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To describe the coexistence of mutations of both the multiple endocrine neoplasia type 1 (MEN1) and type 2 (MEN2) genes in a large Italian family and evaluate if it could be associated with more aggressive clinical manifestations of the two syndromes. Blood samples were obtained for genetic and biochemical analyses. The RET gene exons (8, 10, 11, 13, 14, 15, 16, 18) and the MEN1 coding regions, including the exon-intron boundaries, were amplified by PCR and directly sequenced. We identified two germline mutations in the proband: the first one, K666M, located at the exon 11 of RET proto-oncogene and the second one, IVS4+1G>T, located in the MEN1 gene. The functional characterization of IVS4+1G>T variation, located in the splicing donor site of exon 4 of MEN1 gene, caused the in-frame junction of exon 3 to exon 5, thus obtaining a shorter protein. The same proband's germline mutations were found in 16 relatives out of 21 screened subjects: 8 carried IVS4+1G>T, 4 RET K666M, and 4 both the mutations. This is the second report in literature of coexistence in the same family of germline mutations of both RET proto-oncogene and MEN1 gene. The simultaneous presence of the two mutations was not apparently associated with more aggressive diseases, since at last follow-up all patients appeared to be disease-free or well compensated by medical therapy; finally, no one exhibited metastatic diseases.

The papillary thyroid microcarcinoma (PTMC) is a subtype of the papillary thyroid carcinoma (PTC) 1 cm or less in diameter, bilateral and multifocal in a percentage of 15-20%. We describe our experience on the surgical treatment of 217 patient treated between 2005 and 2008. Our therapeutic algorithm for PTMC includes always total thyroidectomy with surgical exploration of the median cervical compartment and recurrent laryngeal nerve lymph node dissection, reserving the median lymph node dissection only to the cases with pathological lymph nodes and the lateral compartment lymphectomy to the cases that show suspect nodes with or without positive cytology. We usually perform total thyroidectomy rather than partial one, in relation to the high rate of multifocality of papillary microcarcinoma, to reduce rate of recurrencies and to better utilize I131 with diagnostic and curative aims. Complete central compartment dissection is mandatory when pathological nodes are present at surgical exploration. It prevents nodal recurrencies and decrease number of re-operations, that have a greater number of complications or morbidity, including hypoparathyroidism and inferior laryngeal nerve lesions. The rate of nodal metastases is not affected by the site of primitive tumor, but the tumor size does. The rate of nodal metastases varies from 55.7% for tumors 5 mm or less in diameter, to 73.7% for tumors sized from 5 to 10 mm, and is affected from the capsular infiltration, the presence of multiple foci, and the histological type, i.e. sclerosing type. All patients presenting papillary microcarcinoma with invasion of the capsule and extension to the perithyroid tissues, sclerosing histological type, multifocal and/or metastatic to the regional nodes, were treated with radiometabolic therapy and suppressing l-tiroxin administration, according to the guidelines of the Multidisciplinary Group for the Thyroid Cancer of our Institution.

Background: Serum thyroglobulin (Tg) stimulation by recombinant human TSH (rhTSH), in combination with neck ultrasonography (US), is an important tool in the first follow-up of differentiated epithelial cell thyroid carcinoma (DTC) patients. The objective of this study was to investigate if a second rhTSH stimulation, performed 2-3 years later, is of clinical utility in the follow-up of these patients., Methods: One hundred and one consecutive ambulatory DTC patients were studied. The great majority of them (89/101) were low-risk patients, being stage I or II at tumor node metastasis (TNM) staging classification. All study patients had been treated by surgery and radioiodine ablation, and exhibited, at first rhTSH follow-up, either undetectable Tg (1-5 ng/mL) (rhTSH1-Tg+, n = 12 patients considered with uncertain prognosis), with no US evidence of residual disease. In all patients, serum Tg measurement after a second rhTSH stimulation and neck US were performed., Results: At the second follow-up, all 89 rhTSH1-Tg-patients showed a negative US, and Tg became low positive only in one case, whereas it remained undetectable in the other patients. The overall negative predictive value of rhTSH1-Tg- was, then, 98.9%. Out of the remaining 12 patients (i.e., rhTSH1-Tg+ patients), 2 showed disease persistence/recurrence (with a positive predictive value of rhTSH1-Tg+ of 16.7%) and 6 became Tg-., Conclusions: A second rhTSH stimulation is useless in DTC patients who were rhTSH-Tg and imaging negative at first follow-up, while it is suggested in patients with detectable, although low, rhTSH-Tg levels at first follow-up: in the absence of clinical or US evidence of disease persistence, these patients should not be retreated by radioiodine, but simply scheduled for a later rhTSH stimulation.

Context: Mutations of the HRPT2 gene have recently been implicated in the development of parathyroid carcinoma., Objective: The objective of this study was early diagnosis of parathyroid tumor in a family with germline HRPT2 mutation., Patients, Methods, and Results: In a 40-yr-old male previously treated for parathyroid atypical adenoma, we screened the 17 translated HRPT2 exons and their exon-intron boundaries and found a germline frameshift mutation in exon 7 (685delAGAG) predicting a premature stop codon at nucleotides 767-769. Nine family members (age, 33.9 +/- 19.8 yr, mean +/- SD) also carry the mutation, but eight have had normal serum calcium. Biochemical and ultrasonographic evaluation uncovered a 27-yr-old hypercalcemic carrier niece with an atypical parathyroid adenoma, and a 43-yr-old normocalcemic carrier sister was found by ultrasonography to have an extrathyroidal nodule, which proved to be parathyroid carcinoma. The index case, 12 yr after surgery, was normocalcemic, but ultrasonography revealed an extrathyroidal nodule in the contralateral hemithyroid tissue that proved to be atypical adenoma., Conclusions: Our report confirms that germline mutations of HRPT2 gene may be associated with multiple parathyroid neoplasms. Our experience suggests that longitudinal surveillance by serum biochemistry alone may not be 100% sensitive, and addition of routine neck ultrasonography is a readily accepted adjunct that may facilitate earlier disease detection in some families.

Context: Although the prognosis of papillary thyroid microcarcinoma (PTMC) is usually excellent, the optimal follow-up strategy has never been investigated., Objective: The objective of the study was to investigate the role of neck ultrasonography (US), whole-body scintigraphy (WBS), and serum thyroglobulin levels (Tg) after recombinant human (rh) TSH in the follow-up of very low-risk PTMC patients., Design: The study was a 5-yr observational study based on a 6- to 12-month follow-up after near total thyroidectomy., Setting: The study population consisted of ambulatory patients., Patients: Eighty consecutive patients diagnosed with PTMC, who had not undergone postoperative radioiodine treatment because of unifocal tumor without lymph node metastases and who did not have anti-Tg antibodies, were included., Main Outcome Measures: WBS and Tg after both rhTSH and neck US were measured., Results: rhTSH-Tg was 1 ng/ml or less in 45 (Tg-) and more than 1 in 35 (Tg+) patients. WBS showed no pathological uptake in any patient. US identified node metastases in two Tg (+) and one Tg (-) patients. rhTSH-Tg levels positively correlated with thyroid bed iodine uptake (r = 0.40, P < 0.0001). To date (32 +/- 13 months after surgery), all node-negative patients have undetectable Tg levels on LT(4) treatment and negative US., Conclusions: For the initial follow-up of PTMC patients without risk factors and anti-Tg antibodies and who did not undergo radioiodine treatment: 1) WBS is useless; 2) US is highly sensitive in detecting node metastases; and 3) detectable rhTSH-Tg levels mainly depend on small normal tissue remnants. In this subgroup of PTMC patients, neck US might be regarded as a primary tool for the initial follow-up.

The activity of TSH, the main regulator of growth and differentiation in the thyroid, has been mainly related to the activation of the adenylyl cyclase cascade. TSH also activates phospholipase-C and -A2; these effects, however, have been reported to require concentrations of the hormone up to 1000-fold higher than those effective on adenylyl cyclase, suggesting that the main physiological mechanism involved in the action of TSH is the activation of this enzyme. Using primary cultures of human thyroids, we here show that physiological concentrations of TSH (0.01-10 mU/L) are also able to increase intracellular Ca2+ levels. Cells were loaded with the fluorescent Ca2+ probe fura-2 and analyzed by single cell Ca2+ recording. The basal Ca2+ level was 105 +/- 30 nmol/L, and physiological concentrations of TSH increased it by 2- to 7-fold. The Ca2+ increase was transient and lasted up to 10 min. It is also shown that the TSH-dependent Ca2+ increase involves both the activation of phospholipase-C and the entry of extracellular Ca2+. TSH (100-10000 mU/L) increased cAMP levels by up to 20-fold in parallel experiments performed on the same cell preparations. These data demonstrate that physiological concentrations of TSH are able to increase cytosolic Ca2+ levels, indicating that this second messenger might directly mediate the action of this hormone in the thyroid.