Fine needle aspiration (FNA) of the thyroid
Thyroid nodules are common, present in 5-7% of the U.S. adult population. The vast majority are benign, and most cases of thyroid cancer are curable by surgery if detected early. Fine needle aspiration (FNA) of the thyroid is currently the most accurate procedure to distinguish benign thyroid lesions and malignant ones, reducing the rate of unnecessary thyroid surgery for patients with benign nodules and triaging patients with thyroid cancer to appropriate surgery.
About 60-70% of thyroid nodules are classified cytologically as benign, and 4-10% of nodules are cytologically deemed malignant. (1) However, the remaining 20-30% have equivocal findings (inclusive, indeterminate, atypical or suspicious), usually due to overlapping cytologic features between benign and malignant nodules; these nodules usually require surgery for a final diagnosis.
The current guidelines recommend repeat FNA for patients with a diagnosis of “atypia of undetermined significance” and lobectomy with or without intraoperative pathology consultation for those with a suspicious diagnosis. (2)
Approximately 80% of patients with indeterminate cytology undergo surgical resection, postoperative evaluation reveals a malignancy rate ranging from 6-30%, making this clinical process one with very low specificity. (3)
Preoperative planning of optimal surgical management in patients with equivocal cytologic results is challenging, as different thyroid malignancies may require different surgical procedures (e.g. unilateral lobectomy versus total or sub-total thyroidectomy with or without lymph node dissection) depending on several factors, including histologic subtype and risk-stratification strategies (tumor size, patient age, etc.) If a diagnosis cannot be made intraoperatively, a lobectomy is typically performed, and if on postoperative histology the lesion is malignant, a second surgical intervention may be necessary for completion thyroidectomy.
Most thyroid cancers originate from thyroid follicular cells and include well-differentiated papillary thyroid carcinoma (PTC) (80% of all thyroid cancers) and follicular carcinoma (15%). Poorly differentiated and anaplastic thyroid carcinomas are uncommon and can arise de novo or from preexisting well-differentiated papillary or follicular carcinomas. Medullary thyroid carcinoma originates from parafollicular or C cells and accounts for approximately 3% of all thyroid cancers.
The diagnosis of malignancy in the case of PTC is primarily based on cytologic features. If a FNA in a case of PTC is indeterminate, intraoperative consultation is most often diagnostic, although its efficacy and therefore use will vary between institutions, surgeons, and pathologists.
For follicular carcinoma, the presence of invasion of the tumor capsule or of blood vessels is diagnostic and cannot be determined by cytology, as tissue sampling is necessary to observe these histologic characteristics. Intraoperative diagnosis of follicular carcinoma is challenging and often not feasible, as extensive sampling of the tumor and capsule is usually necessary and performed on postoperative permanent sections.
New approaches for improving the diagnostic accuracy of thyroid FNA include molecular analysis for somatic genetic alterations, in order to more accurately classify which patients need to proceed to surgery (and may include the extent of surgery necessary) versus those patients who do not need surgery and can be safely followed.
Molecular markers associated with thyroid cancer
Various molecular markers have been discovered in thyroid cancer. The 4 gene mutations that are the most common, and carry the highest impact on tumor diagnosis and prognosis, are BRAF and RAS point mutations and RET/PTC and PAX8/PPARγ rearrangements.
Papillary carcinomas carry point mutations of the BRAF and RAS genes as well as RET/PTC and TRK rearrangements, all of which are able to activate the mitogen-activated protein kinase (MAPK) pathway. (4) These mutually exclusive mutations are found in more than 70% of papillary carcinomas. (4) BRAF mutations are highly specific for PTC. Follicular carcinomas harbor either RAS mutations or PAX8/PPARγ rearrangement. These mutations are also mutually exclusive and identified in 70-75% of follicular carcinomas. (4) Genetic alterations involving the PI3K/AKT signaling pathway also occur in thyroid tumors, although they are rare in well-differentiated thyroid cancer and have higher prevalence in less differentiated thyroid carcinomas. (4) Additional mutations known to occur in poorly differentiated and anaplastic carcinomas involve the TP53 and CTNNB1 genes. Medullary carcinomas, which can be familial or sporadic, frequently possess point mutations located in the RET gene.
There are no specific markers for benign thyroid lesions.
Commercially available panels of molecular markers utilizing FNA specimens from the thyroid include miRInform™ (Asuragen) and Veracyte® (Afirma).
miRInform is a panel of 7 analytically validated molecular markers (KRAS, BRAF, HRAS, NRAS, RET/PTC 1, RET/PTC3 and PAX8/PPARγ).
Veracyte offers a proprietary “gene expression classifier” which claims to classify a thyroid nodule with indeterminate cytology as benign with greater than 95% negative predictive value or as suspicious.
These commercially available, laboratory-developed tests are regulated under the Clinical Laboratory Improvement Amendments (CLIA). Premarket approval from the U.S. Food and Drug Administration (FDA) is not required when the assay is performed in a laboratory that is licensed by CLIA for high-complexity testing.