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E Fiore, T Rago, F Latrofa, M A Provenzale, P Piaggi, A Delitala, M Scutari, F Basolo, G Di Coscio, L Grasso, A Pinchera and P Vitti

The possible association between Hashimoto's thyroiditis (HT) and papillary thyroid carcinoma (PTC) is a still debated issue. We analyzed the frequency of PTC, TSH levels and thyroid autoantibodies (TAb) in 13 738 patients (9824 untreated and 3914 under l-thyroxine, l-T4). Patients with nodular-HT (n=1593) had high titer of TAb and/or hypothyroidism. Patients with nodular goiter (NG) were subdivided in TAb−NG (n=8812) with undetectable TAb and TAb+NG (n=3395) with positive TAb. Among untreated patients, those with nodular-HT showed higher frequency of PTC (9.4%) compared with both TAb−NG (6.4%; P=0.002) and TAb+NG (6.5%; P=0.009) and presented also higher serum TSH (median 1.30 vs 0.71 μU/ml, P<0.001 and 0.70 μU/ml, P<0.001 respectively). Independently of clinical diagnosis, patients with high titer of TAb showed a higher frequency of PTC (9.3%) compared to patients with low titer (6.8%, P<0.001) or negative TAb (6.3%, P<0.001) and presented also higher serum TSH (median 1.16 vs 0.75 μU/ml, P<0.001 and 0.72 μU/ml, P<0.001 respectively). PTC frequency was strongly related with serum TSH (odds ratio (OR)=1.111), slightly related with anti-thyroglobulin antibodies (OR=1.001), and unrelated with anti-thyroperoxidase antibodies. In the l-T4-treated group, when only patients with serum TSH levels below the median value (0.90 μU/ml) were considered, no significant difference in PTC frequency was found between nodular-HT, TAb−NG and TAb+NG. In conclusion, the frequency of PTC is significantly higher in nodular-HT than in NG and is associated with increased levels of serum TSH. Treatment with l-T4 reduces TSH levels and decreases the occurrence of clinically detectable PTC.

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E Fiore, T Rago, M A Provenzale, M Scutari, C Ugolini, F Basolo, G Di Coscio, P Miccoli, L Grasso, A Pinchera and P Vitti

The risk of papillary thyroid cancer (PTC) is related to serum TSH, and the development of thyroid autonomy by reducing TSH levels decreases the frequency of PTC in patients with nodular goiter. Our aim was to investigate the effect of l-thyroxine (l-T4) on the frequency of PTC diagnosed by cytology in a large series of patients with nodular goiter untreated (n=20 055) or treated with l-T4 (n=7859). l-T4-treated patients with respect to untreated patients presented significantly lower serum TSH (median, interquartile range: 0.30 μU/ml, 0.08–0.62 μU/ml versus 0.70 μU/ml, 0.38–1.14 μU/ml; P<0.0001) and prevalence of PTC (3.2 vs 5.1%; P<0.0001). The frequency of PTC was closely related to serum TSH, with it being lowest in patients with TSH below the normal range (<0.4 μU/ml; 189/10 059, 1.9%) and highest in patients with TSH above the normal range (>3.4 μU/ml; 21/127, 16.5%), also showing a progressive increase from the lower to the upper quartile of normal range. A significantly higher proportion of l-T4-treated patients (6650/7859, 84.6%) had serum TSH below the median (0.90 μU/ml) with respect to untreated patients (12 599/20 055, 62.8%; χ 2 P value <0.0001), with it being included in the range of TSH associated with a lower frequency of PTC. The relationship between serum TSH and frequency of PTC was unrelated to the type of nodularity (solitary versus multinodular) and was not age dependent. In conclusion, patients with nodular goiter, treatment with l-T4 is responsible for the reduction of serum TSH and is associated with a decreased frequency of PTC.

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E Fiore, T Rago, M A Provenzale, M Scutari, C Ugolini, F Basolo, G Di Coscio, P Berti, L Grasso, R Elisei, A Pinchera and P Vitti

Higher TSH values, even within normal ranges, have been associated with a greater risk of thyroid malignancy. The relationship between TSH and papillary thyroid cancer (PTC) has been analyzed in 10 178 patients submitted to fine needle aspiration of thyroid nodules with a cytology of PTC (n=497) or benign thyroid nodular disease (BTND, n=9681). In 942 patients, submitted to surgery (521 from BTND and 421 from PTC), the histological diagnosis confirmed an elevated specificity (99.6%) and sensitivity (98.1%) of cytology. TSH levels were significantly higher in PTC than in BTND both in the cytological and histological series and also in patients with a clinical diagnosis of multinodular goiter (MNG) and single/isolate nodule (S/I). A significant age-dependent development of thyroid autonomy (TSH <0.4 μU/ml) was observed in patients with benign thyroid disease, but not in those with PTC, diagnosed both on cytology and histology. In patients with MNG, the frequency of thyroid autonomy was higher and the risk of PTC was lower compared to those with S/I. In all patients, the presence of thyroid auto-antibodies (TAb) was associated with a significant increase of TSH. However, both in TAb positive and TAb negative patients TSH levels were significantly higher in PTC than in BTND. Our data confirm a direct relationship between TSH levels and risk of PTC in patients with nodular thyroid diseases. Thyroid autonomy conceivably protects against the risk of PTC, while thyroid autoimmunity does not play a significant role.

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B Cosci, A Vivaldi, C Romei, F Gemignani, S Landi, R Ciampi, A Tacito, E Molinaro, L Agate, V Bottici, V Cappagli, D Viola, P Piaggi, P Vitti, A Pinchera and R Elisei

Germline and somatic RET oncogene mutations are found in 98% hereditary and 40% sporadic medullary thyroid carcinomas. Our aim was to analyse by in silico and in vitro assays the transforming activity of six rare RET mutations (T338I, V648I, M918V, A883T, S904F and M848T). Six known RET mutations were used as controls. The in silico analysis showed the highest score value (i.e. 65) for S904F, M848T, M918T and C634R, whereas L790F, G691S, T338I and V648I had 0 score. Intermediate score values were obtained by A883T (score=55), M918V, V804M and Y791F (score=15). The in vitro focus formation assay showed that cells transfected with S904F, M918T, M848T or C634R generated the largest number of focus formation units (FFU). Intermediate numbers of FFU were observed in cells transfected with M918V, V804M, Y791F or A883T, while cells transfected with L790F, G691S, T338I or V648I showed a number of FFU similar to control cells. A positive correlation between the in silico score and in vitro FFU was found (P=0.0005). Only cells transfected with M918T or C634R grew faster and generated higher number of colonies in soft agar than control cells. However, the cells that were transfected with V804M produced an intermediate number of colonies. In conclusion, two of the six rare RET mutations, S904F and M848T possessed a relatively high transforming activity but a low aggressiveness; the other four mutations T338I, V648I, M918V and A883T were low or non-transforming, and their ability to induce tumoural transformation might be related to particular genetic conditions.