BACKGROUND:The American Thyroid Association (ATA) guideline revisions in 2009 and 2015 encouraged a shift toward less extensive surgery and reduced use of radioactive iodine (RAI) in the management of patients with low-risk papillary thyroid carcinoma (PTC). The aim of this study was to evaluate the real-world impact of these guideline changes on treatment patterns, complications, and oncologic outcomes. METHODS:In this retrospective cohort study conducted at a high-volume tertiary center in South Korea, we analyzed 31,861 patients treated for PTCs measuring ≤4 cm during 2004-2020. Patients were stratified into three temporal cohorts (triad 0 2004-2009; triad 1: 2010-2015; and triad 2: 2016-2020), and exact matching was performed to balance clinicopathologic characteristics across the groups. Segmented regression analysis was used to identify treatment pattern shifts. Postoperative complications and disease-free survival (DFS) were compared across the matched cohorts by using conditional logistic and stratified Cox regression analyses. Five-year restricted mean survival time (RMST) analysis was performed to adjust for follow-up variation. RESULTS:After guideline implementation, total thyroidectomies and RAI use significantly declined. Permanent hypocalcemia decreased from 2.7% to 0.2% (p < 0.001) while transient complications remained stable. Although recurrence rates were lowest in the most recent era (1.3%), DFS analysis revealed higher hazard ratios for recurrence in triad 2 versus earlier cohorts (triad 2 vs. 0 hazard ratio: 1.520, confidence interval: 1.160-1.980). However, 5-year DFS and RMST comparisons revealed no significant differences. CONCLUSIONS:ATA guideline-driven de-escalation strategies were successfully implemented in real-world practice in this study, reducing overtreatment and surgical morbidity without compromising short-term oncologic outcomes.

Telomerase reverse transcriptase (TERT) promoter mutations are associated with aggressive clinicopathological features of papillary thyroid cancer (PTC). However, their independent prognostic value remains unclear. This study aimed to evaluate the prognostic significance of TERT promoter mutations (TPMs) in predicting early treatment outcomes and event-free survival (EFS) in patients with PTC. We retrospectively analyzed a prospective cohort; patients underwent surgery at a single tertiary referral center between 2019 and 2022. Patients underwent thyroidectomy, selective postoperative radioactive iodine ablation, and levothyroxine suppression therapy. Propensity score matching (PSM, 1:1) was applied to adjust for baseline clinicopathological differences. Of 10,642 patients with available molecular data, 115 (1.1%) harbored TPMs. After PSM, 90 matched pairs of patients with TERT-wild-type and TERT-mutant tumors were analyzed. Early treatment responses at 1 and 2 years post-treatment and EFS were evaluated. Early treatment responses did not differ significantly between groups at 1 year (P = 0.212) and 2 years (P = 0.571). However, patients with TERT-mutant tumors had fewer excellent responses and higher rates of structural incomplete response. During follow-up, the TERT-mutant group experienced more recurrences and one disease-specific death. Cumulative EFS was significantly poorer in the TERT-mutant group than in the TERT-wild-type group (P = 0.022). Despite their low prevalence, TPMs were independently associated with adverse oncological outcomes, including higher rates of recurrence and mortality. TPMs may serve as valuable prognostic markers for early risk stratification in PTC.

BackgroundThe increase in the older population globally presents unique challenges in thyroid cancer management. Age is a crucial prognostic factor in differentiated thyroid carcinoma (DTC); however, its effect on surgical outcomes in older patients is unclear. Therefore, we aimed to evaluate the clinical characteristics, postoperative complications, and long-term outcomes of DTC in older patients and determine the effect of advanced age on recurrence risk and surgical morbidity.MethodsA retrospective cohort study including 27,427 patients who underwent thyroidectomy for DTC between 2003 and 2019 was conducted. Patients were stratified into three age groups: Group A (16–64 years), Group B (65–74 years), and Group C (≥75 years). Clinicopathological characteristics, postoperative complications, and recurrence rates were analyzed. Multivariate Cox regression was performed to identify predictors of recurrence.ResultsOlder patients had more aggressive tumor features, including higher rates of extrathyroidal extension (Group C: 70.6% vs. Group A: 51.6%, p<0.0001) and distant metastasis (p=0.0006). Postoperative complications, including seroma (Group C: 15.58% vs. Group A: 2.85%, p<0.0001) and recurrent laryngeal nerve injury (Group C: 2.16% vs. Group A: 0.45%, p=0.0001), were more common in older patients. Recurrence risk increased with age (Group C: hazard ratio 1.894, 95% confidence interval: 1.156–3.104, p=0.0113). Despite higher risks, more extensive surgery was associated with improved survival in older patients.ConclusionsAdvanced age is associated with more aggressive DTC and increased recurrence risk, yet thyroidectomy remains a viable treatment option. Close surveillance is essential to optimize outcomes in older patients.

Transaxillary robotic thyroidectomy (TART) has become increasingly adopted for differentiated thyroid cancer (DTC), yet long-term locoregional recurrence patterns remain insufficiently defined. Therefore, we aimed to characterize recurrence patterns using a compartment-based anatomic mapping approach in a large TART cohort. We retrospectively analyzed 10,504 patients with DTC who underwent TART at a single institution from 2007 to 2024. Recurrence occurred in 97 patients (0.9

Papillary thyroid carcinoma (PTC) generally has a favorable prognosis; however, overtreatment persists because of the lack of reliable noninvasive risk stratification tools. This study developed a radiomics-based approach to enhance the preoperative assessment of PTC. Imaging features from 255 patients were analyzed, and three tumor clusters were identified via unsupervised clustering, with one cluster (Cluster 2) displaying favorable clinical and molecular profiles. A radiomics score was constructed and validated internally and externally, achieving high diagnostic accuracy (area under the curve of 0.98) and independently predicting benign features such as a lower N stage and favorable treatment responses. Transcriptomic analysis revealed immune activation and survival-related gene expression in Cluster 2. The model demonstrated robust performance in stratifying patients for active surveillance and may complement current diagnostic frameworks, offering a precise, noninvasive tool to guide clinical decision-making.

Background: The incidence of thyroid cancer has rapidly increased worldwide, and familial aggregation of the disease has been increasingly recognized. This study aimed to evaluate the prevalence, clinicopathological characteristics, and long-term outcomes of familial non-medullary thyroid cancer (FNMTC) in a large institutional cohort. Methods: Patients with non-medullary thyroid cancer (NMTC) who had undergone surgery were classified as sporadic NMTC (SNMTC) or FNMTC based on family history. Clinicopathological features at diagnosis and surgery were compared, and prognostic outcomes were analyzed in patients with follow-up data. Results: Among the 46,572 NMTC patients, 3829 (8.2%) had FNMTC, and 42,743 (91.8%) had SNMTC. FNMTC was more prevalent in women and occurred at a younger age. Its proportion increased over time, peaking in the 35–59 age group. FNMTC showed higher rates of bilaterality (23.5% vs. 17.5%, p < 0.001), multifocality (39.0% vs. 30.5%, p < 0.001), and central lymph node metastasis (41.5% vs. 38.8%, p = 0.001), despite smaller tumors (0.9 ± 0.7 cm vs. 1.0 ± 0.9 cm, p < 0.001). Recurrence rates were similar between the two groups (1.9% vs. 2.3%, p = 0.1), but overall survival was higher in the FNMTC group (99.6% vs. 98.6%, p < 0.001). Family history, extracapsular extension, lymph node metastasis, and tumor size independently predicted recurrence. Family history significantly impacted recurrence-free survival in the intermediate-to-high-risk group (HR = 1.65, p < 0.001) but not in low-risk patients. Conclusions: FNMTC represents a distinct NMTC subset with more extensive local disease but favorable survival, warranting risk-adapted management, particularly for intermediate-to-high-risk patients.

Background/Objectives: Despite its increasing incidence in older patients, parathyroidectomy for primary hyperparathyroidism (PHPT) is frequently deferred owing to risks and age-related comorbidities and the limited evidence of age-specific surgical safety and biochemical outcomes. We evaluate age-related differences in clinical characteristics, perioperative outcomes, postoperative complications, and biochemical responses, including bone turnover markers, after parathyroidectomy for PHPT. Methods: We retrospectively enrolled 596 patients who underwent parathyroidectomy between 2009 and 2022, stratified into three age groups: <65, 65–74, and ≥75 years (Group A, n = 401; Group B, n = 141; and Group C, n = 54, respectively). Demographics, comorbidities, operative details, complications, pathology, and biochemical parameters were compared between the groups. Results: Older patients exhibited a higher prevalence of hypertension, cardiovascular disease, diabetes, osteoporosis, and chronic kidney disease (all p < 0.01), whereas multiple endocrine neoplasias were more frequent in younger patients (p = 0.002). Younger patients had a longer operation time (p = 0.006). There were no significant intergroup differences in postoperative hospital stay and complication rates, including transient hypoparathyroidism, hungry bone syndrome, and recurrent laryngeal nerve injury. Pathologic diagnoses were comparable, with single adenoma being most common (81.0–86.2%). The postoperative calcium and parathyroid hormone levels normalized in all groups. Younger patients had higher baseline bone turnover markers and demonstrated greater absolute reductions postoperatively (p = 0.030 and p = 0.042, respectively); however, improvements were observed in all age groups. Conclusions: When appropriately selected, parathyroidectomy is safe and effective in all age groups, including older patients with comorbidities. Considering its evident biochemical and skeletal benefits, age should not preclude surgical intervention for PHPT.

BACKGROUND:COVID-19 pandemic profoundly impacted global health, yet its effects on autoimmune thyroid diseases, particularly chronic lymphocytic thyroiditis (CLT), remain unclear. We aimed to evaluate how clinical, laboratory, and radiological features of CLT changed across distinct phases of the pandemic. METHODS:In this single-institutional retrospective study, we included 7717 patients who underwent thyroidectomy with histologically confirmed CLT from January 2015 to August 2024, excluding those with concurrent autoimmune diseases or incomplete clinical data. Patients' data were stratified into pre-pandemic (before January 2020), pandemic (January 2020-October 2021), and post-pandemic (after October 2021) periods. Demographics, thyroid function tests, autoantibody titers (thyroid peroxidase antibody [TPOAb] and thyroglobulin antibody [TgAb]), ultrasonographic features, and thyroid hormone dosages were compared. Predictors for disease-related outcomes were identified using monthly aggregated interrupted time series analyses. RESULTS:Age distribution was consistent among groups, but the proportion of female sex significantly decreased (90.0 % pre-pandemic, 87.0 % post-pandemic; p < 0.001) and body mass index increased (23.3 ± 3.5 kg/m2 pre-pandemic, 23.6 ± 3.3 kg/m2 post-pandemic; p < 0.001). TPOAb levels were significantly elevated during the pandemic (145.6 ± 275.6 IU/mL) and post-pandemic periods (172.4 ± 273.4 IU/mL) compared to pre-pandemic levels (103.5 ± 270 IU/mL, p < 0.001). TgAb levels were predominantly elevated during the pandemic period (320.4 ± 548.9 vs. 242.8 ± 585 IU/mL pre-pandemic, p < 0.001). Ultrasound features suggestive of CLT, autoantibody positivity and elevated TSH levels were all significantly associated with an increased prevalence after the pandemic (p < 0.05). CONCLUSIONS:The COVID-19 pandemic significantly influenced CLT characteristics, including altered autoantibody profiles, radiological manifestations, and increased thyroid hormone requirements. Therefore, consideration of pandemic-driven changes during patient management is urged.

Purpose:Glycolytic enzymes have been extensively studied in various cancer types, revealing their aggressive characteristics and roles in tumor progression. This study aimed to determine whether the expression of glycolytic enzymes is associated with aggressiveness in the presence or absence of chronic lymphocytic thyroiditis (CLT). Methods:The expression of hexokinase 2, lactate dehydrogenase A (LDHA), pyruvate kinase isoform M2 (PKM2), glucose transporter 1 (GLUT1), and monocarboxylate transporter 4 (MCT4) was examined in 233 papillary thyroid carcinoma (PTC) specimens by immunohistochemistry. We evaluated whether the expression of these glycolytic enzymes correlates with lymph node metastasis, extrathyroidal extension (ETE), and recurrence rate, both with and without CLT. In addition, we analyzed the correlation between glycolytic enzyme messenger RNA expression and risk factors in PTC using The Cancer Genome Atlas. Results:All glycolytic enzymes and transporter proteins were overexpressed in PTC compared with normal tissue. PKM2 expression was most highly correlated with the other glycolytic enzymes. High PKM2 expression was significantly linked to increased recurrence risk in patients without CLT (hazard ratio, 1.76; 95% confidence interval, 1.01-3.06; P = 0.046), but this association was not observed in those with CLT. Conclusion:Overexpression of LDHA, PKM2, GLUT1, and MCT4 is associated with PTC. CLT is significantly associated with an increased incidence of gross ETE and, paradoxically, with a reduced recurrence rate in PTC. LDHA expression was lower in the presence of CLT, whereas PKM2 remained consistently linked to a higher recurrence rate in its absence. Among the evaluated glycolytic enzymes, PKM2 may serve as a biomarker for recurrence in PTC.

Long non-coding RNAs (lncRNAs) regulate the progression and metastasis of high-grade serous carcinoma ovarian cancer (HGSC). However, HGSC is yet to be classified based on these transcripts. In addition, the crosstalk between master transcriptional factors (MTFs) and lncRNAs remains unclear. Therefore, we aimed to classify HGSC based on lncRNA expression and identify the integrated MTFs for highly correlated mRNAs and lncRNAs. Unsupervised clustering was conducted using highly expressed lncRNAs derived from 367 HGSC samples obtained from The Cancer Genome Atlas. DNA mutations, somatic copy number alterations, microRNA expression, and DNA methylome were analyzed to identify the genetic and epigenetic factors affecting unsupervised clustering. Multiple Sample Virtual Inference of Protein-activity by Enriched Regulon analysis (msViper) was conducted to identify transcription factors simultaneously exhibiting positive correlation with lncRNAs and mRNAs in each cluster. In vitro analyses were performed to determine if these lncRNAs regulate both the MTFs and target genes. Functional analysis enabled the lncRNA-based classification of HGSC into five groups: "Immune," "EMT," "Estrogen response," "EMT-Androgen response," and "Differentiation" groups. The EMT-Androgen response group showed poor prognosis in the oncologic outcome. Of the transcription factors selected in this group, three MTFs with the highest eigenvector centrality scores were identified (MSC, AEBP1, CREB3L1). However, seven lncRNAs exerted a higher centrality than the selected MTFs. Our results suggest that HGSC can be classified based on lncRNA expression and characterized using molecular features. Therefore, lncRNAs and MTFs may synergistically contribute to molecular features of HGSC that could be indicators for personalized medicine.

Telomerase reverse transcriptase promoter mutation (pTERT MT) promotes human carcinogenesis via aberrant expression of telomerase reverse transcriptase (TERT). However, the tumorigenic impact of TERT expression independent of pTERT MT remains unclear despite numerous mechanisms of TERT being suggested. To tackle this issue, we employed comprehensive bioinformatics to assess biological variations noticed among different TERT expression mechanisms. Papillary thyroid cancer (PTC) with pTERT MT (pTERT MT PTC) presented aggressive clinical behavior and exhibited biological profiles associated with cellular immortality and genomic instability. PTC with TERT expression but without pTERT MT (TERT (+) PTC), also exhibited poor clinicopathological characteristics and was enriched with immune responses. In accordance, c-MYC/E2F and nuclear factor kappa B (NFκB) were dominant transcription factors in pTERT MT PTC and TERT (+) PTC, respectively. Notably, we revealed TERT hypermethylated oncological region (THOR) as a potential TERT expressing mechanism in TERT (+) PTC patients. Furthermore, three unique subtypes of papillary thyroid cancer were deciphered using a combination of machine learning-based scoring systems. Our proposed scoring system was clinically significant, especially in microcarcinoma, predicting survival outcomes and inferring therapeutic responses to radioactive iodine therapy. Finally, our analysis was expanded to endocrine-related cancers, unveiling various regulatory mechanisms of TERT with poor clinical outcomes and biological behaviors.

Background Fine-needle aspiration biopsy (FNAB) is a good diagnostic tool for thyroid nodules; however, its high false-negative rate for giant nodules remains controversial. Many clinicians recommend surgical resection for nodules >4 cm owing to an increased risk of malignancy and an increased false-negative rate. This study aimed to examine the feasibility of this approach and investigate the incidence of malignancy in thyroid nodules >4 cm without suspicious cytology based on medical records in our center. Methods This was a retrospective analysis of 453 patients that underwent preoperative FNAB for nodules measuring >4 cm between January 2017 and August 2022 at Severance Hospital, Seoul. Results Among the 453 patients, 140 nodules were benign and 119 were indeterminate. Among 259 patients, the final pathology results were divided into benign (149) and cancerous (110) groups, and the prevalence of malignancy was 38.9% in the benign group and 55.5% in the indeterminate group. Among the malignancies, follicular carcinoma and follicular variants of papillary carcinoma were observed in 83% of the cytologically benign group and 62.8% of the indeterminate group. Conclusion Preoperative FNAB had high false-negative rates and low diagnostic accuracy in patients with thyroid nodules >4 cm without suspicious cytologic features; therefore, diagnostic surgery may be considered a treatment option.

Background: Radiation exposure is a well-known risk factor for papillary thyroid cancer (PTC). South Korea has 24 nuclear reactors in operation; however, no molecular biological analysis has been performed on patients with PTC living near nuclear power plants.Methods: We retrospectively included patients with PTC (n=512) divided into three groups according to their place of residence at the time of operation: inland areas (n=300), coastal areas far from nuclear power plants (n=134), and nuclear power plant areas (n=78). After propensity score matching (1:1:1) by age, sex, and surgical procedure, the frequency of representative driver mutations and gene expression profiles were compared (n=50 per group). Epithelial-mesenchymal transition (EMT), BRAF, thyroid differentiation, and radiation scores were calculated and compared.Results: No significant difference was observed in clinicopathological characteristics, including radiation exposure history and the frequency of incidentally discovered thyroid cancer, among the three groups. BRAFV600E mutation was most frequently detected in the groups, with no difference among the three groups. Furthermore, gene expression profiles showed no statistically significant difference. EMT and BRAF scores were higher in our cohort than in cohorts from Chernobyl tissue bank and The Cancer Genome Atlas Thyroid Cancer; however, there was no difference according to the place of residence. Radiation scores were highest in the Chernobyl tissue bank but exhibited no difference according to the place of residence.Conclusion: Differences in clinicopathological characteristics, frequency of representative driver mutations, and gene expression profiles were not observed according to patients’ region of residence in South Korea.

Lymph node metastasis (LNM) is the most important prognostic factor and a crucial indicator in the development of treatment strategies for patients with papillary thyroid carcinoma (PTC).1, 2 A vast majority (25%–60%) of patients with PTC undergo thyroidectomy with neck node dissection.3 However, researchers continue to debate whether LNM is leading to over-treatment of patients with PTC.1, 4 Interestingly, we have noted that upon stratifying LNM risk in PTC and clinical outcomes according to distinct molecular characteristics, LNM showing enrichment of genes related to inflammation and epithelial–mesenchymal transition (EMT) were more aggressive than metabolically adapted LNM, and this was applicable in other tumours. A flowchart of this study is displayed in Figure S1. For discovery, we ran differential gene expression analysis based on the negative binomial distribution (DESEQ2) for 97 patients without LNM [LNM (−)] and 195 patients with LNM [LNM (+)] from our PTC patient cohort (Table S1). One hundred four differentially expressed genes (DEGs) were upregulated in LNM (+), whereas the other 140 DEGs were downregulated (Figure 1A). In LNM (+) specimens, DAVID software revealed significant clustering of up-regulated genes related with EMT pathways (Figure S2A–C). Subsequent analysis of DEGs using the K-means unsupervised clustering algorithm was performed to define marked molecular subtypes, wherein K = 2 showed the greatest classification outcome with a cophenetic coefficient value of.736 (Figure 1B, Figures S3 and S4). To develop a predictive scoring model, we employed LASSO regression and 18 gene signatures that effectively deciphered molecular subtypes with an area under curve value of .97 (Figure 1C–E, Figures S5A–C and S6A,B). We then characterised the molecular characteristics of differently defined clusters by evaluating hallmark gene sets of a molecular signature database using single sample gene set enrichment analysis (ssGSEA).5 PTC patients from Cluster 1 in both our cohort and TCGA shared up-regulated patterns of metabolism-related hallmark pathways. PTC patients from Cluster 2 in both our cohort and TCGA exhibited common enrichment of EMT and immune response (Figure 2A, Figure S7). These differences in enrichment were not noted when patient samples were compared according to LNM status (Figure S8A,B). We noticed a dominant proportion of LNM (+) patients (133 [80.6%]) in Cluster 2 in our cohort. Remarkably, 80 N1b (cancer with lateral neck node metastasis) patient samples (48.5%) were allocated in Cluster 2, while 32 (25.2%) N1a (cancer with central neck node metastasis) and 30 (23.6%) N1b patient samples were in Cluster 1. The odds ratio to observe LNM in Cluster 2 was 4.098 (Figure 2B). Validation with an odds ratio of 4.691 was observed for LNM in Cluster 2, which indicates a strong clinical association between Cluster 2 and LNM (Figure S9). We then set out to determine the prognostic significance of our signature genes related with disease progression or recurrence by integrating clinical survival data from the TCGA database. In doing so, we noted that patients with LNM and high LASSO scores in Cluster 2 (upper two thirds of the designated cluster) displayed significant differences in their prognosis, compared to those with low LASSO scores (lower two-thirds of the designated cluster) among LNM patients in Cluster 1 (Figure 2C). Interestingly, aggressive outcomes were also noticed in N1a patients from Cluster 2 (Figure 2D). This is a crucial issue, as it is not clear whether pathological N1a metastasis can serve as a risk factor in patients with PTC.6 Furthermore, we evaluated thyroid differentiation scores and other important PTC-related oncogenic pathways and found corroborating evidence of biological aggressiveness in Cluster 2 (Figure 2E–L, Table S2). Meanwhile, progression-free survival according to LNM status or the presence of BRAF mutation, a unique genomic marker of PTC, did not show prognostic significance (Figure S10A,B). Additionally, we compared demographic and genomic information from PTC patients between different molecular clusters, as well as multivariate linear regression with LASSO score, to seek for any potential clinical relevance (Tables 1 and S3). Notably, BRAFV600E mutation, T stage, degree of LNM, and extrathyroidal extension (ETE) differed significantly between two clusters, and depth of ETE exhibited a significant proportionate relationship with LASSO score, suggesting a greater chance of severe metastasis in Cluster 2 PTC patients (Tables S4–S6). Our gene expression program was extended to actual LNM samples of PTC by applying it to public databases, GSE60542 and GSE151179 (Figure 3A, S11A–F).7, 8 Also, we challenged the applicability of our gene expression program in LNM of other tumour types and incorporated datasets of breast cancer and melanoma from TCGA, GSE56493, and GSE65904.9, 10 Likewise, molecular subtypes were deciphered using our proposed LASSO gene expression program, and identified molecular characteristics were validated in both primary tumour and LNM (Figure 3A). Moreover, LASSO scores of paired primary tumour and LNM samples showed significant relevance, suggesting preservation of molecular profiles after disease progression (Figure S12A–E). Analogous tendencies were observed in poorly differentiated thyroid carcinoma and anaplastic thyroid cancer patients in GSE76039 (Figure S13A,B). To expand the program's clinical significance, we analysed treatment responses to radioiodine therapy among PTC patients in GSE151179. Notably, significant radioactive iodine (RAI) uptake was found in Cluster 1 with markedly lower LASSO scores than patients without radioiodine uptake (Figure 3B,C). In addition, LASSO scores were higher in patients who underwent RAI treatment (RAIT) (Figure 3D) and in an intermediate- or high-dose group, compared to no treatment or low-dose group (Figure S14A, S14B). LASSO scores also showed a clear tendency to increase as suppressed Tg increased among all patients who underwent RAIT (Figure 3E) and patients who underwent high-dose RAIT (Figure S14C). Finally, we observed concordance between the aggressive outcomes noticed in Cluster 2 primary tumours with LNM and LNM samples from other tumour types (Figure 3F–K). Herein, we report two potential distinct LNM molecular subtypes of PTC with different clinical outcomes in terms of LNM and biological features. Proposed signatures were conserved throughout disease progression and validated in other thyroid cancer data and different tumour types. An EMT/inflammation axis, which we suggest as an aggressive LNM mechanism, requires support from additional studies for potential application in clinical settings. We thank Ji Young Kim, Hee Chang Yu, and Hoyoung Kim for their excellent technical support. The authors declare that they have no competing interests. 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The raised prevalence of obesity has increased the incidence of obesity-related metabolic diseases such as dyslipidemia (DL) and non-alcoholic fatty liver disease (NAFLD), along with the development and progression of various types of cancer, including thyroid cancer. In this study, we investigated whether thyroid cancer in patients with DL and NAFLD could be a risk factor for other cancers. To achieve our goal, we generated two independent cohorts from our institution and from the National Health Insurance System in South Korea. Based on the ICD-10 code, we conducted exact matching (1:5 matching) and estimated the overall risk of thyroid cancer for other cancers in patients with DL or NAFLD. Univariate and multivariate analyses showed that the hazard ratio (HR) of thyroid cancer was 2.007 (95% Confidence Interval [CI], 1.597–2.522) and 2.092 (95% CI, 1.546–2.829), respectively in the institutional cohort and 1.329 (95% CI, 1.153–1.533) and 1.301 (95% CI, 1.115–1.517), respectively in the nationwide cohort. Risk analysis revealed a significant increase in the HR in lip, tongue, mouth, lung, bone, joint, soft tissue, skin, brain, male cancers and lymphoma after thyroid cancer occurred. Thyroid cancer in patients with DL or NAFLD might be a valuable factor for predicting the development of other cancers.

We aimed to investigate the effect of thyroid hormone administration on the risk of second primary cancer in patients who underwent thyroidectomy for differentiated thyroid cancer. Data were extracted from the medical billing data of the Health Insurance Review and Assessment Service in South Korea. Patients between 19 and 80 years old who underwent thyroid surgery at least once between January 2009 and June 2020 were included. Data of patients with second primary cancer and control patients with matched age, sex, operation date, and follow-up duration were extracted at a ratio of 1:4. A nested case–control analysis was performed to exclude length bias to confirm the correlation between the duration of thyroid hormone administration, dose, and incidence of second primary cancer. Of the 261,598 patients who underwent surgery for thyroid cancer included in the study, 11,790 with second primary cancer and 47,160 without second primary cancer were matched. The average dose of thyroid hormone increased the adjusted odds ratio (OR) for both low (≤ 50 μg, OR 1.29, confidence interval (CI) 1.12–1.48) and high (< 100 μg, OR 1.24, CI 1.12–1.37) doses. Analyzing over time, the adjusted OR of second primary cancer increased, especially in short (≤ 1 year) (OR 1.19; CI 1.06–1.34) and long (> 5 years) duration (OR 1.25; CI 1.10–1.41). In conclusion, insufficient and excessive thyroid hormone replacement might be linked to increased second primary cancer in patients who underwent thyroidectomy for differentiated thyroid cancer.