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Normal C Cells

The parafollicular C cells represent about 1% of all thyroid cells and are located at the basal layer of the follicle (Figure 21.9). At variance with thyroid follicular cells, which derive from endo-derm, C cells originate from the neural crest and migrate to the final location along with the ulti-mobranchial body, during embryonic development [110,111]. Although C cells have several features that differentiate them from follicular epithelium, there is evidence to suggest the possible origin of the follicular and parafollicular C cells from a common ancestral cell. Critical neurotrophic growth factors, including glial-derived neurotrophic factor (GDNF), which is a natural ligand of RET receptor, as well as nerve growth factor (NGF) and other neurotrophins, seem to play a central role in promoting the differentiation of cells deriving from the neural crest [112].

There are specific features that make the C cell a separate entity from a follicular cell: (a) the peculiar distribution in the thyroid gland,

Figure 21.9 Schematic representation (A) and immunohistochemistry for calcitonin showing normal parafollicular C cells in normal thyroid tissue (B, x100): the parafollicular C cells are located at the basal layer of the follicle.
Thyroid Parafollicular Cell Hyperplasia

Figure 21.10 Different stages in the development of hereditary MTC. A Normal parafollicular C cells; B slight C-cell hyperplasia (CCH); C diffuse CCH; D focal CCH; E nodular CCH; F MTC. Immunohistochemistry for calcitonin (Ventana Medical System antibody, 1:100; x100). (Kindly provided by Professor F. Basolo, Department of Pathology, University of Pisa, Italy.)

Figure 21.10 Different stages in the development of hereditary MTC. A Normal parafollicular C cells; B slight C-cell hyperplasia (CCH); C diffuse CCH; D focal CCH; E nodular CCH; F MTC. Immunohistochemistry for calcitonin (Ventana Medical System antibody, 1:100; x100). (Kindly provided by Professor F. Basolo, Department of Pathology, University of Pisa, Italy.)

which is prevalent at the junction of the upper third and the lower two thirds and along the central vertical axis of each thyroid lobe; (b) the growth and functional independence from TSH, as well as the inability to take up iodine; and (c) the production and secretion of calci-tonin, a biogenic amine, which is almost exclusively produced by both normal and malignant C cells.

C-Cell Hyperplasia

The definition of C-cell hyperplasia has changed over the years, especially after the introduction of RET genetic screening and the histological examination of apparently normal thyroid glands of mutated gene carriers that usually show an increased number of C cells. Studies of both human normal thyroid and thyroids affected by lymphocytic thyroiditis have demonstrated that one can see up to 50 C cells per 1 and 3 low power fields respectively, without correlation with any pathological status [98,113]. According to these findings, this is at present the most widely accepted definition of

C-cell hyperplasia, even though this criterion may be not respected in the presence of cyto-logically evident atypia [114].

According to the number and the distribution of C cells either a diffuse, focal, or nodular C-cell hyperplasia can be distinguished (Figure 21.10). It is likely that they represent progressive stages through which the normal C cell is transformed into a tumoral cell. While there is general agreement in considering C-cell hyperplasia the preneoplastic lesion of the hereditary form of medullary thyroid carcinoma, little is known about the relationship between C-cell hyperpla-sia and the sporadic form. Nevertheless, about 30% of sporadic medullary thyroid carcinoma is associated with C-cell hyperplasia [115].

Several authors would like to distinguish two types of C-cell hyperplasia: primary or neoplastic C-cell hyperplasia, which is related to the hereditary form of medullary thyroid carcinoma, and secondary or non-neoplastic C-cell hyperplasia, which may be observed in other thyroid diseases (thyroiditis and follicular or papillary microcarcinoma) and in about 20% of normal subjects [116,117]. However, the pathological definition and clinical significance of secondary C-cell hyperplasia remains unclear.

Medullary Thyroid Carcinoma

Under macroscopic examination, medullary thyroid carcinoma shows a hard and firm consistency and is either chalky white or red in color on cross-section. Histologically, medullary thyroid carcinoma is pleomorphic with spindle-shaped or rounded cells characteristically organized in a nested pattern. Mitoses are not very frequent, nuclei are usually uniform, and the eosinophilic cytoplasm is characterized by the presence of secretory granules. Deposits of amyloid substance are frequently (60-80%) observed between tumoral cells [118].

Sometimes there is difficulty distinguishing medullary thyroid carcinoma from anaplastic carcinoma, Hurthle cell carcinoma or insular carcinoma, especially if pseudopapillary elements or giants cells are present. Positive immunohistochemistry for calcitonin is diagnostic of medullary thyroid carcinoma. Immu-nohistochemistry for chromogranin A and carcinoembryonic antigen may also be useful [115] (Figure 21.11).

Histopathological description of medullary thyroid carcinoma must include the number and the distribution of tumoral foci as well as the simultaneous presence of C-cell hyperplasia. This information is of practical usefulness because bilaterality, multicentricity, and C-cell hyperplasia are considered the histological hallmarks of the hereditary forms [22].

A mixed form of medullary thyroid carcinoma is also described [119]. It is characterized by the simultaneous presence of parafolli-cular and follicular cell features, with positive immunohistochemistry for both calcitonin and thyroglobulin. In this regard, it is worth noting that the association of medullary and papillary thyroid carcinoma in the same thyroid gland seems to be quite frequent [120,121]. Molecular studies have shown that genes theoretically specific for the parafollicular C cells (i.e. normal RET gene) are expressed in papillary thyroid carcinoma and that genes theoretically specific for follicular cells (e.g. thyroglobulin, TSH receptor, thyroid transcription factor 1) are expressed in medullary thyroid carcinoma [122-124]. Despite all these observations, it is still controversial whether the mixed medullary thyroid carcinoma is a real separate histological entity, originating from an ancestral stem cell able to differentiate as both follicular and parafollicular cell, or the consequence of the collision of two distinct tumors, medullary and papillary, originating in the same thyroid gland.

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