No prognostic or molecular disparity between synchronous and metachronous metastases in differentiated thyroid cancer: insight from middle eastern cohort

Abstract

Background: Whether synchronous (SDM) and metachronous (MDM) metastases in differentiated thyroid cancer (DTC) differ in clinical behavior or molecular profiles remains unclear. Prior studies suggest poorer outcomes in metachronous cases but regional molecular profiles and clinical outcome are not well defined. We aimed to assess whether molecular alterations, immune landscape, metastatic sites and survival outcomes differ between SDM and MDM DTC in a large Middle Eastern cohort.

Materials and method: Among 1,822 DTC patients, 178 developed distant metastases-88 (4.8%) SDM and 90 (4.9%) MDM. Clinicopathological features, mutational status, PD-L1 expression and radioactive iodine (RAI) response were compared. Kaplan-Meier analysis assessed overall survival (OS) and thyroid cancer-specific survival (TCSS).

Results: Molecular alterations were largely similar between SDM and MDM groups. TERT mutation alone occurred in 16.9% of SDM vs. 19.7% of MDM. BRAF V600E mutation alone was significantly higher in MDM cases (22.2% vs 10.4%). TERT and BRAF V600E co-mutations were comparable (22.1% vs 30.9%) between the two groups. NRAS, HRAS and TP53 mutations showed no significant difference. RAI refractoriness was 57.9% (SDM) vs 67.8% (MDM) and PD-L1 high expression was 42.2% (SDM) vs 54.5% (MDM). Cancer-specific mortality was 8.6% in SDM and 13.8% in MDM groups. Metastatic patterns revealed the lung as the most common site (69.3% SDM vs. 84.4% MDM), followed by bone (37.5% vs. 26.7%), brain (5.7% vs. 3.3%) and liver (1.1% in synchronous only). Multiple-organ metastasis were observed in 11.4% of SDM and 13.3% MDM patients. However, Kaplan Meier curves showed no statistically significant differences in OS or TCSS by metastatic timing or metastatic site.

Conclusion: In this Middle Eastern cohort, no consistent molecular or clinical disparities across most parameters. These findings suggest the timing of metastasis may not independently influence prognosis and highlight the relevance of individualized, biology-driven management strategies.

Keywords: differentiated thyroid cancer; metachronous metastasis; middle east; prognosis; synchronous metastasis.