A Putative Otu Domain-containing Protein 1 Deubiquitinating Enzyme Is Differentially Expressed In Thyroid Cancer And Identifies Less-aggressive Tumours.

This study aimed to identify novel biomarkers for thyroid carcinoma diagnosis and prognosis. We have constructed a human single-chain variable fragment (scFv) antibody library that was selected against tumour thyroid cells using the BRASIL method (biopanning and rapid analysis of selective interactive ligands) and phage display technology. One highly reactive clone, scFv-C1, with specific binding to papillary thyroid tumour proteins was confirmed by ELISA, which was further tested against a tissue microarray that comprised of 229 thyroid tissues, including: 110 carcinomas (38 papillary thyroid carcinomas (PTCs), 42 follicular carcinomas, 30 follicular variants of PTC), 18 normal thyroid tissues, 49 nodular goitres (NG) and 52 follicular adenomas. The scFv-C1 was able to distinguish carcinomas from benign lesions (P=0.0001) and reacted preferentially against T1 and T2 tumour stages (P=0.0108). We have further identified an OTU domain-containing protein 1, DUBA-7 deubiquitinating enzyme as the scFv-binding antigen using two-dimensional polyacrylamide gel electrophoresis and mass spectrometry. The strategy of screening and identifying a cell-surface-binding antibody against thyroid tissues was highly effective and resulted in a useful biomarker that recognises malignancy among thyroid nodules and may help identify lower-risk cases that can benefit from less-aggressive management.

[repeated Fine-needle Aspiration Cytology For The Diagnosis And Follow-up Of Thyroid Nodules].

The recently-proposed Bethesda reporting system has offered clinical recommendations for each category of reported thyroid cytology, including repeated fine-needle aspiration (FNA) for non-diagnostic and atypia/follicular lesions of undetermined significance, but there are no sound indications for repeated examination after an initial benign exam. To investigate the clinical validity of repeated FNA in the management of patients with thyroid nodules. The present study evaluated 412 consecutive patients who had repeated aspiration biopsies of thyroid nodules after an initial non-diagnostic, atypia/follicular lesion of undetermined significance, or benign cytology. The majority of patients were female (93.5%) ranging from 13 to 83 years. Non-diagnostic cytology was the most common indication for a repeated examination in 237 patients (57.5%), followed by benign (36.8%), and A/FLUS (5.6%) cytology. A repeated examination altered the initial diagnosis in 70.5% and 78.3% of the non-diagnostic and A/FLUS patients, respectively, whereas only 28.9% of patients with a benign cytology presented with a different diagnosis on a sequential FNA. Repeat FNA is a valuable procedure in cases with initial non-diagnostic or A/FLUS cytology, but its routine use for patients with an initial benign examination appears to not increase the expected likelihood of a malignant finding.

The Role Of The Inflammatory Microenvironment In Thyroid Carcinogenesis.

Immune responses against thyroid carcinomas have long been demonstrated and associations between inflammatory microenvironment and thyroid carcinomas repeatedly reported. This scenario has prompted scientists throughout the world to unveil how the inflammatory microenvironment is established in thyroid tumors and what is its influence on the outcome of patients with thyroid carcinoma. Many studies have reported the role of evasion from the immune system in tumor progression and reinforced the weakness of the innate immune response toward thyroid cancer spread in advanced stages. Translational studies have provided evidence that an increased density of tumor-associated macrophages in poorly differentiated thyroid carcinoma (DTC) is associated with an aggressive phenotype at diagnosis and decreased cancer-related survival, whereas well-DTC microenvironment enriched with macrophages is correlated with improved disease-free survival. It is possible that these different results are related to different microenvironments. Several studies have provided evidence that patients whose tumors are not infiltrated by lymphocytes present a high recurrence rate, suggesting that the presence of lymphocytes in the tumor microenvironment may favor the prognosis of patients with thyroid carcinoma. However, the effect of lymphocytes and other immune cells on patient outcome seems to result from complex interactions between the tumor and immune system, and the molecular pattern of cytokines and chemokines helps to explain the involvement of the immune system in thyroid tumor progression. The inflammatory microenvironment may help to characterize aggressive tumors and to identify patients who would benefit from a more invasive approach, probably sparing the vast majority of patients with an indolent disease from unnecessary procedures.

Diagnosis, Treatment, And Follow-up Of Medullary Thyroid Carcinoma: Recommendations By The Thyroid Department Of The Brazilian Society Of Endocrinology And Metabolism.

Medullary thyroid carcinoma (MTC) originates in the thyroid parafollicular cells and represents 3-4% of the malignant neoplasms that affect this gland. Approximately 25% of these cases are hereditary due to activating mutations in the REarranged during Transfection (RET) proto-oncogene. The course of MTC is indolent, and survival rates depend on the tumor stage at diagnosis. The present article describes clinical evidence-based guidelines for the diagnosis, treatment, and follow-up of MTC. The aim of the consensus described herein, which was elaborated by Brazilian experts and sponsored by the Thyroid Department of the Brazilian Society of Endocrinology and Metabolism, was to discuss the diagnosis, treatment, and follow-up of individuals with MTC in accordance with the latest evidence reported in the literature. After clinical questions were elaborated, the available literature was initially surveyed for evidence in the MedLine-PubMed database, followed by the Embase and Scientific Electronic Library Online/Latin American and Caribbean Health Science Literature (SciELO/Lilacs) databases. The strength of evidence was assessed according to the Oxford classification of evidence levels, which is based on study design, and the best evidence available for each question was selected. Eleven questions corresponded to MTC diagnosis, 8 corresponded to its surgical treatment, and 13 corresponded to follow-up, for a total of 32 recommendations. The present article discusses the clinical and molecular diagnosis, initial surgical treatment, and postoperative management of MTC, as well as the therapeutic options for metastatic disease. MTC should be suspected in individuals who present with thyroid nodules and family histories of MTC, associations with pheochromocytoma and hyperparathyroidism, and/or typical phenotypic characteristics such as ganglioneuromatosis and Marfanoid habitus. Fine-needle nodule aspiration, serum calcitonin measurements, and anatomical-pathological examinations are useful for diagnostic confirmation. Surgery represents the only curative therapeutic strategy. The therapeutic options for metastatic disease remain limited and are restricted to disease control. Judicious postoperative assessments that focus on the identification of residual or recurrent disease are of paramount importance when defining the follow-up and later therapeutic management strategies.

Is Thyroid Stunning Clinically Relevant? A Retrospective Analysis Of 208 Patients.

Current guidelines have advised against the performance of (131)I-iodide diagnostic whole body scintigraphy (dxWBS) to minimize the occurrence of stunning, and to guarantee the efficiency of radioiodine therapy (RIT). The aim of the study was to evaluate the impact of stunning on the efficacy of RIT and disease outcome. This retrospective analysis included 208 patients with differentiated thyroid cancer managed according to a same protocol and followed up for 12-159 months (mean 30 ± 69 months). Patients received RIT in doses ranging from 3,700 to 11,100 MBq (100 mCi to 300 mCi). Post-RIT-whole body scintigraphy images were performed 10 days after RIT in all patients. In addition, images were also performed 24-48 hours after therapy in 22 patients. Outcome was classified as no evidence of disease (NED), stable disease (SD) and progressive disease (PD). Thyroid stunning occurred in 40 patients (19.2%), including 26 patients with NED and 14 patients with SD. A multivariate analysis showed no association between disease outcome and the occurrence of stunning (p = 0.3476). The efficacy of RIT and disease outcome do not seem to be related to thyroid stunning.

The Influence Of The Environment On The Development Of Thyroid Tumors: A New Appraisal.

Most epidemiological studies concerning differentiated thyroid cancers (DTC) indicate an increasing incidence over the last two decades. This increase might be partially explained by the better access to health services worldwide, but clinicopathological analyses do not fully support this hypothesis, indicating that there are carcinogenetic factors behind this noticeable increasing incidence. Although we have undoubtedly understood the biology and molecular pathways underlying thyroid carcinogenesis in a better way, we have made very little progresses in identifying a risk profile for DTC, and our knowledge of risk factors is very similar to what we knew 30-40 years ago. In addition to ionizing radiation exposure, the most documented and established risk factor for DTC, we also investigated the role of other factors, including eating habits, tobacco smoking, living in a volcanic area, xenobiotics, and viruses, which could be involved in thyroid carcinogenesis, thus, contributing to the increase in DTC incidence rates observed.

Cd8+ Tumour-infiltrating Lymphocytes And Cox2 Expression May Predict Relapse In Differentiated Thyroid Cancer.

There is an increasing rate of papillary thyroid carcinomas that may never progress to cause symptoms or death. Predicting outcome and determining tumour aggressiveness could help diminish the number of patients submitted to aggressive treatments. We aimed to evaluate whether markers of the immune system response and of tumour-associated inflammation could predict outcome of differentiated thyroid cancer (DTC) patients. Retrospective cohort study. We studied 399 consecutive patients, including 325 papillary and 74 follicular thyroid carcinomas. Immune cell markers were evaluated using immunohistochemistry, including tumour-associated macrophages (CD68) and subsets of tumour-infiltrating lymphocytes (TIL), such as CD3, CD4, CD8, CD16, CD20, CD45RO, GRANZYME B, CD69 and CD25. We also investigated the expression of cyclooxygenase 2 (COX2) in tumour cells and the presence of concurrent lymphocytic infiltration characterizing chronic thyroiditis. Concurrent lymphocytic infiltration characterizing chronic thyroiditis was observed in 29% of the cases. Among all the immunological parameters evaluated, only the enrichment of CD8+ lymphocytes (P = 0·001) and expression of COX2 (P =0·01) were associated with recurrence. A multivariate model analysis identified CD8+ TIL/COX2 as independent risk factor for recurrence. A multivariate analysis using Cox's proportional-hazards model adjusted for the presence of concurrent chronic thyroiditis demonstrated that the presence of concurrent chronic thyroiditis had no effect on prognostic prediction mediated by CD8+ TIL and COX2. In conclusion, we suggest the use of a relatively simple pathology tool to help select cases that may benefit of a more aggressive approach sparing the majority of patients from unnecessary procedures.

Immune Response In Thyroid Cancer: Widening The Boundaries.

The association between thyroid cancer and thyroid inflammation has been repeatedly reported and highly debated in the literature. In fact, both molecular and epidemiological data suggest that these diseases are closely related and this association reinforces that the immune system is important for thyroid cancer progression. Innate immunity is the first line of defensive response. Unlike innate immune responses, adaptive responses are highly specific to the particular antigen that induced them. Both branches of the immune system may interact in antitumor immune response. Major effector cells of the immune system that directly target thyroid cancer cells include dendritic cells, macrophages, polymorphonuclear leukocytes, mast cells, and lymphocytes. A mixture of immune cells may infiltrate thyroid cancer microenvironment and the balance of protumor and antitumor activity of these cells may be associated with prognosis. Herein, we describe some evidences that immune response may be important for thyroid cancer progression and may help us identify more aggressive tumors, sparing the vast majority of patients from costly unnecessary invasive procedures. The future trend in thyroid cancer is an individualized therapy.

Polymorphisms Of Cell Cycle Control Genes Influence The Development Of Sporadic Medullary Thyroid Carcinoma.

The role of key cell cycle regulation genes such as, CDKN1B, CDKN2A, CDKN2B, and CDKN2C in sporadic medullary thyroid carcinoma (s-MTC) is still largely unknown. In order to evaluate the influence of inherited polymorphisms of these genes on the pathogenesis of s-MTC, we used TaqMan SNP genotyping to examine 45 s-MTC patients carefully matched with 98 controls. A multivariate logistic regression analysis demonstrated that CDKN1B and CDKN2A genes were related to s-MTC susceptibility. The rs2066827*GT+GG CDKN1B genotype was more frequent in s-MTC patients (62.22%) than in controls (40.21%), increasing the susceptibility to s-MTC (OR=2.47; 95% CI=1.048-5.833; P=0.038). By contrast, the rs11515*CG+GG of CDKN2A gene was more frequent in the controls (32.65%) than in patients (15.56%), reducing the risk for s-MTC (OR=0.174; 95% CI=0.048-0.627; P=0.0075). A stepwise regression analysis indicated that two genotypes together could explain 11% of the total s-MTC risk. In addition, a relationship was found between disease progression and the presence of alterations in the CDKN1A (rs1801270), CDKN2C (rs12885), and CDKN2B (rs1063192) genes. WT rs1801270 CDKN1A patients presented extrathyroidal tumor extension more frequently (92%) than polymorphic CDKN1A rs1801270 patients (50%; P=0.0376). Patients with the WT CDKN2C gene (rs12885) presented larger tumors (2.9±1.8 cm) than polymorphic patients (1.5±0.7 cm; P=0.0324). On the other hand, patients with the polymorphic CDKN2B gene (rs1063192) presented distant metastases (36.3%; P=0.0261). In summary, we demonstrated that CDKN1B and CDKN2A genes are associated with susceptibility, whereas the inherited genetic profile of CDKN1A, CDKN2B, and CDKN2C is associated with aggressive features of tumors. This study suggests that profiling cell cycle genes may help define the risk and characterize s-MTC aggressiveness.

Value Of Sentinel Lymph Node Biopsy In Papillary Thyroid Cancer: Initial Results Of A Prospective Trial.

The objectives of the study were to evaluate the performance of sentinel lymph node biopsy (SLNB) in detecting occult metastases in papillary thyroid carcinoma (PTC) and to correlate their presence to tumor and patient characteristics. Twenty-three clinically node-negative PTC patients (21 females, mean age 48.4 years) were prospectively enrolled. Patients were submitted to sentinel lymph node (SLN) lymphoscintigraphy prior to total thyroidectomy. Ultrasound-guided peritumoral injections of (99m)Tc-phytate (7.4 MBq) were performed. Cervical single-photon emission computed tomography and computed tomography (SPECT/CT) images were acquired 15 min after radiotracer injection and 2 h prior to surgery. Intra-operatively, SLNs were located with a gamma probe and removed along with non-SLNs located in the same neck compartment. Papillary thyroid carcinoma, SLNs and non-SLNs were submitted to histopathology analysis. Sentinel lymph nodes were located in levels: II in 34.7 % of patients; III in 26 %; IV in 30.4 %; V in 4.3 %; VI in 82.6 % and VII in 4.3 %. Metastases in the SLN were noted in seven patients (30.4 %), in non-SLN in three patients (13.1 %), and in the lateral compartments in 20 % of patients. There were significant associations between lymph node (LN) metastases and the presence of angio-lymphatic invasion (p = 0.04), extra-thyroid extension (p = 0.03) and tumor size (p = 0.003). No correlations were noted among LN metastases and patient age, gender, stimulated thyroglobulin levels, positive surgical margins, aggressive histology and multifocal lesions. Sentinel lymph node biopsy can detect occult metastases in PTC. The risk of a metastatic SLN was associated with extra-thyroid extension, larger tumors and angio-lymphatic invasion. This may help guide future neck dissection, patient surveillance and radioiodine therapy doses.

Two Novel Mutations In The Thyroid Hormone Receptor β In Patients With Resistance To Thyroid Hormone (rth β): Clinical, Biochemical, And Molecular Data.

The syndrome of resistance to thyroid hormone (RTH β) is an inherited disorder characterized by variable tissue hyposensitivity to 3,5,30-l-triiodothyronine (T3), with persistent elevation of free-circulating T3 (FT3) and free thyroxine (FT4) levels in association with nonsuppressed serum thyrotropin (TSH). Clinical presentation is variable and the molecular analysis of THRB gene provides a short cut diagnosis. Here, we describe 2 cases in which RTH β was suspected on the basis of laboratory findings. The diagnosis was confirmed by direct THRB sequencing that revealed 2 novel mutations: the heterozygous p.Ala317Ser in subject 1 and the heterozygous p.Arg438Pro in subject 2. Both mutations were shown to be deleterious by SIFT, PolyPhen, and Align GV-GD predictive methods.

Conservative Management For Lingual Thyroid Ectopic.

Lingual thyroid gland is a rare clinical entity. The presence of an ectopic thyroid gland located at the base of the tongue may be presented with symptoms like dysphagia, dysphonia, and upper airway obstruction. We are introducing a case of an 8-year-old girl who had lingual thyroid that presented dysphagia and foreign body sensation in the throat. The diagnostic was reached with clinical examination, thyroid scintigraphy with Tc(99m) and ultrasound. A laryngoscopy was performed which confirmed a spherical mass at base of tongue. Investigation should include thyroid function tests. In this case we observed subclinical hypothyroidism. There are different types of surgical approaches for the treatment of this condition; however, the treatment with Levothyroxine Sodium allowed the stabilization of TSH levels and clinical improvement of symptoms in a follow-up of 2 years.

Polymorphism In Lep And Lepr May Modify Leptin Levels And Represent Risk Factors For Thyroid Cancer.

Purpose. To understand the role of polymorphisms in the LEP (rs7799039 and rs2167270) and LEPR (rs1137101 and rs1137100) genes in DTC susceptibility and their effect on leptin levels. Methods. We studied 153 patients with DTC and 234 controls through TaqMan SNP Genotyping and ELISA, comparing these data to the clinicopathological data of patients with DTC. Results. Patients with AA genotype of rs7799039 had higher levels of serum leptin (9.22 ± 0.98 ng/mL) than those with AG genotype (10.07 ± 0.60 ng/mL; P = 0.005). Individuals with AG genotype of rs2167270 also produced higher serum leptin levels (10.05 ± 0.59 ng/mL) than the subjects with GG genotype (9.52 ± 0.79 ng/mL; P < 0.05). A multivariate logistic regression adjusted for gender, age, and BMI showed that the AG genotype of rs7799039 was an independent risk for DTC (OR, 11.689; P = 0.0183; 95% CI, 1.516-90.119). Similarly, AG and GG genotypes of rs1137101 increased the susceptibility to DTC (OR, 3.747; P = 0.027; 95% CI, 1.161-12.092 and OR, 5.437; P = 0.013; 95% CI, 1.426-20.729). Conclusions. We demonstrated that rs7799039 and rs2167270 polymorphisms modify the serum leptin concentrations in patients with DTC. Furthermore, polymorphisms rs7799039 and rs1137101 increase the risk of DTC development, although they do not correlate with tumor aggressiveness.

Cumulative doses of radioiodine in the treatment of differentiated thyroid carcinoma: knowing when to stop

OBJECTIVE: Evaluate the efficacy of cumulative doses (CDs) of 131I-iodide therapy (RIT) in differentiated thyroid cancer (DTC). SUBJECTS AND METHODS: The probability of progressive disease according to CDs was evaluated in patients < 45 years old and > 45 years old and correlated to tumor-node-metastasis (TNM), thyroglobulin values, histological types and variants, age, and zduration of the disease. RESULTS: At the end of a follow-up period of 69 ± 56 months, 85 out of 150 DTC patients submitted to fixed doses RIT had no evidence of disease, 47 had stable disease and 18 had progressive disease. Higher CDs were used in the more aggressive variants (p < 0.0001), higher TNM stages (p < 0.0001), and follicular carcinomas (p = 0.0034). Probability of disease progression was higher with CDs > 600 mCi in patients > 45 years old and with CDs > 800 mCi in patients < 45 years. CONCLUSION: Although some patients may still respond to high CDs, the impact of further RIT should be carefully evaluated and other treatment strategies may be warranted.

Comparative analysis of the new guidelines and consensuses for the management of hypothyroidism, thyroid nodules, and differentiated thyroid cancer

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