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PubMed1998

Comparison of metabolic and receptor imaging in recurrent medullary thyroid carcinoma with histopathological findings.

Early diagnosis of metastases of medullary thyroid carcinoma (MTC) provides the optimal condition for curative outcome. The aim of this study was to appraise the detection of metastases in patients with recurrent MTC using [111In-DTPA-d-Phe1]-pentetreotide and pentavalent technetium-99m dimercaptosuccinic acid [99mTc(V)-DMSA] in comparison with histopathological findings. Eighteen MTC patients with persistently elevated tumour marker (calcitonin, carcinoembryonic antigen) levels underwent somatostatin receptor scintigraphy using [111In-DTPA-d-Phe1]-pentetreotide (222 MBq) with early (4 h after injection) and delayed (24 h) whole-body scans and single-photon emission tomography (SPET) imaging. Metabolic whole-body and SPET imaging using 500 MBq 99mTc(V)-DMSA was performed 4 h after injection. Metabolic and receptor imaging revealed 51 sites of focal accumulation in the 18 patients investigated. Comparison with histological findings revealed that metabolic and receptor imaging had a sensitivity of 84% for the diagnosis of MTC. Using [111In-DTPA-d-Phe1]-pentetreotide, SPET discovered four lymph node metastases in two patients in whom planar views had previously identified only one lymph node metastasis, and provided no new information in the other 16 patients. In comparison, SPET studies [using 99mTc(V)-DMSA] additionally localized eight lymph node metastases in four patients and confirmed the diagnosis of hepatic metastases (n=5) in another patient in whom conventional imaging modalities and planar views had previously detected only three liver metastases. Overall, lesion detection sensitivities for 99mTc(V)-DMSA and [111In-DTPA-D-Phe1]-pentetreotide were 69% and 29%, respectively. Five surgically removed foci were adjudged false-positive with respect to MTC metastases. False-positve results were caused by lymphadenitis, an enchondroma and a pheochromocytoma (histologically proven). The smallest lesion identified by metabolic imaging was a 6 mm in diameter lymph node metastasis located in the upper mediastinum. Somatostatin receptor scintigraphy only demonstrated tumour sizes more than 1 cm in diameter. These preliminary results suggest that the combination of metabolic [99mTc(V)-DMSA] and receptor ([111In-DTPA-D-Phe1]-pentetreotide) imaging is more sensitive for tumour localization in patients with recurrent MTC than the use of only one radiopharmaceutical. However, neither 99mTc(V)-DMSA nor [111In-DTPA-D-Phe1]-pentetreotide is specific for MTC and false-positive scintigraphic findings have to be considered. Furthermore, somatostatin receptor scintigraphy cannot visualize small tumour sites (<1 cm). Further studies are needed to evaluate the role of combined metabolic and receptor imaging in the management of patients with recurrent MTC.

Carcinoma, Medullary↗
PubMed2000

Unilateral surgery supported by germline RET oncogene mutation analysis in patients with sporadic medullary thyroid carcinoma.

Compared to hereditary medullary thyroid carcinoma (MTC), sporadic MTC tends to be unicentric and confined to one lobe. Patients with sporadic MTC usually undergo total thyroidectomy because of a possible hereditary or bilateral process. We evaluated the usefulness of germline RET oncogene mutation analysis in surgery for apparently sporadic MTC and performed unilateral surgery on patients without detectable mutation. In 36 patients with a preoperative diagnosis of apparently sporadic MTC, we performed germline RET oncogene mutation analyses: before surgery in 8 recent patients and after surgery in 28 who had been treated before 1996. Of the latter, 5 had bilateral MTC. DNA samples were extracted from their peripheral blood, and the polymerase chain reaction products of the RET proto-oncogene were analyzed using single-strand conformation polymorphism analysis and the direct sequencing methods. Before 1996 we often performed total thyroidectomy but changed to hemithyroidectomy thereafter, except in one patient with associated Graves' ophthalmopathy. Our minimal standard practice included systematic central and ipsilateral neck dissection. The outcome was assessed in terms of gastrin- and calcium-stimulated plasma calcitonin levels. Germline RET mutations were found in six patients. Five of these patients had bilateral MTC, whereas all 30 patients without mutation had unilateral disease. Hemithyroidectomy in seven of our recent patients resulted in normalization of plasma calcitonin levels in all, although four were found to have microscopic lymph node involvement. In conclusion, hemithyroidectomy with systematic central and ipsilateral neck dissection is an appropriate procedure for patients with sporadic MTC without detectable germline RET mutations.

Adult↗
PubMed2006

The risk of medullary thyroid carcinoma in patients with Hirschsprung's disease.

Hirschsprung's disease (HD) can be associated with the development of neuroendocrine tumours such as medullary thyroid carcinoma (MTC). The RET proto-oncogene is the major gene responsible for both HD and MTC. Mutations in exon 10 (codons 609, 611, 618, 620) were found in patients with co-occurrence of HD and MTC. The aim of the study was to screen the MTC risk in patients with HD. The prospective and retrospective genetic analyses comprised 56 HD patients (41 males, 15 females, aged 0-47). The prospective subgroup of patients consisted of 34 patients (25 boys, 9 girls) operated on between June 2003 and December 2005. The retrospective subgroup comprised 22 patients (16 boys, 6 girls) of 194 patients who were operated on between December 1979 and May 2003, non-systematically chosen preferably for total colonic aganglionosis (TCA). DNAs were isolated from blood and resected segments of aganglionic bowel. The HD patients and nine available family members (2 HD) were tested for RET mutations in exons 10, 11, 13, 14, 15 and 16. Direct double-stranded fluorescent sequencing revealed typical germline heterozygous MTC risk RET mutations in 3/56 (5.4%) female HD patients: Cys609Tyr, Cys620Arg (both exon 10) and Tyr791Phe (exon 13). Two of these patients had TCA and one patient had classical type of HD. One TCA patient developed clinical stage of MTC and underwent total thyroidectomy (TTE). The other two RET positive HD patients (aged 7 and 25 years) are screened for calcitonin level and they are without TTE till now. Two family members (mothers of TCA patients) with detected RET mutation underwent prophylactic TTE with MTC finding. Results showed the benefit of systematic RET mutation screening in HD patients in order to identify the risk of MTC in preclinical stage of the disease in patients with HD and their family members. We recommend to investigate not only exon 10 but also exon 13.

Adolescent↗
PubMed1985

Serotonin (5-hydroxytryptamine) in medullary thyroid carcinoma with or without pheochromocytoma.

An increased synthesis of serotonin by medullary thyroid carcinoma (MTC) has been postulated because an increased concentration of serotonin in the MTC cells and an increased urinary excretion of 5-hydroxyindoleacetic acid have been observed in some patients with MTC. Ten patients with sporadic MTC and 18 patients with familial MTC of either the MEN-IIa or MEN-IIb types were investigated. Three of the patients with MEN-IIa and the patient with MEN-IIb had concomitant pheochromocytomas. The concentrations of serotonin in serum were measured in order to investigate the contributions of the MTC and pheochromocytoma to the overall synthesis of serotonin. The concentrations of serotonin in sera from patients with MTC or MEN-IIa without pheochromocytomas were not different from the concentrations measured in healthy subjects (P greater than 0.10). The four patients with MEN-II syndromes with pheochromocytomas had increased concentrations of serotonin in sera (P less than 0.01), and decreases in the concentrations occurred following adrenalectomy in all four patients. The results show that the MTC made only little if any contribution to the overall synthesis of serotonin in the 28 patients studied; and serotonin was produced in pheochromocytoma tissue from four patients with MEN-II syndromes with pheochromocytoma.

Adolescent↗
PubMed1994

Magnetization transfer contrast imaging of hepatic neoplasms.

A method of performing magnetization transfer contrast (MTC) using a pulse sequence based on a series of on-resonance binomial pulses preceding a conventional spin-echo sequence has been recently described. We investigated this technique in the evaluation of circumscribed hepatic neoplasms on a 0.5 T imager. Conventional spin-echo imaging was performed in 18 patients with hepatic neoplasms, 15 with primary or metastatic hepatic neoplasms, and 3 with cavernous hemangiomas. The T1-weighted sequence was repeated following MTC saturation in 7 patients and the proton density sequence was repeated following MTC saturation in 13 patients (both were used in two patients). The mean lesion-to-liver contrast for neoplasms worsened with T1-MTC (0.87 vs. 1.04), but improved slightly with proton density-MTC (1.10 vs. 1.22) when compared to the corresponding non-MTC spin-echo images. However, these differences were not statistically significant (p = .19 and p = .16, respectively). The limited data on cavernous hemangiomas does not suggest these have consistently different MTC imaging characteristics from other hepatic neoplasms. In conclusion, MTC imaging using a binomial saturation pulse did not offer significant improvement in contrast between hepatic neoplasms and normal liver. Refinements of the binomial pulse sequence will be necessary if a consistent improvement in lesion sensitivity is to be achieved. Evaluation of its role in increasing diagnostic specificity will require further investigation.

Adenoma↗
PubMed2004

RET signals through focal adhesion kinase in medullary thyroid cancer cells.

BACKGROUND: The RET proto-oncogene is implicated in medullary thyroid cancer (MTC) and has been shown to signal indirectly to focal adhesion kinase (FAK) in cell types other than MTC. We have previously shown that FAK is phosphorylated in MTC cells. We hypothesized that inhibition of RET with pharmacologic inhibitors or by depletion with siRNA would decrease FAK phosphorylation in MTC cells, thereby implicating a RET-FAK signaling pathway. METHODS: Human MTC cells (TT cells) were treated with pharmacologic inhibitors or transfected with RET siRNA. Total protein was detected by immunoblotting. Phosphorylated FAK was detected by immunoprecipitating total FAK and immunoblotting with antiphosphotyrosine. RESULTS: Treatment of MTC cells with the inhibitor PP2 significantly inhibited RET phosphorylation and, to a lesser extent, FAK phosphorylation. Imatinib mesylate inhibited FAK phosphorylation only at high doses. RET siRNA significantly decreased RET expression and FAK phosphorylation. CONCLUSIONS: RET signals through FAK in MTC cells. Whether this is due to a direct or indirect interaction is not yet clear. PP2 or a similar inhibitor might be a useful treatment for MTC.

Antineoplastic Agents↗
PubMed2006

Antisurvivin oligonucleotides inhibit growth and induce apoptosis in human medullary thyroid carcinoma cells.

Survivin is a novel member of the inhibitor of apoptosis protein (IAP) family, which is known to be over-expressed in various carcinomas and associated with their biologically aggressive characteristics. The aim of this study was to investigate survivin expression in human medullary thyroid carcinoma (MTC) and a MTC cell line TT, correlate survivin expression with clinicopathologic features of MTC, and test effects of antisurvivin oligonucleotides (ASODNs) on growth and apoptosis of TT cells. Survivin expression was immunohistochemically determined in formalin-fixed and paraffin-embedded specimens obtained from 10 cases of normal thyroid (NT) and 10 cases of MTC, and in TT cells. In TT cells, we confirmed survivin expression and its down-regulation by ASODNs using RT-PCR and Western blot analyses, and investigated effects of ASODNs on viability and growth by MTT assay and apoptosis by apoptotic analyses including DNA laddering assay, acridine orange/ethidium bromide staining and flow cytometric cell cycle analysis. Immunohistochemical analysis showed high survivin expression in MTC and TT cells, whereas no immunoreactivity was detectable in NT. Statistical analyses revealed no significant correlation of survivin expression with the clinicopathologic features of MTC. In TT cells, survivin expression at both mRNA and protein levels was confirmed and could be down-regulated by ASODNs concomitant with decrease in viability and growth, and increase in apoptosis. Our results suggest that survivin plays an important role in MTC independent of the conventional clinicopathologic factors, and ASODNs is a promising survivin-targeted gene therapy for MTC.

Adult↗
PubMed1997

Age-Related Disease Penetrance in a Large Medullary Thyroid Cancer Family With a Codon 609 RET Gene Mutation.

Background: Familial medullary thyroid cancer (MTC) is a form of type 2 multiple endocrine neoplasia in which individuals develop MTC as the sole phenotypic manifestation of their disease. A previous study has suggested that patients with familial MTC may have a later age of onset (and more indolent course) of MTC than is observed in individuals with multiple endocrine neoplasia type 2A. Methods and Results: The age-related penetrance of MRC, C-cell hyperlasia, and a positive pentagastrin test for carriers of a codon 609 mutation of the RET gene in a large MTC family was determined. Pentagastrin testing and surgical pathology findings for patients who had thyroidectomies were correlated with RET sequence analysis findings. The penetrance of this mutation for the development of MTC was 0% at age 20, 10% at age 20, 10% at age 30, 50% at age 45, and approximately 100% at age 60. The ages of onset of C-cell hyperplasia and a positive pentagastrin stimulation test were similar, and both preceded the age of onset of MTC. Carriers of the mutated gene in this family had a later age of onset of disease that has been reported for families with multiple endocrine neoplasia type 2A and 2B syndromes. Conclusions: These results may have implications for the clinical management of MTC families with a 609 mutation.

Journal Article↗
PubMed2000

[Predictive genetic investigations. Individualization of diagnosis and treatment in families with multiple endocrine neoplasia type II].

BACKGROUND AND OBJECTIVE: When multiple endocrine neoplasia type 2 (MEN2) is suspected, genetic tests are at the centre of screening procedures. It was the aim of this study to compare the diagnostic value of molecular biological investigations with that of conventional biochemical tests. PATIENTS AND METHODS: The study cohort consisted of all 144 patients cared for in our department since 1990 with the suspected diagnosis of MEN2 (evidence of a medullary thyroid carcinoma [MTC]), coexistence of two MEN2 tumours or a family history of MEN2. 14 of the 144 patients (from 12 families) were already known to have an hereditary MTC, while the remaining 130 had been referred for further diagnostic investigations. RESULTS: An hereditary MTC was diagnosed in 22 of the 130 patients, a sporadic MTC in 32, while no definitive classification was possible in 20 MTC patients without a positive family history and on whom no mutation analysis had been performed. MEN2 was excluded in 56 family members. All 22 patients with newly diagnosed MTC had abnormally high calcitonin levels. A germ-line mutation in the RET proto-oncogene was found in 8 of the 9 families who had undergone molecular biological tests. The investigate results led to a thyroidectomy in 19 of the 22 patients with hereditary MTC; in all of them the surgical specimen showed C-cell hyperplasia and/o MTC. CONCLUSION: These results emphasize the importance of genetic tests in family screening. Preoperative measurement of calcitonin remains essential in MEN2 families in whom a germ-line mutation is not known. The choice of the appropriate diagnostic test must be individualized to the particular patients so that optimal results are obtained.

Adolescent↗
PubMed2006

Overexpression of the NOTCH1 intracellular domain inhibits cell proliferation and alters the neuroendocrine phenotype of medullary thyroid cancer cells.

The role of NOTCH1 as an oncogene or tumor suppressor appears to be cell type-specific. Medullary thyroid cancer (MTC) cells characteristically express the transcription factor ASCL1 (achaete-scute complex-like 1) as well as high levels of the neuroendocrine (NE) markers calcitonin and chromogranin A (CgA). In this study, we show that the active NOTCH1 intracellular domain is absent in human MTC tumor tissue samples and MTC-TT cells. To determine the effects of NOTCH1 expression, we created a doxycycline-inducible NOTCH1 intracellular domain in MTC cells (TT-NOTCH cells). Treatment of TT-NOTCH cells with doxycycline led to dose-dependent induction of NOTCH1 protein with corresponding decreases in ASCL1 protein and NE hormones. ASCL1 promoter-reporter assay and Northern analysis revealed that ASCL1 reduction by NOTCH1 activation is predominantly via silencing of ASCL1 gene transcription. Overexpression of ASCL1 in MTC cells indicated that CgA expression is highly dependent on the levels of ASCL1. This was further confirmed by experiments using small interfering RNA against ASCL1, in which reduction in ASCL1 led to reduction in both CgA and calcitonin. Furthermore, we demonstrate that NOTCH1 signaling activation leads to ERK1/2 phosphorylation, but that reduction in NE markers is independent of ERK1/2 activation. Activation of NOTCH1 resulted in significant MTC cell growth inhibition. Notably, reduction in MTC cell growth was dependent on the level of NOTCH1 protein present. Moreover, no increase in growth upon expression of ASCL1 in NOTCH1-activated cells was observed, indicating that the growth suppression observed upon NOTCH1 activation is independent of ASCL1 reduction. Mechanistically, we show that MTC cell growth inhibition by NOTCH1 is mediated by cell cycle arrest associated with up-regulation of p21.

Basic Helix-Loop-Helix Proteins↗
PubMed1999

Brain metastases from medullary thyroid carcinoma in a patient with multiple endocrine neoplasia type 2A.

Medullary thyroid carcinoma (MTC) is an uncommon thyroid cancer occurring in less than 10% of patients with thyroid cancer. Brain metastasis from MTC is exceedingly rare. Only six cases of brain metastasis from MTC have been reported in the literature and none had MTC as a part of multiple endocrine neoplasia (MEN) syndrome. We report a 42-year-old Caucasian male with MEN 2A who presented with neurological symptoms 25 years after total thyroidectomy with lymphadenectomy for MTC metastatic to local lymph nodes. A brain magnetic resonance imaging (MRI) showed a 4-cm cystic mass and a 1-cm nodule in the left frontal-parietal lobe in addition to a 0.8-cm cystic mass in the left frontal lobe and multiple tiny cerebellar metastatic lesions. Partial resection of the cerebral metastasis followed by whole brain radiotherapy resulted in resolution of the neurological symptoms. However, the patient had multiple systemic metastasis from the MTC and he died of systemic complications due to metastatic MTC. To our knowledge this is the first report of brain metastases from MTC in a patient with MEN 2A.

Adult↗
PubMed2004

Medullary and papillary tumors are frequently associated in the same thyroid gland without evidence of reciprocal influence in their biologic behavior.

Papillary thyroid microcarcinoma (mPTC), is a very frequent incidental finding with a frequency varying from a few percent to 35% at postmortem histopathologic examinations. However, the presence of mPTC in patients undergoing thyroidectomy for multinodular goiter (MNG) and for Graves' disease (GD) has been found to be lower. Patients with medullary thyroid carcinoma (MTC) and papillary thyroid carcinoma (PTC) association have been published as anecdotal case reports, as well as kindred with familial MTC or multiple endocrine neoplasia (MEN) 2A with some members simultaneously affected by MTC and PTC. We studied the prevalence and the biological behavior of MTC associated with PTC, with particular attention to those cases in which a mPTC was incidentally found. Twenty-seven of 196 (13.8%) MTC cases showed an association with PTC and in particular 21 of 190 (11.05%) with an incidental mPTC. This percentage is higher than that reported in the literature on the association of mPTC with GD (2.8%-4.5%) and MNG (3%). Also the percentage of the more general association of MTC/PTC, not restricted to mPTC, found in our series (13.8%) is higher than that reported in studies that analyzed the prevalence of PTC (any size) in patients treated for MNG (7.5%). A similarly high percentage of MTC/PTC had not been reported before and in particular there are no reports on large series of MTC/PTC. We also analyzed the epidemiologic, clinical, and pathologic features of MTC associated and not associated with PTC without finding any difference. In particular the outcome of the MTC did not appear to be influenced by the presence of the PTC and the specific radioiodine treatments. Moreover, although we cannot completely exclude a shared pathogenic event as the cause of both MTC and PTC, the molecular analysis of RET gene alterations did not show any common mutation.

Adult↗
PubMed2005

Paraganglioma-like medullary thyroid carcinoma: a rare entity.

OBJECTIVE: The wide variety of rare histologic variants of medullary thyroid carcinoma (MTC) may make the differential diagnosis difficult. Pathologic examination of the resected specimen will not always be able to confirm the diagnosis, leaving the surgeon with an uncertainty as to what type of resection is best for the patient. The following report describes the case of a 58-year-old man with the rare diagnosis of paraganglioma-like MTC. METHODS: The patient presented with markedly elevated calcitonin (CT) and carcinoembryonic antigen (CEA) levels. A 1-cm tumor was detected in the right lobe of the thyroid. Based on the clinical diagnosis of MTC, we performed a total thyroidectomy with lymphadenectomy of the central and right lateral compartments. Paraffin sections of the resected specimen were stained with hematoxylin and eosin (H&E) and immunohistochemically characterized using antibodies to CT, CEA, chromogranin A, thyroglobulin, synaptophysin, sustentacular cells (SCs), low- and high-molecular cytokeratins (CK 5/6, 7, 18, 20), epidermal growth factor-receptor (EGFR), thyroid transcription factor-1 (TTF-1), bcl-2, Melan A, C-kit, neuron-specific enolase (NSE), and galectin-3. The patient's blood and tumor tissue were examined for mutations in the RET-protooncogene. RESULTS: H&E staining of both frozen and permanent sections was unable to differentiate benign from malignant tissue. Typical morphologic characteristics for MTC were completely absent. Only the additional finding of positivity for synaptophysin and numerous SC cells visible in-between neoplastic cells made the diagnosis of paraganglioma-like MTC possible. Sequencing of the RET proto-oncogene revealed no mutations. CONCLUSIONS: There are subgroups of MTC that present clinically similar to classic MTC, but in which missing typical morphologic characteristics make histopathology diagnosis difficult. In these cases, diagnosis, operative decisions, and follow-up strategies should be based on preoperative biochemical markers, imaging findings, and clinical parameters in accordance to the guidelines for classic MTC.

Carcinoma, Medullary↗
PubMed2005

RET proto-oncogene: a review and update of genotype-phenotype correlations in hereditary medullary thyroid cancer and associated endocrine tumors.

Hereditary medullary thyroid carcinoma (MTC) is caused by autosomal dominant gain-of-function mutations in the RET proto-oncogene. Associations between specific RET mutations (genotype) and the aggressiveness of MTC and presence or absence of other endocrine neoplasms (phenotype) are well documented. Mutations in six exons (10, 11, 13, 14, 15, and 16) located in either cysteine-rich or tyrosine kinase domains cause one of three distinctive clinical subtypes: familial MTC, multiple endocrine neoplasia (MEN) type 2A (including variants with Hirschsprung's disease and cutaneous lichen amyloidosis), and MEN 2B. Hallmarks of MEN 2A include MTC, pheochromocytoma, and hyperparathyroidism. MEN 2B is associated with an earlier onset of MTC and pheochromocytoma, the absence of hyperparathyroidism, and the presence of striking physical stigmata (e.g., coarse facies, ganglioneuromatosis, and marfanoid habitus). Familial MTC is not associated with other endocrine neoplasms; however, the accurate distinction between familial MTC and MEN 2A may be difficult in kindreds with small size, incomplete histories, or a predominance of young individuals who may not have yet fully manifested the syndrome. Genetic testing detects greater than 95% of mutation carriers and is considered the standard of care for all first-degree relatives of patients with newly diagnosed MTC. Recommendations on the timing of prophylactic thyroidectomy and the extent of surgery are based upon a model that utilizes genotype- phenotype correlations to stratify mutations into three risk levels.

Carcinoma, Medullary↗
PubMed1995

Low frequency of germline mutations in the RET proto-oncogene in patients with apparently sporadic medullary thyroid carcinoma.

BACKGROUND AND OBJECTIVES: Medullary thyroid carcinoma (MTC) occurs both sporadically and in the autosomal dominantly inherited multiple endocrine neoplasia (MEN) type 2 syndromes. The distinction between true sporadic MTC and a new mutation familial case is important for future clinical management of both the patient and family. The susceptibility gene for MEN 2 is the RET proto-oncogene. Systematic analysis for germline mutations of the RET proto-oncogene was performed in a series of 67 patients with apparently sporadic MTC to determine whether they were true sporadic cases or unsuspected de novo MEN 2 cases. DESIGN AND PATIENTS: Sixty-seven unselected patients with sporadic MTC were randomly ascertained from clinic patients from four centres. The diagnosis of MTC was confirmed by histopathology. Germline DNA was extracted from peripheral blood leucocytes or from paraffin-embedded tissue and subsequently used for polymerase chain reaction amplification. MEASUREMENTS: Polymerase chain reaction based RET mutation analysis was performed by direct double-stranded cycle sequencing of exons 10, 11, 13 and 16, within which the majority of MEN2 mutations have been shown to occur. RESULTS: In this series, there was one proven case of germline mutation in RET codon 620, which previously has been shown to be responsible for MEN 2, thus indicating heritable disease. No germline mutation in codon 918, typical of MEN 2B, was found. CONCLUSIONS: A figure of 1.5% germline mutations in 67 apparently sporadic MTC is lower than the incidence of familial disease reported in previous series involving clinical and biochemical screening. The presence of a germline mutation in the RET proto-oncogene in a patient with MTC indicates heritable disease. The absence of germline RET exon 10, 11, 13 or 16 mutation appears to rule out MEN 2A to a high probability, although the presence of a familial form of MTC other than classical MEN 2A cannot be excluded conclusively.

Adolescent↗
PubMed1994

Routine measurement of serum calcitonin in nodular thyroid diseases allows the preoperative diagnosis of unsuspected sporadic medullary thyroid carcinoma.

To assess whether routine measurement of serum calcitonin (CT) could improve the preoperative diagnosis of sporadic medullary thyroid carcinoma (MTC), 1385 consecutive patients presenting for nodular thyroid disease during the year 1991 were submitted to serum CT determination and fine needle aspiration cytology (FNAC). The clinical diagnosis was nontoxic nodular goiter in 1197 (86.4%) patients, toxic multinodular goiter in 65 (4.7%), autonomously functioning thyroid nodule (AFTN) in 64 (4.6%), and autoimmune thyroid disease (Graves' disease or Hashimoto's thyroiditis) with nodule(s) in 59 (4.3%). As controls, 177 patients with nonnodular thyroid disease and 32 normal subjects were also studied. Patients with FNAC suspicious of any kind of thyroid carcinoma and patients with elevated basal and pentagastrin-stimulated serum CT, regardless of the results of FNAC, were submitted to surgery. Eight (0.57%) patients (7 with nontoxic nodular goiter and 1 with AFTN) had elevated basal serum CT levels, ranging between 55-10,000 pg/mL. The pentagastrin test was abnormal in all of them. FNAC was suggestive of MTC in 2, thyroid carcinoma in 1, benign nodule in 3, and inadequate in 2. By histology, immunohistochemistry, and Northern blot analysis of total tumor RNAs, MTC was confirmed in all patients, including the 1 with AFTN, who had the association of microfollicular adenoma and a small MTC in the same lobe. After surgery, serum CT decreased to undetectable levels in 7 patients and remained undetectable in 6 of them during a mean follow-up of 22 months, although 1 of them had a positive response to pentagastrin. Forty-four patients in the group with normal serum CT levels had FNAC suspicious for differentiated thyroid carcinoma and were treated by surgery. Differentiated thyroid carcinoma, mostly papillary, was confirmed at histology in 43 subjects (3.1% of all thyroid nodules). In conclusion, the results of our study indicate that serum CT measurement is useful for the screening of sporadic MTC in patients with thyroid nodule(s). The prevalence of MTC, diagnosed by serum CT measurement in a 12-month period, among an unselected series of 1385 patients with nodular thyroid disease was surprisingly high: 0.57% of all thyroid nodules and 15.7% of all thyroid carcinomas. Serum CT measurement was superior to FNAC in suggesting the diagnosis of MTC and was devoid of falsely positive results. Increasing the diagnostic accuracy helped the surgeon to perform more radical treatment of MTC, thus achieving frequent normalization of postoperative serum CT levels. Whether this result indicates definitive cure remains to be established on the basis of longer follow-up.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1986

Imaging and uptake mechanism of 131I-meta-iodobenzylguanidine in medullary thyroid carcinoma.

131I-meta-iodobenzylguanidine (131I-MIBG) was also taken up by medullary thyroid carcinoma (MTC) as well as by pheochromocytoma in two patients with Sipple's syndrome. However, the mechanism of 131I-MIBG uptake by MTC has not been clarified yet. We measured tissue catecholamine levels in three MTC, since MTC can produce several active substances. Catecholamines were detected in various amounts in all MTC, but not in normal thyroid tissues. These findings suggest that MTC can produce catecholamines and therefore, 131I-MIBG is taken up and stored in catecholamine vesicles of MTC, like pheochromocytoma and neuroblastoma. We conclude that 131I-MIBG may be applied not only to diagnosis but also for the treatment of patients with MTC.

3-Iodobenzylguanidine↗
PubMed2000

Cutting edge: C-C chemokine receptor 6 is essential for arrest of a subset of memory T cells on activated dermal microvascular endothelial cells under physiologic flow conditions in vitro.

Memory T cells (mTC) express multiple chemokine receptors (including CCR4 and CCR6) that may potentially be involved in their arrest on inflamed endothelia. Herein, we specifically addressed whether CCR6 is required for mTC to arrest on TNF-alpha-activated human dermal microvascular endothelial cells (HDMEC) in vitro under shear stress conditions. Recombinant liver and activation-regulated chemokine (LARC)/CCL20 (a CCR6 ligand) induced firm arrest of cutaneous lymphocyte Ag(+) mTC in a flow chamber system using purified substrates. Strikingly, desensitization of CCR6 with LARC, but not thymus and activation-regulated chemokine/CCL17 or secondary lymphoid tissue chemokine/CCL21, caused a 50-75% decrease (p < 0. 001) in arrest of mTC on HDMEC, which was indistinguishable from the reduction observed when total mTC were treated with pertussis toxin (p > 0.5). CCR6-depleted mTC also had a markedly reduced ability to arrest on HDMEC. Our results suggest that LARC production by activated endothelial cells and CCR6 expression by mTC may be critical components in the pertussis toxin-sensitive arrest of mTC on activated HDMEC.

Cell Adhesion↗