Thyroid Nodule - can molecular tests improve fine-needle aspiration cytology diagnostic assessment?

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Thyroid Nodule - can molecular tests improve fine-needle aspiration cytology diagnostic assessment?

Terça, 24.10.2017

Fine-needle aspiration (FNA) has high sensitivity and specificity in distinguishing benign from malignant thyroid lesions. However, in 5-20% of the cases belonging to the indeterminate cytology categories (follicular neoplasms and atypia of undetermined significance) it is not possible to discriminate between benign and malignant tumours. As a consequence of this limitation, patients with such diagnoses have to be submitted to diagnostic rather than to curative thyroid surgery.

The need to improve the diagnostic performance of FNA cytology in the setting of indeterminate results has led to the search for diagnostic biomarkers. Several molecular tests, such as gene expression classifier (GEC), mutational panel, targeted next-generation sequencing (tNGS)  and the combination of mutation detection and miRNA have been applied to cytology in recent years.

The panel of the study herein summarized reviewed the evidence supporting the diagnostic value of mutations assessment (including at least BRAF, NRAS, HRAS, KRAS, PAX8/PPARG, RET/PTC) via targeted next generation sequencing and of a microarray gene expression classifier (GEC) test. The known occurrence of RAS mutations and PAX8-PPRG rearrangements, in histologically benign nodules is a major limitation to mutation detection panels. In the same way, the recent classification of  the encapsulated non-invasive follicular variant of papillary thyroid carcinoma (WHO,4th edition, 2017) as “non-invasive follicular thyroid neoplasm with papillary-like nuclear features –NIFTP” has contributed to diminish the diagnostic value of mutations assessment. Furthermore, the introduction of the NIFTP entity has changed the utility of predictive values of molecular tests since NIFTP displays frequent mutations and is an “almost benign” tumour from the clinical standpoint.

The reduction of the risk of malignancy in the indeterminate categories will probably switch the molecular diagnosis towards a rule-out cytology approach as a consequence of the increased negative predictive value and the absence of clinical significance in terms of malignancy of the detection of several genetic structural alterations.


Autores e Afiliações:

Paschke R1, Cantara S2, Crescenzi A3, Jarzab B4, Musholt TJ5, Sobrinho Simoes M6.

1 Division of Endocrinology and Metabolism, Departments of Medicine, Pathology, Oncology and Arnie Charbonneau Cancer Institute, Calgary, AB, Canada.

2 Department of Medical, Surgical, and Neurological Sciences, Endocrinology Section, University of Siena, Siena, Italy.

3 Pathology Unit, University Hospital Campus Bio-Medico, Rome, Italy.

4 Department of Nuclear Medicine and Endocrine Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute of Oncology, Gliwice Branch, Gliwice, Poland.

5 Endocrine Surgery Section, Department of General, Visceral, and Transplantation Surgery, University Medicine of the Johannes Gutenberg-University Mainz, Mainz, Germany.

6 Institute of Molecular Pathology and Immunology, University of Porto, Porto, Portugal.



Molecular fine-needle aspiration (FNA) cytology diagnostics has the potential to address the inherent limitation of FNA cytology which is an indeterminate (atypia of undetermined significance/follicular lesion of undetermined significance follicular neoplasm) cytology. Because of the emerging role of molecular FNA cytology diagnostics, the European Thyroid Association convened a panel of international experts to review methodological aspects, indications, results, and limitations of molecular FNA cytology diagnostics. The panel reviewed the evidence for the diagnostic value of mutation panel assessment (including at least BRAFNRASHRASKRASPAX8/PPARGRET/PTC) of targeted next generation sequencing and of a microarray gene expression classifier (GEC) test in the diagnostic assessment of an indeterminate cytologythyroid nodule. Moreover, possible surgical consequences of molecular FNA diagnostic results of thyroid nodules and the evidence that analysis of a molecular FNA diagnostic panel of somatic mutations or a microarray GEC test can alter the follow-up were reviewed. Moleculartests may help clinicians to drive patient care and the surgical decision if the analysis is performed in specialized laboratories. These molecular tests require standardization of performance characteristics and appropriate calibration as well as analytic validation before clinical interpretation.


Revista: European Thyroid Journal