Genome-Wide Association Studies of Autoimmune Thyroid Diseases, Thyroid Function, and Thyroid Cancer

황보율,박영주 대한내분비학회 2018 Endocrinology and metabolism Vol.33 No.2

Thyroid diseases, including autoimmune thyroid diseases and thyroid cancer, are known to have high heritability. Family and twin studies have indicated that genetics plays a major role in the development of thyroid diseases. Thyroid function, represented by thyroid stimulating hormone (TSH) and free thyroxine (T4), is also known to be partly genetically determined. Before the era of genome-wide association studies (GWAS), the ability to identify genes responsible for susceptibility to thyroid disease was limited. Over the past decade, GWAS have been used to identify genes involved in many complex diseases, including various phenotypes of the thyroid gland. In GWAS of autoimmune thyroid diseases, many susceptibility loci associated with autoimmunity (human leukocyte antigen [HLA], protein tyrosine phosphatase, non-receptor type 22 [PTPN22], cytotoxic T-lymphocyte associated protein 4 [CTLA4], and interleukin 2 receptor subunit alpha [IL2RA]) or thyroid-specific genes (thyroid stimulating hormone receptor [TSHR] and forkhead box E1 [FOXE1]) have been identified. Regarding thyroid function, many susceptibility loci for levels of TSH and free T4 have been identified through genome-wide analyses. In GWAS of differentiated thyroid cancer, associations at FOXE1, MAP3K12 binding inhibitory protein 1 (MBIP)-NK2 homeobox 1 (NKX2-1), disrupted in renal carcinoma 3 (DIRC3), neuregulin 1 (NRG1), and pecanex-like 2 (PCNXL2) have been commonly identified in people of European and Korean ancestry, and many other susceptibility loci have been found in specific populations. Through GWAS of various thyroid-related phenotypes, many susceptibility loci have been found, providing insights into the pathogenesis of thyroid diseases and disease co-clustering within families and individuals

Evaluation and Management of Bone Health in Patients with Thyroid Diseases: A Position Statement of the Korean Thyroid Association

홍아람,강호철 대한내분비학회 2023 Endocrinology and metabolism Vol.38 No.2

Thyroid hormones play an important physiological role in maintaining adult bone structure and strength. Consequently, thyroid dysfunction is related to skeletal outcomes. Overt hyperthyroidism is an established cause of high bone turnover with accelerated bone loss, leading to osteoporosis and increased fracture risk. Hyperthyroidism induced by thyroid-stimulating hormone-suppressive therapy in patients with differentiated thyroid cancer is a cause of secondary osteoporosis. In contrast, there is a lack of evidence on the negative impact of hypothyroidism on bone health. Considering the clinical updates on the importance of bone health in thyroid dysfunction, the Task Force from the Clinical Practice Guidelines Development Committee of the Korean Thyroid Association recently developed a position statement on the evaluation and management of bone health of patients with thyroid diseases, particularly focused on endogenous hyperthyroidism and thyroid-stimulating hormone-suppressive therapy-associated hyperthyroidism in patients with differentiated thyroid cancer. Herein, we review the Korean Thyroid Association’s position statement on the evaluation and management of bone health associated with thyroid diseases.

갑상선암 환자에서 진행성 대장 선종 혹은 대장암 발생의 상관관계

김다민 ( Da Min Kim ),김정하 ( Jung Ha Kim ),박준영 ( Jun Young Park ),전병우 ( Byung Woo Jun ),송림화 ( Lim Hwa Song ),정현애 ( Hyun Ae Jung ),김영호 ( Young Ho Kim ) 대한장연구학회 2011 Intestinal Research Vol.9 No.3

Background/Aims: Colorectal cancer and thyroid cancer are common diseases with relatively higher survival rates compared with other cancers. The number of patients identified with colorectal cancer or thyroid cancer who develop multiple primary malignancy during long-term follow-up is increasing with advances in diagnostic techniques and treatment modalities. However, the association between colorectal cancer and thyroid cancer is uncertain, and few data have been reported in Korea. This study examined the association between thyroid cancer and colorectal neoplasm. Methods: We retrospectively investigated 363 patients who underwent a colonoscopy, among patients diagnosed with thyroid cancer between January 2004 and December 2008 at Samsung Medical Center. The control group was comprised of 2,494 patients who underwent screening colonoscopy for the first time within the study period at the center for health promotion at Samsung Medical Center between March 2004 and December 2005. Results: The detection rates in patients with thyroid cancer were 4.7% (17/363) for advanced adenomas and 2.8% (10/363) for colorectal cancer. In the control group, it was 3.2% (79/2,494) for advanced adenomas and 0.3% (7/2,494) for colorectal cancer. A multivariate analysis revealed that the presence of thyroid cancer had an odds ratio of 1.893 (95% confidence interval, 0.868-4.128, P=0.109) in favor of finding at least one advanced colorectal neoplasm. Conclusions: The results indicate that thyroid cancer is not associated with advanced colorectal neoplasm. Survivors of thyroid and colorectal cancer live longer and hence are at risk for second primary cancers. Therefore, further studies that prospectively evaluate the association between thyroid cancer and colorectal advanced neoplasm are needed. (Intest Res 2011;9:206-210)

갑상선 악성종양 및 양성종양에서 Fra - 1 표현에 대한 연구

김용현(Youg Hyun Kim),오정헌(Jeong Heon Oh),김난희(Nan Hee Kim),최경묵(Kyung Muk Choi),김상진(Sang Jin Kim),백세현(Sei Hyun Baik),최동섭(Dong Seop Choi),이응석(Eung Seok Lee) 대한내과학회 2000 대한내과학회지 Vol.59 No.4

Background : Differential diagnosis of thyroid nodule is important in deciding treatment modality and fine needle aspiration is a good method to do so. But, sometimes, it has limitation in use because of inadequate test material and difficulty in interpreting it. Among the study of oncogene and tumor suppresor gene on the origin of thyroid tumor, expression of Fra-1, one of AP-1 system, is increased in thyroid neoplasm. So there is a possibility that it would be used as a method for differential diagnosis of thyroid nodule. We tried to know whether presence or absence of Fra-1 expression can be used as a diagnostic method in differential diagnosis of thyroid nodule using immuno- histochemical(IHC) staining method.Methods : In 4 types of thyroid tumor that was confirmed by histologic diagnosis after operation(30 cases of papillary cancer, 10 cases of follicular cancer, 16 cases of follicular adenoma, 18 cases of adenomatous goiter), IHC staining method was performed to evaluate the expression of Fra-1.Results : In papillary and follicular thyroid cancer, the expression of Fra-1 was stronger than benign thyroid tumor, but there was no difference in Fra-1 expression between two types of carcinoma. Weak expression of Fra-1 was observed in all cases of follicular adenoma, and it was also weakly expressed in 6 out 18 cases of adenomatous goiter. Conclusion : The expression of Fra-1 was stronger in thyroid cancer than in benign thyroid adenoma, but it was impossible to differentiate thyroid cancer from benign thyroid adenoma by the presence or absence of Fra-1 expression using IHC staining method.(Korean J Med 59:398-403, 2000)

Update from the 2022 World Health Organization Classification of Thyroid Tumors: A Standardized Diagnostic Approach

정찬권,Andrey Bychkov,Kennichi Kakudo 대한내분비학회 2022 Endocrinology and metabolism Vol.37 No.5

The fifth edition of the World Health Organization (WHO) histologic classification of thyroid neoplasms released in 2022 includes newly recognized tumor types, subtypes, and a grading system. Follicular cell-derived neoplasms are categorized into three families (classes): benign tumors, low-risk neoplasms, and malignant neoplasms. The terms “follicular nodular disease” and “differentiated high-grade thyroid carcinoma” are introduced to account for multifocal hyperplastic/neoplastic lesions and differentiated thyroid carcinomas with high-grade features, respectively. The term “Hürthle cells” is replaced with “oncocytic cells.” Invasive encapsulated follicular and cribriform morular variants of papillary thyroid carcinoma (PTC) are now redefined as distinct tumor types, given their different genetic alterations and clinicopathologic characteristics from other PTC subtypes. The term “variant” to describe a subclass of tumor has been replaced with the term “subtype.” Instead, the term “variant” is reserved to describe genetic alterations. A histologic grading system based on the mitotic count, necrosis, and/or the Ki67 index is used to identify high-grade follicular-cell derived carcinomas and medullary thyroid carcinomas. The 2022 WHO classification introduces the following new categories: “salivary gland-type carcinomas of the thyroid” and “thyroid tumors of uncertain histogenesis.” This review summarizes the major changes in the 2022 WHO classification and their clinical relevance.

갑상선암의 분자표지자들에 관한 고찰

한재준,홍기숙 이화여자대학교 의과학연구소 2012 EMJ (Ewha medical journal) Vol.35 No.1

The incidence of thyroid cancer has been rapidly increased in Korea. Although fine needle aspiration cytology is recommended for diagnosis of cancer, there are some limitations. Patients with indeterminate or suspicious cytology category in which malignancy cannot be ruled out usually undergone a thyroidectomy, however, only 10∼25% of them finally diagnosed as cancer. According to the progress in understanding molecular mechanism, some mutations or other molecular alterations have been studied for the diagnostic and prognostic markers for thyroid cancer. The majority of papillary thyroid cancers have BRAF and RAS mutations or RET/PTC rearrangement, and approximately 80% of follicular thyroid cancers harbor a RAS mutation or PAX8/PPARg rearrangement. These genetic alterations are mostly studied and current clinical guidelines suggested that these molecular markers may help management for patients with indeterminate cytology. In addition, recent studies demonstrated the high sensitivity and specificity of thyroid-stimulating hormone receptor mRNA in diagnosing cancer in patients with indeterminate cytology. For the detection of recurrent or residual thyroid cancer, serum thyroglobulin is the only circulating marker in clinical practice. However, it lacks sensitivity and is unreliable specifically in the presence of antibodies to thyroglobulin. Recent studies demonstrated a significant role of measuring the mRNA of thyroglobulin, thyroid peroxidase, thyroid-stimulating hormone receptor, and sodium/iodine symporter in peripheral blood for monitoring of the recurrence of thyroid cancer.

Bone Mineral Density in Thyroid Cancer Patients: Data from the Korea National Health and Nutrition Examination Survey

Myung Chul Chang 대한갑상선-내분비외과학회 2017 The Koreran journal of Endocrine Surgery Vol.17 No.4

Purpose: There are conflicting results about bone mineral density (BMD) after thyroid-stimulating hormone (TSH) suppression in thyroid cancer treatment. This study used the Korea National Health and Nutrition Examination Survey (KNHANES) data to investigate BMD of thyroid cancer patients in Korea. Methods: The data were collected from 2008 to 2011 of the KNHANES IV-V. Among a total of 37,753 participants, 18,618 subjects were included. Osteopenia and osteoporosis were evaluated according the past history of thyroid cancer. Subgroups of women and post-menopausal women were analyzed using the same method. Results: Among the 18,618 subjects, 80 thyroid cancer cases were observed. There was no significant difference in osteopenia and osteoporosis with or without thyroid cancer history (P=0.783). In the subgroup analyses of women, no difference was observed in BMD according thyroid cancer history (P=0.685). In the post-menopausal women, osteopenia and osteoporosis were less frequent in thyroid cancer cases in univariate analysis (P=0.003), but that was not significant in multivariate analysis (P=0.095). Conclusion: Although the KNHANES had a small number of thyroid cancer cases, no data about TSH suppression, and short follow-up periods, no significant difference in BMD with or without thyroid cancer was observed. The subgroup analyses of women and post-menopausal women showed similar results.

Updates in the Pathologic Classification of Thyroid Neoplasms: A Review of the World Health Organization Classification

Yanhua Bai,Kennichi Kakudo,정찬권 대한내분비학회 2020 Endocrinology and metabolism Vol.35 No.4

Advances in medical sciences and evidence-based medicine have led to momentous changes in classification and management of thyroid neoplasms. Much progress has been made toward avoiding overdiagnosis and overtreatment of thyroid cancers. The new 2017 World Health Organization (WHO) classification of thyroid neoplasms updated the diagnostic criteria and molecular and genetic characteristics reflecting the biology and behavior of the tumors, and newly introduced the category of borderline malignancy or uncertain malignant potential. Some neoplasms were subclassified, renamed, or redefined as a specific entity. This review introduces changes in the fourth edition WHO classification of thyroid tumors and updates the contemporary diagnosis and classification of thyroid tumors. We also discuss several challenges with the proposal of new diagnostic entities, since they have unique histopathologic and molecular features and clinical relevance.

여포성 종양의 진단과 치료에 있어서의 문제점들

김원배 대한갑상선학회 2012 International Journal of Thyroidology Vol.5 No.2

Thyroid follicular adenoma and hyperplastic adenomatoid nodule may show overlapping cytologic pattern with thyroid follicular carcinoma and follicular variant of thyroid papillary carcinoma. Fine-needle aspiration cytology (FNAC) has limited role in differential diagnosis of those lesions showing high cellularity and absence of colloid. Those lesions are conventionally termed ‘follicular neoplasm’. As diagnostic hallmarks of follicular carcinoma (vascular- and capsular invasion) cannot be detected by cytology, verification by histology after surgery is mandatory. However, only 20% of patients with thyroid nodules diagnosed cytologically as ‘follicular neoplasm’are finally diagnosed as carcinoma after surgery. Therefore, there have been many trials to differentiate follicular adenoma (FA) from follicular carcinoma (FTC) in preoperative setting. Among those trials are 1) cell morphometry analysis by computer graphics, analysis of telomerase expression level, quantitation of specific protein markers, or intensive cytological analysis using FNAC specimens, 2) ultrasonographic evaluation,dynamic MRI, or MR spectroscopy for thyroid nodules and 3) gene expression profile analysis for thyroid nodules by microarray technique, all showing limited success or limitations hampering clinical application. Similarly,intra-operative frozen section analysis of thyroid nodule had been known to be of no diagnostic utility in a prospective, randomized trial. Current management strategy for ‘follicular neoplasm’ is initial surgery for diagnostic purpose to get pathologic diagnosis. If the nodule is diagnosed finally as FTC, completion thyroidectomy with or without radioactive iodine therapy is recommended in most cases. Minimally invasive FTC (without vascular invasion) is known to have excellent prognosis in most cases, so traditionally those patients had undergone unilateral operation without completion thyroidectomy. But, there had been reported cases showing distant metastasis and/or recurrence in patients with ‘minimally invasive FTC’. One of problems in diagnosis of ‘minimally invasive FTC’ is lack of international standardization for pathologic diagnosis. Optimal surgical extent for cases with FTC is not known yet. It might have been due to lack of risk stratification of patients which is unique to FTC (not well differentiated thyroid cancer as a whole), lack of biomarker predicting prognosis of FTC, and lack of controlled trial for management of patients with FTC. In near future, application of molecular diagnostic markers is expected to improve our management strategy for thyroid nodules diagnosed as ‘follicular neoplasm’, if molecular pathogenesis of FA and of FTC are comprehensively understood.

Postoperative Thyroid-Stimulating Hormone Levels Did Not Affect Recurrence after Thyroid Lobectomy in Patients with Papillary Thyroid Cancer

이명철,김민주,최훈성,조선욱,이국행,박영주,박도준 대한내분비학회 2019 Endocrinology and metabolism Vol.34 No.2

Background: Thyroid-stimulating hormone (TSH) suppression is recommended for patients who undergo thyroidectomy for differentiated thyroid cancer (DTC). However, the impact of TSH suppression on clinical outcomes in low-risk DTC remains uncertain. Therefore, we investigated the effects of postoperative TSH levels on recurrence in patients with low-risk DTC after thyroid lobectomy. Methods: Patients (n=1,528) who underwent thyroid lobectomy for papillary thyroid carcinoma between 2000 and 2012 were included in this study. According to the mean and dominant TSH values during the entire follow-up period or 5 years, patients were divided into four groups (<0.5, 0.5 to 1.9, 2.0 to 4.4, and ≥4.5 mIU/L). Recurrence-free survival was compared among the groups. Results: During the 5.6 years of follow-up, 21 patients (1.4%) experienced recurrence. Mean TSH levels were within the recommended low-normal range (0.5 to 1.9 mIU/L) during the total follow-up period or 5 years in 38.1% or 36.0% of patients. The meanand dominant TSH values did not affect recurrence-free survival. Adjustment for other risk factors did not alter the results. Conclusion: Serum TSH levels did not affect short-term recurrence in patients with low-risk DTC after thyroid lobectomy. TSHsuppression should be conducted more selectively