Background: Increased incidence of small differentiated thyroid cancer (DTC) has emphasized the need for risk stratification and individualized disease management for these low risk DTCs. The aim was to validate a new dynamic risk stratification (DRS) system for prediction of structural recurrent/persistent disease in patients with DTC treated without radioactive iodine (RAI) remnant ablation therapy. Methods: This historical cohort study included 357 patients with DTC treated with lobectomy or total thyroidectomy without RAI therapy. We stratified patient response to initial treatment as excellent, indeterminate, biochemical incomplete, and structural incomplete according to the DRS system. Results: During a median 8.6 year of follow-up, 3.6% patients had structural recurrent DTC. The response was excellent in 71.7% patients, indeterminate in 18.5%, biochemical incomplete in 8.4%, and structural incomplete in 1.4%. There were significant differences in disease-free survival among the DRS groups (p < 0.001). The hazard ratio (HR) of recurrent/persistent disease was significantly higher in biochemical incomplete group (HR = 20.8, p < 0.001) and structural incomplete group (HR = 243.3, p < 0.001) compared with the excellent group. However, the tumor node metastasis (TNM) staging system and the American Thyroid Association (ATA) initial risk classification did not effectively predict recurrence of DTC. Conclusions: The new DRS system was effective for predicting risk of recurrent/persistent disease in patients with DTC who underwent lobectomy or total thyroidectomy without RAI remnant ablation.

Background Total thyroidectomy and cervical lymph node (LN) dissection is generally recommended in patients with medullary thyroid carcinoma (MTC). However, there is no clear evidence for whom to perform prophylactic lateral neck dissection in MTC patients without evident lateral cervical lymph node (LCLN) metastasis in preoperative images. This study evaluated the preoperative features for predicting the LCLN metastasis of MTC. Methods We included 26 MTC patients with LCLN metastasis at initial surgery (N1b group) and 47 MTC patients without any LN metastasis or recurrence of disease (N0-NED group). We evaluated the association between LCLN metastasis and preoperative clinical and sonographic characteristics (size, location, solid component, shape, margin, echogenicity, calcification, and subcapsular location of the tumor). Results There were no significant differences in age and sex between the N1b and N0-NED groups. Preoperative serum levels of calcitonin (Ctn) above 65 pg/mL were associated with LCLN metastasis (p < 0.001). In preoperative neck ultrasonography (US), patients in the N1b group were more commonly found with a larger tumor (>1.5 cm) of irregular shape with a spiculated margin and a subcapsular location than those in the N0-NED group (p = 0.029, p < 0.001, p < 0.001, and p < 0.001, respectively). Increases in the number of these LCLN metastasis-related features were significantly associated with higher risk for LCLN metastasis (p < 0.001). The presence of two or more predictors was an appropriate cut-off point for predicting LCLN metastasis of MTC with 73.1% sensitivity and 91.5% specificity. Conclusions MTC tumors with high preoperative Ctn levels (>65 pg/mL), larger size (>1.5 cm), irregular shape, spiculated margins, and subcapsular locations in the neck US are at higher risk for LCLN metastasis. MTC patents with less than two predictors might be suitable for treatment without prophylactic LCLN dissection.

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.

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.

The diagnosis of encapsulated follicular-patterned thyroid carcinoma (EFPTC) is challenging, and the detection of capsular invasion and/or vascular invasion is essential in distinguishing benign lesions from malignant lesions. In this study, we present a modified transverse-vertical gross examination method with additional vertical cuts at the upper and lower ends of thyroid nodules. In addition, we compared the clinicopathological characteristics of patients with EFPTC between conventional and modified methods. The diagnostic rate of follicular thyroid carcinoma and invasive encapsulated follicular variant of papillary thyroid carcinoma was higher with the modified method (p = 0.003 and p = 0.028, respectively). Furthermore, the paraffin block number and the number of capsular invasion per centimeter were significantly higher with the modified method (p < 0.001 and p = 0.007, respectively). However, vascular invasion was not significantly different between the two methods (p = 0.771). The possibility of identifying capsular invasion was around two times higher with the modified method (odds ratio = 1.91, 95% confidence interval = 1.20–3.07, p = 0.007). A total of 38 samples (23%) in the modified transverse-vertical group had capsular and/or vascular invasion in the additional vertical cuts of the upper/lower ends of the tumor. Our modified transverse-vertical gross examination method was more effective than the conventional transverse examination method for the detection of capsular invasion in EFPTC. This modified gross examination method might allow a better differential diagnosis among various encapsulated micro-follicular proliferative lesions.