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  • Review Article
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Pathogenetic mechanisms in thyroid follicular-cell neoplasia

Nature Reviews Cancer volume 6, pages 292–306 (2006)Cite this article

Key Points

  • Thyroid tumours are the most common malignancy of endocrine organs, and incidence rates have steadily increased over recent decades.

  • Most carcinomas that are derived from follicular epithelial cells are indolent tumours that can be effectively managed. However, a subset of these tumours can behave aggressively, and there is currently no effective form of treatment.

  • Radiation exposure, iodine intake, lymphocytic thyroiditis, hormonal factors and family history all alter the risk of thyroid carcinoma.

  • Alterations in key signalling effectors seem to be the hallmark of distinct forms of thyroid neoplasia.

  • Mutations or rearrangements that involve mitogen-activated protein kinase (MAPK)-pathway effectors seem to be required for transformation.

  • Signalling through growth factors and their receptors is considered essential for cancer progression, and some of these growth factors have been identified as modifiers of the behaviour of transformed thyroid cells.

  • Cell-cycle regulators and adhesion molecules are altered in thyroid carcinomas, typically through epigenetic mechanisms that indicate progression to poorly differentiated or undifferentiated forms.

  • Several molecules that are involved in the pathogenesis of thyroid cancers are emerging as diagnostic and/or prognostic tools for patient management.

Abstract

Thyroid cancer is one of the few malignancies that are increasing in incidence. Recent advances have improved our understanding of its pathogenesis; these include the identification of genetic alterations that activate a common effector pathway involving the RET–Ras–BRAF signalling cascade, and other unique chromosomal rearrangements. Some of these have been associated with radiation exposure as a pathogenetic mechanism. Defects in transcriptional and post-transcriptional regulation of adhesion molecules and cell-cycle control elements seem to affect tumour progression. This information can provide powerful ancillary diagnostic tools and can also be used to identify new therapeutic targets.

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Figure 1: The thyroid gland.
Figure 2: Model of multi-step carcinogenesis of thyroid neoplasms.
Figure 3: Cell signalling pathways in follicular cells.
Figure 4: Cell–cell and cell–matrix interactions in thyroid cancer cells.
Figure 5: Cell-cycle regulation in follicular cells.

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Acknowledgements

Some of the work reviewed here was supported by grants from the Canadian Institutes of Health Research and the Toronto Medical Laboratories. The authors apologize to the many colleagues whose work is not quoted directly owing to size restrictions of this Review.

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Authors and Affiliations

  1. Department of Pathology, University Health Network and Toronto Medical Laboratories and Department of Laboratory Medicine and Pathology, University of Toronto, 200 Elizabeth Street, Toronto, M5G 2C4, Ontario, Canada

    Tetsuo Kondo & Sylvia L. Asa

  2. Freeman Centre for Endocrine Oncology and Ontario Cancer Institute, 610 University Avenue, Toronto, M5G 2M9, Ontario, Canada

    Tetsuo Kondo, Shereen Ezzat & Sylvia L. Asa

  3. Department of Medicine, Mount Sinai Hospital and University of Toronto, 600 Elizabeth Street, Toronto, M5G 1X5, Ontario, Canada

    Shereen Ezzat

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  3. Sylvia L. Asa
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Corresponding author

Correspondence to Sylvia L. Asa.

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DATABASES

National Cancer Institute

Thyroid cancer

FURTHER INFORMATION

American Thyroid Association

Endocrine Society

Genbank

Glossary

C cells

Parafollicular cells of the thyroid that have a clear cytoplasm and are members of the peptide-hormone-secreting family (also known as 'neuroendocrine' cells). These cells are mainly involved in the production of calcitonin.

Adenoma

A benign epithelial tumour in which the cells form recognizable glandular (in this case follicular) structures or in which the cells are clearly derived from glandular (follicular) epithelium.

Well-differentiated thyroid carcinoma

A carcinoma that is composed of well-differentiated follicular epithelial cells. There are two main groups — papillary and follicular carcinoma — each of which has variants. These tumours generally have a good prognosis.

Poorly-differentiated thyroid carcinoma

A neoplasm derived from follicular epithelial cells that shows loss of structural and functional differentiation. Characteristically, these lesions show widely infiltrative growth, necrosis, vascular invasion and numerous mitotic figures.

Undifferentiated thyroid carcinoma

A tumour that is composed wholly or partially of undifferentiated cells without structural follicular-cell differentiation. There are three main morphological patterns: squamoid, pleomorphic giant cell and spindle cell. These tumours have a very poor prognosis.

Papillary carcinoma

Carcinomas that are composed of well-differentiated follicular epithelial cells and are characterized by distinctive nuclear features. Variants include classical forms with papillary architecture, follicular variants, oncocytic, tall-cell, solid and cribriform types, each with distinct growth patterns and behaviours.

Follicular carcinoma

A tumour that is composed of well-differentiated follicular epithelial cells and lacks nuclear features of papillary carcinoma. These tumours are capable of vascular invasion, which distinguishes them from follicular adenoma. Variants include oncocytic and clear-cell types.

Thyroiditis

A disease of the thyroid that is caused by inflammation.

Goitre

Enlargement of the thyroid gland. A goitre can be associated with normal, increased or decreased thyroid hormone levels in the blood, and might be due to primary thyroid disease or caused by infiltration or stimulation of the gland by hormones and other factors.

Follicles

The small spherical components of the thyroid gland that are lined by epithelium and contain colloid in varying amounts. The colloid provides storage for the thyroid-hormone precursor thyroglobulin.

Hypothyroidism

Results from a deficiency of thyroid hormone, and is characterized by a decrease in basal metabolic rate and by tiredness, lethargy and sensitivity to cold, as well as other, secondary symptoms.

Microcarcinoma

A tumour defined as less than 1 cm in maximum dimension. It is a recognized variant of papillary thyroid carcinoma, is common, is often multifocal, and is usually considered to be an incidental finding that has no clinical significance.

De-differentiation

Loss of the differentiated characteristics that define mature cells with the full capacity for normal physiological function. In the thyroid, these characteristics include formation of thyroid follicles and production of thyroglobulin and the sodium iodide symporter.

MIB-1 index

A proliferation index that is determined by immunolabelling with the monoclonal antibody MIB-1. This antibody identifies the Ki-67 nuclear protein that is expressed throughout the active cell cycle but is absent in resting cells.

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Kondo, T., Ezzat, S. & Asa, S. Pathogenetic mechanisms in thyroid follicular-cell neoplasia. Nat Rev Cancer 6, 292–306 (2006). https://doi.org/10.1038/nrc1836

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  • DOI: https://doi.org/10.1038/nrc1836

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