Thyroid nodule pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]
Overview
[Pathogen name] is usually transmitted via the [transmission route] route to the human host. Following transmission/ingestion, the [pathogen] uses the [entry site] to invade the [cell name] cell. On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of [disease name]. On microscopic histopathological analysis, [feature1], [feature2], and [feature3] are characteristic findings of [disease name]. [Disease name] is transmitted in [mode of genetic transmission] pattern. [Disease/malignancy name] arises from [cell name]s, which are [cell type] cells that are normally involved in [function of cells]. Development of [disease name] is the result from multiple genetic mutations. Genes involved in the pathogenesis of [disease name] include [gene1], [gene2], and [gene3]. The progression to [disease name] usually involves the [molecular pathway]. The pathophysiology of [disease name] depends on the histological subtype.
Pathogenesis
Common causes
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Hyperplastic nodules
- The proliferative activity of the thyroid is very low.
- The thyroid however shows the ability to proliferate rapidly in response to appropriate stimuli.
- iodine deficiency directly or indirectly is the principal potent stimulator of the replicative potential of the gland.
- industrial chemicals, diet, goitrogens, antithyroid drugs
- DDT, polychlorinated byphenyls and tobacco have been implicated in goitrogenesis.
- Mechanism of action:
- Acting as an initiators but need the promoter action of other chemicals that induce a rise in TSH.
- May be related to high prevalence of thyroid hyperplasia and nodules are found in iodine-sufficient areas
In thyroid cells there are three distinct pathways for signal transduction: 1) receptor/adenylate cyclase/protein kinase A system; 2) receptor/phospholipase C pathways; and 3) receptor/phospholipase A2 system (intracellular metabolism of prostaglandins).
TSH activates both the adenylate cyclase and phospholipase C pathways.
Activation of phosholipase C and phospholipase A2 have only a minor or absent effect on thyroid growth.
The signal generated by the cAMP-dependent pathways is then transduced into the nucleus where transcription factors–upon phosphorylation–induce the expression of cAMP-inducible genes [97]. In figure 3 the pathway of signal transduction from the plasma membrane to the promoter elements in the nucleus is schematized. It has been definitely established that TSH has a main mitogenic role, through cAMP, Gs proteins (G-protein heterotrimeric α-, β- and γ-subunits coded by the gsp gene which, binding to GTP, relays the TSH signal from its receptor to adenyl cyclase) and protein kinase A, which activates the metabolic cascade leading to the stimulation of growth
However, to produce hyperplasia overproduction of cAMP must be continuous, as it occurs in mutations constitutive of the genes which regulate cAMP production. Constitutive cAMP overproduction has been demonstrated to be due to point mutation of the TSH receptor [70] or Gs protein
Constitutive cAMP overproduction not only stimulates growth but also function.
Thyroid overgrowth stimulants:
Effectors of thyroid growth: external effectors are hormones, immunoglobulins and nutrients. Cells of the stromal apparatus (endothelium, lymphocytes, fibroblasts, monocytes/macrophages) cross-talk with follicular cells by the cytokines. A group of cytokines is produced by and acts on the thyroid cell itself. Most cytokines stimulate growth directly or through TSH. TGFβ, IFNγ, IL-6 and somatostatin exert an action of differentiation or inhibition of growth.
Hyperplasia development phase:
Thyroid cells produce the angiogenic vascular endothelial growth factor/vascular permeability factor (VEGF/VPF) sensitive to TSH stimulation, which binds to specific receptors on endothelial cells and induces neovascularization by sprouting of new capillaries. In turn, endothelial cells produce growth factors that increase thyroid hyperplasia. Sprouting of new capillaries is accompanied by the production of proteolytic enzymes, which facilitate the expansion in the extracellular matrix.
Neoplasia development phase:
each follicle is composed of different clones of cells (polyclonal) but during nodule formation they replicate in a simultaneous and coordinated manner, so each follicle of the nodule reproduces the same heterogeneity of the mother follicle. When a neoplasm arises in the nodule, then the neoplastic follicle shows a monoclonal pattern, suggesting that cancer arises from a single cell.
activated oncogenes are considered the underlying event leading to uncontrolled cell growth.
Colloid nodule
These nodules are produced as a defect of intraluminal thyroglobulin reabsorption.
By the process of macro- (pseudopods) and micro-pinocytosis (microvilli), the colloid is reabsorbed into the follicular cells, forming colloid droplets, whereas newly synthesized thyroglobulin is compacted into exocytotic vesicles and secreted into the colloid. An imbalance of such equilibrium produces a colloid appearance.
the combined actions of TSH and iodine excess produces a colloid goitre
iodine has been found to inhibit the protease activity of thyroid lysosomes [82], thereby inhibiting endocytosis buit for this effect large doses of iodine (Lugol solution) is needed
iodine reduces the expression of the TSH receptor on the surface of thyroid cells and hence colloid reabsorption
Maybe in colloid nodules the mechanism of stocking thyroglobulin into ‘globules’ is lost, part of the thyroglobulin is no longer osmotically inert and consequently an enormous enlargement of the follicles and flattening of the epithelium takes place, giving the histological appearance of ‘colloid follicle’.
Cystic nodules
- True cysts
- Pseudo cysts
hyperplasia of thyroid nodules proceed towards necrosis, colliquation and ultimately to pseudocyst formation
necrosis is due to a relative insufficiency of blood supply, which is inadequate for the growth of the replicating neoplasia [60, 94] or is due to an imbalance between angiogenesis and cell growth where replicating cells do not outgrow but gradually compress neovascularization, leading to cell damage, necrosis and colliquation
autoimmunity might participate in the formation of the serum-like cyst
An increased concentration of VEGF/VPF has been found in the fluid of thyroid cysts, particularly in the fluid of rapidly enlarging or recurrent cysts. This finding suggests that VEGF/VPF stimulates vascular permeability and promotes accumulation of fluid.
Cysts may also be considered as the end result of apoptosis
Thyroiditic nodule
Nodular lymphocytic thyroiditis includes two different entities: lymphocyte thyroiditis growing as a nodule in a hyperplastic or normal gland; and lymphocytic thyroiditis associated with other nodular thyroid diseases.
In Hashimoto thyroiditis, by scintigraphy solitary or dominant cold nodules are common
by cytology and ultrasonography thyroiditic nodules are easily diagnosed
- Gooitrogenics:
- Complex anions and inorganic atoms (iodine, lithium, CLO4–, TcO4–, BF4–), thiocyanate (SCN–)
- Thionamides that are used in the treatment of hyperthyroidism
- Goitrin, isolated in plants of the genus brassica
- Aniline derivatives (sulfonamides, tolbutamide, sulfaguanidine, sulfamethoxazole, etc.)
- Phenol derivatives and polyhydroxyphenols
- Flavonoids act on thyroid metabolism by interacting with the nuclear receptor for thyroid hormones. Flavonoids such as vitaxin and others are inhibitors of TPO
- pesticides, environmental toxins such as isomers of DDD and DDT, polychlorinated biphenyls
- Carcinogenics:
- Thionamid compounds: thiourea, methimazole, ethylenethiourea (ETU), thiouracil, propylthiouracil
- Aminotriazole: herbicide
- Acetylaminofluorene (AAF). Use: insecticide
- Oxydianiline (ODA). Use: Azo-Dye
- Methylene benzenamine. Use: Dye intermediate
- Nitrosamines
- Nitrosoureas (NMU), (NBU), (ENU). Use: derivatives (BCNU, CCNU, MeCCNU) are drugs against tumors. Streptozocin (naturally occurring nitrosourea) is used in the treatment of islet-cell carcinoma of the pancreas).
Less common causes
- Piogenic infection
- Tuberculosis
- de Quervain’s thyroiditis
- Fibrosing (Riedel’s) thyroiditis,
- Parasites
- Dyshormonogenesis
- Amyloidosis
- Plasma cell granuloma
- Histiocytosis X
Genetics
- Some diseases are genetic, and have particular inheritance patterns, and express different phenotypes.
- The effect that genetics may have on the pathophysiology of a disease can be described in this section.
- familial nonmedullary thyroid cancer (FNMTC):
- rare
- related to non-medullary tumors
- Inheritance: autosomal dominant with incomplete penetrance and variable expressivity
- earlier age of thyroid cancer onset
- more benign thyroid nodules
- Associated with multifocal disease
- Associated with a higher rate of locoregional recurrence
| Principal oncogenes and growth factors involved in thyroid carcinogenesis. | Gene mechanism | Mutation effect | Neoplasia |
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| N&H ras | ras-constitutively bound to GAP (GTPase-activating protein) | Activation of adenylate cyclase and calcium channels |
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| RET (Receptor for glial-derived neurotrophic GF) |
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| gsp | Ribosylated GS-α at arginine 201 | Impairing of GTPase activity | Hot adenomas |
| c-MET (α and β subunit) | Increased receptors for HGF/SF | Enhancement of receptor kinase activity | Ca. papillary (aggressive) |
| TRK | Receptor for NGF | Mitogen activated TK cascade | Ca. papillary |
| EGF / EGF-R | Lack of activation of p21/Waf l gene expression | Loss of regulation at the critical G1 to S phase | Ca. anaplastic |
| p53 | Lack of activation of p21/Waf l gene expression | Loss of regulation at the critical G1 to S phase | Ca. anaplastic
Papillary Follicular |
Associated Conditions
- Preoperative serum TSH is an independent risk factor for predicting malignancy in a thyroid nodule, and is associated with: 18160464 23731273
- Higher differentiated thyroid cancer stage
- Gross extrathyroidal extension
- Neck node metastases
Gross Pathology
- Gross pathology refers to macroscopic or larger scale manifestations of disease in organs, tissues and body cavities. The term is commonly used by pathologist to refer to diagnostically useful findings made during the gross examination portion of surgical specimen processing or an autopsy.
- This section is a good place to include pictures. Search for copyleft images on The Pathology Wiki [1] and Ask Dr. Wiki [2].
Microscopic pathology
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| Cytology classification | Referred to | FNA | Surgical biopsy | May be seen in: | FNA cytology | |
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| Follicular lesions | Benign (macrofollicular) |
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| Follicular neoplasm/microfollicular |
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| Follicular lesion of undetermined significance (FLUS) | + | common, especially in nodular goiters. |
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| Atypia of undetermined significance (AUS) | ||||||
| Hürthle cells |
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| Papillary cancer |
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+ | Epithelioid giant cells
Psammoma bodies
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| Medullary cancer | + | Medullary cancer |
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| Anaplastic thyroid cancer | +
Large needle biopsy if needed |
Anaplastic thyroid cancer |
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Microscopic Pathology
- Microscopic pathology is the disease process as it occurs at the microscopic level.
- This section is a good place to include pictures. Search for copyleft images on The Pathology Wiki [3] and Ask Dr. Wiki [4].
- Both polyclonal and monoclonal nodules appear similar on fine needle aspiration (FNA) (macrofollicular) and are benign 8426623
- Thus, the diagnosis of follicular cancer in situ does not exist, because vascular or capsular invasion is required to make the diagnosis of follicular cancer. 8420446