Development, Validation, and Implementation of Cytologically Indeterminate Thyroid Nodule Molecular Testing
Date
2024-04-17
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Abstract
Introduction: Genetic testing is increasingly used to diagnose or rule out thyroid cancer in indeterminate fine-needle aspirations. The research in this dissertation aimed to locally develop and validate a novel molecular test (ThyroSPEC), explore ancillary risk stratification, and measure the impacts of introducing molecular testing at the population level including for therapy selection. Methods: Comprehensive clinical data were collected prospectively for the first 615 consecutive patients with indeterminate thyroid nodules (ITNs) in a centralized healthcare system following implementation of ThyroSPEC. Accuracy of molecular testing and the impact of the introduction of molecular testing were calculated. A 16-miRNA panel was developed and validated in 127 air-dried smear indeterminate thyroid FNAC specimens and 157 liquid thyroid FNAC specimens. In a separate study on therapy selection, 86 high risk thyroid cancer patients were retrospectively identified and screened for NTRK fusions and RET fusions/mutations with molecular tests including ThyroSPEC. Results: A locally developed, low-cost molecular test achieved an NPV of 76-91% and a PPV of 46-65% in ITNs using only residual biopsy material. Following implementation of molecular testing, diagnostic yield increased 14% (p=0.2442) and repeat FNAs decreased by 24% (p=0.05). A miRNA expression classifier achieved sensitivity of 100% and specificity of 83% in the air-dried smear sample type as an adjunct to ThyroSPEC. However, miRNA expression was indistinguishable between benign and malignant tumors in local liquid cytology specimens. Molecular testing of advanced thyroid cancer patients resulted in the detection of NTRK or RET fusions in up to 40% of systematically defined patient subsets. Conclusion: Introduction of molecular testing offers clinical benefits, even in a low resection rate setting, and directly influences surgical decision-making. ThyroSPEC improved preoperative risk stratification of indeterminate thyroid nodules but requires further stratification for negative test results and intermediate risk mutations. This research also presented a novel miRNA expression classifier that could be used to incrementally risk stratify indeterminate air-dried smear FNAC and suggests that methanol-based preservation of thyroid liquid FNAC may hinder use of miRNA expression levels for molecular diagnostics. Our findings also indicate that ThyroSPEC may be suitable to detect NTRK and RET fusions in advanced thyroid cancers.
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Keywords
thyroid, cancer, therapy selection, genomics, indeterminate, cytopathology, diagnostics, molecular, oncology
Citation
Stewardson, P. (2024). Development, validation, and implementation of cytologically indeterminate thyroid nodule molecular testing (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca.