Molecular Characterization of Upper Pole Thyroid Nodules

Introduction

• Thyroid nodules are common, and the vast majority are benign.¹
• While radiologic criteria can effectively stratify nodules by malignancy risk, these approaches are imperfect, subjecting patients with benign lesions to over-surveillance and over-treatment.¹
• Thyroid nodule location is an independent risk factor for thyroid cancer with isthmus nodules having the highest risk,² at least partially attributed to distinct molecular features.³
• Among lobar nodules, those from the upper poles have been associated with increased risk for malignancy,^{2, 4, 5} though the molecular basis of this association remains unclear.

Methods

• A retrospective evaluation of samples for which Afirma Genomic Sequencing Classifier (GSC) was ordered as part of routine clinical care from January 2018 to December 2024.
• Inclusion criteria:
  • Samples that passed quality control (QC) for Afirma GSC testing
  • Samples with (B)ethesda III–VI cytology
  • Samples where the nodule location was designated (upper, middle, lower) within a thyroid lobe
• Exclusion criteria:
  • Samples that failed (QC)
  • Samples from the isthmus or where only thyroid lobe laterality was documented
• Clinical and molecular features were compared between upper lobe thyroid nodules and those from other locations.
  • p-values were computed using a Fishers-Exact for categorical variables, Mann-Whitney U-test for continuous variable with permutation testing for 1K iterations, and chi-square test with permutation testing for 2k iterations.

Conclusions

• Upper pole nodules were smaller, though had a higher proportion of B V/VI cytology, GSC-S, and BRAFp.V600E.
• Some gene expression signatures associated with aggressive disease were also higher in upper pole nodules.
• A study limitation is the lack of clinical outcomes data including histopathology of surgical specimens if thyroidectomy was pursued.
• These data suggest that upper pole nodules harbor more suspicious features than those arising from other lobar locations. Whether this information alters clinical practice requires further evaluation.