Preoperative High Level of Circulating Tumor Cells is an Independent Risk Factor for Central Lymph Node Metastasis in Papillary Thyroid Carcinoma with Maximum Lesion Diameter &le;1.0 cm

Ming Yu, Jiaqin Deng, Yihua Gu, Yeqian Lai

Department of Thyroid Surgery, Meizhou People’s Hospital, Meizhou Academy of Medical Sciences, Meizhou, People’s Republic of China

Correspondence: Ming Yu, Department of Thyroid Surgery, Meizhou People’s Hospital, Meizhou, People’s Republic of China, Email [email protected]

Objective: Circulating tumor cell (CTC) has been used to assist in the diagnosis and progression assessment of solid tumors, but the relationship between preoperative CTCs levels and central lymph node metastasis (CLNM) of papillary thyroid carcinoma (PTC) needs to be clarified.
Methods: Data on clinical features (age, gender, Hashimoto’s thyroiditis, multifocal, maximum lesion diameter, invaded capsule, clinical stage, and status of lymph node metastasis) of PTC patients treated at our hospital between June 2021 and April 2023 were retrospectively collected. The relationship between the CTCs level and these clinical features was analyzed, especially the relationship between the CTCs level and CLNM.
Results: A total of 705 PTC patients were included, and there were 333 (47.2%) patients with CLNM. Patients with a high CTCs level had higher proportions of multifocality, maximum lesion diameter > 1cm, and CLNM than those in patients with a low CTCs level. Tumor size was connected to CTCs level, patients with a high CTCs level had a higher proportion of CLNM than those with a low CTCs level in PTC with maximum lesion diameter ≤ 1cm (45.3% vs 29.7%) (p=0.001). Logistic regression analysis showed that age < 55 years old (odds ratio (OR): 2.612, 95% confidence interval (CI): 1.565– 4.361, p< 0.001), invaded capsule (OR: 1.662, 95% CI: 1.098– 2.517, p=0.016), and high CTCs level (≥ 8.7 FU/3mL, OR: 2.141, 95% CI: 1.431– 3.203, p< 0.001) were associated with CLNM in PTC with maximum lesion diameter ≤ 1cm.
Conclusion: In PTC patients with maximum lesion diameter ≤ 1cm, patients with high preoperative CTCs level (≥ 8.7FU/3mL), age < 55 years old, and capsular invasion were prone to CLNM. However, similar results were not observed in patients with maximum lesion diameter > 1cm.

Keywords: papillary thyroid carcinoma, circulating tumor cell, central lymph node metastasis, lymph node metastasis

Introduction

Thyroid carcinoma is one of the most common malignancies of the endocrine system with increasing incidence.^1,2 The global cancer statistics in 2020 showed that there were 586,000 new cases, ranking ninth in the global incidence of cancer, and the incidence of women is about 3 times that of men.³ According to the statistics of the National Cancer Center of China in 2022, thyroid cancer ranking 7th in the incidence of cancer in China.⁴ Papillary thyroid cancer (PTC) is one of the least aggressive types of thyroid cancer and rarely develops distant metastases. However, compared with other types of thyroid cancer, PTC has a higher proportion of lymph node metastasis.^5–8 The process of lymph node metastasis (LNM) in PTC is generally from the central lymph node to the lateral cervical lymph node, and a few patients have skip lymph node metastasis.⁹ The central cervical region is the most common lymph node metastasis site for PTC, and the incidence of central lymph node metastasis (CLNM) is about 30%-90%, but the preoperative detection rate is low.^10,11

LNM is an important factor affecting the prognosis of PTC, it is very important to evaluate LNM, especially CLNM, in PTC patients.¹² There is no doubt that therapeutic lymph node dissection should be performed in patients with high suspicion and certainty of CLNM, but more researches are needed to provide guidance to clinicians on whether patients with negative lymph node metastases should undergo prophylactic central lymph node dissection.^13–15 Ultrasound and computed tomography (CT) are the methods for screening thyroid nodules and evaluating cervical lymph nodes, but the sensitivity of these methods is disputed.^10,16 On the other hand, ultrasonography (US)-guided fine needle aspiration cytology (UG-FNAC) provides fewer cells for pathological examination and can only observe cell changes, which cannot fully reflect the overall situation of tissue structure.^17,18 Therefore, it is of great value to analyze the risk factors of CLNM according to the clinical characteristics of PTC patients, to provide a simple tool for clinicians to predict the CLNM of PTC.

Several factors have been identified as risk factors for CLNM in PTC patients, such as gender, age, body mass index (BMI), tumor size, multifocality, and B-Raf proto-oncogene (BRAF) V600E mutation.^19–22 Circulating tumor cell (CTC) is a type of tumor cell released by tumor tissue into the peripheral blood spontaneously or by the primary site or metastasis due to clinical procedures.²³ At present, CTC has been widely used for early screening, disease monitoring, and prognosis assessment of solid tumors, especially breast cancer,²⁴ lung cancer,²⁵ and colorectal cancer.²⁶ Several studies have found that CTCs are associated with the clinical stage,²⁷ and prognosis^28,29 of thyroid cancer. High CTCs levels are associated with distant metastasis in differentiated thyroid cancer (DTC) patients.²⁸ Due to the convenient sample source of CTCs detection, and the fact that CTCs detection can provide a lot of information for the clinical management of PTC patients, the role of CTC in the individualized diagnosis and treatment of thyroid cancer is becoming more and more obvious. However, the relationship between CTCs level and clinicopathological features of PTC patients remains unclear. The aim of this study was to investigate the relationship between the CTCs level and the clinical features, especially the relationship between the CTCs level and CLNM.

Materials and Methods

Subjects

This study retrospectively analyzed 705 patients with PTC who were admitted to Meizhou People’s Hospital from June 2021 to April 2023. Inclusion criteria: (1) thyroid surgery was performed and PTC was diagnosed by pathologic examination; (2) the patient’s medical records are complete; (3) patients with thyroid cancer as the primary tumor and no co-existing tumors of other types. Exclusion criteria: (1) patients with other thyroid malignancies, or a history of thyroid surgery, and neck irradiation; (2) patients with malignant tumors of other sites; (3) thyroid cancer patients with pathologic types other than PTC. This study was supported by the Ethics Committee of the Meizhou People’s Hospital.

Data Collection

The clinicopathological features of the patients collected, such as basic demographic information (age and gender), preoperative circulating tumor cells (CTCs), and pathological data (Hashimoto’s thyroiditis, multifocal, maximum lesion diameter, invaded capsule, clinical stage, and status of lymph node metastasis). Patients were divided into age groups of <55 years old and ≥55 years old. According to the size of the tumor diameter, the patients were divided into papillary thyroid microcarcinoma (PTMC) (maximum lesion diameter ≤1cm) and PTC with maximum lesion diameter >1cm.^30,31 According to whether or not the patients had LNM, they were divided into two groups: the patients with LNM and the patients without LNM (including CLNM and lateral cervical lymph node metastasis).^32,33

Peripheral blood CTCs were enriched and quantified using the CytoploRare Kit according to product manuals (Genosaber Biotech, Shanghai, China) based on reverse transcription-polymerase chain reaction (RT-PCR) technique. CTCs ≥8.7 FU/3mL is the threshold in the instructions of the CTC test kit, and CTCs ≥8.7 FU/3mL (folate receptor-positive CTCs unit in 3mL blood) is interpreted as CTC-positive in this study.

Statistical Analysis

SPSS statistical software (version 26.0, IBM Inc., USA) was used for data analysis. Chi-square test or Fisher’s exact test were used to evaluate the relationship between different CTCs levels and clinicopathological features of PTC patients. Since tumor size was connected to CTCs level,³⁴ the relationship between CTCs levels and clinicopathological features in patients with different tumor sizes were also analyzed. Univariate analysis and multivariate logistic regression analysis were used to evaluate the relationship between the clinicopathological features and CLNM in PTC patients with maximum lesion diameter ≤1cm. p<0.05 was set as statistically significant.

Results

Clinicopathological Features of PTC Patients

Among the 705 patients with PTC, 134 (19.0%) were male patients, 571 (81.0%) were female patients, and 546 (77.4%) cases aged <55 years, and 159 (22.6%) cases aged ≥55 years. There were 394 (55.9%) PTC patients with preoperative CTC-positive, and 311 (44.1%) patients with CTC <8.7 FU/3mL. There were 190 (27.0%), 231 (32.8%), 249 (35.3%), and 326 (46.2%) patients with Hashimoto’s thyroiditis, multifocal, maximum lesion diameter >1cm, and invaded capsule, respectively. There were 333 (47.2%) patients with CLNM and 103 (14.6%) patients with lateral cervical lymph node metastasis (Table 1).

Table 1 The Clinicopathological Features of PTC Patients

Comparison of Clinicopathological Features Among PTC Patients with CTCs Negative or Positive

Compared with patients with CTCs <8.7 FU/3mL, PTC patients with CTCs ≥8.7 FU/3mL had a higher proportion of multifocality (36.3% vs 28.3%) (p=0.029), and maximum lesion diameter >1cm (40.6% vs 28.6%) (p=0.001), and CLNM (52.5% vs 40.5%) (p=0.002). There was no statistically significant difference in distributions of gender and age, and proportions of Hashimoto’s thyroiditis, invaded capsule, T stage, and lateral cervical lymph node metastasis between patients with different CTCs levels (Table 2).

Table 2 Comparison of Clinicopathological Features Among PTC Patients with CTCs Negative or Positive

Comparison of Clinicopathological Features of Different CTCs Levels Among PTC Patients with Maximum Lesion Diameter ≤1cm, and Maximum Lesion Diameter >1cm, Respectively

In PTC patients with maximum lesion diameter ≤1cm, patients with CTCs ≥8.7 FU/3mL had a higher proportion of CLNM (45.3% vs 29.7%) (p=0.001) than that in patients with CTCs <8.7 FU/3mL. No difference in other clinicopathological features were found between different CTCs levels. In PTC patients with maximum lesion diameter >1cm, no clinicopathological features associated with CTCs level were found (Table 3).

Table 3 Comparison of Clinicopathological Features of Different CTCs Levels Among PTC Patients with Maximum Lesion Diameter ≤1cm, and Maximum Lesion Diameter >1cm, Respectively

Logistic Regression Analysis of Risk Factors of CLNM in PTC with Maximum Lesion Diameter ≤1cm

Age <55 years old (odds ratio (OR): 2.428, 95% confidence interval (CI): 1.480–3.984, p<0.001), invaded capsule (OR: 1.719, 95% CI: 1.163–2.540, p=0.007), and high preoperative CTCs level (≥8.7/<8.7 FU/3mL, OR: 1.957, 95% CI: 1.330–2.880, p=0.001) were found significantly associated with CLNM in PTC with maximum lesion diameter ≤1cm by univariate analysis. And age <55 years old (OR: 2.612, 95% CI: 1.565–4.361, p<0.001), invaded capsule (OR: 1.662, 95% CI: 1.098–2.517, p=0.016), and high preoperative CTCs level (≥8.7/<8.7 FU/3mL, OR: 2.141, 95% CI: 1.431–3.203, p<0.001) were independently associated with CLNM in PTC with maximum lesion diameter ≤1cm showed in multivariate regression logistic analysis (Table 4).

Table 4 Logistic Regression Analysis of Risk Factors of CLNM in PTC with Maximum Lesion Diameter ≤1cm

Discussion

Thyroid cancer is mainly diagnosed by UG-FNAC and is classified according to the cell of origin.^35,36 Although UG-FNAC is the gold standard for thyroid cancer diagnosis, there are still some inaccuracies.³⁷ PTC is an inert cancer with good prognosis, but it has a high probability of cervical LNM.³⁸ At present, thyroid surgery is one of the effective treatment methods for thyroid cancer, but there are still inconsistent views on the scope of lymph node dissection during surgery.^39,40 Comprehensive regional lymph node dissection may reduce the recurrence rate, but excessive lymph node dissection may increase the risk of recurrent laryngeal nerve injury.^41–43 Preoperative prediction and evaluation of lymph node metastasis of thyroid cancer can provide basis for the selection of surgical methods. In recent years, non-invasive liquid biopsy has attracted much attention, and the detection of circulating tumor markers based on CTCs has important clinical value.^44,45

Since Ringel et al confirmed the existence of CTCs in peripheral blood of patients with recurrent and distant metastatic thyroid cancer in 1998,⁴⁶ more and more studies have begun to pay attention to the application value of CTCs in thyroid cancer. The results of a prospective study by Xu et al showed that CTCs were effective diagnostic markers for thyroid nodules.⁴⁷ The findings of some studies suggested that high CTCs levels were associated with worse overall survival (OS),²⁹ and shorter progression-free survival (PFS)⁴⁸ in patients with thyroid cancer. Liang et al found that CTC was a reliable index for the diagnosis of thyroid cancer with recurrence and distant metastasis.⁴⁹ Regarding the role of CTCs in LNM in PTC patients, Zeng et al found that there was significant difference in the number of CTCs between N0 and N1 patients with thyroid cancer.⁵⁰ The results of this study also suggested that high preoperative CTCs level (≥8.7/FU/3mL) was an independent risk factor for CLNM in PTC with maximum lesion diameter ≤1cm. At present, most studies have shown that CTCs detection can provide some useful information for the diagnosis, treatment, and monitoring of thyroid cancer, but its role in the individualized diagnosis and treatment of thyroid cancer is still unable to be evaluated.⁵¹ In addition, different analysis methods for CTCs may produce different results. At present, there is a lack of recognized CTCs detection methods with high sensitivity and specificity.^52,53 Therefore, further improvement of CTCs detection technology and effective isolation of single CTC for molecular characterization analysis will be of great significance for its clinical application in thyroid cancer.

Regarding the role of age in LNM of thyroid cancer, a study showed that there was a higher risk of LNM in older patients with PTC.⁵⁴ However, Mao et al showed that younger patients with PTC have a higher risk of LNM.⁵⁵ Similarly, Zhang et al showed that the proportion of LNM in older patients with PTC was relatively small.⁵⁶ Some studies have also shown that age was significantly correlated with CLNM.^57–60 The results of this study also suggested that age is an independent risk factor for CLNM, with PTC patients aged <55 years old having a greater risk of CLNM than patients ≥55 years of age. Study suggested that the relationship between age difference and disease severity may be related to differentially expressed genes, such as low expression of extracellular matrix protein 1 (ECM1),⁶¹ but its role in tumorigenesis has not been fully elucidated.

Thyroid cancer is more prevalent in women adults.⁶² Several studies have shown that estrogen is a powerful stimulating factor for benign and malignant thyroid nodules, and circulating estrogen increases women’s susceptibility to thyroid proliferative diseases and tumor transformation, which is one of the reasons why thyroid cancer is more common in women.^63,64 In addition, several studies have reported that CLNM is more likely to occur in male patients with PTC, and PTC is more aggressive and has worse prognosis in males.^20,59,60,65 This study did not find a relationship between gender and CLNM. Moreover, some studies also showed that without Hashimoto’s thyroiditis,^59,66,67 and multifocal,^{59,60,68–70} and invasion capsule^71,72 were independent risk predictors of CLNM in papillary thyroid microcarcinoma (PTMC). But this study did not get the same results.

In this study, age <55 years old, invaded capsule, and high preoperative CTCs level (≥8.7 FU/3mL) were independent risk factors for CLNM in PTC with maximum lesion diameter ≤1cm. Prophylactic central lymph node dissection in PTMC remains controversial,^59,73 it is necessary to combine factors such as age, capsule invasion, and CTC level, rather than fixed surgical methods, to obtain greater benefits of individualized treatment. The results of this study provide meaningful information for the risk assessment of CLNM in PTC with maximum lesion diameter ≤1cm. Of course, this study inevitably has some shortcomings that need to be improved. First of all, as this study is a single-center retrospective study, the possibility of case selection bias resulting in results bias cannot be ruled out. Secondly, patients with PTC who are in remission may still experience an increase in the number of CTCs,²⁷ so the assessment of CTC levels on the progression of PTC patients still needs to be confirmed by more studies. In addition, to demonstrate the clinical value of CTCs in evaluating lymph node metastasis of thyroid cancer, more cases need to be collected for validation, so multi-center studies are needed in the future to further investigate the risk factors and clinical interventions for CLNM of thyroid cancer.

Conclusions

High preoperative CTCs level (≥8.7 FU/3mL), age <55 years old, and invaded capsule were independent risk factors for CLNM in PTC with maximum lesion diameter ≤1cm. In other words, in PTC patients with maximum lesion diameter ≤1cm, patients with high preoperative CTCs level (≥ 8.7FU/3mL), age <55 years old, and capsular invasion were prone to CLNM. Whereas there was no relationship between the levels of CTCs and LNM in patients with PTC whose tumor size was >1 cm. It provides valuable reference data for the risk assessment of CLNM in PTC.

Data Sharing Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Ethics Approval and Consent to Participate

All participants were informed on the study procedures and goals and the informed consent from all the participants was obtained. The study was performed under the guidance of the Declaration of Helsinki and approved by the Ethics Committee of Medicine, Meizhou People’s Hospital.

Acknowledgments

The author would like to thank other colleagues whom were not listed in the authorship of Department of Thyroid Surgery, Meizhou People’s Hospital for their helpful comments on the manuscript.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

This study was supported by the Scientific Research Cultivation Project of Meizhou People’s Hospital (Grant No.: PY-C2023046).

Disclosure

The authors declare that they have no competing interests in this work.

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Preoperative High Level of Circulating Tumor Cells is an Independent Risk Factor for Central Lymph Node Metastasis in Papillary Thyroid Carcinoma with Maximum Lesion Diameter ≤1.0 cm