Can current molecular tests help in the diagnosis of indeterminate thyroid nodule FNAB?

Abstract

Approximately 15-30% of all thyroid nodules evaluated with fine-needle aspiration biopsy (FNAB) are classified as cytologically indeterminate. The stepwise unraveling of the molecular etiology of thyroid nodules has provided the basis for a better understanding of indeterminate samples and an opportunity to decrease diagnostic surgery in this group of patients. Over the last 15 years, several studies have tested different methodologies to detect somatic mutations (by polymerase chain reaction and next-generation sequencing, for example), and to identify differentially expressed genes or microRNA, aiming at developing molecular tests to improve the presurgical diagnosis of cytologically indeterminate nodules. In this review, we will provide an overview of the currently available molecular tests and the impact of mutation testing on the diagnosis of thyroid cancer. We will also review current published data and future perspectives in molecular testing of thyroid nodule FNAB and describe the current Brazilian experience with this diagnostic approach. Based on currently available data, especially for countries outside the US-Europe axis, a rational use of these tests must be made to avoid errors with regard to test indication and interpretation of test outcomes. In addition to clinical, radiological, and cytological features, we still need to determine local malignancy rates and conduct more independent validation and comparative performance studies of these tests before including them into our routine approach to indeterminate FNAB.

Bayesian Assessment of Diagnostic Strategy for a Thyroid Nodule Involving a Combination of Clinical Synthetic Features and Molecular Data

“…However, in the dataset used here, mismatched B5 samples were largely underestimated, and samples were malignant; genes were expected to predict malignancy. This corresponds with the results reported in [15], [28] where negative predictive values (NPV) (Equation 4) for suspicious cytological findings (B5) during the internal evaluation were 85% and even lower in independent ones. NPV is defined as follows:…”

“…A comparison of the main characteristics of the tests [4] and their analysis by independent evaluation [28] show a significant difference between the performance reported by the test creators and what was actually achieved in the evaluation. It stands to reason that in real-life it is harder to select a perfect group of patients, and the test would be carried out in a less meticulous way than in a clinical trial.…”

Preoperative detection of malignancy in fine-needle aspiration cytology (FNAC) smears with indeterminate cytology (Bethesda III, IV) by a combined molecular classifier

“…NPV does not differ significantly among the four tests and ranges from 92% to 96%. PPV values of ThyroSeq v2 and ThyGenX/ThyraMIR are comparable (74%–78%), unlike those of Afirma-GEC and RosettaGX Reveal, where this parameter is 37% and 43%–59%, respectively 14 17 21 22…”

Are the anatomical, clinical, and ultrasound characteristics of thyroid nodules with Bethesda III or IV cytology and ACR TI-RADS 3, 4, or 5 able to refine the indications for molecular diagnostic tests?

“…This is close to the risk of malignancy for II-B cytology (28), and a minimum sensitivity above 86% is required to keep the NPV above 95% for a wide range of disease prevalences. There is no consensus on the minimum PPV necessary to consider a rule test adequate; however, a specificity rate above 87% would result in a PPV above 70% for a disease with a prevalence rate above 25% (29). The two tests available in Brazil have an NPV and sensitivity greater than 94% (30)(31)(32).…”