Autocrine activation of platelet-derived growth factor receptor α in metastatic papillary thyroid cancer

Abstract

Metastatic dissemination of papillary thyroid cancer has been reported to be strongly associated with expression of platelet-derived growth factor (PDGFR) α and altered TTF1 function. However, the status of PDGF ligands in papillary thyroid cancer and the potential role of these ligands in metastatic disease are obscure. We assessed the prevalence of PDGF ligands in benign and malignant thyroid tumors to determine if ligand upregulation is associated with α-isoform (PDGF-AA or PDGF-BB) or the β-isoform (PDGF-BB or PDGF-DD) of PDGFR in individual tumors. The immunohistochemical expression of PDGFRα, PDGF-AA, PDGF-BB, and PDGF-DD was surveyed in follicular adenomas (n=55), papillary thyroid carcinomas (103 with and 59 without nodal metastases), and lymph node metastasis (n=12). There is an augmented tendency for PDGF-AA expression in node-positive papillary thyroid cancer metastases (P<.0001). Although PDGF-BB and -DD were commonly identified, there was no relationship between the presence of these cytokines and malignant disease or metastases. Logistic regression demonstrated that PDGF-AA expression was significantly associated with the presence of PDGFRα (odds ratio=4.6, P=.004) and recurrent disease. When either PDGFRα or PDGF-AA was used to predict the presence of metastases, the sensitivity achieved was 86% and 88%, respectively, whereas specificities were lower at 71% and 61%, respectively. The augmented coexpression of PDGF-AA and PDGFRα in metastatic papillary thyroid cancers suggests that an autocrine signaling loop may contribute to nodal infiltration. Combined testing for the expression of PDGF-AA and PDGFRα may identify those patients with papillary thyroid cancer at risk of metastatic disease and resistance to therapy.