Primary Medullary Thyroid Carcinoma Research Articles

Risk factor analysis of distant metastases in patients with primary medullary thyroid cancer: a population-based study.

Medullary thyroid carcinoma has a high rate of recurrence and distant metastasis. The aim of this study was to investigate the risk factors for distant metastasis in patients with primary medullary thyroid carcinoma. Patients diagnosed with primary medullary thyroid cancer between 2010 and 2015 were enrolled using the Surveillance, Epidemiology, and End Results (SEER) database. Patient demographics and tumor clinicopathological features were evaluated to identify potential risk factors for distant metastasis in patients with primary medullary thyroid cancer. Univariate and multivariate logistic regression analyses were used to determine independent risk factors for distant metastasis in patients with primary medullary thyroid carcinoma. All statistical analyses were performed using SPSS statistical software (version 27.0). A two-tailed P < 0.05 was considered statistically significant. We collected 685 patients with primary medullary thyroid carcinoma, 40 of whom (5.84%) developed distant metastases. Univariate logistic regression analysis showed that except marital status, age, sex, race, pT stage, N stage, multifocal and capsular infiltration were significantly correlated with distant metastasis of medullary thyroid carcinoma. Multivariate logistic regression analysis showed that patients aged ≤ 18years or > 55years, Black race, higher pT stage and N stage were independent risk factors for distant metastasis of medullary thyroid carcinoma. This study found that ≤ 18years or > 55years, black race, higher pT stage and N stage were significantly associated with distant metastasis of medullary thyroid cancer. This is important for clinicians to identify patients at high risk of distant metastasis in a timely manner.

Oncologic outcomes of calcitonin-negative medullary thyroid carcinoma.

Calcitonin (Ct)-negative medullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor. This study aimed to clarify its incidence, clinicopathologic characteristics, management, and treatment outcome. We retrospectively analyzed data of patients with primary MTC. Patients were divided into two groups according to the preoperative serum Ct level (Ct-negative and Ct-positive). The demographic, pathologic, and molecular characteristics, and treatment outcomes were compared between the two groups. In the Ct-negative group, we analyzed the association between the operation type and treatment outcome. Of the total 312 patients, 24 were diagnosed with Ct-negative MTC. The rate of lymph node metastasis was significantly higher in the Ct-positive than in the Ct-negative group (47.9% vs. 0%, p<0.001). The proportion of patients with Ki-67 ≤10% was significantly higher in the Ct-negative than in the Ct-positive group (87.5% vs. 38.2%, p<0.001). Excellent response was achieved by 91.7% and 34.7% of patients in the Ct-negative and Ct-positive groups, respectively (p<0.001). In the Ct-negative group, excellent response was achieved by all female patients, but only 50% of male patients. Ct-negative MTC is rare and unlikely to develop lymph node metastasis. Unilateral lobectomy tends to provide a satisfactory chance of excellent response; however, this requires further validation.

Medullary thyroid carcinoma a relatively uncommon entity: A case report

Introduction: Medullary thyroid carcinoma is an uncommon primary thyroid tumour (5-10% of all thyroid malignancies) arising from parafollicular cells or C-cells. Most tumours are sporadic (75-80%) and familial syndrome multiple endocrine neoplasia; MEN-2A, MEN-2B and familial MTC in 20 to 25% cases. Case Report: We report a case of primary medullary thyroid carcinoma in a 30 years old male patient presented with complaint of midline neck swelling. On fine needle aspiration cytology diagnosis of medullary carcinoma was suggested with a differential of SETTLE (spindle epithelial tumor with thymus like differentiation). The swelling was excised and send for histopathological examination which revealed polygonal to plump spindle shaped tumor cells, arranged in lobules separated by fibrous septa, having abundant eosinophilic granular cytoplasm with round to oval nuclei, finely stippled nuclear chromatin and indistinct nucleoli and diagnosed as primary medullary thyroid carcinoma, confirmed on immunohistochemistry. Conclusion: MTC is the first human malignancy known to be associated with tumour marker and hormone calcitonin. Immunohistochemistry has definite role in confirmation of diagnosis. Keywords: Amyloid, Medullary carcinoma, Procalcitonin, Synaptophysin.

Octreotide and pasireotide effects on medullary thyroid carcinoma (MTC) cells growth, migration and invasion

Medullary thyroid carcinoma (MTC) is a rare neuroendocrine neoplasm of the parafollicular thyroid C cells. Although somatostatin receptors are expressed by MTCs, treatment with octreotide has shown poor efficacy, whereas recently pasireotide has demonstrated antiproliferative effects in persistent postoperative MTCs.Aim of this study was to test the effects of octreotide and pasireotide on MTC cells proliferation, cell cycle proteins expression, MAPK activation, apoptosis, calcitonin secretion, migration and invasion in TT cell line as well as in primary MTC cultured cells. Our results showed that both octreotide and pasireotide reduced TT cell proliferation (−35.2 ± 12.1%, p < 0.001, and −25.3 ± 24.8%, p < 0.05, at 10−8 M, respectively), with concomitant inhibition of ERK phosphorylation and cyclin D1 expression. This cytostatic effect was accompanied by a proapoptotic action, with an increase of caspase3/7 activity of 1.5-fold. Moreover, both octreotide and pasireotide inhibited cell migration (−50.9 ± 11.3%, p < 0.01, and −40.5 ± 17%, p < 0.05, respectively) and invasion (−61.3 ± 35.1%, p < 0.05, and −49.7 ± 18%, p < 0.01, respectively). No effect was observed on calcitonin secretion. We then tried to extend these observations to primary cultures (n = 5). Octreotide and/or pasireotide were effective in reducing cells proliferation in 3 out of 5 tumors, and to induce cell apoptosis in 1 out of 3 MTCs. Both octreotide and pasireotide were able to reduce cell migration in all MTC tested. SST2, SST3 and SST5 were expressed in all MTC, with a tendency to increased expression of SST2 in RET mutated vs wild type MTCs. In agreement, inhibition of mutated RET in TT cells reduced SST2 expression.In conclusion, we demonstrated that octreotide and pasireotide inhibited cell proliferation and invasiveness in a subset of MTC, supporting their potential use in the control of tumor growth.

Prognostic value of numbers of metastatic lymph node in medullary thyroid carcinoma: A population-based study using the SEER 18 database.

Lymph node (LN) metastases are widely considered as a vital assessment of disease progression, as well as an essential indicator for biochemical cure of medullary thyroid carcinoma (MTC). Prognostic effect of numbers of metastatic LN has not been fully studied and the optimal cut-point of LN numbers has not been established. This population-based study designed to investigate prognostic value of numbers of positive LN and determinate the prognostic factors.Data were generated from Surveillance, Epidemiology, and End Results (SEER) database between 1998 and 2013. X-tile program was applied and cut points for division of LN numbers as low-, medium- and high-risk were 0, 1 to 10, and ≥11. The relationship between numbers of metastatic LN, age, tumor size, extent of tumor, and radiotherapy on overall survival (OS) and disease-specific survival (DSS) were evaluated.A total of 1466 diagnosed primary MTC patients without metastases were eligible for analysis in current study. 945 (64%) patients were classified as no positive LNs, 327 (22%) as 1 to 10 positive LNs, 194 (14%) as ≥11 positive LNs. Patients with older age, tumor size, ≥11 positive LN were associated with unfavorable OS. Those dispensed with radiation had statistically better prognosis than the others. When stratified by age, there was a significant difference in patients ≥45 years within LN categories (log-rank P < .001). When stratified by tumor size, a significant correlation was noted between rising numbers of involved nodes and falling rates of OS in tumor measuring >2cm setting (2–4 cm setting, log-rank P = .003 and >4 cm setting, log-rank P = .014, separately). There was no statistical difference of the area under the curve (AUC) for OS and DSS prediction between LN group and N stage, suggesting the 2 LN systems had the same predictive power for OS and DSS.Numbers of metastatic LN showed prognostic power in survival analysis and remained an independent survival predictor which can be evaluated in MTC treatment decisions for optimum assessment.

18F]DOPA PET/ceCT in diagnosis and staging of primary medullary thyroid carcinoma prior to surgery

PurposeMedullary thyroid carcinoma (MTC) is characterized by a high rate of metastasis. In this study we evaluated the ability of [18F]DOPA PET/ceCT to stage MTC in patients with suspicious thyroid nodules and pathologically elevated serum calcitonin (Ctn) levels prior to total thyroidectomy and lymph node (LN) dissection.MethodsA group of 32 patients with sonographically suspicious thyroid nodules and pathologically elevated basal Ctn (bCtn) and stimulated Ctn (sCtn) levels underwent DOPA PET/ceCT prior to surgery. Postoperative histology served as the standard of reference for ultrasonography and DOPA PET/ceCT region-based LN staging. Univariate and multivariate regression analyses as well as receiver operating characteristic analysis were used to evaluate the correlations between preoperative and histological parameters and postoperative tumour persistence or relapse.ResultsPrimary MTC was histologically verified in all patients. Of the 32 patients, 28 showed increased DOPA decarboxylase activity in the primary tumour (sensitivity 88%, mean SUVmax 10.5). Undetected tumours were exclusively staged pT1a. The sensitivities of DOPA PET in the detection of central and lateral metastatic neck LN were 53% and 73%, in contrast to 20% and 39%, respectively, for neck ultrasonography. Preoperative bCtn and carcinoembryonic antigen levels as well as cN1b status and the number of involved neck regions on DOPA PET/ceCT were predictive of postoperative tumour persistence/relapse in the univariate regression analysis (P < 0.05). Only DOPA PET/ceCT cN1b status remained significant in the multivariate analysis (P = 0.016, relative risk 4.02).ConclusionThis study revealed that DOPA PET/ceCT has high sensitivity in the detection of primary MTC and superior sensitivity in the detection of LN metastases compared to ultrasonography. DOPA PET/ceCT identification of N1b status predicts postoperative tumour persistence. Thus, implementation of a DOPA-guided LN dissection might improve surgical success.

Lymph node metastases and elevated postoperative calcitonin: Predictors of poor survival in medullary thyroid carcinoma

BackgroundTotal thyroidectomy is the treatment of choice for medullary thyroid carcinoma (MTC), but the extent of neck dissection is controversial. Lymph node metastases, distant metastases, and old age are known predictors of poor survival.PatientsPatients treated for primary MTC at Helsinki University Hospital from 1990 to 2009 were included (n = 54). Their clinical characteristics, treatment, and outcome were analysed retrospectively, these patients were followed until death or their last follow-up date.ResultsAt last follow-up (3.4–23 years), of 54 MTC patients, 19 (35%) were disease-free, 17 (32%) were alive with disease, and 12 (22%) had died of MTC; six patients died of unrelated causes (11%). All disease-free patients were node negative and had normal postoperative calcitonin level. Of 19 disease-free patients, only four (21%) had undergone lymph node dissection. All patients who died of MTC were Stage IV at diagnosis and died with distant metastases. Disease-specific five–and 10-year survival was 84% and 76.2%. Advanced T-stage (p = 0.004), lymph node metastases (p < 0.001), distant metastases (p < 0.001), stage (p < 0.001), and elevated postoperative calcitonin (p < 0.001) significantly associated with survival.ConclusionsLymph node metastasis and elevated postoperative calcitonin are important prognostic factors. Patients with lymph node metastasis and/or elevated postoperative calcitonin with present treatments cannot become disease-free, but most of them can live a long life with metastasis.

VEGF, VEGFR3, and PDGFRB protein expression is influenced by RAS mutations in medullary thyroid carcinoma.

Tyrosine kinase inhibitors (TKIs) have achieved remarkable clinical results in medullary thyroid carcinoma (MTC) patients. However, the considerable variability in patient response to treatment with TKIs remains largely unexplained. There is evidence that it could be due, at least in part, to alterations in genes associated with the disease via their effect on the expression of TKI targets. The objective of this study was to evaluate the influence of RAS mutations on the expression levels in MTC tumors of eight key TKI target proteins. We assessed by immunohistochemistry the expression of EGFR, KIT, MET, PDGFRB, VEGF, VEGFR1, VEGFR2, and VEGFR3 in a series of 84 primary MTC tumors that had previously been molecularly characterized, including 14 RAS-positive, 18 RET(M918T)-positive, and 24 RET(C634)-positive tumors, as well as 15 wild-type tumors with no mutations in the RET or RAS genes. In contrast to RET-positive tumors, RAS-positive tumors expressed neither PDGFRB nor MET (p=0.0060 and 0.047, respectively). Similarly, fewer RAS-positive than RET-related tumors expressed VEGFR3 (p=0.00062). Finally, wild-type tumors expressed VEGF more often than both RAS- and RET-positive tumors (p=0.0082 and 0.011, respectively). This is the first study identifying that the expression of TKI targets differs according to the presence of RAS mutations in MTC. This information could potentially be used to select the most beneficial TKI treatment for these patients.

Calcium/Calmodulin-Dependent Protein Kinase II and Its Endogenous Inhibitor α in Medullary Thyroid Cancer

Calcium/calmodulin-dependent kinase II (CaMKII) is involved in the regulation of cell proliferation. Its endogenous inhibitor (hCaKIINα) is expressed in some cell types. We determined the role of CaMKII in RET-stimulated proliferation and hCaMKIINα in medullary thyroid carcinoma (MTC). We analyzed the role of RET mutants on CaMKII activation in NIH3T3 and in MTC cell lines, and determined the effect of CaMKII inhibition on RET/ERK pathway and cell proliferation. Then the expression of hCaKIINα mRNA was determined by real-time PCR in primary MTC and it was correlated with some clinicopathologic parameters. RET(C634Y) and RET(M918T) mutants expressed in NIH3T3 cells induced CaMKII activation. CaMKII was activated in unstimulated MTC cells carrying the same RET mutants and it was inhibited by RET inhibition. Inhibition of CaMKII in these cells induced a reduction of Raf-1, MEK, and ERK phosphorylation, cyclin D expression, and cell proliferation. hCaKIINα mRNA expression in primary MTC was very variable and did not correlate with gender and age at diagnosis. Serum calcitonin, (R(2) = 0.032; P = 0.017), tumor volume (P = 0.0079), lymph node metastasis (P = 0.033), and staging (P = 0.0652) were negatively correlated with the hCaKIINα mRNA expression. CaMKII is activated by RET mutants and is activated at baseline in MTC cells where it mediates the oncogenic pathway leading to cell proliferation. The mRNA expression of its endogenous inhibitor hCaKIINα inversely correlates with the severity of MTC. CaMKII might represent a new target for MTC therapy and hCaKIINα is a marker of disease extension.

A miRNA signature associated with human metastatic medullary thyroid carcinoma.

MicroRNAs (miRNAs) represent a class of small, non-coding RNAs that control gene expression by targeting mRNA and triggering either translational repression or RNA degradation. The objective of our study was to evaluate the involvement of miRNAs in human medullary thyroid carcinoma (MTC) and to identify the markers of metastatic cells and aggressive tumour behaviour. Using matched primary and metastatic tumour samples, we identified a subset of miRNAs aberrantly regulated in metastatic MTC. Deregulated miRNAs were confirmed by quantitative real-time PCR and validated by in situ hybridisation on a large independent set of primary and metastatic MTC samples. Our results uncovered ten miRNAs that were significantly expressed and deregulated in metastatic tumours: miR-10a, miR-200b/-200c, miR-7 and miR-29c were down-regulated and miR-130a, miR-138, miR-193a-3p, miR-373 and miR-498 were up-regulated. Bioinformatic approaches revealed potential miRNA targets and signals involved in metastatic MTC pathways. Migration, proliferation and invasion assays were performed in cell lines treated with miR-200 antagomirs to ascertain a direct role for this miRNA in MTC tumourigenesis. We show that the members of miR-200 family regulate the expression of E-cadherin by directly targeting ZEB1 and ZEB2 mRNA and through the enhanced expression of tumour growth factor β (TGFβ)-2 and TGFβ-1. Overall, the treated cells shifted to a mesenchymal phenotype, thereby acquiring an aggressive phenotype with increased motility and invasion. Our data identify a robust miRNA signature associated with metastatic MTC and distinct biological processes, e.g., TGFβ signalling pathway, providing new potential insights into the mechanisms of MTC metastasis.

Routine preoperative 111In-octreotide scintigraphy in patients with medullary thyroid cancer

Surgery is the only potential cure for patients with medullary thyroid carcinoma (MTC). Preoperative ultrasound, computed tomography and magnetic resonance imaging are not sensitive enough for detection of microscopic disease. The aim of this study was to investigate if routine preoperative (111)In-labelled (DTPA-D-Phe(1))-octreotide scintigraphy (SRS) could be used as a staging procedure in planning primary surgery in patients with MTC. This study included patients with primary sporadic clinically overt MTC diagnosed between 1996 and 2009. All patients underwent conventional imaging of neck and thorax and SRS prior to standardised surgery. The findings on SRS were correlated to the findings on conventional imaging, histopathology and to postoperative biochemical results and survival. A total of 19 patients with sporadic MTC were enrolled. Median follow-up was 77(9-184) months. SRS visualised the primary tumour in 16 (84%) patients. Fifteen (79%) patients had locoregional lymph node metastases, but SRS detected metastatic lesions in only 8 (53%) patients. In three patients with distant spread, SRS failed to detect metastatic lesions in two. At latest follow-up, six (32%) patients had died, nine (47%) patients were alive with elevated tumour markers, and four (21%) patients were considered in complete biochemical remission. This study provided further evidence that SRS, compared to conventional imaging, is fairly sensitive for detection of primary MTC but not metastatic disease. Although preoperative SRS may be of prognostic value, there is no indication for its routine use as a staging procedure in planning primary surgery.

Abstract 1730: RET tyrosine kinase receptor represses Noxa transcription and prevents genotoxic or endoplasmic reticulum stress-induced apoptosis.

Abstract One of the hallmarks of human cancers is the intrinsic or acquired resistance to apoptosis. Apoptosis resistance contributes to carcinogenesis, tumor progression, and treatment resistance. Patients with medullary thyroid carcinoma (MTC) have been shown to be resistant to standard chemotherapy and conventional radiotherapy. Dominant activating mutations in the RET protooncogene are the cause of hereditary MTC and are found in more than 40% of sporadic cases. Despite an ever-growing wealth of information about RET's role in cell survival/proliferation, a detailed understanding of how this tyrosine kinase receptor acts to prevent cell death in tumorigenesis remains elusive. We hypothesized that activated RET prevents apoptosis by repressing the transcription of the proapoptotic gene Noxa in the nucleus in response to genotoxic or endoplasmic reticulum (ER) stress. Here we report that activated RET translocates to the nucleus in cultured MTC cells as well as MTC primary tumor tissues. RET is recruited to the Noxa promoter and is able to repress its transcription. The formation of the RET-Noxa promoter complex depends on RET expression and requires the tyrosine kinase activity of RET. Additionally, stable depletion of RET in MTC cells, using lentiviral shRNA, sensitizes MTC cells to genotoxic or endoplasmic reticulum stress. We specifically show that RET is recruited to the Activating Transcription Factor 4 (ATF4) binding site on the Noxa promoter. RET physically interacts with ATF4 and phosphorylates ATF4 leading to the blockage of its transcriptional activity. Moreover, RET knockdown is associated with increased ATF4-dependent expression of Noxa. Inhibition of RET kinase activity by sunitinib results in ATF4 activation, induction of Noxa expression and apoptosis. Conversely, silencing of ATF4 in MTC cells decreased sunitinib-mediated Noxa induction and apoptosis. ATF4 protein levels markedly decreased and/or localized in the cytoplasm of 60% of primary MTC (n=40) and associated with poor overall survival. Our data suggest that RET activating mutations confers resistance to chemotherapeutic agents by preventing apoptosis through inhibition of ATF4 activity and repression of proapoptotic gene Noxa. These findings reveal the importance of nuclear localization of RET, as newly discovered modulator of nuclear gene expression. This newly identified interaction between RET kinase and ATF4 has important implication for MTC and other RET/ATF4-mediated cancer types. Since ATF4 transcription is induced by endoplasmic reticulum stress, and activation of ATF4 induces cell cycle arrest and apoptosis, the concept of promoting endoplasmic reticulum stress in combination with tyrosine kinase inhibitors could be considered as a therapeutic strategy for cancer. Citation Format: Rozita Bagheri-Yarmand, Anupama E Gururaj, Michelle Williams, Zamal Ahmed, Jean E Ladbury, Oliver Bogler, Sue-chen Huang, Gilbert G Cote, Robert F Gagel. RET tyrosine kinase receptor represses Noxa transcription and prevents genotoxic or endoplasmic reticulum stress-induced apoptosis. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1730. doi:10.1158/1538-7445.AM2013-1730

Activation of the mTOR Pathway in Primary Medullary Thyroid Carcinoma and Lymph Node Metastases

Understanding the molecular pathogenesis of medullary thyroid carcinoma (MTC) is prerequisite to the design of targeted therapies for patients with advanced disease. We studied by immunohistochemistry the phosphorylation status of proteins of the RAS/MEK/ERK and PI3K/AKT/mTOR pathways in 53 MTC tissues (18 hereditary, 35 sporadic), including 51 primary MTCs and 2 cases with only lymph node metastases (LNM). We also studied 21 autologous LNMs, matched to 21 primary MTCs. Staining was graded on a 0 to 4 scale (S score) based on the percentage of positive cells. We also studied the functional relevance of the mTOR pathway by measuring cell viability, motility, and tumorigenicity upon mTOR chemical blockade. Phosphorylation of ribosomal protein S6 (pS6), a downstream target of mTOR, was evident (S ≥ 1) in 49 (96%) of 51 primary MTC samples. This was associated with activation of AKT (phospho-Ser473, S > 1) in 79% of cases studied. Activation of pS6 was also observed (S ≥ 1) in 7 (70%) of 10 hereditary C-cell hyperplasia specimens, possibly representing an early stage of C-cell transformation. It is noteworthy that 22 (96%) of 23 LNMs had a high pS6 positivity (S ≥ 3), which was increased compared with autologous matched primary MTCs (P = 0.024). Chemical mTOR blockade blunted viability (P < 0.01), motility (P < 0.01), and tumorigenicity (P < 0.01) of human MTC cells. The AKT/mTOR pathway is activated in MTC, particularly, in LNMs. This pathway sustains malignant features of MTC cell models. These findings suggest that targeting mTOR might be efficacious in patients with advanced MTC.

Genetic alterations in a primary medullary thyroid carcinoma and its lymph node metastasis in a patient with 15 years follow-up

BackgroundAssociation between DNA alterations and clinical parameters as recurrence, survival or prognosis has been found in a variety of tumors. A clear association between Medullary Thyroid Carcinoma (MTC) and RET oncogene mutation has been accepted. Specifically M918T RET mutation represents the main genetic event in most cases of sporadic MTC (SMTC) and limited chromosomal alterations analyses have been performed.MethodsIn the present work, a comparative genomic hybridization (CGH) study was performed using DNA from a primary tumor in a M918T RET mutation-positive SMTC patient and from its lymph node metastasis to investigate additional genetic alterations. We studied a patient with 15 years of follow-up and persistence of disease, confirmed by periodical elevated serum calcitonin (CT) levels.ResultsOnly 3 chromosomal imbalances were identified in the primary tumor, gain of 18p, and loss of 6p and 16p region, whereas 25 chromosomal imbalances were identified in the metastasis (9 gains and 16 losses).ConclusionThe chromosomal changes 6p-, 16p-, 18p + could determine in part the oncogenic phenotype in the primary M918T RET positive tumor and probably related to persistence of high serum CT levels in this patient. The additional chromosomal changes observed could be related to the metastasis phenotype. We suggest that some genes mapped at 6p, 16p and 18p chromosomal regions, could act as genes associated to cancer and could be related to persistent SMTC and good prognosis.Virtual slidesThe virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1720753793691097

Occult Primary Medullary Thyroid Carcinoma Presenting with Pituitary and Parotid Metastases: Case Report and Review of the Literature

Occult Primary Medullary Thyroid Carcinoma Presenting with Pituitary and Parotid Metastases: Case Report and Review of the Literature

Activation of the mTOR pathway in primary medullary thyroid carcinoma and lymph node metastases.

10598 Background: Medullary thyroid carcinoma (MTC), a rare tumor arising from C-cells, is characterized by RET proto-oncogene activation in all familial and roughly half of sporadic cases. Convent...

Evaluation of systemic targeting of RET oncogene-based MTC with tumor-selective peptide-tagged Ad vectors in clinical mouse models

Significant advantage of targeted antitumoral treatment consists in the possibility to restrict maximum therapeutic efficacy to the malignant cell population by reducing toxicity in healthy tissues. Using different clinical models for aggressive medullary thyroid carcinoma (MTC), we have recently identified peptide ligands that bind highly selective to tumor cells. By linking the most convincing SRESPHP peptide to an adenoviral (Ad) vector expressing the MTC-related oncogene inhibitor RETΔTK, gene transfer was specifically directed to neoplastic tissue after systemic virus administration. We show that peptide-mediated delivery of RETΔTK significantly enhanced apoptosis, resulting in a strong inhibition of orthotopic and xenograft tumor growth. Conversely, tumors treated with controls expanded their initial size without notable cell death. According to the therapeutic effect, strong virus accumulation was found exclusively in thyroid carcinomas. Strikingly, application of native tropism depleted viral vector linked to tumor-selective peptide was accompanied by a substantial reduction of Ad binding to the liver. Of note, single systemic injection of a low dose (10e8 pfu/mouse) of MTC-specific Ad.RETΔTK induced regression of multiple tumors at different sites in all treated animals. In sum, our results open up the possibility for an efficient cancer cell-specific therapy of primary MTC, their migrating populations and potentially metastases.

Medullary Thyroid Cancer: New Targeted Molecular Therapies

Medullary thyroid carcinoma (MTC) is a rare tumor arising from neural crest-derived parafollicular C cells. Metastatic MTC patients are incurable because the cancer does not respond to radiotherapy or chemotherapy. The elucidation over the past two decades of multiple genetic abnormalities in MTC has provided specific targets for therapy. The identification of activating mutations of the RET tyrosine kinase receptor (TKR) in both hereditary and sporadic MTC makes this malignancy an excellent model to examine the effect of a group of small organic molecule tyrosine kinase inhibitors (TKIs) for treatment of metastatic MTC. Clinical trials with several TKIs targeting RET and other TKRs have shown positive results with generally tolerable toxicity. Approximately one-third to one-half of MTC patients have a reduction in tumor size up to 50%, with the longest treatment duration of approximately four years. The most common treatment-related toxicities are rash, nausea and diarrhea. Despite promising initial results these studies are in their early stages; however, the possibility of testing the sensitivity of primary MTC cells from each subject to different TKIs could increase the effectiveness of the treatment. A brief outline on current patents that are the focus on the treatment of Thyroid Cancer has also been provided in this review.

High Resolution Array-Comparative Genomic Hybridization Profiling Reveals Deoxyribonucleic Acid Copy Number Alterations Associated with Medullary Thyroid Carcinoma

Activating mutations in the RET protooncogene have been demonstrated in multiple endocrine neoplasia 2 and sporadic medullary thyroid carcinoma (MTC). However, the complete genetic etiology underlying MTC tumorigenesis remains unclear. Our objective was to define more precisely the chromosomal regions and uncover novel genes associated with MTC tumorigenesis. In this study, we used high resolution array-based comparative genomic hybridization to define tumor-associated copy number alterations (CNA) in 30 primary MTCs: 20 sporadic tumors (50% of which harbored RET mutation), and 10 hereditary. We identified 98 CNA, including 76 genomic allelic losses, two gains, and 20 copy number variations associated with MTC. Across sporadic and hereditary groups, there was a similar and overlapping pattern of predominant allelic loss. There were 29 regions containing at least 30% CNA in the 30 tumor samples. The most frequent allelic loss occurred in four loci, 7q36.1, 12p13.31, 13q12.11, and 19p13.3-11. No regions were found to be uniquely altered in the hereditary tumors. There were 21 CNA specific to sporadic MTC, with loss of 11q23.3 uniquely altered in RET negative tumors. Pathway analysis found cellular growth and proliferation as the most significant overall target, and cell death as the most significant pathway targeted in sporadic MTC. Our findings underscore the importance of candidate tumor suppressor genes together with RET alterations in MTCs. Despite of RET status, all MTC might share similar oncogenetic mechanisms. Dysfunction of cell proliferation and cell death may both be involved in MTC tumorigenesis.

Role of FNA cytology and immunochemistry in the diagnosis and management of medullary thyroid carcinoma: Report of six cases and review of the literature

Medullary thyroid carcinoma (MTC) is a rare neuroendocrine thyroid malignancy. This study retrospectively reviewed 10 fine-needle aspiration samples from six MTC patients. Aspirated specimens were from thyroid (3), cervical lymph nodes (5), left lung (1), and anterior chest wall (1). Cytomorphology consisted predominantly of plasmacytoid cells (3 cases), spindle cells (2 cases), and epithelioid cells (1 case). However, all specimens had a mixture of other cell types and "salt and pepper" chromatin. Only one specimen showed Congo-red-positive amyloid. Calcitonin was expressed in 7/7 specimens. Four patients underwent surgical excision and MTC was confirmed in all four. Follow-up studies included serum calcitonin (3/6 cases) and imaging (2/6 cases). One patient had MTC associated with multiple endocrine neoplasia IIA syndrome and one had familial MTC with a history of MTC in mother. In conclusion, the cytomorphology of MTC is typical and calcitonin immunostain is a reliable method for confirming primary or metastatic MTC. Early cytological diagnosis of MTC positively impacted patient management. Follow-up with serum calcitonin and imaging is helpful in the early detection of recurrences.