Risk factors for the occurrence and recurrence of papillary thyroid carcinoma with Hashimoto's thyroiditis based on next- generation sequencing

doi:10.21203/rs.3.rs-5294297/v1

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Risk factors for the occurrence and recurrence of papillary thyroid carcinoma with Hashimoto's thyroiditis based on next- generation sequencing

https://doi.org/10.21203/rs.3.rs-5294297/v1

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Purpose To investigate the risk factors for the occurrence and recurrence of Hashimoto's thyroiditis (HT) combined with PTC using Next-Generation Sequencing (NGS).

Methods 249 patients who underwent thyroid cancer surgery in the First Affiliated Hospital of Anhui Medical University from October 2020 to December 2020 were included, and the clinical data, NGS results and 4-year follow-up recurrence were collected, analyzing the related risk factors causing HT combined with PTC and its risk factors for recurrence.

Results patients with RET rearrangement-positive patients in the HT group had a higher lymph node metastasis(LNM) and recurrence rate (P < 0.05); and patients with BRAF mutation in the HT group had more males and were more often seen with multifocal ( P < 0.05). Binary logistic regression analysis suggested that multifocal, RET rearrangement, low age, and lymph node negativity were risk factors for HT combined with PTC. The results of univariate COX analysis showed that the number of cancer foci, LNM, extrathyroidal extension(ETE), recurrence risk stratification, TSH, RET rearrangement positivity, and RET rearrangement interaction with Hashimoto's effect were risk factors for recurrence after PTC. The results of multifactorial COX regression analysis showed that ETE, recurrence risk stratification were risk factors for recurrence after PTC surgery.

Conclusions BRAF mutations are lower in HT combined with PTC but do not have a significant role in recurrence, and the recurrence rate of PTC combined with HT is higher if accompanied by RET rearrangement, and more caution is needed for intraoperative clearance in such patients.

Hashimoto's thyroiditis

papillary thyroid carcinoma

next-generation sequencing

RET rearrangement

Hashimoto's thyroiditis (HT) is an autoimmune inflammatory disease of the thyroid gland. Papillary Thyroid Carcinoma (PTC) is the most prevalent subtype of thyroid cancer and has a favorable prognosis, but it can also present with lymph node metastasis(LNM) at an early stage, and distant metastasis at a later stage of disease progression. Since Dailey et al^[1] first found the association between HT and PTC in 1955, more in-depth studies have been carried out, and HT and PTC are more inclined to point to a better clinical prognosis^[2], however, there are still some articles^[3] pointing out that the combination of HT with PTC has a higher degree of malignancy and LNM rate. Moreover, HT-induced reactive hyperplasia of lymph nodes^[4] increases the difficulty of preoperative assessment of LNM and intraoperative lymph node clearance, which may lead to a residual cancer that is more likely to recur. In addition, the pathogenesis of HT combined with PTC is still in exploration, and although it has entered the genetic, endocrine, and immune levels, how the HT environment contributes to the development of normal glandular tissues into carcinoma has not been elucidated^[5]. Next-Generation Sequencing (NGS), as a next-generation sequencing technology, can detect more unknown and rare mutations with its high throughput, high depth, and high sensitivity, and is now widely used in basic or clinical studies of various cancers^[6]. The aim of this study is to use NGS technology to detect relevant gene mutations and explore the risk factors for the occurrence and recurrence of HT combined with PTC, so as to provide more references for clinical diagnosis and treatment.

1.1 General information

This study is a prospective study, and 249 patients who underwent thyroid cancer surgery in the First Affiliated Hospital of Anhui Medical University from October 2020 to December 2020 were consecutively included. Clinical data including age, gender, thyroid function, tumor diameter, postoperative pathology with or without extra glandular invasion, number of cancer foci, presence of LNM, and TNM staging of the tumor were collected.TNM staging was based on the staging definition criteria in the eighth edition of the American Joint Committee on Cancer (AJCC). The HT group was divided into the HT group (n = 44) and the NHT group (n = 205) according to whether the tumors were combined with HT, the RET group was divided into the positive group (n = 7) and the negative group (n = 37) according to whether the RET was rearranged, and the BRAF group was divided into the positive group (n = 23) and the negative group (n = 21) according to whether the BRAF was mutated, so as to compare the relevant indexes of the different subgroups and to analyze the risk factors and factors of the combination of PTC with HT. and its risk factors for recurrence of combined PTC.

Inclusion criteria: 1) postoperative pathologic diagnosis of PTC; 2) consent to NGS testing; 3) cooperation with follow-up. Exclusion criteria: 1) Sample pathology type not PTC; 2) Incomplete information on either clinical data, postoperative pathology or genetic testing; 3) Other as deemed inappropriate by the researchers. All patients signed an informed consent form, and the study was approved by the Ethics Committee of the First Affiliated Hospital of Anhui Medical University.

1.2 Tumor tissue gene sequencing

Fresh tissue specimens were collected, and the extracted DNA and RNA samples were used for library construction. NGS technology was applied for nucleic acid sequencing, and the data were filtered and compared with the nucleic acid sequences in the library, so as to analyze and detect the related genes.

1.3 Postoperative follow-up

Postoperative TSH suppression treatment, regular review of thyroid function, thyroid ultrasound. Postoperative follow-up of all postoperative patients was conducted by means of teleconnection or outpatient review, and the follow-up deadline was October 1, 2024.

1.4 Statistical analysis

The study was statistically analyzed using SPSS version 25.0. Categorical variables were analyzed by chi-square test or Fisher's exact test, and expressed as the number of cases and percentage; continuous variables were analyzed by t-test or Mann-Whitney U-test, and non-normal measurements were described by quartiles [M (Q1-Q3)]; coexisting influences were analyzed by binary logistic regression analysis; Log-rank test and Cox regression were performed for recurrence influence factor analysis; P < 0.05 was statistically different.

2.1 Basic information and NGS results of the HT and NHT groups.

Compared with the NHT group, patients in the HT group were younger, had higher TGAb, less ETE, more frequent multifocality, lower LNM rate, lower BRAF mutation rate, and higher RET rearrangement rate (P < 0.05). There were no statistical differences between the two groups in gender composition, maximum tumor diameter, recurrence rate, TERT mutation, NRAS/HRAS mutation, TSHR mutation, TP53 mutation, PIK3CA mutation, and NTRK1 mutation (P > 0.05). (Table 1, Figs. 1–10)

Table 1

Comparison of basic information between HT group and NHT group
Characteristics	HT(n = 44)	NHT(n = 205)	t/Z(X²)	P-value
Age	41(31.25,49)	45(33.5,53)	2.431	0.016
Sex			(0.024)	0.877
Male	13(29.55%)	63(30.73%)
Female	31(70.45%)	142(69.27%)
ETE			(4.758)
Yes	1(2.27%)	32(15.61%)
No	43(97.73%)	173(84.39%)
Tumor Diameter(cm)	0.95(0.5,1.2)	0.8(0.5,1.2)	0.457	0.648
Multifocality			(4.330)	0.037
No	26(59.09%)	153(74.63%)
Yes	18(40.91%)	52(25.37%)
LNM			(4.584)	0.032
No	28(63.64%)	94(45.85%)
Yes	16(36.36%)	111(54.15%)
TGAb	269(61.95,417)	14.73(4.98,28.07)	-	< 0.001
BRAF Mutation			(4.391)	0.036
Yes	23(52.27%)	141(68.78%)
No	21(47.73%)	64(31.22%)
RET Rearrangement			(4.489)	0.034
Yes	7(15.91%)	13(6.34%)
No	37(84.09%)	192(93.66%)
TERT Mutation			(< 0.001)	1.000
Yes	2(4.55%)	11(5.37%)
No	42(95.45%)	194(94.63%)
NRAS/HRAS Mutation				0.594
Yes	0(0.00%)	6(2.93%)
No	44(100.00%)	199(97.07%)
TSHR Mutation			(< 0.001)	1.000
Yes	1(2.27%)	2(0.98%)
No	43(97.73%)	203(99.02%)
TP53 Mutation				0.590
Yes	0(0.00%)	5(2.44%)
No	44(100.00%)	200(97.56%)
PIK3CA Mutation			(2.812)	0.140
Yes	2(4.55%)	1(0.49%)
No	42(95.45%)	204(99.51%)
Recurrence			0.524	0.469
Yes	2(4.55%)	19(9.27%)
No	42(95.45%)	186(90.73%)

In the NGS results, gene mutations were detected in 195 patients (78.31%) out of 249 PTC specimens. Among them, 159 cases (63.86%) had single gene mutations and 36 cases (14.46%) had 2 or more gene mutations. Among the detected genes, the mutation rate of BRAF gene was the highest 65.86% (164 cases), and the rest were RET (20 cases), TERT (13 cases), NRAS/HRAS, TP53 mutation (5 cases), TSHR (3 cases), and PIK3CA (3 cases) (the rest of the mutated genes were less than or equal to 1 case and were not discussed).

2.2.1 Comparison of basic information between RET rearrangement-positive and negative groups in the HT group.RET rearrangement-positive patients had higher rates of LNM and lateral cervical lymph node metastasis (LLNM), and a higher recurrence rate (P < 0.05), while all other clinical characteristics did not show any statistically significant difference with the negative group (Table 2).

Table 2

Comparison of basic information between RET rearrangement-positive and negative groups in the HT group
Characteristics	RET Rearrangement		t/Z(X²)	P-value
Characteristics	Positive(n = 7)	Negative(n = 37)	t/Z(X²)	P-value
Age	34(25,50)	41(32,49)	-0.627	0.531
Sex			(< 0.001)	1.000
Male	2(28.57%)	11(29.73%)
Female	5(71.43%)	26(70.27%)
ETE				0.159
Yes	1(14.29%)	0(0.00%)
No	6(85.71%)	37(100.00%)
Tumor Diameter(cm)	1(0.6,3)	0.9(0.5,1.2)	-0.903	0.377
Multifocality			(< 0.001)	1.000
No	4(57.14%)	22(59.46%)
Yes	3(42.86%)	15(40.54%)
LNM				< 0.001
No	0(0.00%)	28(75.68%)
Yes	7(100.00%)	9(24.32%)
LLNM			(5.750)	0.016
No	5(71.43%)	30(81.08%)
Yes	2(28.57%)	7(18.92%)
Recurrence				0.022
Yes	2(28.57%)	0(0.00%)
No	5(71.43%)	37(100.00%)

2.2.2 Comparison of basic data between the BRAF mutation-positive and negative groups in the HT group: more males and more multifoci were seen in the BRAF mutation-positive patients (P < 0.05), and there was no statistically significant difference between the other clinical characteristics and recurrence rate and the negative group (Table 3).

Table 3

Comparison of basic information between BRAF mutation positive and negative groups in HT group
Characteristics	BRAF Mutation		t/Z(X²)	P-value
Characteristics	Positive(n = 23)	Negative(n = 21)	t/Z(X²)	P-value
Age	37(27,47)	42(34,50)	-1.558	0.112
Sex			(6.006)	0.014
Male	11(47.83%)	2(9.52%)
Female	12(52.17%)	19(90.48%)
ETE				1.000
Yes	1(4.35%)	0(0.00%)
No	22(95.65%)	21(100.00%)
Tumor Diameter(cm)	1(0.4,1.2)	0.9(0.55,1.2)	-0.756	0.450
Multifocality			(4.859)	0.027
No	10(43.47%)	16(76.19%)
Yes	13(56.52%)	5(23.80%)
LNM			(2.736)	0.098
No	12(52.17%)	16(76.19%)
Yes	11(47.83%)	5(23.80%)
LLNM			(0.243)	0.622
No	16(69.57%)	16(76.19%)
Yes	7(30.43%)	5(23.80%)
Recurrence			(< 0.001)	1.000
Yes	1(4.35%)	1(4.76%)
No	22(95.65%)	20(95.24%)

2.3 Analysis of independent risk factors causing HT combined with PTC. After analyzing by binary logistic regression according to the assignment table (Table 4), it showed that multifocal (P < 0.0011,OR = 4.376,OR 95%CI: 1.930 ~ 9.920), RET rearrangement (P = 0.020,OR = 4.739,OR 95%CI: 1.279 ~ 17.553) had a significant positive effect on HT combined PTC relationship, advanced age (P = 0.017,OR = 0.958,OR 95%CI: 0.925 ~ 0.992), LNM(P = 0.002,OR = 0.255,OR 95%CI: 0.106 ~ 0.611) had a statistically significant negative impact relationship, and ETE, TgAb, and BRAF mutation did not constitute a statistically significant impact (P < 0.05). (Fig. 11)

Table 4

Multi-factor assignment table
Variant	Assignment
ETE	Yes = 1, No = 0
LNM	Yes = 1, No = 0
Multifocality	Yes = 1, No = 0
BRAF Mutation	Yes = 1, No = 0
RET Rearrangement	Yes = 1, No = 0

2.4 Analysis of recurrence

Follow-up for four years, the median follow-up time was 38.1 months.Log-rank test showed that the total recurrence rate in HT group was 4.55%(2/44), and the total recurrence rate in NHT group was 9.27%(19/205), the difference between them was not statistically significant (X² = 0.772,P = 0.380); the BRAF mutation-positive recurrence rate in HT group was 4.35%(1/23), and the total recurrence rate in NHT group was 4.76%(1/23), and the difference between them was not statistically significant (X² = 0.007,P = 0.935); the total recurrence rate of HT group was 4.35%(1/23) and that of NHT group was 4.76%(1/21). 4.76% (1/21) of total recurrence rate in NHT group, the difference was not statistically significant (X² = 0.007,P = 0.935); 28.57% (2/7) of RET rearrangement-positive recurrence rate in HT group and 0% (0/37) of total recurrence rate in NHT group, the difference was statistically significant (X² = 11.403,P = 0.001).

2.5.1 Univariate cox regression was used to analyze the influencing factors of overall patient recurrence. The results suggested that multifocal, LNM, ETE, higher recurrence risk stratification, higher TSH, positive RET rearrangement, and RET rearrangement interacting with Hashimoto's effect were all correlates of postoperative recurrence after PTC (P < 0.05). (Table 5)

Table 5

Univariate cox regression analysis of factors influencing overall patient recurrence
Characteristics	β	SE	Wald	P	HR (95% CI)
Age	0.182	0.469	0.150	0.698	1.200 (0.478 ~ 3.009)
Sex	0.034	0.019	3.206	0.073	1.035 (0.997 ~ 1.074)
Tumor Diameter(cm)	0.134	0.255	0.274	0.601	1.143 (0.693 ~ 1.885)
	1.615	0.469	11.858	0.001	5.027 (2.005 ~ 12.604)
LNM	1.780	0.627	8.058	0.005	5.927 (1.735 ~ 20.250)
ETE	3.159	0.518	37.248	0.000	23.554 (8.540 ~ 64.967)
Recurrence risk stratification
1			35.364	0.000
2	2.955	0.659	20.140	0.000	19.208 (5.284 ~ 69.826)
3	4.117	0.693	35.326	0.000	61.352 (15.786 ~ 238.448)
TSH	0.038	0.010	14.977	0.000	1.039 (1.019 ~ 1.059)
Coexistence with HT	-0.644	0.745	0.746	0.388	0.525(0.122 ~ 2.264)
BRAF Mutation	0.691	0.560	1.523	0.217	1.995(0.666 ~ 5.977)
RET Rearrangement	1.248	0.562	4.928	0.026	3.483(1.157 ~ 10.484)
RET Rearrangement * Coexistence with HT	1.608	0.747	4.631	0.031	4.991(1.154 ~ 21.585)
BRAF Mutation * Coexistence with HT	-0.659	1.026	0.412	0.521	0.518 (0.069 ~ 3.866)
BRAF Mutation * RET Rearrangement	1.755	1.032	2.893	0.089	5.783 (0.766 ~ 43.682)

2.5.2 Multifactorial COX analysis, variables statistically associated with prognosis in unifactorial analysis were subjected to multifactorial analysis, which showed that TSH, multifocal, LNM, combined with Hashimoto, and RET rearrangement had no effect on the postoperative recurrence of PTC (P < 0.05), and only the ETE (P = 0.001, HR = 7.410, HR 95%CI:2.301–23.864) and higher recurrence risk stratification (P = 0.003,HR = 14.610,HR 95%CI:2.454–86.972) had some effect on recurrence.

In our study, we found that PTC patients with combined HT were younger, had higher preoperative TGAb index, postoperative pathology suggested less ETE, more frequent multifocality, and lower LNM(p < 0.05), and the results of binary logistic analysis also suggested that low age, multifocality, lymph node-negativity, and RET rearrangement were the independent risk factors for the occurrence of PTC in combined HT. This is basically in line with previous studies by scholars^[7][8][9], where the clinical features of low age, less ETE and negative lymph nodes tend to suggest a better prognosis. Multifocality is also more common in PTC with combined HT^[10]. While TgAb, a clinical diagnostic indicator of HT, is regarded as an independent risk factor for the development of LNM in PTC with HT^[11].HT occurs more frequently in women, which may be related to estrogen and progesterone^[12], and a study suggested that men with PTC with HT had a lower incidence but were more likely to develop LLNM ^[10], but we did not find a statistically significant difference between the two sexes in the two groups. significance.

BRAF mutations are currently recognized as molecular markers of PTC prognosis and often indicate a poorer prognosis for PTC. One study^[5] noted that BRAF mutations were detected in HT, but the lower rate of BRAF mutations may be related to the relatively better prognosis of patients with PTC combined with HT. However, it has also been reported^[13] that BRAF mutation is an important risk factor for LNM in PTC combined with HT. At the molecular level, RET chromosomal rearrangements and BRAF mutations activate the mitogen-activated protein kinase (MAPK) pathway, which in turn promotes tumor development^[14], and RET rearrangements are more common in PTC cases with HT. Unlike the more common RET mutations in medullary thyroid carcinoma (MTC) and MEN2, the most common pro-carcinogenic variant of the RET gene in PTC is RET rearrangement^[15]. Among them, the occurrence of RET rearrangement is relatively complex and has been the focus of scientific research exploration in recent years. Rhoden et al^[16] detected RET rearrangement in both non-tumor follicular cells of HT and PTC, and concluded that it may play a similar molecular mechanism role between the two. There are two controversial hypotheses about RET rearrangement: one is that chronic inflammation in HT induces RET rearrangement and promotes cancer, and the other is that RET rearrangement leads to inflammation and autoimmunity, which may exert anti-tumor effects. The HT group in this study had a lower BRAF mutation rate and a higher RET rearrangement rate. The recurrence rate of PTC patients with combined HT was 4.55%, which was lower than that of the NHT group (9.27%), and also lower than the 8%-28% of ordinary PTC reported in previous clinical studies ^[17], although the recurrence rate was not statistically significantly different from that of the NHT group, we further subgrouped and found that the rate of LNM and recurrence was higher in the RET-positive patients in the HT group (P < 0.05). And the one-way cox regression analysis suggested that RET rearrangement positivity and RET rearrangement interacting with Hashimoto's effect might be the potential risk factors for their recurrence, although only ETE and risk stratification for recurrence were retained as independent predictors of recurrence after inclusion of multifactorial regression analysis. We believe that the current role of RET rearrangement needs to be further explored in the future.

The present study has the following limitations. Although NGS detects genes more comprehensively, the overall sample size was limited and from a single center, and secondly, the follow-up did not include factors such as postoperative chemotherapy and radiotherapy in the study, which may affect the comprehensive assessment of recurrence factors. Expanded sample size, multicenter validation, and inclusion of additional clinical factors need to be discussed.

Therefore, in this study, we concluded that multifocal, RET rearrangement, low age, and lymph node negativity can assist in the preoperative diagnosis of HT combined with PTC, BRAF mutation is lower in HT combined with PTC and has no significant effect on recurrence, and the recurrence rate of PTC combined with HT is higher if accompanied by RET rearrangement, which requires clinicians to emphasize the extent of lymph node dissection and removal of glands in these patients during the operation and to strengthen the follow-up after the operation. In these patients, clinicians should pay more attention to the clearance of lymph nodes and the extent of the resected gland, and strengthen postoperative follow-up.

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

The authors have no relevant financial or non-financial interests to disclose.

This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of the First Affiliated Hospital of Anhui Medical University（Quick-PJ-2022-13-44）.

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Wanxue Zhang. The first draft of the manuscript was written by Wanxue Zhang and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

The datasets analysed during the current study are available from the corresponding author on reasonable request.

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

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No competing interests reported.

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Risk factors for the occurrence and recurrence of papillary thyroid carcinoma with Hashimoto's thyroiditis based on next- generation sequencing

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