Appropriately positioned molecular testing for cytologically indeterminate thyroid nodules in an optimized thyroid nodule diagnostic pathway has incremental impact in addition to clinical assessment, cytology and ultrasound malignancy risk

Jiahui Wu; Paul Stewardson; Markus Eszlinger; Moosa Khalil; Sana Ghaznavi; Erik Nohr; Adrian Box; Ralf Paschke

doi:10.1530/endoabs.101.PS2-12-08

PS2-12-08

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Endocrine Abstracts (2024) 101 PS2-12-08 | DOI: 10.1530/endoabs.101.PS2-12-08

ETA2024 Poster Presentations Diagnosis of thyroid cancer-1 (10 abstracts)

Appropriately positioned molecular testing for cytologically indeterminate thyroid nodules in an optimized thyroid nodule diagnostic pathway has incremental impact in addition to clinical assessment, cytology and ultrasound malignancy risk

Jiahui Wu ¹ , Paul Stewardson ² , Markus Eszlinger ³ , Moosa Khalil ⁴ , Sana Ghaznavi ⁵ , Erik Nohr ⁶ , Adrian Box ⁴ & Ralf Paschke ⁷

Err

Author affiliations

¹University of Calgary, Arnie Charbonneau Cancer Institute, Cumming School of Medicine, Calgary, Canada; ²University of Calgary, University of Calgary, Department of Medical Science, Calgary, Canada; ³Institute of Pathology, Molecular Pathology, Cumming School of Medicine, Halle (Saale), Germany; ⁴University of Calgary, Cumming School of Medicine, Department of Pathology and Laboratory Medicine, Calgary, Ab, Canada; ⁵University of Calgary, Department of Medicine, Section of Endocrinology, Calgary, Canada; ⁶University of Calgary, Canada; ⁷Department of Medicine, Cumming School of Medicine, University of Calgary, Calgary, Canada

Objective: Molecular test (MT) of cytologically indeterminate thyroid nodules (ITNs) needs to be appropriately focused on clinical situations where it can influence decision making. We therefore evaluated MT as an adjunct to an optimized integrated interdisciplinary thyroid nodule diagnostic pathway.

Methods: 1024 consecutive ITNs were included, each underwent reflexive ThyroSPEC MT between July 30, 2020, and October 30, 2023. A multivariate regression model was built to assess the rates of malignancy (ROM) for ThyroSPEC MT categories and other clinical variables. A nomogram was generated based on the model as a graphical tool to compute the overall ROM in clinical practice.

Results: The model achieved a cross-validated AUC of 0.83. Patients with high-risk mutations or malignant molecular markers exhibited significantly higher odds (152.8 times) of malignancy compared to those with mutation-negative or benign molecular marker results. The ThyroSPEC MT demonstrated a negative predictive value of 92% [CI 84-97%] for ATA low suspicion or TR3 category and 89% [CI 83-94%] for ATA intermediate suspicion or TR4 category. Mutation was the predominant reason for surgery in 55% of patients with intermediate-risk mutations and in 100% of patients with malignant molecular marker and high-risk mutations. 40% of patients opted against surgery despite positive mutation results (64 intermediate-risk mutation, 4 malignant molecular marker or high-risk mutation) due to patient preference based on informed, shared decision-making. However, among patients with a benign mutation, 38% of cases were under surveillance because of the benign mutation, while 19% of cases under surveillance were due to patient preference.

Model result
Covariate	OR (95% CI)	P
ThyroSPEC High-risk Mutations or Malignant molecular markers (vs. Mutation Negative or Benign Molecular Marker)	152.8 (18.8, 1245.0)	<0.0001
ThyroSPEC Intermediate-risk Mutations (vs. Mutation Negative or Benign Molecular Marker)	5.7 (3.2, 10.1)	<0.0001
Max nodule size >5 (vs. 0-2)	4.3 (1.6, 11.5)	0.003
Bethesda Nuclear Atypia (vs. no atypia mentioned)	4.3 (2.2, 8.3)	<0.0001
USMR 5 (vs. 1-3)	2.9 (1.3, 6.4)	0.009
USMR 4 (vs. 1-3)	1.8 (1.0, 3.4)	0.063
Palpation Discovery yes (vs. no)	1.8 (1.1, 3.2)	0.033
Bethesda BIV (vs. BIII)	1.6 (0.8, 3.0)	0.161
USMR 1-3: ATA benign–low risk, ACR-TIRADS 1–3
USMR 4: ATA intermediate risk, ACR-TIRADS 4
USMR 5: ATA high risk, ACR-TIRADS 5

Conclusions: High-risk mutations or malignant molecular markers were associated with significantly higher odds of histological malignancy and always impacted clinical management. For the most frequent intermediate-risk mutation nodules, integrating the ROM of the MT results with the ROM of additional clinical variables may further improve clinical decision making. Overall, these results highlight the importance of appropriately positioning and interpreting MTs as an adjunct to an optimized integrated interdisciplinary thyroid nodule diagnostic pathway to further improve diagnostic impact.Model result