Min Ji Jeon

Obesity is a risk factor for thyroid cancer in a large, ultrasonographically screened population

OBJECTIVE Obesity is a well-known risk factor for many cancers, including those of the esophagus, colon, kidney, breast, and skin. However, there are few reports on the relationship between obesity and thyroid cancer. We conducted this study to determine whether obesity is a risk factor for thyroid cancer by systematically screening a selected population by ultrasonography. DESIGN AND METHODS We obtained data from 15,068 subjects that underwent a routine health checkup from 2007 to 2008 at the Health Screening and Promotion Center of Asan Medical Center. Thyroid ultrasonography was included in the checkup, and suspicious nodules were examined by ultrasonography-guided aspiration. Those with a history of thyroid disease or family history of thyroid cancer were excluded from this study. RESULTS In total, 15,068 subjects, 8491 men and 6577 women, were screened by thyroid ultrasonography. Fine-needle aspiration cytology was performed in 1427 of these patients based on the predefined criteria and thyroid cancer was diagnosed in 267 patients. The prevalence of thyroid cancer in women was associated with a high BMI (per 5 kg/m(2) increase) (odds ratios (OR)=1.63, 95% CI 1.24-2.10, P<0.001), after adjustment for age, smoking status, and TSH levels. There was no positive correlation between the prevalence of thyroid cancer in men and a high BMI (OR=1.16, 95% CI 0.85-1.57, P=0.336). There was no association between age, fasting serum insulin, or basal TSH levels and thyroid cancer in either gender. CONCLUSIONS Obesity was associated with a higher prevalence of thyroid cancer in women when evaluated in a routine health checkup setting. This association between risk factor and disease was unrelated to serum insulin and TSH levels. Additional studies are needed to understand the mechanism(s) behind the association of obesity with thyroid cancer risk.

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.

The prognostic value of the metastatic lymph node ratio and maximal metastatic tumor size in pathological N1a papillary thyroid carcinoma

OBJECTIVE The presence of central neck lymph node (LN) metastases (defined as pN1a according to Tumor Node Metastasis classification) in papillary thyroid cancer (PTC) is known as an independent risk factor for recurrence. Extent of LN metastasis and the completeness of removal of metastatic LN must have an impact on prognosis but they are not easy to measure. Moreover, the significance of the size of metastatic tumors in LNs has not been clarified. This study was to evaluate the impact of the extent of LN metastasis and size of metastatic tumors on the recurrence in pathological N1a PTC. DESIGN This retrospective observational cohort study enrolled 292 PTC patients who underwent total thyroidectomy with central neck dissection from 1999 to 2005. LN ratio was defined as the number of metastatic LNs divided by the number of removed LNs, which was regarded as variable reflecting both extent of LN metastasis and completeness of resection, and LN size as the maximal diameter of tumor in metastatic LN. RESULTS The significant risk factors for recurrence in univariate analysis were large primary tumor size (defined as larger than 2 cm), high LN ratio (defined as higher than 0.4), and presence of macrometastasis (defined as larger than 0.2 cm). Age, sex, clinical node status, and microscopic perithyroidal extension had no effect on recurrence. In multivariate analysis, high LN ratio and presence of macrometastasis were independent risk factors for recurrence. CONCLUSION LN ratio and size of metastatic nodes had a significant prognostic value in pathological N1a PTC. We suggest that risk stratification of pathological N1a PTC according to the pattern of LN metastasis such as LN ratio and size would give valuable information to clinicians.

Serum antithyroglobulin antibodies interfere with thyroglobulin detection in fine-needle aspirates of metastatic neck nodes in papillary thyroid carcinoma.

CONTEXT It is recommended to measure thyroglobulin (Tg) levels in the needle washout fluids from fine-needle aspirations (FNAs) in patients with papillary thyroid carcinoma (PTC) who have ultrasonographically suspicious metastatic lymph nodes (LNs). However, it is not clear whether serum anti-Tg antibodies (TgAbs) interfere with the detection of Tg in needle washout fluids from FNAs (FNA-Tg). OBJECTIVE The objective of the study was to evaluate the influence of serum TgAbs on FNA-Tg detection. DESIGN AND SETTINGS This retrospective observational cohort study enrolled 207 patients with conventional PTC in whom FNA-Tg values had been measured. All patients initially underwent total thyroidectomy and remnant ablation. FNA-Tg levels were measured from ultrasonographically suspicious metastatic LNs of 0.5 cm or greater in the longest diameter. RESULTS From 207 patients, 263 LNs were evaluated. Final histopathology was available for 92 LNs, of which 88 (96%) were malignant. FNA-Tg levels were lower in the LNs from serum TgAb-positive patients than in those from TgAb-negative patients (P < 0.001). In four of 13 metastatic LNs from TgAb-positive patients, the FNA-Tg levels were below 10 μg/liter including one in which both FNA-Tg and serum-stimulated Tg levels were below 1 μg/liter and stained positively for Tg in pathology. There was also one malignant LN with negative for FNA-Tg, serum-stimulated Tg, and serum TgAb but that nonetheless stained intensely for Tg. However, there were no malignant LNs with both negative cytology and negative FNA-Tg. A diagnosis based on FNA-Tg had a lower sensitivity and negative predictive value in the TgAb-positive group than in the TgAb-negative group. CONCLUSION FNA-Tg measurement is highly reliable in the diagnosis of neck metastases in PTC patients, even in cases of negative-stimulated Tg or positive TgAb. However, high-serum TgAb levels could interfere with FNA-Tg measurements and thereby result in falsely low FNA-Tg levels.

Low Levels of Serum Vitamin D3 Are Associated with Autoimmune Thyroid Disease in Pre-Menopausal Women

BACKGROUND Low serum vitamin D levels have been associated with several autoimmune diseases, but their association with thyroid autoimmunity is unclear. We evaluated the association of serum vitamin D levels with the prevalence of autoimmune thyroid disease (AITD). METHODS Our cross-sectional study included subjects who underwent routine health checkups, which included assays of serum 25-hydroxy vitamin D3 [25(OH)D3] and anti-thyroid peroxidase antibody (TPO-Ab), as well as thyroid ultrasonography (US) between 2008 and 2012 at the Asan Medical Center. We defined AITD according to the levels of TPO-Ab and US findings. RESULTS A total of 6685 subjects (58% male; 42% female) were enrolled for this study. Overall prevalence of TPO-Ab positivity and both TPO-Ab/US positivity were 10.1% (6.3% male; 15.3% female) and 5.4% (2.3% male; 9.7% female) respectively. In female subjects, mean serum 25(OH)D3 levels were significantly lower in the TPO-Ab(+) (22.0 vs. 23.5 ng/mL, p=0.030) and TPO-Ab(+)/US(+) groups (21.6 vs. 23.4 ng/mL, p=0.027) compared with the control group, respectively. According to the levels of serum 25(OH)D3, the prevalence of TPO-Ab positivity (21.2%, 15.5%, and 12.6% in deficient, insufficient, and sufficient group, respectively; p=0.001) and both TPO-Ab and US positivity (14.7%, 9.9%, and 7.1% in deficient, insufficient, and sufficient group, respectively; p<0.001) decreased in female subjects. Interestingly, this pattern was significant only in pre-menopausal women (p=0.003 and p<0.001; respectively), but not in postmenopausal women. Multivariate analysis indicated that the adjusted odds ratios (OR) for AITD among those in the 25(OH)D3-deficient [TPO-Ab(+): OR 1.95, p=0.001; TPO-Ab(+)/US(+): OR 2.36, p<0.001] and -insufficient groups [TPO-Ab(+): OR 1.31, p=0.043; TPO-Ab(+)/US(+): OR 1.50, p=0.017] were significantly increased when compared with the sufficient group. CONCLUSIONS The levels of serum vitamin D were significantly lower in pre-menopausal women with AITD. Vitamin D deficiency and insufficiency were significantly associated with AITD in pre-menopausal women.

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.

Effects of Low-Dose and High-Dose Postoperative Radioiodine Therapy on the Clinical Outcome in Patients with Small Differentiated Thyroid Cancer Having Microscopic Extrathyroidal Extension

BACKGROUND It is unclear whether differentiated thyroid cancer (DTC) patients classified as intermediate risk based on the presence of microscopic extrathyroidal extension (ETE) should be treated with low or high doses of radioiodine (RAI) after surgery. We evaluated success rates and long-term clinical outcomes of patients with DTC of small tumor size, microscopic ETE, and no cervical lymph node (LN) metastasis treated either with a low (1.1 GBq) or high RAI dose (5.5 GBq). METHODS This is a retrospective analysis of a historical cohort from 2000 to 2010 in a tertiary referral hospital. A total of 176 patients with small (≤2 cm) DTC, microscopic ETE, and no cervical LN metastasis were included. Ninety-six patients were treated with 1.1 GBq (LO group) and 80 patients with 5.5 GBq (HI group). Successful RAI therapy was defined as (i) negative stimulated thyroglobulin (Tg) in the absence of Tg antibodies, and (ii) absence of remnant thyroid tissue and of abnormal cervical LNs on ultrasonography. Clinical recurrence was defined as the reappearance of disease after ablation, which was confirmed by cytologically or pathologically proven malignant tissue or of distant metastatic lesions. RESULTS There was no significant difference in the rate of successful RAI therapy between the LO and HI groups (p=0.75). In a subgroup analysis based on tumor size, success rates were not different between the LO group (34/35, 97%) and the HI group (50/56, 89%) in patients with a tumor size of 1-2 cm (p=0.24). In patients with smaller tumor size (≤1 cm), there was no significant difference in success rates between the LO (59/61, 97%) and HI groups (22/24, 92%; p=0.30). No patient had clinical recurrences in either group during the median 7.2 years of follow-up. CONCLUSIONS Low-dose RAI therapy is sufficient to treat DTC patients classified as intermediate risk just by the presence of microscopic ETE.

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.

Association Between Expression of X-Linked Inhibitor of Apoptosis Protein and the Clinical Outcome in a BRAFV600E-Prevalent Papillary Thyroid Cancer Population

BACKGROUND The X-linked inhibitor of apoptosis protein (XIAP) is associated with carcinogenesis, cancer progression, and metastasis through inhibition of the caspase-mediated apoptotic pathway. The BRAF(V600E) mutation is the most common genetic alteration and an established prognostic marker in papillary thyroid cancer (PTC). The prevalence of the BRAF mutation is very high and is up to 80% in Korean PTC patients. In the present study, we evaluated the potential role of XIAP expression as a novel prognostic marker to predict recurrence, in combination with the BRAF(V600E) mutational status. METHODS The study enrolled 164 patients with conventional PTC who underwent bilateral thyroidectomy followed by immediate (131)I ablation. The presence of the BRAF(V600E) mutation was evaluated by direct sequencing. The degree of XIAP expression was evaluated by immunohistochemical (IHC) staining using a monoclonal antibody. RESULTS The BRAF(V600E) mutation was found in 123 of 164 patients (75%) with classical PTC. XIAP expression was positive in 128 of 164 patients (75%), and positive XIAP expression was significantly associated with the presence of lateral cervical lymph node metastases (p=0.01). XIAP expression was more frequent in BRAF(V600E) mutated PTCs than in BRAF wild type PTCs (p=0.048). The BRAF(V600E) mutation was significantly associated with cancer recurrence in study subjects (hazard ratio=2.98, p=0.039). PTCs positive for the BRAF(V600E) mutation but negative for XIAP expression had a significantly higher rate of recurrent PTC (hazard ratio=4.53, p=0.012). CONCLUSION The evaluation of XIAP expression and BRAF mutational analysis was more useful for the prediction of cancer recurrence in patients with PTC than BRAF genotype alone.

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.