Total thyroidectomy for differentiated thyroid cancer

From March 1987 through March 1996, a total thyroidectomy ('IT) has been performed on 258 patients treated in our centre. Of them 39 TT have been performed on cancer patients (29 female, 10 male, mean age 66.5) 19 for papillary tumours, 9 for follicular carcinomas, 9 for mixed papillary follicular carcinomas, 1 for an indifferentiated cancer and 1 for a lymphoma. By total thyroidectomy we mean a total extracapsular intervention. The morbidity rate for this intervention has been: I patient had a temporary recurrent nerve palsy, 2 patients had a transitory hypocalcemia, while only one patient suffered from permanent hypoealcemia. We support TT as the right approach in patients suffering from differentiated thyroid cancer for the following reasons: i) In patients in whom a preoperative diagnosis of differentiated thyroid cancer has been clearly obtained, TT allows a good ontological radicality and an accurate surgical evaluation of neck lymph-nodes metastases. Moreover if distant micrometastases are detected, postoperative radioactive iodine therapy may be successfully used. ii) In patients with an unclear preoperative evaluation due to undetermined cytology or frozen section, for whom the literature reports a frequency of carcinoma ranging from 20 to 60%, TT avoids the need for a re-intervention to remove additional thyroid tissue. iii) In trained hands TT gives a low rate of complications that in addition to the advantages above explained makes this surgical approach to be preferred to less invasive interventions

Sodium iodide symporter expression and radioiodine distribution in extrathyroidal tissues

The functional role of the sodium iodide symporter (NIS) in extrathyroidal tissues was investigated by examining its mRNA and protein expression, together with the evidence of radioiodine (I-131) uptake in 302 patients who underwent I-131 total body scanning, following the administration of high doses of I-131 for a papillary or follicular thyroid carcinoma. By using a real-time kinetic quantitative RT-PCR and immunohistochemistry, the expression of NIS protein was detected mainly in secretory tissues. In parallel, I-131 uptake was evidenced in the majority of patients in the salivary glands (in 39%) and stomach (in 78%), but was found in breast in only 4 young female patients. These data demonstrate a strong correlation between the organ radioactivity distribution, as observed in vivo, and NIS protein expression. Interestingly, I-131 is rarely concentrated by mammary glands, even when large doses are administered. Moreover, a I-131 transfer in secretion fluids may represent a potential source of contamination responsible for false positive images and diagnostic pitfalls. (C) 2004, Editrice Kurtis

Solitary skin metastasis from papillary thyroid carcinoma

Although cutaneous lesions in patients with history of thyroid cancer are rare, the present report describes the appearance of a small skin metastasis that grew in situ over about 20 years from the initial diagnosis without any local or distant metastases

APE/Ref-1 is increased in nuclear fractions of human thyroid hyperfunctioning nodules

Apurinic/apyrimidinic endonuclease APE/Ref-1 is a multifunctional protein provided with DNA repair, transcription-factor regulation and anti-apoptotic activities. We have previously reported that, in thyroid cells, TSH regulates both the synthesis and nuclear translocation of APE/Ref-1. We have also shown that nuclear levels of this protein are reduced both in thyroid carcinoma tissues and cell lines. In the present study, APE/Ref-1 expression and cellular localization were analysed by Western blot in hyperfunctioning thyroid nodules from patients with toxic adenoma and/or toxic multinodular goiter. The total content of APE/Ref-1 protein was increased in the majority of the hyperfunctioning tissues with respect to normal adjacent tissue. There was also an increase in the nuclear levels of APE/Ref-1, suggesting enhanced cytoplasm-to-nucleus translocation of the protein in addition to its increased rate of synthesis. These results demonstrate that the phenomenon of nuclear translocation of APE/Ref-1 hypothesized on the basis of cell culture experiments does actually occur in vivo. Together with previous observations in thyroid carcinomas and tumoral cell lines, our findings suggest a two-stage model of APE/Ref-1 behaviour during malignant thyrocyte transformation: an early stage characterized by simple hyperplasia and upregulation of APE/Ref-1 in the nuclear compartment of the cell and a later stage in which nuclear levels of the protein drop to below-normal levels as the cell becomes progressively undifferentiated. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved

Modulation of thyroid-specific gene expression in normal and nodular human thyroid tissues from adults: An in vivo effect of thyrotropin

*Bruno R, * Ferretti E (* Equal contributors) CONTEXT: Evidence from in vitro studies or animal models has shown that TSH affects thyrocytes by thyroid-specific expression modulation. OBJECTIVE:The objective of our study was to analyze the role of TSH in human thyroid gene expression in vivo. DESIGN/SETTING: Thirty-nine normal thyroid tissues were collected at the same center. STUDY SUBJECTS: Patients were divided into two groups based on serum TSH levels: 17 with normal TSH levels (1-4 mU/liter; group 1) and 22 with TSH levels below 0.5 mU/liter (group 2). Intervention: Group 2 underwent thyroidectomy after suppressive L-T4 therapy. MAIN OUTCOME MEASURES: mRNA levels of thyroid genes such as sodium/iodide symporter (NIS), apical iodide transporter, pendrin, thyroglobulin, thyroperoxidase, TSH receptor, paired box transcription factor 8, and thyroid transcription factor-1 were evaluated by quantitative PCR. RESULTS: The reduction of TSH stimulation causes decreases in NIS and apical iodide transporter gene expression in normal tissues and more limited reductions in thyroglobulin, thyroperoxidase, and paired box transcription factor 8, but it has no significant effect on TSH receptor, pendrin, or thyroid transcription factor-1. Comparison of NIS levels in normal and nodular tissues from the same patient confirmed that it is differentially expressed in nodules only in the presence of normal TSH (P < 0.01). In patients with suppressed TSH, nodular NIS levels were similar to those in normal tissues. CONCLUSIONS: Our data represent the first demonstration in human thyroid tissues that TSH contributes to the regulation of thyrocyte differentiation by modulating thyroid gene levels. It exerts a particularly important effect on the transcription of NIS, which becomes very low after prolonged TSH suppression

Expression of adenylyl cyclase types III and VI in human hyperfunctioning thyroid nodules

Hyperfunctioning thyroid nodules are characterized by the presence of spontaneous somatic mutations responsible for constitutive activation of the cAMP pathway. However, alterations affecting other elements of the cAMP signaling system may counteract the effects of the mutations. In this study, the expression of the adenylyl cyclase (AC) types III and VI was investigated by Western blot in 18 hyperfunctioning thyroid nodules; in 12 samples, we also assessed the presence of TSH receptor! (TSHR) or gsp mutations and levels of AC VI and III mRNA. We found that the expression of nodular AC VI (but not AC 111) was significantly lower (85.1% of normal, P = 0.014) than the expression of both adenylyl cycles types of perinodular tissue from the same patients. Slightly, but not significant differences were detected in nodules with or without mutations and AC protein levels generally showed correlation with the levels of the transcripts detected by RT-PCR. In addition, AC III and AC VI expression levels within a given nodule were characterized by a significant positive correlation. These findings indicate that a diminished expression of AC type VI may be part of the mechanisms occurring in the hyperfunctioning nodules, independently of the presence of TSHR or gsp mutations, which influence the resulting phenotype. (C) 2003 Elsevier Science Ireland Ltd. All rights reserved

Growth Factor Receptors Gene Expression and Akt Phosphorylation in Benign Human Thyroid Nodules are Unaffected by Chronic Thyrotropin Suppression

Levothyroxine (L-T4)-based suppression of thyrotropin (TSH) secretion is widely used to prevent the growth of benign thyroid nodules, although the effectiveness of this approach has been demonstrated only in a subset of patients. In this study, we analyzed the in vivo effects of L-T4-mediated TSH suppression on elements of insulin/IGF-1-dependent growth-regulating pathways in tissues from patients with benign thyroid nodules. Nodular and non-nodular tissue specimens were collected from 63 patients undergoing thyroidectomy. 32 had received preoperative TSH suppressive therapy with TSH levels consistently below 0.5mU/l (L-T4 group). TSH suppression had not been used in the other 31, and their TSH levels were normal (0.8-4mU/l (control group). Quantitative RT-PCR was used to measure mRNA levels for TSH receptor, IGF1, IGF-1 receptor, insulin receptor, insulin receptor substrate 1 in nodular and non-nodular tissues from the 2 groups. Akt and phosphorylated Akt protein levels were detected by Western blot. Mean levels of mRNA for all genes tested were similar in the 2 groups, in both nodular and non-nodular tissues. The 2 groups were also similar in terms of phosphorylated Akt protein levels (measured by densitometric scan in 10 randomly selected nodules from each group). This is the first demonstration based on the study of human thyroid tissues that TSH suppression does not affect the expression of components of the insulin/IGF-1-dependent signaling pathways regulating thyrocyte growth. This may explain the lack of effectiveness of TSH-suppressive therapy in a substantial percentage of benign thyroid nodules

Analysis of RET proto-oncogene abnormalities in patients with MEN 2A, MEN 2B, familial or sporadic medullary thyroid carcinoma

Medullary thyroid carcinoma (MTC) may occur either as a sporadic or familial (FMTC) disease. Multiple endocrine neoplasia (MEN) type 2, inherited as an autosomal dominant disease, is characterized by coexistence of MTC with other endocrine neoplasia. Activating mutations of the RET proto-oncogene, involving the somatic or the germinal cell lineage, are found in both inherited and acquired forms. In this study, RET mutations were screened in 47 individuals either affected by MTC or belonging to families with hereditary MTC. Exons 10, 11, 13, 14, 15 and 16 of the RET gene were amplified by polymerase chain reaction and examined by DNA sequence and/or restriction enzyme analysis to detect mutations in purified amplicons. Six MEN 2A families with a germline mutation at codon 634, one FMTC family carrying a mutation at codon 618 and two MEN 2B families with a mutation at codon 918 were identified. In affected members of a MEN 2A family no known RET mutations were observed. Besides, we identified a germline mutation in a patient with apparently sporadic MTC and in two out of three sons, indicating the presence of a sporadic misclassified familial disease. In all of the families examined we were able to distinguish the affected vs unaffected (not at risk) members. A somatic mutation of codon 918 was detected in three out of ten patients with apparently sporadic MTC