Molecular Variants and Their Risks for Malignancy in Cytologically Indeterminate Thyroid Nodules.

Area of Science:

• Genomics
• Oncology
• Molecular Diagnostics

Background:

• Gene panels are used for hereditary cancer predisposition and somatic alterations in solid tumors.
• Targeted variant panels are increasingly used for thyroid nodules with indeterminate fine-needle aspiration (FNA) results.

Purpose of the Study:

• To systematically review and calculate pooled prevalence and positive predictive values (PPVs) for malignancy of genetic alterations in cytologically indeterminate thyroid nodules (ITNs).

Main Methods:

• Systematic review of studies published between 2009 and 2018 on preoperative FNA specimens from ITNs.
• Included genetic data from 61 studies (>4600 ITNs) that underwent surgical resection.
• Calculated pooled prevalence and PPVs for specific genes and variants.

Main Results:

• 26% of ITNs contained at least one variant or fusion; however, half lacked detailed reporting.
• High PPV for malignancy was observed for BRAF (98%).
• Other reported alterations like PAX8/PPARG, HRAS, and NRAS had lower PPVs (38-55%).

Conclusions:

• The predictive value of genomic alterations for thyroid nodule malignancy varies significantly by specific variant or fusion.
• Limited reporting and small sample sizes for most alterations impact confidence in PPV estimates.
• Improved reporting of genomic alterations alongside clinical data is needed for better cancer prediction and prognosis assessment.