Thyroid nodule pathophysiology

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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 frominflammation 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, N&H ras, RET, Gsp, C-MET, TRK, EGF / EGF-R, and P53.


A summary of thyroid nodule pathophysiology is presented in the slides below: [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][6][19][20][21][22][23][24][25][26][27][28][29][30][31]

(a) Hyperplastic nodules

1. TSH role in thyroid nodule formation

2. Thyroid overgrowth stimulants:

Thyroid normally has a low proliferative activity, although it can start proliferation rapidly in response to certain stimulants. Stimulants mainly act through TSH mediated activity and production. The following stimulants appear to have the most important role in pathogenesis of hyperplastic nodules:[32][33]

3. Hyperplasia development phase:
4. 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
  • Activation of oncogenes is considered the underlying event leading to uncontrolled cell growth.

(b) Neoplastic nodules

Papillary thyroid carcinoma


ERK: extracellular signal-regulated kinase; MAPK: mitogen-activated protein kinase

(c) Colloid and cystic nodules

1. Colloid nodules

  • The colloid nodules consist of colloid droplets and thyroglobulin vesicles.
  • Thyroid gland keeps a balance between colloid and thyroglobulin production by regulating the secretion of thyroglobulin into colloid and reabsorption of colloid into thyroid follicular cells. This regulation is maintained by macro-pinocytosis (pseudopods) and micro-pinocytosis (microvilli).
  • Any imbalance between secretion and reabsorption of thyroglobulin leads to a disruption of the equilibrium, and produces a colloid appeared thyroid nodule. These nodules may also be produced as a defect of intraluminal thyroglobulin reabsorption. 

2. Iodine related nodules pathogenesis:

Iodine excess can lead to colloid nodules in thyroid gland, leading to a colloid goitre:

Another mechanism that may lead to colloid goitre formation is loss of thyroglobulin packaging ability, that may lead to an enormous enlargement of the follicles and flattening of the epithelium.

3. Cystic thyroid nodules

Cystic thyroid nodules may be classified into the following types:

(d) Thyroiditic nodule

Nodular lymphocytic thyroiditis almost always present in combination with other thyroiditic diseases. They can also present as a part of infection. It has been shown that the ability of super-antigens (SAgs) to activate the immune system may play a role in the course of autoimmune disorders. In most of these cases, the mechanism of nodular lesion is the same as the mechanism of the main disease, implying that the thyroid nodule is a part of normal disease pattern. Many of these nodules are not identifiable based on physical exam, and are detected during thyroid scintigraphy. The most important thyroiditic diseases that may present as lymphocytic nodular thyroid are:


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 occur in a familial order. The most important category of familial thyroid cancers are due to genetic mutations, and are called familial non-medullary thyroid cancer (FNMTC), with the following features:

The most important genetic mutations associated with thyroid neoplasia development

Oncogenes and growth factors Gene mechanism Mutation effect Neoplasia
N&H ras
  • Encodes a receptor for glial-derived neurotrophic GF
  • Fusion proteins with constitutive thyrosine kinase activities
  • Dimerization of RET thyrosine kinase receptors (TRK)
  • Hot adenomas
C-MET (α and β subunit)
  • Increased receptors for HGF/SF
  • Enhancement of receptor kinase activity
  • Mitogen activated TK cascade
  • Lack of activation of p21/Waf l gene expression
  • Loss of regulation at the critical G1 to S phase

Associated Conditions

Preoperative serum TSH is an independent risk factor for predicting malignancy in a thyroid nodule, and is associated with:[42][43]

Gross Pathology

Microscopic Pathology

Diagnostic speciemen feature: the presence of at least six follicular cell groups, each containing 10–15 cells derived from at least two aspirates of a nodule[44][45][46][45]

Cytology classification Also referred to as: Efficient diagnosis May be seen in: FNA cytology
FNA Surgical biopsy
Follicular lesions  Benign (macrofollicular) +
  • 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  +
  • 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) +
  • Commonly, especially in nodular goiters
  • FLUS:
    • The lesion has approximately equal number of macrofollicular fragments and microfollicles
  • AUS:
  • Mostly due to compromised speciemens:
    • Poor fixation or obscuring blood (FLUS)
Atypia of undetermined significance (AUS)
Hürthle cells  +
Papillary cancer
  • The follicular variant of papillary cancer
+ Epithelioid giant cells

Psammoma bodies

Medullary cancer  +
  • Medullary cancer
Anaplastic thyroid cancer +

Neoplastic thyroid nodules subclassification microscopic pathology:

Neoplasm Subclass Features
Follicular thyroid lesions Minimally invasive follicular carcinoma
  • Only invasion of the capsule of the tumor without vascular invasion
Widely invasive follicular carcinoma
  • Extensive invasion of the tumor capsule
  • A multinodular tumor without a well-defined capsule invading the normal thyroid surrounding the tumor
  • Extensive vascular invasion (>4 foci of angioinvasion)
Encapsulated follicular variant of papillary thyroid cancer
  • Minor vascular invasion (≤4 foci of angioinvasion within the tumor or capsule of the tumor) with or without capsular invasion
Infiltrative variant of papillary thyroid cancer
Papillary thyroid cancer Tall cell variant
Insular varient
Columnar variant
  • Elongated cells with palisading nuclei
Hürthle or oxyphilic variant
Clear cell variant
Diffuse sclerosing variant
Cribriform morular variant
Hobnail variant
  • Multifocal with variably sized complex papillary structures lined by cells
  • Cells with increased nuclear to cytoplasmatic ratios
  • Apically placed nuclei that lead to a surface bulge (hobnail appearance)


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