Various Roles of Hashimoto's Thyroiditis and Thyroid Function in Papillary Thyroid Micro- and Macro-carcinoma

doi:10.21203/rs.3.rs-3926627/v1

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Various Roles of Hashimoto's Thyroiditis and Thyroid Function in Papillary Thyroid Micro- and Macro-carcinoma

https://doi.org/10.21203/rs.3.rs-3926627/v1

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Background

Thyroid cancer (TC) is one of the most prevalent endocrine cancers. Moreover, patients with Hashimoto's thyroiditis (HT) are more prone to malignant tumors. The incidence of papillary thyroid carcinoma (PTC) combined with HT is on the rise. However, a definitive consensus remains elusive.

Methods

We retrospectively analyzed the clinical and pathological data of 2049 patients with PTC (1033 with HT and 1016 without HT). We explored its influence on extrathyroidal extension (ETE), central lymph node metastasis (CLNM), and RAF kinase, B-type (BRAF) mutations through univariate and multivariate logistic regression analyses.

Results

Patients with PTC and HT exhibited a lower prevalence of ETE compared to those without HT (5.6% vs. 8.1%, P = 0.017). Notably, this trend persisted in the case of BRAF (V600E) mutations (90.1% vs. 96.2%, P < 0.001), indicating a consistent association. Multivariate logistic regression analysis revealed that HT independently predicted a reduced risk of BRAF(V600E) mutation in both PTMC (OR: 0.35, 95% CI: 0.20–0.63) and PTC (OR: 0.40, 95% CI: 0.23–0.68), even after meticulous adjustment for age and sex. Furthermore, hypothyroidism emerged as a significant risk factor for an increased prevalence of ETE in patients with PTC (OR: 2.27, 95% CI: 1.17–6.21), but not in patients with PTMC.

Conclusion

In conclusion, HT may reduce the occurrence of BRAF mutations in patients with PTC and PTMC, whereas patients with PTC and hypothyroidism have an elevated risk of ETE. Further research is needed to explore the underlying mechanisms and ascertain potential clinical implications.

papillary thyroid carcinoma

Hashimoto's thyroiditis

hypothyroidism

BRAF

Thyroid cancer (TC) is one of the most prevalent endocrine cancers, with recently increasing global incidence (1). According to the 2020 GLOBOCAN database, the prevalence of TC reached 10.1 cases per 100,000 in women and 3.1 cases per 100,000 in men worldwide. Notably, the incidence in women exhibits significant regional disparities(2). TC ranks fifth among malignant tumors affecting American women, third among malignancies in Chinese women, and has the highest incidence in South Korea, with 45 cases per 100,000 people(2–4). Within the spectrum of TCs, papillary thyroid carcinoma (PTC) is the predominant subtype, constituting approximately 90% of all cases, with more than half of newly diagnosed cases classified as papillary thyroid microcarcinoma (PTMC)(5). Although the TC mortality rates have remained relatively stable and low, instances of extrathyroidal invasion, lymph node metastasis, and distant metastasis are encountered at initial diagnosis in certain cases, particularly among patients with RAF kinase, B-type (BRAF) mutations(6).

Hashimoto's thyroiditis (HT), also referred to as autoimmune thyroiditis disease, is an autoimmune disorder characterized by lymphocyte infiltration of the thyroid parenchyma and the presence of specific anti-thyroid antibodies(7). As one of the most prevalent autoimmune disorders, the prevalence of HT has significantly increased recently(8). The primary adverse consequence of HT lies in its propensity to induce hypothyroidism. Furthermore, a heightened susceptibility to cardiovascular disease, malignant tumors, and other related diseases among patients with HT. The incidence of PTC combined with HT continues to rise(3), and the underlying causes are linked to an elevation in thyroid-specific antibodies and serum thyroid stimulating hormone (TSH) levels. Nevertheless, a definitive consensus on this matter remains elusive. Hence, we retrospectively analyzed patients with PTC to evaluate the influence of HT on PTMC and PTC and explore its impact on extrathyroidal extension (ETE), lymphocytic central neck lymph node metastasis (LNM), and BRAF mutations. These findings lay the groundwork for subsequent exploration of related mechanisms and treatment modalities.

This study retrospectively analyzed patients with PTC to evaluate the influence of HT and thyroid function PTC and explore its impact on ETE, CLNM, and BRAF mutations.

We retrospectively analyzed the clinical data of 2049 patients with pathologically confirmed PTC who underwent thyroid surgery (total thyroidectomy, thyroid lobectomy with or without isthmusectomy) at The First Hospital of China Medical University from January 2019 to April 2021. Histopathological assessments were conducted through microscopic examination by a panel of two or more proficient pathologists. The evaluation encompassed several histopathological parameters, including the cellular composition of the primary lesion, tumor dimensions (measured as the greatest diameter of the largest lesion), ETE, the presence of lymph node metastasis (LNM), and underlying thyroid conditions such as HT. HT was assessed by identifying histopathological characteristics, including lymphoplasmacytic infiltration, fibrotic tissue presence, lymphatic follicular formation, parenchymal atrophy, and other relevant features throughout the entire thyroid gland(7, 9). Of the 2049 patients with PTC, 1033 had HT and 1016 did not have HT); moreover, 623 patients had PTMC with HT).

For all patients, information was obtained through a retrospective analysis of electronic clinical records, including general characteristics (age and sex), clinicopathological characteristics, thyroid function test results (FT3, FT4, and TSH levels), thyroid autoimmune antibody profiles (thyroid peroxidase and thyroglobulin antibodies), ultrasonography findings, BRAF(V600E) mutation status, tumor stage, presence of ETE, and LNM. The normal reference range and diagnostic criteria for thyroid diseases are presented in Supplementary Table 1. BRAF(V600E) mutation analysis was performed at the Molecular Diagnostics Laboratory department, The First Hospital of China Medical University. DNA samples for molecular analysis were extracted from materials or postoperative surgical specimens, following the manufacturer's prescribed protocols.

Statistical analysis was conducted using SPSS version 22.0. P < 0.05 was considered statistically significant. Continuous variables are presented as mean plus standard deviation (S.D.), whereas categorical variables are expressed as case numbers accompanied by percentages (%). To compare the clinicopathological traits of patients, categorical variables were assessed with the T-test, and continuous variables were evaluated using Student's t-test. Univariate and multivariate logistic regression analyses were performed to calculate the odds ratios (ORs) for ETE, lateral lymph node metastasis (LLNM), and BRAF(V600E) mutation based on thyroid function status.

The study protocols were approved by the Medical Ethics Committee of China Medical University.

A comprehensive review was conducted on 2049 patients who underwent thyroid surgery and were pathologically diagnosed with PTC. Among these individuals, 1033 were identified as having HT, and 623 cases were classified as PTMC. The average age of the entire cohort, which comprised 386 males and 1663 females, was 45.28 ± 11.36 (range: 14–78) years.

Table 1 provides details regarding the distribution of age and sex within each subgroup (PTC with HT and without HT). When comparing patients with PTC, those with HT exhibited a slightly younger age, though this difference was not statistically significant (P = 0.102). Notably, those with HT also displayed a significantly higher proportion of females than those without HT (P < 0.001).

Table 1

demographic characteristics of 2049 patients with papillary thyroid carcinoma
characteristics	All patients with PTC (n = 2049)
	without AIT (n = 1016)	with AIT (n = 1033)	P value
	No. (%)	No. (%)
Age(years)
Mean ± S.D.	45.61 ± 11.45	44.97 ± 11.27	0.102
< 50	649(63.9)	674(65.2)
≥ 50	367(36.1)	359(34.8)	0.274
sex
male	280(27.6)	106(10.2)
female	736(72.4)	927(89.7)	< 0.001
thyroid function
euthyroid	959(94.4)	916(88.7)
hypo	38(3.7)	47(4.5)
hyper	19(1.9)	70(6.8)	< 0.001
thyroid hormone
Mean ± S.D.
FT4	12.95 ± 1.58	12.74 ± 1.81	0.003
FT3	4.48 ± 0.87	4.36 ± 0.84	< 0.001
Med(IQR)
TSH	1.39(0.96–1.96)	1.79(1.14–2.73)	< 0.001
TPOAb	0.63(0.34–1.21)	33.10(1.95-231.38)	< 0.001
TGAb	1.40(0.91–2.32)	37.10(8.87-165.54)	< 0.001
PTMC
< 1	580(57.1)	623(60.3)
> 1	436(42.9)	410(39.7)	0.075
Multifocality
absent	220(21.7)	216(20.9)
present	796(78.3)	817(79.1)	0.360
ETE
absent	934(91.9)	975(94.4)
present	82(8.1)	58(5.6)	0.017
LLNM
absent	637(62.7)	682(66.0)
present	379(37.3)	351(34.0)	0.064
BRAF
positive	977(96.2)	931(90.1)
negative	39(3.8)	102(9.9)	< 0.001
HT, Hashimoto's Thyroiditis; PTC, papillary thyroid carcinoma; PTMC, papillary thyroid microcarcinoma; ETE, extrathyroidal extension; LLNM, lateral lymph node metastasis; S.D, standard deviation.

No statistically significant differences were observed in terms of PTC size (P = 0.057), multifocality (P = 0.36), or the occurrence of lateral cervical lymph node metastasis (P = 0.064). However, the prevalence of ETE was notably higher in the non-HT group than in the HT group (8.1% vs. 5.6%, P = 0.017). A parallel pattern emerged concerning the presence of the BRAF(V600E) mutation, with a higher prevalence in the non-HT group than in the HT group (96.2% vs. 90.1%, P < 0.001).

Univariate and multivariate analyses were used to elucidate the associations between ETE (Table 2), LLNM (Table 3), and BRAF(V600E) mutation (Table 4) and the clinicopathological characteristics of PTMC and PTC (> 1 cm). The analysis revealed a significant correlation between the presence of hypothyroidism and ETE in the PTC (> 1 cm) group. Importantly, this correlation remained robust even after adjusting for age, sex, and the presence of HT (OR: 3.24, P = 0.007). However, neither hypothyroidism nor hyperthyroidism demonstrated a significant impact on LLNM in either PTMC or PTC (> 1 cm). HT was significantly negatively correlated with the BRAF(V600E) mutation in patients with PTC in the multivariate analysis (OR: 0.396, P < 0.001) (Table 4). The influences of sex and age on ETE, LLNM, and BRAF(V600E) mutation varied, aligning with prior research findings.

Table 2

Association between ETE and clinicopathological characteristics of PTMC and PTC(> 1cm)
clinicopathological characteristics	PTMC^e				PTC^f
clinicopathological characteristics	univariate anaylysis		Multivariate analysis		univariate analysis		Multivariate analysis
	OR(95% CI) ^d	P value	OR(95% CI)	P value	OR(95% CI)	P value	OR(95% CI)	P value
Age (per year)	1.03(1.004–1.057)	0.022	1.031(1.004–1.057)	0.022	1.031(1.011–1.051)	0.002	1.032(1.012–1.053)	0.002
Female^a	0.863(0.437–1.704)	0.671	0.882(0.434–1.796)	0.730	1.163(0.648–2.086)	0.613	1.155(0.634–2.104)	0.638
AIT^b	0.703(0.403–1.225)	0.213	0.704(0.394–1.259)	0.237	0.689(0.439–1.083)	0.106	0.63(0.392–1.014)	0.057
Hyperthyroidism^c	1.614(0.483–5.397)	0.437	1.813(0.536–6.128)	0.338	1.675(0.681–4.124)	0.262	1.766(0.705–4.426)	0.225
Hypothyroidism^c	1.474(0.442–4.912)	0.528	1.606(0.475–5.434)	0.446	2.373(1.054–5.342)	0.037	3.24(1.386–7.571)	0.007
a: comparing to male.
b:HT, Hashimoto's thyroiditis
c: comparing to euthyroid.
d: OR, odds ratio; CI, confidence interval
e: PTMC, Papillary thyroid microcarcinoma; PTC, Papillary carcinoma (Tumor diameter > 1cm)
B, significance probability; S.E standard error; Sig, significance probability; Exp(B) odds ratio, CI, confidence interval.

Table 3

Association between LLNM and clinicopathological characteristics of PTMC and PTC(> 1cm)
clinicopathological characteristics	PTMC^e				PTC^f
clinicopathological characteristics	univariate anaylysis		Multivariate analysis		univariate analysis		Multivariate analysis
	OR(95% CI) ^d	P value	OR(95% CI)	P value	OR(95% CI)	P value	OR(95% CI)	P value
Age (per year)	0.948(0.936–0.959)	< .001	0.949(0.937–0.961)	< .001	0.956(0.944–0.968)	< .001	0.956(0.944–0.968)	< .001
Female^a	0.544(0.404–0.734)	< .001	0.581(0.421–0.802)	< .001	0.593(0.42–0.836)	0.003	0.683(0.475–0.982)	0.04
AIT^b	0.951(0.745–1.214)	0.687	1.031(0.791–1.345)	0.82	0.79(0.601–1.039)	0.092	0.802(0.599–1.075)	0.14
Hyperthyroidism^c	1.489(0.809–2.74)	0.201	1.383(0.731–2.616)	0.318	1.565(0.828–2.96)	0.168	1.438(0.747–2.768)	0.278
Hypothyroidism^c	1.083(0.588–1.994)	0.798	1.183(0.626–2.237)	0.604	0.85(0.441–1.638)	0.627	0.773(0.388–1.541)	0.464
a: comparing to male.
b:HT, Hashimoto's thyroiditis
c: comparing to euthyroid.
d: OR, odds ratio; CI, confidence interval
e: PTMC, Papillary thyroid microcarcinoma; PTC, Papillary carcinoma (Tumor diameter > 1cm)
B, significance probability; S.E standard error; Sig, significance probability; Exp(B) odds ratio, CI, confidence interval.

Table 4

Association between BRAF and clinicopathological characteristics of PTMC and PTC(> 1cm)
clinicopathological characteristics	PTMC^e				PTC^f
clinicopathological characteristics	univariate anaylysis		Multivariate analysis		univariate analysis		Multivariate analysis
	OR(95% CI) ^d	P value	OR(95% CI)	P value	OR(95% CI)	P value	OR(95% CI)	P value
Age (per year)	1.013(0.99–1.036)	0.275	1.011(0.988–1.034)	0.363	1.001(0.981–1.022)	0.927	0.999(0.978–1.02)	0.930
Female^a	0.904(0.477–1.713)	0.757	1.295(0.659–2.544)	0.454	0.585(0.285–1.204)	0.145	0.713(0.341–1.491)	0.368
AIT^b	0.352(0.203–0.609)	< .001	0.351(0.198–0.625)	< .001	0.364(0.215–0.618)	< .001	0.396(0.230–0.680)	< .001
Hyperthyroidism^c	0.45(0.171–1.181)	0.105	0.529(0.199–1.409)	0.203	0.765(0.263–2.221)	0.622	0.737(0.249–2.177)	0.581
Hypothyroidism^c	0.403(0.165–0.984)	0.046	0.489(0.198–1.209)	0.121	0.401(0.17–0.944)	0.036	0.525(0.219–1.259)	0.149
a: comparing to male.
b:HT, Hashimoto's thyroiditis
c: comparing to euthyroid.
d: OR, odds ratio; CI, confidence interval
e: PTMC, Papillary thyroid microcarcinoma; PTC, Papillary carcinoma (Tumor diameter > 1cm)
B, significance probability; S.E standard error; Sig, significance probability; Exp(B) odds ratio, CI, confidence interval.

The association between HT and TC has been the subject of ongoing debate since its first mention in 1955(10). TC ranks highest among endocrine cancers, responsible for 586,000 cases globally in 2020, ranking ninth in incidence across both sexes and fifth among females(11). Over the past two decades, the incidence of differentiated TC, particularly PTC, accounting for approximately 85% of TC cases), has been on the rise. HT, an autoimmune disorder characterized by inflammatory cell infiltration and thyroid cell destruction, presents a multifaceted clinical landscape(12). The course of chronic thyroid damage can manifest as normal, hyperactive, or diminished thyroid function. Moreover, prolonged suffering from HT eventually leads to hypothyroidism, marked by elevated serum TSH levels(13). Chronic inflammatory stimuli are known to give rise to precancerous lesions; for example, hepatitis is strongly linked to liver cancer(14). In contrast, the association between HT and PTC remains a subject of debate. HT has been identified in 20–50% of PTC cases, elevating the risk of PTC(15, 16). In 2022, Ren et al. conducted a comprehensive meta-analysis, consolidating data from 39 independent studies, concluding that HT plays a dual role in patients with TC. Controversy persists regarding disease progression and prognosis in patients with PTC with or without HT after PTC diagnosis, given immune cell activation in HT and potential thyroid dysfunction, which complicates the PTC microenvironment.

Our primary aim was to elucidate the clinicopathological disparities in patients with PTC based on their thyroid status and the presence of BRAF mutations. Although previous studies have extensively explored PTC prognosis with HT, they have not thoroughly examined the impact of abnormal thyroid function on PTC outcomes. Thus, we aimed to fill this crucial knowledge gap, offering valuable insights into the intricate relationship between HT, thyroid function, and PTC. This, in turn, advances our understanding of TC pathogenesis and informs patient management.

In the present study, we conducted univariate and multivariate analyses including HT, thyroid status, LLNM, ETE, and BRAF mutation. The findings independently indicate that HT predicts a lower prevalence of BRAF mutation in patients with PTMC and PTC (> 1 cm) (Table 4). Additionally, hypothyroidism increases the risk of a higher ETE prevalence in patients with PTC (> 1 cm) but not in those with PTMC (Table 2).

A cohort study involving 9,210 patients demonstrated that concurrent HT was associated with a reduced risk of ETE (OR: 0.44; 95% confidence interval (CI): 0.36–0.54)(17). Table 1 also corroborates these findings, as patients with HT exhibited lower ETE prevalence compared to those without (5.6% vs. 8.1%, P < 0.017). Our multivariate analysis supports these results although statistical significance was not achieved (Table 2). Furthermore, we identified a robust association between hypothyroidism and ETE in patients with PTC (> 1 cm) (OR: 3.24, 95% CI: 1.386–7.571). This finding deviates from some previous studies, which did not establish a link between subclinical hypothyroidism and ETE in patients with PTC(18). The underlying mechanism behind this phenomenon may be tied to the assessment of serum TSH levels. Several studies have indicated that higher TSH levels are associated with more aggressive characteristics and poorer outcomes in patients with PTC(19–21). Nevertheless, the role of T3 and T4 in this phenomenon remains uncertain.

Prior research has demonstrated a higher incidence of lymph node metastasis in male patients with PTC(22). In the present study, we observed similar sex-related differences in the frequency of LLNM, irrespective of tumor size (Table 3). An association between HT and a reduced BRAF(V600E) mutation frequency has also been indicated(23, 24). Our findings align with this, revealing a significantly lower occurrence of BRAF(V600E) mutation in patients with PTC and HT (90.1% vs. 96.2%, P < 0.01). Multivariate analysis revealed a negative association between HT and BRAF(V600E) mutation prevalence in both PTMC (OR: 0.351, 95% CI: 0.198–0.625) and PTC (> 1 cm) (OR: 0.396, 95% CI: 0.23–0.68). PTC combined with HT triggers systemic and local immune activation, involving various T cell subtypes and macrophages(25). This profoundly impacts the biological behavior of BRAF mutations and the progression of other tumors. Given the limited number of studies on this topic, additional research is needed to clarify the interaction between immune status in HT and TPC cells within the tumor microenvironment.

Nonetheless, our study has some limitations. First, due to its retrospective design, complete patient information was not attainable. Additional prospective studies may be warranted to elucidate the relationship between PTC and various thyroid statuses. Second, as this study solely focused on patients with PTC, the results may not apply to other types of TC.

In summary, HT may reduce the occurrence of BRAF mutations in patients with PTC and PTMC, whereas patients with PTC and hypothyroidism have an elevated risk of ETE. These findings hint at a potential protective effect of HT against BRAF mutation in patients with PTC while also influencing the risk of ETE in PTC cases. Further research is needed to explore the underlying mechanisms and ascertain potential clinical implications.

Acknowledgments and disclosures

Ethics approval and consent to participate

The study protocols were approved by the Medical Ethics Committee of China Medical University, and informed consent to participates were acquired.

Competing interests

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Data availability statement

The authors will furnish the raw data pertaining to the conclusions of this article upon request via email.

Funding

This study was supported by the China Postdoctoral Science Foundation (Grant # 2022YFC3602300).

Authors' contributions

ZL conceived this study; ZLS and ZM directed the study. ZL drafted the manuscript. ZLS collected and ZL analyzed the data and performed the statistical analyses. All authors contributed to the article and approved the submitted version.

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No competing interests reported.

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Various Roles of Hashimoto's Thyroiditis and Thyroid Function in Papillary Thyroid Micro- and Macro-carcinoma

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