1990s, two Japanese institutions, the Kuma Hospital and the Cancer Institute Hospital (CIH), have conducted prospective clinical studies of active surveillance (AS) in low-risk (T1aN0M0) PTMC. These studies show good results, low cancer growth rates, and lymph node metastasis with no deaths during AS (34–37). Active surveillance has been proposed as a first-line treatment for low-risk PTMC because tumors grow slowly, have low mortality and metastasis rate, and are safer and less expensive than surgery (38). However, AS is unsuitable for some PTMC patients, such as those with central lymph node metastasis (CLNM) (11). The disease progression of PTMC during active surveillance varied greatly according to age at onset. People in their 20s and 30s were more likely to develop disease progression than people over 50 (39). An Australian study found that surgery costs the same as 16.2 years of active surveillance (40). Moreover, AS was not recommended in the following conditions: lymph node metastasis, tumors involving or attached to the esophageal or recurrent laryngeal nerves, and age under 20 (41).

Cluster 5 was concerned about BRAF (V600E), which accounts for 60-80% of papillary thyroid carcinoma (PTC) and is a prognostic marker for risk stratification in PTC patients (42). Li Fei’s research suggested that BRAF mutations were associated with multifocal thyroid cancer, extrathyroidal extension, lymph node metastasis, and advanced stages regardless of age (43). However, a recent study by Kim Kwangsoon showed that BRAF mutation is not a risk factor for lateral neck lymph node metastasis (44). In addition to the BRAF gene, TERT promoter mutation has been reported as a newly discovered prognostic PTC gene mutation (45). However, the probability of TERT mutation is low (46). Liu et al. first reported a link between mutations of the TERT promoter and BRAF (V600E) in PTC, and subsequent studies further demonstrated the coexistence of TERT promoter and BRAF(V600E) mutations in thyroid cancers and their association with the most aggressive PTC clinical factors and worse prognosis (47–50).

The keyword co-occurrence (Figure 7) using CiteSpace 5.8R3 exhibited the trending topics in this field, while burst keywords represented the frontier topic. Burst keywords revealed the change of research hotspot. The recent burst of keywords, in particular, indicated underlying trends and possible frontiers in PTMC. It was seen that individual treatment with PTMC will be proposed more in the future, specifically “Risk stratification” and “radiofrequency ablation.”

Risk stratification is important for managing thyroid cancer. Patients with no family history of thyroid cancer or personal head and neck irradiation, no lymph node or distant metastasis at diagnosis, ETE, unifocal micro-PTC, no aggressive histological features (tall-cell, hobnail subtypes), and no vascular invasion were considered low-risk patients (51). Unfortunately, some of these data are available only after surgery. Tumor size is one of the recognized risk factors for thyroid cancer. In addition, there were many factors associated with poor prognosis, such as extensive fibrosis (52), age (more than 55 years) (53), tumor multifocality, and lymph node metastasis at presentation (54).

Thermal ablation (TA) has been widely used and regarded as a safe and effective treatment for low-risk PTMC. There have been many studies related to the safety of TA. In a retrospective clinical trial involving 311 patients, there was no difference in the recurrence rate and disease-free survival rate of low-risk PTMC between TA and lobectomy groups. However, there were significantly fewer patients with postoperative hypoparathyroidism than in the operation group (55). In addition, TA exhibited good efficacy in treating thyroid cancer lymph node metastasis, with a reduced rate of metastatic lymph nodes in 208 patients (412 lymph nodes) of 93%–94% (56). However, using TA in treating PTMC remains controversial, with many opposing voices in China. In a single-center study, 23 patients with thyroid cancer treated with TA underwent surgery again, and five had FNAB results inconsistent with postoperative pathology, demonstrating lymph node metastasis (57). In another retrospective study, 12 patients underwent surgery after TA treatment, with lymph node metastasis in 66.7% (8/12) of patients. Adhesion of post-ablation lesions with strap muscle was observed in six cases. Strap muscle was found to be cauterized in five cases, and notably, the recurrent laryngeal nerve was involved in one case (58). So, lymph node or distant metastasis before and after ablation in patients with primary PTMC is difficult to assess (59).

Guidelines and consensus differ slightly between associations regarding the scope of application of TA for PTMC. The American Thyroid Association Management Guidelines in 2015 and the South Korean Thyroid Radiofrequency Guidelines in 2017 recommend that TA should be employed only in high-risk surgery patients and those who refuse additional surgery (59, 60). The 2018 Austrian practice guidelines do not recommend TA in malignant thyroid nodules (61). In 2018, the Chinese expert consensus proposed the indications for PTMC treatment by TA, but only under very strict conditions. Non-pathological high-risk subtypes, tumor diameter ≤5 mm, no lymph nodes or distant transfer of evidence, and so on are examples of nine items that must be met simultaneously (62). The 2021 European Thyroid Association practice guidelines and the 2021 international multidisciplinary consensus statement suggest that TA should be considered for PTMC patients who are at risk of surgery, have a short life expectancy, have other medical conditions, are unwilling to have surgery, or want to stop AS (63, 64). The international mainstream association guidelines and statements still consider surgery the first choice for PTMC patients. TA is a relatively new technology that has emerged in recent years. After treatment, the follow-up time is insufficient, and the long-term safety and efficacy have not been evaluated.

Some deficiencies should be taken into account when interpreting the results of this study. First, the publications were derived solely from the Web of Science Core Collection databases. Second, only English-language publications were included in our analysis. Furthermore, new publications may subsequently be added to the December 2021 queue, but the database was not updated at the time of retrieval. However, this part of the literature was very small and will not cause a large error in the analysis. Despite these limitations, this study reveals the future research trends and hot spots in this field to some extent and uses bibliometrics to sort out this field for later researchers.

To sum up, this study summarizes the global research trends of PTMC. Thyroid was the top productive journal. China has the largest number of publications, and the USA has the most citations. The University of Ulsan of Korea has done a great deal of research in this area and has contributed the most publications. The main research topics were the recurrence and metastasis of PTMC and the application of ultrasound in PTMC. Research frontiers were risk stratification of PTMC, active monitoring, and thermal ablation for PTMC. We believe these findings will provide useful information for researchers to explore PTMC further.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

This study is a bibliometric analysis of the articles related to papillary thyroid microcarcinoma, and the data were obtained from the Clarivate Analytics Web of Science Core Collection database, so ethical approval and consent to participate were not necessary for this paper. Informed consent was obtained from all individual participants included in the study.

This work was conceived by Hao Zhang and Zhongqing Wang. Data was collected and downloaded by Kefan Chen, Dalin Zhang, Ting Zhang and Liang He. The visualization work was performed by Kefan Chen and Wei Sun. The manuscript was written by Kefan Chen and Wei Sun. Hao Zhang, Zhongqing Wang, Dalin Zhang, Ting Zhang and Liang He helped to revise manuscript and proposed constructive opinions. All authors contributed to the article and approved the submitted version.

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.

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