Materiały źródłowe

• #1 Thyroid Nodule – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK535422/

  Thyroid nodules are more common in the general population than most patients believe. Up to 60% of adults will have at least one thyroid nodule, whether incidentally noted or obviously palpated. […] This activity reviews the types of thyroid nodules, their background pathophysiology, risk factors in the development of malignancy, appropriate imaging modalities, and candidacy for biopsy. […] A broad spectrum of disorders is associated with nodules of the thyroid, from benign to malignant conditions that may have indolent or very aggressive clinical courses. […] Ionizing radiation is a known risk factor for both benign and malignant nodules of the thyroid. […] The association between thyroid irradiation and tumorigenesis is well-known. Radiation may cause a wide range of somatic mutations that increase the risk of cancer, particularly in radiation-sensitive organs such as the thyroid.

• #2 Thyroid nodule pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Thyroid_nodule_pathophysiology

  Thyroid nodules may arise from different cells in thyroid parenchyma. The pathogenesis of developing a thyroid nodule may differ based on the type of the nodule, and whether it is malignant or benign. […] Basically thyroid nodules may develop secondary to hyperplasia, mutations and resultant carcinoma, excess colloid accumulation, or from inflammation of thyroid tissue.

• #3 Pathogenesis of thyroid nodules: histological classification? – PubMed

  https://pubmed.ncbi.nlm.nih.gov/11237284/

  Thyroid nodule genesis may be considered as an amplification of thyroid heterogeneity due to genetic and/or epigenetic mechanisms. […] We classified the thyroid nodules in five types with distinct histological features: hyperplastic, neoplastic, colloid, cystic and thyroiditic nodules. […] Hyperplastic: Thyrocyte proliferation is under the control of TSH but several other paracrine and autocrine factors are secreted by follicular cells, the stromal apparatus and the lymphocytes, which are implicated in initiation and perpetuation of thyroid hyperplasia. Growth occurs mainly through TSHR, cAMP and PKA. Constitutive cAMP overproduction has been shown to be due to point mutation of the TSHR or Gs protein, producing overgrowth and hyperfunction. […] Neoplastic: Several activated oncogenes have been identified in thyroid malignancies. Oncogenes relevant to the thyroid carcinogenesis are: mutated TSHR and gsp (constitutive activation of cAMP); TRK (receptor for NGF); RET/PTC (phosphorylation of tyrosine kinase receptor)–an isoform of this oncogene is induced by radiation: ras (it encodes Gs proteins transducing mitogenic signals); and c-MET (receptor for hepatocyte growth factor). The evolution of a differentiated thyroid cancer towards an undifferentiated cancer is due to a mutation of a family of proteins (i.e., p53), which acts as a brake, preventing the genomic instability of cancer. It is suggested that a tumor initiates by RET or ras and possibly progresses–as a result of additional mutations and by p53 mutation–to anaplastic carcinoma.

• #4 Pathogenesis of thyroid nodules: histological classification? – PubMed

  https://pubmed.ncbi.nlm.nih.gov/11237284/

  Colloid: Flattening of the epithelium and dilatation of follicles containing viscous material–made up by a concentrated solution of thyroglobulin (hTg)–is the characteristic of the colloid nodule. A defect of intraluminal reabsorption of hTg has been suggested but not proven. […] Cystic: It is estimated that between 15 and 40% of thyroid nodules are partly or entirely cystic. The 'true cyst’ is rare; most of the so-called cystic nodules are 'pseudocysts’, which follow necrosis and colliquation. Necrosis issues as an imbalance between growth and the precisely regulated process of angiogenesis. More recently, the VEGF/VPF has been found to be at the origin of recent and recurrent cysts. Immunotoxic and apoptotic mechanisms have also been suggested. […] Thyroiditic: Nodular lymphocytic thyroiditis (NLT) includes two different entities: 1) lymphocyte thyroiditis growing as a nodule in a hyperplastic or normal gland, and 2) lymphocyte thyroiditis associated in the same nodule with other nodular diseases of the thyroid: papillary thyroid carcinoma and lymphoma have been found to be associated to chronic lymphocytic thyroiditis.

• #5 Thyroid nodule pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Thyroid_nodule_pathophysiology

  Thyroid nodules may arise from different cells in the thyroid parenchyma. The pathogenesis of developing a thyroid nodule may differ based on the type of the nodule, and whether it is malignant or benign. Basically thyroid nodules may develop secondary to hyperplasia, mutations and resultant carcinoma, excess colloid accumulation, or from inflammation of thyroid tissue. Genetic mutation is considered as one of the most important mechanisms of developing thyroid nodules, especially neoplastic thyroid nodules. Most of these mutations occur as somatic mutations, while some may exhibit familial inheritance. The most important variety of familial thyroid cancers are caused by genetic mutations, and are called familial non-medullary thyroid cancer (FNMTC). Other important genes related to thyroid nodule formation include, NH ras, RET, Gsp, C-MET, TRK, EGF / EGF-R, and P53.

• #6 Thyroid nodule pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Thyroid_nodule_pathophysiology

  Thyroid nodules may arise from different cells in thyroid parenchyma. The pathogenesis of developing a thyroid nodule may differ based on the type of the nodule, and whether it is malignant or benign. […] Basically thyroid nodules may develop secondary to hyperplasia, mutations and resultant carcinoma, excess colloid accumulation, or from inflammation of thyroid tissue.

• #7 A Review of the Pathogenesis and Management of Multinodular Goiter | IntechOpen

  https://www.intechopen.com/chapters/46424

  The pathogenesis of MNG encompasses processes of diffuse follicular hyperplasia, focal nodular proliferation and eventual acquisition of functional automaticity. The development of MNG is a result of long-term exposure of the thyroid gland to proliferative stimuli, such as iodine deficiency, goitrogens and inborn error of thyroid hormone synthesis. All of the above results in insufficient thyroid hormone production and stimulate pituitary secretion of thyroid stimulating hormone (TSH). […] TSH is a glycoprotein with stimulatory effect on the trophic and iodine metabolism pathway in the thyroid follicular cells. TSH binding to the cell membrane G protein-coupled receptor activates the cAMP and phospholipase C signalling pathways, which in turn upregulates the process of iodine uptake and organification, thyroglobulin synthesis, iodotyrosine coupling and iodothyronine (T3, T4) secretion, leading to a short-term response in thyroid hormone production.

• #8 A Review of the Pathogenesis and Management of Multinodular Goiter | IntechOpen

  https://www.intechopen.com/chapters/46424

  Nodule formation is postulated to be the result of both an inherent and acquired heterogeneity in proliferative and functional upregulation of the follicular cells. The thyroid follicular cells are inherently heterogeneous with regard to thyroid hormone production and proliferation in response to TSH stimulation, such that under intermediate level of stimulation, a subpopulation of follicular cells outgrows other cells and expand into macroscopic nodules. […] On the other hand, follicular cells acquiring activating somatic mutations in the cell proliferation pathways can expand clonally to form a nodule. About 60 70% of nodules form by the later mechanism and are monoclonal in origin. Somatic mutations leading to constitutive activation of TSH receptors are found in about 60% of autonomously functioning nodules. The remaining 40% of functioning nodules are TSH receptor mutation negative with poorly understood genetic mechanism behind.

• #9 A Note on Thyroid Nodule Heterogeneity

  https://www.longdom.org/open-access/a-note-on-thyroid-nodule-heterogeneity-87330.html

  Thyroid nodule beginning might be considered as an intensification of thyroid heterogeneity due to hereditary or potentially epigenetic instruments. […] Development happens basically through TSHR, cAMP and Protein Kinase A (PKA). Constitutive cAMP overproduction has been demonstrated to be because of point transformation of the TSHR or Gs protein, creating excess and hyper function. […] Several oncogenes have been distinguished in thyroid malignancies. Zmieniony Thyroid Stimulating Hormone Receptor (TSHR) constitutive actuation of Cyclic Adenosine Mono Phosphate (cAMP)); Tyrosine Kinases (TrK) (receptor for Nerve Growth Factor (NGF)); Rearranged during transfection/ phosphorylation of tyrosine kinase receptor an is in the form of this oncogene is instigated by radiation (it encodes Gs proteins transducing mito genic signs); and Mesenchymal Epithelial Transition Factor (c-MET) (receptor for hepatocyte development factor) these are applicable to oncogenes for thyroid carcinogenesis. The development of a separated thyroid malignancy towards an undifferentiated disease is because of a transformation of a group of proteins (i.e., p53), which goes about as a brake, forestalling the genomic flimsiness of disease. It is proposed that a growth starts by Rearranged during transfection perhaps advances because of extra changes and by p53 transformation to anaplastic carcinoma.

• #10 Thyroid Nodule | SpringerLink

  https://link.springer.com/10.1007/978-3-319-29195-6_6-1

  Benign thyroid nodules are highly prevalent in iodine-deficient areas. […] Hot thyroid nodules (autonomously functioning thyroid nodules, AFTNs) are mainly due to mutations which confer a constitutive activation of the cAMP cascade (e.g., TSHR and Gs mutations) which results in a stimulation of growth and function. […] In contrast, the molecular etiology of cold thyroid nodules (CTNs) is still largely unknown. […] Gene expression analysis reveals evidence for increased expression of cell cycle-associated genes and Gq-protein-protein kinase C signaling in cold thyroid nodules. […] Krohn K, Paschke R. Mechanisms of disease: hydrogen peroxide, DNA damage and mutagenesis in the development of thyroid tumors. Nat Clin Pract Endocrinol Metab. 2007;3(10):71320.

• #11 Autonomously Functioning Thyroid Nodules and Other Causes of Thyrotoxicosis | Clinical Gate

  https://clinicalgate.com/autonomously-functioning-thyroid-nodules-and-other-causes-of-thyrotoxicosis/

  Autonomously Functioning Thyroid Nodules (AFTNs) are defined as (mostly) single nodules present in the thyroid gland that produce and secrete thyroid hormone independent of stimulation by TSH. […] From a histologic point of view, two types of nodules may be discerned: a monoclonal and a polyclonal type. […] At the genetic level, two types of monoclonal autonomously functioning nodules have been reported. […] Both mutations lead to constitutive activation of the adenylate cyclase system, probably also activation of the inositol phosphates pathways in the follicular cell, and to autonomy of the follicle. […] Mutations of the TSHR gene, and with a much lower prevalence, the Gs gene, play a major (principal) role in the pathogenesis of AFTN. […] Although some believe that iodine deficiency can increase mutation rate and functional expression of autonomy in AFTN, others consider the fundamental process of goitrogenesis in (multi)nodular goiter as independent from iodine deficiency but operating through mechanisms that are innate to the hereditary and acquired heterogeneity among the thyrocytes themselves. […] An important study by Fuhrer and co-workers showed that a panel of different activating TSHR mutations caused different functional and morphologic responses in vitro in rat and human primary thyrocytes. […] Finally, other mutated genes causing AFTN may be located in the AMP cascade.

• #12 Genetic molecular testing of thyroid nodules – Yaniv – Annals of Thyroid

  https://aot.amegroups.org/article/view/7350/html

  Genomic studies of thyroid cancer have revealed two signaling pathways that play a crucial role in thyroid growth and proliferation. These pathways are the mitogen-activating protein kinase (MAPK) pathway and the Phosphatidylinositol-3-kinase (PI3K)/AKT pathway. Mutations in kinases and transcription factors involved in these pathways initiate the development and progression of thyroid cancer. When these key targets in the respective pathway undergo mutations or genetic rearrangements, they become constitutively active, leading to the translocation of transcription factors into the nucleus. This translocation results in the upregulation of genes that promote tumorigenesis and cancer progression. Mutations in key regulators of the MAPK pathway are present in approximately 70% of all papillary thyroid carcinoma (PTC) cases.

• #13 Genetic molecular testing of thyroid nodules – Yaniv – Annals of Thyroid

  https://aot.amegroups.org/article/view/7350/html

  One notable mutation is the BRAFV600E mutant protein, which was first described in thyroid cancer by Cohen et al. This mutation leads to the activation of the BRAF kinase independently of its upstream target, RAS. The BRAFV600E kinase domain is approximately 500 times more active than the wild type BRAF kinase. This mutation is considered one of the fundamental initiating events in the development and progression of PTC. Additionally, the BRAFV600E mutation inhibits proapoptotic genes, further contributing to the survival and proliferation of cancer cells. A meta-analysis of 18 studies, encompassing 2,766 thyroid FNA samples, demonstrated that among the 581 cases that tested positive for the BRAF mutation, 580 were diagnosed as papillary thyroid cancers. Therefore, the presence of a BRAF V600E mutation in a thyroid nodule is highly indicative of the presence of papillary thyroid cancer.

• #14 Genetic molecular testing of thyroid nodules – Yaniv – Annals of Thyroid

  https://aot.amegroups.org/article/view/7350/html

  The PI3K/AKT signaling pathway plays a vital role in regulating various cellular processes, including apoptosis, proliferation, cell cycle progression, angiogenesis, cytoskeleton integrity, and energy metabolism. Within this pathway, one of the frequently mutated targets is RAS, which acts as an upstream kinase of BRAF kinase. Mutations in RAS result in its continuous activation in a GTP-bound state. Among the three isoforms of RAS (NRAS, HRAS, and KRAS), NRAS is the most commonly mutated in human thyroid cancer. […] RAS mutations are considered premalignant mutations, meaning that additional mutations are required to initiate the development of cancer. In a recent meta-analysis, the specificity (the ability to accurately identify absence of disease) and positive predictive value (PPV) (the likelihood of correctly identifying the presence of disease) of RAS mutations were found to have average values of 23% and 82%, respectively. This suggests that while RAS mutations can provide useful diagnostic information, they are not highly specific indicators of thyroid cancer on their own.

• #15 Genetic molecular testing of thyroid nodules – Yaniv – Annals of Thyroid

  https://aot.amegroups.org/article/view/7350/html

  In another study, differences in outcomes were observed when comparing RAS mutation subtypes. The probability of a malignant outcome followed a specific order among the mutation subtypes: KRAS (100%), NRAS (74%), and HRAS (56%). It is important to note that this study specifically focused on follicular adenoma and carcinoma cases, limiting its generalizability to other types of thyroid cancer. […] In addition to mutations, constitutive activation of both the MAPK and PI3K-AKT pathways can also result from gene translocations. One of the most common types of translocations observed in thyroid cancer is called RET/PTC, which was initially described in PTC by Fusco et al. These translocations involving the RET gene have shown average values of specificity (18%) and PPV (87%). It is worth noting that these RET/PTC translocations are now commonly referred to as RET fusions.

• #16 Genetic molecular testing of thyroid nodules – Yaniv – Annals of Thyroid

  https://aot.amegroups.org/article/view/7350/html

  The PAX8/peroxisome proliferator-activated receptor- (PPAR) rearrangement is a result of a translocation known as (2;3)(q13;p25), which leads to the fusion of the PAX8 gene and the PPAR gene. This specific translocation is observed in approximately 30-60% of follicular thyroid cancer (FTC) cases and in 38% of the follicular variant of papillary thyroid cancer (FVPTC) cases. […] Although the aforementioned mutations and other mutations have been extensively studied, and some mutations and fusions are pathognomonic for malignancy in an indeterminate thyroid nodule (e.g., BRAF V600E mutation, RET fusion), none of these mutations can stand alone as a diagnostic test for cancer. […] Indeed, considering multiple factors is crucial in the evaluation and diagnosis of thyroid nodules. While genetic mutations, such as RAS mutations, are present in a significant proportion of FTC and papillary thyroid carcinoma cases, their specificity for malignancy is limited. RAS mutations are observed in approximately 40-50% of FTC cases and 10-20% of PTC cases. However, it is important to note that RAS mutations are not specific indicators of malignancy, as they can also be found in 20-40% of follicular adenomas and are the predominant mutations in noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP).

• #17 Genetic molecular testing of thyroid nodules – Yaniv – Annals of Thyroid

  https://aot.amegroups.org/article/view/7350/html

  The presence of RAS mutations alone cannot be relied upon as a definitive diagnostic marker for malignancy. The recent shift in the classification of NIFTP and the recalibration of the risk of malignancy in RAS FNA nodules further highlights the complexity of interpreting these mutations in relation to the true incidence of carcinomas, malignancies, adenomas, and NIFTP cases. […] Therefore, it is essential to integrate genetic mutation analysis with other diagnostic criteria, including clinical history, physical examination, radiographic assessment, and cytological evaluation, to accurately assess the risk of malignancy in thyroid nodules. The combination of these factors allows for a comprehensive evaluation and diagnosis of thyroid nodules. […] RET fusions (RET/PTC translocations) are detected in approximately 10% of patients with PTC. In a retrospective study, the presence of RET/PTC fusions in indeterminate thyroid nodules was associated with malignancy in 60% of cases, with no false positives. RET fusions are generally considered pathognomonic for malignancy in indeterminate thyroid nodules. Similarly, other fusions such as NTRK fusions found in indeterminate thyroid nodules are also typically indicative of malignancy. NTRK fusions can be observed in around 23% of sporadic PTC cases. Like RET fusions, NTRK fusions are a recombination of parts of NTRK genes with parts of any of a large number of genes leading to activation of RAS and the MAPK and PI3K/AKT pathways. All types of NTRK fusions seem to be associated with a 100% probability of malignancy, since they have not been found in benign nodules in large histopathological series.

• #18 Colloid Nodular Goiter – Endocrine Surgery | UCLA Health

  https://www.uclahealth.org/medical-services/surgery/endocrine-surgery/patient-resources/patient-education/endocrine-surgery-encyclopedia/colloid-nodular-goiter

  Colloid nodular goiter occurs when the thyroid gland is unable to meet the metabolic demands of the body with sufficient hormone production. The thyroid gland compensates by enlarging, which usually overcomes mild deficiencies of thyroid hormone. […] If the thyroid gland is then re-exposed to iodine, the nodules may produce thyroid hormone independently. Occasionally, the nodules may produce too much thyroid hormone, causing thyrotoxicosis. This is called a toxic nodular goiter. […] Colloid nodular goiters are also known as endemic goiters and are usually caused by inadequate iodine in diet. They tend to occur in certain geographical areas with iodine-depleted soil, usually areas away from the sea coast. An area is defined as endemic for goiter if more than 10 % of children aged 6 to 12 years have goiters. […] A simple goiter may progress to a toxic nodular goiter. […] Thyrotoxicosis may occur spontaneously with iodine re-exposure.

• #19 A Review of the Pathology, Diagnosis and Management of Colloid Goitre – touchENDOCRINOLOGY

  https://touchendocrinology.com/thyroid/journal-articles/a-review-of-the-pathology-diagnosis-and-management-of-colloid-goitre/

  There are many mechanisms and aetiologies that cause colloid goitre. A number of possible factors leading to colloidal goitre include foods that block the hormonal synthesis, mutations in thyroid-stimulating hormone (TSH) receptors, globulin stimulation of thyroid development, growth hormone, insulin-like growth factor 1 (IGF-1) and genetic factors. An iodine-deficient diet is also known to lead to colloid nodular goitres. The most important factor of colloid goitre appearance is a reduction in TSH stimulation for a prolonged period of time. Pathologically, these are often known as hyperplastic and colloid nodules, sometimes they may also be described as adenomatous. In cases of diffuse goitre, there will be follicular cell hyperplasia. In chronic settings with continued TSH stimulation, some follicles become autonomous and secrete hormones that will depress other areas, which then involute. This leads to multinodular goitre with areas of focal hyperplasia and areas of involution and fibrosis. The thyroid gland stores the thyroid hormone in an acellular glycoprotein called colloid. Histologically, the initial stage of colloid goitre is cellular hyperplasia of the thyroid acini, followed by a micronodular and macronodular formation, which is often indistinguishable from normal thyroid parenchyma, even on histological examination. Hyperplastic nodules are often subject to liquefying degeneration, accumulating blood, serous fluids and colloidal substances.

• #20 :: KJR :: Korean Journal of Radiology

  https://www.kjronline.org/DOIx.php?id=10.3348/kjr.2018.0599

  Degenerating nodules (DNs), which primarily manifest as benign thyroid nodules, are one of the main causes of discordance in ultrasonography (US) and cytological assessments. Intranodular hemorrhage is one of the mechanisms contributing to discordant nodules, and an impaired blood supply may explain further DN shrinkage and infarction. […] In solid nodules, iatrogenic injury by FNA/CNB can cause venous thrombosis and/or internal bleeding, which are mechanisms that potentially lead to nodule degeneration. Intranodular hemorrhage (spontaneous or FNA-induced hemorrhage) compressing peripheral nodule tissues is believed to be one of the initial mechanisms of DN development. Hemorrhage usually occurs in thyroid nodules and may be associated with their rich blood supply. The prevalence of hemorrhage within thyroid nodules after biopsy is reportedly between 26.5% and 93.3%, whereas even in patients who do not undergo FNA, the hemorrhage rate is still as high as 33.3%. An impaired blood supply due to venous thrombosis and hematoma regression may explain the further shrinkage and infarction that occurs later in the degradation process.

• #21 Thyroid Nodules | American Thyroid Association

  https://www.thyroid.org/thyroid-nodules/

  We do not know what causes most thyroid nodules but they are extremely common. […] Hashimotos thyroiditis, which is the most common cause of hypothyroidism, is associated with an increased risk of thyroid nodules. […] Iodine deficiency, which is very uncommon in the United States, is also known to cause thyroid nodules.

• #22 Thyroid Nodules and Obesity

  https://www.mdpi.com/2075-1729/13/6/1292

  A widely discussed topic in the pathophysiology of thyroid nodules is the role of obesity, a state that leads to increased systemic inflammatory markers. Leptin plays a vital role in forming thyroid nodules and cancer through several mechanisms. […] Together with chronic inflammation, there is an augmentation in the secretion of tumor necrosis factor (TNF) and the cytokine interleukin 6 (IL-6), which contributed to cancer development, progression and metastasis. In addition, leptin exerts a modulatory action in the growth, proliferation and invasion of thyroid carcinoma cell lines via activating various signal pathways, such as Janus kinase/signal transducer and activator of transcription, mitogen-activated protein kinase (MAPK) and/or phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt).

• #23 The genetic landscape of benign thyroid nodules revealed by whole exome and transcriptome sequencing | Nature Communications

  https://www.nature.com/articles/ncomms15533

  The genomic alterations for benign thyroid nodule, especially adenomatoid nodule, one of the most common types of hyperplasia lesion, are ill-studied. […] Somatic mutation of BRAF (22/32) is only detected in PTC, while mutations in SPOP (4/38), ZNF148 (6/38) and EZH1 (3/38) are found enriched in adenomatoid nodule. […] Our findings reveal that benign nodules possess a unique molecular signature that differs from PTC and provide genomic evidence for the conventional belief that PTC and benign nodules have independent origin. […] While the genetic alterations for benign hyperplasia thyroid nodule, especially adenomatoid nodule, one of the most common hyperplasia lesions and undistinguished from follicular thyroid carcinoma in fine need aspiration, are ill-studied. […] We found 24.3% of adenomatoid nodule carried mutually exclusive SPOP P94R, EZH1 Q571R and ZNF148 mutations, a unique molecular signature that differs from PTC.

• #24 The genetic landscape of benign thyroid nodules revealed by whole exome and transcriptome sequencing | Nature Communications

  https://www.nature.com/articles/ncomms15533

  To gain insight into the genetic mechanism of thyroid nodule development, we examined 127 DNA and 40 RNA samples, from 21 patients with coincident benign nodule and PTC (TB patients), and eight patients with benign nodule burden only (SB patients) by whole-exome and transcriptome sequencing. […] The coincident benign nodule and PTC also gave us an opportunity to provide genomic evidence for the conventional belief that benign nodule and PTC has independent origin. […] The mutation landscape for benign nodules was completely different from PTCs. […] We observed mutually exclusive mutation of ZNF148 (21.4%), SPOP (14.3%) and EZH1 (10.7%) in benign nodules, but not PTC or normal thyroid. […] Our studies identified a common characteristic genetic profile of benign nodules, mutually exclusive mutation of SPOP, ZNF148 and EZH1 was observed in 24.3% of the adenomatoid nodules but not in matched PTC tumours.

• #25 The genetic landscape of benign thyroid nodules revealed by whole exome and transcriptome sequencing | Nature Communications

  https://www.nature.com/articles/ncomms15533

  Our findings are more consistent with a causal role on the formation of benign nodules than neoplastic transformation. […] The formation of thyroid nodular structure in adenomatoid nodule is probably an early stimulus that causes enlargement of the thyroid, such as Iodine deficiency, nutritional goitrogens or autoimmunity, followed by local proliferation of follicular epithelial cell due to somatic EZH1 mutations, a genetic path different from thyroid cancer. […] Our data provide strong evidence that benign thyroid nodules have a genetic and transcriptome landscape that is distinct with PTC tumours.

• #26 Involvement of CYP1A1, GST, 72TP53 polymorphisms in the pathogenesis of thyroid nodules – Genetics and Molecular Research (GMR)

  https://geneticsmr.com/2010/11/04/involvement-of-cyp1a1-gst-72tp53-polymorphisms-in-the-pathogenesis-of-thyroid-nodules/

  Specific genotypes appear to be related to the development of thyroid disease. […] We examined whether polymorphisms of the genes CYP1A1, GSTM1, GSTT1, and TP53 at codon 72 are associated with increased risk for thyroid nodules. […] The null genotypes of GSTM1 and GSTT1 genes were predominant in patients with nodules, indicating that individuals that possess these genotypes have a predisposition for thyroid disease. […] The genotype p53Arg Arg was associated with a low risk for thyroid cancer (OR = 0.15; P 0.0001), indicating that the arginine allele in homozygosis could have a protective effect against carcinogenesis. […] On the other hand, the p53ArgPro genotype was significantly associated with malignant neoplastic nodules (OR = 3.65; P = 0.001). […] Interindividual variation in susceptibility to thyroid diseases could provide new perspectives for early diagnosis, prognosis and treatment, indicating which patients with thyroid nodules will benefit from treatment, depending on specific polymorphic profiles.

• #27 Thyroid Nodule – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK535422/

  RET proto-oncogene translocations have been found in thyroid malignancies associated with ionizing irradiation. The presence of RET/PCT translocations has been described in follicular adenomas presenting after irradiation. […] The pathophysiology of a thyroid nodule will vary depending on the lesion. Several disorders may cause thyroid nodules. The most common type is benign macrofollicular nodules, representing either monoclonal adenomas or colloid nodules in multinodular goiter. […] Follicular neoplasms may represent a diagnostic problem as these only differ from follicular carcinomas by lack of vascular or capsular invasion.

• #28 (PDF) Thyroid Nodules and Thyroid Cancer

  https://www.academia.edu/80821181/Thyroid_Nodules_and_Thyroid_Cancer

  a clear association between radiation exposure (from radiotherapy or fallout) and incidence of papillary thyroid carcinoma. […] papillary thyroid cancers in patients exposed to radiation from the Chernobyl accident could be completely distinguished from sporadic papillary thyroid cancers in patients with no history of radiation exposure, on the basis of gene expression patterns involving seven genes (ie, SFRP1, MMP1, ESM1, COL13A1, BAALC, PAGE1). […] Ionizing radiation is the most important environmental factor to induce PTC, especially in children. […] In PTC development, basically two types of genetic alterations, fusion oncogenes, mainly RET/PTC, and a point mutation, mainly BRAFV600E, are thought to play a key role as driver oncogenes. […] BRAF (V600E) mutation is the most frequent genetic alteration in papillary thyroid carcinomas (PTCs) that are 80-90% of all thyroid cancers. […] The association between BRAF (V600E) and extra-thyroid invasion was also found in micro-PTCs.

• #29 Toxic Nodular Goiter: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/120497-overview

  Toxic nodular goiter (TNG) represents a spectrum of disease ranging from a single hyperfunctioning nodule (toxic adenoma) within a multinodular thyroid to a gland with multiple areas of hyperfunction. The natural history of a multinodular goiter involves variable growth of individual nodules; this may progress to hemorrhage and degeneration, followed by healing and fibrosis. Calcification may be found in areas of previous hemorrhage. […] Some nodules may develop autonomous function. Autonomous hyperactivity is conferred by somatic mutations of the thyrotropin, or thyroid-stimulating hormone (TSH), receptor in 20-80% of toxic adenomas and some nodules of multinodular goiters. […] Functional autonomy of the thyroid gland appears to be related to iodine deficiency. Various mechanisms have been implicated, but the molecular pathogenesis is poorly understood.

• #30 Toxic Nodular Goiter: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/120497-overview

  Increased thyroid cell replication predisposes single cells to somatic mutations of the TSH receptor. Constitutive activation of the TSH receptor may generate autocrine factors that promote further growth, resulting in clonal proliferation. Cell clones then produce multiple nodules. […] Somatic mutations of the TSH receptors and G protein confer constitutive activation to the cyclic adenosine monophosphate (cAMP) cascade of the inositol phosphate pathways. These mutations may be responsible for functional autonomy of the thyroid in 20-80% of cases. […] These mutations are found in autonomously functioning thyroid nodules, solitary and within a multinodular gland. Nonfunctioning thyroid nodules within the same gland lack these mutations. […] The reported frequency of these mutations varies widely, ranging from 10-80%. Higher incidence is reported in patients with iodine deficiency.

• #31 Oestrogen action on thyroid progenitor cells: relevant for the pathogenesis of thyroid nodules? in: Journal of Endocrinology Volume 218 Issue 1 (2013)

  https://joe.bioscientifica.com/view/journals/joe/218/1/125.xml

  Benign and malignant thyroid nodules are more prevalent in females than in males. Experimental data suggest that the proliferative effect of oestrogen rather than polymorphisms is responsible for this gender difference. […] In conclusion, oestrogen stimulated the growth and simultaneously inhibited the differentiation of thyroid nodule-derived stem/progenitor cells. From these data and based on the concept of cellular heterogeneity, we hypothesize a supportive role of oestrogen in the propagation of thyroid stem/progenitor cells leading to the selection of a progeny of growth-prone cells with a decreased differentiation. These cells may be the origin of hypofunctioning or non-functioning thyroid nodules in females. […] Herein, we report for the first time that thyroid stem and progenitor cells are also targets of oestrogen action.

• #32 Oestrogen action on thyroid progenitor cells: relevant for the pathogenesis of thyroid nodules? in: Journal of Endocrinology Volume 218 Issue 1 (2013)

  https://joe.bioscientifica.com/view/journals/joe/218/1/125.xml

  E2 also promoted the formation of single stem cell-derived thyrospheres. On the other side, in response to E2 stimulation, the levels of thyroid differentiation markers such as TSHR, thyroid symporter peroxidase (TPO) and sodium iodide (NIS) were markedly decreased with a maximal inhibition of TSH-induced NIS expression. […] Oestrogen action on thyroid stem/progenitor cells, i.e. stimulation of growth and inhibition of differentiation, in particular, of NIS expression, generates a progeny of cells with a higher proliferation rate and a reduced differentiation. […] In conclusion, we hypothesize a supportive role of oestrogen in the propagation of thyroid stem/progenitor cells that may lead to the selection of a progeny of growth-prone cells with a decreased function. These cells may be the origin of hypofunctioning or non-functioning thyroid nodules in females.

• #33 A Mechanism Exploration of Metabolic Syndrome Causing Nodular Thyroid Disease

  https://www.epistemonikos.org/pt/documents/1750398fb0d13f1fdda1b5266211d0a293ddcb31

  Metabolic syndrome (MS) and its components have been demonstrated to facilitate the prevalence of thyroid nodules (TNs). […] The underlying pathogenesis needs to be elucidated. […] Patients with MS have a higher prevalence of TNs, probably due to the elevated TSH and inflammatory levels in vivo. […] Among the components of MS, glucose intolerance contributes most to the development of TNs.

• #34 Thyroid Nodules and Obesity

  https://www.mdpi.com/2075-1729/13/6/1292

  Through several proposed mechanisms, aberrant endogenous estrogen levels have been suggested to play a vital role in the development of both benign and malignant nodules. Metabolic syndrome triggers the development of thyroid nodules by stimulating thyroid proliferation and angiogenesis due to hyperinsulinemia, hyperglycemia and dyslipidemia. […] Insulin resistance influences the distribution and structure of the thyroid blood vessels. Insulin growth factor 1 (IGF-1) and insulin affect the regulation of the expression of thyroid genes and the proliferation and differentiation of thyroid cells. […] TSH can promote the differentiation of pre-adipocytes to mature adipocytes but also, in the presence of insulin, TSH possesses mitogenic properties. This review aims to summarize the underlying mechanisms explaining the role of obesity in the pathophysiology of thyroid nodules and discuss potential clinical implications.

• #35 Thieme E-Journals – Experimental and Clinical Endocrinology & Diabetes / Abstract

  https://www.thieme-connect.com/products/ejournals/abstract/10.1055/s-2006-932903

  Oxidative stress due to an imbalance between pro-and antioxidative factors could be an important mechanism in the pathogenesis of thyroid diseases. […] The present study suggests increased oxidative stress as a feature of benign and malignant thyroid nodules. […] Distinct subcellular localisation of 8oxoG labelling in these pathologies may reflect different degrees of mitochondrial or nuclear oxidative DNA damage, which, if accompanied by defective DNA repair, is known to increase risk for mutational events. […] This may propagate e.g. cell proliferation and dedifferentiation and could thus lead to thyroid cell transformation.

• #36 Senescent thyrocytes and thyroid tumor cells induce M2-like macrophage polarization of human monocytes via a PGE2-dependent mechanism | Journal of Experimental & Clinical Cancer Research | Full Text

  https://jeccr.biomedcentral.com/articles/10.1186/s13046-019-1198-8

  Human monocytes exposed to CM from senescent thyrocytes and thyroid tumor cell lines undergo M2-like polarization, showing high CD206 and low MHC II markers, and upregulation of CCL17 secretion. […] Our results demonstrate that both senescent thyrocytes and thyroid tumor cell lines trigger M2-like macrophage polarization that is related to PGE2 secretion. […] The co-expression of PTGS2 gene and M2 markers in human thyroid carcinoma highlights the possibility to counteract tumor growth through COX-2 inhibition. […] Our data demonstrate that both senescent cells and tumor cell lines induce M2-like polarization. […] Our results strongly suggest a protumoral effect of PGE2 mediated by its action on macrophages. Thus, COX-2 inhibition might represent a therapeutic strategy which, by modulating the activity of TAMs, would restore an antitumor immune response and counteract thyroid tumor growth.

• #37 Biomedicines | Special Issue : Thyroid Nodule: Updates on the Molecular Mechanism and Diagnosis

  https://www.mdpi.com/journal/biomedicines/special_issues/O25GA3J638

  The Special Issue „Thyroid Nodule: Updates on the Molecular Mechanism and Diagnosis” focuses on the growing importance of characterizing thyroid nodules with maximum accuracy. […] The accuracy certainly derives from the knowledge of the molecular mechanisms underlying formation of thyroid nodules and from the use of more precise diagnostic tools. […] The purpose of this Special Issue is to analyze the molecular mechanisms underlying the formation of thyroid nodules and to take stock of the updates present in the most recent literature regarding a more precise instrumental diagnosis, combining new experiments.

• #38 TSH levels and thyroid nodules correlation in autoimmune thyroiditis | ECE2008 | 10th European Congress of Endocrinology | Endocrine Abstracts

  https://www.endocrine-abstracts.org/ea/0016/ea0016p801

  The role of TSH in the pathogenesis of thyroid nodule (TN) is controversial. […] Results show TSH seems to play no role in the TN growth, because higher levels are not associated to bigger TN, while TAb presence determines a lesser TN growth.

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