TGF-beta/Smad pathway and BRAF mutation play different roles in circumscribed and infiltrative papillary thyroid carcinoma

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Poorly circumscribed growth pattern, extra-thyroid extension and high intratumoural lymph vessel density are significantly associated to nodal metastatization in papillary thyroid carcinoma (PTC). It was also shown that transforming growth factor beta (TGF-beta)/Smad-dependent pathway activity is associated with local invasion, nodal metastatization and BRAF-mutated PTCs. We analysed the immunoexpression of TGF-beta, Smad2/Smad3, Smad4 and Smad7 in a series of 42 cases of classic PTC and 33 cases of follicular variant of PTC with known clinico-pathological and follow-up data, as well as BRAF and RAS status. The 75 PTCs were divided into poorly circumscribed (PCPTC) (n = 53) and well circumscribed (WCPTC) (n = 22) according to their borders. Nodal metastases were not detected in any WCPTC regardless of the presence of immunoexpression for TGF-beta, Smad2/Smad3, Smad4 and Smad7 and occurrence of BRAF mutation (in 20% of WCPTCs). Increased cytoplasmatic expression of TGF-beta at the periphery of PCPTC was associated to morphological features of invasiveness, featuring the so-called epithelial-to-mesenchymal transition (EMT), and presence of nodal metastases, as well as to the occurrence of BRAF mutation which did not significantly alter, per se, the frequency of nodal metastases. The nuclear expression of Smad7 was more frequent in WCPTCs than in PCPTCs and was associated with unicentricity and absence of extra-thyroid extension, vascular invasion and nodal metastases. We conclude that nodal metastases are associated to poorly circumscribed, locally invasive PTCs that exhibit low levels of nuclear Smad7 and a peripheral EMT phenotype displaying TGF-beta overexpression, regardless of the occurrence of BRAF mutation.