Discrimination of Benign and Malignant Thyroid Nodules by Molecular Profiling

A new diagnosis of thyroid carcinoma is predicted to affect 23,600 people this year in the United States.1 The Surveillance, Epidemiology, and End Results database documents a recent rise in the number of cases of thyroid carcinoma, with an estimated increase of 3% per year in the incidence of thyroid cancer.1,2 Although the incidence of thyroid cancer appears to be increasing, the number of patients evaluated with a thyroid nodule to exclude carcinoma remains far greater. Currently, diagnostic tests for thyroid nodules are not sensitive or specific enough given the large number of benign lesions found with imaging today.3,4 The introduction of fine-needle aspiration (FNA) approximately 30 years ago significantly enhanced the ability of the clinician to diagnose and appropriately treat thyroid nodules.5,6 A reduction of more than 30% in the number of operations performed for benign disease was observed after FNA became widely used in the 1980s.7 However, since the introduction of thyroid FNA, there have been no major advances in the diagnosis of thyroid cancer, nor has the pathologic diagnosis of thyroid cancer led to better treatment algorithms.8,9 Perhaps the most important diagnostic dilemma that remains is how to manage the patient with an “indeterminate” cytology.10–14 Although the majority of these nodules ultimately prove to be either benign hyperplastic nodules or follicular adenomas, 20% to 30% prove to be follicular carcinomas or follicular variants of papillary thyroid carcinoma (FVPTCs).4,9,15,16 The patient, surgeon, and endocrinologist are left guessing as to what might be the best surgical treatment and, frequently, this decision is made on “gut feeling” or social factors. A second shortfall of FNA is the inability to reliably identify more aggressive tumors.17,18 Although this can sometimes be determined on a clinical basis, this is not usually the case.19,20 Invasiveness and many nuclear features indicative of carcinoma are not discernible on cytology and only after surgical resection can these features be reliably diagnosed.21 Identification of more aggressive tumors preoperatively would permit more extensive surgery when indicated. The recent application of microarray analysis to tumor biology has provided a new opportunity to study and understand cancer biology, including the identification of new genes involved in carcinogenesis and the ability to classify tumors based on gene expression profiles.22–24 We have turned to microarray analysis to characterize and classify benign and malignant follicular thyroid tumors and papillary thyroid tumors. We have identified known and unknown genes that have not been previously associated with thyroid carcinogenesis and have separately been able to reliably distinguish between benign and malignant follicular thyroid tumors, as well as benign thyroid nodules and papillary thyroid carcinomas.25,26 Here we report the ability to differentiate all common benign and malignant thyroid nodules using gene expression profiling. Additionally, we show that molecular profiling can be used to classify tumors as high risk or low risk. These studies provide a foundation for the future addition of gene profiling to thyroid FNA and ultimately enhance the office diagnosis of thyroid nodules.