molecular pathology of thyroid cytology

Fine-needle aspiration (FNA) cytology is a common approach to evaluate thyroid nodules. It offers definitive diagnosis of a benign or malignant nodule in the majority of cases. However, 10-25% of nodules yield one of three indeterminate cytologic diagnoses, leading to suboptimal management of these patients.

Atypia of undetermined significance/follicular lesion of undermined significance (AUS/FLUS) is a common indeterminate diagnosis, with the cancer risk ranging from 6% to 48%.

Targets

 BRAF : BRAF-V600E
 RET

Tools

 gene expression classifier (GEC)

• Afirma gene expression classifier / Afirma GEC

 ThyGenX

 ThyroSeq
 *The ThyroSeq v2.1 panel includes 14 genes analyzed for point mutations and 42 types of gene fusions occurring in thyroid cancer.

• The most frequently mutated genes were NRAS and HRAS.
• ThyroSeq v2.1 was able to classify 20/22 cancers correctly, showing a sensitivity of 90.9% [confidence interval (CI) 78.8-100], specificity of 92.1% [CI 86.0-98.2], positive predictive value of 76.9% [CI 60.7-93.1], and negative predictive value of 97.2% [CI 78.8-100], with an overall accuracy of 91.8% [CI 86.4-97.3]. (26621130)
• the ThyroSeq v2.1 multi-gene NGS panel of molecular markers provides both high sensitivity and high specificity for cancer detection in thyroid nodules with AUS/FLUS cytology, which should allow improved management for these patients.

Open references

 Local molecular analysis of indeterminate thyroid no
ules. Gill MS, Nayan S, Kocovski L, Cutz JC, Archibald SD, Jackson BS, Young JE, Gupta MK.J Otolaryngol Head Neck Surg. 2015 Dec 1;44:52. doi : 10.1186/s40463-015-0106-2 PMID: 26621130 Free

 Molecular Testing of Thyroid Nodules: A Review of Current Available Tests for Fine-Needle Aspiration Specimens. Zhang M, Lin O. Arch Pathol Lab Med. 2016 Aug 24.
PMID: 27557410 Free

 Molecular Diagnosis for Indeterminate Thyroid Nodules on Fine Needle Aspiration. Expert Rev Mol Diagn. 2013;13(6):613-623. http://www.medscape.com/viewarticle/809127

Paywall references

 Clinical, Sonographic, and Pathologic Characteristics of RAS-positive versus BRAF-positive Thyroid Carcinoma. Kakarmath S, Heller HT, Alexander CA, Cibas ES, Krane JF, Barletta JA, Lindeman NI, Frates MC, Benson CB, Gawande AA, Cho NL, Nehs M, Moore FD, Marqusee E, Kim MI, Larsen PR, Kwong N, Angell TE, Alexander EK. J Clin Endocrinol Metab. 2016 Sep 30:jc20162620. PMID: 27689252

 Molecular cytopathology for thyroid nodules: A review of methodology and test performance. Nishino M. Cancer Cytopathol. 2016 Jan;124(1):14-27. doi : 10.1002/cncy.21612 PMID: 26348024

 AACE/ACE disease state commentary: molecular diagnostic testing of thyroid nodules with indeterminate cytopathology. Bernet V, Hupart KH, Parangi S, Woeber KA. Endocr Pract. 2014 Apr;20(4):360-3. doi : 10.4158/EP14066.PS PMID: 24727662

 Analytical performance verification of a molecular diagnostic for cytology-indeterminate thyroid nodules. Walsh PS, Wilde JI, Tom EY, Reynolds JD, Chen DC, Chudova DI, Pagan M, Pankratz DG, Wong M, Veitch J, Friedman L, Monroe R, Steward DL, Lupo MA, Lanman RB, Kennedy GC. J Clin Endocrinol Metab. 2012 Dec;97(12):E2297-306. doi : 10.1210/jc.2012-1923 PMID: 23087323