Lígia Vera Montalli da Assumpção

Impact of previous thyroid autoimmune diseases on prognosis of patients with well-differentiated thyroid cancer.

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.

Smoking and susceptibility to thyroid cancer: an inverse association with CYP1A1 allelic variants

In contrast to most human malignancies, epidemiologic studies have frequently reported a reduced risk of differentiated thyroid cancer in tobacco consumers. Cytochrome P4501A1 (CYP1A1) gene variants may be related to an increased capacity to activate polycyclic aromatic hydrocarbons, producing highly reactive electrophilic intermediates that might damage DNA. Hence, the germline inheritance of a wild-type CYP1A1 gene may decrease the susceptibility for thyroid cancer. The present study was designed to investigate CYP1A1 (m1 and m2) role in thyroid tumorigenesis and its connection with GSTM1, GSTT1, GSTP1, GSTO1, and codon 72 of p53 genotypes. A total of 248 patients with thyroid nodules, including 67 benign goiters, 13 follicular adenomas, 136 papillary carcinomas, and 32 follicular carcinomas, and 277 controls with similar ethnic backgrounds were interviewed on their lifetime dietary and occupational histories, smoking habit, previous diseases, and other anamnestic data. DNA was extracted from a blood sample and submitted to PCR-restriction fragment length polymorphism assays. The wild-type CYP1A1m1 genotype was more frequent among papillary carcinoma patients (74.26%) than in the control population (62.45%; P=0.0147), reducing the risk for this type of cancer (odds ratio=0.564; 95% confidence interval=0.357-0.894). A multiple logistic regression analysis showed an inverse correlation between cigarette smoking (P=0.0385) and CYP1A1 germline inheritance (P=0.0237) with the susceptibility to papillary carcinomas. We were not able to find any correlation between smoking, clinical features, parameters of aggressiveness at diagnosis or during follow-up, and any of the GST or CYP genotypes considered separately or in different combinations. We suggest that CYP1A1 genotype might be associated with the reported reduced risk to papillary carcinomas among smokers.

Low expression of sodium iodide symporter identifies aggressive thyroid tumors

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.

Obesity and Excess Protein and Carbohydrate Consumption Are Risk Factors for Thyroid Cancer

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/m2) 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.

Identifying a Risk Profile for Thyroid Cancer

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.

Interleukin-10 but not interleukin-18 may be associated with the immune response against well-differentiated thyroid cancer

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 Hashimotos 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.

Role of the N-Acetyltransferase 2 Detoxification System in Thyroid Cancer Susceptibility

Purpose: Genetic polymorphisms in genes encoding for enzymes involved in the biotransformation of carcinogens have been shown to be relevant as risk for cancer and may be of considerable importance from a public health point of view. Considering that N-acetyltransferase 2 (NAT2) polymorphisms modulate the response to ionizing radiation, the strongest risk factor recognized to cause differentiated thyroid cancer (DTC) thus far, we sought to determine the influence of NAT2 detoxification system on thyroid cancer susceptibility. Experimental Design: We conducted a prospective case-control study, comparing 195 patients presenting with DTC that were previously genotyped for GSTT1, GSTM1, GSTP1, and CYP1A1, comprising 164 papillary carcinomas and 31 follicular carcinomas, with 196 control individuals paired for gender, age, ethnicity, diet routine, lifetime occupational history, smoking history, general health conditions, and previous diseases. We used PCR-RFLP assays and the combination of 6 variant alleles to define 18 NAT2 haplotypes that characterized slow, intermediate, or rapid phenotypes. Results: A multivariate logistic regression analysis identified the presence of *12A and the absence of *12B, *13, *14B, *14D, *6A, and *7A NAT2 haplotypes as risk factors for DTC. The inheritance of a rapid acetylation phenotype doubled the risk for a papillary carcinoma (odds ratio, 2.024; 95% confidence interval, 1.252-3.272). We found no relationship between genotypes and clinical, pathologic, or laboratory features of patients or between genotypes and outcome. Conclusions: We showed that NAT2 genotypes and the NAT2 rapid acetylation phenotype are important susceptibility factors for DTC, suggesting that NAT2 detoxification system is involved in this tumor pathogenesis.

Evidence that polymorphisms in detoxification genes modulate the susceptibility for sporadic medullary thyroid carcinoma

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.

Câncer diferenciado da tiróide: fatores prognósticos e tratamento

ABSTRACT Thyroid Cancer: Prognostic Factors and Treatment. Because most differentiated thyroid carcinomas have an excellent prog -nosis, some authors have claimed that these patients are suffering fromover treatment. Grouping patient- and tumor-specific factors have beenproposed for prognostic stratification, but no clinicopathologic stagingwas demonstrated to be useful at the present time. More recently, mol-ecular genetic tools have been used to identify and understand how theprimary tumor progresses and many molecular markers have been pro-posed in order to distinguish the subset of patients at risk of developingmetastasis. Here we analyzed some of them, with emphasis on theexpression of NIS, a determinant of prognosis since the functional integri-ty of the iodine transport is essential to assure an uptake of radioiodinehigh enough to detect and destroy any tumoral thyroid tissue. Morerecent observations on how some relevant molecular genetics aspectsof thyroid cancer impact new potential therapeutic approaches arealso discussed.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.

The impact of gender in differentiated thyroid cancer

A recently published study in Clinical Endocrinology discusses the differences between male and female patients with sporadic differentiated thyroid cancers. On a retrospective analysis of data from 587 papillary and 232 follicular cases, Machens et al. found advanced tumour stages significantly more often in male patients with papillary thyroid carcinomas (PTC). The authors infer that male patients with PTC would have a higher risk of local tumour persistence and recurrence because of frequent lymph node metastases. They conclude that male sex is a significant factor predictive of cancer-specific death and suggest that it would constitute an ominous prognostic marker of advanced thyroid cancer. Unfortunately, Machens et al. do not present follow-up data. In addition, the inclusion of medullary thyroid cancer patients, a type of cancer that is very different from well-differentiated thyroid cancer in terms of aetiology, behaviour and outcome and correspond to an unusually very high percentage of the studied population, considerably weaken these conclusions. Also, the fact that this cross-sectional study includes re-operated patients and that 15·9% of them were not submitted to central lymph node dissection are important confounders impairing the understanding of the impact of gender in the initial extent of the disease and its outcome. In our institution, well-differentiated thyroid cancer patients are submitted routinely to total thyroidectomy with central lymph node compartment dissection and postoperative radioiodine ablation. In a cohort of 172 patients, prospectively followed up for 12– 352 months (mean ± SD, 32 ± 59 months), we also have a large predominance of females: 80% of the sporadic PTC and 89% of the follicular thyroid cancer (FTC) cases. Six patients died during our follow-up. The age of our patients is very similar to that reported by Machens et al. (44 ± 14 and 49 ± 18 years old for PTC and FTC, respectively), and there are no significant differences concerning gender and histopathology. We detected lymph node metastases in 29% of our PTC patients and 9% of the FTC patients by the time of the initial diagnosis with similar distribution in men and women. The female : male ratio was 16 : 4 and 2 : 1 in patients with lymph node metastases of PTC and FTC, respectively (P = 0·9, Fisher exact test). Confirming a previous report, our data suggest that lymph node metastases have little or no influence, either in PTC or in FTC carcinomas, on patients’ prognoses. Disease-free rates were similar on univariate analysis in patients with papillary and with follicular carcinomas, with and without neck node metastases (P = 0·19 and P = 0·08 for PTC and FTC, respectively). Multivariate analysis for disease-free survival and overall survival rates also failed to demonstrate that the presence of initial neck node involvement could influence the outcome of patients’ well-differentiated thyroid carcinoma. However, we recognize that the log rank value for FTC patients with lymph nodes was only marginally nonsignificant (P = 0·0570) and that this group do have more men with lymph nodes metastases. In agreement with Machens et al. we also found sex (P = 0·027), age (P = 0·002), and the presence of distant metastases (P = 0·000) to be important prognostic factors on Cox univariate analysis, while multivariate analysis identified only histology and initial distant metastases to influence mortality. The presence of distant metastases by the time of the diagnosis increased the odds for a lower diseasefree rate: 8·366 times for PTC and 7·373 times for FTC patients. Hence, we believe that the presence of distant metastases may be responsible for men’s worse prognosis. On the other hand, we strongly agree with Machens et al. on the influence of sex on the manifestation of sporadic thyroid cancer. Indeed, examining thyroid glands from 166 consecutive autopsies and 261 thyroids that were surgically resected for benign thyroid diseases, we found 32 papillary microcarcinomas, corresponding to 7·8% of autopsies and 7·2% of surgical material, with a higher incidence between 30 and 49 years of age. Both genders were similarly affected: 9·3% of the men and 8·8% of the women in autopsy series, and 6·2% of the men and 7·3% of the women in surgical series. The disparity between the reported cancer incidence and the male : female ratio in Brazil (0·3% of the men and 1% of the women) suggest that hormonal factors may favour the subsequent development of clinical lesions in women.