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

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 [4] and tobacco [21] 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

1. True cysts
2. 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
N&H ras	ras-constitutively bound to GAP (GTPase-activating protein)	Activation of adenylate cyclase and calcium channels	Adenoma Ca. papillary Follicular Anaplastic
RET (Receptor for glial-derived neurotrophic GF)	Fusion proteins with constitutive TK activities Dimerization of RET TKR	Mitogenic through constitutive activation of TKR Increased auto-phosphorylation and alteration of substrate specificity	Ca. papillary MEN 2A FMTC MEN 2B
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
Follicular lesions	Benign (macrofollicular)	Adenomatoid adenoma Hyperplastic adenoma Colloid adenoma	+		Normal thyroid tissue Sporadic nodular goiter Monoclonal macrofollicular tumors Hyperplastic nodules Colloid adenomas (most common)	May have areas of cystic degeneration with cellular debris and hemosiderin-laden macrophages Cellular characteristics: Small and flat Uniform in size Non-crowded Smeared colloid is seen in the background Follicle size may vary, with a few microfollicles interspersed among the macrofollicles, especially if the sample was obtained from an area close to the capsule of the lesion Colloid: May smear across the slide or occasionally aggregated into droplets due to disruption of follicles during FNA Stains blue on a Papanicolaou stain May be abundant in the background of macrofollicular lesions
	Follicular neoplasm/microfollicular	Cellular adenoma Indeterminate adenoma Trabecular adenoma		+	Follicular adenomas Follicular carcinomas Follicular variant of papillary cancer Occasionally from autonomously functioning thyroid nodules	Well-developed microfollicles Crowding of cells May form clusters and clumps Scant colloid Varying nuclear atypia Varying cellular pleomorphism Follicular carcinoma: Focal microscopic invasion Cellular or trabecular adenomas: Lesions with less definite or no follicle formation May show vascular or capsule invasion
	Follicular lesion of undetermined significance (FLUS)		+		common, especially in nodular goiters.	FLUS: the lesion has approximately equal number of macrofollicular fragments and microfollicles AUS: cells with mild nuclear atypia Mostly due to compromised speciemens: Poor fixation or obscuring blood (FLUS)
	Atypia of undetermined significance (AUS)
	Hürthle cells	Oncocytes Askanazy cells Oxyphil cells	+		Focal Hürthle-cell change: Degenerating macrofollicular lesions Hashimoto's thyroiditis	Large polyclonal cells Oxyphil cytoplasm Considered benign if there is no evidence of vascular or capsular invasion Considered malignant if invasion is present Hürthle-cell cancer Follicular cancer Oxyphil cell type cancer
Papillary cancer		The follicular variant of papillary cancer		+	Epithelioid giant cells Papillary cancer Degenerating areas of macrofollicular nodules Subacute granulomatous thyroiditis Psammoma bodies Papillary carcinoma Benign thyroid lesions	Large cells and nuclei  Ground glass appearance of cytoplasm  Nuclei appearance: Clefts  Grooves  Holes  Intranuclear cytoplasmic inclusions = Orphan Annie eyes  Small nucleoli  Psammoma bodies Small laminated calcifications Sticky colloid Colloid "stick" to debris and cell clusters, instead of smearing across the slide Epithelioid giant cells Can also be seen in: Degenerating areas of macrofollicular nodules Subacute granulomatous thyroiditis
Medullary cancer				+	Medullary cancer	Spindle-shaped cells Frequently pleomorphic cells without follicle development Supporting stroma may frequently stains for amyloid Red cytoplasmic granules Eccentrically placed nuclei Slightly granular Cytoplasm that may be configured as a tear drop or cytoplasmic tail
Anaplastic thyroid cancer			+ Large needle biopsy if needed		Anaplastic thyroid cancer	Spindle cells Pleomorphic giant cell Squamoid Mitosis Numerous mitotic figures Atypical mitoses Extensive necrosis.

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