Hyemi Kwon

NRAS codon 61 mutation is associated with distant metastasis in patients with follicular thyroid carcinoma.

BACKGROUND Known factors related to distant metastases in follicular thyroid carcinoma (FTC) included age, primary tumor size, and invasiveness. Distant metastasis is a main cause of death in FTC patients. Several studies showed that the presence of RAS mutations is also associated with poor clinical outcomes. We analyzed RAS mutations in FTC with distant metastases, FTC without a distant metastasis, follicular adenoma (FA), and nodular hyperplasia (NH). Furthermore, we elucidated the relationship between RAS mutations and clinical outcomes in FTC patients. METHODS We selected patients who underwent a thyroidectomy for FTC with distant metastases (n=28), size matched FTC specimens without a distant metastasis (n=28), FA (n=17), and NH (n=12). NRAS, HRAS, and KRAS mutations were assessed using direct sequencing. RESULTS Among 85 patients, 39 patients (46%) had RAS mutations. The NRAS codon 61 mutation (n=21; 25%) was the most common point mutation. HRAS codon 61, KRAS codon 12/13, and KRAS codon 61 mutations were found in 7, 6, and 4 patients, respectively. A NRAS codon 12/13 mutation was found in only 1 patient, and a HRAS codon 12/13 mutation was not found. RAS mutations were significantly more common in the FTC than FA or NH groups. Especially, the NRAS codon 61 mutation was associated with distant metastasis in patients with FTC. CONCLUSIONS The presence of a RAS mutation, especially a NRAS codon 61 mutation, was significantly associated with the distant metastasis. The NRAS codon 61 mutation status might be a potential prognostic factor in FTC patients.

Standardized Thyroid Cancer Mortality in Korea between 1985 and 2010

Background The prevalence of thyroid cancer has increased very rapidly in Korea. However, there is no published report focusing on thyroid cancer mortality in Korea. In this study, we aimed to evaluate standardized thyroid cancer mortality using data from Statistics Korea (the Statistical Office of Korea). Methods Population and mortality data from 1985 to 2010 were obtained from Statistics Korea. Age-standardized rates of thyroid cancer mortality were calculated according to the standard population of Korea, as well as World Health Organization (WHO) standard population and International Cancer Survival Standard (ICSS) population weights. Results The crude thyroid cancer mortality rate increased from 0.1 to 0.7 per 100,000 between 1985 and 2010. The pattern was the same for both sexes. The age-standardized mortality rate (ASMR) for thyroid cancer for Korean resident registration population increased from 0.19 to 0.67 between 1985 and 2000. However, it decreased slightly, from 0.67 to 0.55, between 2000 and 2010. When mortality was adjusted using the WHO standard population and ICSS population weights, the ASMR similarly increased until 2000, and then decreased between 2000 and 2010. Conclusion Thyroid cancer mortality increased until 2000 in Korea. It started to decrease from 2000.

Recent Changes in the Clinical Outcome of Papillary Thyroid Carcinoma With Cervical Lymph Node Metastasis

CONTEXT The prognosis of papillary thyroid cancer (PTC) with cervical lymph node (LN) metastasis has changed with increased detection of subclinical metastatic LNs. The number and size of metastatic LNs were proposed as new prognostic factors in PTC with cervical LN metastasis (N1). OBJECTIVE The objective of the study was to evaluate changes in N1 PTC characteristics and clinical outcome over time and to confirm the prognostic value of the number and size of metastatic LNs. DESIGN AND PATIENTS This study included 1815 N1 PTC patients diagnosed between 1997 and 2011. Patients were classified into three risk groups according to the number and size of metastatic LNs: very low risk, five or fewer and 0.2 cm or less; low risk, five or fewer and 0.2 cm or greater; and high risk, more than five. MAIN OUTCOME MEASURES Response to initial therapy and disease-free survival (DFS) was measured. RESULTS Metastatic LNs became smaller, and the ratio of metastatic LNs, which represents the extent of LN involvement and the completeness of surgery, decreased significantly over time. The proportion of patients with excellent response significantly increased from 33% to 67% over time (P < .001). These improvements were more evident in the low- and high-risk groups than in the very low-risk group. The DFS 5 years after initial surgery was also significantly increased from 73% to 91% over time (P < .001). The new LN classification was strongly associated with outcome. Patients in the very low-risk group had longer DFS than those in the low- and high-risk groups during the study period. CONCLUSIONS The clinical outcome of N1 PTC has significantly changed over time with the earlier detection of thyroid cancers with less extensive LN involvement. More complete surgical neck dissection also might be responsible for these changes. The number and size of metastatic LNs are important prognostic factors of recurrence in N1 PTC.

Genomic Alterations of Anaplastic Thyroid Carcinoma Detected by Targeted Massive Parallel Sequencing in a BRAFV600E Mutation-Prevalent Area

BACKGROUND Anaplastic thyroid carcinoma (ATC), the most aggressive type of thyroid cancer, has no effective therapy. Due to its dismal prognosis, it is vital to understand the genetic alterations of ATC and identify effective molecular targets. Targeted next-generation sequencing was performed to investigate the mutational profile of ATC using a massive parallel sequencing approach. METHODS DNA from formalin-fixed, paraffin-embedded archival samples of 11 ATCs and normal matched pairs were used. A total of 48 genetic alterations were identified by targeted exome sequencing. These alterations were validated by mass spectrometric genotyping and direct Sanger sequencing. RESULTS The most commonly mutated gene was BRAF, identified in 10 samples (91%), all showing the V600E point mutation. A KRAS point mutation was observed in the one sample (9%) without the BRAF(V600E) mutation. All 11 ATCs harbored BRAF or RAS mutations, reflecting the possibility that differentiated thyroid carcinomas progress to ATCs after the accumulation of mutations. A loss of function mutation of TP53 was observed in eight samples (73%), a PIK3CA mutation was observed in two samples (18%), and a frameshift mutation of PTEN was observed in one sample (9%). Twenty-eight novel mutated genes were found that had not previously been associated with ATC. Of these, loss of function mutations of NF2, KMT2D, and PKHD1 were repeatedly seen in three samples (27%), two samples (18%), and two samples (18%), respectively. Using direct Sanger sequencing, two samples (18%) were also found with a RASAL1 mutation. KMT2D and RASAL1 mutations were significantly associated with shorter ATC patient survival. CONCLUSIONS This comprehensive analysis of ATCs using targeted massive parallel sequencing identified several novel mutations in ATCs, such as loss of function mutations of NF2 or KMT2D. Future studies are needed to confirm the role of these novel mutations as independent drivers of ATC development.

Reference interval for thyrotropin in a ultrasonography screened Korean population

Background/Aims The diagnostic accuracy of thyroid dysfunctions is primarily affected by the validity of the reference interval for serum thyroid-stimulating hormone (TSH). Thus, the present study aimed to establish a reference interval for TSH using a normal Korean population. Methods This study included 19,465 subjects who were recruited after undergoing routine health check-ups. Subjects with overt thyroid disease, a prior history of thyroid disease, or a family history of thyroid cancer were excluded from the present analyses. The reference range for serum TSH was evaluated in a normal Korean reference population which was defined according to criteria based on the guidelines of the National Academy of Clinical Biochemistry, ultrasound (US) findings, and smoking status. Sex and age were also taken into consideration when evaluating the distribution of serum TSH levels in different groups. Results In the presence of positive anti-thyroid peroxidase antibodies or abnormal US findings, the central 95 percentile interval of the serum TSH levels was widened. Additionally, the distribution of serum TSH levels shifted toward lower values in the current smokers group. The reference interval for TSH obtained using a normal Korean reference population was 0.73 to 7.06 mIU/L. The serum TSH levels were higher in females than in males in all groups, and there were no age-dependent shifts. Conclusions The present findings demonstrate that the serum TSH reference interval in a normal Korean reference population was higher than that in other countries. This result suggests that the upper and lower limits of the TSH reference interval, which was previously defined by studies from Western countries, should be raised for Korean populations.

Active Surveillance for Patients With Papillary Thyroid Microcarcinoma: A Single Center’s Experience in Korea

Context Papillary thyroid microcarcinoma (PTMC) usually has an excellent prognosis. Objective To evaluate the three-dimensional structures of PTMCs, using serial neck ultrasonography (US) in patients under active surveillance. Design and Setting A retrospective cohort study. Participants In total, 192 patients diagnosed with PTMC under active surveillance for >1 year were included in a median 30-month follow-up. Changes in tumor size were evaluated not only using the maximal tumor diameter but also the tumor volume. Results The median age of patients was 51.3 years and 145 patients (76%) were female. The median initial maximal tumor diameter and tumor volume were 5.5 mm and 48.8 mm3, respectively. The tumor size increased in 27 patients (14%); 23 patients showed a tumor volume increase >50% without a maximal diameter increase of ≥3 mm. The other four patients had both an increasing tumor volume and increasing maximal tumor diameter ≥3 mm. One patient (0.5%) had newly appeared cervical lymph node (LN) metastasis at 3 years after the initial diagnosis. There were no significant risk factors associated with increased tumor size, such as age, sex, or Hashimoto thyroiditis. Twenty-four patients (13%) underwent delayed thyroid surgery at a median of 31.2 months and seven (29%) had cervical LN metastasis on pathologic examination. Conclusion Some PTMCs could grow significantly after a relatively short period of active surveillance. We also found that the change in tumor volume was more sensitive to detect tumor progression than the change in the maximal tumor diameter.

Impact of Reclassification on Thyroid Nodules with Architectural Atypia: From Non-Invasive Encapsulated Follicular Variant Papillary Thyroid Carcinomas to Non-Invasive Follicular Thyroid Neoplasm with Papillary-Like Nuclear Features

Background The follicular variant of papillary thyroid cancer (FVPTC), especially the encapsulated non-invasive subtype, is a controversial entity. Recent study suggested using ‘non-invasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP)’ for these indolent carcinomas. We evaluated the impact of reclassification from non-invasive encapsulated FVPTCs (EFVPTCs) to NIFTPs in the diagnosis of thyroid nodules with architectural atypia. Methods We reviewed 1301 thyroid nodules with architectural atypia in core needle biopsy (CNB) specimens obtained from March 2012 to February 2013. Nodules were classified into atypia of undetermined significance with architectural atypia (AUS-A, 984, 76%) or follicular neoplasm/suspicious for a follicular neoplasm (FN/SFN, 317, 24%). Among them, diagnostic surgery was performed in 384 nodules (30%). Results In total, 160 nodules (42%) presented final malignant diagnoses including 39 non-invasive encapsulated FVPTCs (10%). The malignancy rate was estimated to be 7–35% in AUS-A nodules and 28–49% in FN/SFN nodules. After reclassification, the malignancy rate was much decreased and estimated to be 5–24% in AUS-A nodules, and 23–39% in FN/SFN nodules. Thyroid nodules with final malignant diagnoses were significantly more likely to have a FN/SFN CNB diagnosis, malignant US features and concomitant nuclear atypia in CNB specimens. However, these factors could not differentiate NIFTPs from other malignancies. Conclusions After reclassification of non-invasive EFVPTCs to NIFTPs, the malignancy rate of thyroid nodules with architectural atypia in CNB specimens was decreased. However, there were no preoperative factors differentiating other malignancies from NIFTPs. The presence of malignant US features or concomitant nuclear atypia might help clinicians deciding diagnostic surgery but, these features also might indicate NIFTPs.

Changing trends in the clinicopathological features and clinical outcomes of medullary thyroid carcinoma.

The early detection of papillary thyroid cancer has contributed to the increase in the incidence and improved clinical outcomes. However, recent changes of medullary thyroid carcinoma (MTC) over time remain unclear. We evaluated changes of the clinicopathological characteristics and clinical outcomes in patients with MTC in recent years.

Association between neck ultrasonographic findings and clinico‐pathological features in the follicular variant of papillary thyroid carcinoma

The follicular variant of papillary thyroid carcinoma (FVPTC) has multiple histological subtypes. Clinical outcomes of FVPTC are variable depending on the subtypes. This study evaluated the association of pre‐operative ultrasonographic (US) findings and clinico‐pathological features of FVPTC.

A cut‐off value of basal serum calcitonin for detecting macroscopic medullary thyroid carcinoma

Serum calcitonin (CT) level is used to detect medullary thyroid carcinoma (MTC), but the cut‐off level is unclear. We aimed at identifying the optimal cut‐off value of basal serum CT levels for detecting MTC.