Diagnostic utility of RAS mutation testing for refining cytologically indeterminate thyroid nodules

Authors

  • Isabel R. Riccio School of Medicine, Tulane University, New Orleans, LA 70112, USA https://orcid.org/0000-0003-4449-0374
  • Alexandra C. LaForteza Division of Endocrine and Oncologic Surgery, Department of Surgery, School of Medicine, Tulane University, New Orleans, LA 70112, USA https://orcid.org/0009-0003-2874-372X
  • Mohammad H. Hussein Division of Endocrine and Oncologic Surgery, Department of Surgery, School of Medicine, Tulane University, New Orleans, LA 70112, USA https://orcid.org/0000-0001-8278-7094
  • Joshua P. Linhuber School of Medicine, Tulane University, New Orleans, LA 70112, USA https://orcid.org/0009-0001-5096-3767
  • Peter P. Issa School of Medicine, Tulane University, New Orleans, LA 70112, USA https://orcid.org/0000-0002-5248-3142
  • Jonathan Staav School of Medicine, Tulane University, New Orleans, LA 70112, USA https://orcid.org/0009-0005-2174-5380
  • Manal Said Fawzy Department of Biochemistry, Faculty of Medicine, Northern Border University, Arar, Saudi Arabia, E-mail: manal.darwish@nbu.du.sa https://orcid.org/0000-0003-1252-8403
  • Eman A. Toraih Division of Endocrine and Oncologic Surgery, Department of Surgery, School of Medicine, Tulane University, New Orleans, LA 70112, USA, E-mail: etoraih@tulane.edu https://orcid.org/0000-0001-9267-3787
  • Emad Kandil Division of Endocrine and Oncologic Surgery, Department of Surgery, School of Medicine, Tulane University, New Orleans, LA 70112, USA https://orcid.org/0000-0001-5895-4403

DOI:

https://doi.org/10.17179/excli2024-6975

Keywords:

genomic mutations, indeterminate thyroid nodules, fine needle aspiration cytology, thyroid carcinoma, diagnostic accuracy, personalized medicine

Abstract

RAS mutations are prevalent in indeterminate thyroid nodules, but their association with malignancy risk and utility for diagnosis remains unclear. We performed a systematic review and meta-analysis to establish the clinical value of RAS mutation testing for cytologically indeterminate thyroid nodules. PubMed and Embase were systematically searched for relevant studies. Thirty studies comprising 13,328 nodules met the inclusion criteria. Random effects meta-analysis synthesized pooled estimates of RAS mutation rates, risk of malignancy with RAS positivity, and histologic subtype outcomes. The pooled mutation rate was 31 % (95 % CI 19-44 %) among 5,307 indeterminate nodules. NRAS mutations predominated at 67 % compared to HRAS (24 %) and KRAS (12 %). The malignancy rate with RAS mutations was 58 % (95 %CI=48-68 %). RAS positivity increased malignancy risk 1.7-fold (RR 1.68, 95 %CI=1.21-2.34, p=0.002), with significant between-study heterogeneity (I2=89 %). Excluding one outlier study increased the relative risk to 1.75 (95 %CI=1.54-1.98) and I2 to 14 %. Funnel plot asymmetry and Egger's test (p=0.03) indicated potential publication bias. Among RAS-positive malignant nodules, 38.6 % were follicular variant papillary carcinoma, 34.1 % classical variant, and 23.2 % follicular carcinoma. No statistically significant difference in the odds of harboring RAS mutation was found between subtypes. In conclusion, RAS mutation testing demonstrates clinical utility for refining the diagnosis of cytologically indeterminate thyroid nodules. Positivity confers a 1.7-fold increased malignancy risk, supporting use for personalized decision-making regarding surgery vs. monitoring. Follicular variant papillary carcinoma constitutes the most common RAS-positive malignant histological subtype.

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Published

2024-02-15

How to Cite

Riccio, I. R., LaForteza, A. C., Hussein, M. H., Linhuber, J. P., Issa, P. P., Staav, J., … Kandil, E. (2024). Diagnostic utility of RAS mutation testing for refining cytologically indeterminate thyroid nodules. EXCLI Journal, 23, 283–299. https://doi.org/10.17179/excli2024-6975

Issue

Vol. 23 (2024)

Section

Review articles

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Copyright (c) 2024 Isabel R. Riccio, Alexandra C. Laforteza, Mohammad H. Hussein, Joshua P. Linhuber, Peter P. Issa, Jonathan Staav, Manal S. Fawzy, Eman A. Toraih, Emad Kandil

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