Search

The definition of poorly differentiated thyroid carcinoma has been the source of great controversy in the pathology literature.1 Many definitions and schemes have been proposed, but little consensus exists about what defines a poorly differentiated thyroid carcinoma (PDTCA). Because of this, the clinical behavior is not well defined and the clinicopathologic features affecting prognosis remain largely unknown.

Lipophilic derivatives of the antitumor drug gemcitabine (GEM) with the potential for improving drug loading in lipid-based colloidal carriers, like liposomes or lipid nanoparticles, are described. GEM free base was conjugated to lipoamino acids bearing an alkyl side chain of different length, by either a carbodiimide-assisted or an ethylchloroformiate-assisted coupling reaction, to obtain N4-acyl GEM derivatives. These compounds retained the same in vitro cell growth inhibitory activity of the parent drug against two lines of human anaplastic thyroid cancer cells. Stability studies suggested that the observed activity was due mainly to intact derivatives and not to released GEM. Accordingly, these amphiphilic derivatives can be proposed in a further step for the encapsulation in liposomes or lipid nanocarriers, to achieve as a final goal an improvement of the pharmacokinetics and therapeutic activity of GEM. Drug Dev Res 2010. © 2010 Wiley-Liss, Inc.

Anaplastic carcinoma of the thyroid gland, which is one of the most aggressive, malignant tumors in humans, is considered to originate from preexisting differentiated thyroid cancer. To define the genetic alterations associated with such progression, we examined nine cases of anaplastic thyroid carcinoma for mutation in exons 4-9 of the p53 tumor suppressor gene. Preliminary screening for mutation by RNase protection analysis demonstrated that two out of nine anaplastic carcinomas contained sequence alterations in the p53 gene. Subsequent DNA sequencing identified the mutated nucleotides in these two cases; one was a nonsense mutation at codon 165, and the other was a single-base deletion at codon 176 resulting in the creation of a stop codon downstream due to frameshift. The fact that no mutations were detected in coexisting foci of papillary carcinomas from the same patients shows that these mutations of the p53 gene occurred after development of papillary carcinomas. These results suggest that p53 gene mutation triggers the progression from differentiated into anaplastic carcinoma in the human thyroid gland.

Although the majority of thyroid cancer patients presenting to our surgical endocrinology clinics present with resectable and often curable disease, patients may rarely present with a history and physical findings suggestive of an anaplastic thyroid cancer. The endocrine surgeon should recognize, diagnose, and treat this patient urgently and promptly. The clinical course and findings from two patients who presented to our endocrine surgery clinic recently are summarized below from the patients’ clinical notes.

Anaplastic thyroid carcinoma (ATC) is rare but one of the most aggressive human cancers. It carries a dismal prognosis with average survival of 6 months. It is characteristically diagnosed in patients older than 60 years. We report the case of a young patient with ATC, in whom disease-free survival exceeds 2 years, and review the related literature.A 26-year-old woman presented with a rapidly growing anterior neck mass. A neck computed tomography scan showed a 3.5-cm left thyroid mass extending into the lateral neck. Fine-needle aspiration biopsy showed a malignant tumor. A subsequent core biopsy showed an undifferentiated epithelial carcinoma. A total thyroidectomy and left modified radical neck dissection were performed. Histopathology and immunohistochemical analysis confirmed an ATC. Postoperatively, the patient received radiation with concurrent chemotherapy. Serial follow-up imaging studies showed no evidence of residual or recurrent disease or metastases, and patient remains alive, free of disease, over 2 years.ATC is usually a disease of the elderly but should be considered in the differential diagnosis of any patient who presents with a rapidly enlarging anterior neck mass. A rapid and thorough investigation should be initiated. This unusual case highlights that this aggressive thyroid cancer may occur in the young. It also emphasizes the role of aggressive surgery, if resectable.

Resume But/Objectif L’objectif de cette etude est de decrire retrospectivement les caracteristiques epidemiologiques, cliniques, les modalites therapeutiques, les facteurs pronostiques et la survie d’une population de patients atteints d’un carcinome anaplasique de la thyroide (CAT) repertories dans la region Auvergne et de comparer ces donnees a celles de la litterature. Materiel et methodes L’analyse a ete realisee a partir d’une banque de donnees informatiques d’un registre regional renseigne par les professionnels de sante prenant en charge les cancers thyroidiens de la region. Resultats Vingt-six CAT parmi les 1500 cancers ont ete recenses sur 16 ans. Le sex-ratio H/F etait de 1/2,7 et l’âge moyen de 72,1 ans ; des antecedents thyroidiens etaient presents dans 76,9 % des cas et la taille tumorale moyenne a la decouverte etait de 7,35 cm, un stade N1 en cours de maladie etait constate dans 6,5 % des cas et M1 dans 34,6 % des cas. Une chirurgie a ete realisee dans 84,6 % des cas, une radiotherapie dans 53,8 % des cas et une chimiotherapie dans 19,2 % des cas. La moyenne de survie etait de neuf mois et la mediane de survie de quatre mois. Conclusion Nos resultats montrent en analyse univariee que le grand âge, un depassement capsulaire, un envahissement ganglionnaire, la presence d’un residu tumoral apres chirurgie et l’absence de traitement multimodal en particulier de radiotherapie chez les patients sans residu tumoral apres chirurgie sont des facteurs de mauvais pronostic. Apres analyse multivariee, un âge superieur a 75 ans, suivi de l’invasion capsulaire puis de l’envahissement ganglionnaire et enfin le fait d’etre une femme sont des facteurs de mauvais pronostic.

Anaplastic thyroid carcinomas are very aggressive cancers and metastasize frequently to the lungs and pleura. The cardiac metastases of thyroid cancers are rare. The diagnosis before the death is rare. We present a case of anaplastic thyroid carcinoma with metastatic involvement of the heart. It was presented with atrial fibrillation. The echocardiography demonstrated a solid mass in interventricular septum. One week later the patient died of heart failure. We call attention of clinicians that during the follow up of thyroid cancer such arrythmias may be the harbinger of a cardiac metastasis.

This study aimed to investigate the prognostic influence of DNA flow cytometry and RAS gene mutations in patients with poorly differentiated (PDTC) and anaplastic thyroid carcinoma (ATC). The series consisted of 26 patients with PDTC and ATC, and a median follow-up of 10 months (range 1-138). DNA ploidy and S-phase fraction (SPF) were assessed by flow cytometry on frozen samples. RAS point mutations were detected using PCR techniques. Disease staging and tumour angioinvasion were included as prognostic parameters for survival analysis. Nineteen patients (73.1%) succumbed to the disease (median time 5 months; range 1-45). Eighteen tumours (69.2%) were classified as DNA aneuploid. Median SPF was 5.6% (range 1.9-23.1), which was used as a cut-off value to distinguish between low versus high cell proliferation. Three of 20 (15%) patients presented N-RAS gene mutations in codon 61. DNA aneuploidy was most frequently found in female patients (p=0.034). Kaplan-Meier and Cox regression analyses showed that only DNA aneuploidy (p=0.044 and p=0.055, respectively) and high SPF (p=0.001 and p=0.006, respectively) significantly correlated with worse survival. The results indicate that aneuploidy and high SPF are biomarkers of poor clinical outcome in PDTC and ATC, which may provide useful prognostic information with a potentially therapeutic impact in patient management. publishersversion published

Anaplastic thyroid carcinoma (ATC) is one of the most aggressive solid tumors in humans. The use of positron emission tomography (PET) with 18F-fluorodeoxyglucose (18F-FDG) in ATC has not been studied, and only a few case reports have been published. The objective of this study was to investigate the potential contribution of 18F-FDG PET to the clinical management of patients with ATC.All patients with ATC studied with 18F-FDG PET from August 2001 through March 2007 were included. The PET results were correlated with computed tomography, ultrasound, magnetic resonance imaging, bone scan, histology, and clinical follow-up. The FDG uptake was semiquantified as maximum standard uptake value. Any change in the treatment plan as a direct result of the PET findings as documented in the clinical notes was recorded.Sixteen patients were included. True-positive PET findings were seen for all primary tumors, in all nine patients with lymph node metastases, in five out of eight patients with lung metastases, and in two patients with distant metastases other than lung metastases. In 8 of the 16 patients, the medical records reported a direct impact of the PET findings on the clinical management.ATC demonstrates intense uptake on 18F-FDG PET images. In 8 of the 16 patients (50%), the medical records reported a direct impact of the PET findings on the management of the patient. PET may improve disease detection and have an impact on the management of patients with ATC relative to other imaging modalities.

In this study, we evaluated the activity of two novel pyrazolopyrimidine derivatives (Si 34 and Si 35) against ARO cells, a human anaplastic thyroid cancer cell line. ARO cells exposed to different concentrations of the drugs showed a reduced growth rate and an increase of mortality. After 72 h incubation, doses of 5 and 10 microM Si 34 determined a decrease of cell counts by approximately 25% and approximately 75% compared with those of control cells respectively. Similar findings were observed using Si 35. Treatment with both Si 34 and Si 35 at 10 microM increased cell mortality also ( approximately 29% and approximately 18% respectively). At these concentrations, a decrease in cyclin D1 levels was observed. To improve the biopharmaceutical properties, a liposome formulation was prepared. When entrapped in unilamellar liposomes, Si 34 exerted its cytotoxic effects even at lower doses (maximal inhibition at 5 microM) and after shorter incubation time (48 h) either in ARO or other thyroid cancer cell lines. The effects were associated with weak apoptotic death. Inhibition of epidermal growth factor-stimulated src and ERK phosphorylation, as well as reduction of migration properties of ARO cells was also observed. Moreover, the growth of tumor xenografts induced in severe combined immunodeficiency (SCID) mice was inhibited by i.v. administration of 25-50 mg/kg of the drug liposomal formulation. In conclusion, the liposomal preparation of this novel pyrazolopyrimidine derivative appears to be a promising tool for the treatment of anaplasic thyroid cancer.

Between 1970 and 1987, 20,028 fine needle aspirates (FNA) of the thyroid have been examined in the Department of Pathology of the University of Innsbruck, Austria. During this period 92 cases of anaplastic carcinoma and 16 cases of malignant haemangioendothelioma (MHE) of the thyroid were diagnosed. Forty-three out of these 108 highly malignant tumours of the thyroid underwent FNA pre-operatively (39.1%). Thirty-seven FNA contained numerous cells of a highly malignant tumour. Five specimens (11.8%) contained only necrotic material and inflammatory cells. In one case of an anaplastic carcinoma no malignant cells could be demonstrated in FNA. We conclude that pre-operative FNA of highly malignant thyroid tumours may contribute substantially to subsequent clinical management.

Thyroid cancer is an uncommon malignancy that accounts for roughly 1% of all new cancers. Although anaplastic lesions constitute fewer than 5% of thyroid cancers, they represent over half of thyroid cancer-related deaths. The relative rarity of anaplastic thyroid cancer, its aggressive nature, and its rapidly fatal course have contributed to the difficulty in developing effective treatment for this disease. Radiation, chemotherapy, and surgery are rarely curative, but combinations of these modalities appear to offer greater benefit than any single treatment. New treatment modalities are desperately required, and promising molecular-based therapies are being investigated.

Free 211At has been proposed for therapy of anaplastic thyroid carcinoma (ATC). However, no extensive biodistribution study comparing tumor-bearing and nontumor-bearing mice has previously been performed. The aim of this study was to perform a complete evaluation of the biodistribution of 211At, both for normal and ATC-bearing mice. For comparison, the biodistribution of 125I- was simultaneously studied. Dosimetric evaluations were performed to investigate if (211)At can be used for therapy of ATC.Athymic nude mice were subcutaneously injected with either of two human ATC cell lines, HTh83 and KAT-4. Tumor-bearing and nontumor-bearing mice were injected intravenously with 0.3 MBq 211At and 0.3 MBq 125I- simultaneously. The mice were sacrificed 4-24 hours after injection, and the activity concentrations in tissues were determined.Except for the thyroid, the concentration of 211At was higher than that of 125I- in the tissues. The uptake of 211At was primarily high in NIS-expressing organs. Furthermore, the absorbed doses to these organs were higher than both tumor types.The biodistribution of 211At and 125I- differed in this animal model. The higher mean absorbed dose from 211At in several organs than in tumor tissue restricts the possibility of using free 211At for therapy of ATC.

Anaplastic thyroid carcinoma is a rare but very aggressive neoplasm with a poor prognosis and clinical outcome. It is characterized by the onset of a large symptomatic thyroid mass compromising airways and having a high propensity for metastasis at initial presentation and during its accele

Anaplastic thyroid carcinoma (ATC) is a tumor with bad prognosis and long-term survival is very low. However, appropriate combinations of chemotherapy, surgery, and radition have been reported to potentially improve the treatment results for ATC. We describe a case of refractory ATC successfully treated with high-dose chemotherapy (HDC) followed by autologous peripheral blood stem cell transplantation (auto-PBSCT). There has not been any evidence of recurrence for 10 years after auto-PBSCT. To the best of our knowledge, this is the first case of ATC that has been followed up for a long-term period after HDC with auto-PBSCT. This case suggests that intensive therapeutic approach such as HDC with auto-PBSCT may be useful.

e22205 Background: Anaplastic thyroid carcinoma (ATC) is the most aggressive thyroid cancer. Despite recent efforts aimed at defining its most common molecular alterations, there is still no effect...

A 63-year-old woman presented with a right anterior neck mass that enlarged rapidly over 2 months. She had dysphagia but did not have hoarseness, dyspnoea or thyrotoxic symptoms. Preoperative CT scan revealed a 7.6×8.8×7.3 cm mass, well-defined, heterogeneously enhancing with coarse calcifications arising from the right thyroid lobe. It encased the right common carotid artery and infiltrated the right internal jugular, external jugular and brachiocephalic veins. It extended inferiorly up to the level of the thoracic inlet. There were multiple enlarged lymph nodes in the neck. There was evidence of lung metastases as well. Fine-needle aspiration was suspicious for papillary thyroid carcinoma, but the behaviour and …

Anaplastic thyroid carcinoma (ATC) is one of the most aggressive malignancies and prognostic outlook remains very dismal. Treatment most often is palliative in intent attempting to relieve the patients from local compressive symptoms in the neck. Radical surgery, radiotherapy (RT), and chemotherapy have not been tested in large prospective trials, and current evidence from retrospective series and small trials indicate only marginal survival benefits. Given the poor prognostic and therapeutic outlook, patients must be encouraged to be actively involved in the decision making process. We report the case of an elderly patient who had no response to palliative RT, and was treated with oral metronomic chemotherapy. The response to oral metronomic chemotherapy was dramatic, and the patient has enjoyed complete freedom from symptoms as well as radiologically exhibits a complete regression. Thus, we document the first ever use of a simple, cost-effective, and convenient oral metronomic chemotherapeutic regimen delivering a remarkable response in an elderly patient with ATC.

We tested the suitability of the chimeric monoclonal anti-human CD44 splice version 6 antibody (cMAb U36) for targeting and visualising human anaplastic thyroid carcinoma with PET. We also performed experiments aimed at elucidating the relation between tumour interstitial fluid pressure (TIFP) and the tumour uptake of antibodies.The affinity and specificity of the cMAb U36 for KAT-4 cells were evaluated in vitro, as was the Na+/I- symporter (NIS) expression. Biodistribution studies were performed on KAT-4 carcinoma-bearing mice injected with 124I-cMAb U36 or free iodine. Biodistribution studies were also performed in animals treated with the specific TGF-beta1 and -beta3 inhibitor Fc:TbetaRII, which lowers TIFP. Treated and non-treated animals were scanned by microPET.Cultured human undifferentiated/anaplastic thyroid carcinoma KAT-4 cells expressed low levels of NIS and uptake of free iodine was insignificant. The cMAb U36 expressed an affinity (KD) of 11+/-2 nM. Tumour radioactivity uptake reached maximum values 48 h after injection of 124I-cMAb U36 (approximately 22%IA/g). KAT-4 carcinomas were readily identified in all 124I-immuno-PET images. Radioactivity tumour uptake in Fc:TbetaRII-treated animals was significantly lower at 24 and 48 h after injection, and five times higher thyroid uptake was also noted.We successfully used 124I-cMAb U36 to visualise CD44v6-expressing human anaplastic thyroid carcinoma. Given the lack of NIS expression in KAT-4, tumour visualisation is not due to free iodine uptake. Lowering the TIFP in KAT-4 carcinomas did not increase the uptake of mAbs into tumour tissue.

Anaplastic thyroid carcinoma (ATC) is one of the most malignant tumors in humans, and currently there is no effective treatment. In the present study we investigated the effect of an endogenous estrogen metabolite, 2-methoxyestradiol (2-ME), on the growth of human ATC cells. 2-ME treatment had a strong growth inhibitory effect on five human ATC cell lines (HTh7, HTh 74, HTh83, C643, and SW1736), but showed no effect on one cell line (KAT-4). Cell cycle analysis of the growth-inhibited cells showed that 2-ME induced a G2/M-arrest, followed by an increased fraction of cells in sub-G1. Analysis of internucleosomal DNA laddering as well as DNA fragmentation in a terminal deoxynucleotide transferase-mediated dUTP nick-end labeling (TUNEL) assay demonstrated a high number of cells undergoing apoptosis after 2-ME treatment. An increased activation of caspase-3 and caspase-8 by 2-ME was observed, and inhibition of caspase-3 decreased the apoptotic effect. Addition of 2-ME increased activity of p38 mitogen-activated protein kinase (MAPK) in the sensitive HTh7 as well as the refractory KAT-4 cells, however, activation of stress-activated protein kinase/c-jun aminoterminal kinase (SAPK/JNK) was seen only in the HTh7 cells. Inhibitors of p38 MAPK and SAPK/JNK significantly attenuated the 2-ME effect. Taken together, our data demonstrate an antiproliferative and apoptotic effect of 2-ME on ATC cells involving activation of MAPKs.

Anaplastic thyroid carcinoma (ATC) is one of the most aggressive malignancies. We tried to elucidate the possible prognostic factors.A retrospective review was conducted of ATC patients in National Taiwan University Hospital from 1978 to 2003. Their demographic characteristics, clinical presentations, laboratory data and treatment modalities were reviewed. Possible prognostic factors for survival were evaluated.Forty-five patients (14 males and 31 females) of mean age 61.9 +/- 12.6 yr were included in this study. The median survival time was 94 days (range 6 to 776 days). The overall survival rate was 27% at 6 months and 10% at 1 yr. Thirty-two patients receiving intervention regimens had a median survival of 106 days, while 13 patients receiving palliative therapy had a median survival of 39 days. The difference in survival is statistically significant (logrank test, p = 0.017). Adjusted with sex and age, increment in white blood cell count (per 10(9)/l) and serum albumin (per 1.0 g/l) had a hazard ratio of 1.12 (Cox regression, p0.001) and 0.92 (p = 0.041), respectively. Patients with leukocytosis [white blood cell (WBC) count10(10)/l] or hypoalbuminemia (serum albumin35 g/l) had significant shorter survival than patients without leukocytosis or hypoalbuminemia (logrank test p = 0.008 and p = 0.032, respectively). Patients with serum T4 levels lower than 64.35 nmol/l had significantly shorter survival than patients without hypothyroxinemia (median survival 24 vs 128 days, logrank test, p = 0.004).ATC is an aggressive malignancy. Leukocytosis, hypoalbuminemia and hypothyroxinemia indicated poor prognosis. Survival time might be prolonged if intervention treatment is tolerable.

Anaplastic thyroid cancer is an endocrine malignancy. Its rare and rapidly lethal disease course has made it challenging to study. Little is known regarding the expression by anaplastic tumors of molecular targets for new human anticancer agents that have been studied in the preclinical or clinical setting. The objective of this work was to evaluate the expression profile of anaplastic thyroid tumors for molecular targets for treatment.Of the 94 cases of anaplastic thyroid cancers diagnosed and treated in British Columbia, Canada over a 20-year period (1984-2004), 32 cases (34%) had adequate archival tissue available for evaluation. A tissue microarray was constructed from these anaplastic thyroid tumors and immunohistochemistry was utilized to evaluate expression of 31 molecular markers. The markers evaluated were: epidermal growth factor receptor (EGFR), HER2, HER3, HER4, ER, PR, uPA-R, clusterin, E-cadherin, beta-catenin, AMF-R, c-kit, VEGF, ILK, aurora A, aurora B, aurora C, RET, CA-IX, IGF1-R, p53, MDM2, p21, Bcl-2, cyclin D1, cyclin E, p27, calcitonin, MIB-1, TTF-1, and thyroglobulin.A single tumor with strong calcitonin expression was identified as a poorly differentiated medullary carcinoma and excluded from the study cohort. The mean age of the anaplastic cohort was 66 years; 16 patients (51%) were females, and the median patient survival was 23 weeks. A wide range in molecular marker expression was observed by the anaplastic thyroid cancer tumors (0-100%). The therapeutic targets most frequently and most strongly overexpressed by the anaplastic tumors were: beta-catenin (41%), aurora A (41%), cyclin E (67%), cyclin D1 (77%), and EGFR (84%).Anaplastic thyroid tumors exhibit considerable derangement of their cell cycle and multiple signal transduction pathways that leads to uncontrolled cellular proliferation and the development of genomic instability. This report is the first to comprehensively evaluate a panel of molecular targets for therapy of anaplastic thyroid cancer and supports the development of clinical trials with agents such as cetuximab, small-molecule tyrosine kinase inhibitors, and aurora kinase inhibitors, which may offer new hope for individuals diagnosed with this fatal thyroid malignancy.

The purpose of this chapter is to present indications for using external beam radiation therapy (EBRT) in patients with Medullary and Anaplastic thyroid cancer. Radiotherapy dose schedules and techniques are in the subject of other chapters in this section of this book. MEDULLARY THYROID CANCER

Molecular mechanisms in the development and progression of thyroid carcinomas are still not fully understood. In the present thesis the highly malignant anaplastic thyroid carcinoma (ATC) was used to study regulation of apoptosis and tumor interstitial fluid pressure (IFP). Addition of a natural estrogen metabolite, 2-Methoxyestradiol (2-ME), induced a G2/M cell cycle arrest and apoptosis in five out of six human ATC cell lines. Treatment with 2-ME induced DNA-fragmentation as well as activation of caspase-3. Inhibitors of JNK and p38 MAPKs activity decreased the effect of 2-ME suggesting involvement in the induction of apoptosis. Solid tumors have an elevated IFP. High IFP forms or reflects a barrier for exchange of molecules between microvessels and surrounding tissue. The mechanisms for the generation of the high IFP were investigated using a specific TGF-β inhibitor in an ATC model in athymic mice. Tumor IFP was lowered in TGF-β inhibitor-treated compared to control mice. Affymetrix microarray analysis showed a decreased expression of macrophage-associated genes in treated tumors. Furthermore, the number and activity of tumor-associated macrophages was reduced after TGF-β inhibition. A decreased protein leakage together with an increased coverage of α-smooth-muscle actin (SMA)-expressing cells indicated vessel normalization. An adjuvant treatment with the TGF-β inhibitor resulted in an increased treatment efficacy of doxorubicin. Thus, TGF-β inhibitor-treatment suggests improved microvessel function which results in a lowering of tumor IFP and increased tumor drug uptake. To create a model for specific inactivation of genes in the thyroid, a transgenic mouse with a thyrocyte-specific expression of Cre recombinase was generated. The thyroglobulin promoter together with an inducible Cre recombinase (creERT2) was used. Two transgenic founder lines were identified expressing cre mRNA solely in the thyroid. Functional activity of the CreERT2 protein was demonstrated by using a ROSA26-LacZ reporter mouse.

We previously demonstrated that restoration of TP53 activity in anaplastic thyroid carcinoma inhibits cell growth and induces expression of thyroid differentiation markers. Here, we investigated whether TP53 status may condition the expression of therapeutic genes driven by retroviral LTR or tissue-specific enhancer elements. The TP53-defective ARO anaplastic thyroid carcinoma cells were transfected with TP53(Val135), which exhibits wild-type activity at 32 degrees C, and transduced with retroviral vectors, in which therapeutic genes were driven either by wild-type LTR or by a reshuffled LTR containing thyroglobulin (TG) enhancer. Both at 37 and 32 degrees C, expression of transgenes driven by TG enhancer was 10-fold lower than that obtained with wild-type LTR retroviral vector. TP53(Val135) transfer into ARO cells repressed transcription from wild-type LTR but increased expression of TG-driven therapeutic genes. This effect was markedly enhanced by cell culture at 32 degrees C and by TSH treatment. Cytotoxic effects shown after ganciclovir treatment paralleled therapeutic gene expression levels. In conclusion, TP53 status in the tumor cell can influence expression of therapeutic genes. When using retroviral-vector-based gene therapy, wild-type LTR vectors should be employed to target TP53-defective tumors, whereas thyroid-specific promoters should be used for transcriptional targeting of thyroid carcinomas carrying wild-type TP53.