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Introduction: To perform a head-to-head comparison of the uptake pattern of F-18 fluorodeoxyglucose in positron emission computed tomography (FDG PET/CT) in radioiodine refractory thyroid carcinomas (RAIR) in the same patient under elevated TSH levels ( e TSH) and suppressed TSH levels ( s TSH)., Methods: FDG PET/CT studies were performed under two conditions: levothyroxine intake ( s TSH) and 30 days after hormonal withdrawal ( e TSH). SUVmax values and the number of lesions detected (local recurrence and metastases in cervical and distant lymph nodes, lungs and bone) where blindly evaluated. Blood serum TSH and Tg levels were obtained prior to both studies. FDG PET/CT imaging, neck ultrasound, biopsy and follow-up were considered the reference standard., Results: Fifteen patients performed both e TSH and s TSH FDG PET/CT studies. Both were positive for metastases in 80% of the patients. e TSH FDG PET/CT studies did not reveal increased uptake (p = 0.0640) and did not demonstrate a higher number of lesions (p = 0.320) when compared to sTSH FDG PET/CT studies. There was no change in the clinical management of these patients., Conclusions: e TSH FDG PET/CT in patients with RAIR did not show more metastases in comparison to s TSH FDG PET/CT and there was no impact in clinical management of patients. Elevating TSH levels (whether by hormonal withdrawal or recombinant TSH) in patients being submitted to FDG PET/CT may not be necessary., (© 2020 Published by Elsevier Ltd.)

Objective: TSH-suppression is a therapy for thyroid cancer management, but it may lead to adverse effects, which should be balanced with its benefits. Previous studies evaluating the consequences of TSH suppression on insulin sensitivity have only been done with indirect techniques, and results were controversial. Therefore, we aimed to assess insulin sensitivity in patients with thyroid cancer and suppressed thyroid-stimulating hormone (TSH) with the most appropriate direct method (hyperinsulinemic-euglycemic clamp) in order to get a more conclusive response about the topic., Methods: A group of 20 non-obese and non-diabetic thyroid cancer patients with suppressed TSH underwent a hyperinsulinemic-euglycemic clamp to evaluate insulin sensitivity. Their results were compared to the results of a sex and body mass index (BMI) -paired control group composed of 20 healthy volunteers., Results: Patients were all female, aged 36.8 ± 10.2 years-old, with mean TSH 0.1 ± 0.1 μIU/mL and mean BMI 26.2 ± 3.3 kg/m 2 . Insulin sensitivity, determined by the insulin-stimulated glucose uptake (M-value), was lower in the patients group (4.2 ± 1.6 mg/min*kg versus 5.8 ± 1.7, age-adjusted p-value = 0.0205)., Conclusion: This study shows for the first time that subclinical thyrotoxicosis in patients with thyroid cancer is associated with insulin resistance, as measured by hyperinsulinemic-euglycemic clamp technique. Such finding may be taken into consideration by clinicians when balancing risks and benefits of TSH-suppression therapy in thyroid cancer patients.

Background: Radioiodine-refractory thyroid carcinomas (RAIRs) are characterized by reduced expression of sodium-iodine symporter, rising serum thyroglobulin levels, and negative whole-body radioiodine scans. Interestingly, RAIRs continue to express somatostatin receptors and can be identified with Ga-DOTATATE PET/CT imaging., Objective: The objective of this study was to compare lesion detectability in Ga-DOTATATE PET/CT performed with elevated thyroid-stimulating hormone (eTSH) levels with suppressed thyroid-stimulating hormone (sTSH) levels., Patients and Methods: Fifteen patients with RAIR were prospectively enrolled in this pilot study. All patients underwent two Ga-DOTATATE PET/CT studies: with sTSH and with eTSH (after 30 days of levothyroxine withdrawal). All studies were blindly evaluated for differences pertaining to maximum standardized uptake values, detection of local recurrence, cervical lymph node (LN) metastases, cervical levels involved, distant LN metastases, lung metastases, and bone metastases. Reference standard consisted of fluorine-18-fluorodeoxyglucose PET/CT imaging, neck ultrasound, biopsy, and follow-up., Results: Ga-DOTATATE PET/CT performed with both sTSH or eTSH was highly sensitive (91-100%) for detecting RAIR metastases. Ga-DOTATATE PET/CT with eTSH detected a higher total number of lesions (P=0.002), higher rate of cervical and distant LN metastases (P=0.002 and 0.0313, respectively), and significantly higher maximum standardized uptake values for cervical and distant LN metastases (P=0.0010 and 0.0078, respectively) when compared with sTSH., Conclusion: Ga-DOTATATE PET/CT presents a high sensitivity in detecting metastatic lesions in patients with RAIR. Detectability increases with iodine-resistance, both with and without higher thyroid-stimulating hormone levels. These findings might improve staging and subsequent treatment planning, especially with radiolabeled somatostatin analogs.

Objective: The transcriptional repressor DREAM is involved in thyroid-specific gene expression, thyroid enlargement and nodular development, but its clinical utility is still uncertain. In this study we aimed to investigate whether DREAM mRNA levels differ in different thyroid tumors and how this possible difference would allow the use of DREAM gene expression as molecular marker for diagnostic and/or prognosis purpose., Materials and Methods: We quantified DREAM gene mRNA levels and investigated its mutational status, relating its expression and genetic changes to diagnostic and prognostic features of 200 thyroid tumors, being 101 malignant [99 papillary thyroid carcinomas (PTC) and 2 anaplastic thyroid carcinomas] and 99 benign thyroid lesions [49 goiter and 50 follicular adenomas (FA)]., Results: Levels of mRNA of DREAM gene were higher in benign (0.7909 ± 0.6274 AU) than in malignant (0.3373 ± 0.6274 AU) thyroid lesions (p < 0.0001). DREAM gene expression was able to identify malignancy with 66.7% sensitivity, 85.4% specificity, 84.2% positive predictive value (PPV), 68.7% negative predictive value (NPV), and 75.3% accuracy. DREAM mRNA levels were also useful distinguishing the follicular lesions FA and FVPTC with 70.2% sensitivity, 73.5% specificity, 78.5% PPV, 64.1% NPV, and 71.6% accuracy. However, DREAM gene expression was neither associated with clinical features of tumor aggressiveness, nor with recurrence or survival. Six different genetic changes in non-coding regions of DREAM gene were also found, not related to DREAM gene expression or tumor features., Conclusion: We suggest that DREAM gene expression may help diagnose thyroid nodules, identifying malignancy and characterizing follicular-patterned thyroid lesions; however, it is not useful as a prognostic marker.

Purpose: The role of thyroid-specific transcription factors in thyroid malignancy is still poorly understood, so we investigate thyroid-specific transcription factors gene expression both in benign and in malignant thyroid nodules, aiming to study a possible clinical utility of these molecules., Methods: We quantified TTF-1, FOXE1 and PAX8 mRNA levels, relating their expression to diagnostic and prognostic features of thyroid tumors. RNA was extracted from 4 normal thyroid tissues, 101 malignant [99 papillary thyroid carcinomas (PTC) and 2 anaplastic thyroid carcinomas] and 99 benign thyroid lesion tissues [49 goiter and 50 follicular adenomas (FA)]., Results: Levels of mRNA of both FOXE1 (P < 0.0001) and PAX8 (P < 0.0001) genes, but not TTF-1 (P = 0.7056), were higher in benign than in malignant thyroid lesions. FOXE1 was able to identify malignant nodules with 75.8 % sensitivity, 76.1 % specificity, 75.8 % positive predictive value, 76.1 % negative predictive value and 75.9 % accuracy. PAX8 was able to identify malignancy with 60.6 % sensitivity, 81.1 % specificity, 76.9 % positive predictive value, 66.4 % negative predictive value and 70.6 % accuracy. Both FOXE1 and PAX8 gene expression patterns were also able to differentiate FA from the follicular variant of PTC-FVPTC. However, the investigated gene expression was neither associated with any clinical feature of tumor aggressiveness nor associated with recurrence or survival., Conclusions: We suggest that FOXE1 and PAX8 gene expression patterns may help to diagnose thyroid nodules, identifying malignancy and characterizing follicular-patterned thyroid lesions, but are not determinants of thyroid tumor progression.

Objective: Treatment of differentiated thyroid carcinoma (DTC) includes suppression of TSH with levothyroxine therapy, which may negatively influence bone mineral density (BMD), but the effects are controversial. We aimed to evaluate the relationship between TSH-suppressive therapy and BMD in postmenopausal women with DTC., Methodology: Cross-sectional study that assessed BMD by densitometry and risk factors for decreased BMD in 109 postmenopausal women under TSH-suppressive therapy for DTC, compared to an age-matched euthyroid women control group. Conditions that might have affected BMD were exclusion criteria., Results: Patients were 58.4 ± 8.3 years-old, mean serum TSH was 0.21 ± 0.28μIU/ml. In BMD evaluation, T-scores were -1.09 ± 1.43 SD (lumbar spine) and -0.12 ± 1.18 SD (total femur). No significant differences were found between lumbar or femoral T-scores of patients and control group. Multivariate logistic regression analysis evidenced that low BMI and low mean TSH levels (assessed in the year of BMD measurement) were factors significantly related to lower lumbar and spinal BMD., Conclusion: Although low TSH levels and low BMI were correlated with lower BMD, it was not observed an increased prevalence of osteopenia or osteoporosis in this cohort of post-menopausal women under levothyroxine treatment for DTC, when compared to age-matched control women. Nevertheless, such risk factors should be carefully observed in individual patients at high risk of decrease in BMD.

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.

Purpose: Differentiated thyroid cancer (DTC) includes papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC). They have different biological behavior but are frequently analyzed together in studies. We aimed to identify factors associated with mortality in those two different cancer subtypes., Methods: Case series study, with clinical-pathological analysis of the characteristics of 424 patients with PTC and 89 patients with FTC, correlating them to survival rates in a single institution., Results: Patients were followed from 1983 to 2011. Mean follow-up time was 9.4 years for FTC (range 1-36.6 years) and 6.8 years for PTC (range 1.1-30.7 years). Mean age at diagnosis was 51.2 ± 15.5 for FTC and 41 ± 14.7 years for PTC. 50.62% of FTC nodules sized 1.1-4 cm and 20% of PTC sized ≤1 cm. Cox multiple regression analysis evidenced distant metastasis at diagnosis (p = 0.0038; relative risk (RR) 41.247, 95% confidence interval (CI) 3.317-512.986), lymph node metastasis at diagnosis (p = 0.0081; RR 50.98, 95% CI 2.783-934.026) and vascular/lymphatic invasion (p = 0.0039; RR 40.424, 95% CI 3.287-497.177) as factors related to mortality in FTC patients. For PTC, the factors were distant metastasis at diagnosis (p < 0.0001; RR 32.5, 95% CI 6.676-158.543) and degree of differentiation (poor versus well differentiated, p = 0.003; RR 10.4, 95% CI 2.218-49.487)., Conclusion: The common factor that influenced mortality for FTC and PTC patients was distant metastasis at diagnosis, increasing mortality rate by 41 times in FTC and 30 times in PTC patients. The different factors influencing mortality for different DTC types highlight the importance of analyzing them separately.

Background: 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., Methods: 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., Results: 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)., Conclusion: 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., (© 2014 European Society of Endocrinology.)

Objective: 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., Subjects and Methods: 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)., Results: 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)., Conclusion: The efficacy of RIT and disease outcome do not seem to be related to thyroid stunning.

Cervical uptake detected by 131I whole body scintigraphy (131I-WBS) may be due to thyroid remnants or loco-regional metastases. We describe a patient with follicular carcinoma submitted to total thyroidectomy. 131I-WBS showed left cervical linear uptake and focal areas of uptake in the abdomen and pelvis. SPECT/CT images demonstrated a potential thrombus in the left jugular vein (confirmed by doppler neck ultrasound and MRI) as well as bone metastases. The patient was submitted to thrombectomy and histopathology confirmed metastasis of follicular carcinoma.

A disparity in gender incidence has been reported in both papillary thyroid carcinoma (PTC) and chronic lymphocytic thyroiditis (CLT) diseases frequently associated and whose incidence has been increasing in parallel. We aimed to analyze differences in morphometric variables between male and female PTC patients and their relationship with the presence of concurrent CLT. The nuclear texture features of 100 hematoxylin-eosin stained nuclei from 100 consecutive classic PTC patients enrolled in our service were compared with their clinical and pathological features, including the presence of CLT. All patients were submitted to a standard management protocol and followed-up for 13-248 months (Mo = 117 months). Chromatin in women tended to present a denser and more homogeneous structure, in a less mottled pattern, with higher values of energy (p = 0.008) and diagonal moment (p = 0.032) than men. Concurrent CLT was more prevalent in women (41.42%) than in men (13.33%, p = 0.04) and was associated with higher cluster prominence values (p = 0.027), a parameter that indicates a predominance of high nuclear contrasted heterochromatin. A multivariate logistic regression analysis showed that higher cluster prominence was independently correlated with chromatin in patients who presented CLT but did not demonstrate any association between concurrent CLT and gender. We were unable to demonstrate any association between gender and any characteristic of tumor aggressiveness or patients outcome. Our results suggest that chromatin texture of hematoxylin-eosin stained nuclei in paraffin sections of PTC cells is related to both gender and concurrent CLT.

Context: Different inherited profiles of genes involved in cellular mechanisms of activation and detoxification of carcinogenic products can provide specific protection or determine the risk for cancer. Low-penetrance polymorphic genes related to the biotransformation of environmental toxins have been associated with susceptibility to and the phenotype of, human tumours., Objective: To investigate the role of germline inheritance of polymorphisms in CYP1A2*F, CYP1A1 m1, GSTP1, NAT2 and TP53 genes in hereditary medullary thyroid carcinoma (HMTC) patients., Design: This study was developed in University of Campinas (Unicamp)., Patients: We studied 132 patients with HMTC, 88 first-degree relatives of HMTC patients and 575 control individuals., Measurements: All patients with MTC and their relatives were sequenced for the RET gene and five genes were genotyped using TaqMan(®) system., Results: We observed that the inheritance of CYP1A2*F (OR = 2·10; 95% CI = 1·11-3·97; P = 0·022), GSTP1 (OR = 4·41; 95% CI = 2·47-7·88; P < 0·001) and NAT2 (OR = 2·54; 95% CI = 1·16-5·58; P = 0·020) variants increased the risk for HMTC. In addition, multiple regression analysis showed that the inheritance of GSTP1 polymorphisms was associated with the diagnosis in older patients (B = 8·0229; 95% IC = ± 5·5735; P = 0·0054). Concerning the group of HTMC relatives, CYP1A2*F (OR = 2:40; 95% CI = 1·19-4·86; P = 0·015), CYP1A1 m1 (OR = 2·79; 95% CI = 1:04-7·51; P = 0·042), GSTP1 (OR = 2·86; 95% IC = 1·53-5·32; P < 0·001) and NAT2 (OR = 2·25; 95% IC = 1·20-4·22; P = 0·012) were associated with HMTC risk., Conclusions: We have demonstrated that the inheritance of specific genes determining the individual response to environmental toxins may contribute to the risk and phenotypic variability that exists in patients with HMTC. Moreover, we identified a group at risk in relatives of HMTC patients., (© 2012 John Wiley & Sons Ltd.)

Background: Levothyroxine (L-T4) treatment aims to minimize the risk of differentiated thyroid cancer (DTC) recurrence and should be tailored to patient risk stratification and potential morbidity from adverse effects., Aim: To evaluate the effectiveness of current recommendations on L-T4 treatment of DTC patients in clinical practice., Material and Methods: We submitted to in-person interviews and revised the charts of 139 low-risk (LR) and 57 not-low-risk (NLR) DTC patients. A second evaluation made 24-60 months after surgery reclassified 131 patients who maintained (thyroglobulin) Tg≤2 ng/dl with no evidence of relapse/recurrence as LR, whereas the remaining 65 cases were considered NLR., Results: Only 27% LR patients were appropriately controlled; 18% were kept suppressed; 49% maintained serum TSH levels between 0.11-0.4 mU/l; 21% had TSH=2.5- 4.5 mU/l; and 12% TSH>4.5 mU/l. Among the NLR patients, 24 (37%) of the patients presented serum TSH levels above goal, including 13 (20%) patients with TSH>4.5 mU/l. There were 4 NLR elders whose TSH levels were kept between 0.41 and 4.5 for medical reasons; likewise, 28 NLR patients maintained with low but not undetectable serum TSH levels had cardiovascular and/or bone risk factors, but all the remaining 24 NLR patients were not adequately controlled because of poor treatment compliance. On the other hand, 45% of 152 inappropriately controlled patients presented risks for bone fractures, including 33 patients kept with low serum TSH levels without medical indication., Conclusion: We concluded that guidelines are not adequately applied and alternative strategies aiming to increase adherence are urgently needed for DTC patients.

Aim: Polymorphic low-penetrance genes have been consistently associated with the susceptibility to a series of human tumors, including differentiated thyroid cancer., Methods: To determine their role in medullary thyroid cancer (MTC), we used TaqMan SNP method to genotype 47 sporadic MTC (s-MTC) and a control group of 578 healthy individuals for CYP1A2*F, CYP1A1m1, GSTP1, NAT2 and 72TP53. A logistic regression analysis showed that NAT2C/C (OR=3.87; 95% CI=2.11-7.10; P=2.2×10(-5)) and TP53C/C genotypes (OR=3.87; 95% CI=1.78-6.10; P=2.8×10(-4)) inheritance increased the risk of s-MTC. A stepwise regression analysis indicated that TP53C/C genotype contributes with 8.07% of the s-MTC risk., Results: We were unable to identify any relationship between NAT2 and TP53 polymorphisms suggesting they are independent factors of risk to s-MTC. In addition, there was no association between the investigated genes and clinical or pathological features of aggressiveness of the tumors or the outcome of MTC patients., Conclusion: In conclusion, we demonstrated that detoxification genes and apoptotic and cell cycle control genes are involved in the susceptibility of s-MTC and may modulate the susceptibility to the disease.

Conflicting data concerning the association between obesity and differentiated thyroid cancer (DTC) may be attributed to the lack of records showing dietary intake and inadequate evaluation of nutrient composition. We evaluated 115 DTC patients carefully paired with 103 healthy control individuals by using a structured questionnaire, including a 24-h recordatory during 3 days, to investigate calorie intake and macronutrient (proteins, carbohydrates, and lipids) composition of the diet. We observed that excess weight (body mass index > 25 kg/m(2)) increased individual susceptibility to DTC [odds ratio (OR) = 3.787; 95% confidence interval (CI) = 1.115-6.814; P < 0.0001). This augmented risk was evident in women (OR = 1.925; 95% CI = 1.110-3.338; P = 0.0259) but not in men (P = 0.3498). Excess calorie intake was more frequent in patients with DTC than in controls (OR = 5.890; 95% CI = 3.124-11.103; P < 0.0001), and both excess protein (OR = 4.601; 95% CI = 1.634-12.954; P = 0.0039) and carbohydrate (OR = 4.905; 95% CI = 2.593-9.278; P < 0.0001) consumption were associated with an increased risk of DTC, contrarily to lipid/fiber intake and physical activity (P = 0.894 and 0.5932, respectively). In conclusion, our data indicate that overweight and risk of DTC are associated with higher protein and carbohydrate consumption than the rates recommended by the World Health Organization. The nutritional orientation should be part of preventive strategy targets designed to combat the increasing incidence of both obesity and DTC.

Objectives: The aim of this study was to investigate the role of the interleukin-18 +105A/C and interleukin-10 -1082A/G germline polymorphisms in the development and outcome of differentiated thyroid carcinoma associated or not with concurrent thyroiditis., Methods: We studied 346 patients with differentiated thyroid carcinomas, comprising 292 papillary carcinomas and 54 follicular carcinomas, who were followed up for 12-298 months (mean 76.10 ± 68.23 months) according to a standard protocol. We genotyped 200 patients and 144 control individuals for the interleukin-18 +105A/C polymorphism, and we genotyped 183 patients and 137 controls for the interleukin-10 -1082A/G polymorphism., Results: Interleukin-18 polymorphisms were not associated with chronic lymphocytic thyroiditis or any clinical or pathological feature of tumor aggressiveness. However, there was an association between the presence of interleukin-10 variants and chronic lymphocytic thyroiditis. Chronic lymphocytic thyroiditis was present in 21.74% of differentiated thyroid carcinoma patients, most frequently affecting women previously diagnosed with Hashimoto's thyroiditis who had received a lower 131I cumulative dose and did not present lymph node metastases., Conclusions: We conclude that the inheritance of a G allele at the interleukin-10 -1082A/G polymorphism may favor a concurrent thyroid autoimmunity in differentiated thyroid carcinoma patients, and this autoimmunity may favor a better prognosis for these patients.

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.

The large use of simple and effective diagnostic tools has significantly contributed to the increase in diagnosis of thyroid cancer over the past years. However, there is compelling evidence that most micropapillary carcinomas have an indolent behavior and may never evolve into clinical cancers. Therefore, there is an urgent need for new tools able to predict which thyroid cancers will remain silent, and which thyroid cancers will present an aggressive behavior. There are a number of well-established clinical predictors of malignancy and recent studies have suggested that some of the patients laboratory data and image methods may be useful. Molecular markers have also been increasingly tested and some of them appear to be very promising, such as BRAF, a few GST genes and p53 polymorphisms. In addition, modern tools, such as immunocytochemical markers, and the measure of the fractal nature of chromatin organization may increase the specificity of the pathological diagnosis of malignancy and help ascertain the prognosis. Guidelines designed to select nodules for further evaluation, as well as new methods aimed at distinguishing carcinomas of higher aggressiveness among the usually indolent thyroid tumors are an utmost necessity.

Nonmedullary thyroid carcinoma, originating from thyroid epithelial cells, is the most frequent thyroid malignant neoplasia. Since 1955, there has been increasing evidence that this cancer may have a familial predisposition. It is now established that around 4.2% of all nonmedullary thyroid carcinomas occurs on the background of familial predisposition. These cases are often more aggressive, due to early onset, multifocality and a higher percentual of recurrences. An autossomal dominant inheritance pattern appears likely in most families, although the exact genes responsible for this syndrome have not yet been identified. Patients affected by this cancer should be treated with total thyroidectomy routinely and, in most cases, lymph node dissection, followed by iodine ablation and TSH suppressive therapy with levothyroxine. Some authors also recommend that first-degree relatives of patients with nonmedullary thyroid cancer (especially women) should be submitted to neck ultrasound for thyroid cancer screening, aiming early diagnosis for better treatment results.

The trend of increasing thyroid cancer has been recognized in Brazil as well as all over the world for several decades. The large use of simple and effective diagnostic tools has significantly contributed to this trend. It is estimated that small carcinomas found at surgery for benign thyroid disorders and by ultrasonography will be identified at greater frequency in the further years. Part of these tumors occurs in low-risk patients that may benefit of less aggressive management strategies. However, the characterization of low-risk patient is still confusing and we lack adequate markers to tell apart patients that may present a troublesome progression of the disease. Furthermore, the use of new follow-up methods has recently changed some guidelines. A multidisciplinary team, including basic scientists, endocrinologists, nuclear medicine physicians, thyroid surgeons and endocrine pathologists reviewed the pertinent literature and, based on their experience, propose some management guidelines for Brazilian patients with low-risk thyroid carcinomas.

Aims: To investigate the usefulness of immunohistochemical expression and immunolocalization of a panel of thyroid malignancy markers including HBME-1, cytokeratin (CK) 19 and galectin-3., Methods and Results: We evaluated 170 thyroid lesions including 148 neoplastic lesions [84 papillary carcinomas (PC), 38 follicular carcinomas (FC), 18 follicular adenomas, one hyalinizing trabecular tumour, five medullary carcinomas, two anaplastic carcinomas] and 22 non-neoplastic lesions (12 adenomatous nodules and 10 Hashimoto's thyroiditis). HBME-1, galectin-3 and CK 19 were expressed in 94%, 72.6%, 72.6% of PCs and in 63%, 21%, 21% of FCs. The three markers were mostly negative in all normal tissues. Although the most helpful marker in terms of sensitivity and specificity for the follicular variant of PC and for FC diagnosis was HBME-1, when we consider the differentiation between cases of follicular variant of papillary carcinoma (FVPC) and FC or adenoma, in terms of percentage of positive cells, galectin-3 and CK 19 were more relevant., Conclusions: HBME-1 is the most sensitive marker for thyroid malignancy but the three markers may be useful in specific cases. This panel of markers is useful to differentiate the follicular patterned lesions, with special reference to the FVPC.

A new class of glutathione S-transferase enzymes named omega (GSTO) has been recently identified and shown to be expressed in a wide range of human tissues. A genetic polymorphism of the GSTO1 gene causing an alanine-to-aspartate (A140D) substitution in amino acid 140 produces a variant with lowered enzyme activities in the biotransformation of inorganic arsenic, a common contaminant of drinking water in many regions of the world and a well-known carcinogen. In order to investigate the role of GSTO1 inheritance pattern on thyroid cancer risk we used a polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP)-sequencing approach to compare the genotypes of 173 (87 women, 86 men; 18-81 years old; 47+/-18 years old) healthy control individuals with those of 145 patients with thyroid nodules (84 women, 61 men; 17-81 years old; 49+/-14 years old) including 17 follicular carcinomas, 76 papillary carcinomas, 21 follicular adenomas and 31 multinodular goiters. The incidence of GSTO1 variants was similar in the control population and population with the benign and malignant nodules. There was no association between genotype and the patients' clinical features, tumour parameters of aggressiveness at diagnosis or behaviour during follow-up. We conclude that GSTO1 variants do not influence the risk for thyroid nodules or their pathologic and clinical characteristics.

A common germline polymorphism of p53 gene produces an Arginine to Proline change at aminoacid position 72. The resulting codon 72 variants have been reported associated with tumor susceptibility since they reduce p53 ability to activate apoptosis. Codon 72 polymorphism may play a role in subside vulnerability to different carcinogens and might account for ethnic variations in cancer frequency. Using an allele-specific polymerase chain reaction (PCR), we tested peripheral blood samples from 98 patients with thyroid cancer, including 21 follicular (FC) and 77 papillary carcinomas (PC), 44 patients with benign nodules, including 14 follicular adenomas and 30 goiters and 153 healthy individuals from the same geographical region. Data on lifetime occupational history, smoking history, general health conditions, previous diseases and other anamnestic data were obtained through interviews. Patients with FC (Pro/Pro = 19.0%, Arg/Arg = 42.9%, Arg/Pro = 38%) and with PC (Pro/Pro = 10.3%, Arg/Arg = 36.36%, Arg/Pro = 53.24%) showed a significant overrepresentation of codon 72 variants compared to the control population (Pro/Pro = 1.9%, Arg/Arg = 33.3%, Arg/Pro = 64.7%) (P = 0.0015). The Pro/Pro genotype, after adjusting for gender, age, tobacco and drugs, was associated with a markedly higher risk of FC (OR=9.714; CI: 2.334-40.436) and of PC (OR=5.299; CI: 2.334-40.436). These results provide evidence that p53 polymorphism is implicated in thyroid carcinogenesis and that individuals harboring the Pro/Pro genotype have an increased risk of developing thyroid cancer., (Copyright 2004 Elsevier Ireland Ltd.)

Screening tools are of utmost necessity in order to identify individuals at risk for thyroid nodule cancer. The polymorphic inheritance of human drug-metabolizing enzymes, such as those encoded by the Glutathione-S-Transferase (GST) system, plays an important role in the development of most human cancers. GSTP1 enzyme is the most important detoxification enzyme in human head and neck tissues. An aminoacid substitution (1105V) in the GSTP1 gene result in two genotypes, GSTP1AB and GSTP1BB. Those produce a variant enzyme with lower activity and less capability of effective detoxification of carcinogens than the wild type GSTP1AA. In order to look for the influence of GSTP1 enzymes inheritance pattern on thyroid cancer risk we used a PCR-SSCP-sequencing approach to compare the genotypes of 98 malignant nodules, including 77 papillary carcinomas (PC) and 21 follicular carcinomas (FC), to 44 benign nodules and to 157 healthy control individuals. Individuals with history of previous thyroid disease, exposure to radiation and antecedents of malignancy were excluded. Patients with PC and FC showed a significant over-representation of the variants of GSTP1 allele compared to the control population (p < 0.0001 The risk for thyroid cancer in individuals with the variant GSTP1 enzymes, after adjusting for gender, age, tobacco and drugs use, increased 7,092 (CI: 2,307-21,802) and 9,625 (CI: 2.484-37.291) times for PC and FC, respectively. We suggest that GST genotype may be associated with an increased susceptibility to thyroid cancer. GSTP1 profiling from peripheral blood may be a simple and useful tool in the screening for thyroid nodule malignancy. Glutathione-S-Transferase system; GSTP; Thyroid cancer; Screening., (Copyright 2004 Elsevier Ltd.)

Because most differentiated thyroid carcinomas have an excellent prognosis, some authors have claimed that these patients are suffering from over treatment. Grouping patient- and tumor-specific factors have been proposed for prognostic stratification, but no clinicopathologic staging was demonstrated to be useful at the present time. More recently, molecular genetic tools have been used to identify and understand how the primary tumor progresses and many molecular markers have been proposed in order to distinguish the subset of patients at risk of developing metastasis. Here we analyzed some of them, with emphasis on the expression of NIS, a determinant of prognosis since the functional integrity of the iodine transport is essential to assure an uptake of radioiodine high enough to detect and destroy any tumoral thyroid tissue. More recent observations on how some relevant molecular genetics aspects of thyroid cancer impact new potential therapeutic approaches are also discussed.

A decreased radioiodine uptake is frequently detected in differentiated thyroid carcinomas (DTC) and is associated with high recurrence rate and reduced survival. We investigated the correlation between NIS mRNA expression levels in the primary tumor and patient outcome using a quantitative real-time RT-PCR method. NIS expression was decreased in 17 DTC (21.04+/-39.66 pg Eq) compared to four autoimmune thyroid disease (180.51+/-92.63 pg Eq) and 14 normal tissues (75.71+/-66.98 pg Eq) (p<0.0001). The 17 thyroid differentiated carcinoma patients were submitted to surgery complemented by radioiodine ablation and had at least 24 months of follow-up, under levothyroxine continued suppressive therapy. According to their outcome, we could characterize a group of papillary carcinoma patients with aggressive carcinomas, whose NIS mRNA levels were markedly lower than a group with non-aggressive carcinomas (0.62+/-0.79 versus 54.87+/-53.79; p<0.005). We suggest that the quantification of NIS mRNA relative levels in the primary tumor may predict poor outcome.

Autoimmune phenomena are frequently associated with differentiated thyroid carcinomas. However, the significance of thyroid gland autoimmune aggression on the outcome of these patients is still controversial. To address this issue, we studied 173 patients (123 with papillary and 50 with follicular carcinomas) who underwent surgery complemented by radioiodine ablation and followed up for 0.5-29 (6 +/- 5.76) years. Analysis of the prognostic factors revealed that higher age, male gender, larger nodule size, follicular tumors, presence of metastases at diagnosis, grade of differentiation, and stage correlated positively with the occurrence of death, metastasis and/or recurrence, while the presence of antibodies and the previous history of autoimmune disease correlated negatively with these events. Long distant metastases increased the odds for a lower disease-free rate for patients with papillary (8.366 times) and follicular (7.373 times) carcinoma. However, univariate and multivariate analysis failed to demonstrate that neck node involvement could influence the outcome for patients with well-differentiated thyroid carcinoma. The odds for patients with previous history of thyroid autoimmune disease (p < 0.02) or with thyroid autoantibodies (p < 0.001) to have a worse outcome were lower than for patients with no evidence of autoimmune activity, suggesting that autoimmune activity against the gland may exert a protective effect on the outcome of differentiated thyroid carcinoma patients.

Susceptibility to chemical carcinogens plays an important role in the development of most cancers. Several polymorphisms of human drug-metabolizing enzymes influence this individual susceptibility. The genes that encode the isoenzymes of the glutathione s-transferase (GST) system present a polymorphic inheritance. The GST mu 1 (GSTM1) and GST theta 1 (GSTT1) genes have a null allele variant in which the entire gene is absent. The null genotype for both enzymes has been associated with many different types of tumors. To look for the influence of the inheritance pattern of these enzymes on thyroid cancer risk, we used a triplex PCR that included beta-globin gene as a DNA quality control to compare 300 normal individuals of our population to 116 goiter patients. There were 49 cases of benign and 67 cases of malignant nodules: 50 papillary and 17 follicular carcinomas. Comparison between thyroid tumor specimens and normal corresponding samples of 35 cancer patients demonstrated identical patterns, suggesting that the GST system is not involved in the process of follicular dedifferentiation. There was no statistical difference between the prevalence of the deleted alleles in the normal individuals and in the goiter patients. However, papillary carcinoma patients (10%) and follicular carcinoma patients (17%) presented a higher prevalence of the null genotype than the normal population individuals (5%; P < 0.05). We found a 2.6 increased risk of thyroid cancer in individuals with the GSTT1 and GSTM1 combined null inheritance, suggesting that this genotype may be associated with an increased susceptibility to thyroid cancer.

A case of breast adenocarcinoma metastatic to the pituitary gland in a 57-year-old Brazilian female is presented. The computerized imaging may cause differential diagnostic confusion between a benign primary pituitary process and metastatic disease. Resolution of doubts by surgery is important for determining appropriate treatment.