Abstract
Distinguishing between follicular thyroid cancer (FTC) and follicular thyroid adenoma (FTA) constitutes a long-standing diagnostic problem resulting in equivocal histopathological diagnoses. There is therefore a need for additional molecular markers. To identify molecular differences between FTC and FTA, we analyzed the gene expression microarray data of 52 follicular neoplasms. We also performed a meta-analysis involving 14 studies employing high throughput methods (365 follicular neoplasms analyzed). Based on these two analyses, we selected 18 genes differentially expressed between FTA and FTC. We validated them by quantitative real-time polymerase chain reaction (qRT-PCR) in an independent set of 71 follicular neoplasms from formaldehyde-fixed paraffin embedded (FFPE) tissue material. We confirmed differential expression for 7 genes (CPQ, PLVAP, TFF3, ACVRL1, ZFYVE21, FAM189A2, and CLEC3B). Finally, we created a classifier that distinguished between FTC and FTA with an accuracy of 78%, sensitivity of 76%, and specificity of 80%, based on the expression of 4 genes (CPQ, PLVAP, TFF3, ACVRL1). In our study, we have demonstrated that meta-analysis is a valuable method for selecting possible molecular markers. Based on our results, we conclude that there might exist a plausible limit of gene classifier accuracy of approximately 80%, when follicular tumors are discriminated based on formalin-fixed postoperative material.
Highlights
IntroductionAccording to World Health Organization (WHO) follicular adenoma is a benign, encapsulated tumor of the thyroid showing follicular cell differentiation [1]
Follicular neoplasms are the most controversial area in the thyroid pathology
To select potential molecular markers useful in the distinction between follicular thyroid adenoma (FTA) and follicular thyroid cancer (FTC), we considered genes that were differentially expressed in the primary and secondary microarray datasets
Summary
According to World Health Organization (WHO) follicular adenoma is a benign, encapsulated tumor of the thyroid showing follicular cell differentiation [1]. This tumor demonstrates no evidence of capsular or vascular invasion. Follicular carcinoma is a malignant tumor showing evidence of follicular cell differentiation. According to the literature data and our experience there is a group of patients with only partial capsular invasion but presenting metastases of follicular carcinoma [2]. Yamashina analyzed entire circumference of tumor capsules of follicular neoplasms and observed that tumors with only capsular invasion in initial sections presented vascular invasion on additional slices adjacent to tumor capsule [3]. It would be advisable to evaluate gene expression of follicular adenomas and follicular carcinomas
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