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ORIGINAL ARTICLE
Year : 2020  |  Volume : 16  |  Issue : 5  |  Page : 1056-1062

Ultrasonic identification and regression analysis of 294 thyroid follicular tumors


1 Department of Ultrasound, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital); Institute of Cancer and Basic Medicine (IBMC), Chinese Academy of Sciences, Hangzhou, China
2 Department of Pathology, Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital); Institute of Cancer and Basic Medicine (IBMC), Chinese Academy of Sciences, Hangzhou, China

Date of Submission25-Oct-2019
Date of Decision01-Jan-2020
Date of Acceptance26-Mar-2020
Date of Web Publication29-Sep-2020

Correspondence Address:
Chen Yang
Department of Ultrasound,Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou 310022, China; Institute of Cancer and Basic Medicine (IBMC), Chinese Academy of Sciences, Hangzhou 310022
China
Dong Xu
Department of Ultrasound,Cancer Hospital of the University of Chinese Academy of Sciences (Zhejiang Cancer Hospital), Hangzhou 310022, China; Institute of Cancer and Basic Medicine (IBMC), Chinese Academy of Sciences, Hangzhou 310022
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jcrt.JCRT_913_19

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 > Abstract 


Context: We analyzed the clinical features and ultrasound image features of follicular thyroid carcinoma (FTC) and follicular thyroid adenoma (FTA).
Aims: This study aimed to identify ultrasonographic differences and correlations between FTC and FTA. Meanwhile, ultrasonographic manifestations of thyroid follicular tumor were also retrospectively analyzed.
Settings and Design: Using pathological results as the gold standard, the clinical and ultrasonic image characteristics of FTA and FTC were statistically analyzed, and the differences were analyzed.
Materials and Methods: A total of 304 patients who were diagnosed with FTC or FTA by pathology after thyroidectomy from March 2009 to March 2018 were enrolled in this study. Their ultrasonic images were analyzed; image features were extracted and correlation analyses for these features were conducted. Differences in ultrasonic images between FTC and FTA were also compared.
Statistical Analysis Used: Independent sample t-test; Wilcoxon rank sum test; A Chi-square test: Univariate and multivariate logistic regression analyses.
Results: When performing ultrasound diagnosis, attention should be paid to identify FTC and FTA in terms of age, nodular goiter conditions, nodular boundary conditions, internal echo, calcification, blood flow signals, thyroid imaging reporting and data system (TI-RADS) grading and cystic solidity conditions. Moreover, a multivariate logistic regression showed that the boundaries were unclear, and cystic degeneration, TI-RADS, hypoecho, nodular goiter, macrocalcification and microcalcification were associated with FTC. Among them, macrocalcification is a protective factor for thyroid follicular tumors, and other indicators are risk factors.
Conclusion: Ultrasound can provide valuable information for the identification of follicular neoplasms, but further research in this area is still necessary.

Keywords: Follicular thyroid adenoma, follicular thyroid carcinoma, ultrasound signal


How to cite this article:
Ou D, Yao J, Jin J, Yan M, Shi K, Zheng Q, Yang C, Xu D. Ultrasonic identification and regression analysis of 294 thyroid follicular tumors. J Can Res Ther 2020;16:1056-62

How to cite this URL:
Ou D, Yao J, Jin J, Yan M, Shi K, Zheng Q, Yang C, Xu D. Ultrasonic identification and regression analysis of 294 thyroid follicular tumors. J Can Res Ther [serial online] 2020 [cited 2020 Oct 26];16:1056-62. Available from: https://www.cancerjournal.net/text.asp?2020/16/5/1056/296453

Di Ou and Jincao Yao contributed equally to this work





 > Introduction Top


Follicular thyroid carcinoma (FTC) is the second most common thyroid malignant cancer after papillary thyroid carcinoma (PTC) and accounts for 10%–15% of all thyroid tumors.[1] In 2009, Park et al. proposed [2] that the thyroid imaging reporting and data system (TI-RADS) could be used to evaluate the nature of thyroid nodules, which gained widespread attention and recognition. However, some scholars have reported [3] that the accuracy rate of TI-RADS for evaluating PTC is 97%, while the accuracy rate for evaluating FTC is only 52%. Patients with FTC are generally older and always have worse prognosis than patients with PTC,[4] which makes it quite difficult to confirm FTC. In the course of ultrasound diagnosis, the presentation of FTC is often confused with that of follicular thyroid adenomas (FTAs).[5] Therefore, it is important to identify FTC and FTA during the process of ultrasound diagnosis.


 > Materials and Methods Top


Patients

A total of 304 patients who were treated in the Zhejiang Cancer Hospital (ZJCH) from March 2009 to 2018 were enrolled in this study. After diagnosis and treatment, thyroidectomy, subtotal or unilateral resection would be performed after obtaining the patients' informed consent. Preoperative ultrasound diagnoses were performed for patients treated in ZJCH, and no thyroid surgeries were conducted before their visits. Histopathological diagnosis after surgery should be regarded as the gold standard for this study. However, patients with Hurthle cell carcinoma, mixed FTC and medullary thyroid carcinoma were excluded from this study. Two patients were also excluded from the study because they were exposed to radioactive materials at an early age. Eight patients were not included in the study because of the coexistence of other systemic malignancies. Finally, a total of 294 patients were enrolled in this study. The average age of the 69 patients with FTC (23 males and 46 females) was 52.03 ± 14.269 years. Seven patients had double or multiple nodules. The average age of 225 patients with FTA (71 males and 154 females) was 46.57 ± 12.729 years, of which 11 patients had double or multiple nodules. Institutional review board approval was obtained for this retrospective study, and the requirement for informed consent was waived.

Ultrasound images

The Esaote Mylab90 (Esaote S.P.A; Genoa, Provincia Di Genova, Italy), Logic E9 (General Electric Company, Fairfield, Connecticut, USA), Philips iU22 (ROYAL PHILIPS; Amsterdam, The Netherlands), and Toshiba 790A (Toshiba Corporation; Tokyo, Japan) ultrasound systems were applied. The probe models included LA523, ML6-15, L12-5, and PLT-805AT, and the probe frequency was 5–13 MHz. Patients were placed in supine position to take appropriate sections for the observation of thyroid nodules. Ultrasonographic features of benign and malignant thyroid nodules were stored and recorded. During the process of ultrasound diagnosis, the following points should be considered: parameters (including tumor size, echo status, homogeneity, calcification, and aspect ratio >1); whether the shape is regular (the spherical or ellipsoidal nodules are attributed to shape rules; if the nodules are angulated, they are considered to be irregular); whether the boundary is clear; whether there is sound halo; Doppler blood flow grading [Figure 1] (according to the report presented by Frates et al.,[6] the blood flow of follicular tumors can be divided into 5 types: 0 means no blood flow; 1 indicates no peripheral annular blood flow, but a little bit of internal blood flow; 2 shows peripheral annular blood flow, but no internal blood flow signal; 3 presents peripheral blood flow and internal blood flow signal and 4 means peripheral annular blood flow and internal blood flow signal are more abundant) and any other things worth noting. The cut-off value for calcification should be 2 mm. Macrocalcification were defined as ≥2 mm while microcalcifications were defined as n2 mm. If microcalcification and macrocalcifications were simultaneously present in the nodule, they were classified into the microcalcification group [Figure 2] and [Figure 3]. Ultrasound images of all patients were analyzed by two ultrasound chief physicians from the picture archiving and communication system for retrospective interpretation analysis, and opinions were agreed upon by consensus. Finally, all nodules were evaluated according to the thyroid TI-RADS grading standard published by American College of Radiology (ACR) in 2017.[7]
Figure 1: Ultrasound image from a 66-year-old woman with follicular thyroid carcinoma.The boundary of this nodule is clear, but the internal echo is uneven, and the Doppler flow imaging shows a rich blood flow signal around its interior and inside

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Figure 2: (a) Ultrasound image from a 27-year-old woman with follicular thyroid carcinoma. (b) This nodule has annular calcification

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Figure 3: Ultrasound image from a 32-year-old woman with follicular thyroid carcinoma. There are clusters of calcification in this nodule

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Statistical analysis

Statistical analysis was performed using SPSS for Windows (Version 19.0; SPSS, Chicago, IL). Tumors enrolled in this study were numbered, and pathological results were connected with tumors shown under the ultrasound. The characteristics of each nodule were recorded as described in the above-mentioned method. Continuous variables (e.g., nodule size) were analyzed using an independent sample t-test and summarized as mean ± standard deviation; ordered classification data (e.g., TI-RADS classification and Doppler flow status) were assessed using the Wilcoxon rank sum test; disordered binary data were evaluated using a Chi-square test.

Finally, all variables were analyzed by both univariate and multivariate logistic regression analyses, while follicular adenoma and follicular carcinoma were taken as binary results. Pathological results of two groups are FC and FA, respectively, which could be regarded as dependent variables. Eleven ultrasound features of collected FTA nodules were regarded as independent variables. After that, a two-class logistic model was established (inclusion criteria: P < 0.05).


 > Results Top


Clinical data of 294 FTC and FTA patients (including the age and gender ratio of patients, and the condition of combined nodular goiter, multiple nodules, and complication of Hashimoto's thyroiditis [HT]) were summarized in [Table 1]. After preliminary studies, we found that FTC patients were slightly older than FTA patients (P = 0.003), and patients in the FTC group had more nodular goiter complications than the FTA group.
Table 1: Clinical data and pathological results

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Sonographic characteristics of 312 nodules enrolled in this study were also presented [Table 2]. On ultrasound FTA presented rare regular boundary and shape. In terms of internal echo, FTA had no high specificity in terms of uniformity, inhomogeneity and cystic nature, but it could be seen from the data that solid, inhomogeneous and echogenic nodules accounted for 77.6% of FTC [Figure 4]. Regarding echo levels, most FTA and FTC were hypoechoic, but FTC had a lower proportion of hypoechoic echo. Moreover, both for FTA and FTC, examination by ultrasound Doppler showed that the blood flow signal in Class II accounted for the largest proportion. In addition, both FTA and FTC had normal nodules without calcification. In cases of calcified nodules, most FTCs showed microcalcifications and most FTAs showed macrocalcifications. Finally, the latest TI-RADS classification of thyroid nodules was conducted according to ACR guidelines. As shown in [Table 2], although the currently-accepted TI-RADS was more accurate for the diagnosis of PTC by ultrasound, it had a higher degree of accuracy in judging FC malignancy than FA (the 4 categories were considered to be more malignant). In this study, 36.8% of FTCs were divided into 4 categories, and 14.0% of the FTAs were divided into 4 categories. However, we found that 61.8% of the nodules were still divided into the third category, indicating that, although FTC had certain signs of malignancy, this classification system could still not be fully applied to predict FTC.
Table 2: Ultrasound performances of follicular thyroid adenoma and follicular thyroid carcinoma

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Figure 4: Ultrasound image from a 54-year-old man with follicular thyroid carcinoma. This nodule looks like a fusion of two nodules. In addition, there is a certain cystic liquefaction necrosis area in this nodule

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In this study, we used univariate and multivariate logistic regression analysis to analyze 11 related parameters. Results showed that some ultrasonographic and clinical features were associated with FTC [Table 3]. In multivariate analysis, parameters such as unclear boundaries (P = 0.002), cystic degeneration (P = 0.000), hypoecho (P = 0.039), TI-RADS (P = 0.048), nodular goiter (P = 0.009), macrocalcification (P = 0.000) and microcalcification (P = 0.016) were statistically significant. Among them, macrocalcification was a protective factor for thyroid follicular tumors, and other indicators were risk factors.
Table 3: Multivariate analysis of follicular thyroid carcinoma

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 > Discussion Top


The incidence rate of thyroid cancer has been increasing year by year and this is mainly because of the improvement in awareness of the importance of the patients' physical examination and the development of inspection techniques. Among worldwide malignant tumors, thyroid cancer only accounts for 1%–2%.[8] However, it remains the most common endocrine malignancy. Ultrasound, as a routine examination item, plays an increasingly important role in the diagnosis of thyroid nodules.[9] Under ultrasound examination, lesions with a minimum diameter of about 1 mm can be found. As a result of the joint efforts of sonographers, the rate of ultrasound accuracy in determining PTC has achieved 97%, but only half of the PTC patients can be diagnosed with FTC. Another prospective study [10] also showed that 86.5% of sonographic characteristics in classic thyroid cancer can be present in nonfollicular tumors, while only 18.2% can be found in follicular cancer. This is mainly because FTC does not have all the features of so-called thyroid malignancy including calcification, marginal irregularity, hypoecho, aspect ratio disorder, etc.[11] Thus its presentation is often confused with FTA and thus always judged as benign nodules.[12]

As mentioned earlier, FTC is the second most common malignant tumor originating from the thyroid gland. Although studies have shown that the incidence rate of FTC in the whole world has declined in recent years, the incidence rate in developing countries remains high.[13] In fact, in areas with iodine deficiency, the incidence rate of FTC is often relatively higher, and the decrease in incidence rate in recent years is closely related to the improvement of general living standards.[14] The frequency of FTC is the highest among patients aged 45–49 years and 60–70 years, and the female-male ratio is 3:1.[15] Most researchers are interested in FTC, mainly because the preoperative diagnosis of this type of malignancy is still elusive. To date, it is still not easy to clearly diagnose FTC even in histological examinations.[13],[16] FTC is more aggressive and has a greater tendency to metastasize than PTC.[16] In more than 20% of cases, distant metastases, especially lung and bone metastases have already occurred at the time of initial diagnosis.[1] Accurate confirmation of FTC at the time of the original visit is a challenge for sonographers. On ultrasound images, FTC and FTA seem to have the same ultrasound presentation such as single and hypoechoic nodule; inhomogeneous internal structure, irregular border, missing or discontinuous surrounding halos, larger lesions, and sometimes cystic features.[15] Even pathologists are still arguing whether FTC directly develops from the follicular thyroid cells or FTA, which also contributes to the difficulty of distinguishing them.[17] As sonographers, we can try and find clues on ultrasound images, to help provide ideas and contribute to the diagnosis and even future treatment of the patient.

Age and gender

Among 294 patients enrolled in this study, FTC patients were about 50-year-old and 30% of them were males. This is consistent with the findings of many reports which showed that FTC mainly occurred in older females.[1],[15],[18] FTC patients were older, which seems to be consistent with the hypothesis that FTC develops from FTA.[19] However, the reason why patients with malignant tumors are older is partially due to aging, accumulation of gene mutations and so on. There are also some reports arguing that age is a risk factor for FTC.[14] For study about this problem, it should be a point that requires continuous attention.

Volume

At present, tumor size is also listed as a risk factor for the development of FTC. In terms of the general pattern of tumor development, benign tumors grow at a slower rate and their growth pattern is expansive. Malignant tumors have a faster growth rate and are invasive. Therefore the larger the tumor, the higher the degree of malignancy will be. However so far, there is no evidence that rapid growth is a hallmark of malignant tumors. In thyroid tumors, it has been reported that growth rate of tumors is related to their nature. However, when growth rates were compared between different tumors (benign or malignant), the differences were not significant. This study found no significant difference in tumor volume between the FTA and FTC groups, and there was no correlation between volume and FTC development. In addition to the previous evidence that growth rates of FTA and FTC were not related to the nature of tumors, there are two other reasons to support the author's analysis. First, in terms of the biological behavior of FTC, the early growth mode of FTC is slow although more invasive and malignant than the PTC.[20] Second, due to the improvements in awareness of the importance of physical examinations, most patients receive further examination because of the “thyroid nodules found during physical examination” at the hospital. It is difficult to control the duration of the disease, thus it is difficult to assess the degree of malignancy through the size of the thyroid at the time of the patient's visit.

Combined nodular goiter

Nodular goiter originates from a common diffuse goiter. Disease progression leads to diffuse proliferation from follicular epithelium to focal hyperplasia, and degeneration appears in some areas. Finally, due to the repeated alternation of long-term proliferative lesions and degenerative lesions, nodules in different developing stages appear in the gland. In recent years, some studies have also analyzed the effect of iodine deficiency and endemic goiter on the occurrence of FTC, and the results are highly relevant.[21] Although this research did not explore whether patients had a history of iodine deficiency, it found that complications of nodular goiter not only showed differences between FTA and FTC, but also had a certain correlational relationship with the development of FTC. This is because patients with nodular goiter may come from iodine-deficient areas. Generally, the incidence rate of FTC in areas with iodine deficiency can reach 40%.[4],[22],[23] Given the increased risk of FTC in areas with iodine deficiency and endemic goiter, these two factors are considered to be triggers of the pathogenesis of FTC.[23] Therefore, in the following ultrasound examinations, sonographers should also pay more attention to patients' medical history and existence of other nodules, so as to make a more accurate judgment.

Affiliation of Hashimoto's thyroiditis

The relationship between HT and thyroid cancer is long-standing. As early as 1863, Rudolf Virchow [24] oticed leukocytes in tumor tissues and suggested it has a correlation with cancer development. In 1955, the association between HT and PTC was first described by Dailey et al.[25] At present, only the correlation between HT and PTC has been studied, while systematic reports on the correlation between HT and thyroid carcinoma (TC) are scarce.[26] As a result, there are also fewer studies on the correlation between FTC and HT.[21] Only in 2017, some scholars carried out systematic reports and showed that HT is not related with FTC. That finding is consistent with this study, indicating that HT is not a risk factor for the occurrence of FTC and had no effect in identifying FTA and FTC.

Single and multiple

In the diagnosis of FTC or FTA, ultrasound images always show single nodules, but this study indicated that 4.9% and 10.1% of FTA, FTC patients had double or multiple nodules. Although the difference between the two was not obvious, this is a reminder that a careful examination of every nodule in the thyroid gland is important in order to avoided misdiagnosis.

Ultrasound signal-tumor margin

From a pathological perspective, the most essential difference between FTA and FTC is whether there is vascular and/or capsule infiltration of the tumor.[16] Previously-published reports believed that vascular invasion is the main prognostic factor, and that invasion of the capsule is not significant. However, recent literature seems to indicate that extensive invasion by itself is an unfavorable prognostic factor, while single vascular invasion is not.[4],[14],[16] Whether the edge of the tumor is smooth and continuous acts as evidence for sonographers to macroscopically judge whether the tumor capsule has invaded normal tissues. There are deviations in the definition of capsule integrity in different cases, but unsmooth or interrupted FTC capsule occurred more frequently in FTC, assuming that the diagnoses were made under the same criteria and judgments were performed by the same physician in this study. This finding is in line with most of the reported FTA and FTC results.[27],[28]

Irregular shape: more than 90% of FTCs and FTAs are spherical or ellipsoidal in shape, indicating that most follicular tumors grow relatively even and the shape of growth is more regular. However, studies have shown that the number of FTC formation angles is still larger than that of FTA, indicating that the growth rate of different sites or different components in the tumor is not the same, which may be related to deeper molecular level changes. Related studies have shown that thyroid nodules carrying rat sarcoma (RAS) mutations or rearranged during transfection (RET) proto-oncogene rearrangements produce chimeric cytoplasmic kinases faster than wild-type RAS or wild-type RET.[29] The primary carcinogenic driving factors for FTC were mitogen-activated protein kinase (MAPK) and PI3K/AKT pathway,[18] and such changes influenced the same MAPK cascade, which resulted in the stimulation of the cell cycle and cell proliferation.[29]

Internal echo

This study divided the internal echo into solid and homogenous nodules, solid and inhomogeneous nodules and cystic nodules. Tian HY et al. reported [30] that focal cystic formation (mainly solid or mixed echogenic structures) can be more easily found in FTC than in FTA. This may because of the invasiveness and necrotic blood vessels of FTC. The same results were obtained in other studies. On the other hand, rapid proliferation of malignant cells and different growth rates at different sites can also lead to the formation of cystic structures.[30] The cystic formation does not undergo autolysis and behaves like a benign adenoma, and degenerative cystic formation also will not appear.

Hypoechoic

Most follicular neoplasms exhibit low internal echo, which is a common phenomenon. Internal hypoecho should be analyzed together with the cystic changes described above. If there is no cystic change in a nodule and the internal echo is low, rapid and disordered follicular cell growth is occurring. This disordered growth can also result in the loss of a normal array of follicles in normal thyroid parenchymal tissue, which in turn results in lower echo on two-dimensional ultrasound images. The normal arrangement of follicles is lost, which makes the tissue become less echogenic than adjacent normal parenchyma. In the results of our study, the low echo of the ultrasound image was not statistically significant in the univariate regression analysis, while in the multivariate analysis the P value was <0.05, indicating that in the context of multiple factors “low echo” is still important in identifying FTC and FTA. Although the analysis results were presented like this, we could hardly distinguish the difference between malignant proliferation and benign proliferation on the ultrasound level.

TI-RADS classification: though the number of the circumstances where FTC were categorized to 4th category nodules was more than FTA, there are still a few nodules which are divided into 3th category. However, if misdiagnosis is considered every time after a nodule has been classified into the third category (suspected benign lesions, the odds of malignancy <5%), we found that more than half FTCs fail to show a predominantly malignant tendency in the preoperative ultrasound examination. This suggests that doctor and patient should still combine FNA or continue follow-up observation if the thyroid nodule was classified into TI-RADS 3.

Calcification

Microcalcification in the thyroid gland is commonly seen in malignant tumors, and macrocalcification, including annular calcification, is often considered to be benign or indicative of FTA. Meanwhile, macrocalcification also occurs in some FTCs and undifferentiated carcinoma. This study showed that FTC had less macrocalcifications and more microcalcifications compared with those in FTA. But in fact, in both of them more than half of the nodules had no calcifications. Therefore, calcification was not specific for the identification of these two nodule types, but results from the correlation analysis suggest that both macrocalcifications and microcalcifications were positively related to the occurrence of FTC. Some studies have mentioned that, for some cystic thyroid nodules with eggshell calcification, follicular carcinoma should be taken into consideration.[27],[31]

Halo

Halo is the thin edge of the echo which can be seen around the nodule. Some scholars have reported [22],[27] that the halo appears more frequently around FTA and has some significance in the identification of PTC and follicular neoplasms. However, this study showed that halo is not statistically significant for FTA and FTC.

Color Doppler

Blood flow in the two types of nodules is abundant, and most of the blood flow signal in FTA nodules is rated as Class 2. Previous studies have indicated that solid hypervascular thyroid nodules had a high likelihood of malignancy [with a proportion of nearly 42%).[32] Relevant research has since confirmed their results. Unfortunately, FTC and FTA had different blood flow signals, and so this indicator cannot be used for differential diagnosis.

Although a few articles have reported on the ultrasonic characteristics of FTA and FTC, this research still has certain research and clinical significance. First of all, we comprehensively analyzed the ultrasound characteristics of FTA and FTC, and the statistical research on clinical characteristics of those was also included. Moreover, compared with similar types of researches, this report contained 294 cases which were significant with such a large scale of patients on the circumstances where the clinical incidence of such tumor is relatively low, so it would be much more convincing. Finally, this article conducted an in-depth analysis of possible mechanisms from a pathological perspective to distinguish the meaningful ultrasound features of FTA and FTC, laying a foundation for subsequent research.

When carrying out ultrasound diagnosis, care should be taken to identify FTC and FTA in terms of age, nodular goiter conditions, nodular boundary conditions, internal echo, calcification, blood flow signals, TI-RADS grading and cystic solidity conditions. Unclear boundaries, low echo, combined nodular goiters, highly classified TI-RADS, and calcification are associated with FTC.


 > Conclusion Top


Ultrasonic features can be utilized to make preliminary differential Diagnosis of FTA and FTC, which will provide effective information for clinical treatment, but further research in this area is still necessary.

Financial support and sponsorship

This study is funded by two funds that are the National Natural Science Foundation of China (NO.81871370) and Zhejiang Provincial Natural Science Foundation of China (No. LSD19H180001).

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3]



 

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