Risk factors associated with aggressive tumor phenotypes in papillary thyroid microcarcinoma: a systematic review and meta-analysis

Introduction: In line with current guidelines, risk stratification in papillary thyroid microcarcinoma (PTMC) has shifted from simple diameter-based assessments to evaluation of individual tumor biology. Therefore, this study aimed to investigate how baseline clinical and molecular risk factors influence aggressive PTMC phenotypes. Methods: Registered in PROSPERO (CRD42024603662), we searched PubMed, Embase, and Cochrane through February 14, 2025. We analyzed risk factors for lymph node metastasis (LNM) and extrathyroidal extension (ETE) utilizing data from surgical cohorts of patients with PTMC, calculating pooled odds ratios (OR) and 95% confidence intervals (CI). Results: A total of 274 articles we found increased odds of central lymph node metastasis (CLNM) associated with male sex (OR = 1.86; CI:1.73-2.00), age (7 mm OR = 2.26; CI:2.00-2.56 and OR = 1.81; CI:1.11-2.96), multifocality (OR = 1.96; CI:1.78-2.16), bilaterality (OR = 1.70; CI:1.45-2.00) and BRAFV600E mutation (OR = 1.51; CI:1.25-1.82). Lateral lymph node metastasis (LLNM) was associated with male sex (OR = 1.69; CI:1.51-1.90), age (7 mm, OR = 2.34; CI:1.68-3.25 and OR = 3.71; CI:3.15-4.36), multifocality (OR = 1.98; CI:1.46-2.70) and bilaterality (OR = 1.91; CI:1.22-3.00). For ETE, risk factors were as follows: tumor size (>5 mm OR = 3.00; CI:2.03-4.45), multifocality (OR = 2.41; CI:1.99-2.91), bilaterality (OR = 2.58; CI:1.26-5.27), and BRAFV600E mutation (OR = 2.19; CI:1.61-2.97). Conclusion: mutation are clinically relevant risk factors for aggressive PTMC phenotypes. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/view/CRD42024603662, identifier CRD42024603662.