Clinical Outcome and Prognosis of Differentiated Thyroid Carcinoma with Distant Metastasis

doi:10.21203/rs.3.rs-4839819/v1

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Clinical Outcome and Prognosis of Differentiated Thyroid Carcinoma with Distant Metastasis

https://doi.org/10.21203/rs.3.rs-4839819/v1

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Objective

To investigate the risk and prognostic factors of Radioactive iodide (RAI)-refractory (RAIR) in distant metastatic (DM) differentiated thyroid cancer (DTC).

Methods

DM-DTC patients who received iodine-131 radiation therapy were enrolled in this cohort study. After exclusion, 75 DTC radioiodine therapy resistant patients and 53 treatment effective patients were finally included. The clinical data, BRAFV600E and TERT promoter mutations were compared between these two groups to predict the risks of RAIR. Patients with RAIR-DM-DTC were followed up to further explore the risk factors for disease progression after iodine refractory.

Results

Univariate analysis showed that TERTp mutation, age at diagnosis, mean maximum tumor diameter, lymph node metastasis, synchronous metastasis or heterochronous metastasis, mean cumulative dose of RAI and preoperative Tg (pre-Tg) were statistically different between the RAIR and RAIE (radioiodine efficient) groups. Logistic regression analysis further found that the TERTp mutation may be risk factors for iodine refractory occurrence. During the follow-up of RAIR-DM-DTC patients, 41 patients developed disease progression and 24 patients had good disease control.

Conclusions

We found that TERTp mutation was correlated with the poor curative effect of RAI therapy in DM-DTC. Once iodine refractory occurs, patients aged 55 years or older are more likely to develop disease progression.

Distant metastasis

Radioiodine therapy resistance

Differentiated thyroid carcinoma

Thyroid cancer, as one of the most common endocrine cancers, has seen a surge in incidence in recent years. Differentiated thyroid carcinoma (DTC) usually has a good prognosis after surgery, radioactive iodine (RAI) therapy, and/or thyroid stimulating hormone (TSH) suppression[1]. Nonetheless, approximately 10% of DTC patients experience disease recurrence, characterized by extensive lymph node metastases (LNM) and distant metastases (DM)[2]. One third of patients with DM will be cured by RAI and have a near-normal life expectancy[3].While patients with radioactive iodine-refractory DTC (RAIR-DTC) have a poor prognosis, with a 10-year survival rate of 10%[4]. Early identification of RAIR-DTC can suggest clinicians to intervene early in these tumors to improve the prognosis of RAIR-DTC. In this context, it is important for clinicians to be able to risk stratification of patients with DM-DTC and to be able to identify those at risk of poor prognosis who may benefit from novel systemic therapies or clinical trials starting early. Therefore, the development of comprehensive prognostic groups for patients with distant metastases of thyroid cancer is important to tailor treatment to disease severity.

It has been reported that molecular features may drive early identification of radioiodine uptake status[5]. Two major genetic alterations have been studied as markers for adjuvant clinical outcomes in thyroid tumor. Raf proto-oncogene (BRAF) V600E mutation is the most common genetic alteration in papillary thyroid cancer (PTC), which is an important marker associated with higher recurrence rate and disease-specific mortality by activating mitogen activated protein kinase (MAPK) signaling pathway[6]. Telomerase reverse transcriptase (TERT) promoter mutations are present in two somatic mutations chr5, 1,295,228C>T (C228T) and 1,295,250 C>T (C250T), which is another key oncogene associated with poor clinicopathological outcome of PTC[7]. BRAFV600E and TERTp mutations have been confirmed to be closely related to radioiodine-refractory DM-PTC[8, 9], but these findings still need to be confirmed and generalized by further studies. Once RAIR occurs in patients, it does not mean disease progression, so what are the risk factors for disease progression in DM-DTC-RAIR patients? This issue has not been studied yet.

This study retrospectively analyzed 128 cases of DM-DTC patients with iodine-131 treatment in our institution to explore the risk factors of RAIR in DM-DTC. The study also followed 65 patients with RAIR-DM-DTC. The median follow-up of patients was 35.1 months.

1. Patient and tissue samples

This retrospective study collected 128 DTC patients with DM, all these patients received radioiodine therapy in Jiang yuan Hospital from January 2007 to August 2023. According to the 2015 ATA(American Thyroid Association) Guidelines for the Management of Adult thyroid Nodules and differentiated thyroid cancer[10] and iodine-131 whole-body scan (WBS), iodine uptake ability of metastatic foci was determined, then patients were divided into RAIR group (n = 75) and RAIE (Radioiodine efficient) group (n = 53). The detailed project design process is shown in Fig. 1. Patients who met the following inclusion criteria were selected:(1) thyroidectomy or subtotal resection was performed and DTC was confirmed by pathology; (2) There is distant metastasis; (3) At least one iodine-131 treatment; (4) The follow-up time of the last treatment was more than 6 months. The exclusion criteria are one of the following: (1) no regular follow-up, lack of imaging serological data; (2) Patients with other serious diseases or malignant tumors; (3) Residual thyroid tissue in the neck; (4) Tg antibody was positive. CT examination of other organs is performed in those patients who show symptoms indicating damage or abnormal uptake on the post-treatment scan. Tumor response is classified as complete when the criteria for a good biochemical and structural response are met. Patients with incomplete structural responses were divided into partial responses according to RECIST 1.1 criteria (at least 30% reduction in the sum of the longest diameter of the measured target lesion, using the sum of the longest diameter at baseline as reference; Progressive disease (maximum total diameter increase of 20% or more); Stable disease (neither sufficient contraction to meet the criteria for partial remission nor sufficient increase to meet the criteria for progressive disease). Synchronous metastasis, defined as 6 months after surgery, perioperative stage research or iodine-131 WBS for the first time found in distant metastasis with reference to previous studies[11].Follow-up was defined as the time from iodine-refractory diagnosis of thyroid cancer to the last examination at our hospital on July 15, 2024.This study follows the principles of the Helsinki Declaration and was approved by the Ethics Review Committee of the Institute of Atomic Medicine of Jiangsu Province (approval number: YLK202322). All enrolled patients signed informed consent.

2. Treatment method and Criterion

Patients were required to have a low-iodine diet for one month before iodine-131 treatment and to stop taking thyroxine tablets or levothyroxine for 3 weeks to allow TSH levels to rise above 30 mU/L. The first dose of ¹³¹I was 3.70–5.55 GBq according to the results of iodine-131 systemic phenomenon, and the dose of ¹³¹I was 5.55–7.40 GBq for those with distant functional metastasis. DM was determined through chest CT, 18F-FDG PET/CT, bone scan, WBS or WBS after radioiodine therapy, combined with thyroglobulin level. Post-treatment WBS was performed on the 7th day after treatment. Serological efficacy was evaluated 4 to 6 months after the last treatment. Stimulated Tg levels (sTg) after levothyroxine were discontinued for 3 weeks and TSH level reached 30 mU /L was used as serological index to evaluate the treatment response to RAI. The sTg of the last ¹³¹I treatment was compared with the basic sTg before the first ¹³¹I treatment. The serologic response was categorized as up (> 20% increase in sTg compared with first radioiodine therapy), down (> 20% decrease), or stable (-20% to + 20%). At the end of follow-up, the radioiodine therapy response was classified as disease control or refractory. Oral administration of levothyroxine was started 3 days after ¹³¹I treatment, and the patient was reexamined 3–6 months after treatment. According to the examination results, whether the patient chose to receive iodine-131 treatment again or not was determined. The RAIR criteria are divided into four categories according to the 2015 ATA Management Guidelines^[10].The diagnostic criteria for RAIE were as follows: Iodine-131 imaging showed that the primary lesion or metastasis disappeared, and serum Tg below 1ug/L after TSH inhibition and stimulation were considered cured. Iodine-131 imaging showed that the metastasis disappeared, or the lesion became smaller, and the Tg level decreased, indicating improvement or stability. Iodine refractory risk factors were analyzed: age, gender, maximum tumor diameter, cervical lymph node metastasis, multifocal, distant metastatic site, ATA risk stratification, pre-Tg, metastatic type, extrathyroidal extension (ETE), cumulative radioactive iodine dose, BRAF and TERTp mutation.

3. DNA Extraction and Gene Mutation Detection

Genetic mutations were confirmed by paraffin-embedded tissue specimens. Genomic DNA was extracted from DTC samples according to procedure using a paraffin Tissue DNA extraction Kit, QIAamp DNA FFPE Tissue Kit (QIAGEN, Germany). Paraffin-embedded tissues were deparaffinized with xylene and washed twice with ethanol. After ethanol volatilization, the tissues were lysed with enzyme I and proteinase K at a final concentration of 1 µg/mL. Human TERT gene promoter mutation detection kit (Genetron, Beijing, China) was used for fluorescence polymerase chain reaction (PCR)assay (Roche Light Cycler Type 480 Ⅱ PCR instrument). PCR amplification 37 ℃ for 3min; 95 ℃ for 3 min; 95 ℃ for 15 s, 65 ℃ for 45 s, 15 cycles; 95 ℃ for 15 s, 60 ℃ for 1 min, 25 cycles; Fluorescein (FAM) Carboxyfluorescein and Carboxy-X-rhodamine (ROX) channels were used to acquire fluorescence signals. Human B-Raf proto-oncogene, serine/threonine kinase, BRAFV600E mutation detection kit (AmoyDx, Xiamen, China) was used for fluorescence PCR assay, amplification 95℃ for 5 min; 95℃ for 25 s, 64℃ for 20 s, 72℃ for 20 s, 15 cycles; 93℃ for 25 s, 60℃ for 35 s, 72℃ for 20 s, 31 cycles. FAM and VIC signals were collected at 60℃.

4.Statistical analysis

Statistical analysis was performed using SPSS version 26.0 (IBM Corporation). Continuous variables are presented as medians and ranges, categorical variables are presented as numbers and percentages, and measurement data are presented as the mean and standard deviation (SD). The independent-sample t test was used to compare clinical quantitative variables. Comparison of qualitative data between groups by chi-square test or Fisher exact probability method. P < 0.05 was considered statistically significant. The multivariate Logistic regression analysis was adopted for the single factor analysis with statistical significance.

1. Demographics and disease characteristics

According to inclusion and exclusion criteria, 128 patients with DM were enrolled in the present study. After RAI therapy, 53 patients were diagnosed with RAIE, and 75 patients were RAIR. There were no statistically significant differences between these two groups in terms of gender, histological types, multifocality, extrathyroidal extension, metastatic target organs, BRAF V600E mutation and ATA risk (Table 1). Notably, the median age of RAIR-DTC patients was significantly higher than that of patients with RAIE-DTC (p < 0.001). The mean maximum tumor diameter was 3.09 ± 1.64 cm in the RAIR group and 2.39 ± 1.53 cm in the RAIE group (p = 0.014). In the RAIR group, 30 patients (40%) had more than 5 lymph nodes metastasis and 41 patients (54.7%) had no more than 5 lymph nodes metastasis. In the RAIE group, 32 patients (60.4%) had more than 5 lymph nodes metastasis, and 18 patients (33.9%) had no more than 5 lymph nodes metastasis (p = 0.018). The mean cumulative dose of RAI in the RAIR group (486.8 ± 303.2mCi) was higher than that in the RAIE group (364.34 ± 193.4mCi) (p = 0.011). Synchronous metastasis was detected in 38 (50.7%) of patients in the RAIR group and 38 (71.7%) of patients in the RAIE group, metachronous metastasis was diagnosed in 49.3% of patients in the RAIR group and 28.3% of patients in the RAIE group (p = 0.017). Pre-Tg data were obtained from 60 patients in RAIR group and 45 patients in RAIE group. Serum pre-Tg levels in RAIR group (382.53 ± 679.34 ng/ml) were significantly higher than that in RAIE group (74.75 ± 107.79 ng/ml) (p = 0.005). Notably, the mutation rate of TERTp in RAIR-DTC patients was 53.97% (24/63), which was markedly higher than that in RAIE group 2.17% (1/46, p < 0.001), and all mutations were TERTp C228T, no C250T mutation was found. The BRAF V600E mutation rate in the RAIR group (25/64, 39.06%) was comparable to that in RAIE group (20/50, 40.00%).

Table 1

Baseline characteristics of the patients with distant metastasis.
	RAIR (n = 75)	RAIE (n = 53)	P value
Age (years)	56 (14–82)	40 (14–79)	< 0.001
Sex			0.32
Male	32 (42.7%)	18 (34.0%)
Female	43 (57.3%)	35 (66.0%)
Histological subtype			0.431
PTC	58 (77.3%)	44 (83.0%)
FTC	17 (22.7%)	9 (17.0%)
Tumor size (cm)	3.09 ± 1.64	2.39 ± 1.53	0.014
Multifocality			0.126
Yes	24 (32.0%)	24 (45.3%)
No	51 (68.0%)	29 (54.7%)
Extrathyroidal extension			0.465
Yes	50 (66.7%)	32 (60.4%)
No	25 (33.3%)	21 (39.6%)
Lymph node metastasis			0.018
N > 5	30 (40.0%)	32 (60.4%)
N ≤ 5	41 (54.7)	18 (34.0%)
Undissected/unknown	4 (5.3%)	3 (5.6%)
Site of distant metastasis			0.076
Lung	48 (64.0%)	44 (83.0%)
bone	4 (5.3%)	3 (5.6%)
Lung & bone	22 (29.3%)	6 (11.3%)
Other	1 (1.3%)	0
ATA risk stratification			0.694
Low risk	3 (4.0%)	3 (5.6%)
Intermediate risk	20 (26.7%)	17 (32.1%)
High risk	52 (69.3%)	33 (62.3%)
RAI accumulation (mCi)	486.80 ± 303.18	364.34 ± 193.43	0.011
Pre-Tg (ng/ml)	382.53 ± 679.34	74.75 ± 107.79	0.005
Types of metastases			0.017
synchronous	38 (50.7%)	38 (71.7%)
metachronous	37 (49.3%)	15 (28.3%)
BRAF V600E mutation			0.919
Yes	25 (33.3%)	20 (37.7%)
No	39 (52.0%)	30 (56.6%)
unknown	11 (14.7%)	3 (5.6%)
TERTp mutation			< 0.001
Yes	24 (32.0%)	1 (1.9%)
No	39 (52.0%)	45 (84.9%)
unknown	12 (16.0%)	7 (13.2%)
Abbreviations: ATA, American Thyroid Association; RAI, radioactive iodine; Pre-Tg, preoperative thyroglobulin
Continuous variables are presented as medians and ranges, categorical variables are presented as numbers and percentages, and measurement data are presented as the mean and standard deviation (SD). The independent-sample t test was used to compare clinical quantitative variables. Comparison of qualitative data between groups by chi-square test or Fisher exact probability method. P < 0.05 was considered statistically significant. The difference between BRAF V600E and TERTp mutation and no mutation in the two groups were compared respectively.

2. Risk factors of RAIR-DTC

Multivariate Logistic regression analysis further found that pre-Tg and TERTp mutations were notable risk factors for iodine resistance (Table 2). However, regarding the influence of pre-Tg values, the odds ratio was only 1.005, which we believed was of no clinical significance. Coexistence of BRAF V600E and TERTp was studied in 62 RAIR patients and 45 RAIE patients. In addition, the prevalence of BRAF V600E and TERTp mutations in RAIR and RAIE groups were 20.97% (13/62) and 2.22% (1/45), respectively. Four patients died in the RAIR group during follow-up, all of them harbored TERTp mutation, and two of them simultaneously harbored BRAF V600E and TERTp mutations. Among 13 patients who coexisted with BRAFV600E and TERTp mutations, 9 patients had no iodine uptake in their metastatic lesions. RAI uptake capacity of metastatic lesions was suppressed in TERTp mutated patients when compared with TERTp wild type patients (13/24 vs. 14/38, p = 0.180; Table 3).

Table 2

Logistic regression analysis of factors predicting the RAIR at the end of follow-up.
	Univariate OR	95%CI	P
Diameter (cm)	1.1283	0.738–1.722	0.578
Pre-Tg (ng/ml)	1.005	1.001–1.009	0.011
TERTp mutation
No	Ref
Yes	1.26E-8	1.26E-8-1.26E-8	< 0.001
Types of metastasis
Synchronous	Ref
Metachronous	2.394	0.679–8.442	0.175
RAI accumulation (mCi)	1.001	0.998–1.005	0.51
Age (year)
< 55	Ref
≥ 55	1.025	0.981–1.071	0.266
Lymph node metastasis
N > 5	Ref
N ≤ 5	1.51	0.158–14.399	0.72
Abbreviations:OR,odd ratio.
Diameter refers to the maximum diameter of the tumor.Age refers to the age at which the patient was first diagnosed with thyroid cancer by surgery.The multivariate Logistic regression analysis was adopted for the single factor analysis with statistical significance. P < 0.05 was considered statistically significant.

Table 3

Iodine uptake capacity distribution of distant metastases in RAIR-DTC patients in different mutation types. *BRAF* is B-Raf proto-oncogenic filament/threonine protein kinase; RAIR-DTC is radioiodine-refractory differentiated thyroid cancer. *TERTp* is telomerase reverse transcriptase promoter; “+” means positive mutation, “-” means negative mutation; A indicates that the metastases do not take iodine, B indicates that the metastases that used to take iodine lose their iodine uptake capacity after ¹³¹I treatment, C indicates that the metastases do not take iodine in part, and D indicates that the metastases maintain their iodine uptake capacity but the disease progresses.
group	Patientnumber	Iodine uptake characteristics
group	Patientnumber	A	B	C	D
BRAFV600E⁺/TERTp⁺	13	9	1	0	3
BRAFV600E⁺/TERTp⁻	11	4	4	2	1
BRAFV600E⁻/TERTp⁺	11	4	3	0	4
BRAFV600E⁻/TERTp⁻	27	10	5	4	8

3.The prognosis of RAIR-DTC

In RAIR group, 65 patients attended routine follow-up in our hospital. The median follow-up of patients was 35.1 months. By the time of enrollment, 24 patients were well controlled by TSH suppression therapy. However, another 41 patients were in disease progression. There were no statistical differences between these two groups in BRAF V600E mutation, TERTp mutation, multifocality, ATA risk stratification, gender, lymph node metastasis, pre-Tg and maximum tumor diameter. The age of patients with progressive disease were higher, especially in the higher proportion of patients aged over 55 years (p = 0.043; Table 4). Twenty patients were administered with tyrosine kinase inhibitors (TKI) treatment, while twenty-one were maintained with active surveillance (AS). Possible reasons were financial issue and concern about adverse reactions. One patient, who refuse to accept TKI treatment, died from thyroid cancer 9.3 years after surgery.

Table 4

Clinical characteristics of different outcomes in RAIR-MD-DTC.
Characteristics	Non-progressed group (n = 24)	Progressed group (n = 41)	p
Age (year)			0.043
< 55	15 (62.5%)	15 (36.6%)
≥ 55	9 (37.5%)	26 (63.4%)
BRAF V600E mutation
No	12 (50.0%)	20 (48.8%)	0.836
Yes	8 (33.3%)	15 (36.6%)
Unknown	4 (16.7%)	6 (14.6%)
TERTp Mutation
No	14 (58.3%)	20 (48.8%)	0.345
Yes	6 (25.0%)	15 (36.6%)
unknown	4 (16.7%)	6 (14.6%)
Multifocality
No	16 (66.7%)	27 (65.9%)	0.947
Yes	8 (33.3%)	14 (34.1%)
ATA risk stratification
Low risk	2 (8.3%)	1 (2.4%)	0.119
Intermediate risk	9 (37.5%)	8 (19.5%)
High risk	13 (54.2%)	32 (78.1%)
Extrathyroidal extension
No	7 (29.2%)	13 (31.7%)	0.776
Yes	17 (70.8%)	28 (68.3%)
Sex
Male	10 (41.7%)	17 (41.5%)	0.987
Female	14 (58.3%)	24 (58.5%)
Lymph node metastasis
n > 5	10 (41.7%)	14 (34.1%)	0.554
n ≤ 5	13 (54.2%)	25 (61.0%)
unknown	1 (4.1%)	2 (4.9%)
Pre-Tg	272.96 ± 358.60	488.26 ± 879.91	0.530
Tumor size(cm)	2.63 ± 1.34	3.21 ± 1.76	0.054
Continuous variables are presented as medians and ranges, categorical variables are presented as numbers and percentages, and measurement data are presented as the mean and standard deviation (SD). The independent-sample t test was used to compare clinical quantitative variables. Comparison of qualitative data between groups by chi-square test or Fisher exact probability method. P < 0.05 was considered statistically significant.

Table 5

Treatment-emergent adverse events
Adverse events	Grades 1–2, n (%)	Grades 3–4, n (%)	Any grade, n (%)
Alopecia	3 (15%)	0	3 (15%)
Diarrhea	7 (46.7%)	0	7 (46.7%)
Hypertension	11 (55%)	2 (10%)	13 (65%)
Hand-foot skin syndrome	12 (60%)	4 (20%)	16 (80%)
Albuminuria	5 (25%)	3 (15%)	8 (40%)
Abnormal liver function	3 (15%)	1 (5%)	4 (20%)
Generalized weakness	8 (40%)	0	8 (40%)
Hypocalcemia	3 (15%)	0	3 (15%)
Nausea and vomiting	3 (15%)	0	3 (15%)
Thrombocytopenia	2 (10%)	1 (5%)	3 (15%)
Myodynia	4 (20%)	0	4 (20%)
Weight loss	4 (20%)	0	4 (20%)

The poor prognosis of metastatic DTC is closely related to the development of resistance to RAI therapy. The disabling of RAI uptake proposed a particularly severe challenge to patient management. On the one hand, the early detection of RAIR-DTC to further adjust the scope of operation and treatment provides guidance. On the other hand, the early detection of RAIR-DTC can avoid unnecessary ¹³¹I repeat treatment. The BRAF V600E mutation was reported to be a promising molecular marker for predicting decreased iodine uptake in DM^[8], and co-mutations of BRAF V600E and TERTp mutations may be predictors of RAI resistance in patients with DM[12].The co-mutations develop into a genetic background by activating a novel BRAF/MAP kinase/FOS/GABP/TERT pathway system[13].This may provide a molecular explanation for the link between the two mutations and the loss of RAI activity, which renders tumors resistant to RAI treatment and thus leads to poor clinical outcomes. In the DM-DTC patients in the present study, the BRAF mutation rate was 39.5% (45/114) and the TERTp mutation rate was 22.9% (25/109), which was like that reported in the literature[12]. In this study, the prevalence of coexisting BRAF V600E and TERTp mutations was 13.08% (14/107). Of the 14 co-mutation patients, 13 developed RAI resistance, and 9 of these patients, the metastases did not uptake iodine. These results confirmed that the co-mutation of BRAF and TERTp was associated with RAI resistance. The TERTp mutation rate detected in RAIR group was much higher than that in the RAIE group. TERTp mutation rate was correlated with the aggressiveness of thyroid cancer[14]. In this study, three patients were histologically diagnosed with the high-cell subtype (one of the most aggressive histologic subtypes), and two of them had TERTp mutations. Four patients of RAIR group died, all of which were TERTp mutations, suggesting that TERTp mutations may be associated with poor prognosis. Consistent with previous findings, we believe that TERTp mutation of DM-DTC may be a risk factor for iodine-resistant diseases[12].

This study found that age of 55 years or older was a risk factor for disease progression in the RAIR group. Patient age at the time of thyroid cancer diagnosis is a well-established prognostic factor for thyroid cancer survival[15].Most studies have also indicated that age is an important factor affecting the efficacy of ¹³¹I treatment of thyroid cancer metastases. Age is an important prognostic factor and was adopted by the UICC TNM classification system[16], AMES[17] and MACIS[18]. Older patients are often diagnosed with larger tumors and are more likely to advance to advanced stages. Therefore, age is a key factor in the prognosis and staging of thyroid cancer. It has been reported that the long-term survival of patients with distant metastasis depends, among other factors, on age and the degree of radioactive iodine uptake in patients with DM[19]. DTC patients aged > 60 years still have a significant decline in survival compared with DTC patients aged < 45 years[20]. This study is the first to present risk factors for disease progression in DM-DTC aged 55 years or older with RAIR, which is somewhat innovative. More data are expected to further validate and discover more risk factors.

There are some limitations to this retrospective study. Due to the short follow-up time and small number of enrolled patients, it is not possible to further analyze the impact of initial targeting time on patient prognosis, nor the risk factors for disease progression in iodine-resistant patients. No other important genes for iodine metabolism were included in the human analysis, so follow-up collection of cases treated in accordance with the guidelines will continue and known genome-wide testing will be performed when conditions permit. In future studies, the detection of primary and metastatic lesions in the same case will be considered to make the study more accurate. Our research has an important clinical significance for patients and clinicians. Disease prognosis of specificity, and overall survival of different groups can be used to inform treatment decisions and how to customize according to the severity of disease best long-term monitoring. For example, patients with characteristics associated with low survival may require closer follow-up and the possibility of starting a systemic treatment regimen earlier, leading to more intensive treatment. Conversely, patients with characteristics associated with poorer survival may require less intensive treatment and may be able to transition earlier from specialist to primary care physicians for long-term monitoring than patients with poorer survival. In addition, our study identifies those patients at highest risk for poor survival outcomes that can be used to influence clinicians' recommendations regarding recruitment and recruitment for thyroid cancer clinical trials.

The present study indicated that TERTp mutation could serve as independent predictors of iodine-refractory development in DTC patients with DM, which could guide treatment selection during surgery and follow-up. Age 55 years or older was a risk factor for disease progression in patients with RAIR-DM-DTC.

Ethics approval

This study follows the principles of the Helsinki Declaration and was approved by the Ethics Review Committee of the Institute of Atomic Medicine of Jiangsu Province (approval number: YLK202322).

Consent to participate

Informed consent was obtained from all individual participants included in the study.

Consent for publication

The authors affirm that research participants provided informed consent for publication.

Competing interests

The authors declare no competing interests.

Author Contribution

All authors contributed to the study conception and design. Data collection and analysis were performed by CCS, ASL, TTW and MDL. The first draft of the manuscript was written by CCS. The genetic testing was done by GMC,SCX revised the article, JZ contributed to the study conception and design and ASZ screened and followed up the enrolled patients. all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Verburg, F.A., et al., Life expectancy is reduced in differentiated thyroid cancer patients >/= 45 years old with extensive local tumor invasion, lateral lymph node, or distant metastases at diagnosis and normal in all other DTC patients. J Clin Endocrinol Metab, 2013. 98(1): p. 172–80.

No competing interests reported.

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Clinical Outcome and Prognosis of Differentiated Thyroid Carcinoma with Distant Metastasis

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Abstract

Objective

Methods

Results

Conclusions

Figures

Introduction

Materials and methods

1. Patient and tissue samples

2. Treatment method and Criterion

3. DNA Extraction and Gene Mutation Detection

4.Statistical analysis

Results

1. Demographics and disease characteristics

2. Risk factors of RAIR-DTC

3.The prognosis of RAIR-DTC

Discussion

Conclusion

Declarations

Author Contribution

Data availability

References

Additional Declarations

Status:

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