Do thyroid nodules in the isthmus carry a higher risk of malignancy? A systematic review and meta-analysis

The isthmus connects the two lateral lobes of the thyroid gland. It remains unclear whether nodules in the isthmus signify a higher risk of thyroid malignancy.

We searched PubMed, Scopus, and the Web of Science Core Collection through June 2025 for English literature containing sufficient information to analyze the risk of malignancy for thyroid nodules in different locations. Non-English studies, pediatric populations, research focused on small subsets with specific characteristics, and animal or tissue studies were excluded. Random-effects meta-analyses were conducted to estimate the pooled odds ratios (OR), and the JBI Critical Appraisal Checklist was used for quality assessment. The study was registered with PROSPERO (CRD420251103875).

We included 27 studies with 33,474 patients. The median age was 49 years, and 78% were female. Isthmus nodules were associated with higher odds of thyroid cancer (OR 1.46; 95% confidence interval [CI] 1.08 to 1.98). To address moderate heterogeneity, a sensitivity analysis excluding studies with a potentially high risk of bias revealed a consistent trend with a pooled OR of 1.90 (95% CI, 1.38 to 2.60).

This meta-analysis demonstrates an increased risk of malignancy for thyroid nodules in the isthmus compared to those in the lobes. Although the findings suggest a potential benefit of lowering the biopsy threshold for isthmus nodules, this should be interpreted with caution due to the observational design and possible biases.