Development, Validation, and Implementation of Cytologically Indeterminate Thyroid Nodule Molecular Testing

Stewardson, Paul

Development, Validation, and Implementation of Cytologically Indeterminate Thyroid Nodule Molecular Testing

dc.contributor.advisor	Eszlinger, Markus
dc.contributor.advisor	Paschke, Ralf
dc.contributor.author	Stewardson, Paul
dc.contributor.committeemember	Demetrick, Douglas J.
dc.contributor.committeemember	Bose, Pinaki
dc.contributor.committeemember	Morris, Donald
dc.contributor.committeemember	Wiseman, Sam M.
dc.date	2024-05
dc.date.accessioned	2024-04-19T20:36:59Z
dc.date.available	2024-04-19T20:36:59Z
dc.date.issued	2024-04-17
dc.description.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.
dc.identifier.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.
dc.identifier.uri	https://hdl.handle.net/1880/118431
dc.language.iso	en
dc.publisher.faculty	Cumming School of Medicine
dc.publisher.institution	University of Calgary
dc.rights	University of Calgary graduate students retain copyright ownership and moral rights for their thesis. You may use this material in any way that is permitted by the Copyright Act or through licensing that has been assigned to the document. For uses that are not allowable under copyright legislation or licensing, you are required to seek permission.
dc.subject	thyroid
dc.subject	cancer
dc.subject	therapy selection
dc.subject	genomics
dc.subject	indeterminate
dc.subject	cytopathology
dc.subject	diagnostics
dc.subject	molecular
dc.subject	oncology
dc.subject.classification	Oncology
dc.subject.classification	Biology--Molecular
dc.title	Development, Validation, and Implementation of Cytologically Indeterminate Thyroid Nodule Molecular Testing
dc.type	doctoral thesis
thesis.degree.discipline	Medicine – Medical Sciences
thesis.degree.grantor	University of Calgary
thesis.degree.name	Doctor of Philosophy (PhD)
ucalgary.thesis.accesssetbystudent	I do not require a thesis withhold – my thesis will have open access and can be viewed and downloaded publicly as soon as possible.