RESUMO
OBJECTIVE: This study investigated the significance of serum hypoxia-inducible factor (HIF)-1α/HIF-2 α and Chitinase 3-Like protein 1 (YKL-40) levels in the assessment of vascular invasion and prognostic outcomes in patients with Follicular Thyroid Cancer (FTC). METHODS: This prospective study comprised 83 patients diagnosed with FTC, who were subsequently categorized into a recurrence group (17 cases) and a non-recurrence group (66 cases). The pathological features of tumor vascular invasion were classified. Serum HIF-1α/HIF-2α and YKL-40 were quantified using a dual antibody sandwich enzyme-linked immunosorbent assay, while serum Thyroglobulin (Tg) levels were measured using an electrochemiluminescence immunoassay method. The Spearman test was employed to assess the correlation between serum factors, and the predictive value of diagnostic factors was determined using receiver operating characteristic curve analysis. A Cox proportional hazards regression model was utilized to analyze independent factors influencing prognosis. RESULTS: Serum HIF-1α, HIF-2α, YKL-40, and Tg were elevated in patients exhibiting higher vascular invasion. A significant positive correlation was observed between Tg and HIF-1α, as well as between HIF-1α and YKL-40. The cut-off values for HIF-1α and YKL-40 in predicting recurrence were 48.25 pg/mL and 60.15 ng/mL, respectively. Patients exceeding these cut-off values experienced a lower recurrence-free survival rate. Furthermore, serum levels surpassing the cut-off value, in conjunction with vascular invasion (v2+), were identified as independent risk factors for recurrence in patients with FTC. CONCLUSION: Serum HIF-1α/HIF-2α and YKL-40 levels correlate with vascular invasion in FTC, and the combination of HIF-1α and YKL-40 predicts recurrence in patients with FTC.
Assuntos
Adenocarcinoma Folicular , Fatores de Transcrição Hélice-Alça-Hélice Básicos , Biomarcadores Tumorais , Proteína 1 Semelhante à Quitinase-3 , Subunidade alfa do Fator 1 Induzível por Hipóxia , Invasividade Neoplásica , Valor Preditivo dos Testes , Humanos , Proteína 1 Semelhante à Quitinase-3/sangue , Feminino , Masculino , Subunidade alfa do Fator 1 Induzível por Hipóxia/sangue , Pessoa de Meia-Idade , Prognóstico , Adulto , Adenocarcinoma Folicular/sangue , Adenocarcinoma Folicular/patologia , Adenocarcinoma Folicular/mortalidade , Estudos Prospectivos , Fatores de Transcrição Hélice-Alça-Hélice Básicos/sangue , Biomarcadores Tumorais/sangue , Neoplasias da Glândula Tireoide/sangue , Neoplasias da Glândula Tireoide/patologia , Neoplasias da Glândula Tireoide/mortalidade , Idoso , Recidiva Local de Neoplasia/sangue , Recidiva Local de Neoplasia/patologia , Ensaio de Imunoadsorção Enzimática , Valores de Referência , Adulto Jovem , Estatísticas não Paramétricas , Curva ROCRESUMO
Background: Thyroid tumor is a common endocrine tumor that accounts for up to 3.8% of all tumors in dogs. Most of them are malignant and usually nonfunctional in dogs. 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) is an imaging modality that detects intracellular accumulation of radioactive deoxyglucose administered in the body and is used in combination with computed tomography to provide functional information with exact anatomical localization. It is used in human medicine to detect residual or recurrent head and neck neoplasm after treatments, such as surgical resection. This report describes the first case of diagnosing recurrent thyroid carcinoma (TC) through FDG-PET in a dog. Case: A 9-year-old castrated male Maltese dog presented with a palpable mobile mass in the right ventral cervical region. Radiography and ultrasonography (US) showed a radiopaque mass adjacent to the trachea, and the right thyroid gland was enlarged on computed tomography. The surgically excised mass was encapsulated and measured to be 2.3 × 1.0 × 3.4 cm (width x length x height) in size. Histopathologically, the mass was diagnosed as differentiated follicular TC, and gross and vascular invasions were observed. To prevent recurrence, postoperative carboplatin chemotherapy was performed for 5 months. Two months after completion of chemotherapy, a nodule of approximately 7 mm in diameter was detected in the thyroidectomy bed by US. FDG-PET scanning was performed as an effective means of evaluating the malignancy, local recurrence, and metastasis of differentiated follicular TC. The nodule had the dimensions of 2.8 × 5.9 × 8.6 mm, a maximum standardized uptake value (SUV) of 8.49, and a mean SUV of 5.6. The results of FDG-PET suggested the recurrence of TC; therefore, the second chemotherapy protocol using toceranib was applied for 16 months. After initiation of the 2nd chemotherapy, follow-up examinations were conducted approximately every 4 months. On the 134th day, although the nodule was not palpated, its size was observed to have increased to 5.0 × 3.8 × 13.6 mm on cervical US on the 232nd day, showing heterogeneous and hypoechoic parenchyma. On the 405th day, the tumor was enlarged to a size of 13.4 × 12.9 × 22 mm and identified as a lobular, amorphous shape, and its heterogeneity was increased. Moreover, 2 pulmonary nodules with well-defined margins were found on radiography in the left caudal lung lobe (9 × 10 mm and 12 × 12 mm [width × length]); thus, lung metastasis was suspected. On the 536th day, anorexia and lethargy occurred, and the dog was lost to follow-up. Discussion: In the present case, local recurrence of TC was suspected based on cervical US. Although US was useful as a screening tool, additional examinations were necessary for evaluating local invasiveness, malignancy, and nodal/distant metastasis. FDG-PET can detect recurrence at an early stage because it can sense increased tumor metabolism through physiologic absorption of FDG, even before the beginning of anatomic change in the lesion. Therefore, FDG-PET can assist in treatment planning and provide better prognosis. In humans, focal FDG uptake and a high maximum SUV in the thyroid gland on FDG-PET were associated with a higher risk of cancer. Because there was no evidence of neoplasia except the thyroid lesion during the FDG-PET examination, the tumor showed an increasingly malignant pattern of the thyroid gland on US during the follow-up period, and the metastatic pulmonary nodules were identified on the 650th day after the thyroidectomy, the present case was diagnosed as recurrent TC. This report describes the use of FDG-PET for diagnosing local recurrence of TC, pointing to FDG-PET as a potential strategy to evaluate loco-regional recurrence and distant metastasis of TC.
Assuntos
Animais , Masculino , Cães , Neoplasias da Glândula Tireoide/diagnóstico por imagem , Carboplatina/uso terapêutico , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/veterinária , Tireoidectomia/veterináriaRESUMO
Background: The differential diagnosis of thyroid nodules using fine-needle aspiration biopsy (FNAB) is challenging due to the inherent limitation of the cytology tests. The use of molecular markers has potential to complement the FNAB-based diagnosis and avoid unnecessary surgeries. In this study, we aimed to identify DNA methylation biomarkers and to develop a diagnostic tool useful for thyroid lesions. Methods: Genome-wide DNA methylation profiles (Illumina 450K) of papillary thyroid carcinoma (PTC = 60) and follicular thyroid carcinoma (FTC = 10) were compared with non-neoplastic thyroid tissue samples (NT = 50) and benign thyroid lesions (BTL = 17). The results were confirmed in publicly available databases from the Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) using the same DNA methylation platform. Two classifiers were trained to discriminate FTC and PTC from BTL. To increase the applicability of the method, six differentially methylated CpGs were selected and evaluated in 161 thyroid tumors and 69 BTL postsurgical specimens and 55 prospectively collected FNAB using bisulfite-pyrosequencing. Results: DNA methylation analysis revealed 2130 and 19 differentially methylated CpGs in PTC and FTC, respectively. The CpGs confirmed by GEO and TCGA databases showing high areas under the receiver operating characteristic curve in all sample sets were used to train our diagnostic classifier. The model based on six CpGs was able to differentiate benign from malignant thyroid lesions with 94.3% sensitivity and 82.4% specificity. A similar performance was found applying the algorithm to TCGA and GEO external data sets (91.3-97.4% sensitivity and 87.5% specificity). We successfully evaluated the classifiers using a bisulfite-pyrosequencing technique, achieving 90.7% sensitivity and 75.4% specificity in surgical specimens (five of six CpGs). The study comprising FNAB cytology materials corroborated the applicability and performance of the methodology, demonstrating 86.7% sensitivity and 89.5% specificity in confirmed malignant tumors, and 100% sensitivity and 89% specificity in cases with indeterminate cytology. Conclusions: A novel diagnostic tool with potential application in preoperative screening of thyroid nodules is reported here. The proposed protocol has the potential to avoid unnecessary thyroidectomies.
Assuntos
Metilação de DNA , Neoplasias da Glândula Tireoide/diagnóstico , Nódulo da Glândula Tireoide/diagnóstico , Adenocarcinoma Folicular/diagnóstico , Adulto , Idoso , Biópsia por Agulha Fina , Ilhas de CpG , Diagnóstico Diferencial , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Câncer Papilífero da Tireoide/diagnóstico , Neoplasias da Glândula Tireoide/genética , Neoplasias da Glândula Tireoide/patologiaRESUMO
ANTECEDENTES: El carcinoma folicular de tiroides puede producir metástasis a distancia, siendo las localizaciones más habituales el pulmón y el hueso. Las metástasis cerebrales son inusuales, y es poco habitual que aparezcan como primera manifestación de cáncer. CASO CLÍNICO: Paciente varón de 80 años, que tras una caída al suelo comenzó con alteración del comportamiento, desorientación y pérdida del control de esfínteres. La tomografía computarizada cerebral evidenció una masa en el lóbulo frontal derecho. Se realizó la extirpación de la lesión cerebral, cuyo estudio histológico informó de metástasis de carcinoma folicular de tiroides. CONCLUSIÓN: La manifestación de la enfermedad con metástasis cerebrales es muy infrecuente, y empeora el pronóstico notablemente. BACKGROUND: Follicular thyroid carcinoma can produce distant metastases, generally occur to lung followed by bone. Brain metastases are unusual, and onset manifestation is little frequently. CLINICAL CASE: A 80-years old men presented disturbance behavior, desorientation and loss of sphincters after fallin to the ground. Computed tomography scan showed a lesion in the right frontal lobe. The patient underwent a craniotomy to remove the brain tumor, histopathology confirmed of follicular thyroid carcinoma metastases. CONCLUSION: At initial diagnosis brain metastasis are extremely rare, with adverse prognosis.
Assuntos
Adenocarcinoma Folicular/secundário , Neoplasias Encefálicas/secundário , Lobo Frontal , Neoplasias da Glândula Tireoide/patologia , Adenocarcinoma Folicular/diagnóstico , Idoso de 80 Anos ou mais , Humanos , Masculino , Neoplasias da Glândula Tireoide/diagnósticoRESUMO
We previously reported that ABI3 expression is lost in follicular thyroid carcinomas and its restoration significantly inhibited cell growth, invasiveness, migration, and reduced tumor growth in vivo. The mechanistic basis by which ABI3 exerts its tumor suppressive effects is not fully understood. In this study, we show that ABI3 is a phosphoprotein. Using proteomic array analysis, we showed that ABI3 modulated distinct cancer-related pathways in thyroid cancer cells. The KEA analysis found that PI3K substrates were enriched and forced expression of ABI3 markedly decreased the phosphorylation of AKT and the downstream-targeted protein pGSK3ß. We next used immunoprecipitation combined with mass spectrometry to identify ABI3-interacting proteins that may be involved in modulating/integrating signaling pathways. We identified 37 ABI3 partners, including several components of the canonical WAVE regulatory complex (WRC) such as WAVE2/CYF1P1/NAP1, suggesting that ABI3 function might be regulated through WRC. Both, pharmacological inhibition of the PI3K/AKT pathway and mutation at residue S342 of ABI3, which is predicted to be phosphorylated by AKT, provided evidences that the non-phosphorylated form of ABI3 is preferentially present in the WRC protein complex. Collectively, our findings suggest that ABI3 might be a downstream mediator of the PI3K/AKT pathway that might disrupt WRC via ABI3 phosphorylation.
RESUMO
We previously reported that ABI3 expression was decreased in thyroid cancer tissues and that ectopic expression of ABI3 in a follicular thyroid carcinoma cell line delayed cell cycle progression and inhibited cell proliferation, invasion, migration and tumor formation in athymic mice. These data indicated that ABI3 is a tumor suppressor gene; however the mechanism through which ABI3 is silenced in thyroid carcinomas is unknown. We here show that treatment of four follicular thyroid carcinoma cell lines with 5-aza-dC induced demethylation of a specific region of the ABI3 promoter and restored ABI3 expression. In contrast, 5-aza-dC treatment did not restore ABI3 expression in a non-thyroid cell line, suggesting a tissue-specific regulation. We additionally show that 8 CpG sites located within the ABI3 promoter are hypermethylated in most thyroid carcinoma samples and the degree of methylation correlated with ABI3 expression. Narrowing the region to specific CpG sites, the CpG4-6 sites showed the largest difference between benign and malignant lesions. In silico analysis revealed that these CpG sites flank a canonical binding site for NKX2-1, a thyroid specific transcriptional factor. Analysis of thyroid samples shows a correlation between NKX2-1 and ABI3 expression. In vitro assays demonstrate that NKX2-1 was required for ABI3 expression. Luciferase assay further confirmed the promoter activity of this region, which was increased when the cells were co-transfected with NKX2-1. Our study shows that the transcriptional silencing of ABI3 in cancer cells occurs via methylation and uncovered a previously unrecognized role for NKX2-1 in the regulation of ABI3.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Neoplasias da Glândula Tireoide/genética , Fator Nuclear 1 de Tireoide/metabolismo , Transcrição Gênica , Proteínas Supressoras de Tumor , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Ilhas de CpG , Inativação Gênica , Humanos , Regiões Promotoras Genéticas , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia , Células Tumorais CultivadasRESUMO
We previously showed that C1orf24 expression is increased in thyroid carcinomas. Nonetheless, the mechanism underlying C1orf24 deregulation is not fully understood. It has been widely demonstrated that microRNAs are involved in post-transcriptional gene regulation in several diseases, including cancer. Using in silico prediction approach, five microRNAs that bind to the 3'-untranslated region (3'-UTR) of C1orf24 were identified. The expression of two selected microRNAs (miR-17-5p, miR-106b) and the expression of C1orf24 were tested in 48 benign and malignant thyroid lesions and in five thyroid carcinoma cell lines. miR-106b was down-regulated in thyroid cancer specimens and thyroid carcinoma cell lines, while C1orf24 expression was markedly increased. To demonstrate that miR-106b reduces C1orf24 expression, follicular (WRO) and papillary (TPC1) thyroid carcinoma cell lines were transiently transfected with miR-106b mimic. Ectopic expression of the miR-106b mimic significantly inhibits C1orf24 mRNA and protein expression in both WRO and TPC1 cells. Dual-luciferase report assays demonstrated that miR-106b directly targets C1orf24 by binding its 3'-UTR. Moreover, miR-106b-mediated down-regulation of C1orf24 expression increased apoptosis and inhibited migration. We additionally demonstrated that siRNA against C1orf24 significantly decreased its expression, inhibited cell migration and cell cycle progression while induced apoptosis. In summary, our findings not only provide new insights into molecular mechanism associated with C1orf24 overexpression in thyroid carcinomas but also show that C1orf24 might increase proliferation and cell migration. Thus, decreasing C1orf24 levels, by restoring miR-106b function, may have therapeutic implications.
Assuntos
Apoptose/genética , Biomarcadores Tumorais/genética , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Proteínas de Neoplasias/genética , Neoplasias da Glândula Tireoide/genética , Regiões 3' não Traduzidas/genética , Sequência de Bases , Biomarcadores Tumorais/metabolismo , Western Blotting , Ciclo Celular/genética , Linhagem Celular Tumoral , Movimento Celular/genética , Técnicas de Silenciamento de Genes , Humanos , Invasividade Neoplásica , Proteínas de Neoplasias/metabolismo , Interferência de RNA , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologiaRESUMO
Fine-Needle Aspiration (FNA) is the most widely used and cost-effective preoperative test for the initial evaluation of a thyroid nodule, although it has limited diagnostic accuracy for several types of tumors. Patients will often receive cytological report of indeterminate cytology and are referred to surgery for a more accurate diagnosis. An improved test would help physicians rapidly focus treatment on true malignancies and avoid some unnecessary treatment of benign tumors. This review will discuss current molecular markers that may improve thyroid nodule diagnosis.
RESUMO
Los carcinomas de la glándula tiroides son poco usuales en edad pediátrica, pero su presencia ha aumentado durante los últimos años; posiblemente, debido al incremento en la irradiación de la cabeza, cuello y mediastino. Entre estas neoplasias, el carcinoma papilar es el más habitual, y los carcinomas foliculares verdaderos son, por el contrario, bastante raros y se asocian al bocio endémico, a alteraciones genéticas y al incremento de los niveles de TSH. Sus características morfológicas son particulares y ayudan a su diagnóstico, el cual ha sido redefinido recientemente. Describiremos el caso de una adolescente de 13 años con carcinoma folicular de tiroides mínimamente invasivo, con nódulo tiroideo hipocaptante en el polo inferior del lóbulo izquierdo, de 6 meses de evolución. La punción aspiración con aguja fina demostró una lesión de células foliculares sospechosa de neoplasia. Se realizó lobectomía tiroidea, con reporte de carcinoma folicular mínimamente invasivo.
Thyroid carcinomas are rare during childhood and adolescence. They have increased recently probably due to a higher frequency radiation over the head, neck and mediastinum. The papillary carcinoma is the most common and true follicular carcinoma is far less common. Follicular thyroid carcinoma is associated with endemic goiter, genetic disorders, and increased TSH levels. Its morphological characteristics are peculiar and have been recently redefined, thus helping the diagnosis. A minimally invasive follicular thyroid carcinoma in 13 years old girl is described, presenting a hypocaptant thyroid nodule in the left lobe lower pole. The fine needle aspiration biopsy revealed a follicular cell lesion suspicious of malignancy. Thyroid lobectomy was performed reporting minimally invasive follicular carcinoma.
Assuntos
Humanos , Masculino , Adolescente , Carcinoma Papilar , Doenças Genéticas Inatas , Bócio Endêmico , Procedimentos Cirúrgicos Minimamente Invasivos , Neoplasias da Glândula Tireoide , Nódulo da Glândula Tireoide , Colômbia , Irradiação Craniana , Neoplasias do MediastinoRESUMO
Com o uso da ultra-sonografia de alta resolução, a prevalência de nódulos tem aumentado e, conseqüentemente, o número de punção aspirativa por agulha fina (PAAF), que é o método de escolha para diagnóstico inicial. Um dos maiores dilemas clínicos para o citologista é o diagnóstico diferencial das lesões foliculares comumente agrupadas na classe padrão folicular. Neste artigo de revisão, discutiremos quais são as lesões que podem ser assim classificadas e os marcadores moleculares, identificados por nós ou por outros grupos, que são capazes de distinguir as lesões benignas das malignas.
There are an increasing number of thyroid nodules found by ultrasound and sampled by fine needle aspiration (FNA). A clinical problem is the accurate distinction between benign and malignant forms of follicular lesion. In this review we discuss the thyroid lesions that are common sources of diagnostic error, and grouped together as follicular patterned lesion, and the molecular markers identified by us and others, and that are able to distinguish the benign from the malignant ones.