ThyroSPEC™

Prospective validation

 ThyroSPEC™ underwent prospective validation on indeterminate FNAC specimens with available histology in the Southern Alberta and Calgary Healthcare region with centralized FNAC.

  • All specimens were collected as residual material from liquid ThinPrep FNAC
  • These specimens were prospectively consecutively collected over 2 years in Calgary’s centralized cytology center in an ongoing study
  • A guidelines-based thyroid nodule pathway (PCN pathway) including thyroid nodule ultrasound malignancy risk stratification (EFN white paper) and determination of local malignancy risk for each Bethesda category (Ghaznavi et al., CJD, 2018) has recently been implemented for the AHS Calgary Health Care Region
  • Histologic diagnosis is the gold standard against which ThyroSPEC™ diagnosis was evaluated
  • Therefore, only FNAC from patients who underwent resection were included, resulting in a cohort enriched for malignancy due to triage
  • Sample set:

Diagnostic Performance in the AHS Calgary Health Care Region

According to the mutation detected, ThyroSPECTM management recommendations vary from surveillance or lobectomy to total thyroidectomy. The latter recommendation can avoid the burden and morbidity of a completion thyroidectomy and save or prioritize surgeries.

For the 64 analyzed AUS/FLUS FNAC specimens, ThyroSPEC™ showed the following test parameters (Stewardson et al., ATA, 2019):

Sensitivity55%
Specificity88%
Positive Likelihood Ratio4.5
Negative Likelihood Ratio0.5
Detection Threshold10% allelic frequency

For the 34 analyzed FN/SFN FNAC specimens, ThyroSPEC™ showed the following test parameters (Stewardson et al., ATA, 2019):

Sensitivity38%
Specificity75%
Positive Likelihood Ratio1.5
Negative Likelihood Ratio0.8
Detection Threshold10% allelic frequency

The respective local risk of malignancy affects the NPV and PPV of the molecular test and is therefore necessary for proper interpretation of molecular diagnostics.

The validation cohort risk of malignancy (48% and 39% for AUS/FLUS and FN/SFN, respectively) in our ThyroSPEC™ study reflects a cohort enriched for malignancy, not a representative sample, because a high proportion of surgeries took place shortly after the FNA. Data for the AHS Calgary Health Care Region show a risk of malignancy of 26% for the 21% resected AUS/FLUS nodules and 43% for the 56% resected FN/SFN nodules (Ghaznavi et al., CJD, 2018).

Moreover, only a subset of indeterminate (AUS/FLUS and FN/SFN) cases undergo excision. Therefore, estimating the risk of malignancy based on histology alone overestimates the risk of malignancy due to selection bias (The Bethesda System for Reporting Thyroid Cytopathology, second edition, 2018).

On the other hand, when calculating the risk of malignancy using the total number of indeterminate (AUS/FLUS and FN/SFN, respectively) specimens (regardless of surgical follow-up) as the denominator, assuming that unresected nodules are benign, the risk of malignancy is underestimated. The actual risk of malignancy lies between the values obtained using these two different calculations and requires interpolation (The Bethesda System for Reporting Thyroid Cytopathology, second edition, 2018).

Therefore, the real risk of malignancy for the local Southern Alberta and Calgary Healthcare region and the corresponding predictive values for AUS/FLUS FNAC will be between …

risk of malignancy5.5% – 26%
ThyroSPECTM PPV22% – 63%
ThyroSPECTM NPV97% – 85%

The real risk of malignancy for the local Southern Alberta and Calgary Healthcare region and the corresponding predictive values for FN/SFN FNAC will be between …

risk of malignancy24% – 43%
ThyroSPECTM35% – 56%
ThyroSPECTM81% – 64%
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