A Thyroid Genetic Classifier Correctly Predicts Benign Nodules with Indeterminate Cytology: Two Independent, Multicenter, Prospective Validation Trials.

Background: Although most thyroid nodules with indeterminate cytology are benign, in most of the world, surgery remains as the most frequent diagnostic approach. We have previously reported a 10-gene thyroid genetic classifier, which accurately predicts benign thyroid nodules. The assay is a prototype diagnostic kit suitable for reference laboratory testing and could potentially avoid unnecessary diagnostic surgery in patients with indeterminate thyroid cytology. Methods: Classifier performance was tested in two independent, ethnically diverse, prospective multicenter trials (TGCT-1/Chile and TGCT-2/USA). A total of 4061 fine-needle aspirations were collected from 15 institutions, of which 897 (22%) were called indeterminate. The clinical site was blind to the classifier score and the clinical laboratory blind to the pathology report. A matched surgical pathology and valid classifier score was available for 270 samples. Results: Cohorts showed significant differences, including (i) clinical site patient source (academic, 43% and 97% for TGCT-1 and -2, respectively); (ii) ethnic diversity, with a greater proportion of the Hispanic population (40% vs. 3%) for TGCT-1 and a greater proportion of African American (11% vs. 0%) and Asian (10% vs. 1%) populations for TGCT-2; and (iii) tumor size (mean of 1.7 and 2.5 cm for TGCT-1 and -2, respectively). Overall, there were no differences in the histopathological profile between cohorts. Forty-one of 155 and 45 of 115 nodules were malignant (cancer prevalence of 26% and 39% for TGCT-1 and -2, respectively). The classifier predicted 37 of 41 and 41 of 45 malignant nodules, yielding a sensitivity of 90% [95% confidence interval; CI 77-97] and 91% [95% CI 79-98] for TGCT-1 and -2, respectively. One hundred one of 114 and 61 of 70 nodules were correctly predicted as benign, yielding a specificity of 89% [95% CI 82-94] and 87% [95% CI 77-94], respectively. The negative predictive values for TGCT-1 and TGCT-2 were 96% and 94%, respectively, whereas the positive predictive values were 74% and 82%, respectively. The overall accuracy for both cohorts was 89%. Conclusions: Clinical validation of the classifier demonstrates equivalent performance in two independent and ethnically diverse cohorts, accurately predicting benign thyroid nodules that can undergo surveillance as an alternative to diagnostic surgery.

Molecular markers in thyroid fine-needle aspiration biopsy: a prospective study.

BACKGROUND: Fine-needle aspiration biopsy (FNAB) is the most accurate study in the preoperative evaluation of patients with thyroid nodules. However, one of its limitations is the indeterminate or suspicious sample which accounts for 15% to 25% of the cases; both follicular and Hürthle cell neoplasms are included in this category. OBJECTIVE: To assess the accuracy of the molecular markers HBME-1 and galectin-3 in suspicious or indeterminate FNABs comparing the results with the histologic diagnosis of the thyroidectomy specimen. MATERIALS AND METHODS: A prospective study was carried out at 2 Health Centers in Santiago, Chile. From July 2003 to March 2008, 418 FNABs with indeterminate or suspicious diagnosis were immunostained with HBME-1 and galectin-3. Immunohistochemistry was performed on a clot obtained by FNAB, which was formalin-fixed and paraffin-embedded. The results were matched with the definitive histologic diagnosis of the thyroidectomy specimen. RESULTS: Of 418 patients submitted to FNAB with immunohistochemistry, 138 patients underwent surgery. The sensitivity, specificity, positive predictive value, and negative predictive value were 78.67%, 84.13%, 85.51%, and 76.81%, respectively, for HBME-1 and 82.67%, 80.95%, 83.78%, and 79.69%, respectively, for galectin-3. Whereas the results for both markers combined were 94.74%, 75.81%, 82.76%, and 92.16%. CONCLUSIONS: With the combined use of HBME-1 and galectin-3 in indeterminate FNABs, a 10% increase in sensitivity is achieved. These markers show excellent sensitivity and specificity and may improve patient's selection for surgery.