Factors related to mortality in patients with papillary and follicular thyroid cancer in long-term follow-up.

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.

Both gender and concurrent chronic lymphocytic thyroiditis may influence the nuclear texture of papillary thyroid carcinomas cells.

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.

Investigation of the clinical utility of adhesion molecules in the management of thyroid nodules.

To better understand the relationship among cell adhesion molecules (CAM) and investigate the clinical diagnostic and prognostic application of ICAM-1 (ICAM1), LFA-1 (ITGAL), and L-selectin (SELL) proteins and mRNA corresponding expression in thyroid cancer. Gene expression was evaluated by RT-qPCR, and protein expression was evaluated by immunohistochemistry. We evaluated 275 patients (218 women, 57 men, 48.4 ± 14.5 years old), including 102 benign and 173 malignant nodules. The 143 papillary thyroid carcinoma (PTC) and 30 follicular thyroid carcinoma (FTC) patients were managed according to current guidelines and followed-up for 78.7 ± 54.2 months. Malignant and benign nodules differed concerning mRNA (p = 0.0027) and protein (p = 0.0020 for nuclear) expression of L-selectin and ICAM-1 (mRNA: p = 0.0001 and protein: p = 0.0014) and protein expression of LFA-1 (p = 0.0168), but not mRNA expression of LFA-1 (p = 0.2131). SELL expression was more intense in malignant tumors (p = 0.0027). ICAM1 (p = 0.0064) and ITGAL (p = 0.0244) mRNA expression was higher in tumors with lymphocyte infiltrate. ICAM-1 expression correlated with younger age at diagnosis (p = 0.0312) and smaller tumor size (p = 0.0443). Also, LFA-1 expression correlated with higher age at diagnosis (p = 0.0376) and was more intense at stage III and IV (p = 0.0077). In general, the protein expression of the 3 CAM decreased as the process of cellular dedifferentiation occurred. We suggest that the SELL and ICAM1 genes and L-selectin and LFA-1 protein expression may help confirm malignancy and assist in the histological characterization of follicular patterned lesions, but we were unable to correlate these CAMs with patient outcomes.

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/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.

RORγt may Influence the Microenvironment of Thyroid Cancer Predicting Favorable Prognosis.

We aimed to investigate the role of RORγt (Retinoic acid-related orphan receptor gamma) in the tumor microenvironment of differentiated thyroid carcinoma. We retrospectively analyzed 56 patients (48 papillary and 8 follicular thyroid carcinomas). Immunohistochemical expression of RORγt was compared to other immune markers previously investigated by our group, clinical and pathological information. All patients presented cytoplasmic expression of RORγt in thyroid tumor cells. Seven (12.5%) patients presented no nuclear expression of RORγt. Positivity was few (up to 10%) in 14 patients; 10 to 50% in 5 patients (8.9%); and more than 50% in 30 patients (53.6%). Nuclear RORγt positivity was associated with absence of distant metastasis at diagnosis (p = 0.013) and the need of less cumulative doses of radioactive iodine (p = 0.039). Patients whose tumors were positive for nuclear RORγt presented higher 10-years relapse-free survival rate than those patients who were negative for RORγt (p = 0.023). We classified the patients according to the clustering of immunological immunohistochemical markers. We were able to distinguish a subset (A) of 38 patients who presented high expression of nuclear RORγt and tended to be scarce in proinflammatory immune markers. Other 16 patients integrated a second subset (B) whose tumor microenvironment accumulated proinflammatory markers and presented low expression of nuclear nuclear RORγt. Distant metastasis at diagnosis were more frequent among patients from cluster B than from cluster A (p = 0.008). Our results reinforce that the expression of RORγt together with other immune markers might help predict the prognosis of patients with thyroid cancer and help individualize clinical management.

Low BMI and low TSH value as risk factors related to lower bone mineral density in postmenospausal women under levothyroxine therapy for differentiated thyroid carcinoma.

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.

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.

The null genotype of glutathione s-transferase M1 and T1 locus increases the risk for thyroid cancer.

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.

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 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.

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 percent 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.