Fine-Needle Aspiration of the Thyroid Gland: The 2017 Bethesda System

Introduction

Fine-needle aspiration (FNA) is an essential test in the evaluation of a patient with a thyroid nodule. The result of the FNA determines, in large part, whether a patient can be followed clinically or referred for surgery. Guidelines have been established for selecting a nodule for aspiration. Once the decision has been made to perform an FNA, its value can be enhanced by attention to technical details. In general, smaller needles (25 and 27 G) are superior to larger ones; a shorter “dwell time” (the time the needle is kept in the lesion) is often superior to longer dwell times, which introduce more blood; and rapid oscillations within the nodule (two to five per second) are better than slow excursions with the needle. Communication between the operator (if the FNA is not performed by a pathologist) and the pathologist is essential. The pathologist’s interpretation is greatly aided if essential clinical information (e.g., history of hypothyroidism, etc.) is provided on the requisition form. The Bethesda System for Reporting Thyroid Cytopathology (TBSRTC) has standardized the reporting of thyroid cytopathology and consists of six diagnostic categories.

Indications for Thyroid FNA

Thyroid nodules are discovered either by palpation or by an imaging study. A palpable thyroid nodule should undergo further evaluation to determine whether an FNA is warranted. Before the decision is made, a serum thyroid stimulating hormone level (TSH) and thyroid ultrasound (US) should be obtained. Patients with a normal or elevated serum TSH level should proceed to a thyroid US to determine whether an FNA needs to be performed. Those with a depressed serum TSH should have a radionuclide thyroid scan, the results of which should be correlated with the sonographic findings. Functioning thyroid nodules in the absence of significant clinical findings do not require an FNA because the incidence of malignancy is exceedingly low. A nodule that appears either iso- or hypofunctioning on radionuclide scan should be considered for FNA, based on the US findings.

Incidental thyroid nodules (i.e.,incidentalomas) are detected by US, ¹⁸ F-fluorodeoxyglucose-positron emission tomography ( ¹⁸ FDG-PET), sestamibi, computed tomography (CT), and magnetic resonance imaging (MRI) scans. Incidental thyroid nodules detected by US should undergo a dedicated thyroid sonographic evaluation. Lesions with a maximum diameter greater than 1.0 to 1.5 cm should be considered for biopsy unless they are simple cysts or septated cysts with no solid elements. FNA may also occasionally be replaced by periodic follow-up for nodules of borderline size (between 1.0 and 1.5 cm in maximum diameter) if the nodules have sonographic features that are strongly associated with benign cytology.

A nodule of any size with sonographically suspicious features should also be considered for FNA. Sonographically suspicious features include microcalcifications, hypoechoic solid nodules, irregular/lobulated margins, intranodular vascularity, and nodal metastases (or signs of extracapsular spread). The recommendation for FNA is controversial because it includes patients with microcarcinomas, in whom a survival benefit after an FNA diagnosis has not been documented. If the FNA reveals that the nodule is malignant, surgery is generally recommended, but the natural history of papillary microcarcinomas is not well understood. Most remain indolent, as implied by the 13% prevalence of micropapillary cancers in the United States at autopsy examination. A minority of cases follow a more aggressive course; this subgroup might be identified by sonographic evidence of lateral cervical node metastases, tumor multifocality, extrathyroidal invasion, or cytopathologic features that suggest a high-grade malignancy.

Incidentalomas detected by ¹⁸ FDG-PET (2% to 3% of all PET scans) are unusual but have a substantial risk of cancer of approximately 35%. A focally ¹⁸ FDG-PET–avid thyroid nodule is much more likely to represent thyroid cancer than metastatic disease to the thyroid, even in patients with an extrathyroidal malignancy. Therefore a focal nodule that is ¹⁸ FDG-PET-avid is an indication for FNA. Diffuse increased uptake on ¹⁸ FDG-PET does not warrant FNA unless thyroid sonography detects a discrete nodule.

Thyroid incidentalomas detected on sestamibi scans have a high risk of cancer that ranges from 22% to 66%. All focal hot nodules detected on sestamibi scans and confirmed by US to be a discrete nodules should undergo FNA.

Thyroid incidentalomas detected by CT or MRI are seen in at least 16% of patients evaluated by neck CT or MRI. The risk of cancer in one study was predicted at 10%, but it included only a limited number of patients who went on to FNA. CT and MRI features cannot determine the risk of malignancy, except in very advanced cases that are unlikely to be incidental. Until more data are available, incidentalomas seen on CT or MRI should undergo dedicated thyroid sonographic evaluation. Any nodule with sonographically suspicious features (as mentioned previously) should be considered for FNA, especially if the nodule has a maximum diameter greater than 1.0 to 1.5 cm.

FNA Technique

The core-needle biopsy (CNB) is a procedure that involves the use of spring-activated large bore needles (18 G to 21 G), which produces a small tissue fragment. The advantage of this technique is a larger amount of cells, which may decrease the rate of inadequate diagnoses and may allow the application of ancillary studies. The disadvantages of CNB include the increased rate of complications, such as hemorrhage, local pain, as well as difficulty in performing multiple samplings of the lesion. Some organizations have endorsed the use of CNB only in cases of repeated nondiagnostic yields using conventional cytology.

FNA of the thyroid gland can be processed by making conventional smears (CS), either air-dried or ethanol-fixed, or by using the thin-layer or liquid-based cytology (LBC) technique. LBC was originally developed for application to gynecologic cervical smears, and CS was the traditional method for decades. Both CS and LBC are acceptable methods, and some laboratories prefer to use a combination of CS and LBC. In addition, a formalin-fixed cell block can be made in selected cases for the purpose of performing ancillary studies.

The LBC technique is based on a two-step procedure: (1) the fixation of the FNA material in an alcohol-based solution (methanol or ethanol depending on the technique, discussed later), and (2) the automated processing of the material to obtain a thin layer of representative cells. LBC uses an innovative, computer-assisted device that allows the transfer of the fixed and partially disaggregated cells onto a single slide. The two most common methods for processing the cytologic samples use an alcohol-based fixative solution. In the first method (ThinPrep™ system, Hologic Co., Marlborough, Massachusetts), the cells are aspirated from a methanol-based solution (Cytolit™) then filtered and transferred onto a positively charged slide with a gentle positive pressure. In the second method (BD SurePath™ liquid-based technique, Wokingham Berkshire, UK), the cells are collected in an ethanol-based solution (CytoRich™), centrifuged twice, then slowly sedimentated onto a poly L-lysinated slide, and then eventually stained with a specific hematoxylin-eosin stain. The final result for both methods is one slide for each lesion where all cells are concentrated in a thin layer on the central area of the slide measuring 20 square mm for ThinPrep and 13 square mm for SurePath. The LBC method enables the storage of a variable amount of cells in a preservative solution for up to 6 months after the biopsy and the making of a cell block directly from the leftover material.

If pathologists perform the FNA and perform rapid on-site evaluation (ROSE), the adequacy of the sample will likely be higher; however, this requires a significant investment of resources. Treating clinicians, who are more familiar with the clinical picture, more often perform the FNA themselves. The different rates of inadequacy of FNA carried out by treating clinicians suggest that experience is an essential requisite to obtaining an adequate cytologic sample. However, regardless of the subspecialty of the operator, the procedure should be carried out with appropriate frequency and information exchange between the clinicians (e.g., pathologists, endocrinologists, and surgeons) who treat the patient.

Accuracy of Thyroid FNA

Thyroid FNA is widely accepted as a highly cost-effective and accurate means of evaluating a thyroid nodule. For the diagnosis of papillary thyroid carcinoma, FNA is considered by some to be at least as accurate as frozen section, reflecting the importance of nuclear cytology for diagnosing papillary carcinoma. False-negative and false-positive thyroid FNA diagnoses occur, but such occurrences are uncommon, averaging less than 5% and 1%, respectively. Errors are a result of both sampling and interpretation. In experienced hands, the diagnostic accuracy of thyroid FNA for technically satisfactory specimens is greater than 95%, with positive predictive values of 89% to 98% and negative predictive values of 94% to 99%. However, these values are dependent on how the “atypia of undetermined significance/follicular neoplasm of undetermined significance” and “suspicious for a follicular neoplasm” categories are used in the calculations. The risk of malignancy (ROM) can vary depending on how noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) is incorporated into the calculations. Sensitivities for thyroid FNA range from 43% to 98% and specificities range from 72% to 100%. These wide ranges, in part, reflect the skill of the person performing the FNA as well as the expertise of the cytopathologist interpreting the specimens. For the evaluation of cystic thyroid lesions, FNA is reported to have a low sensitivity (40%), because cystic aspirates will often yield cyst contents only (e.g., foam cells, hemosiderin-laden macrophages, and acellular debris) with rare epithelial cells. Caution is warranted in interpreting cystic thyroid aspirates because a subset of thyroid cysts represent cystic papillary carcinomas.

Reporting Terminology: The Bethesda System

For clarity of communication, TBSRTC recommends that each report begin with one of six general diagnostic categories ( Box 11.1 ). For some categories, TBSRTC offers a choice of two names; a consensus was not reached at the National Cancer Institute (NCI) conference on a single name for these categories. Each of the categories has an implied cancer risk that links it to an evidence-based management guideline ( Table 11.1 ). The term “indeterminate” is not advised for reporting thyroid FNA results because its meaning is not sufficiently specific and its use has been highly variable.