Suk Kyeong Kim

Surgical Results of Thyroid Nodules according to a Management Guideline Based on the BRAFV600E Mutation Status

CONTEXT In Korea, where PTC comprises about 90-95% of the reported thyroid cancers, the prevalence of BRAF(V600E) mutation in papillary thyroid carcinoma (PTC) is above 80%. OBJECTIVE We analyzed the surgical result according to a management guideline based on the BRAF(V600E) mutation status of thyroid nodules. DESIGN A total of 865 thyroid nodules were prospectively analyzed for their cytology and BRAF(V600E) mutation status by pyrosequencing. For the patients who had a diagnosis of atypical cells of undetermined significance (ACUS), we recommended surgery when there was positivity for BRAF(V600E) mutation or the nodules were clinically suspicious. RESULTS Among 865 cases, 504, 141, 54, 140, 10, and 16 were diagnosed as benign, ACUS, suspicious for malignancy, malignant, suspicious for follicular neoplasm, and nondiagnostic, respectively. None of the 504 benign, 45 (31.9%) of the 141 ACUS, 46 (85.2%) of the 54 suspicious for malignancy, 129 (92.1%) of the 140 malignant, and one (10%) of the 10 suspicious for follicular neoplasm cases showed BRAF(V600E) mutation. Surgery was recommended to all 45 patients with BRAF(V600E) mutation-positive ACUS nodules; among them, 30 patients underwent surgery, 29 had PTC, and one had nodular hyperplasia. All the patients diagnosed as suspicious for malignancy or malignant were advised to undergo an operation, and they turned out to have PTCs regardless of their BRAF(V600E) mutation status. CONCLUSIONS We found that performing BRAF(V600E) mutation analysis on the fine-needle aspiration biopsy specimens was of great help to make a therapeutic decision for thyroid nodules when the fine-needle aspiration biopsy results were equivocal.

Clinical and Pathological Features and the BRAFV600E Mutation in Patients with Papillary Thyroid Carcinoma with and without Concurrent Hashimoto Thyroiditis

BACKGROUND It has been reported that patients with papillary thyroid carcinoma (PTC) have a high incidence of background Hashimoto thyroiditis (HT); however, the linkage of HT to PTC is controversial. Recent studies have shown that the prevalence of activating point mutations in BRAFV600E is much higher (73-86%) in Korea than in Western countries (29-69%), and associated with a poor prognosis in PTC. The purpose of the present study was to investigate the frequency of the BRAFV600E mutation in PTC with and without HT, and to determine clinical and pathological features that were associated with concomitant HT and PTC. METHODS Fine-needle aspiration slides from 101 patients with surgically confirmed PTC were studied. The DNA was extracted from the atypical cells that were scraped from slides. It was then analyzed for the BRAFV600E mutation by pyrosequencing. In addition, the presence of background HT in surgical specimens and other clinical and pathological features of the patients were characterized. RESULTS HT was present in 37 (36.6%) of the patients. The BRAFV600E mutation was present in 27 (72.9%) of patients with HT but was present in 61 (95.3%) of patients without HT ( p#0.01). The inverse correlation of concurrent HT with the BRAFV600E mutation was significant for both males and females ( p < 0.01). The presence of background HT was not associated with tumor size, extrathyroidal invasion, lymph node (LN) metastasis, or tumor stage. The patients were younger in the group without background HT (44.1 +/- 13.2 vs. 49.8 +/- 13.9, p 1/40.05). The BRAFV600E mutation was present in 88 (87.1%) of the 101 patients with PTC. The presence of the BRAFV600E mutation was significantly associated with LN metastasis ( p < 0.02; odds ratio, 6.24; 95% confidence interval, 1.51-25.79). CONCLUSION In Korean patients with PTC, the BRAFV600E mutation is associated with a lower frequency of background HT and a high frequency of LN metastasis.

BRAF Mutation Analysis and Sonography as Adjuncts to Fine-Needle Aspiration Cytology of Papillary Thyroid Carcinoma: Their Relationships and Roles

OBJECTIVE The objective of our study was to evaluate the relationships between BRAF mutation status, sonography findings, and fine-needle aspiration cytology features in patients with papillary thyroid carcinoma (PTC) and to evaluate the diagnostic merits of BRAF mutation status and sonography findings as adjuncts to cytologic diagnoses. MATERIALS AND METHODS From March 2006 through June 2008, clinicopathologic factors, sonography findings, cytology results, and BRAF mutation status were evaluated in 524 patients (437 women and 87 men) with 553 thyroid nodules; of the 170 malignant nodules, 164 were PTCs. Clinicopathologic factors, sonography findings, and cytology results were correlated with BRAF status. The diagnostic sensitivities and specificities of sonography, cytology, and BRAF analysis and their combinations were compared. RESULTS The V600E mutation of BRAF (BRAF(V600E)) was detected in 141 of 170 malignant thyroid nodules (82.9%) (140 PTCs and one follicular variant of PTC). Multiple logistic regression revealed that BRAF status was not associated with sonography features with the exception of a negative relation between BRAF(V600E) and an irregular shape (p = 0.004). An indeterminate cytology result was more frequent for BRAF-negative PTC than BRAF-positive PTC (p = 0.035). By adding BRAF status to cytology, diagnostic sensitivity for PTC was significantly increased (94.1%) as compared with cytology alone (81.8%) (p < 0.001). The triple combination-that is, sonography, cytology, and BRAF analysis-showed higher sensitivity than BRAF plus cytology (98.2% vs 94.1%, respectively) (p < 0.05). CONCLUSION The sonography features of PTC, other than an irregular shape, are not related to BRAF status and the combination of sonography and BRAF testing would increase the diagnostic accuracy of cytologic diagnoses of PTC.

Prognostic Significance of TERT Promoter Mutations in Papillary Thyroid Carcinomas in a BRAF(V600E) Mutation-Prevalent Population.

BACKGROUND The role of telomerase reverse transcriptase (TERT) promoter mutations in differentiated thyroid cancer has been well established. These mutations have a significantly higher prevalence in aggressive thyroid tumors, including widely invasive oncocytic carcinomas, poorly differentiated carcinomas, and anaplastic thyroid carcinomas. Interestingly, in some studies, TERT mutations were found to be more common in tumors with a BRAF(V600E) mutation. However, mutational analysis of TERT promoter mutations in thyroid tumors has not been previously performed for patients in Korea, where the BRAF(V600E) mutation in papillary thyroid carcinoma (PTC) is particularly prevalent. This study analyzed TERT promoter mutations in various thyroid tumors and examined their relationship with clinicopathologic factors and the BRAF(V600E) mutation in PTC cases. METHODS Using 242 preoperative fine-needle aspiration biopsy specimens (including 207 PTCs) with confirmed histopathological diagnosis of the biopsied thyroid nodules, the TERT promoter status (C228T and C250T) was analyzed, and the relationship with clinicopathologic factors and the BRAF(V600E) mutation in PTC cases was examined. RESULTS Of 242 patients, 14.5% (30/207), 26.7% (4/15), 50% (1/2), and 60% (2/5) of PTCs, follicular thyroid carcinomas, poorly differentiated carcinomas, and anaplastic thyroid carcinomas harbored a TERT(C228T) mutation, respectively. The TERT(C228T) mutation was associated with recurrence (p = 0.03). However, no association with other clinicopathologic factors in PTC was found. Coexistence of TERT(C228T) and BRAF(V600E) mutations was found in 13.0% of PTCs and was significantly associated with older age and advanced stage compared with the group negative for either mutation. The TERT(C228T) mutation status was an independent prognostic factor for recurrence-free survival (hazard ratio = 3.08 [confidence interval 1.042-9.079]; p = 0.042) in patients with PTC in multivariate analysis. CONCLUSIONS Identification of TERT promoter mutations in preoperative fine-needle aspiration biopsy specimens may help in better characterizing the prognosis and triaging thyroid cancer patients for appropriate treatment.

RAS mutations in indeterminate thyroid nodules are predictive of the follicular variant of papillary thyroid carcinoma.

RAS mutations are the most common mutations in thyroid nodules with indeterminate cytology by fine‐needle aspiration cytology (FNAC), and are mutually exclusive with BRAF mutations. However, the diagnostic utility of RAS mutation analysis is uncertain. We evaluated the diagnostic utility of RAS mutation analysis in indeterminate thyroid nodules.

Preoperative RAS Mutational Analysis Is of Great Value in Predicting Follicular Variant of Papillary Thyroid Carcinoma

Follicular variant of papillary thyroid carcinoma (FVPTC), particularly the encapsulated subtype, often causes a diagnostic dilemma. We reconfirmed the molecular profiles in a large number of FVPTCs and investigated the efficacy of the preoperative mutational analysis in indeterminate thyroid nodules. BRAF V600E/K601E and RAS mutational analysis was performed on 187 FVPTCs. Of these, 132 (70.6%) had a point mutation in one of the BRAF V600E (n = 57), BRAF K601E (n = 11), or RAS (n = 64) genes. All mutations were mutually exclusive. The most common RAS mutations were at NRAS codon 61. FNA aspirates from 564 indeterminate nodules were prospectively tested for BRAF and RAS mutation and the surgical outcome was correlated with the mutational status. Fifty-seven and 47 cases were positive for BRAF and RAS mutation, respectively. Twenty-seven RAS-positive patients underwent surgery and all except one patient had FVPTC. The PPV and accuracy of RAS mutational analysis for predicting FVPTC were 96% and 84%, respectively. BRAF or RAS mutations were present in more than two-thirds of FVPTCs and these were mutually exclusive. BRAF mutational analysis followed by N, H, and KRAS codon 61 mutational analysis in indeterminate thyroid nodules would streamline the management of patients with malignancies, mostly FVPTC.

Is an Oral Glucose Tolerance Test Still Valid for Diagnosing Diabetes Mellitus

Background We evaluated the diagnostic rate of diabetes using fasting plasma glucose (FPG), 2-hour plasma glucose (2h PG) after 75 g oral glucose tolerance test (OGTT), and glycosylated hemoglobin (HbA1c) levels, and we elucidated the pathophysiologic characteristics and risk factors that give rise to diabetes in patients with prediabetes. Methods The data of 236 patients who had the OGTT at Konkuk University Hospital were analyzed. Fasting, 30, and 120 minutes blood glucose levels and insulin levels were measured. The diagnostic rate of diabetes was assessed using FPG, 2h PG, and HbA1c levels. The clinical data and insulin resistance and secretion evaluations were compared using indexes according to the fasting glucose level. Results Among 236 subjects, 97 (41.1%) were diabetics and 102 (43.2%) were prediabetics. The rate of diabetes diagnosis by one of the individual criteria was 56.7%, 53.6%, and 84.5% for FPG, HbA1c, and 2h PG, respectively. When two criteria were used to diagnose diabetes, 72.2% of the diabetic patients were identified by FPG and HbA1c, while 100% were identified by FPG and 2h PG, and 91.7% were identified by 2h PG and HbA1c. The HbA1c cut-off value for 2h PG ≥200 mg/dL was 6.1%, and the FPG cut-off value was 115 mg/dL. In impaired fasting glucose subjects, the HbA1c level, Matsuda index, and insulinogenic index were associated with risk of occurrence of overt diabetes (P<0.01). Conclusion This study suggests that performing additional OGTT for patients with FPG ≥110 mg/dL or HbA1c ≥6.1% is helpful to reclassify their glucose tolerance status and evaluate their potential for progressing to overt diabetes.

The Association between Midnight Salivary Cortisol and Metabolic Syndrome in Korean Adults

Background The common characteristics of metabolic syndrome (MetS) and Cushings syndrome suggest that excess cortisol may be involved in the pathogenesis of MetS. Salivary cortisol measurements are simple and can be surrogates for plasma free cortisol, which is the most biologically active form. We evaluated the association between levels of midnight salivary cortisol and MetS in Korean adults. Methods A total of 46 subjects, aged 20 to 70 years, who visited the Health Care Center at Konkuk University Hospital from August 2008 to August 2009 were enrolled. We compared the levels of midnight salivary cortisol in subjects with MetS with those in subjects without MetS. We analyzed the associations between midnight salivary cortisol levels and components of MetS. Results Midnight salivary cortisol levels were higher in the MetS group (70±42.4 ng/dL, n=12) than that in the group without MetS (48.1±36.8 ng/dL, n=34) (P=0.001). Positive correlations were observed between midnight salivary cortisol levels and waist circumference, fasting blood glucose, and homeostasis model assessment of insulin resistance. The risk for MetS was significantly higher in subjects with midnight salivary cortisol levels ≥100 ng/dL than in those with levels <50 ng/dL (odds ratio, 5.9; 95% confidence interval, 2.35 to 36.4). Conclusion The results showed a positive correlation between midnight salivary cortisol levels and MetS, suggesting that hypercortisolism may be related to MetS.

Effects of thyroid hormone withdrawal on metabolic and cardiovascular parameters during radioactive iodine therapy in differentiated thyroid cancer

Objective To investigate the cardiometabolic effects of a severe hypothyroid state induced by withdrawal of thyroid hormone replacement before radioactive iodine therapy. Methods Patients with thyroid cancer who were scheduled to receive radioactive iodine ablation were enrolled. Cardiometabolic parameters were measured using blood samples taken immediately before levothyroxine withdrawal, 4 weeks following withdrawal (on radiotherapy day), and 4 weeks following reinstitution of levothyroxine. Results Out of 48 patients (age 49.4 ± 10.5 years; 77.1% [37/48] female), the severe hypothyroid state induced by levothyroxine withdrawal significantly aggravated the majority of lipid parameters, particularly in patients with a greater number of metabolic syndrome components. Fasting plasma glucose levels and homeostatic model assessment values for insulin resistance and β-cell function significantly decreased following levothyroxine withdrawal. Serum high-sensitivity C-reactive protein, fibrinogen and cystatin C levels significantly decreased, and homocysteine levels increased during the severe hypothyroid state. All of these changes were reversed by levothyroxine reinstitution. Conclusions Severe hypothyroid state induced pronounced changes in cardiometabolic parameters. Further studies should identify the long-term effects of changes in these parameters on cardiovascular morbidity and mortality in relation to thyroid disease.

Analysis of predictability of F‐18 fluorodeoxyglucose‐PET/CT in the recurrence of papillary thyroid carcinoma

Whether preoperative F‐18 fluorodeoxyglucose (FDG)‐positron emission tomography/computed tomography (PET/CT) can predict recurrence of papillary thyroid carcinoma (PTC) remains unclear. Herein, we evaluated the potential of primary tumor FDG avidity for the prediction of tumor recurrence in PTC patients. A total of 412 PTC patients (72 males, 340 females; age: 47.2 ± 12.2 years; range: 17–84 years) who underwent FDG‐PET/CT prior to total thyroidectomy (n = 350), subtotal thyroidectomy (n = 2), or lobectomy (n = 60) from 2007 to 2011 were analyzed. The predictive ability for recurrence was investigated among various clinicopathological factors, BRAFV600E mutation, and preoperative FDG avidity of the primary tumor using Kaplan–Meier (univariate) and Cox proportional hazards regression (multivariate) analyses. Of the 412 patients, 19 (4.6%) experienced recurrence, which was confirmed either by pathology (n = 17) or high serum thyroglobulin level (n = 2), during a mean follow‐up period of 43.9 ± 16.6 months. Of the 412 patients, 237 (57.5%) had FDG‐avid tumors (maximum standardized uptake value, 7.1 ± 7.0; range: 1.6–50.5). Kaplan–Meier analysis revealed that tumor size (P = 0.0054), FDG avidity of the tumor (P = 0.0049), extrathyroidal extension (P = 0.0212), and lymph node (LN) stage (P < 0.0001) were significant predictors for recurrence. However, only LN stage remained a significant predictor in the multivariate analysis (P < 0.0001). Patients with FDG‐avid tumors had higher LN stage (P < 0.0001), larger tumor size (P < 0.0001), and more frequent extrathyroidal extension (P < 0.0001). In conclusion, FDG avidity of the primary tumor in preoperative FDG‐PET/CT could not predict the recurrence of PTC. LN stage was the only identified predictor of PTC recurrence.