Nodule Formation

With increasing age, most thyroid glands and goiters become nodular. Initially, many goiters are diffuse; however, with intermittent stimulation, some diffuse goiters outgrow their blood supply and become nodular (Fig. 4-2).20,21 Some thyroid cells are more sensitive to growth factors and become larger nodules. If these nodules trap and organify iodine, the nodule may be "hot" or autonomous rather than "cold." Hot nodules are associated with TSHR and gsp mutations.

In general, formation of thyroid nodules can be explained by the following mechanisms.

Heterogeneous Subpopulation of Thyrocytes with Different Proliferation Rates that Cause Focal Hyperplasia or Nodular Transformation Time. Derwahl and Studer investigated the pathogenesis of this heterogeneity and suggested that multinodular goiters are "true" benign neoplasms due to intrinsically higher growth rates of some thyrocytes.22,23 However, most, but not all, nodules in a multinodular goiter are polyclonal when compared to true neoplasms.24 Kopp and associates have also documented that both monoclonal and polyclonal nodules can be present within the same multinodular thyroid gland.25

Somatic Mutations and Clonality of the Thyroid Nodules. Different somatic mutations of the TSHR have been identified.26 Mutations in oncogenes such as ras appear

FIGURE 4-2. Nodular goiter can involve either one or both lobes of the thyroid gland.

to be early mutations because they are present in both benign and malignant thyroid nodules.

Scarring, Necrosis, and Hemorrhage. For thyroid nodules to grow, angiogenesis and new vessel formation are required. These newly formed capillary vessels are often fragile and are sometimes unable to adequately supply the growing thyroid tissue. This may result in areas of ischemic necrosis and hemorrhage within the goiter. Inflammation and granulation tissue replace the necrotic areas, ultimately resulting in fibrosis, scarring, and calcification. The resulting network of inelastic fibrous bands' connective tissue leads to nodularity because it interferes with smooth growth of thyroid parenchyma.1

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