The relationship between Hashimoto’s thyroiditis and thyroid papillary carcinoma: Trying to explain the paradox

The relationship between Hashimoto’s thyroiditis and thyroid papillary carcinoma: Trying to explain the paradox | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article The relationship between Hashimoto’s thyroiditis and thyroid papillary carcinoma: Trying to explain the paradox Imad Abdien El Hag, Khalid Aburas, Shuaa Asiri This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-8877989/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Hashimoto’s thyroiditis (HT) and papillary thyroid microcarcinoma (PTMC) often coexist. Their relationship is paradoxical and unclear. Materials and Methods This retrospective study reviews 1,509 thyroidectomies from 2018–2025, focusing on PTMC cases compared with benign thyroidectomy controls to assess the link between PTMC and HT. Results 37% of PTMC cases have HT, versus 27% of controls. The odds ratio (OR) for PTMC among HT patients is 1.6 (95% CI: 1.046–2.46; p = 0.03), indicating an increased risk. The risk is higher in euthyroid HT, with 63% prevalence in PTMC vs. 12% in controls. The OR for PTMC in euthyroid HT is 13 (95% CI: 4.53–37.04; P < 0.0001). PTMC occurs at a younger age with HT (40 vs. 44; p < 0.05). HT with PTMC reduces lymph node metastasis (LNM) without affecting tumor size. The tumor immune microenvironment (TIME) differs: the immune-inflamed “hot” subtype is more common in HT, while the immune-desert (ID) subtype is more common in non-HT cases. The “hot” type is immunosuppressive and is associated with increased lymph node metastasis, particularly in non-HT-associated PTC. Conclusion Euthyroid HT is associated with increased PTMC risk, likely arising early in chronic inflammation before autoimmunity. The dominant “hot” TIME subtype appears immunosuppressive, suggesting a potential role for immunotherapy in PTC. Figures Figure 1 Figure 2 Figure 3 Introduction Hashimoto’s thyroiditis (HT) and papillary thyroid carcinoma (PTC) are common in women and frequently co-occur, although their relationship remains complex. HT is associated with an increased risk of PTC, yet PTC in patients with HT tends to exhibit slower growth and a more favorable prognosis ( 1 , 2 ). Autoimmunity and cancer were traditionally viewed as opposing processes: autoimmunity results from a loss of immune tolerance to self-antigens, whereas cancer progression relies on increased immune tolerance that enables tumor immune escape. Recent immunological research has shown that these processes are interconnected through immune checkpoint pathways, particularly the programmed cell death protein 1 (PD-1)- PD-L1 axis and regulatory T cells (Tregs) ( 3 ). These checkpoints suppress T-cell activation by promoting Tregs and limiting self-reactive effector T cells, thereby maintaining immune tolerance ( 4 ). PD-1 is primarily expressed on immune cells, while PD-L1 is found on both immune and non-immune cells, including epithelial cells. Tumor cells can exploit PD-L1 overexpression to evade immune surveillance and facilitate unchecked growth ( 5 ). Disruption of the PD-1/PD-L1 pathway—through genetic polymorphisms or prolonged immune exhaustion during chronic inflammation—can impair immune tolerance and contribute to autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and type 1 diabetes ( 6 ). Although a direct role for the PD-1/PD-L1 pathway in HT has not been definitively established, variable expression of PD-1 and PD-L1 has been reported in HT, with lower levels observed in vivo than in vitro. Notably, immune checkpoint inhibitor therapy targeting PD-1/PD-L1 is associated with a high incidence of autoimmune thyroid disease ( 7 , 8 ). An intact PD-1/PD-L1 pathway may contribute to the persistence of HT and limit early remission ( 7 , 9 , 10 ). Autoimmune thyroiditis develops along a morphological and functional spectrum. Early disease is characterized by a less destructive chronic inflammatory phase, while later stages involve extensive tissue damage and oncocytic metaplasia ( 11 , 12 ). Early HT is often associated with lower thyroid-stimulating hormone (euth-TSH) levels and lower titers of thyroid peroxidase (TPO) antibodies ( 12 ). This phase may be sustained by a functional PD-1/PD-L1 system, whereas chronic immune activation eventually leads to pathway exhaustion, increased autoantibody production, and hypothyroidism. Histologically, HT is marked by lymphoplasmacytic infiltration and secondary lymphoid follicle formation, changes that are indistinguishable from reactive lymphocytic thyroiditis. The diagnosis of HT becomes clear once these features are accompanied by autoantibody production, destructive changes, and elevated TSH levels. While autoantibodies are present in approximately 95% of cases, early stages may exhibit normal TSH due to compensatory thyroid function and are often identified incidentally during fine-needle aspiration or thyroidectomy performed for other indications ( 13 ). To further explore the association between HT and PTC, we conducted an observational study of histologically confirmed HT cases with papillary thyroid microcarcinoma (PTMC). Serum TPO antibody and TSH levels were analyzed and compared with those of a benign control group, and histological sections were reviewed to characterize the local immune response. PTMC was selected because of its high diagnostic frequency at our institution ( 14 ), its stronger association with HT ( 15 ), and its capacity to elicit localized immune responses comparable to those observed in established PTC. Material and methods PTMC cases diagnosed incidentally or preoperatively in complete or partial thyroidectomies performed between 2018 and 2025 were retrieved from the archives of the Department of Laboratory Medicine and Pathology at Security Force Hospital, Riyadh, Saudi Arabia. An equal number of age- and sex-matched controls was selected from the same time frame as consecutive benign thyroidectomies for comparative analysis. Each group is divided into two subgroups based on the presence or absence of histologically confirmed HT. TPO and TSH levels were measured as part of the initial workup prior to initiation of medical or surgical therapy. TSH levels are classified as euthyroid (4.0 mmol/L) or hypothyroid (<4.0 mmol/L). The prevalence rates of HT, TPO positivity, and TSH levels are reported for each group in Table 1. The relationship between histologically confirmed HT, TPO positivity, and hypothyroid versus euthyroid TSH levels (hypo-TSH vs. euth-TSH) with the risk of developing PTMC was analyzed and compared independently. The strength of the association between HT, TPO positivity (>34 IU/ml), TSH levels, and the development of PTMC was reported as an odds ratio (OR) in Table 1. Pathological features associated with aggressive behavior, including tumor size, morphological subtype, multiplicity, bilaterality, margin involvement, and central lymph node metastasis, were documented and compared between the groups (Table 2). The number of lymph nodes identified in each group and subgroup is recorded and compared. The tumor immune microenvironment type (TIME) surrounding PTCM on histological sections is classified into three categories based on the level of cell infiltration within and around the tumor. The immune desert (ID) group has fewer lymphocytes both within and outside the tumor (Figure 1). The immune-excluded (IE) group shows clear lymphocyte infiltration around the tumor but few within it (Figure 2). The immunoinflammatory (Inf) group exhibits extensive lymphocytic infiltration of the tumor (Figure 3) (16). These categories are linked to the presence or absence of HT, tumor size, and lymph node metastasis (Table 4). The SPSS program is used for statistical analysis and data management. A two-tailed chi-square (X 2 ) test is used to assess differences in proportions, while a two-tailed t-test is used to compare means, like age and tumor size. Results Study population: This study includes 195 consecutive cases of the PTMC group diagnosed between 2018 and 2025, among 1509 partial or complete thyroidectomies. The patients' ages ranged from 20 to 89, with a mean age of 43.5 ± 12. The cases consisted of 166 females and 29 males, with an F/M ratio of 6:1. An age- and sex-matched control group included an equal number (195) of consecutive cases of benign partial or total thyroidectomies from the same time frame, all without a prior history of thyroid cancer. This group comprised 163 females and 32 males, resulting in a female-to-male ratio of 5:1. The patients’ ages ranged from 15 to 80 years, with a mean age of 43.5 ± 12. The prevalence of HT, preoperative TPO positivity, and TSH levels in the PTMC group compared to the control group: Findings are summarized in Table 1. The study involved 390 cases, evenly split between the PTMC and benign (control) groups. A total of 124 cases had an HT-morphologically confirmed diagnosis, with 72 PTMC and 52 benign. The non-HT group comprised 266 cases, including 123 PTMC and 143 benign lesions. Preoperative TPO records were accessible for 137 (70%) cases in the PTMC group and 134 (69%) in the control group. Preoperative TSH records were available for 162 cases (83%) in the PTMC group and for all cases (100%) in the control group. The prevalence of HT among MPTC cases is 37%, which is notably higher than the 27% observed in benign cases. As a result, the odds ratio (OR) for developing MPTC with HT presence is 1.6 (95% CI: 1.046 –246; p = 0.03), indicating a statistically significant increase in risk. Hypothyroid TSH levels are found in 65% of the entire HT population and 20% of the non-AT population. The difference is statistically significant at p < 0.0001 level (X 2 =139.25) PTMC is more commonly seen in euthyroid HT. Sixty-three percent of HT cases with PTMT are euthyroid, compared to only 12% of benign HT cases. As a result, euthyroid HT cases are at a greater risk of developing PTMC, with an odds ratio of 13 (95% CI: 4.53–37.04; P< 0.0001). Notably, HT associated with PTMC was diagnosed at a significantly younger age than HT in the control group (t = 2.050; p = 0.04). Pathological features of aggressive behavior in PTMC associated with HT, TPO autoantibody positivity, and TSH levels: The results are presented in Tables 2A, 2B, and 2C. There is no significant difference among subgroups in tumor size, focality, bilaterality, or margin involvement; however, PTMC tends to be multifocal and bilateral with less margin involvement in HT. The presence of HT, TPO positivity, and TSH level has no effect on tumor burden or margin status. The only notable differences are the number of lymph nodes identified and the LNM rate. A total of 17 out of 169 LNM cases were reported, with the majority (82%) involving only the central lymph nodes. Lateral lymph node involvement was seen in just 3 cases (18%). The HT subgroup had a higher average number of harvested lymph nodes (4.7) than the non-HT group (1.9). Despite this, the HT group had significantly fewer lymph node metastases (LNM; 4.4% with HT versus 14% in the non-HT group). There is also a trend, though not statistically significant, for PTMC associated with non-HT to reach a margin more often than PTMC associated with HT (25% vs. 18%). TPO positivity and hypothyroidism do not influence lymph node metastatic status in PTMC. Tumor immune microenvironment types (TIME) and their distribution in HT and non-HT groups. There are statistically significant differences in the distribution of TIME between PTMC cases linked to HT and those not linked to HT (X2 = 44.65; p < 0.0001). In some cases, the immune-inflamed subtype is most common (64%), followed by immune-excluded (25%) and immune desert (11%). Conversely, PTMC cases not linked to HT mainly show the immune desert subtype (51%), with immune-excluded and immune-inflamed types at 30% and 19%, respectively. Overall, immune-inflamed subtypes are present in 36% of PTMC cases regardless of HT status (Table 3). The influence of TIME subtypes on tumor size and lymph node metastatic status The results in Table 4 show that the TIME of the type ID “cold" correlates with smaller tumor sizes, fewer harvested lymph nodes, and lower rates of LNM. Conversely, the “hot” subtype is associated with larger tumors, more harvested lymph nodes, and a higher incidence of LNM. The IE subtypes are intermediate, positioned between these two groups (Table 4A). When comparing PTMC cases with and without HT, the “hot” (Inf) pattern, which is more common in HT than in non-HT (68% vs. 20%), was strongly associated with a higher rate of LNM in non-HT cases (P < 0.0001; Fisher's exact test). There was no difference in the ID pattern between the HT and non-HT groups with respect to the number of lymph nodes removed or the incidence of LNM. However, in non-HT cases, the IE pattern showed a noticeable trend toward increased LNM, although this was not statistically significant (Table 4B). Discussion Thyroid diseases, both benign and malignant, are common in Saudi Arabia. Thyroid cancer ranked seventh globally and third nationally in 2022, with incidence rising from fewer than 2 to 14 cases per 100,000 over the past three decades. Mortality rates have nearly tripled, particularly among males (17). Hypothyroidism, most commonly caused by Hashimoto’s thyroiditis (HT), is also highly prevalent, affecting 10.3%–25.5% of the population, with a mean prevalence of 17.4%, significantly exceeding the global average of 7.5% (18,19). Because papillary thyroid carcinoma (PTC) and HT frequently coexist, their etiological and prognostic relationship has attracted considerable research interest (20). HT is a chronic autoimmune inflammatory disorder characterized by lymphoplasmacytic infiltration, fibrosis, and autoantibody production. Proinflammatory microenvironmental changes, angiogenesis, immune dysregulation, and hormonal alterations may interact with genetic events, promoting carcinogenesis and influencing tumor behavior. Although studies evaluating the association between HT and PTC have yielded mixed results, most evidence supports a significant association, with HT occurring more frequently in PTC than in benign thyroid disease (1,21,22). HT has also been linked to multifocality, bilaterality, reduced extrathyroidal extension, fewer lymph node metastases, and improved recurrence-free survival (22). This paradox suggests that while HT increases the risk of PTC, it may also confer a less aggressive tumor phenotype. Data from the Middle East remains limited. A Saudi study found no association between follicular epithelial dysplasia, autoantibody positivity, or hypothyroidism in HT and PTC (23). Similarly, an Egyptian institutional study reported no increased risk of PTC in HT, although HT was associated with tumor multiplicity without affecting lymph node metastasis or extrathyroidal extension (24). In the Middle East, PTC has been shown to be associated with PDL-1 overexpression, BRAF 6000 mutations, and poor prognosis (25). This retrospective case-control study examined the association between HT—including serological (TPO) and functional (TSH) parameters—and papillary thyroid microcarcinoma (PTMC) in a Saudi population. While no association was observed between TPO positivity and PTMC, HT was significantly associated with PTMC (OR = 1.6). Notably, PTMC in HT patients was strongly associated with euthyroid TSH levels (OR = 13; 95% CI: 4.53–37.04; P < 0.0001). This inverse relationship between HT and hypothyroidism contrasts with prior studies showing increased PTC risk with elevated TSH levels (26,27). Importantly, TSH levels in our cohort were measured at diagnosis before thyroxine therapy, unlike previous studies (28) Our findings suggest that PTMC develops during the early chronic inflammatory phase of HT, before progression to overt autoimmune destruction. This is supported by the younger age at diagnosis and preserved thyroid function in HT-associated PTMC. These observations align with proposed mechanisms in which chronic inflammation promotes carcinogenesis prior to immune-mediated tissue destruction (29). Elevated TPO levels in this context may reflect early innate immune activation preceding adaptive autoimmunity (30). Genetic evidence further supports inflammation-driven carcinogenesis. Regional gene-expression studies indicate that PTC arising in HT is more closely associated with oxidative stress- and inflammation-related oncogenic pathways than with autoimmunity per se (31). Similarly, RET/PTC rearrangements were not associated with HT-related PTC, suggesting alternative oncogenic mechanisms (32) In our cohort, HT did not significantly affect tumor size but was associated with higher rates of multifocality and bilaterality, reduced surgical margin involvement, and significantly lower lymph node metastasis. These findings are consistent with prior reports (1,21,22). To explore potential mechanisms, we analyzed the tumor immune microenvironment (TIME). Using morphological classification, immune-desert (ID) and immune-excluded (IE) patterns were associated with smaller tumors and fewer lymph node metastases than immune-inflammatory (“hot”) tumors, contrary to traditional assumptions (33). These findings are better explained by the cancer immunity cycle model, in which ID represents early immune recognition, IE reflects partial immune penetration limited by fibrosis, and the “hot” pattern corresponds to immune exhaustion and checkpoint activation (34). While the “hot” pattern was associated with higher overall lymph node metastasis, HT-associated “hot” tumors showed significantly lower metastasis than non-HT cases. This supports observations that HT-related PTC exhibits a more active antitumor immune response (16), despite contradicting reports of increased metastasis. The differential behavior likely reflects variations in the proportions of cytotoxic T cells and regulatory T cells, as well as in immune checkpoint expression. In HT, reduced PD-1 expression and preserved immune surveillance may limit tumor progression, whereas non-HT tumors exhibit greater immune evasion via PD-1/PD-L1 signaling (4,33). Overall, our findings support a model in which chronic inflammation initiates PTMC during early HT, while subsequent autoimmune processes modulate tumor aggressiveness. This dynamic interplay between inflammation, immunity, and cancer aligns with established phases of cancer immunoediting: elimination, equilibrium, and immune escape (35). In conclusion, Hashimoto’s thyroiditis (HT), an autoimmune condition, significantly increases the risk of developing papillary thyroid carcinoma (PTC), particularly among young, euthyroid women. Paradoxically, HT is also associated with less aggressive tumor characteristics, including a lower incidence of lymph node metastasis. These seemingly contradictory observations likely reflect the complex, not yet fully understood interplay among chronic inflammation, autoimmunity, and tumor immune surveillance. Notably, the predominance of a “hot” immune microenvironment in PTC—regardless of the presence of HT, and the consequent reduction in tumor immunogenicity suggest that selected cases of advanced or complicated PTC may benefit from immunotherapeutic approaches. Declarations Human ethics declaration: This study received approval from the research committee at Security Force Hospital in Riyadh, in accordance with the Saudi Arabia National Committee of Bioethics (NCBE), under accreditation number H-01-R-069. Acknowledgements: None Author contributions: Imad Abdien EL Hag: Conceptualization, statistical analysis, read the histology slides, and wrote the manuscript (lead). Kamal Aburas: Collected and categorized the preliminary data (equal). Shuaa Asiri: Edited the manuscript (equal). Disclosure statement: Imad Abdien El Hag: The author declares no conflict of interest. Kamal Aburas: The author declares no conflict of interest. Shuaa Asiri: The author declares no conflict of interest. Funding statement: Imad Abdien El Hag: The author receives no financial support for the research. Kamal Aburas: The author receives no financial support for the research. Shuaa Asiri: The author receives no financial support for the research. References Lai X, Xia Y, Zhang B, et al. A meta-analysis of Hashimoto’s thyroiditis and papillary thyroid carcinoma risk. Oncotarget . 2017;8(37):62414–62424. doi:10.18632/oncotarget.18620 Osborne D, Choudhary R, Vyas A, et al. Hashimoto’s thyroiditis effects on papillary thyroid carcinoma outcomes: a systematic review. Cureus . 2022;14(8):e28054. doi:10.7759/cureus.28054 Sakowska J, Arcimowicz Ł, Jankowiak M, et al. 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Variable HT Non-HT PTMC Control PTMC Control No. cases 72/195(37%) 52/195 (27%) 123/195 (63%) 143/195 (73% TPO Positive 45/57 (79%) 41/47 (87%) 21/80(26%) 12/96 (13 %) Euth-TSH 27/43(63%) 6/52 (12%) 106/119 (89%) 104/143 (72%) Age 40.0 ± 10 44 ± 9 46 ± 12 44 ± 13 Table 2 A. Pathological features of aggressive behavior associated with HT Parameter HT Non-HT P value Tumor size 5.5 ± 2.8 5.3 ± 2.6 = .664 Involved margin 13/72 (18 %) 31/123 (25%) = .250 Multiplicity 28/72 (39%) 40/123 (33%) = .369 Bilaterality 20/72 (28%) 26/123 (21%) =.360 No. Lymph node 4.7 ± 7.9 1.9 ± 4.1 =.001 Positive Lymph node 3/68 (4.4 %) 14/101 (14 %) <.05 Table 2 B. Pathological features of aggressive behavior related to TPO positivity Parameter Positive TPO Negative TPO P value Tumor size 5.8 ± 2.6 5.4 ± 2.6 = .434 Involved margin 14/33 (42%) 52/104 (50%) = .449 Multiplicity 22/64 (34%) 26/71 (37%) = .786 Bilaterality 16/64 (25%) 17/71 (23%) = .887 No. Lymph node 4.4 ± 8 2.0 ± 2.6 <.02 Positive Lymph node 6/60 (10%) 9/58 (16%) = .152 Table 2 C. Pathological features of aggressive behavior linked to TSH level Parameter Hypo-TSH Euth-TSH P value Tumor size 5.5 ± 2.8 5.3 ± 2.6 = .656 Involved margin 10/52 (19%) 33/149 (22%) = .659 Multiplicity 14/42 (33%) 53/149 (36%) = .789 Bilaterality 9/42 (21%) 38/149 (26%) = .589 No. Lymph node 4.1 ± 9.7 2.7 ± 4.3 = .165 Positive Lymph node 4/35(11%) 13/130 (10%) = . 703 Table 3. Distribution of TIME subtypes among PTMC cases with and without HT. Variables ID IE Inf Total HT 8 (11%) 18 (25%) 46 (64%) 72 Non-HT 62 (51%) 36 (29%) 24 (20%) 122 Total 70 (36%) 54 (28%) 70 (36%0 194 Table 4A. Tumor size and prevalence of lymph node metastasis of PTMC in various patterns of TIME Variable ID IE Inf P value Tumor size 4.7 ± 2.5 5.2 ± 2.5 6.2 ± 2.6 <0.01 No. of Lymph node 1.2 ±2.1 2.4 ±3.1 5.0 ±8.8 <0.001 Lymph-node metastasis 1 6 9 <.05 Table 4B. Prevalence of lymph node metastasis in various TIME patterns, HT vs non-HT associated Variable ID IE Inf HT 0/7 0/17 3/44 (7%) Non-HT 1/50 6/30 6/20 (30%) P values P = 1.000 P = 0.074 P <0.0001 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-8877989","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":596489495,"identity":"ef2db2da-6cc5-4897-95cc-90e2e67839ac","order_by":0,"name":"Imad Abdien El Hag","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAAyUlEQVRIiWNgGAWjYBACNiCWACI5fhAvoYB4LRbGkg0gLQZE2gTUUpG44QCISYwWPrHDD2/z5kgwbj6/OvHDAwMGeX6xAwQcJp1mbM27TYLZ7MbbzRJAhxnOnJ1ASEuCmTRQC5vZjbMbQFoSDG4T1JL+DaSFx3jG2c0/iNSSA7ZFwoC/dxuxtuQUW87dJmEgcYN3m0WCgQRhv8jPTt944+22uvr+/rObb/6osJHnlyagBQEkwColiFUOAvwHSFE9CkbBKBgFIwkAANE2PWIPPe2mAAAAAElFTkSuQmCC","orcid":"","institution":"Security Force Hospital","correspondingAuthor":true,"prefix":"","firstName":"Imad","middleName":"Abdien El","lastName":"Hag","suffix":""},{"id":596489496,"identity":"15817a71-7a16-491b-bb56-67b22c0cfeca","order_by":1,"name":"Khalid Aburas","email":"","orcid":"","institution":"Security Force Hospital","correspondingAuthor":false,"prefix":"","firstName":"Khalid","middleName":"","lastName":"Aburas","suffix":""},{"id":596489498,"identity":"d9bdae6d-e8ae-4ccc-b37c-d2435eacf27c","order_by":2,"name":"Shuaa Asiri","email":"","orcid":"","institution":"Security Force Hospital","correspondingAuthor":false,"prefix":"","firstName":"Shuaa","middleName":"","lastName":"Asiri","suffix":""}],"badges":[],"createdAt":"2026-02-14 07:38:45","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-8877989/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-8877989/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":103567873,"identity":"a7589640-28ab-421e-b775-5ec9aa84c524","added_by":"auto","created_at":"2026-02-27 07:36:08","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":143285,"visible":true,"origin":"","legend":"\u003cp\u003eH\u0026amp;E-stained section (10X) from a case of PTC showing no inflammatory infiltrate, neither within nor around the tumor, consistent with an immune-desert (ID) “cold” microenvironment.\u003c/p\u003e","description":"","filename":"FigureoneMedium.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8877989/v1/1c3add5d76bd17b3d65a67e8.jpeg"},{"id":103567874,"identity":"49e9f8c2-ef62-4e69-a8bb-1bbfb39e4d8a","added_by":"auto","created_at":"2026-02-27 07:36:08","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":127566,"visible":true,"origin":"","legend":"\u003cp\u003eH\u0026amp;E-stained section (10X) from PTC carcinoma showing dense inflammatory infiltrate only around the tumor, indicating an immune-excluded (IE) microenvironment.\u003c/p\u003e","description":"","filename":"FiguretwoMedium.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8877989/v1/e7de337a8345ab1aa650ee00.jpeg"},{"id":103567875,"identity":"f28c4f92-16c1-4faf-abf8-1742bee4b199","added_by":"auto","created_at":"2026-02-27 07:36:08","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":169596,"visible":true,"origin":"","legend":"\u003cp\u003eImmune-inflamed (Inf) “hot” pattern in a PTC from the HT case, showing dense inflammatory infiltrate within the tumor.\u003c/p\u003e","description":"","filename":"FigurethreeMedium.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-8877989/v1/6a980c707a9f244f39d68796.jpeg"},{"id":106094589,"identity":"e2a6e0a1-a800-4972-9eeb-5bc553c2f504","added_by":"auto","created_at":"2026-04-03 11:42:56","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1162184,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-8877989/v1/a638f0aa-e167-491f-8fad-dd72a23f46e7.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"The relationship between Hashimoto’s thyroiditis and thyroid papillary carcinoma: Trying to explain the paradox","fulltext":[{"header":"Introduction","content":"\u003cp\u003eHashimoto\u0026rsquo;s thyroiditis (HT) and papillary thyroid carcinoma (PTC) are common in women and frequently co-occur, although their relationship remains complex. HT is associated with an increased risk of PTC, yet PTC in patients with HT tends to exhibit slower growth and a more favorable prognosis (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAutoimmunity and cancer were traditionally viewed as opposing processes: autoimmunity results from a loss of immune tolerance to self-antigens, whereas cancer progression relies on increased immune tolerance that enables tumor immune escape. Recent immunological research has shown that these processes are interconnected through immune checkpoint pathways, particularly the programmed cell death protein 1 (PD-1)- PD-L1 axis and regulatory T cells (Tregs) (\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). These checkpoints suppress T-cell activation by promoting Tregs and limiting self-reactive effector T cells, thereby maintaining immune tolerance (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). PD-1 is primarily expressed on immune cells, while PD-L1 is found on both immune and non-immune cells, including epithelial cells. Tumor cells can exploit PD-L1 overexpression to evade immune surveillance and facilitate unchecked growth (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eDisruption of the PD-1/PD-L1 pathway\u0026mdash;through genetic polymorphisms or prolonged immune exhaustion during chronic inflammation\u0026mdash;can impair immune tolerance and contribute to autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, and type 1 diabetes (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Although a direct role for the PD-1/PD-L1 pathway in HT has not been definitively established, variable expression of PD-1 and PD-L1 has been reported in HT, with lower levels observed in vivo than in vitro. Notably, immune checkpoint inhibitor therapy targeting PD-1/PD-L1 is associated with a high incidence of autoimmune thyroid disease (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). An intact PD-1/PD-L1 pathway may contribute to the persistence of HT and limit early remission (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e, \u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAutoimmune thyroiditis develops along a morphological and functional spectrum. Early disease is characterized by a less destructive chronic inflammatory phase, while later stages involve extensive tissue damage and oncocytic metaplasia (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). Early HT is often associated with lower thyroid-stimulating hormone (euth-TSH) levels and lower titers of thyroid peroxidase (TPO) antibodies (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). This phase may be sustained by a functional PD-1/PD-L1 system, whereas chronic immune activation eventually leads to pathway exhaustion, increased autoantibody production, and hypothyroidism.\u003c/p\u003e \u003cp\u003eHistologically, HT is marked by lymphoplasmacytic infiltration and secondary lymphoid follicle formation, changes that are indistinguishable from reactive lymphocytic thyroiditis. The diagnosis of HT becomes clear once these features are accompanied by autoantibody production, destructive changes, and elevated TSH levels. While autoantibodies are present in approximately 95% of cases, early stages may exhibit normal TSH due to compensatory thyroid function and are often identified incidentally during fine-needle aspiration or thyroidectomy performed for other indications (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eTo further explore the association between HT and PTC, we conducted an observational study of histologically confirmed HT cases with papillary thyroid microcarcinoma (PTMC). Serum TPO antibody and TSH levels were analyzed and compared with those of a benign control group, and histological sections were reviewed to characterize the local immune response. PTMC was selected because of its high diagnostic frequency at our institution (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e), its stronger association with HT (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e), and its capacity to elicit localized immune responses comparable to those observed in established PTC.\u003c/p\u003e"},{"header":"Material and methods","content":"\u003cp\u003ePTMC cases diagnosed incidentally or preoperatively in complete or partial thyroidectomies performed between 2018 and 2025 were retrieved from the archives of the Department of Laboratory Medicine and Pathology at Security Force Hospital, Riyadh, Saudi Arabia. An equal number of age- and sex-matched controls was selected from the same time frame as consecutive benign thyroidectomies for comparative analysis. Each group is divided into two subgroups based on the presence or absence of histologically confirmed HT. TPO and TSH levels were measured as part of the initial workup prior to initiation of medical or surgical therapy. TSH levels are classified as euthyroid (4.0 mmol/L) or hypothyroid (\u0026lt;4.0 mmol/L). The prevalence rates of HT, TPO positivity, and TSH levels are reported for each group in Table 1.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe relationship between histologically confirmed HT, TPO positivity, and hypothyroid versus euthyroid TSH levels (hypo-TSH vs. euth-TSH) with the risk of developing PTMC was analyzed and compared independently. The strength of the association between HT, TPO positivity (\u0026gt;34 IU/ml), TSH levels, and the development of PTMC was reported as an odds ratio (OR) in Table 1.\u003c/p\u003e\n\u003cp\u003ePathological features associated with aggressive behavior, including tumor size, morphological subtype, multiplicity, bilaterality, margin involvement, and central lymph node metastasis, were documented and compared between the groups (Table 2). The number of lymph nodes identified in each group and subgroup is recorded and compared.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe tumor immune microenvironment type (TIME) surrounding PTCM on histological sections is classified into three categories based on the level of cell infiltration within and around the tumor. The immune desert (ID) group has fewer lymphocytes both within and outside the tumor (Figure 1). The immune-excluded (IE) group shows clear lymphocyte infiltration around the tumor but few within it (Figure 2). The immunoinflammatory (Inf) group exhibits extensive lymphocytic infiltration of the tumor (Figure 3) (16). These categories are linked to the presence or absence of HT, tumor size, and lymph node metastasis (Table 4).\u003c/p\u003e\n\u003cp\u003eThe SPSS program is used for statistical analysis and data management. A two-tailed chi-square (X \u003csup\u003e2\u003c/sup\u003e) test is used to assess differences in proportions, while a two-tailed t-test is used to compare means, like age and tumor size.\u0026nbsp;\u003c/p\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eStudy population:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study includes 195 consecutive cases of the PTMC group diagnosed between 2018 and 2025, among 1509 partial or complete thyroidectomies. \u0026nbsp;The patients\u0026apos; ages ranged from 20 to 89, with a mean age of 43.5\u0026nbsp;\u0026plusmn;\u0026nbsp;12. The cases consisted of 166 females and 29 males, with an F/M ratio of 6:1.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAn age- and sex-matched control group included an equal number (195) of consecutive cases of benign partial or total thyroidectomies from the same time frame, all without a prior history of thyroid cancer. This group comprised 163 females and 32 males, resulting in a female-to-male ratio of 5:1. The patients\u0026rsquo; ages ranged from 15 to 80 years, with a mean age of 43.5\u0026nbsp;\u0026plusmn;\u0026nbsp;12.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eThe prevalence of HT, preoperative TPO positivity, and TSH levels in the PTMC group compared to the control group:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFindings are summarized in Table 1. The study involved 390 cases, evenly split between the PTMC and benign (control) groups. A total of 124 cases had an HT-morphologically confirmed diagnosis, with 72 PTMC and 52 benign. The non-HT group comprised 266 cases, including 123 PTMC and 143 benign lesions.\u003c/p\u003e\n\u003cp\u003ePreoperative TPO records were accessible for 137 (70%) cases in the PTMC group and 134 (69%) in the control group. Preoperative TSH records were available for 162 cases (83%) in the PTMC group and for all cases (100%) in the control group. \u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe prevalence of HT among MPTC cases is 37%, which is notably higher than the 27% observed in benign cases. As a result, the odds ratio (OR) for developing MPTC with HT presence is 1.6 (95% CI: 1.046 \u0026ndash;246; p = 0.03), indicating a statistically significant increase in risk.\u003c/p\u003e\n\u003cp\u003eHypothyroid TSH levels are found in 65% of the entire HT population and 20% of the non-AT population. The difference is statistically significant at p \u0026lt; 0.0001 level (X\u003csup\u003e2\u0026nbsp;\u003c/sup\u003e=139.25)\u003c/p\u003e\n\u003cp\u003ePTMC is more commonly seen in euthyroid HT. Sixty-three percent of HT cases with PTMT are euthyroid, compared to only 12% of benign HT cases. As a result, euthyroid HT cases are at a greater risk of developing PTMC, with an odds ratio of 13 (95% CI: 4.53\u0026ndash;37.04; P\u0026lt; 0.0001).\u003c/p\u003e\n\u003cp\u003eNotably, HT associated with PTMC was diagnosed at a significantly younger age than HT in the control group (t = 2.050; p = 0.04).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003ePathological features of aggressive behavior in PTMC associated with HT, TPO autoantibody positivity, and TSH levels:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe results are presented in Tables 2A, 2B, and 2C. There is no significant difference among subgroups in tumor size, focality, bilaterality, or margin involvement; however, PTMC tends to be multifocal and bilateral with less margin involvement in HT.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe presence of HT, TPO positivity, and TSH level has no effect on tumor burden or margin status. The only notable differences are the number of lymph nodes identified and the LNM rate.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eA total of 17 out of 169 LNM cases were reported, with the majority (82%) involving only the central lymph nodes. Lateral lymph node involvement was seen in just 3 cases (18%). The HT subgroup had a higher average number of harvested lymph nodes (4.7) than the non-HT group (1.9). Despite this, the HT group had significantly fewer lymph node metastases (LNM; 4.4% with HT versus 14% in the non-HT group).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThere is also a trend, though not statistically significant, for PTMC associated with non-HT to reach a margin more often than PTMC associated with HT (25% vs. 18%).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTPO positivity and hypothyroidism do not influence lymph node metastatic status in PTMC.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eTumor immune microenvironment types (TIME) and their distribution in HT and non-HT groups.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThere are statistically significant differences in the distribution of TIME between PTMC cases linked to HT and those not linked to HT (X2 = 44.65; p \u0026lt; 0.0001). In some cases, the immune-inflamed subtype is most common (64%), followed by immune-excluded (25%) and immune desert (11%). Conversely, PTMC cases not linked to HT mainly show the immune desert subtype (51%), with immune-excluded and immune-inflamed types at 30% and 19%, respectively.\u0026nbsp;Overall, immune-inflamed subtypes are present in 36% of PTMC cases regardless of HT status (Table 3).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eThe influence of TIME subtypes on tumor size and lymph node metastatic status\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe results in Table 4 show that the TIME of the type ID \u0026ldquo;cold\u0026quot; correlates with smaller tumor sizes, fewer harvested lymph nodes, and lower rates of LNM. Conversely, the \u0026ldquo;hot\u0026rdquo; subtype is associated with larger tumors, more harvested lymph nodes, and a higher incidence of LNM. The IE subtypes are intermediate, positioned between these two groups (Table 4A).\u003c/p\u003e\n\u003cp\u003eWhen comparing PTMC cases with and without HT, the \u0026ldquo;hot\u0026rdquo; (Inf) pattern, which is more common in HT than in non-HT (68% vs. 20%), was strongly associated with a higher rate of LNM in non-HT cases (P \u0026lt; 0.0001; Fisher\u0026apos;s exact test). There was no difference in the ID pattern between the HT and non-HT groups with respect to the number of lymph nodes removed or the incidence of LNM. However, in non-HT cases, the IE pattern showed a noticeable trend toward increased LNM, although this was not statistically significant (Table 4B).\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThyroid diseases, both benign and malignant, are common in Saudi Arabia. Thyroid cancer ranked seventh globally and third nationally in 2022, with incidence rising from fewer than 2 to 14 cases per 100,000 over the past three decades. Mortality rates have nearly tripled, particularly among males (17). Hypothyroidism, most commonly caused by Hashimoto\u0026rsquo;s thyroiditis (HT), is also highly prevalent, affecting 10.3%\u0026ndash;25.5% of the population, with a mean prevalence of 17.4%, significantly exceeding the global average of 7.5% (18,19).\u003c/p\u003e\n\u003cp\u003eBecause papillary thyroid carcinoma (PTC) and HT frequently coexist, their etiological and prognostic relationship has attracted considerable research interest (20). HT is a chronic autoimmune inflammatory disorder characterized by lymphoplasmacytic infiltration, fibrosis, and autoantibody production. Proinflammatory microenvironmental changes, angiogenesis, immune dysregulation, and hormonal alterations may interact with genetic events, promoting carcinogenesis and influencing tumor behavior.\u003c/p\u003e\n\u003cp\u003eAlthough studies evaluating the association between HT and PTC have yielded mixed results, most evidence supports a significant association, with HT occurring more frequently in PTC than in benign thyroid disease (1,21,22). HT has also been linked to multifocality, bilaterality, reduced extrathyroidal extension, fewer lymph node metastases, and improved recurrence-free survival (22). This paradox suggests that while HT increases the risk of PTC, it may also confer a less aggressive tumor phenotype.\u003c/p\u003e\n\u003cp\u003eData from the Middle East remains limited. A Saudi study found no association between follicular epithelial dysplasia, autoantibody positivity, or hypothyroidism in HT and PTC (23). \u0026nbsp;Similarly, an Egyptian institutional study reported no increased risk of PTC in HT, although HT was associated with tumor multiplicity without affecting lymph node metastasis or extrathyroidal extension (24). In the Middle East, PTC has been shown to be associated with PDL-1 overexpression, BRAF 6000 mutations, and poor prognosis (25).\u003c/p\u003e\n\u003cp\u003eThis retrospective case-control study examined the association between HT\u0026mdash;including serological (TPO) and functional (TSH) parameters\u0026mdash;and papillary thyroid microcarcinoma (PTMC) in a Saudi population. While no association was observed between TPO positivity and PTMC, HT was significantly associated with PTMC (OR = 1.6). Notably, PTMC in HT patients was strongly associated with euthyroid TSH levels (OR = 13; 95% CI: 4.53\u0026ndash;37.04; P \u0026lt; 0.0001). This inverse relationship between HT and hypothyroidism contrasts with prior studies showing increased PTC risk with elevated TSH levels (26,27). Importantly, TSH levels in our cohort were measured at diagnosis before thyroxine therapy, unlike previous studies (28)\u003c/p\u003e\n\u003cp\u003eOur findings suggest that PTMC develops during the early chronic inflammatory phase of HT, before progression to overt autoimmune destruction. This is supported by the younger age at diagnosis and preserved thyroid function in HT-associated PTMC. These observations align with proposed mechanisms in which chronic inflammation promotes carcinogenesis prior to immune-mediated tissue destruction (29). Elevated TPO levels in this context may reflect early innate immune activation preceding adaptive autoimmunity (30).\u003c/p\u003e\n\u003cp\u003eGenetic evidence further supports inflammation-driven carcinogenesis. Regional gene-expression studies indicate that PTC arising in HT is more closely associated with oxidative stress- and inflammation-related oncogenic pathways than with autoimmunity per se (31). Similarly, RET/PTC rearrangements were not associated with HT-related PTC, suggesting alternative oncogenic mechanisms (32)\u003c/p\u003e\n\u003cp\u003eIn our cohort, HT did not significantly affect tumor size but was associated with higher rates of multifocality and bilaterality, reduced surgical margin involvement, and significantly lower lymph node metastasis. These findings are consistent with prior reports (1,21,22). To explore potential mechanisms, we analyzed the tumor immune microenvironment (TIME).\u003c/p\u003e\n\u003cp\u003eUsing morphological classification, immune-desert (ID) and immune-excluded (IE) patterns were associated with smaller tumors and fewer lymph node metastases than immune-inflammatory (\u0026ldquo;hot\u0026rdquo;) tumors, contrary to traditional assumptions (33). These findings are better explained by the cancer immunity cycle model, in which ID represents early immune recognition, IE reflects partial immune penetration limited by fibrosis, and the \u0026ldquo;hot\u0026rdquo; pattern corresponds to immune exhaustion and checkpoint activation (34).\u003c/p\u003e\n\u003cp\u003eWhile the \u0026ldquo;hot\u0026rdquo; pattern was associated with higher overall lymph node metastasis, HT-associated \u0026ldquo;hot\u0026rdquo; tumors showed significantly lower metastasis than non-HT cases. This supports observations that HT-related PTC exhibits a more active antitumor immune response (16), despite contradicting reports of increased metastasis. The differential behavior likely reflects variations in the proportions of cytotoxic T cells and regulatory T cells, as well as in immune checkpoint expression. In HT, reduced PD-1 expression and preserved immune surveillance may limit tumor progression, whereas non-HT tumors exhibit greater immune evasion via PD-1/PD-L1 signaling (4,33).\u003c/p\u003e\n\u003cp\u003eOverall, our findings support a model in which chronic inflammation initiates PTMC during early HT, while subsequent autoimmune processes modulate tumor aggressiveness. This dynamic interplay between inflammation, immunity, and cancer aligns with established phases of cancer immunoediting: elimination, equilibrium, and immune escape (35).\u003c/p\u003e\n\u003cp\u003eIn conclusion, Hashimoto\u0026rsquo;s thyroiditis (HT), an autoimmune condition, significantly increases the risk of developing papillary thyroid carcinoma (PTC), particularly among young, euthyroid women. Paradoxically, HT is also associated with less aggressive tumor characteristics, including a lower incidence of lymph node metastasis. These seemingly contradictory observations likely reflect the complex, not yet fully understood interplay among chronic inflammation, autoimmunity, and tumor immune surveillance. Notably, the predominance of a \u0026ldquo;hot\u0026rdquo; immune microenvironment in PTC\u0026mdash;regardless of the presence of HT, and the consequent reduction in tumor immunogenicity suggest that selected cases of advanced or complicated PTC may benefit from immunotherapeutic approaches.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eHuman ethics declaration:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study received approval from the research committee at Security Force Hospital in Riyadh, in accordance with the Saudi Arabia National Committee of Bioethics (NCBE), under accreditation number H-01-R-069.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u003c/strong\u003e\u003c/p\u003e\n\u003cul\u003e\n \u003cli\u003eNone\u0026nbsp;\u003c/li\u003e\n\u003c/ul\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor contributions:\u003c/strong\u003e\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003eImad Abdien EL Hag: Conceptualization, statistical analysis, read the histology slides, and wrote the manuscript (lead).\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eKamal Aburas: Collected and categorized the preliminary data (equal).\u003c/li\u003e\n \u003cli\u003eShuaa Asiri: Edited the manuscript (equal).\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e\u003cstrong\u003eDisclosure statement:\u003c/strong\u003e\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003eImad Abdien El Hag: The author declares no conflict of interest.\u003c/li\u003e\n \u003cli\u003eKamal Aburas: The author declares no conflict of interest.\u003c/li\u003e\n \u003cli\u003eShuaa Asiri: The author declares no conflict of interest.\u003c/li\u003e\n\u003c/ol\u003e\n\u003cp\u003e\u003cstrong\u003eFunding statement:\u003c/strong\u003e\u003c/p\u003e\n\u003col\u003e\n \u003cli\u003eImad Abdien El Hag: The author receives no financial support for the research.\u0026nbsp;\u003c/li\u003e\n \u003cli\u003eKamal Aburas: The author receives no financial support for the research.\u003c/li\u003e\n \u003cli\u003eShuaa Asiri: The author receives no financial support for the research.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eLai X, Xia Y, Zhang B,\u0026nbsp;\u003cstrong\u003eet al.\u003c/strong\u003e A meta-analysis of Hashimoto\u0026rsquo;s thyroiditis and papillary thyroid carcinoma risk.\u0026nbsp;\u003cem\u003eOncotarget\u003c/em\u003e. 2017;8(37):62414\u0026ndash;62424. doi:10.18632/oncotarget.18620\u003c/li\u003e\n \u003cli\u003eOsborne D, Choudhary R, Vyas A,\u0026nbsp;\u003cstrong\u003eet al.\u003c/strong\u003e Hashimoto\u0026rsquo;s thyroiditis effects on papillary thyroid carcinoma outcomes: a systematic review.\u0026nbsp;\u003cem\u003eCureus\u003c/em\u003e. 2022;14(8):e28054. doi:10.7759/cureus.28054\u003c/li\u003e\n \u003cli\u003eSakowska J, Arcimowicz Ł, Jankowiak M,\u0026nbsp;\u003cstrong\u003eet al.\u003c/strong\u003e Autoimmunity and cancer\u0026mdash;two sides of the same coin.\u0026nbsp;\u003cem\u003eFront Immunol\u003c/em\u003e. 2022;13:793234. doi:10.3389/fimmu.2022.793234\u003c/li\u003e\n \u003cli\u003eFrancisco LM, Sage PT, Sharpe AH. 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Oncology meets immunology: the cancer-immunity cycle.\u0026nbsp;\u003cem\u003eImmunity\u003c/em\u003e. 2013;39(1):1\u0026ndash;10. doi:10.1016/j.immuni.2013.07.012\u003c/li\u003e\n \u003cli\u003eBinnewies M, Roberts EW, Kersten K,\u0026nbsp;\u003cstrong\u003eet al.\u003c/strong\u003e Understanding the tumor immune microenvironment (TIME) for effective therapy.\u0026nbsp;\u003cem\u003eNat Med\u003c/em\u003e. 2018;24(5):541\u0026ndash;550. doi:10.1038/s41591-018-0014-x\u003c/li\u003e\n \u003cli\u003eGalassi C, Chan TA, Vitale I,\u0026nbsp;\u003cstrong\u003eet al.\u003c/strong\u003e The hallmarks of cancer immune evasion.\u0026nbsp;\u003cem\u003eCancer Cell\u003c/em\u003e. 2024;42(11):1825\u0026ndash;1863. doi:10.1016/j.ccell.2024.09.010\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable1. Prevalence of HT, high serum TPO, and euth-TSH in the PTMC vs. the control group.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd rowspan=\"2\" valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eVariable\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 234px;\"\u003e\n \u003cp\u003eHT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd colspan=\"2\" valign=\"top\" style=\"width: 276px;\"\u003e\n \u003cp\u003eNon-HT\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003ePTMC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eControl\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003ePTMC\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003eControl\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eNo. cases\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e72/195(37%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e52/195 (27%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e123/195 (63%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e143/195 (73%\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eTPO Positive\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e45/57 (79%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e41/47 (87%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e21/80(26%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e12/96 (13 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eEuth-TSH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e27/43(63%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e6/52 (12%)\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e106/119 (89%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e104/143 (72%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eAge\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e40.0\u0026nbsp;\u0026plusmn;\u0026nbsp;10\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e44\u0026nbsp;\u0026plusmn;\u0026nbsp;9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 132px;\"\u003e\n \u003cp\u003e46\u0026nbsp;\u0026plusmn;\u0026nbsp;12\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 144px;\"\u003e\n \u003cp\u003e44\u0026nbsp;\u0026plusmn;\u0026nbsp;13\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eTable 2 A. Pathological features of aggressive behavior associated with HT\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eParameter\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eHT\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNon-HT \u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTumor size\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5.5\u0026nbsp;\u0026plusmn;\u0026nbsp;2.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5.3\u0026nbsp;\u0026plusmn; 2.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e= .664\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eInvolved margin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e13/72 (18 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e31/123 (25%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e= .250\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMultiplicity\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e28/72 (39%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e40/123 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e= .369\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eBilaterality\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e20/72 (28%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e26/123 (21%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e=.360\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNo. Lymph node\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4.7\u0026nbsp;\u0026plusmn;\u0026nbsp;7.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e1.9 \u0026nbsp; \u0026nbsp; \u0026plusmn; 4.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e=.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePositive Lymph node\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e3/68 (4.4 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e14/101 (14 %)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 2 B. Pathological features of aggressive behavior related to TPO positivity\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eParameter\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePositive TPO\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNegative TPO\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTumor size\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5.8 \u0026plusmn; 2.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5.4 \u0026plusmn; 2.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e= .434\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eInvolved margin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e14/33 (42%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e52/104 (50%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e= .449\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMultiplicity\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e22/64 (34%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e26/71 (37%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e= .786\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eBilaterality\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e16/64 (25%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e17/71 (23%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e= .887\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNo. Lymph node\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4.4 \u0026plusmn; 8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2.0 \u0026plusmn; 2.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e\u0026lt;.02\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePositive Lymph node\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e6/60 (10%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e9/58 (16%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e= .152\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eTable 2 C. Pathological features of aggressive behavior linked to TSH level\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eParameter\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eHypo-TSH\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eEuth-TSH\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eTumor size\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5.5\u0026nbsp;\u0026plusmn;\u0026nbsp;2.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e5.3\u0026nbsp;\u0026plusmn;\u0026nbsp;2.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e= .656\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eInvolved margin\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e10/52 (19%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e33/149 (22%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e= .659\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eMultiplicity\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e14/42 (33%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e53/149 (36%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e= .789\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eBilaterality\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e9/42 (21%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e38/149 (26%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e= .589\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003eNo. Lymph node\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4.1\u0026nbsp;\u0026plusmn;\u0026nbsp;9.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e2.7\u0026nbsp;\u0026plusmn;\u0026nbsp;4.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e= .165\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003ePositive Lymph node\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e4/35(11%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e13/130 (10%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\"\u003e\n \u003cp\u003e= . 703\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u003cbr\u003e\u003c/p\u003e\n\u003cp\u003eTable 3. Distribution of TIME subtypes among PTMC cases with and without HT.\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 135px;\"\u003e\n \u003cp\u003eVariables\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003eID\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 127px;\"\u003e\n \u003cp\u003eIE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 127px;\"\u003e\n \u003cp\u003eInf\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eTotal\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 135px;\"\u003e\n \u003cp\u003eHT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e8 (11%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 127px;\"\u003e\n \u003cp\u003e18 (25%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 127px;\"\u003e\n \u003cp\u003e46 (64%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e72\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 135px;\"\u003e\n \u003cp\u003eNon-HT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e62 (51%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 127px;\"\u003e\n \u003cp\u003e36 (29%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 127px;\"\u003e\n \u003cp\u003e24 (20%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e122\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 135px;\"\u003e\n \u003cp\u003eTotal\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 120px;\"\u003e\n \u003cp\u003e70 (36%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 127px;\"\u003e\n \u003cp\u003e54 (28%)\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 127px;\"\u003e\n \u003cp\u003e70 (36%0\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e194\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTable 4A. Tumor size and prevalence of lymph node metastasis of PTMC in various patterns of TIME\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 210px;\"\u003e\n \u003cp\u003eVariable\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003eID\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003eIE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003eInf\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003eP value\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 210px;\"\u003e\n \u003cp\u003eTumor size\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e4.7\u0026nbsp;\u0026plusmn;\u0026nbsp;2.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e5.2\u0026nbsp;\u0026plusmn;\u0026nbsp;2.5\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e6.2\u0026nbsp;\u0026plusmn;\u0026nbsp;2.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u0026lt;0.01\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 210px;\"\u003e\n \u003cp\u003eNo. of Lymph node\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e1.2\u0026nbsp;\u0026plusmn;2.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e2.4\u0026nbsp;\u0026plusmn;3.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e5.0\u0026nbsp;\u0026plusmn;8.8\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u0026lt;0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 210px;\"\u003e\n \u003cp\u003eLymph-node metastasis\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 90px;\"\u003e\n \u003cp\u003e6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 84px;\"\u003e\n \u003cp\u003e9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 78px;\"\u003e\n \u003cp\u003e\u0026lt;.05\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003e\u0026nbsp;\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eTable 4B. Prevalence of lymph node metastasis in various TIME patterns, HT vs non-HT associated\u0026nbsp;\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eVariable\u0026nbsp;\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003eID\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003eIE\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eInf\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eHT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e0/7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e0/17\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e3/44 (7%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eNon-HT\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003e1/50\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003e6/30\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003e6/20 (30%)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd valign=\"top\" style=\"width: 156px;\"\u003e\n \u003cp\u003eP values\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 102px;\"\u003e\n \u003cp\u003eP = 1.000\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 108px;\"\u003e\n \u003cp\u003eP = 0.074\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd valign=\"top\" style=\"width: 114px;\"\u003e\n \u003cp\u003eP \u0026lt;0.0001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n\u003c/table\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-8877989/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-8877989/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eHashimoto\u0026rsquo;s thyroiditis (HT) and papillary thyroid microcarcinoma (PTMC) often coexist. Their relationship is paradoxical and unclear.\u003c/p\u003e\u003ch2\u003eMaterials and Methods\u003c/h2\u003e \u003cp\u003eThis retrospective study reviews 1,509 thyroidectomies from 2018\u0026ndash;2025, focusing on PTMC cases compared with benign thyroidectomy controls to assess the link between PTMC and HT.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003e37% of PTMC cases have HT, versus 27% of controls. The odds ratio (OR) for PTMC among HT patients is 1.6 (95% CI: 1.046\u0026ndash;2.46; p\u0026thinsp;=\u0026thinsp;0.03), indicating an increased risk. The risk is higher in euthyroid HT, with 63% prevalence in PTMC vs. 12% in controls. The OR for PTMC in euthyroid HT is 13 (95% CI: 4.53\u0026ndash;37.04; P\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). PTMC occurs at a younger age with HT (40 vs. 44; p\u0026thinsp;\u0026lt;\u0026thinsp;0.05). HT with PTMC reduces lymph node metastasis (LNM) without affecting tumor size. The tumor immune microenvironment (TIME) differs: the immune-inflamed \u0026ldquo;hot\u0026rdquo; subtype is more common in HT, while the immune-desert (ID) subtype is more common in non-HT cases. The \u0026ldquo;hot\u0026rdquo; type is immunosuppressive and is associated with increased lymph node metastasis, particularly in non-HT-associated PTC.\u003c/p\u003e\u003ch2\u003eConclusion\u003c/h2\u003e \u003cp\u003eEuthyroid HT is associated with increased PTMC risk, likely arising early in chronic inflammation before autoimmunity. The dominant \u0026ldquo;hot\u0026rdquo; TIME subtype appears immunosuppressive, suggesting a potential role for immunotherapy in PTC.\u003c/p\u003e","manuscriptTitle":"The relationship between Hashimoto’s thyroiditis and thyroid papillary carcinoma: Trying to explain the paradox","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-02-27 07:36:02","doi":"10.21203/rs.3.rs-8877989/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"2e253b1f-95a4-48f7-b98d-e168e0a1a961","owner":[],"postedDate":"February 27th, 2026","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2026-04-03T10:26:48+00:00","versionOfRecord":[],"versionCreatedAt":"2026-02-27 07:36:02","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-8877989","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-8877989","identity":"rs-8877989","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}