Methylation Status of TSHr in Well-differentiated Thyroid Cancer by Using Cytologic Material

Background: The role of methylation status of the thyroid stimulating hormone receptor gene (TSHr) in the discrimination of benign and malignant thyroid nodules has already been studied using paraffin blocks and cell lines. As cytological sampling plays an important role in assessment of thyroidal nodules, we have investigated the potential clinical use of TSHr methylation status of fine needle aspiration specimens reported according to Bethesda System.

Method: Sixty nine patients who had both cytological and pathological diagnosis of the same nodule were selected. Four groups were composed according to cytological and pathological diagnoses: Benign (B), papillary thyroid carcinoma (PTC), atypia of unknown significance (AUS) and follicular neoplasia (FN). The latter 2 groups were further sub-classified into 2 as benign (AUS-B and FN-B) and malignant (AUS-M and FN-M) according to final pathological diagnosis. DNAs were isolated from the fine needle aspiration cytology specimens and the methylation status of TSHr promotor region was investigated by using methylation specific polymerase chain reaction.

Results: Overall, TSHr methylation was present in 58% of cases; 71% of malignant and 46% of benign nodules. PTC group showed the highest TSHr methylation rate (87%), followed by 61% in AUS, 44% in B, and 30% in FN (p = 0.016). TSHr methylation rate was significantly higher in PTC group when compared to B (p = 0.013) and FN-B (p = 0.004) groups; but not in FN-M (p = 0.115) or AUS (p = 0.096) groups. All 9 cases of papillary thyroid carcinoma with lymph node metastasis showed TSHr methylation. Positive predictive value, negative predictive value, sensitivity and specificity of TSHr methylation in determination of malignancy were calculated as 60, 66, 71 and 54%, respectively.

Conclusion: The eminent ratio of TSHr methylation in well-differentiated thyroid carcinoma against benign thyroidal nodules adduced that TSHr methylation status can be utilized as a tumor marker for well-differentiated thyroid cancer; however, it has a limited value. The determination of methylation status of TSHr gene had no efficiency on decision of the malignant potential for the nodules which are cytologically classified as atypia of undetermined significance.