Evaluating the Influence of Hashimoto's Thyroiditis on Clinico-Pathological Characteristics and Prognostic Outcomes of Middle Eastern Differentiated Thyroid Carcinoma

Objective Hashimoto's thyroiditis (HT), also known as chronic lymphocytic thyroiditis, represents the most prevalent autoimmune thyroid disorder globally. The potential influence of HT on the clinical and pathological attributes, as well as the clinical outcomes of differentiated thyroid carcinoma (DTC), remains a point of ongoing debate within the medical community. The central focus of this study was to analyze the influence of HT on clinico-pathological characteristics and its prognostic impact in a large cohort of DTC from Middle Eastern ethnicity. Design, Patients, Measurements. An extensive analysis involving 1822 DTC patients was conducted to determine the association with clinico-pathological characteristics as well as prognosis, using Chi-square tests and Kaplan-Meier curves. Results 23.9% (435/1822) of DTC patients were diagnosed with HT. Univariate analysis revealed a positive correlation between presence of HT and clinico-pathological factors such as female gender, younger age, and early stage tumor. In contrast, HT demonstrated a negative association with several aggressive clinical features, including extrathyroidal extension, distant metastasis, recurrent/persistent disease and high-risk categorization by the American Thyroid Association (ATA) guidelines. Despite HT being associated with favorable clinico-pathological features in Middle Eastern DTC patient, our study found no significant influence on overall survival or recurrence-free survival. Conclusion The finding of an association between HT and favorable clinico-pathological characteristics, but lack of impact on prognosis, underscores the complexity of HT-DTC relationship, necessitating further comprehensive research to fully understand these interactions.


Introduction
Hashimoto's thyroiditis (HT), also known as chronic lymphocytic thyroiditis, is the most prevalent autoimmune disorder characterized by chronic infammation of thyroid gland [1].Tis condition is a signifcant contributor to the global incidence of hypothyroidism and causes a wide range of thyroid metabolic and physiological disturbances [2,3].Te worldwide prevalence of HT exhibits marked geographical variability, attributed to genetic, environmental, and lifestyle factors.Intriguingly, the prevalence remains high within iodine-sufcient populations, hinting at the complexity of factors infuencing the onset and progression of this autoimmune disorder [4].In addition, diferentiated thyroid carcinoma (DTC) accounts for a considerable proportion of thyroid malignancies, with its incidence rate steadily increasing globally [5][6][7].Te rise in DTC incidence has been associated with improved diagnostic techniques, environmental factors and possibly an actual increase in disease occurrence [6,8].
Coexistence of HT with DTC was observed for a very long time [9].Ever since, the potential interplay between HT and DTC, particularly regarding the infuence of HT on clinico-pathological features and prognosis of DTC has been a topic of ongoing debate within the medical research community.Te current literature ofers dichotomous perspective, with a subset suggesting signifcant impact of HT on DTC progression and others fnding no such association [10][11][12][13][14][15][16].Tis divergence in scientifc opinion is further emphasized within the Middle Eastern ethnicity, where investigation of the relationship between HT and DTC is relatively sparse [17,18].Given the unique genetic and environmental context of this population, exploring this association within a large cohort of Middle Eastern DTC is crucial to enhancing our understanding of HT-DTC interactions.
Terefore, our study aims to elucidate the prevalence of HT among DTC patients and unravel the potential impact of HT on clinico-pathological features and prognosis of DTC among Middle Eastern individuals.1. Staging of DTC was performed using the eighth edition of American Joint Committee on Cancer (AJCC) staging system [19].Patients were stratifed into low, intermediate and high risk based on 2015 American Tyroid Association (ATA) guidelines [20].Patient follow-up and defnition of persistent/recurrent disease has been described previously by us [21][22][23][24].Briefy, low-risk DTC patients were followed up annually, intermediate risk patients were followed up at 6 months' intervals and high risk patients were followed up at 3 months' intervals.At each follow-up, neck ultrasound, thyroid function tests, thyroglobulin (Tg) levels and thyroglobulin antibodies were performed.FT4, TSH, Tg and anti-Tg antibody levels were measured using commercially available competitive electrochemiluminescence immunoassay (Roche Elecsys).In addition, for high risk patients, whole body scan (WBS) and/or PET CT scan were performed to identify tumor recurrence.Presence of active disease within 12 months post-operatively was defned as persistent disease, whereas patients who had excellent response for at least 12 months post-operatively and later developed active disease were defned as having recurrent disease.

Materials and Methods
Te diagnosis of HT was based on histopathological fnding of lymphoplasmacytic infltration with germinal center and the presence of large follicular cells with abundant granular eosinophilic cytoplasm.
Te study endpoint for our analysis was overall survival (OS) and recurrence-free survival (RFS).OS was defned as the time (in months) from date of initial surgery to the date of death due to any cause.RFS was defned as the time (in months) from date of initial surgery to the date of development of recurrent disease.

Statistical Analysis.
Te associations between clinicopathological variables was performed using contingency table analysis and Chi-square tests.Survival curves were generated using the Kaplan-Meier method.Mantel-Cox logrank test was used to evaluate signifcance.Two-sided tests were used for statistical analyses with a limit of signifcance defned as p value < 0.05.Data analyses was performed using the JMP14.0(SAS Institute, Inc., Cary, NC) software package.
We next sought to determine the role of HT in prognosis of DTC patients.However, no signifcant diference was found between HT and non-HT patients with respect to OS (p � 0.6352) and RFS (p � 0.1482) (Figures 1(a) and 1(b)).

Discussion
Te fndings from this study provide insights into the hypothesized association between HT and DTC.Out of 1822 DTC patients analyzed, 23.9% had concurrent HT, a fnding that aligns with global reports of HT prevalence among DTC patients [25][26][27].Tis co-occurrence highlights the potential interplay between autoimmune process and thyroid tumorigenesis, a subject of ongoing research [28,29].
Our analysis of clinico-pathological characteristics revealed a direct correlation between HT and certain demographic and disease related variables, including female gender, younger age and early tumor stage.Tese observations are consistent with previous studies that have 2 International Journal of Endocrinology reported higher incidence of HT among females and younger individuals, possibly due to hormonal and immunological diferences [30][31][32][33][34]. Furthermore, our fnding of an association with early tumor stage bolsters the hypothesis that autoimmune response inherent in HT could potentially modulate DTC progression, resulting in diagnosis at earlier stage [32,35,36].Interestingly, our study found an inverse relationship between HT and aggressive clinico-pathological features of DTC, such as extrathyroidal extension, distant metastasis, recurrent/persistent disease, and high ATA risk.Tis observation is in concordance with prior studies that reported less aggressive clinical features of DTC in patients with concurrent HT [31,34,37,38].However, despite aforementioned correlations, we found that HT did not signifcantly infuence the overall prognosis of Middle Eastern DTC patients.Tere was no discernible Tis fnding is in contrast to some prior research, which suggested a protective role of HT in DTC prognosis [37,[39][40][41].However, our fndings align with other studies that reported no signifcant impact of HT on DTC outcome [11,42,43].Tis discrepancy highlights the complexity of HT-DTC interaction and underscores the necessity for more comprehensive investigations.Several studies with diferent cohort sizes and ethnic background have attempted to unravel this intricate relationship with variable results.For instance, a study by Lun et al. [32] suggested that the presence of HT was associated with less aggressive clinical features and better prognosis.Similarly, Liang et al. [40] and Ryu and Yoon et al. [41] reported a higher disease-free survival and recurrence-free survival, respectively, in PTC patients with HT compared to those without HT.In contrast, Lee et al. [11] found no signifcant diference in the prognosis of DTC patients with or without HT.Tese contrasting results underline the heterogeneity of fndings in this subject.Moreover, Dobrinja et al. [42] reported an association between the presence of HT and less aggressive features but found no impact on recurrence or survival rate, thereby introducing another facet to our understanding of the HT-DTC relationship.Interestingly, recent metaanalyses by Moon et al. [39] and Lee et al. [15] concluded that HT was associated with favorable prognosis in patients with PTC, primarily through an association with less aggressive tumor characteristics.Another study by Jeong et al. [37] showed that co-existence of HT and DTC was associated with higher disease-free survival rate on univariate analysis, but was not signifcant on multivariate analysis.Tese fndings, in conjunction with ours, underline the existing uncertainty regarding the prognostic role of HT in DTC and the need for a more nuanced understanding of HT-DTC interaction.

Conclusions
In summary, our study shows that, while HT may infuence certain clinico-pathological features in DTC, it does not appear to signifcantly impact prognosis of DTC patients from Middle Eastern ethnicity.Tis observation reinforces the need for future research incorporating larger cohorts and diverse ethnic groups to understand the multifaceted relationship between HT and DTC.

Table 1 :
Clinical and histopathological associations of patients with and without Hashimoto's thyroiditis (HT).