Endocrinology and Metabolism

Original Articles

Fatty Liver Index Dynamics as a Predictor of Hepatocellular Carcinoma in Patients with Type 2 Diabetes Mellitus and Non-Cirrhotic Livers: Eun-Hee Cho, Min Gu Kang, Chang Hun Lee, Shinyoung Oh, Chen Shen, Ha Ram Oh, Young Ran Park, Hyun Lee, Jong Seung Kim, Ji Hyun Park; Received December 15, 2024 Accepted March 13, 2025 Published online May 29, 2025; DOI: https://doi.org/10.3803/EnM.2024.2286 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
Type 2 diabetes mellitus (T2DM) is a significant risk factor for hepatocellular carcinoma (HCC) in patients with nonalcoholic fatty liver disease; however, surveillance strategies for patients with T2DM, especially without cirrhosis, are inadequate. This study examined whether the fatty liver index (FLI) and its dynamic changes can effectively identify patients with T2DM at increased risk for HCC.
Methods
Data from 92,761 individuals with T2DM aged 40 to 79 who underwent two health screenings (2012 to 2015) were analyzed. The FLI, calculated using waist circumference, body mass index, triglycerides, and gamma-glutamyl transferase, was used to stratify patients by baseline FLI and FLI changes between screenings. HCC cases were identified via International Classification of Diseases codes and reimbursement records (2016 to 2020).
Results
Patients with baseline FLI of 30 to 59.9 had a 1.90-fold higher risk (P<0.01) and those with FLI ≥60 had a 2.94-fold higher risk (P<0.01) of developing HCC compared to those with FLI <30. An increase in FLI from <30 to ≥30 resulted in a 2.10-fold higher risk of HCC (P<0.01), while a reduction in FLI from ≥30 to <30 led to a 0.64-fold lower risk (P=0.03). Protective benefits of FLI reduction took approximately 3 years to manifest.
Conclusion
Baseline and dynamic monitoring of FLI effectively identified HCC risk in T2DM patients with non-cirrhotic livers, supporting early detection and intervention.

Clinical Outcomes of Follicular Thyroid Carcinoma Did Not Significantly Differ according to Tumor Size in an Iodine-Excessive Country: Da Eun Leem, Ji Hyun Yoo, Bo Ram Kim, Jung Sun Kim, Tae Hyuk Kim, Sun Wook Kim, Yun Jae Chung, Jae Hoon Chung, Young Lyun Oh; Received January 19, 2025 Accepted March 24, 2025 Published online May 26, 2025; DOI: https://doi.org/10.3803/EnM.2025.2324 [Epub ahead of print]

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Follicular thyroid carcinoma (FTC) measuring <2 cm is generally associated with good prognosis, while tumor size ≥4 cm is regarded as being associated with a poor prognosis. This study aimed to evaluate FTC prognosis by tumor size to investigate whether the 2- and 4-cm criteria are appropriate for assessing prognosis.
Methods
Data of 248 patients with FTC diagnosed between August 1995 and June 2021 were retrospectively analyzed. The population was divided into four groups according to tumor size: <2.0, 2.0–3.9, 4.0–5.9, and ≥6.0 cm. Distant metastasis (DM), recurrence and/or structural persistence (R/SP), cancer-specific death (CSD), and frequency of telomerase reverse transcriptase (TERT) promoter mutations based on tumor size were evaluated.
Results
While the rates of DM, R/SP, and CSD and the frequency of TERT promoter mutations did not differ among the size groups <6 cm, they increase sharply in tumor size ≥6 cm, although statistically insignificant (P=0.608, P=0.248, P=0.089, and P=0.165 respectively). Widely invasive subtypes, and TERT promoter mutations were significantly associated with DM (P=0.009 and P<0.001, respectively). Age ≥55 years, gross extrathyroidal extension, synchronous DM, and TERT promoter mutation were independent risk factors for CSD (P=0.005, P=0.003, P<0.001, and P=0.002, respectively).
Conclusion
DM, R/SP, CSD, and TERT promoter mutations were not uncommon in FTCs <2 cm compared to those in larger FTCs, whereas FTCs ≥6 cm showed a sharp decline in prognosis, although this was statistically insignificant.

Comprehensive Proteomics and Machine Learning Analysis to Distinguish Follicular Adenoma and Follicular Thyroid Carcinoma from Indeterminate Thyroid Nodules: Hee-Sung Ahn, Eyun Song, Chae A Kim, Min Ji Jeon, Yu-Mi Lee, Tea-Yon Sung, Dong Eun Song, Jiyoung Yu, Ji Min Shin, Yeon-Sook Choi, Kyunggon Kim, Won Gu Kim; Received October 16, 2024 Accepted February 24, 2025 Published online April 10, 2025; DOI: https://doi.org/10.3803/EnM.2024.2208 [Epub ahead of print]

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Abstract PDF Supplementary Material PubReader ePub: Background
The preoperative diagnosis of follicular thyroid carcinoma (FTC) is challenging because it cannot be readily distinguished from follicular adenoma (FA) or benign follicular nodular disease (FND) using the sonographic and cytological features typically employed in clinical practice.
Methods
We employed comprehensive proteomics and machine learning (ML) models to identify novel diagnostic biomarkers capable of classifying three subtypes: FTC, FA, and FND. Bottom-up proteomics techniques were applied to quantify proteins in formalin-fixed, paraffin-embedded (FFPE) thyroid tissues. In total, 202 FFPE tissue samples, comprising 62 FNDs, 72 FAs, and 68 FTCs, were analyzed.
Results
Close spectrum-spectrum matching quantified 6,332 proteins, with approximately 9% (780 proteins) differentially expressed among the groups. When applying an ML model to the proteomics data from samples with preoperative indeterminate cytopathology (n=183), we identified distinct protein panels: five proteins (CNDP2, DNAAF5, DYNC1H1, FARSB, and PDCD4) for the FND prediction model, six proteins (DNAAF5, FAM149B1, RPS9, TAGLN2, UPF1, and UQCRC1) for the FA model, and seven proteins (ACTN4, DSTN, MACROH2A1, NUCB1, SPTAN1, TAGLN, and XRCC5) for the FTC model. The classifiers’ performance, evaluated by the median area under the curve values of the random forest models, was 0.832 (95% confidence interval [CI], 0.824 to 0.839) for FND, 0.826 (95% CI, 0.817 to 0.835) for FA, and 0.870 (95% CI, 0.863 to 0.877) for FTC.
Conclusion
Quantitative proteome analysis combined with an ML model yielded an optimized multi‐protein panel that can distinguish FTC from benign subtypes. Our findings indicate that a proteomic approach holds promise for the differential diagnosis of FTC.

Thyroid
Distinct Impacts of Clinicopathological and Mutational Profiles on Long-Term Survival and Recurrence in Medullary Thyroid Carcinoma: Moon Young Oh, Kyong Yeun Jung, Hoonsung Choi, Young Jun Chai, Sun Wook Cho, Su-jin Kim, Kyu Eun Lee, Eun-Jae Chung, Do Joon Park, Young Joo Park, Han-Kwang Yang; Endocrinol Metab. 2024;39(6):877-890. Published online November 5, 2024; DOI: https://doi.org/10.3803/EnM.2024.2027

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Medullary thyroid carcinoma (MTC) has a poorer prognosis than differentiated thyroid cancers; however, comprehensive data on the long-term outcomes of MTC remain scarce. This study investigated the extended clinical outcomes of MTC and aimed to identify prognostic factors.
Methods
Patients diagnosed with MTC between 1980 and 2020 were retrospectively reviewed. Their clinical characteristics, longterm clinical outcomes, and prognostic factors for recurrence and mortality were analyzed.
Results
The study included 226 patients (144 women, 82 men). The disease-specific survival (DSS) rates for all MTC patients at 5-, 10-, 20-, and 30-year intervals were 92.7%, 89.4%, 74.3%, and 68.1%, respectively. The recurrence-free survival (RFS) rates were 71.1%, 56.1%, 40.2%, and 32.1% at these intervals. DSS was comparable between the groups from 1980–2009 and 2010–2020 (P=0.995); however, the 1980–2009 group had significantly lower RFS rates (P=0.031). The 2010–2020 group exhibited greater extents of surgical and lymph node dissection (P=0.003) and smaller tumors (P=0.003). Multivariate analysis identified extrathyroidal extension as the strongest prognostic factor for both RFS and DSS. Age >55 years and tumor size of ≥2 cm were also significant prognostic factors for DSS, while hereditary disease and lymph node metastasis were significant for RFS. Survival analysis after propensity-score matching of rearranged during transfection (RET)-negative and non-screened RET-positive groups showed comparable DSS but longer RFS in the RET-negative group.
Conclusion
Extrathyroidal extension was identified as the strongest prognostic factor for RFS and DSS. Older age and larger tumor size were associated with decreased DSS, while RET mutation and lymph node metastasis significantly impacted RFS.

Review Article

Thyroid
Thyroid Hormone-Mediated Selective Autophagy and Its Implications in Countering Metabolic Dysfunction-Associated Steatotic Liver Disease: Rohit A. Sinha; Endocrinol Metab. 2024;39(5):686-692. Published online October 14, 2024; DOI: https://doi.org/10.3803/EnM.2024.2068

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Abstract PDF PubReader ePub: The influence of thyroid hormone (TH) on liver metabolism has attracted the attention of pharmacologists seeking new treatments for metabolic dysfunction-associated steatotic liver disease (MASLD), an increasingly common metabolic disorder. In this context, the selective induction of autophagy by TH in preclinical models has been identified as a promising mechanism. In this process, TH clears intrahepatic fat through lipophagy while protecting against inflammation and mitochondrial damage in hepatocytes via mitophagy. Furthermore, TH-induced aggrephagy may represent a protective mechanism to mitigate the development of MASLD-associated hepatocellular carcinoma. Considering the defects in autophagy observed during the progression of human MASLD, the induction of autophagy by TH, its metabolites, and its analogs represent a novel strategy to combat hepatic damage across the MASLD spectrum.

Original Articles

Adrenal gland
The Modified S-GRAS Scoring System for Prognosis in Korean with Adrenocortical Carcinoma: Sun Kyung Baek, Seung Hun Lee, Seung Shin Park, Chang Ho Ahn, Sung Hye Kong, Won Woong Kim, Yu-Mi Lee, Su Jin Kim, Dong Eun Song, Tae-Yon Sung, Kyu Eun Lee, Jung Hee Kim, Kyeong Cheon Jung, Jung-Min Koh; Endocrinol Metab. 2024;39(5):803-812. Published online September 25, 2024; DOI: https://doi.org/10.3803/EnM.2024.2086

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Adrenocortical carcinomas (ACCs) are rare tumors with aggressive but varied prognosis. Stage, Grade, Resection status, Age, Symptoms (S-GRAS) score, based on clinical and pathological factors, was found to best stratify the prognosis of European ACC patients. This study assessed the prognostic performance of modified S-GRAS (mS-GRAS) scores including modified grade (mG) by integrating mitotic counts into the Ki67 index (original grade), in Korean ACC patients.
Methods
Patients who underwent surgery for ACC between January 1996 and December 2022 at three medical centers in Korea were retrospectively analyzed. mS-GRAS scores were calculated based on tumor stage, mG (Ki67 index or mitotic counts), resection status, age, and symptoms. Patients were divided into four groups (0–1, 2–3, 4–5, and 6–9 points) based on total mS-GRAS score. The associations of each variable and mS-GRAS score with recurrence and survival were evaluated using Cox regression analysis, Harrell’s concordance index (C-index), and the Kaplan–Meier method.
Results
Data on mS-GRAS components were available for 114 of the 153 patients who underwent surgery for ACC. These 114 patients had recurrence and death rates of 61.4% and 48.2%, respectively. mS-GRAS score was a significantly better predictor of recurrence (C-index=0.829) and death (C-index=0.747) than each component (P<0.05), except for resection status. mS-GRAS scores correlated with shorter progression-free survival (P=8.34E-24) and overall survival (P=2.72E-13).
Conclusion
mS-GRAS scores showed better prognostic performance than tumor stage and grade in Asian patients who underwent surgery for ACC.

Thyroid
Prognosis of Poorly Differentiated Thyroid Carcinoma: A Systematic Review and Meta-Analysis: Ji Young Kim, Jae Kyung Myung, Soyun Kim, Kyung Tae, Yun Young Choi, Soo Jin Lee; Endocrinol Metab. 2024;39(4):590-602. Published online June 27, 2024; DOI: https://doi.org/10.3803/EnM.2024.1927

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Background
Poorly differentiated thyroid carcinoma (PDTC) accounts for a small portion of thyroid carcinomas but contributes to a significant proportion of thyroid carcinoma-associated deaths. The clinicopathological prognostic factors and clinical outcomes of PDTC remain unclear. We aimed to evaluate the clinical outcomes of patients with PDTC after curative treatment.
Methods
A comprehensive search was performed up to September 2023. We included studies investigating treatment outcomes in patients with PDTC who underwent initial surgery. The 5-year disease-free survival (DFS) and overall survival (OS) were extracted. In this meta-analysis, the enrolled PDTC histological criteria included 3rd, 4th, and 5th World Health Organization (WHO) and Memorial Sloan Kettering Cancer Center (MSKCC) classification. A random-effects model was used for the pooled proportion analysis. Meta-regression analysis was conducted to evaluate the prognostic factors.
Results
Twenty retrospective studies published between 2007 and 2023, including 1,294 patients, met all inclusion criteria. Studies that diagnosed PDTC based on various histological criteria including 3rd WHO (n=5), 4th WHO (n=12), 5th WHO (n=2), and MSKCC (n=1) were included. Overall, 5-year DFS and 5-year OS were 49.4% (95% confidence interval [CI], 42.3 to 56.4) and 73.8% (95% CI, 66.5 to 79.9), with moderate heterogeneity of 58% and 55%, respectively. In meta-regression analysis, extrathyroidal extension (ETE) was a prognostic factor for OS.
Conclusion
The meta-analysis of DFS and OS in patients with PDTC show the moderate heterogeneity with a variety of histological criteria. ETE appears to have a significant impact on OS, regardless of histological criteria.

Citations

Citations to this article as recorded by

Aggressive Types of Malignant Thyroid Neoplasms
Maria Boudina, Eleana Zisimopoulou, Persefoni Xirou, Alexandra Chrisoulidou
Journal of Clinical Medicine.2024; 13(20): 6119. CrossRef

Thyroid
Diagnostic Accuracy of Preoperative Radiologic Findings in Papillary Thyroid Microcarcinoma: Discrepancies with the Postoperative Pathologic Diagnosis and Implications for Clinical Outcomes: Ying Li, Seul Ki Kwon, Hoonsung Choi, Yoo Hyung Kim, Sunyoung Kang, Kyeong Cheon Jung, Jae-Kyung Won, Do Joon Park, Young Joo Park, Sun Wook Cho; Endocrinol Metab. 2024;39(3):450-460. Published online May 27, 2024; DOI: https://doi.org/10.3803/EnM.2023.1872

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Abstract PDF Supplementary Material PubReader ePub: Background
The diagnostic accuracy of preoperative radiologic findings in predicting the tumor characteristics and clinical outcomes of papillary thyroid microcarcinoma (PTMC) was evaluated across all risk groups.
Methods
In total, 939 PTMC patients, comprising both low-risk and non-low-risk groups, who underwent surgery were enrolled. The preoperative tumor size and lymph node metastasis (LNM) were evaluated by ultrasonography within 6 months before surgery and compared with the postoperative pathologic findings. Discrepancies between the preoperative and postoperative tumor sizes were analyzed, and clinical outcomes were assessed.
Results
The agreement rate between radiological and pathological tumor size was approximately 60%. Significant discrepancies were noted, including an increase in tumor size in 24.3% of cases. Notably, in 10.8% of patients, the postoperative tumor size exceeded 1 cm, despite being initially classified as 0.5 to 1.0 cm based on preoperative imaging. A postoperative tumor size >1 cm was associated with aggressive pathologic factors such as multiplicity, microscopic extrathyroidal extension, and LNM, as well as a higher risk of distant metastasis. In 30.1% of patients, LNM was diagnosed after surgery despite not being suspected before the procedure. This group was characterized by smaller metastatic foci and lower risks of distant metastasis or recurrence than patients with LNM detected both before and after surgery.
Conclusion
Among all risk groups of PTMCs, a subset showed an increase in tumor size, reaching 1 cm after surgery. These cases require special consideration due to their association with adverse clinical outcomes, including an elevated risk of distant metastasis.

Thyroid Thyroid Cancer Screening
Cost-Utility Analysis of Early Detection with Ultrasonography of Differentiated Thyroid Cancer: A Retrospective Study on a Korean Population: Han-Sang Baek, Jeonghoon Ha, Kwangsoon Kim, Ja Seong Bae, Jeong Soo Kim, Sungju Kim, Dong-Jun Lim, Chul-Min Kim; Endocrinol Metab. 2024;39(2):310-323. Published online April 9, 2024; DOI: https://doi.org/10.3803/EnM.2023.1870

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Background
There is debate about ultrasonography screening for thyroid cancer and its cost-effectiveness. This study aimed to evaluate the cost-effectiveness of early screening (ES) versus symptomatic detection (SD) for differentiated thyroid cancer (DTC) in Korea.
Methods
A Markov decision analysis model was constructed to compare the cost-effectiveness of ES and SD. The model considered direct medical costs, health outcomes, and different diagnostic and treatment pathways. Input data were derived from literature and Korean population studies. Incremental cost-effectiveness ratio (ICER) was calculated. Willingness-to-pay (WTP) threshold was set at USD 100,000 or 20,000 per quality-adjusted life year (QALY) gained. Sensitivity analyses were conducted to address uncertainties of the model’s variables.
Results
In a base case scenario with 50 years of follow-up, ES was found to be cost-effective compared to SD, with an ICER of $2,852 per QALY. With WTP set at $100,000, in the case with follow-up less than 10 years, the SD was cost-effective. Sensitivity analysis showed that variables such as lobectomy probability, age, mortality, and utility scores significantly influenced the ICER. Despite variations in costs and other factors, all ICER values remained below the WTP threshold.
Conclusion
Findings of this study indicate that ES is a cost-effective strategy for DTC screening in the Korean medical system. Early detection and subsequent lobectomy contribute to the cost-effectiveness of ES, while SD at an advanced stage makes ES more cost-effective. Expected follow-up duration should be considered to determine an optimal strategy for DTC screening.

Citations

Citations to this article as recorded by

Conventional and Emerging Diagnostic Approaches for Differentiated Thyroid Carcinoma
Kathelina Kristollari, Abraham Abbey Paul, Sagi Angel, Robert S. Marks
Chemosensors.2024; 12(11): 229. CrossRef

Diabetes, obesity and metabolism
Risk of Pancreatic Cancer and Use of Dipeptidyl Peptidase 4 Inhibitors in Patients with Type 2 Diabetes: A Propensity Score-Matching Analysis: Mee Kyoung Kim, Kyungdo Han, Hyuk-Sang Kwon, Soon Jib Yoo; Endocrinol Metab. 2023;38(4):426-435. Published online July 20, 2023; DOI: https://doi.org/10.3803/EnM.2023.1737

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Background
The effects of dipeptidyl peptidase 4 (DPP-4) inhibitors over the course of long-term treatment remain unclear, and concerns have been raised regarding the role of DPP-4 inhibitors in carcinogenesis in the pancreas. Earlier studies of pancreatic adverse events have reported conflicting results.
Methods
This study analyzed Korean National Health Insurance Service data from January 2009 to December 2012. Patients who had type 2 diabetes mellitus and took two or more oral glucose-lowering drugs (GLDs) were included. Patients prescribed DPP-4 inhibitors (n=51,482) or other GLDs (n=51,482) were matched at a 1:1 ratio using propensity score matching. The risk of pancreatic cancer was calculated using Kaplan-Meier curves and Cox proportional-hazards regression analysis.
Results
During a median follow-up period of 7.95 years, 1,051 new cases of pancreatic cancer were identified. The adjusted hazard ratio (HR) for DPP-4 inhibitor use was 0.99 (95% confidence interval [CI], 0.88 to 1.12) compared with the other GLD group. In an analysis limited to cases diagnosed with pancreatic cancer during hospitalization, the adjusted HR for the use of DPP-4 inhibitors was 1.00 (95% CI, 0.86 to 1.17) compared with patients who took other GLDs. Using the other GLD group as the reference group, no trend was observed for elevated pancreatic cancer risk with increased DPP-4 inhibitor exposure.
Conclusion
In this population-based cohort study, DPP-4 inhibitor use over the course of relatively long-term follow-up showed no significant association with an elevated risk of pancreatic cancer.

Citations

Citations to this article as recorded by

Real-world evidence on the association of novel antidiabetic medication use with cancer risk and protective effects: a systematic review and network meta-analysis
Ahmed S. Kenawy, Yi-Shao Liu, Ayobami Aiyeolemi, Godwin Okoye, Chanhyun Park
Therapeutic Advances in Drug Safety.2025;[Epub] CrossRef
Cholesterol and Cardiovascular Risk in Type 2 Diabetes: The Role of Kidney Function
Ji-Hyun Kim, Seung-Hwan Lee, Kyu Na Lee, Kyungdo Han, Mee Kyoung Kim
Journal of Lipid and Atherosclerosis.2025; 14(2): 190. CrossRef
Diabetes Duration, Cholesterol Levels, and Risk of Cardiovascular Diseases in Individuals With Type 2 Diabetes
Mee Kyoung Kim, Kyu Na Lee, Kyungdo Han, Seung-Hwan Lee
The Journal of Clinical Endocrinology & Metabolism.2024; 109(12): e2317. CrossRef
Anti-Diabetic Therapies and Cancer: From Bench to Bedside
Dimitris Kounatidis, Natalia G. Vallianou, Irene Karampela, Eleni Rebelos, Marina Kouveletsou, Vasileios Dalopoulos, Petros Koufopoulos, Evanthia Diakoumopoulou, Nikolaos Tentolouris, Maria Dalamaga
Biomolecules.2024; 14(11): 1479. CrossRef

Thyroid
Clinicopathological Characteristics and Disease-Free Survival in Patients with Hürthle Cell Carcinoma: A Multicenter Cohort Study in South Korea: Meihua Jin, Eun Sook Kim, Bo Hyun Kim, Hee Kyung Kim, Yea Eun Kang, Min Ji Jeon, Tae Yong Kim, Ho-Cheol Kang, Won Bae Kim, Young Kee Shong, Mijin Kim, Won Gu Kim; Endocrinol Metab. 2021;36(5):1078-1085. Published online October 28, 2021; DOI: https://doi.org/10.3803/EnM.2021.1151

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Background
Hürthle cell carcinoma (HCC), a type of thyroid carcinoma, is rare in South Korea, and few studies have investigated its prognosis.
Methods
This long-term multicenter retrospective cohort study evaluated the clinicopathological features and clinical outcomes in patients with HCC who underwent thyroid surgery between 1996 and 2009.
Results
The mean age of the 97 patients included in the study was 50.3 years, and 26.8% were male. The mean size of the primary tumor was 3.2±1.8 cm, and three (3.1%) patients had distant metastasis at initial diagnosis. Ultrasonographic findings were available for 73 patients; the number of nodules with low-, intermediate-, and high suspicion was 28 (38.4%), 27 (37.0%), and 18 (24.7%), respectively, based on the Korean-Thyroid Imaging Reporting and Data System. Preoperatively, follicular neoplasm (FN) or suspicion for FN accounted for 65.2% of the cases according to the Bethesda category, and 13% had malignancy or suspicious for malignancy. During a median follow-up of 8.5 years, eight (8.2%) patients had persistent/recurrent disease, and none died of HCC. Older age, gross extrathyroidal extension (ETE), and widely invasive types of tumors were significantly associated with distant metastasis (all P<0.01). Gross ETE (hazard ratio [HR], 27.7; 95% confidence interval [CI], 2.2 to 346.4; P=0.01) and widely invasive classification (HR, 6.5; 95% CI, 1.1 to 39.4; P=0.04) were independent risk factors for poor disease-free survival (DFS).
Conclusion
The long-term prognosis of HCC is relatively favorable in South Korea from this study, although this is not a nation-wide data, and gross ETE and widely invasive cancer are significant prognostic factors for DFS. The diagnosis of HCC by ultrasonography and cytopathology remains challenging.

Citations

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Prognostic impact of fibrosclerotic changes in non-papillary, non-anaplastic, follicular cell-derived thyroid carcinomas
Giulia Orlando, Giulia Capella, Giulia Vocino Trucco, Elena Vissio, Jasna Metovic, Francesca Maletta, Marco Volante, Mauro Papotti
Virchows Archiv.2025;[Epub] CrossRef
Molecular Alterations and Comprehensive Clinical Management of Oncocytic Thyroid Carcinoma
Lindsay A. Bischoff, Ian Ganly, Laura Fugazzola, Erin Buczek, William C. Faquin, Bryan R. Haugen, Bryan McIver, Caitlin P. McMullen, Kate Newbold, Daniel J. Rocke, Marika D. Russell, Mabel Ryder, Peter M. Sadow, Eric Sherman, Maisie Shindo, David C. Shonk
JAMA Otolaryngology–Head & Neck Surgery.2024; 150(3): 265. CrossRef
Oncocytic carcinoma of the thyroid: Conclusions from a 20‐year patient cohort
Nelson R. Gruszczynski, Shahzeb S. Hasan, Ana G. Brennan, Julian De La Chapa, Adithya S. Reddy, David N. Martin, Prem P. Batchala, Edward B. Stelow, Eric M. Dowling, Katherine L. Fedder, Jonathan C. Garneau, David C. Shonka
Head & Neck.2024; 46(8): 2042. CrossRef
Oncocytic cell carcinoma of the thyroid with TERT promoter mutation presenting as asphyxia in an elderly: a case report
Xiqian Wang, Yingao Liu, Lijie Chen, Jie Zhang, Ruoyu Jiang, Lei Zhang, Han Yan, Jie Zhang
Frontiers in Endocrinology.2024;[Epub] CrossRef
Clinical Considerations of Oncocytic Thyroid Cancer: A Review
Soo Young Kim
Journal of Endocrine Surgery.2024; 24(3): 49. CrossRef
Mitochondrial Proteome Defined Molecular Pathological Characteristics of Oncocytic Thyroid Tumors
Lu Li, Likun Zhang, Wenhao Jiang, Zhiqiang Gui, Zhihong Wang, Hao Zhang, Yi He, Yi Zhu, Tiannan Guo, Haixia Guan, Zhiyan Liu, Yaoting Sun, Jianqing Gao
Endocrine Pathology.2024; 35(4): 442. CrossRef
Hurthle cell carcinoma: a rare variant of thyroid malignancy – a case report
Yuvraj Adhikari, Anupama Marasini, Nawaraj Adhikari, Laxman D. Paneru, Binit Upadhaya Regmi, Manita Raut
Annals of Medicine & Surgery.2023; 85(5): 1940. CrossRef
Hürthle Cell Carcinoma: Single Center Analysis and Considerations for Surgical Management Based on the Recent Literature
Costanza Chiapponi, Milan J.M. Hartmann, Matthias Schmidt, Michael Faust, Christiane J. Bruns, Anne M. Schultheis, Hakan Alakus
Frontiers in Endocrinology.2022;[Epub] CrossRef

Thyroid
Whole-Exome Sequencing in Papillary Microcarcinoma: Potential Early Biomarkers of Lateral Lymph Node Metastasis: Mijin Kim, Chae Hwa Kwon, Min Hee Jang, Jeong Mi Kim, Eun Heui Kim, Yun Kyung Jeon, Sang Soo Kim, Kyung-Un Choi, In Joo Kim, Meeyoung Park, Bo Hyun Kim; Endocrinol Metab. 2021;36(5):1086-1094. Published online October 28, 2021; DOI: https://doi.org/10.3803/EnM.2021.1132

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Background
Early identification of patients with high-risk papillary thyroid microcarcinoma (PTMC) that is likely to progress has become a critical challenge. We aimed to identify somatic mutations associated with lateral neck lymph node (LN) metastasis (N1b) in patients with PTMC.
Methods
Whole-exome sequencing (WES) of 14 PTMCs with no LN metastasis (N0) and 13 N1b PTMCs was performed using primary tumors and matched normal thyroid tissues.
Results
The mutational burden was comparable in N0 and N1b tumors, as the median number of mutations was 23 (range, 12 to 46) in N0 and 24 (range, 12 to 50) in N1b PTMC (P=0.918). The most frequent mutations were detected in PGS1, SLC4A8, DAAM2, and HELZ in N1b PTMCs alone, and the K158Q mutation in PGS1 (four patients, Fisher’s exact test P=0.041) was significantly enriched in N1b PTMCs. Based on pathway analysis, somatic mutations belonging to the receptor tyrosine kinase-RAS and NOTCH pathways were most frequently affected in N1b PTMCs. We identified four mutations that are predicted to be pathogenic in four genes based on Clinvar and Combined Annotation-Dependent Depletion score: BRAF, USH2A, CFTR, and PHIP. A missense mutation in CFTR and a nonsense mutation in PHIP were detected in N1b PTMCs only, although in one case each. BRAF mutation was detected in both N0 and N1b PTMCs.
Conclusion
This first comprehensive WES analysis of the mutational landscape of N0 and N1b PTMCs identified pathogenic genes that affect biological functions associated with the aggressive phenotype of PTMC.

Citations

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Transcriptome sequencing revealed that lymph node metastasis of papillary thyroid microcarcinoma is associated with high THBS4 expression and PDGFRA+ cancer-associated fibroblasts
LeYin Hu, Yi Lin, JingYu Zheng, Li Wan, Rui Zhao, Yi Ma, JianMin Li
Frontiers in Oncology.2025;[Epub] CrossRef
What can we learn about acid-base transporters in cancer from studying somatic mutations in their genes?
Bobby White, Pawel Swietach
Pflügers Archiv - European Journal of Physiology.2024; 476(4): 673. CrossRef
Comprehensive Long-Read Sequencing Analysis Discloses the Transcriptome Features of Papillary Thyroid Microcarcinoma
Yanqiang Wang, Binbin Zou, Yanyan Zhang, Jin Zhang, Shujing Li, Bo Yu, Zhekun An, Lei Li, Siqian Cui, Yutong Zhang, Jiali Yao, Xiuzhi Shi, Jing Liu
The Journal of Clinical Endocrinology & Metabolism.2024; 109(5): 1263. CrossRef
Feasibility of whole‐exome sequencing in fine‐needle aspiration specimens of papillary thyroid microcarcinoma for the identification of novel gene mutations
Liyuan Ma, Luying Gao, Ya Hu, Xiaoyi Li, Chunhao Liu, Jiang Ji, Xinlong Shi, Aonan Pan, Yuang An, Nengwen Luo, Yu Xia, Yuxin Jiang
Clinical Genetics.2024; 105(5): 567. CrossRef
Multi-omics analysis reveals a molecular landscape of the early recurrence and early metastasis in pan-cancer
Dan-ni He, Na Wang, Xiao-Ling Wen, Xu-Hua Li, Yu Guo, Shu-heng Fu, Fei-fan Xiong, Zhe-yu Wu, Xu Zhu, Xiao-ling Gao, Zhen-zhen Wang, Hong-jiu Wang
Frontiers in Genetics.2023;[Epub] CrossRef

Review Article

Thyroid
Active Surveillance as an Effective Management Option for Low-Risk Papillary Thyroid Microcarcinoma: Min Ji Jeon, Won Gu Kim, Tae Yong Kim, Young Kee Shong, Won Bae Kim; Endocrinol Metab. 2021;36(4):717-724. Published online August 11, 2021; DOI: https://doi.org/10.3803/EnM.2021.1042; Correction in: Endocrinol Metab 2022;37(1):180

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Active surveillance (AS) for low-risk papillary thyroid microcarcinoma (PTMC) has been accepted worldwide as safe and effective. Despite the growing acceptance of AS in the management of low-risk PTMCs, there are barriers to AS in real clinical settings, and it is important to understand and establish appropriate AS protocol from initial evaluation to follow-up. PTMC management strategies should be decided upon after careful consideration of patient and tumor characteristics by a multidisciplinary team of thyroid cancer specialists. Patients should understand the risks and benefits of AS, participate in decision-making and follow structured monitoring strategies. In this review, we discuss clinical outcomes of AS from previous studies, optimal indications and follow-up strategies for AS, and unresolved questions about AS.

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Diagnostic Accuracy of Preoperative Radiologic Findings in Papillary Thyroid Microcarcinoma: Discrepancies with the Postoperative Pathologic Diagnosis and Implications for Clinical Outcomes
Ying Li, Seul Ki Kwon, Hoonsung Choi, Yoo Hyung Kim, Sunyoung Kang, Kyeong Cheon Jung, Jae-Kyung Won, Do Joon Park, Young Joo Park, Sun Wook Cho
Endocrinology and Metabolism.2024; 39(3): 450. CrossRef
Serum thyroglobulin testing after thyroid lobectomy in patients with 1–4 cm papillary thyroid carcinoma
Ahreum Jang, Meihua Jin, Chae A Kim, Min Ji Jeon, Yu-Mi Lee, Tae-Yon Sung, Tae Yong Kim, Won Bae Kim, Young Kee Shong, Won Gu Kim
Endocrine.2023; 81(2): 290. CrossRef
Papillary Thyroid Microcarcinoma: Active Surveillance Against Surgery. Considerations of an Italian Working Group From a Systematic Review
Giuseppina Orlando, Gregorio Scerrino, Alessandro Corigliano, Irene Vitale, Roberta Tutino, Stefano Radellini, Francesco Cupido, Giuseppa Graceffa, Gianfranco Cocorullo, Giuseppe Salamone, Giuseppina Melfa
Frontiers in Oncology.2022;[Epub] CrossRef
Prognosis of Patients with 1–4 cm Papillary Thyroid Cancer Who Underwent Lobectomy: Focus on Gross Extrathyroidal Extension Invading Only the Strap Muscles
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Annals of Surgical Oncology.2022; 29(12): 7835. CrossRef

Original Articles

Thyroid
Association between Iodine Intake, Thyroid Function, and Papillary Thyroid Cancer: A Case-Control Study: Kyungsik Kim, Sun Wook Cho, Young Joo Park, Kyu Eun Lee, Dong-Wook Lee, Sue K. Park; Endocrinol Metab. 2021;36(4):790-799. Published online August 11, 2021; DOI: https://doi.org/10.3803/EnM.2021.1034

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Background
This study aimed to assess the effects of iodine intake, thyroid function, and their combined effect on the risk of papillary thyroid cancer (PTC) and papillary thyroid microcarcinoma (PTMC).
Methods
A case-control study was conducted including 500 community-based controls who had undergone a health check-up, and 446 overall PTC cases (209 PTC and 237 PTMC) from the Thyroid Cancer Longitudinal Study. Urinary iodine concentration (UIC), was used as an indicator of iodine intake, and serum for thyroid function. The risk of PTC and PTMC was estimated using unconditional logistic regression.
Results
Excessive iodine intake (UIC ≥220 μg/gCr) was associated with both PTC (odds ratio [OR], 18.13 95% confidence interval [CI], 8.87 to 37.04) and PTMC (OR, 8.02; 95% CI, 4.64 to 13.87), compared to adequate iodine intake (UIC, 85 to 219 μg/gCr). Free thyroxine (T4) levels ≥1.25 ng/dL were associated with PTC (OR, 1.97; 95% CI, 1.36 to 2.87) and PTMC (OR, 2.98; 95% CI, 2.01 to 4.41), compared to free T4 levels of 0.7 to 1.24 ng/dL. Individuals with excessive iodine intake and high free T4 levels had a greatly increased OR of PTC (OR, 43.48; 95% CI, 12.63 to 149.62), and PTMC (OR, 26.96; 95% CI, 10.26 to 70.89), compared to individuals with adequate iodine intake and low free T4 levels.
Conclusion
Excessive iodine intake using creatinine-adjusted UIC and high free T4 levels may have a synergistic effect on PTC and PTMC. Considering both iodine intake and thyroid function is important to assess PTC and PTMC risk.

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Thyroid
Clinicopathological Characteristics and Recurrence-Free Survival of Rare Variants of Papillary Thyroid Carcinomas in Korea: A Retrospective Study: Mijin Kim, Sun Wook Cho, Young Joo Park, Hwa Young Ahn, Hee Sung Kim, Yong Joon Suh, Dughyun Choi, Bu Kyung Kim, Go Eun Yang, Il-Seok Park, Ka Hee Yi, Chan Kwon Jung, Bo Hyun Kim; Endocrinol Metab. 2021;36(3):619-627. Published online June 10, 2021; DOI: https://doi.org/10.3803/EnM.2021.974

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Background
We aimed to evaluate the clinicopathological features and biological behaviors of Korean thyroid cancer patients with rare variants of papillary thyroid carcinoma (PTC) to address the ambiguity regarding the prognostic consequences of these variants.
Methods
We retrospectively reviewed the medical records of 5,496 patients who underwent thyroid surgery for PTC, between January and December 2012, in nine tertiary hospitals. Rare PTC variants included tall cell (TCV), columnar cell (CCV), diffuse sclerosing (DSV), cribriform-morular (CMV), solid (SV), hobnail, and Warthin-like variants. Recurrence-free survival (RFS) was defined as the time from the date of thyroidectomy until recurrence.
Results
Rare variants accounted for 1.1% (n=63) of the PTC patients; with 0.9% TCV, 0.02% CCV, 0.1% DSV, 0.1% CMV, and 0.1% SV. The mean age of patients and primary tumor size were 42.1±13.1 years and 1.3±0.9 cm, respectively. Extrathyroidal extension and cervical lymph node metastasis were observed in 38 (60.3%) and 37 (58.7%) patients, respectively. Ultrasonographic findings revealed typical malignant features in most cases. During a median follow-up of 7 years, 6.3% of patients experienced a locoregional recurrence. The 5-year RFS rates were 71.4% in patients with DSV or SV, 95.9% for TCV, or CCV, and 100% for other variants. DSV emerged an independent risk factor associated with shorter RFS.
Conclusion
In this multicenter Korean cohort, rare variants accounted for 1.1% of all PTC cases, with TCV being the most frequent subtype. DSV emerged as a significant prognostic factor for RFS.

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Serum thyroglobulin testing after thyroid lobectomy in patients with 1–4 cm papillary thyroid carcinoma
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