Insights in biomarkers complexity and routine clinical practice for the diagnosis of thyroid nodules and cancer.

Background: The differential diagnosis between benign and malignant thyroid nodules continues to be a major challenge in clinical practice. The rising incidence of thyroid neoplasm and the low incidence of aggressive thyroid carcinoma, urges the exploration of strategies to improve the diagnostic accuracy in a pre-surgical phase, particularly for indeterminate nodules, and to prevent unnecessary surgeries. Only in 2022, the 5th WHO Classification of Endocrine and Neuroendocrine Tumors, and in 2023, the 3rd Bethesda System for Reporting Thyroid Cytopathology and the European Thyroid Association included biomarkers in their guidelines. In this review, we discuss the integration of biomarkers within the routine clinical practice for diagnosis of thyroid nodules and cancer. Methodology: The literature search for this review was performed through Pub Med, Science Direct, and Google Scholar. We selected 156 publications with significant contributions to this topic, with the majority (86, or 55.1%) published between January 2019 and March 2024, including some publications from our group during those periods. The inclusion criteria were based on articles published in recognized scientific journals with high contributions to the proposed topic. We excluded articles not emphasizing molecular biomarkers in refine the pre-surgical diagnosis of thyroid nodules. Results: We explored genetic biomarkers, considering the division of thyroid neoplasm into Conclusions: The knowledge of genetic and molecular biomarkers has achieved a high level of complexity, and the difficulties related to its applicability determine that their implementation in clinical practice is not yet a reality. More studies with larger series are needed to optimize their use in routine practice. Additionally, the improvement of new techniques, such as liquid biopsy and/or artificial intelligence, may be the future for a better understanding of molecular biomarkers in thyroid nodular disease.