Fine Needle Aspiration Cytology

Helen H. Wang, MD, DrPH


Thyroid nodules are common clinical findings with an estimated annual incidence rate of 4-8%.[1] At any given time, between 10 and 20 million Americans have clinically detectable thyroid nodules.[1] Thyroid fine needle aspiration (FNA) is the initial test in the management of most patients with a thyroid nodule because it is safe and inexpensive and provides better selection of patients for surgery than any other test.[2] Therefore, thyroid FNA is easily the most common type of FNA specimens in a cytology laboratory. Although it has been widely accepted and practiced since the 1970s, the processing and reporting of thyroid FNA's are still controversial.

Specimen Collection and Processing
Thyroid FNA is obtained under the guidance of palpation or ultrasound, depending on the size of the lesion. Both are processed the same way, i.e. to either make conventional direct smears from the aspirate or to rinse the aspirate into a preservative to make a liquid-based preparation. Two studies that have compared the accuracy of ThinPrep® preparations versus conventional smears for thyroid FNA agreed that these two methods had comparable accuracy for thyroid neoplasms,[3, 4] although one of them showed ThinPrep preparations to have lower overall correlation with histologic diagnosis than direct smears, especially in detecting chronic lymphocytic thyroiditis (62% by ThinPrep versus 92% by direct smears).[4] In addition, some authors have suggested that ThinPrep preparations do not detect diffuse or watery colloid.[3, 5] In study by Tulecke, et al. "tissue-paper-like material" on ThinPrep was found to be associated with abundant colloid on histology and probably represents watery colloid. [6] Overall, colloid seems to be present in less quantity on ThinPrep than on conventional smears. However, ThinPrep is superior to conventional smears, whether fixed in alcohol or left to air-dry, in demonstrating nuclear features that are crucial in the diagnosis of papillary carcinoma. ThinPrep on the other hand appears to break up follicles and presents follicular cells in sheets, groups or even singly more readily than on conventional smears.

Many reporting schemes have been proposed and used in the literature. We have found a reporting scheme based on the probability of finding carcinoma on histology to be helpful to both pathologists and clinicians.

Positive for malignancy
Specimens in this category represent those cases in which a malignancy is found on resections virtually 100% of the time. Papillary carcinoma is the most common malignancy of the thyroid and has specific nuclear features that are easily identified on cytologic samples. Other malignancies that can be diagnosed on cytology with high accuracy include medullary carcinomas, lymphomas, and metastatic carcinomas. Papillary carcinoma is characterized on ThinPrep by sheets and papillary clusters of crowded cells with nuclear enlargement and molding, powdery chromatin, irregular nuclear membranes as evidenced by nuclear grooves and intranuclear cytoplasmic inclusions, and small but prominent and often eosinophilic nucleoli.[7] In contrast, medullary carcinoma is characterized by isolated monomorphic plasmacytoid cells that have a high nucleus:cytoplasm ratio, eccentric nuclei and coarsely granular chromatin with or without a prominent nucleolus. Small, inconspicuous granules fill the cytoplasm. Occasionally, the cells appear spindly, but show the same nuclear features. Lymphomas and metastatic carcinomas of the thyroid are much less common. Their cytologic features depend on their type and site of origin, respectively.

Suspicious for malignancy
When the specimen is not hypercellular or most, but not all, of the above described features for papillary and medullary carcinoma or other malignancy are present, it is reported to be suspicious for malignancy. The positive predictive value (malignancy rate on histology) of "suspicious for papillary carcinoma" ranges from 54 to 84% in the literature, depending on whether another less than definitive category, such as indeterminate, is in the scheme. [7, 8, 9, 10] When an indeterminate category is included in addition to the suspicious category, the PPV for the suspicious category is 64% or higher.[7, 9, 10] Since other types of carcinomas in the thyroid are much less common, their positive predictive values of a suspicious diagnosis have not been reported.

Indeterminate for malignancy
This category in our lab includes those specimens that have a predictive value of malignancy on histology less than 50% (mostly less than 30%) and greater than 10%.[6, 7] This includes those specimens that show a few features of papillary carcinoma, but are insufficient for a suspicious diagnosis.[7] Its positive predictive value ranges from 20 to 54% in the literature.[7, 9, 10, 11] These lesions often represent follicular variant of papillary carcinoma. This diagnostic category also includes follicular and Hürthle cell neoplasms, characterized by scant colloid and follicular cells in microfollicles and crowded groups or single Hürthle cells. The positive predictive value of these lesions for a carcinoma varied from 2 to 91% in the literature,[6, 9, 10, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27] probably due to different definitions of these terms and varying criteria in their scheme as well as on histologic diagnosis, but is less than 30% in most but a few reports.[10, 15, 22, 24, 27]

Most probably benign
This category includes those follicular lesions that show a macrofollicular or mixed micro- and macrofollicular pattern with some to abundant colloid in the background. On ThinPrep macrofollicles are seen as sheets of dozens of evenly spaced follicular cells with good distance between nuclei. The significance of single follicular cells on ThinPrep is uncertain as they are seen in an otherwise micro- or macrofollicular pattern. Since the probability for these lesions to show malignancy (follicular variant of papillary carcinoma or follicular carcinoma) on histology is low but not exactly zero, ranging from 0 to 43% in the literature [6, 9, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 24, 25, 26, 27] with all but three[14, 16, 27] less than 6%, we therefore call it most probably benign instead of unequivocally benign.

Negative for malignant cells consistent with Hashimoto's thyroiditis
We have found that ThinPrep is not optimal for the diagnosis of thyroiditis.[6] Hashimoto's thyroiditis is characterized by sheets or groups of follicular cells with varying degrees of Hürthle cell changes in a background of varying number of lymphocytes and plasma cells with occasional lymphoid and follicular center aggregates. Since lymphocytic/Hashimoto's thyroiditis is a common finding in the thyroid, sampling is critical in ruling out other co-existing more significant lesions.

Sub-optimal cellularity but shows features suggestive of …
Since thyroid FNA essentially triages patients for either surgery or follow-up, we would like to have more than adequate cellularity for a definitive diagnosis for this triage. If the cellularity is sub-optimal (but enough to suggest a diagnosis), we would start the report with this qualifier and then follow with any one of the above categories. This category includes those specimens that show cyst contents (macrophages) with very few follicular cells. We do not have a quantitative threshold for this category but rely on a combination of features, including the amount of colloid, cellular arrangement as well cytologic features, to make this decision.

This category is usually reserved for those specimens that show virtually no, or very few, follicular cells.

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Positive for Papillary Carcinoma