Preoperative Identification of Medullary Thyroid Carcinoma (MTC): Clinical Validation of the Afirma MTC RNA-Sequencing Classifier.

Background: Cytopathological evaluation of thyroid fine-needle aspiration biopsy (FNAB) specimens can fail to raise preoperative suspicion of medullary thyroid carcinoma (MTC). The Afirma RNA-sequencing MTC classifier identifies MTC among FNA samples that are cytologically indeterminate, suspicious, or malignant (Bethesda categories III-VI). In this study we report the development and clinical performance of this MTC classifier. Methods: Algorithm training was performed with a set of 483 FNAB specimens (21 MTC and 462 non-MTC). A support vector machine classifier was developed using 108 differentially expressed genes, which includes the 5 genes in the prior Afirma microarray-based MTC cassette. Results: The final MTC classifier was blindly tested on 211 preoperative FNAB specimens with subsequent surgical pathology, including 21 MTC and 190 non-MTC specimens from benign and malignant thyroid nodules independent from those used in training. The classifier had 100% sensitivity (21/21 MTC FNAB specimens correctly called positive; 95% confidence interval [CI] = 83.9-100%) and 100% specificity (190/190 non-MTC FNAs correctly called negative; CI = 98.1-100%). All positive samples had pathological confirmation of MTC, while all negative samples were negative for MTC on surgical pathology. Conclusions: The RNA-sequencing MTC classifier accurately identified MTC from preoperative thyroid nodule FNAB specimens in an independent validation cohort. This identification may facilitate an MTC-specific preoperative evaluation and resulting treatment.

(124)I PET/CT in Patients with Differentiated Thyroid Cancer: Clinical and Quantitative Image Analysis.

BACKGROUND: Although radioactive iodine (RAI) imaging/therapy is one of the earliest applications of theranostics, there remain a number of unresolved clinical questions as to the optimization of diagnostic techniques/protocols and improvements in patient-specific treatment planning strategies. The objectives of this study were to determine the imaging characteristics and clinical feasibility of (124)I positron emission tomography/computed tomography (PET/CT) for the determination of extent of disease and evaluation of RAI kinetics in its physiologic and neoplastic distribution in patients with differentiated thyroid cancer (DTC). METHODS: The study was designed as a prospective phase II diagnostic trial of patients with confirmed DTC. Following adequate preparation, patients received 2 mCi (124)I in liquid form and sequential whole-body PET/CT imaging was performed at five time points (2-4 h, 24 ± 6 h, 48 ± 6 h, 72 ± 6 h, and 96 ± 6 h post-administration). All patients who had (124)I imaging subsequently underwent RAI treatment with (131)I, with administered activities ranging from 100 to 300 mCi. Post-treatment scans were obtained 5-7 days after RAI treatment. A by-patient and by-lesion analysis of the (124)I images was performed and compared with the post-treatment (131)I scans as well as F-18 FDG PET/CT images. Quantitative image analysis was also performed to determine the total functional volume (mL), activity per functional volume (µCi/mL), and cumulated activity (µCi/h) for remnants, salivary glands, and nodal metastases. RESULTS: Fifteen patients (6 women; Mage = 57 years; range 29-91 years) were enrolled into the study. Forty-six distinct lesions were identified in these 15 patients on (124)I PET/CT images, with a sensitivity of 92.5%. In addition, (124)I identified 22.5% more foci of RAI-avid lesions compared with the planar (131)I post-treatment scans. This study demonstrates different kinetic profiles for normal thyroid remnants (peaked at 24 h with mono-exponential clearance), salivary glands (peaked at 4 h with bi-exponential clearance), and metastatic lesions (protracted retention), as well as individual variations in functional volumes and thus cumulated activities. CONCLUSIONS: (124)I PET/CT is a valuable clinical imaging tool/agent, both in determining the extent of disease in the setting of metastatic DTC and in the functional volumetric and kinetic evaluation of target lesions.