RANKL, OPG, TRAIL, KRas, and c-Fos expression in relation to central lymph node metastases in papillary thyroid carcinoma.

PURPOSE: RANKL, OPG and TRAIL have long been pursued in cancer. Mutated KRas proteins and c-Fos overexpression - well-recognized oncogenic events - have been conceived as coordinators of RANKL, OPG and TRAIL pathways. Considering the paucity in the relevant literature, the purpose of the present study was to investigate whether the expression of these molecules configures a distinct papillary thyroid carcinoma (PTC) subgroup with adverse clinicopathological characteristics. METHODS: RANKL, OPG, TRAIL, KRas, and c-Fos immunohistochemical expression in relation to clinicopathological characteristics of PTC was assessed retrospectively in paraffin-embedded PTC specimens from 114 patients who underwent total thyroidectomy with simultaneous central lymph node dissection (CLND). RESULTS: Expression of RANKL, OPG, TRAIL, Kras and c- Fos was revealed in 78.6, 63.2, 61.4, 47.4, and 73.7% of PTC, respectively. As predominant KRas-expressing PTC histotype emerged the classical PTC (cPTC), comprising 66.7% of PTC. A significant correlation was demonstrated of RANKL, OPG, and TRAIL expression with central lymph node metastasis CLNM (p=0.007, p<0.001, and p=0.002, respectively), concerning especially cPTC as regards to RANKL (p=0.027) and OPG (p=0.006), and both cPTC (p=0.043) and follicular variant of PTC (FVPTC) (p=0.049) with regard to TRAIL. OPG expression associated significantly with multifocality (p=0.045). Multivariable-adjusted logistic regression models characterized TRAIL as independent predictor of CLNM (OR=10.335, 95% CI: 1.23-86.87). CLNM correlated significantly with six pairs of coexpressions: TRAIL-KRas (p=0.011), TRAIL-c-Fos (p=0.006), OPG-c-Fos (p=0.024), RANKL-TRAIL (p<0.001), RANKL-OPG (p<0.001), TRAIL- OPG (p<0.001). CONCLUSION: The present study suggested for the first time that OPG, RANKL, TRAIL expressions, either alone or in concert involving c-Fos and KRas expression, are related to CLNM. Further research is warranted to elucidate whether the examined molecules can be endorsed as indicators of aggressive PTC behavior and guide a personalized therapeutic intervention.