The optimal initial surgical extent for medullary thyroid carcinoma (MTC) remains controversial. Previous studies on serum calcitonin are limited to reporting the calcitonin threshold according to anatomical disease burden. Here, we evaluated whether preoperative calcitonin levels can be used to predict optimal surgical extent. We retrospectively reviewed the 170 patients with MTC at a tertiary Korean hospital from 1994 to 2019. We extracted data on preoperative calcitonin level, primary tumor size and the number and location of lymph node metastases (LNMs). To evaluate disease extent, we divided the patients into five groups: no LNM, central LNM, ipsilateral lateral LNM, contralateral lateral LNM, and distant metastasis. We calculated the positive and negative likelihood ratios (LRs) for multiple categories of preoperative calcitonin levels. Preoperative calcitonin level positively correlated with primary tumor size (rho = 0.744, p < 0.001) and LNM number (rho = 0.537, p < 0.001). Preoperative calcitonin thresholds of 20, 200, and 500 pg/mL were associated with the presence of ipsilateral lateral LNM, contralateral lateral LNM, and distant metastasis, respectively. The negative LRs were 0.1 at a preoperative calcitonin cut-off of 100 pg/mL in the central LNM, 0.18 at a cut-off of 300 pg/mL in the ipsilateral lateral LNM, and 0 at a cut-off of 300 pg/mL in the contralateral lateral LNM. The preoperative calcitonin level correlates with disease extent and has diagnostic value for predicting LNM extent. Our results suggest that the preoperative calcitonin level can be used to determine optimal initial surgical extent.

Our research group has previously shown that the presence of TERT promoter mutations is an independent prognostic factor, by applying the TERT mutation status to the variables of the AJCC 7th edition. This study aimed to determine if TERT mutations could be independent predictors of thyroid cancer-specific mortality based on the AJCC TNM 8th edition, with long-term follow-up. This was a retrospective study of 393 patients with pathologically confirmed differentiated thyroid carcinoma (DTC) after thyroidectomy at a tertiary Korean hospital from 1994 to 2004. The thyroid cancer-specific mortality rate was 6.9% (5.2% for papillary and 15.2% for follicular cancers). TERT promoter mutations were identified in 10.9% (43/393) of DTC cases (9.8% of papillary and 16.7% of follicular cancer) and were associated with older age (p < 0.001), the presence of extrathyroidal invasion (p < 0.001), distant metastasis (p = 0.001), and advanced stage at diagnosis (p < 0.001). The 10-year survival rate in mutant TERT was 67.4% for DTC patients (vs. 98% for wild-type; adjusted hazard ratio (HR) of 9.93, (95% CI: 3.67–26.90)) and 75% for patients with papillary cancer (vs. 99%; 18.55 (4.83–71.18)). In addition, TERT promoter mutations were related to poor prognosis regardless of histologic type (p < 0.001 for both papillary and follicular cancer) or initial stage (p < 0.001, p = 0.004, and p = 0.086 for stages I, II, and III and IV, respectively). TERT promoter mutations comprise an independent poor prognostic factor after adjusting for the clinicopathological risk factors of the AJCC TNM 8th edition, histologic type, and each stage at diagnosis, which could increase prognostic predictability for patients with DTC.

The lymph node ratio (LNR) has been investigated as a prognostic factor in many different types of cancers, including differentiated thyroid cancer; however, reports regarding medullary thyroid cancer (MTC) are limited. Therefore, this study aims to evaluate LNR as a risk factor for structural recurrence in patients with MTC. Medical records of patients treated for MTC in a single tertiary center between 1995 and 2017 were retrospectively reviewed. LNR is defined as the number of metastatic lymph nodes or lymph node metastases (LNM) divided by the number of retrieved lymph nodes or lymph node yield (LNY). In the survival analysis, recurrence-free survival was defined as the time from the date of total thyroidectomy to recurrence or last follow-up. To identify risk factors influencing structural recurrence, univariable and multivariable Cox proportional hazard models were used. A total of 132 patients were enrolled. The mean age of study participants was 49.7 years, and 86 patients (65%) were women. Structural recurrence was identified in 39 patients at the end of the study period, and the median follow-up period was 8.7 years. In univariable analyses, gross extra thyroidal extension, N stage, postoperative serum calcitonin and carcinoembryonic antigen (CEA) levels, and LNR were significant (p < 0.05) predictors of structural recurrence. In multivariable analysis, postoperative serum calcitonin, postoperative serum CEA, and LNR were identified as a predictor of disease-free survival (p < 0.05). LNR can potentially predict structural recurrence as a quantitative evaluation tool for lymph node metastasis in patients with MTC.

Because of the low mortality rate of well-differentiated thyroid cancer (WDTC), investigation of the clinical course leading to death is limited. We analyzed the cause of death and clinical course from diagnosis to death in patients who died of WDTC. A total of 592 WDTC patients died between 1996 and 2018. After exclusion, 79 patients were enrolled and divided into four groups based on their clinical course; that is, inoperable at the time of diagnosis (inoperable), distant metastasis (DM) detected at the time of diagnosis (initial-DM), DM detected during follow-up (late-DM), and loco-regional disease (L-R). Lung (55.6%) in papillary thyroid carcinoma (PTC) and bone (46.7%) in follicular thyroid carcinoma (FTC) were the most common metastasis locations. The most common causes of death were respiratory failure (32.3%) and airway obstruction (30.6%) in PTC, and complications due to immobilization arising from bone metastasis (35.3%) in FTC. Brain metastasis was found in 13.3% of patients and had the worst prognosis. The overall survival (OS) differed significantly (p = 0.001) according to clinical course; the inoperable had the shortest survival, followed by the initial-DM, L-R, and late-DM. However, OS did not differ significantly between PTC and FTC patients with initial-DM (p = 0.83). Other causes of death were far more common than death resulting from WDTC. In patients dying of WDTC, the major cause of death varied by metastatic site. OS differed according to clinical course, but not histologic type. Timing and DM sites differed between PTC and FTC.

Distant metastasis is a poor prognostic factor in medullary thyroid carcinoma (MTC), but the significance of differentiating the characteristics according to the site of distant metastasis remains unclear. This study aimed to evaluate the clinical characteristics and long-term oncologic outcomes in MTC patients with distant metastasis. We identified 46 MTC patients with distant metastasis between 1994 and 2019. Clinical characteristics were compared based on the timing of the detection of distant metastasis. Additionally, survival rates following the detection of distant metastasis were evaluated to compare the clinical significance of metastatic site. The detailed causes of death were also investigated. Of the 46 patients, 15 patients (32.6%) had synchronous distant metastasis and 31 patients (67.4%) had metachronous distant metastasis. There was no clinical difference between these two groups except regarding initial surgical extent. The lung (52.2%) was the most common metastatic site, followed by the bone (28.3%), mediastinum (19.6%), liver (17.4%), adrenal gland (4.3%), brain (4.3%), kidney (2.2%), and pancreas (2.2%). Patients with bone metastasis and multisite metastasis had significantly worse prognoses than those with lung metastasis (hazard ratio: 5.42; p = 0.044 and hazard ratio: 6.11; p = 0.006). Complications due to the progression of distant metastasis, airway obstruction due to tracheal invasion, and complications related to chemotherapy were leading causes of death. In conclusion, there was no difference in clinical characteristics according to the timing of distant metastasis. Oncological outcomes differed by metastatic site.

The role of telomerase reverse transcriptase (TERT) promoter mutations as an independent poor prognostic factor in differentiated thyroid cancer (DTC) patients is well known, but there is no prognostic system that combines the TERT promoter mutation status with tumor-node-metastasis (TNM) stage to predict cancer-specific survival (CSS). A total of 393 patients with pathologically confirmed DTC after thyroidectomy were enrolled. After incorporating wild-type TERT and mutant TERT with stages I, II, and III/IV of the AJCC TNM system 8th edition (TNM-8), we generated six combinations and calculated 10-year and 15-year CSS and adjusted hazard ratios (HRs) for cancer-related death using Cox regression. Then, a new mortality prediction model termed TNM-8T was derived based on the CSS and HR of each combination in the four groups. Of the 393 patients, there were 27 (6.9%) thyroid cancer-related deaths during a median follow-up of 14 years. Patients with a more advanced stage had a lower survival rate (10-year CSS for TNM-8T stage 1, 2, 3, and 4: 98.7%, 93.5%, 77.3%, and 63.0%, respectively; p < 0.001). TNM-8T showed a better spread of CSS (p < 0.001) than TNM-8 (p = 0.002) in the adjusted survival curves. The C-index for mortality risk predictability was 0.880 (95% CI, 0.665–0.957) in TNM-8T and 0.827 (95% CI, 0.622–0.930) in TNM-8 (p < 0.001). TNM-8T, a new prognostic system that incorporates the TERT mutational status into TNM-8, showed superior predictability to TNM-8 in the long-term survival of DTC patients.