Background: Radioiodine (RI) ablation following thyroid-stimulating hormone suppression is an effective treatment for papillary thyroid cancer (PTC), typically leading to favorable outcomes. However, RI-refractory tumors exhibit aggressive behavior and poor prognoses. Recent studies highlight the role of genetic abnormalities in PTC signaling pathways, including the activation of telomerase reverse transcriptase (TERT), and the correlation of mutations with adverse outcomes. Methods: This study analyzed mutations in BRAF V600E and the TERT-promoter genes, comparing clinicopathological features between RI-refractory and RI-responsive PTCs. Among 82 RI-refractory patients, formalin-fixed, paraffin-embedded tissues from initial surgeries were available for 26. Another 89 without distant metastasis over 5 years formed a matched RI-responsive control group. Results: Histopathologically, RI-refractory PTCs showed increased frequencies of small tumor clusters without fibrovascular cores, hobnail features, and a high height-to-width ratio of tumor cells. These tumors were more likely to exhibit necrosis, mitosis, lymph node metastasis, extrathyroidal extension, and involvement of resection margins. TERT-promoter mutations were statistically significantly associated with these aggressive clinicopathologic features. Immunohistochemically, decreased expression of sodium iodide symporter and thyroglobulin stimulating hormone receptor proteins was common in RI-refractory PTCs, along with lower levels of oncogenic proteins such as vascular endothelial cell growth factor, vascular endothelial cell growth factor receptor 2, and nuclear factor kappa-light-chain-enhancer of activated B cells. Total loss of PTEN expression was occasionally observed. In contrast, all cases tested positive for cytoplasmic β-catenin. Conclusions RI-refractory PTCs are linked to TERT mutations and exhibit specific aggressive histopathologic features, particularly in tumor centers.

Background: Radioiodine (RI) ablation following thyroid-stimulating hormone suppression is an effective treatment for papillary thyroid cancer (PTC), typically leading to favorable outcomes. However, RI-refractory tumors exhibit aggressive behavior and poor prognoses. Recent studies highlight the role of genetic abnormalities in PTC signaling pathways, including the activation of telomerase reverse transcriptase (TERT), and the correlation of mutations with adverse outcomes. Methods: This study analyzed mutations in BRAF V600E and the TERT-promoter genes, comparing clinicopathological features between RI-refractory and RI-responsive PTCs. Among 82 RI-refractory patients, formalin-fixed, paraffin-embedded tissues from initial surgeries were available for 26. Another 89 without distant metastasis over 5 years formed a matched RI-responsive control group. Results: Histopathologically, RI-refractory PTCs showed increased frequencies of small tumor clusters without fibrovascular cores, hobnail features, and a high height-to-width ratio of tumor cells. These tumors were more likely to exhibit necrosis, mitosis, lymph node metastasis, extrathyroidal extension, and involvement of resection margins. TERT-promoter mutations were statistically significantly associated with these aggressive clinicopathologic features. Immunohistochemically, decreased expression of sodium iodide symporter and thyroglobulin stimulating hormone receptor proteins was common in RI-refractory PTCs, along with lower levels of oncogenic proteins such as vascular endothelial cell growth factor, vascular endothelial cell growth factor receptor 2, and nuclear factor kappa-light-chain-enhancer of activated B cells. Total loss of PTEN expression was occasionally observed. In contrast, all cases tested positive for cytoplasmic β-catenin. Conclusions RI-refractory PTCs are linked to TERT mutations and exhibit specific aggressive histopathologic features, particularly in tumor centers.

Background: Radioiodine (RI) ablation following thyroid-stimulating hormone suppression is an effective treatment for papillary thyroid cancer (PTC), typically leading to favorable outcomes. However, RI-refractory tumors exhibit aggressive behavior and poor prognoses. Recent studies highlight the role of genetic abnormalities in PTC signaling pathways, including the activation of telomerase reverse transcriptase (TERT), and the correlation of mutations with adverse outcomes. Methods: This study analyzed mutations in BRAF V600E and the TERT-promoter genes, comparing clinicopathological features between RI-refractory and RI-responsive PTCs. Among 82 RI-refractory patients, formalin-fixed, paraffin-embedded tissues from initial surgeries were available for 26. Another 89 without distant metastasis over 5 years formed a matched RI-responsive control group. Results: Histopathologically, RI-refractory PTCs showed increased frequencies of small tumor clusters without fibrovascular cores, hobnail features, and a high height-to-width ratio of tumor cells. These tumors were more likely to exhibit necrosis, mitosis, lymph node metastasis, extrathyroidal extension, and involvement of resection margins. TERT-promoter mutations were statistically significantly associated with these aggressive clinicopathologic features. Immunohistochemically, decreased expression of sodium iodide symporter and thyroglobulin stimulating hormone receptor proteins was common in RI-refractory PTCs, along with lower levels of oncogenic proteins such as vascular endothelial cell growth factor, vascular endothelial cell growth factor receptor 2, and nuclear factor kappa-light-chain-enhancer of activated B cells. Total loss of PTEN expression was occasionally observed. In contrast, all cases tested positive for cytoplasmic β-catenin. Conclusions RI-refractory PTCs are linked to TERT mutations and exhibit specific aggressive histopathologic features, particularly in tumor centers.

Background/Aims: Hypertension (HT) has a significant impact on public health and medical expenses. However, HT is a chronic disease that requires the long-term follow-up of a large number of patients. Methods: The Korean Hypertension Cohort (KHC) study aimed to develop a model for calculating cardiovascular risk in HT patients by linking and utilizing the detailed clinical and longitudinal data from hospitals and the national health insurance claim database, respectively. This cohort had a planned sample size of over 11,000 HT patients and 100,000 non-HT controls. Eligible patients were hypertensive patients, who were presenting for the first time and were diagnosed with HT as a main disease from 2006 to 2011. Long-term survival data over a period of approximately 9 years were obtained from the national health insurance claim and national health examination data. Results: This cohort enrolled 11,083 patients with HT. The mean age was 58.87 ± 11.5 years, 50.5% were male, and 31.4% were never-treated HT. Of the enrolled patients, 32.9% and 37.7% belonged to the high and moderate cardiovascular risk groups, respectively. Initial blood pressures were 149.4 ± 18.5/88.5 ± 12.5 mmHg. During the 2 years hospital data follow-up period, blood pressures lowered to 130.8 ± 14.1/78.0 ± 9.7 mmHg with 1.9 ± 1.0 tablet doses of antihypertensive medication. Cardiovascular events occurred in 7.5% of the overall patients; 8.5%, 8.8%, and 4.7% in the high, moderate, and low risk patients, respectively. Conclusions The KHC study has provided important information on the long-term outcomes of HT patients according to the blood pressure, comorbid diseases, medication, and adherence, as well as health behaviors and health resource use.

Background/Aims: Hypertension (HT) has a significant impact on public health and medical expenses. However, HT is a chronic disease that requires the long-term follow-up of a large number of patients. Methods: The Korean Hypertension Cohort (KHC) study aimed to develop a model for calculating cardiovascular risk in HT patients by linking and utilizing the detailed clinical and longitudinal data from hospitals and the national health insurance claim database, respectively. This cohort had a planned sample size of over 11,000 HT patients and 100,000 non-HT controls. Eligible patients were hypertensive patients, who were presenting for the first time and were diagnosed with HT as a main disease from 2006 to 2011. Long-term survival data over a period of approximately 9 years were obtained from the national health insurance claim and national health examination data. Results: This cohort enrolled 11,083 patients with HT. The mean age was 58.87 ± 11.5 years, 50.5% were male, and 31.4% were never-treated HT. Of the enrolled patients, 32.9% and 37.7% belonged to the high and moderate cardiovascular risk groups, respectively. Initial blood pressures were 149.4 ± 18.5/88.5 ± 12.5 mmHg. During the 2 years hospital data follow-up period, blood pressures lowered to 130.8 ± 14.1/78.0 ± 9.7 mmHg with 1.9 ± 1.0 tablet doses of antihypertensive medication. Cardiovascular events occurred in 7.5% of the overall patients; 8.5%, 8.8%, and 4.7% in the high, moderate, and low risk patients, respectively. Conclusions The KHC study has provided important information on the long-term outcomes of HT patients according to the blood pressure, comorbid diseases, medication, and adherence, as well as health behaviors and health resource use.

BACKGROUND: In the present multi-institutional study, the prevalence and clinicopathologic characteristics of non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) were evaluated among Korean patients who underwent thyroidectomy for papillary thyroid carcinoma (PTC).METHODS: Data from 18,819 patients with PTC from eight university hospitals between January 2012 and February 2018 were retrospectively evaluated. Pathology reports of all PTCs and slides of potential NIFTP cases were reviewed. The strict criterion of no papillae was applied for the diagnosis of NIFTP. Due to assumptions regarding misclassification of NIFTP as non-PTC tumors, the lower boundary of NIFTP prevalence among PTCs was estimated. Mutational analysis for BRAF and three RAS isoforms was performed in 27 randomly selected NIFTP cases.RESULTS: The prevalence of NIFTP was 1.3% (238/18,819) of all PTCs when the same histologic criteria were applied for NIFTP regardless of the tumor size but decreased to 0.8% (152/18,819) when tumors ≥1 cm in size were included. The mean follow-up was 37.7 months and no patient with NIFTP had evidence of lymph node metastasis, distant metastasis, or disease recurrence during the follow-up period. A difference in prevalence of NIFTP before and after NIFTP introduction was not observed. BRAF(V600E) mutation was not found in NIFTP. The mutation rate for the three RAS genes was 55.6% (15/27).CONCLUSIONS: The low prevalence and indolent clinical outcome of NIFTP in Korea was confirmed using the largest number of cases to date. The introduction of NIFTP may have a small overall impact in Korean practice.
Carcinoma, Papillary ; Diagnosis ; Follow-Up Studies ; Genes, ras ; Hospitals, University ; Humans ; Korea ; Lymph Nodes ; Mutation Rate ; Neoplasm Metastasis ; Pathology ; Prevalence ; Protein Isoforms ; Recurrence ; Retrospective Studies ; Thyroid Gland ; Thyroid Neoplasms ; Thyroidectomy

BACKGROUND: Warthin-like variant of papillary thyroid carcinoma (WLV-PTC) is a relatively rare variant of papillary thyroid carcinoma with favorable prognosis. However, preoperative diagnosis using fine-needle aspiration (FNA) specimens is challenging especially with lymphocytic thyroiditis characterized by Hürthle cells and lymphocytic background. To determine a helpful cytological differential point, we compared WLV-PTC FNA findings with conventional papillary thyroid carcinoma with lymphocytic thyroiditis (PTC-LT) and conventional papillary thyroid carcinoma without lymphocytic thyroiditis (PTC) regarding infiltrating inflammatory cells and their distribution. Preoperative diagnosis or potential for WLV-PTC will be helpful for surgeons to decide the scope of operation. METHODS: Of the 8,179 patients treated for papillary thyroid carcinoma between January 2007 and December 2012, 16 patients (0.2%) were pathologically confirmed as WLV-PTC and four cases were available for cytologic review. For comparison, we randomly selected six PTC-LT cases and five PTC cases during the same period. The number of intratumoral and background lymphocytes, histiocytes, neutrophils, and the presence of giant cells were evaluated and compared using conventional smear and ThinPrep preparations. RESULTS: WLV-PTC showed extensive lymphocytic smear with incorporation of thyroid follicular tumor cell clusters and frequent histiocytes. WLV-PTC was associated with higher intratumoral and background lymphocytes and histiocytes compared with PTC-LT or PTC. The difference was more distinct in liquid-based cytology. CONCLUSIONS: The lymphocytic smear pattern and the number of inflammatory cells of WLV-PTC are different from those of PTC-LT or PTC and will be helpful for the differential diagnosis of WLV-PTC in preoperative FNA.
Biopsy, Fine-Needle ; Diagnosis ; Diagnosis, Differential ; Giant Cells ; Hashimoto Disease ; Histiocytes ; Humans ; Lymphocytes ; Neutrophils ; Prognosis ; Surgeons ; Thyroid Gland ; Thyroid Neoplasms ; Thyroiditis, Autoimmune

BACKGROUND: Fine-needle aspiration cytology serves as a safe, economical tool in evaluating thyroid nodules. However, about 30% of the samples are categorized as indeterminate. Hence, many immunocytochemistry markers have been studied, but there has not been a single outstanding marker. We studied the efficacy of CD56 with human bone marrow endothelial cell marker-1 (HBME-1) in diagnosis in the Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) category III. METHODS: We reviewed ThinPrep liquid-based cytology (LBC) samples with Papanicolaou stain from July 1 to December 31, 2016 (2,195 cases) and selected TBSRTC category III cases (n = 363). Twenty-six cases were histologically confirmed as benign (six cases, 23%) or malignant (20 cases, 77%); we stained 26 LBC slides with HBME-1 and CD56 through the cell transfer method. For evaluation of reactivity of immunocytochemistry, we chose atypical follicular cell clusters. RESULTS: CD56 was not reactive in 18 of 20 cases (90%) of malignant nodules and showed cytoplasmic positivity in five of six cases (83%) of benign nodules. CD56 showed high sensitivity (90.0%) and relatively low specificity (83.3%) in detecting malignancy (p = .004). HBME-1 was reactive in 17 of 20 cases (85%) of malignant nodules and was not reactive in five of six cases (83%) of benign nodules. HBME-1 showed slightly lower sensitivity (85.0%) than CD56. The specificity in detecting malignancy by HBME-1 was similar to that of CD56 (83.3%, p = .008). CD56 and HBME-1 tests combined showed lower sensitivity (75.0% vs 90%) and higher specificity (93.8% vs 83.3%) in detecting malignancy compared to using CD56 alone. CONCLUSIONS: Using CD56 alone showed relatively low specificity despite high sensitivity for detecting malignancy. Combining CD56 with HBME-1 could increase the specificity. Thus, we suggest that CD56 could be a useful preoperative marker for differential diagnosis of TBSRTC category III samples.
Biopsy, Fine-Needle ; Bone Marrow ; Cytoplasm ; Diagnosis ; Diagnosis, Differential ; Endothelial Cells ; Humans ; Immunohistochemistry ; Methods ; Sensitivity and Specificity ; Thyroid Gland ; Thyroid Nodule

We reviewed the current status of thyroid fine-needle aspiration cytology (FNAC) in Korea. Thyroid aspiration biopsy was first introduced in Korea in 1977. Currently, radiologists aspirate the thyroid nodule under the guidance of ultrasonography, and cytologic interpretation is only legally approved when a cytopathologist makes the diagnosis. In 2008, eight thyroid-related societies came together to form the Korean Thyroid Association. The Korean Society for Cytopathology and the endocrine pathology study group of the Korean Society for Pathologists have been updating the cytologic diagnostic guidelines. The Bethesda System for Reporting Thyroid Cytopathology was first introduced in 2009, and has been used by up to 94% of institutions by 2016. The average diagnosis rates are as follows for each category: I (12.4%), II (57.9%), III (10.4%), IV (2.9%), V (3.7%), and VI (12.7%). The malignancy rates in surgical cases are as follows for each category: I (28.7%), II (27.8%), III (50.6%), IV (52.3%), V (90.7%), and VI (100.0%). Liquid-based cytology has been used since 2010, and it was utilized by 68% of institutions in 2016. The categorization of thyroid lesions into “atypia of undetermined significance” or “follicular lesion of undetermined significance” is necessary to draw consensus in our society. Immunocytochemistry for galectin-3 and BRAF is used. Additionally, a molecular test for BRAF in thyroid FNACs is actively used. Core biopsies were performed in only 44% of institutions. Even the institutions that perform core biopsies only perform them for less than 3% of all FNACs. However, only 5% of institutions performed core biopsies up to three times more than FNAC.
Biopsy ; Biopsy, Fine-Needle* ; Biopsy, Needle ; Consensus ; Diagnosis ; Galectin 3 ; Immunohistochemistry ; Korea* ; Pathology ; Thyroid Gland* ; Thyroid Neoplasms ; Thyroid Nodule ; Ultrasonography

We describe herein histologic, immunohistochemical, and molecular findings and clinical manifestations of a rare case of an extremely well differentiated papillary thyroid carcinoma (EWD-PTC). Similarly, it is also difficult to diagnose follicular variant papillary thyroid carcinoma (FVPTC), whose diagnosis is still met with controversy. A recently reported entity of well-differentiated tumor of uncertain malignant potential (WDT-UMP) is added to the diagnostic spectrum harboring EWD-PTC and FVPTC. We report this case, because EWD-PTC is different from FVPTC in its papillary architecture, and also from WDT-UMP in its recurrence and metastatic pattern. These morphologically deceptive entities harbored diagnostic difficulties in the past because the diagnosis depended solely on histology. However, they are now diagnosed with more certainty by virtue of immunohistochemical and molecular studies. We experienced a case of EWD-PTC, which had been diagnosed as adenomatous hyperplasia 20 years ago and manifested recurrence with lymph node (LN) metastasis 7 years later. After another 7 years of follow-up, a new thyroid lesion had developed, diagnosed as FVPTC, with LN metastasis of EWD-PTC. One year later, the patient developed metastatic FVPTC in the skull. Immunohistochemically, the EWD-PTC was focally positive for CK19, negative for galectin-3, and focally negative for CD56. Molecular studies revealed BRAF-positivity and K-RAS negativity. The FVPTC in the left thyroid showed both BRAF and K-RAS negativity. In conclusion, EWD-PTC and FVPTC share similar histologic features, but they are different tumors with different molecular biologic and clinical manifestations. A large cohort of EWD-PTC should be included in further study.
Adenocarcinoma, Follicular/pathology/secondary ; Adult ; Carcinoma, Papillary, Follicular/pathology/*secondary ; Female ; Galectin 3/analysis ; Humans ; Hyperplasia/pathology ; Lymphatic Metastasis ; Male ; Middle Aged ; Neoplasm Recurrence, Local/pathology ; Skull Neoplasms/*secondary ; Thyroid Neoplasms/*pathology