Ji Hye Yim

The Outcomes of First Reoperation for Locoregionally Recurrent/Persistent Papillary Thyroid Carcinoma in Patients Who Initially Underwent Total Thyroidectomy and Remnant Ablation

CONTEXT The primary treatment of locoregionally recurrent/persistent papillary thyroid cancer (PTC) is surgical removal by reoperation. However, there had been only limited number of reports on the outcome of reoperation. OBJECTIVE This study was to evaluate the efficacy of the first reoperation for locoregionally recurrent/persistent papillary thyroid carcinoma and the usefulness of stimulated thyroglobulin for evaluating efficacy of reoperation. DESIGN AND SETTINGS This was a retrospective observational cohort study in a tertiary referral hospital. PATIENTS A total of 83 patients, who underwent initial total thyroidectomy and nodal dissection with radioactive iodine remnant ablation, received reoperation for locoregionally recurrent/persistent PTC and were included in this study. Stimulated thyroglobulin levels were assessed before and after reoperation. MAIN OUTCOME MEASURES We assessed biochemical remission (stimulated thyroglobulin <1 ng/ml) after reoperation and evaluated second clinical recurrence-free survival rate according to stimulated thyroglobulin value. RESULTS There was a significant positive correlation between the numbers of resected malignant lymph nodes and the reduction in stimulated thyroglobulin level after reoperation. Biochemical remission was achieved in 51% of patients who underwent first reoperation. Patients with stimulated thyroglobulin level greater than 5 ng/ml after first reoperation had a greater chance of a second clinical recurrence (the estimated 5 yr clinical recurrence free survival rate, 94 ± 3 vs.74 ± 9%, log rank statistics 15.8, df = 1, P < 0.001). CONCLUSION Surgery is an effective option for managing locally recurrent/persistent PTC. Stimulated thyroglobulin is a useful marker for evaluating efficacy of reoperation and predicting second recurrence in locoregionally recurrent/persistent PTC.

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.

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.

Long-term clinical outcome of differentiated thyroid cancer patients with undetectable stimulated thyroglobulin level one year after initial treatment.

BACKGROUND Measurement of the serum thyroglobulin (Tg) level with TSH stimulation (sTg) is the cornerstone of monitoring for the recurrence or persistence of differentiated thyroid cancer (DTC) in patients who have undergone surgery and remnant ablation. However, there have been several reports that an undetectable sTg could not predict the absence of future recurrence. The aim of this study was to evaluate the long-term outcome of DTC patients who achieved biochemical remission (BR, defined as sTg<1 ng/mL) after initial treatment, and to determine the role of repeated sTg measurement in detecting a clinical recurrence. METHODS This is a retrospective observational cohort study in a tertiary referral hospital. There were 1010 DTC patients who achieved BR at 12 months after the initial treatment (surgery and ablation), and they were eligible for analysis. Among them, 787 patients had values of repeated sTg. RESULTS Thirteen out of 1010 (1.3%) patients had clinical recurrences during a median 84 months of follow-up. All of the clinical recurrences were limited to the cervical lymph nodes without clinical evidence of distant metastasis. Among 787 patients with available repeated sTg, 10 had clinical recurrences (5 out of 750 patients with repeated sTg<1 ng/mL and 5 out of 37 patients with repeated sTg ≥ 1 ng/mL). Patients with repeated sTg ≥ 1 ng/mL had a much greater chance of disease recurrence (log-rank statistics=43.7, df=1, p<0.001). CONCLUSIONS About 1% of DTC patients who had sTg<1 ng/mL 12 months after initial treatment had a clinical recurrence. All of clinical recurrences were loco-regional recurrences. Although repeated sTg measurement can be helpful to predict recurrence, we could not recommend it for surveillance in patients with BR due to its very low yield.

Effects of different doses of radioactive iodine for remnant ablation on successful ablation and on long-term recurrences in patients with differentiated thyroid carcinoma.

ObjectivesThe aim of this study was to compare ablation success and disease-free survival (DFS) on the basis of different ablation doses. MethodsThis retrospective study enrolled differentiated thyroid carcinoma patients who underwent total thyroidectomy and radioactive remnant ablation at the Asan Medical Center between January 2000 and December 2004. Radioactive iodine doses of 30 mCi (group A), 80 mCi (group B), and 150 mCi (group C) were administered according to the patients’ risk of recurrences based on the clinicopathologic parameters at the time of surgery. Ablation success was defined as absence of abnormal uptake on diagnostic whole-body scan. ResultsAmong 1024 patients, successful ablation was achieved in 81.7% in group A, in 89.5% in group B, and in 94.8% in group C (P<0.001). A total of 100 patients (9.8%) had clinical recurrences during 6.6 years of median follow-up. DFS was evaluated according to ablation success in each dose group. There were no significant differences in DFS. Side effects of radioactive iodine were negligible with dose up to 80 mCi; however, 2% of patients developed permanent salivary dysfunction in group C. ConclusionIn cases of different ablation doses administered according to patients’ risk of recurrences, we found that a higher dose of radioiodine was associated with a higher rate of ablation success compared with lower doses. However, successful ablation was not associated with a reduction in clinical recurrences. The optimal dose for ablation must be adjusted according to the risk group of individual patients to avoid unnecessary radiation and maximize therapeutic efficacy.

Adjuvant Radioactive Therapy after Reoperation for Locoregionally Recurrent Papillary Thyroid Cancer in Patients Who Initially Underwent Total Thyroidectomy and High-Dose Remnant Ablation

CONTEXT Some patients have elevated stimulated thyroglobulin (sTg) concentrations after reoperation for locoregionally recurrent/persistent papillary thyroid cancer (PTC). Little is known, however, about the efficacy of adjuvant radioactive iodine (RAI) therapy in these patients. OBJECTIVE The objective of the study was to evaluate the efficacy of adjuvant RAI therapy in patients with elevated sTg after reoperation for locally recurrent/persistent PTC. DESIGN AND SETTINGS This was a retrospective observational cohort study in a tertiary referral hospital. PATIENTS We evaluated 45 consecutive patients with sTg greater than 2 ng/ml after reoperation for locoregionally recurrent PTC, all of whom had previously undergone initial total thyroidectomy followed by high-dose RAI remnant ablation. Of these 45 patients, 23 received adjuvant RAI therapy (adjuvant group) and 22 did not (control group). MAIN OUTCOME MEASURES Main outcome measures included changes in sTg concentration after reoperation and disease-free survival. RESULTS Over time, there were no significant differences in mean sTg concentration in the adjuvant (P = 0.35) and control (P = 0.74) groups. Only 15% of patients in the adjuvant group and 33% in the control group showed a greater than 50% decrease in sTg level from baseline. There were no between-group differences in changes (P = 0.83) or percent decrease (P = 0.97) in sTg concentration and no difference in clinical recurrence-free survival (P = 0.20). CONCLUSION In patients who still have elevated sTg after reoperation for locally recurrent/persistent PTC, adjuvant RAI therapy compared with no additional RAI therapy resulted in no significant differences in the subsequent sTg changes or the recurrence-free survival.

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.

Basal STAT3 activities are negatively correlated with tumor size in papillary thyroid carcinomas

Backgrounds: Signal transducer and activators of transcription-3 (STAT3) plays a critical role in promoting survival and cell growth as well as facilitating angiogenesis and metastasis in several cancers. Aim: This investigation focused on evaluation of STAT3 activities in human papillary thyroid cancers (PTC). Methods: STAT3 activities of nuclear extracts of tumor tissue were measured from 35 PTC patients using enzyme-linked immunosorbent assay-based kits. Results: STAT3 activities of PTC tissues were significantly lower than those of surrounding normal thyroid tissues [0.36 (interquartile range 0.24–0.72) vs 0.50 (0.29–1.11) arbitrary units, p<0.01]. We further analyzed the association between STAT3 activity and clinicopathologic factors in PTC tissue. Tumors with size ≥2 cm displayed significantly lower STAT3 activities than those <2 cm [0.25 (0.21–0.37) vs 0.53 (0.37–0.61) arbitrary units, p<0.01]. Notably, tumor size was inversely correlated with STAT3 activities in T1799A BRAF mutation-positive cases (Rs=−0.58, p<0.05), but not mutation-negative cases. Conclusions: STAT3 activities of PTC measured via DNA binding are suppressed in contrast to other human cancers. Tumor size larger than 2 cm is the only clinicopathologic parameter associated with low STAT3 activity. Moreover, tumor size appears inversely correlated with STAT3 activity, specifically in T1799A BRAF mutation-positive cases.

Long-term consequence of elevated thyroglobulin in differentiated thyroid cancer.

BACKGROUND Serum thyroglobulin (Tg) is the most sensitive biomarker for recurrence of differentiated thyroid cancer (DTC). We have assessed the changing pattern of stimulated Tg (sTg) and the clinical course of patients with no structural evidence of disease (NSED), based on imaging studies such as neck ultrasonography (US), fluorodeoxyglucose positron emission tomography, and/or chest computed tomogram (CT). We sought to determine if, in patients with DTC who had been treated with bilateral thyroidectomy and remnant ablation with radioactive iodine, sTg 1 year (sTg1) after initial treatment and repeated sTg measurements, 1-2 years after sTg1, helped predict the long-term outcome with respect to structural recurrence and biochemical remission (BR), which is defined as sTg <1 ng/mL. METHODS We retrospectively assessed the records of patients with DTC who had been treated with bilateral thyroidectomy and remnant ablation with radioactive iodine between 1995 and 2004. The study included 186 patients who had NSED with sTg1 ≥2 ng/mL and subsequent sTg measurements (sTg2) without additional treatment. Patients were classified into three groups based on their sTg1 measurements: Group A, 2-4.9 ng/mL; Group B, 5-19.9 ng/mL; and Group C, ≥20 ng/mL. Patients were also classified into two groups based on whether sTg2, 1-2 years after sTg1, had decreased by ≥50% (Group 1) or had either decreased by <50% or increased (Group 2). sTg was measured every 1-2 years until structural recurrence or BR. RESULTS Patients remaining in NSED showed a decrease in serial sTg. Of patients in Groups A, B, and C, 41%, 17%, and 1%, respectively, achieved BR, and there was a significant difference in the BR rate between Groups 1 and 2 (p<0.001). In patients with structural recurrence, serial sTg generally did not decrease from sTg1. There was a significant difference in the recurrence rate among Groups A, B, and C (p=0.005) and between Groups 1 and 2 (p<0.001). CONCLUSIONS We found that 41% of patients with sTg1 in the range 2-5 ng/mL achieved BR, and that sTg1 and percent change of subsequent sTg were predictive of BR. Repeated sTg measurements are useful for predicting patient prognosis in patients with DTC.