Simone De Leo

Telomerase in differentiated thyroid cancer: Promoter mutations, expression and localization

Telomerase-reverse-transcriptase (TERT) promoter mutations have been recently described in tumors. In the present large series, TERT mutations were found in 12% of papillary thyroid cancers (PTCs) and in 14% of follicular thyroid cancers (FTCs), and were found to significantly correlate with older age at diagnosis and poorer outcome. Interestingly, the prognostic value of TERT mutations resulted to be significantly stronger than that of BRAF(V600E). Moreover, the outcome was not different among tumors with isolated TERT mutation and those with coexistent mutations (TERT/BRAF in PTCs or TERT/RAS in FTCs). TERT rs2853669 polymorphism was found in 44.4% of tumors. At WB, TERT was significantly more expressed in tumors than in normal samples, being the highest levels of expression recorded in TERT mutated cases. At IHC, in tumors and in metastatic lymph-nodes TERT staining was significantly higher in the cytoplasm than in the nucleus, whereas in normal tissue the degree of staining did not differ in the two cellular compartments. In conclusion, TERT mutations were shown to strongly correlate with a poorer outcome in differentiated thyroid tumors, and neither BRAF nor RAS mutation were found to confer an additional effect in the disease persistence. TERT protein was found to be more expressed in neoplastic than in normal tissues, and to display a different cellular localization, suggesting that it could contribute to thyroid cancer progression by mechanisms taking place in the cytoplasm.

Refining Calcium Test for the Diagnosis of Medullary Thyroid Cancer: Cutoffs, Procedures, and Safety

CONTEXT Calcitonin (CT) measurement is crucial to the early diagnosis and the follow-up of medullary thyroid cancer (MTC). If the evaluation of stimulated CT levels is required, a provocative test can be performed, being the high-dose Ca test recently reintroduced in clinical practice. OBJECTIVE Our objective was to identify gender-specific thresholds for MTC diagnosis in a large series of patients who underwent the Ca test. PATIENTS AND METHODS A total of 91 patients (49 females and 42 males) underwent the Ca test (calcium gluconate, 25 mg/kg) before thyroidectomy and both basal CT (bCT) and stimulated CT (sCT) were compared with histological results by receiver operating characteristic plot analyses. To evaluate possible side effects of Ca administration, cardiac function has been extensively studied. RESULTS bCT levels were found to harbor the same accuracy as sCT in the preoperative diagnosis of MTC. The best Ca thresholds for the identification of MTC were >26 and >68 for bCT and >79 and >544 pg/mL for sCT in females and males, respectively. The high tolerability and safety of the Ca test was demonstrated and advice offered to be followed before and during the test. CONCLUSIONS Gender-specific bCT and sCT cutoffs for the identification of C-cell hyperplasia and/or MTC have been defined. The bCT and sCT were found to have a similar accuracy, indicating that serum CT assays with improved functional sensitivity may likely decrease the relevance of the stimulation test in several conditions. Finally, systematic cardiac monitoring confirms the safety of the Ca test.

Incidence of elevation of serum thyroid-stimulating hormone during controlled ovarian hyperstimulation for in vitro fertilization

OBJECTIVE To evaluate the rate of euthyroid women encountering an elevation of serum TSH above the threshold of 2.5 mIU/L during controlled ovarian hyperstimulation (COH) for IVF. STUDY DESIGN Six-month prospective cohort study on 175 consecutive euthyroid women undergoing their first IVF cycle. Serum TSH assessments were performed before COH, at the time of hCG administration and at +16 days after hCG administration. Women were eligible if serum TSH tested the month preceding the IVF cycle was 0.4-2.5 mIU/L. A history of thyroid disorders was an exclusion criterion. RESULTS Serum concentrations of TSH at the three scheduled assessments were 1.5±0.5, 2.2±1.0 and 2.1±1.1 mIU/L, respectively. A statistically significant increase occurred between basal levels and levels at the time of hCG administration (p<0.001). Afterwards, levels remained stable (p=0.49). Serum TSH at the time of hCG administration exceeded the threshold of 2.5 mIU/L in 61 subjects, corresponding to 35% (95% CI: 28-42%). At +16 days after hCG administration, this event was observed in 47 subjects (27%, 95% CI: 21-34%). Baseline characteristics of women who did and did not exceed the threshold were similar apart from basal serum TSH, which was higher in the former group. The OR was 7.6 (95%CI: 2.9-20.2) per mIU/L (p<0.001). Cycle outcome and pregnancy rate were also similar. CONCLUSION Serum TSH exceeds the threshold of 2.5 mIU/L during COH in one out of three women who are euthyroid prior to enter an IVF cycle. Further evidence is warranted to elucidate the clinical relevance of our findings.

The optimal range of RET mutations to be tested: European comments to the guidelines of the American Thyroid Association

In the 9th ETA-CRN Meeting (September 2009, Lisbon) some recommendations from the American Thyroid Association (ATA) guidelines for the management of medullary thyroid cancer (MTC) were discussed by an European Panel of Experts (EPE). Among the 12 ATA recommendations related to hereditary MTC and to the optimal range of RET mutations to be tested (recommendations 1-5 and 9-15), 7 were shared and 5 were not shared by the EPE. In the present paper, the related comments and suggestions will be reported and discussed.

Fetal cell microchimerism in papillary thyroid cancer: A role in the outcome of the disease

Fetal cell microchimerism (FCM) is defined as the persistence of fetal cells in maternal organs and circulation without any apparent rejection and it was hypothesized to protect toward the onset of some neoplastic diseases. To verify the role of FCM in papillary thyroid cancer (PTC), we enrolled 87 parous women with PTC and at least one male pregnancy preceding the diagnosis (PTC‐P), 66 healthy women with 1 or more male children (HC‐P) and 57 nonparous women with PTC (PTC‐NP). The presence of circulating male DNA was assessed by the amplification of the Y chromosome‐specific gene SRY, with a sensitivity of 1 male cell/1 million female cells. A significantly higher frequency of FCM was found in HC‐P than PTC‐P women (63.6% vs. 39.1%, p = 0.004). Among PTC‐P patients, those positive for the presence of FCM (FMC+ve) had a lower prevalence of extrathyroidal extension (p = 0.027) and lymph node metastases (p = 0.044) than those without FCM (FMC−ve). Moreover, FMC+ve patients were more frequently in remission than FMC−ve cases (94.1 vs. 67.9%, p = 0.009). Interestingly, we showed for the first time that the positive effect on tumor presentation and outcome is specifically related to FCM and it is not an effect of pregnancy. In conclusion, circulating FCM is significantly more frequent in healthy parous women than in women with PTC. Moreover, the presence of circulating fetal male cells is associated with a significantly lower extrathyroidal extension and a good prognosis, suggesting a protective role of this phenomenon toward both the onset and the progression of thyroid cancer.

Clinical and molecular analyses of thyroid cancer in patients treated for benign diseases

Incidental thyroid carcinoma (ITC) is defined as a tumor diagnosed at histology after surgical intervention for a benign thyroid disease and, therefore, without a preoperative diagnosis of malignancy. The prevalence of ITCs reported in the 20 papers of the literature is extremely variable (3.3–21.6%), mostly due to the relatively low number of cases included (Ugolini et al. 2007, Bradly et al. 2009, Barczyński et al. 2011, Minuto et al. 2013, Negro et al. 2013), and scanty molecular data are available (Ugolini et al. 2007). A more accurate estimation of the actual prevalence of ITCs is of particular importance for the preoperative counseling of patients undergoing thyroidectomy for a supposed benign disease. Moreover, the definition of the clinical behavior of this category of tumors is crucial for the choice of the best postsurgical treatments and follow-up. The aim of this study was to investigate the prevalence, clinical features, and BRAF mutational status of ITCs of any dimension in a large consecutive cohort of patients referred to our Endocrine Surgery Center for benign thyroid disease. The approval of the Ethical Committee was obtained for this retrospective observational study (#139/2013). Between February 1997 and March 2011, 2045 patients were subjected to thyroidectomy at the Endocrine Surgery Unit for benign disease. The preoperative diagnosis was uninodular or multinodular goiters (MNGs) in 1405 cases, toxic uninodular goiter or toxic MNGs (TMNGs) in 332 cases, Graves’ disease (GD) in 300 cases, Hashimoto’s thyroiditis in six cases, and iatrogenic thyrotoxicosis in two cases. The preoperative diagnosis was based on a benign cytology observed during ultrasound-guided fineneedle aspiration biopsy (FNAB) performed on either thyroid nodules with suspicious ultrasound features or the largest thyroid nodule if no suspicious features were detected. In TMNGs, only nodules with a normal or reduced uptake were subjected to FNAB. All cases with an indeterminate cytology were excluded. The surgical

Correction to: Radioiodine ablation with 1,850 MBq in association with rhTSH in patients with differentiated thyroid cancer

Unfortunately, the fourth author’s middle name was missed out in the original publication of this article. The complete correct name should read as follows.