Marjory Alana Marcello

Clinical and Pathological Implications of Concurrent Autoimmune Thyroid Disorders and Papillary Thyroid Cancer

Cooccurrences of chronic lymphocytic thyroiditis (CLT) and thyroid cancer (DTC) have been repeatedly reported. Both CLT and DTC, mainly papillary thyroid carcinoma (PTC), share some epidemiological and molecular features. In fact, thyroid lymphocytic inflammatory reaction has been observed in association with PTC at variable frequency, although the precise relationship between the two diseases is still debated. It also remains a matter of debate whether the association with a CLT or even an autoimmune disorder could influence the prognosis of PTC. A better understanding about clinical implications of autoimmunity in concurrent thyroid cancer could raise new insights of thyroid cancer immunotherapy. In addition, elucidating the molecular mechanisms involved in autoimmune disease and concurrent cancer allowed us to identify new therapeutic strategies against thyroid cancer. The objective of this article was to review recent literature on the association of these disorders and its potential significance.

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.

Obesity and thyroid cancer

Many studies have provided observational data on the association of obesity and thyroid cancers, but only few of them propose mechanisms that would permit a better understanding of the causal molecular mechanisms of this association. Considering that there is an increasing incidence of both obesity and thyroid cancers, we need to summarize and link recent studies in order to characterize and understand the contribution of obesity-related factors that might affect thyroid cancer development and progression. Adipose tissue is involved in many vital processes, including insulin sensitivity, angiogenesis, regulation of energy balance, activation of the complement system, and responses such as inflammation. Although these processes have their own molecular pathways, they involve the same molecules through which obesity and adipose tissue might exert their roles in carcinogenesis, not only affecting MAPK and PI3K or even insulin pathways, but also recruiting local inflammatory responses that could result in disease formation and progression. This review describes five important issues that might explain the link between excessive weight and thyroid cancer: thyroid hormones, insulin resistance, adipokines, inflammation, and sexual hormones.

Differentiated thyroid carcinomas may elude the immune system by B7H1 upregulation

B7H1 is consistently associated with inhibition of the immune system in many solid tumors. However, there is no report about its impact on differentiated thyroid carcinoma (DTC) presentation, aggressiveness, or evolution. Aiming to investigate the role of B7H1 in DTC and correlate this protein with other tumor-infiltrating immune cells, we studied 407 thyroid nodule tissue samples including 293 from DTC patients, all managed according to a same standard protocol. In addition, we obtained 5 normal and 114 benign thyroid lesions. Eighteen out of the 253 papillary thyroid carcinomas were paired with respective metastatic lymph node tissues. B7H1 (CD274) protein expression was assessed by immunohistochemistry and the gene expression was quantified by real-time PCR. Malignant tissues displayed a more intense B7H1 staining and higher mRNA levels than benign tissues (both P<0.0001). We observed a positive linear correlation between higher age at diagnosis and B7H1 mRNA levels (P=0.02896). Elevated levels of B7H1 protein were associated with the presence of CD4+, CD8+, CD20+, and FoxP3+ lymphocytes (all P<0.05); tumor-associated macrophages (P<0.0001); and the presence of myeloid-derived suppressor cells (P=0.03256). Stage II-IV patients presented higher B7H1 mRNA levels than stage I cases (P=0.03522). On the contrary, a decreased expression of B7H1 protein was observed in lymph node metastasis (P=0.0152). In conclusion, our data demonstrate that B7H1 expression is associated with features of aggressiveness, suggesting that this is an immune evasion mechanism of DTC cells.

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.

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.

Use of sodium iodide symporter expression in differentiated thyroid carcinomas

Objective  We aimed to investigate the use of NIS mRNA and protein expression as a diagnostic and/or prognostic marker in patients with differentiated thyroid cancer (DTC).

Muc-1 Expression May Help Characterize Thyroid Nodules but Does Not Predict Patients’ Outcome

Our purpose was to evaluate MUC1 clinical utility in the diagnosis and prognosis of thyroid cancer patients. We studied the protein expression of MUC1 in 289 thyroid carcinomas and 121 noncancerous thyroid nodules. There were 41 follicular carcinomas (FC) and 248 papillary thyroid carcinomas (PTC) including 149 classic (CPTC), 20 tall cell (TCPTC) and 79 follicular variants (FVPTC). In addition, we used a quantitative real-time PCR (q-PCR) method to measure MUC1 mRNA expression levels in 108 carcinomas, 23 hyperplasias, and 19 FA. According to their serum Tg levels and other evidences of recurrence/metastasis, the patients were classified as free-of-disease (185 cases) or bad outcome (56 cases, 10 deaths). MUC1 protein was identified in 80.2% PTC; 48.8% FC; 68.3% FVPTC; 70% TCPTC; 21.8% FA; 30% hyperplasias and 6% normal thyroid tissues. MUC1 distinguished benign from malignant thyroid tissues (sensitivity = 89%; specificity = 53%). MUC1 also differentiated FC from FA (p = 0.0083). q-PCR mRNA expression of MUC1 also distinguished malignant from benign nodules (Mann–Whitney test, p < 0.0001). However, neither IHC nor mRNA MUC1 expression was associated with any clinical or pathological feature of aggressiveness or outcome. We suggest that MUC1 expression may help differentiate follicular patterned thyroid lesions.

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.

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.