Neoplasia

Early neoplastic lesions are generally monoclonal and arise from a single mutation (or several) in a cell,74 which results in a greater propensity of these cells to multiply more rapidly or to die more slowly than surrounding cells. With the new knowledge of the monoclonal origin of nodules in hyperplastic disease, the dichotomy between hyperplastic and neoplastic transformation has become less distinct. In a hypothetical overlapping gray zone (Fig. 28-5), the growth of both hyperplastic and neoplastic nodules may be dependent on single lesions, in the hyperplastic case arising from cells with inherited high intrinsic growth potential and in the neoplastic case arising from a single normal precursor cell.

Both benign and malignant thyroid neoplasms have been shown to have ras mutations.80 It has, therefore, been

External growth signals

External growth signals

FIGURE 28-4. The "gray zone." Growth stimulation by increased signal pressure from external sources, increased sensitivity toward normal signal pressure, or autocrine-paracrine growth stimulation gives rise to hyperplasia. Single or multiple genetic lesions give different neoplastic transformations in a stepwise way with the appearance of initial nonmetastasizing benign forms. The "gray zone" indicates a possibility of genetic lesions that may change the growth potential in hyperplastic nodules without obvious neoplastic transformation, as well as early lesions in neoplastic tissue.

FIGURE 28-4. The "gray zone." Growth stimulation by increased signal pressure from external sources, increased sensitivity toward normal signal pressure, or autocrine-paracrine growth stimulation gives rise to hyperplasia. Single or multiple genetic lesions give different neoplastic transformations in a stepwise way with the appearance of initial nonmetastasizing benign forms. The "gray zone" indicates a possibility of genetic lesions that may change the growth potential in hyperplastic nodules without obvious neoplastic transformation, as well as early lesions in neoplastic tissue.

proposed that Ha-ra.v activation is an early or initiating event in the development of thyroid oncogenesis. In fact, in vitro transfection of mutant ras genes extended the proliferative life span of cultured rat thyroid follicle cells from less than 3 to more than 15 doubling times.81 The transformed thyroid cells spontaneously mutate and form tumorigenic new cell lines with loss of growth factor dependence and differentiated functions. These ras-transfected tumorigenic cells lose their responsiveness to the growth inhibitor TGF-fSl and have increased nuclear levels of p53 protein.

Benign follicular adenomas appear as single tumors in both normal and hyperplastic thyroid tissue. They form well-delineated firm nodules surrounded by a pseudocapsule. The homogeneous appearance of the epithelial arrangement reflects the currently held opinion that they represent true monoclonal tumors.

Further dedifferentiation to malignant neoplasms seems correlated with specific mutational events. Progression toward the follicular phenotype has been reported to correlate with a loss of function of a gene in the llql3 locus (follicular adenoma)82 and further dedifferentiation in follicular carcinomas with loss of genetic material in chromosome 3p. Activation of the ret oncogene appears to occur only in papillary thyroid carcinomas.83 This protooncogene encodes a transmembrane receptor of the tyrosine kinase family, which fuses with a gene product (RGF) to form a novel chimeric oncogene (ret/PTC3).M p53 mutations have been found primarily in anaplastic thyroid cancers, but one study found them in other thyroid cancers.85 Thus, loss or decreased activity of this gene product, which appears to regulate growth-inhibiting signals at the GrS transition of the cell cycle, seems to correlate with continued cell division despite the presence of multiple unrepaired and tumorigenic gene defects.

Mutations in the retinoblastoma gene Rb have been observed in differentiated and anaplastic thyroid cancers.86 The gene encodes a nuclear phosphoprotein that switches

FIGURE 28-5. Benign thyroid neoplasia. A, The cut surface of a thyroid lobe with a follicular adenoma shows the presence of a well-encapsulated tumor with a smooth and uniform appearance. B, A section in the periphery of the adenoma shows the uniform appearance of the parenchyma architecture with the presence of only a few follicle structures (hematoxylin and eosin).

FIGURE 28-5. Benign thyroid neoplasia. A, The cut surface of a thyroid lobe with a follicular adenoma shows the presence of a well-encapsulated tumor with a smooth and uniform appearance. B, A section in the periphery of the adenoma shows the uniform appearance of the parenchyma architecture with the presence of only a few follicle structures (hematoxylin and eosin).

between a hyper and low-phosphorylated state in a cell cycle-specific manner and acts by regulating the action of transcription factors. Loss of this phosphoprotein deregulates the cell cycle transition. Mutations of p53 and Rb are present in both follicular and papillary forms of thyroid cancers.

The early progression from benign neoplasias into either of the two major forms of differentiated thyroid cancer thus appears to be related to characteristic chromosome and genetic lesions. In more advanced disease with more rapidly growing and aggressive cancers, both major dedifferentiation lines share the loss of p53 and Rb cell cycle regulatory functions.

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