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Molecular Testing for Thyroid FNA & NIFTP


The recognition that NIFTP lesions behave in an indolent fashion has led to a reclassification of these lesions as noninvasive follicular thyroid neoplasms with papillary-like nuclei (NIFTP)


If there is no evidence of capsular or vascular invasion, and if the stringent diagnostic criteria are present the NIFTP tumour which was formerly known as the encapsulated or noninvasive follicular variant of papillary carcinoma has virtually no risk of recurrence or metastatic disease during long-term follow-up.


NIFTP tumors show a molecular phenotype which is more similar to that of follicular adenoma or follicular carcinoma than that of classic papillary carcinoma with RAS gene mutations, PAX8-PPARG gene rearrangements, and absence of BRAF V600E mutations.


Papillary thyroid cancer which accounts for more than 80% of all newly diagnosed thyroid tumors, is either a BRAF V600E or a RAS-driven tumor


BRAF V600E–driven papillary cancers tend to be papillary carcinomas of the classic type or variants of classic papillary carcinoma


RAS-driven thyroid tumors are follicular-patterned lesions including follicular variants of papillary carcinoma, follicular carcinomas, and a subset of follicular adenomas.


Medullary carcinomas of the thyroid are associated with RET gene mutations. Germline RET mutations are present in familial tumors, and somatic mutations are present in sporadic medullary carcinomas. HRAS and KRAS mutations are seen in RET wild-type tumors, which are predominantly sporadic medullary tumors.


Anaplastic or poorly differentiated carcinomas of the thyroid also show a different profile of mutations, including mutations of phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit α, AKT1, tumor protein 53, catenin β1, telomerase reverse transcriptase, and others.


The diagnostic positive and negative predictive values of molecular testing and the clinical decision depend on the risk of malignancy in any particular patient cohort. The Afirma GEC test, for example, performs well as a rule-out test for benign and low-risk thyroid FNA cases, whereas the 7-gene panel is useful as a rule in test & Thyroseq 2 (56 gene panel) is useful for both low & high-risk FNA cases. A BRAF V600E mutation suggests a virtually certain diagnosis of malignancy, and RET PTC or paired box 8/peroxisome proliferator-activated receptor γ rearrangements suggest a higher probability of malignancy in higher risk FNA cases. NIFTP is characterized by RAS mutations or PPARG or THADA gene fusions that can be detected by large multigene panels such as Thyroseq 2.


Molecular testing should ideally have a high positive predictive value for malignancy in both lower risk and higher risk FNA cases across the whole spectrum of FNA malignancy risk (from benign to indeterminate to suspicious for malignancy and malignant).


Molecular testing should also detect non–follicular-derived tumors such as medullary carcinomas and parathyroid lesions.