Young Kee Shong

Purpose Active surveillance (AS) is an alternative treatment approach for small, low-risk papillary thyroid microcarcinoma (PTMC). This study aimed to assess the clinical outcomes of small, highly suspicious nodules lacking initial cytological confirmation. Methods This study included 112 patients with highly suspicious nodules measuring ≤ 10 mm who underwent serial ultrasound at Asan Medical Center, Korea, between 2010 and 2023. Results The median participant age was 51.9 years, and 74.1% were female. The median maximal tumor diameter and tumor volume (TV) were 4.5 (interquartile range [IQR] 3.7–5.2, range 2.2–9.3) mm and 25.2 (IQR 13.1–49.2) mm³, respectively. During a median follow-up period of 4.8 years, four (3.6%) patients showed a ≥ 3 mm increase in maximal diameter, and two (1.8%) developed new lymph node (LN) metastasis. Disease progression was associated with a TV doubling time (TVDT) of < 5 years and a ≥ 75% increase in TV (p = 0.017 and p < 0.005, respectively). Furthermore, 34.8% of patients underwent fine needle aspiration (FNA), primarily at their own request, yielding 46.2%, 5.1%, 41.0%, and 12.8 % malignant, benign, indeterminate, and non-diagnostic results, respectively. Of 18 patients with PTMC, 8 (44.4%) underwent surgery and 10 continued AS, with no LN metastasis during AS and no postoperative recurrence. Conclusion Small, highly suspicious nodules had a low disease progression rate during AS without FNA. Disease progression was associated with a TVDT of < 5 years and a ≥ 75% increase in TV. FNA can be performed more conservatively than it currently is in patients with highly suspicious nodules measuring ≤ 10 mm.

This study was designed to evaluate the prognostic implication of gross extrathyroidal extension (ETE) invading the strap muscles after thyroid lobectomy i

Background Technetium-99 m (^99mTc) pertechnetate thyroid uptake rate can be measured with a gamma probe or gamma camera. This study was performed to compare their diagnostic accuracy for evaluating patients with thyrotoxicosis. Methods We retrospectively reviewed ^99mTc pertechnetate thyroid uptake rate records of patients by both gamma probe and camera methods at a tertiary center in Korea from November 2019 to June 2020. We determined the normal reference ranges of thyroid uptake rate by two methods and compared both methods for differentiating Graves’ disease and thyroiditis in patients with thyrotoxicosis by receiver operating characteristic curve analysis. Results A total of 371 patients (euthyroid 89, Graves 167, and thyroiditis 115) were included. The normal reference range for thyroid uptake rate in euthyroid patients was 0.3–1.9% and 2.0–4.7% for the camera and probe methods, respectively. For differentiating Graves’ disease and thyroiditis, the area under the curve of the camera method (0.988) was significantly greater than that (0.975) of the probe method (p = 0.030). The sensitivity and specificity for the probe method were 92.2% and 91.3%, respectively, with a cut-off value of 3.0%. Those for the camera method were 93.4% and 94.8%, respectively, with a cut-off value of 0.7%. Conclusion ^99mTc pertechnetate thyroid uptake rate measured by the camera method had higher diagnostic accuracy than the probe method for evaluating patients with thyrotoxicosis. Considering the diagnostic accuracy and patient convenience, the thyroid uptake rate measured by the camera method would be a good substitute for the probe method.

The prognosis of BRAF^V600E-mutant papillary thyroid carcinoma (PTC) ranges from indolent to highly aggressive courses. To better define the genetic diversity of this subtype, we evaluated the survival according to the presence of an additional mutation in genes encoding functional groups (FGs) in BRAF^V600E-mutant advanced PTC patients. Targeted next-generation sequencing was performed in primary tumors of 50 BRAF^V600E-mutant PTCs with distant metastasis or aggressive variants. The mutation in genes encoding FGs included alterations in histone methyltransferases, SWI/SNF subunit, and the PI3K/AKT/mTOR pathway. The primary outcome was overall survival (OS). Fifteen patients only had the BRAF^V600E-mutation (group 1), 22 had BRAF^V600E and mutation other than FGs (group 2), and 13 had BRAF^V600E and FG mutation (group 3). OS was significantly lower in patients with FG mutations (p = 0.001) than those without, and group 3 patients had the worst survival (p = 0.004). OS significantly varied among none, one, or two FG mutation sites (p = 0.005). Presence of FG mutation was independently associated with increased mortality (hazard ratio 11.65, 95% confidence interval 1.39–97.58, p = 0.024). Coexistence of mutations in BRAF^V600E and genes encoding FGs was associated with high mortality. Identification of FG mutation in BRAF^V600E-mutant PTCs may be valuable in risk stratifying this subtype.

Background: Some papillary thyroid microcarcinomas (PTMCs) may progress with tumor enlargement or development of new lymph node (LN) metastasis during active surveillance (AS). This study evaluated the relevant predictors of disease progression, especially new cervical LN metastasis. Methods: This was a long-term follow-up study conducted using a previous multicenter cohort of AS in Korea. After excluding 54 (14.2%) patients with a short follow-up duration, 326 PTMC patients were evaluated for tumor kinetics, including changes in tumor volume (TV) and TV doubling time (TVDT). Results: During a median follow-up duration of 4.9 years, 17 (5.2%, 95% confidence intervals [CI] 2.7%–7.6%) patients showed a maximal diameter increase of ≥3 mm after a median 4.0 years of follow-up, while 9 (2.8%, 95% CI 1.0%–4.5%) showed newly developed LN metastasis after a median 2.2 years of follow-up. New cervical LN metastasis occurred exclusively of a maximal diameter increase of ≥3 mm. The prevalence of new development of LN metastasis was higher in patients with TVDT <5 years (7.4%) than in those with TV ≥50% (3.2%). Furthermore, only TVDT <5 years was significantly associated with LN metastasis (P = 0.002). In univariate and multivariate analyses, TVDT <5 years was an independent risk factor for disease progression with respect to new development of LN metastasis (hazard ratio [HR] = 6.51, CI 1.73–24.50; P = 0.002) and tumor enlargement (HR = 20.89, CI 5.78–75.48; P < 0.001). Finally, 86 (22.6%) patients underwent delayed surgery, and the most common reason was anxiety. Conclusions: TVDT <5 years is the best predictor of disease progression during AS in terms of new LN metastasis development as well as tumor enlargement. Determination of TVDT in the early phase of AS could help in predicting disease progression for the precise tailoring of the follow-up intensity of AS and in determining if early surgical intervention is needed.

Purpose: The diagnostic performance of thyroid biopsy is influenced by several factors, including differences in the Bethesda categorization for malignancy, the inclusion or exclusion of non-diagnostic results, the definition used for the final diagnosis, and the definition of an inconclusive diagnosis. The purpose of this study was to provide an understanding of the factors influencing the diagnostic performance of thyroid biopsy. Methods: We collected data retrospectively between January and December 2013 from a cohort of 6,762 thyroid nodules from 6,493 consecutive patients who underwent biopsy. In total, 4,822 nodules from 4,553 patients were included. We calculated the biopsy sensitivity according to the inclusion of different Bethesda categories in the numerator and the exclusion of non-diagnostic results, as well as the diagnostic accuracy according to different definitions of a benign diagnosis. We obtained the conclusive and inconclusive diagnosis rates. Results: The sensitivity increased when more Bethesda categories were included in the numerator and when non-diagnostic results were excluded. When a benign thyroid nodule diagnosis was defined as benign findings on surgical resection, concordant benign results on at least two occasions, or an initial benign biopsy result and follow-up for more than 12 months, the accuracy was higher than when the diagnosis was based on surgical resection alone (91.1% vs. 68.7%). A higher conclusive diagnosis rate was obtained when Bethesda categories I and III were considered inconclusive than when Bethesda categories I, III and IV were considered inconclusive (78.3% vs. 72.8%, P<0.001). Conclusion: Understanding the concepts presented herein is important in order to appropriately interpret the diagnostic performance of thyroid biopsy.

Aggressive variants of papillary thyroid carcinoma (PTC) have been described with increasing frequency and are associated with unfavorable clinical outcomes. However, limited data exist on the comprehensive genetic profile of these variants. We performed targeted next-generation sequencing in 36 patients with aggressive variants of PTC and compared it to PTC from The Cancer Genome Atlas (TCGA) project and poorly differentiated thyroid cancers (PDTCs)/anaplastic thyroid cancers (ATCs) from the Memorial Sloan Kettering Cancer Center (MSKCC). BRAF mutation was the most prevalent (89%) in aggressive variants of PTC compared to that in other thyroid cancers. RAS mutation was identified in one patient (3%), which was less frequent than in others. TERT promoter mutation (17%) ranged between that of PTCs (9%) and PDTCs (40%). Tumor suppressor genes, ZFHX3, TP53, and CHEK2, were mutated in 14%, 3%, and 6% of aggressive variants of PTC, respectively. The mutation rate of TP53 (3%) was significantly higher than that of PTCs (0.7%) and lower than that of ATCs (73%). Mutations in three functional groups, histone methyl transferases, SWI/SNF chromatin remodeling complex, and the PI3K/AKT/mTOR pathway, were present in 11%, 14%, and 11% of samples, respectively. In conclusion, aggressive variants of PTC had higher BRAF and lower NRAS mutation prevalence than other thyroid cancers. The prevalence of mutations in the TERT promoter, TP53, and genes encoding three functional groups ranged between that of PTCs and PDTCs/ATCs.

Background: Advanced thyroid cancers, including differentiated thyroid carcinoma (DTC) with distant metastasis, and anaplastic thyroid carcinoma (ATC), are associated with poor clinical outcomes and limited treatment options. This study aimed to determine the immune profiles of advanced thyroid cancers using fluorescent multiplex immunohistochemistry (F-MIHC) and multispectral imaging (MSI). Methods: Twenty-eight tissue samples were collected from 12 patients who had DTC with distant metastasis and from 16 with ATC. The samples were assessed using F-MIHC and MSI with antibodies against the cell surface molecules, cluster of differentiation (CD)4, CD8, programmed cell death-1 (PD-1), PD ligand 1 (PD-L1), forkhead box protein 3, and cytokeratin (CK). The expression of PD-L1 was evaluated using tumor proportion score (TPS) and combined positive score (CPS). Results: Significantly, more PD-L1-positive tumor cells (CK ⁺ PD-L1 ⁺ ) per mm ² were found in ATC samples than in DTC samples (183.5 vs. 0.03, p < 0.001). Lymphocyte infiltration was significantly increased in ATC compared with DTC, with significantly more PD-L1- or PD-1-positive lymphocytes in ATC samples than in DTC samples. The TPS and CPS for PD-L1 expression were negative in all DTC samples but positive in 81% and 94% of ATC samples, respectively. Conclusions: Immune profiling revealed significant differences between advanced DTC and ATC, particularly in terms of PD-L1 expression and lymphocyte infiltration. Therefore, immune profiling using F-MIHC and MSI can provide invaluable information regarding tumor microenvironments, which could help select candidates for immunotherapy.

Background: We examined the changes in glucose metabolites of papillary thyroid cancer (PTC) and identified phosphoglycerate dehydrogenase (PHGDH) as a potential target. The role of PHGDH in the proliferation and tumorigenesis of thyroid cancer cells and its clinical significance were analyzed. Methods: Glucose metabolites of various thyroid tissues were analyzed via targeted metabolomics analysis. In vitro experiments using shPHGDH s, inhibitor (NCT503), or PHGDH overexpression in thyroid cell lines (BCPAP, 8505C, and Nthy-Ori) were performed. In vivo experiments were performed by using shPHGDH . Human tissue samples and The Cancer Genome Atlas (TCGA) data were used to validate the experimental findings. Results: PHGDH knockdown in BCPAP and 8505c cell lines significantly inhibited cell viability, colony formation, and tumor spheroid formation compared with the control. In addition, treatment with NCT503 showed similar results. PHGDH inhibition by both knockdown and treatment with NCT503 significantly inhibited the expression of embryonic cancer stemness markers ( Oct4 , Sox2 , KLF4 , and Nanog ). PHGDH overexpression in Nthy-Ori cells significantly increased cell viability and colony formation. The stemness markers were significantly increased after PHGDH overexpression. PHGDH knockdown significantly inhibited tumor growth in an in vivo mouse xenograft study using 8505c cells. The protein expression of Oct4 in tumors was significantly reduced after PHGDH knockdown. The associations between PHGDH expression and stemness markers were confirmed in the TCGA data and human thyroid tissue samples. Positive PHGDH protein expression was associated with metastases of PTC. Conclusions: PHGDH expression is induced in thyroid cancer and is associated with stemness and aggressiveness of PTC.