Clinical and molecular impact of concurrent thyroid autoimmune disease and thyroid cancer: From the bench to bedside.

The recent incorporation of immune checkpoint inhibitors targeting the PD-1 (programmed cell death receptor 1) and CTLA-4 (cytotoxic T lymphocyte antigen 4) pathways into the therapeutic armamentarium of cancer has increased the need to understand the correlation between the immune system, autoimmunity, and malignant neoplasms. Both autoimmune thyroid diseases and thyroid cancer are common clinical conditions. The molecular pathology of autoimmune thyroid diseases is characterized by the important impact of the PD-1/PD-L1 axis, an important inhibitory pathway involved in the regulation of T-cell responses. Insufficient inhibitory pathways may prone the thyroid tissue to a self-destructive immune response that leads to hypothyroidism. On the other hand, the PD-1/PD-L1 axis and other co-inhibitory pathways are the cornerstones of the immune escape mechanisms in thyroid cancer, which is a mechanism through which the immune response fails to recognize and eradicate thyroid tumor cells. This common mechanism raises the idea that thyroid autoimmunity and thyroid cancer may be opposite sides of the same coin, meaning that both conditions share similar molecular signatures. When associated with thyroid autoimmunity, thyroid cancer may have a less aggressive presentation, even though the molecular explanation of this clinical consequence is unclear. More studies are warranted to elucidate the molecular link between thyroid autoimmune disease and thyroid cancer. The prognostic impact that thyroid autoimmune disease, especially chronic lymphocytic thyroiditis, may exert on thyroid cancer raises important insights that can help physicians to better individualize the management of patients with thyroid cancer.

Investigating population-level immunosenescence: From bench to bedside.

The immune response is remodeled with aging in a process called immunosenescence. Some immunologists conceive immunosenescence as an adaptation of immunity to the aged immune-environment rather than a merely collapsed reactivity of immune cells against microbes and tumor cells. Others believe on an uninterrupted activation of the innate immune system with aging, leading to a low grade, sterile and chronic proinflammatory state called inflammaging. For instance, it is possible that chronic infection by cytomegalovirus leads to persistent production of viral load. This phenomenon offers periodic stimuli to the immune system that ultimately contribute to the remodeling of the immune response. If investigating immunosenescence at the cellular level is already a difficult task, considering the population level is much more complex. However, by studying immunosenescence at the population level, we can extract valuable results with viable applications. While studies with animal models allow scientists to deepen their understanding of the mechanisms of immunosenescence, studying large populations can bring practical innovations to medicine and the health system. Many researchers and funders have dedicated themselves to producing methods for the evaluation of immunosenescence on a large scale, aiming to elucidate new mechanisms by which diseases are established in the elderly. The description of how the immune response is remodeled with aging emerges as a new tool to identify the subset of subjects in which unhealthy aging is a matter of time, to help better individualize clinical management and select patients who may benefit. of early interventions. This review focuses on functional assays as valuable methods for measuring the remodeling of the immune response with aging and discuss their clinical impact. We also recall fundamental concepts for understanding the aging process of the immune response. In addition, we highlight future prospects for immunosenescence research.

Translating the immune microenvironment of thyroid cancer into clinical practice.

Thyroid cancer is an excellent model for studying tumor immune microenvironment, as it often shows local signs of an immune response. The tumor immune microenvironment of thyroid cancer is the heterogeneous histological space in which tumor cells coexist with host cells. The final composition of this cellular aggregate is associated with the clinical aggressiveness characteristics of the neoplasm. High-performance multiplex technologies suggest that specific genetic signatures of the tumor immune microenvironment may provide data for the delineation of a robust prognostic model. Several proposals integrate clinic, pathologic and immunological information in an attempt to translate the knowledge gained from molecular science into a more personalized approach for the treatment strategy of patients with thyroid cancer. In addition, the tumor immune microenvironment displays multiple molecular connections between cells, revealing complex crosstalk. This interesting network generates several molecular nodes that can be used as targets for immunotherapy. In this scenario, immunotherapy emerges as a promising weapon, mainly for patients with advanced thyroid cancer, both medullary and follicular cell-derived. In fact, although most patients with thyroid cancer have an excellent prognosis with current therapies, around 30% of cases evolve in an unfavorable way, leading to the urgent need to improve immunotherapy for high-risk patients. Preclinical and early clinical investigations are providing optimistic prospects, but more studies are needed to make immunotherapy a more viable and efficient tool for years to come.

The impact of the genetic background in a patient with papillary thyroid cancer and familial adenomatous polyposis.

Thyroid cancer is the most common endocrine malignancy, and papillary thyroid carcinoma (PTC) is the main subtype. The cribriform morular variant is a histological phenotype of PTC characterized by its relationship with familial adenomatous polyposis (FAP). Description of the case: We report the genetic assessment of a 20-year-old female patient diagnosed with a cribriform-morular variant of PTC and FAP. We aimed to assess the genetic background of the reported patient, looking for variants that would help us explain the predisposition to tumorigenesis. Genomic DNA was extracted from peripheral blood lymphocytes, and whole exome sequencing was performed. We applied an overrepresentation and gene-set enrichment analysis to look for an accumulation of effects of variants in multiple genes at the genome. We found an overrepresentation of single nucleotide variants (SNVs) in extracellular matrix interactions and cell adhesion genes. Underrepresentation of SNVs in genes related to the regulation of autophagy and cell cycle control was also observed. We hypothesize that the package of alterations of our patient may help to explain why she presented colonic manifestations and thyroid cancer. Our findings suggest that multiple variants with minor impact, when considered together, may be helpful to characterize one particular clinical condition.

The impact of the genetic background in a patient with papillary thyroid cancer and familial adenomatous polyposis

SUMMARY Thyroid cancer is the most common endocrine malignancy, and papillary thyroid carcinoma (PTC) is the main subtype. The cribriform morular variant is a histological phenotype of PTC characterized by its relationship with familial adenomatous polyposis (FAP). Description of the case: We report the genetic assessment of a 20-year-old female patient diagnosed with a cribriform-morular variant of PTC and FAP. We aimed to assess the genetic background of the reported patient, looking for variants that would help us explain the predisposition to tumorigenesis. Genomic DNA was extracted from peripheral blood lymphocytes, and whole exome sequencing was performed. We applied an overrepresentation and gene-set enrichment analysis to look for an accumulation of effects of variants in multiple genes at the genome. We found an overrepresentation of single nucleotide variants (SNVs) in extracellular matrix interactions and cell adhesion genes. Underrepresentation of SNVs in genes related to the regulation of autophagy and cell cycle control was also observed. We hypothesize that the package of alterations of our patient may help to explain why she presented colonic manifestations and thyroid cancer. Our findings suggest that multiple variants with minor impact, when considered together, may be helpful to characterize one particular clinical condition.

The immune landscape of the microenvironment of thyroid cancer is closely related to differentiation status.

We have read with great interest the article entitled "Identification of an immune-related signature indicating the dedifferentiation of thyroid cells" by Wang et al. Their data reinforce our own previous results, here compiled. Anaplastic thyroid carcinoma had higher stromal scores, immune scores and enrichment of most immune cells than the control groups, suggesting that the immune microenvironment may correlate with differentiation status in thyroid cancer. We previously demonstrated that the differentiation status expressed by the pattern of protein expression may be related to the profile of immune cell infiltration of differentiated thyroid carcinoma. Wang et al. also explored the differences between the high-risk and low-risk score groups of samples. Among the distinct signaling pathways enriched in the high-risk score group, the epithelial to mesenchymal transition, TNFα signaling, and some common immune-related signaling pathways, including the IL-6/JAK/STAT3 pathway, interferon alpha response, interferon gamma response and inflammatory response were observed with high normalized enrichment score. We also investigated the IL-6 protein immune-histochemical expression in a retrospective study of 114 patients with papillary thyroid carcinoma and 39 patients with follicular thyroid carcinoma. We also obtained samples of 14 normal thyroid tissues from autopsies, 50 goiters and 43 follicular adenoma. We found IL-6 more frequently positive among malignant tumors than non-malignant samples. We demonstrated that IL-6 positivity was associated with infiltration of CD3 + cells, CD16 + cells and CD68 + macrophages. In addition, IL-6 expression was associated with infiltration of activated lymphocytes such as Granzyme B + cells and CD69 + cells. IL-6 positivity was not associated with infiltration of CD4+, CD8+, CD20+, FOXP3+, CD25 + cells but IL-6 was associated with tumor expression of PD-L1, FOXP3, IL-17, COX2, IL-1ß, IL-10, CD134, IL-23. In summary, Wang et al. beautiful data reinforce the seminal idea that the immune landscape is closely related to the differentiation status of the tumor. This concept may help select individuals who deserve more careful attention, an essential point in the management of patients with mostly indolent tumors such as those of the thyroid. In fact, our results, here compiled, were obtained with immune-histochemistry, a routine laboratory technique that offers the possibility of simpler and practical execution.

Body Mass Index and Prognosis of COVID-19 Infection. A Systematic Review.

A better understanding of the SARS-CoV-2 virus behavior and possible risk factors implicated in poor outcome has become an urgent need. We performed a systematic review in order to investigate a possible association between body weight and prognosis among patients diagnosed with COVID-19. We searched in Cochrane Library, EMBASE, MEDLINE, WHO-Global Literature on Coronavirus Disease, OpenGrey, and Medrxiv. We used the ROBINS-I tool or Cross-Sectional/Prevalence Study Quality tool from AHRQ, to evaluate the methodological quality of included studies. Nine studies (two prospective cohorts, four retrospective cohorts and three cross-sectional) were included and assessed the relationship between obesity and COVID-19 prognosis. Risk of bias of the included studies ranged from moderate to critical. Clinical and methodological heterogeneity among them precluded meta-analyses. Most of the included studies showed some degree of association to: (a) higher BMI and worse clinical presentation and (b) obesity and need of hospitalization. The results were inconsistent about the impact of obesity on mortality. Based on limited methodological quality studies, obesity seems to predict poor clinical evolution in patients with COVID-19. Further studies with appropriate prospective design are needed to reduce the uncertainty on this evidence.

Remodeling of the Immune Response With Aging: Immunosenescence and Its Potential Impact on COVID-19 Immune Response.

Elderly individuals are the most susceptible to an aggressive form of coronavirus disease (COVID-19), caused by SARS-CoV-2. The remodeling of immune response that is observed among the elderly could explain, at least in part, the age gradient in lethality of COVID-19. In this review, we will discuss the phenomenon of immunosenescence, which entails changes that occur in both innate and adaptive immunity with aging. Furthermore, we will discuss inflamm-aging, a low-grade inflammatory state triggered by continuous antigenic stimulation, which may ultimately increase all-cause mortality. In general, the elderly are less capable of responding to neo-antigens, because of lower naïve T cell frequency. Furthermore, they have an expansion of memory T cells with a shrinkage of the T cell diversity repertoire. When infected by SARS-CoV-2, young people present with a milder disease as they frequently clear the virus through an efficient adaptive immune response. Indeed, antibody-secreting cells and follicular helper T cells are thought to be effectively activated in young patients that present a favorable prognosis. In contrast, the elderly are more prone to an uncontrolled activation of innate immune response that leads to cytokine release syndrome and tissue damage. The failure to trigger an effective adaptive immune response in combination with a higher pro-inflammatory tonus may explain why the elderly do not appropriately control viral replication and the potential clinical consequences triggered by a cytokine storm, endothelial injury, and disseminated organ injury. Enhancing the efficacy of the adaptive immune response may be an important issue both for infection resolution as well as for the appropriate generation of immunity upon vaccination, while inhibiting inflamm-aging will likely emerge as a potential complementary therapeutic approach in the management of patients with severe COVID-19.

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.

Expression of the NEK family in normal and cancer tissue: an immunohistochemical study.

BACKGROUND: The NEK serine/threonine protein kinases are involved in cell cycle checkpoints, DNA damage repair, and apoptosis. Alterations in these pathways are frequently associated with cell malignant cellular transformations. Thyroid cancer is the most common malignant tumour in the endocrine system. Despite good treatment methods, the number of cases has increased significantly in recent years. Here, we studied the expression of NEK1, NEK2, NEK3, and NEK5 in different types of normal and malignant tissues, using tissue microarray analysis, and identified NEKs as potential markers in thyroid malignancy. METHODS: The studied cases comprised multiple cancer tissue microarrays, including breast, colon, esophagus, kidney, lung, pancreas, prostate, stomach, thyroid and uterine cervix, as well as 281 patients who underwent thyroid resection for thyroid cancer or thyroid nodules. The expression of NEK1, NEK2, NEK3, and NEK5 was analyzed by immunohistochemistry. The expression pattern was evaluated in terms of intensity by two methods, semiquantitative and quantitative, and was compared between normal and cancer tissue. RESULTS: We analysed the expression of each member of the NEK family in a tissue-dependent manner. Compared to normal tissue, most of the evaluated proteins showed lower expression in lung tumour. However, in the thyroid, the expression was higher in malignant tissue, especially for NEK 1, NEK3 and NEK5. Concerning characteristics of the thyroid tumour, such as aggressiveness, NEK1 expression was higher in tumours with multifocality and in patients with lymph node metastasis. NEK3 expression was stronger in patients with stage II, that involved metastasis. NEK5, on the other hand, showed high expression in patients with invasion and metastasis and in patients with tumour size > 4 cm. Furthermore, this work, demonstrated for the first time a high specificity and sensitivity of over-expression of NEK1 in classical and follicular variants of papillary thyroid cancer and NEK3 in tall-cell papillary thyroid cancer. CONCLUSION: Taken together, the NEK protein kinases emerge as important proteins in thyroid cancer development and may help to identify malignancy and aggressiveness features during diagnosis. TRIAL REGISTRATION: This study was retrospectively registered.  www.accamargo.org.br/cientistas-pesquisadores/comite-de-etica-em-pequisa-cep.

Immunotherapy against endocrine malignancies: immune checkpoint inhibitors lead the way.

Immune checkpoint inhibitors are agents that act by inhibiting the mechanisms of immune escape displayed by various cancers. The success of immune checkpoint inhibitors against several tumors has promoted a new treatment strategy in clinical oncology, and this has encouraged physicians to increase the number of patients who receive the immune checkpoint therapy. In the present article, we review the main concepts regarding immune checkpoint mechanisms and how cancer disrupts them to undergo immune escape. In addition, we describe the most essential concepts related to immune checkpoint inhibitors. We critically review the literature on preclinical and clinical studies of the immune checkpoint inhibitors as a treatment option for thyroid cancer, ovarian carcinoma, pancreatic adenocarcinoma, adrenocortical carcinoma and neuroendocrine tumors. We present the challenges and the opportunities of using immune checkpoint inhibitors against these endocrine malignancies, highlighting the breakthroughs and pitfalls that have recently emerged.

Immune Escape Mechanism is Impaired in the Microenvironment of Thyroid Lymph Node Metastasis.

We previously identified the infiltration of CD8+ lymphocytes and COX2 expression as an independent factor of risk for recurrence in papillary thyroid carcinoma (PTC) patients. However, the presence of lymph node (LN) metastasis at diagnosis lost its significance in a multivariate model analysis. These results encouraged us to compare the immune cells arrangement in the microenvironment of the LN metastasis and the primary tumor. We studied 104 consecutive PTC patients. Tissue specimens of both primary tumor and LN metastasis at the time of diagnosis were available in 19 out of them. These 19 patients were followed up for 32 to 81 months (64.7 ± 47.5 months). Immune cell markers were investigated using immunohistochemistry and included tumor infiltrating lymphocytes subsets such as CD3, CD4, CD8, CD16, CD20, CD45RO, GRANZYME B, CD69, and CD25. We also investigated the expression of COX2 in tumor cells. Paired t test showed an increase of GRANZYME-B+ lymphocytes density in LN metastasis compared to the corresponding primary tumor, suggesting that LN metastasis is enriched with activated immune cells. In addition, we observed a decrease in COX2 expression levels in LN metastasis compared to the corresponding primary tumors, reinforcing the idea that the immune escape mechanism is impaired in the microenvironment of thyroid LN metastasis. In conclusion, our data demonstrated that the microenvironment of PTC LN metastasis present features that favor an anti-tumor immune response. This may help to explain why the presence of LN metastasis at diagnosis is not a good predictor of PTC patients' survival or disease progression.

Interleukin 10 expression is related to aggressiveness and poor prognosis of patients with thyroid cancer.

Most patients with thyroid cancer will evolve very well with current therapies. However, 10-30% of these patients will present recurrent disease and some of them will eventually die. IL-10 is an anti-inflammatory and immunosuppressive cytokine that can contribute to the immune escape of neoplastic cells. We aimed to investigate IL-10 as a molecular marker to improve the clinical management of patients with thyroid cancer. We retrospectively studied 162 patients with follicular cell-derived thyroid cancer who attended to our institution, including 63 classic papillary thyroid carcinomas, 46 follicular variant of papillary thyroid carcinomas, 11 poorly differentiated thyroid carcinomas and 42 follicular thyroid carcinomas. Patients were treated according to current guidelines and followed-up for 1-150 months. Additionally, we studied 96 samples of non-malignant tissues. We investigated the expression of IL-10 in tumor cells by semiquantitative and quantitative methods. Malignant tissues presented higher positivity (0.773 ± 0.140) than non-malignant samples (0.623 ± 0.190; p < 0.001). Tumors with extrathyroidal invasion at diagnosis presented higher levels of positivity for IL-10 (0.802 ± 0.125) than tumors without extrathyroidal invasion (0.731 ± 0.147; p = 0.004). We observed a positive correlation between tumor size and IL-10 positivity (correlation coefficient = 0.407; p < 0.001). Patients with IL-10 positivity above the median presented lower relapse-free survival rate compared to those patients whose tumors presented IL-10 positivity below the median. We suggest that a simple IL-10 IHC analysis could help selecting patients who would benefit from a more intensive approach.

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.

CD8+ tumour-infiltrating lymphocytes and COX2 expression may predict relapse in differentiated thyroid cancer.

BACKGROUND/OBJECTIVE: 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. DESIGN: Retrospective cohort study. PATIENTS: We studied 399 consecutive patients, including 325 papillary and 74 follicular thyroid carcinomas. MEASUREMENTS: 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. RESULTS: 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. CONCLUSION: 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.

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.

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.

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.

CD8+ TIL recruitment may revert the association of MAGE A3 with aggressive features in thyroid tumors.

BACKGROUND: We aimed to investigate a possible role of MAGE A3 and its associations with infiltrated immune cells in thyroid malignancy, analyzing their utility as a diagnostic and prognostic marker. MATERIALS AND METHODS: We studied 195 malignant tissues: 154 PTCs and 41 FTCs; 102 benign tissues: 51 follicular adenomas and 51 goiter and 17 normal thyroid tissues. MAGE A3 and immune cell markers (CD4 and CD8) were evaluated using immunohistochemistry and compared with clinical pathological features. RESULTS: The semiquantitative analysis and ACIS III analysis showed similar results. MAGE A3 was expressed in more malignant than in benign lesions (P < 0.0001), also helping to discriminate follicular-patterned lesions. It was also higher in tumors in which there was extrathyroidal invasion (P = 0.0206) and in patients with stage II disease (P = 0.0107). MAGE A3+ tumors were more likely to present CD8+ TIL (P = 0.0346), and these tumors were associated with less aggressive features, that is, extrathyroidal invasion and small size. There was a trend of MAGE A3+ CD8+ tumors to evolve free of disease. CONCLUSION: We demonstrated that MAGE A3 and CD8+ TIL infiltration may play an important role in malignant thyroid nodules, presenting an interesting perspective for new researches on DTC immunotherapy.