Clinical, Pathological, and Molecular Characteristics Correlating to the Occurrence of Radioiodine Refractory Differentiated Thyroid Carcinoma: A Systematic Review and Meta-Analysis

Abstract

Background: Recently, radioiodine refractory differentiated thyroid cancer (RR-DTC) has received increasing attention due to its poor prognosis. The roles of clinical, pathological, and molecular features in the development of RR-DTC remain controversial and require additional investigation. This study aimed to evaluate the association between these risk factors and the occurrence of RR-DTC. Methods: We performed a systematic search for relevant literature following the recommendations of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) in PubMed, EMBASE, Medline, SCOPUS, and Web of Science up to the July 15, 2020. Observational studies that investigated the risk factors for RR-DTC were included. Fixed-or random-effects models were used to calculate pooled odds ratios (ORs) or mean differences (MD) with corresponding 95% confidence intervals. Results: We included 13 eligible studies incorporating 1,431 cases, of which 603 were patients with RR-DTC. The pooled analysis indicated that four parameters significantly increased the risk of RR-DTC: extrathyroidal extension (ETE) (OR: 2.28, 95% CI: 1.43-3.64, I 2 = 14%), BRAF V600E mutation (OR: 3.60, 95% CI: 1.74-7.46, I 2 = 69%), TERT promoter mutation (OR: 9.84, 95% CI: 3.60-26.89, I 2 = 61%) and high-risk histological subtype (OR: 1.94, 95% CI: 1.15-3.27, I 2 = 15%), including tall cell variant papillary thyroid carcinoma (PTC), sclerosing diffuse PTC, hobnail variant PTC, follicular thyroid carcinoma (FTC) (including Hürthle cell), and poorly differentiated thyroid carcinoma (PDTC). However, there was no statistical significance regarding sex, age, tumor size, multifocality, or lateral lymph node metastasis. Subgroup and sensitivity analyses were conducted to further confirm the robustness of the results. Luo et al. Predictors of Radioiodine Refractory PTC Conclusions: Histological subtype, ETE, BRAF V600E mutation, and TERT promoter mutation could be considered clinicopathological factors and biomarkers. They could assist in risk stratification, prognostic prediction, and individual therapy options for RR-DTC.

DNA repair pathway activation features in follicular and papillary thyroid tumors, interrogated using 95 experimental RNA sequencing profiles

“…Two decades ago, a connection between thyroid cancer radioactive iodine resistance and activity of sodium iodide symporter gene SLC5A5 was discovered [ 9 ]. Also, BRAF and TERT mutations were found as the predictors of radio iodine refractory thyroid cancer, especially in duet [ 10 , 11 , 12 ]. However, it is clear that the problem has not been solved yet as there are no effective instruments in clinics to predict thyroid cancer resistance to radiation therapy [ 13 ].…”

Targeted Therapy of Papillary Thyroid Cancer: A Comprehensive Genomic Analysis

“…Given the predominance of BRAF mutations in RAI-R DTC (26,27), it is possible that classic papillary thyroid cancer and tall-cell variant more often develop to refractory disease. The second highest frequency of mutation hotspots occurred in the RAS-Pathway.…”

“…Finally, several studies have demonstrated that TERT promoter mutations, particularly in association with BRAF V600E, correlate with negative clinical characteristics such as RAI-refractory disease (27,65). TERT promoter mutations were reported in 36 (9.4%) of 384 informative tumors in the TCGA data (19).…”

Delayed Initial Radioiodine Adjuvant Therapy Does Affect Biochemical Response in Intermediate- to High-Risk Differentiated Thyroid Cancer

“…Generally, most patients (accounts for about 71.8% of DTC patients during the study) completed their first RAT within three months after thyroidectomy, which may better reflect current practice patterns in the care of patients with DTC. An earlier Meta-Analysis detailed that poor clinicopathologic features may relate to the occurrence of radioiodine refractory DTC (16). Tg reduction index and sTg level may be useful in predicting clinical outcomes and potential future disease recurrence in DTC (17)(18)(19).…”

“…An earlier Meta-Analysis detailed that poor clinicopathologic features may relate to the occurrence of radioiodine refractory DTC ( 16 ). Tg reduction index and sTg level may be useful in predicting clinical outcomes and potential future disease recurrence in DTC ( 17 – 19 ).…”