Multiplatform molecular test performance in indeterminate thyroid nodules.

BACKGROUND: Approximately 25% of thyroid nodule fine-needle aspirates (FNAs) have cytology that is indeterminate for malignant disease. Accurate risk stratification of these FNAs with ancillary testing would reduce unnecessary thyroid surgery. METHODS: We evaluated the performance of an ancillary multiplatform test (MPTX) that has three diagnostic categories (negative, moderate, and positive). MPTX includes the combination of a mutation panel (ThyGeNEXT®) and a microRNA risk classifier (ThyraMIR®). A blinded, multicenter study was performed using consensus histopathology diagnosis among three pathologists to validate test performance. RESULTS: Unanimous consensus diagnosis was reached in 197 subjects with indeterminate thyroid nodules; 36% had disease. MPTX had 95% sensitivity (95% CI,86%-99%) and 90% specificity (95% CI,84%-95%) for disease in prevalence adjusted nodules with Bethesda III and IV cytology. Negative MPTX results ruledout disease with 97% negative predictive value (NPV; 95% CI,91%-99%) at a 30% disease prevalence, while positive MPTX results ruledin high risk disease with 75% positive predictive value (PPV; 95% CI,60%-86%). Such results are expected in four out of five Bethesda III and IV nodules tested, including RAS positive nodules in which the microRNA classifier was useful in rulingin disease. 90% of mutation panel false positives were due to analytically verified RAS mutations detected in benign adenomas. Moderate MPTX results had a moderate rate of disease (39%, 95% CI,23%-54%), primarily due to RAS mutations, wherein the possibility of disease could not be excluded. CONCLUSIONS: Our results emphasize that decisions for surgery should not solely be based on RAS or RAS-like mutations. MPTX informs management decisions while accounting for these challenges.

Clinical performance of multiplatform mutation panel and microRNA risk classifier in indeterminate thyroid nodules.

INTRODUCTION: We evaluated the clinical performance of an expanded mutation panel in combination with microRNA classification (MPTX) for the management of indeterminate thyroid nodules. MATERIALS AND METHODS: MPTX included testing of fine-needle aspirates from multiple centers with a combination of ThyGeNEXT mutation panel for strong and weak driver oncogenic changes and ThyraMIR microRNA risk classifier (both from Interpace Diagnostics; Pittsburgh, PA). MPTX test status (positive or negative) and MPTX clinical risk classifications (low, moderate, or high risk) were determined blind to patient outcomes. Surgical pathology and clinical follow-up records of patients from multiple centers were used to determine patient outcomes. MPTX performance was assessed by Kaplan Meier analysis for cancer-free survival of patients, with risk of malignancy determined by hazard ratio (HR). RESULTS: Our study included 140 patients with AUS/FLUS or FN/SFN nodules, of which 13% had malignancy. MPTX negative test status and MPTX low risk results conferred a high probability (94%) that patients would remain cancer-free. MPTX positive test status (HR 11.2, P < 0.001) and MPTX moderate-risk results (HR 8.5, P = 0.001) were significant risk factors for malignancy, each conferring a 53% probability of malignancy. MPTX high-risk results elevated risk of malignancy even more so, conferring a 70% probability of malignancy (HR 38.5, P < 0.001). CONCLUSIONS: MPTX test status accurately stratifies patients for risk of malignancy. Further classification using MPTX clinical risk categories enhances utility by accurately identifying patients at low, moderate, or high risk of malignancy at the low rate of malignancy encountered when clinically managing patients with indeterminate thyroid nodules.

Serum thyroglobulin, high-resolution ultrasound, and lymph node thyroglobulin in diagnosis of differentiated thyroid carcinoma nodal metastases.

CONTEXT: Clinically enlarged cervical lymph nodes in patients with a history of thyroid cancer are usually assessed by fine-needle aspiration biopsy (FNAB) followed by cytology with or without tissue core. Thyroglobulin (Tg) is frequently elevated in malignant FNAB needle-wash specimens and may possibly augment or replace cytology. Furthermore, the combination of undetectable serum Tg and an innocuous ultrasound might altogether obviate the need for biopsy. OBJECTIVES: The objectives of the study were to: 1) determine an appropriate diagnostic cutoff for Tg levels in FNAB; 2) assess the diagnostic performance at this cutoff; and 3) compare serum Tg and FNAB needle-wash Tg levels to determine whether serum Tg levels predict positive Tg FNAB. DESIGN: This was a retrospective study of 122 FNAB samples in 88 athyrotic thyroid cancer patients. RESULTS: Fifty of 52 nonmalignant FNAB samples (96.2%) had Tg 1 ng/ml or less. All 70 malignant FNAB had Tg greater than 1 ng/ml. Of 103 specimens with diagnostic cytology, five (4.9%) had discordant Tg results; in four of these FNAB Tg was concordant with the final diagnosis. Eighteen of 19 (94.7%) FNAB with nondiagnostic (n = 16) or absent (n = 3) cytology were correctly classified by FNAB needle-wash Tg. Undetectable (<0.1 ng/ml) serum Tg was associated with a negative diagnosis in 21 of 23 biopsies (91.7%); the two cancer-positive samples were both serum Tg autoantibody positive and classified as suspicious by ultrasonography. CONCLUSIONS: Nodal FNAB needle-wash Tg measurements complement cytology in thyroid cancer follow-up and might substitute for it. The combination of unremarkable ultrasonography and an undetectable serum Tg in Tg autoantibody-negative patients might obviate the need for FNAB.