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Molecular pathology of thyroid cancer: diagnostic and clinical implications

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There is now a reasonably good understanding of the key oncogenic events involved in the initiation and progression of thyroid cancer. Many of these are characteristic of certain tumor types, and their presence conveys diagnostic and prognostic information. It is not yet clear how this information will be applied to clinical practice. Based on preclinical evidence, mutations of genes encoding certain kinases may also predict response to specific tyrosine kinase inhibitors, although this has not yet been explored systematically in clinical trials.

Section snippets

Papillary thyroid cancer (PTC)

PTCs represent approximately 80% of all thyroid malignancies. The overall incidence of this particular form of thyroid cancer is rising, for reasons that remain unclear but that in part may reflect earlier diagnosis.2 As a rule these are slow-growing tumors that lead to progressive disease relatively infrequently. The pathological diagnosis of PTC relies primarily on the nuclear morphology of the cells. Different variants are described, depending on certain combinations of growth patterns, cell

Follicular thyroid cancer (FTC)

Follicular carcinomas account for 10–15% of thyroid cancers. They are usually unifocal, and have a much lower frequency of lymph-node involvement (<5%) than PTC. By contrast, distant metastases, primarily to lung and bone, are comparatively more frequent at presentation (∼20%).3

Hürthle or oncocytic cell cancer (HCC)

Although this tumor has been considered by some as a distinct clinical entity, the current WHO/AIRC (Italian Association for the Research against Cancer) classification describes HCC as a variant of FTC3 characterized by the aberrant accumulation of mitochondria. HCCs have distinct biological and clinical behaviors. They are more frequently refractory to treatment with radioactive iodine, and have a greater predisposition to develop lymph-node metastases than FTCs.1

Poorly differentiated carcinoma (PDTC) and anaplastic carcinoma (ATC)

PDTCs have a degree of severity intermediate between that of differentiated and anaplastic carcinomas, and are characterized by an infiltrative pattern of growth, necrosis, a higher mitotic index, and vascular invasion.3, 72 ATCs, also called undifferentiated thyroid carcinomas, are highly malignant tumors composed of undifferentiated cells retaining markers of an epithelial lineage. They are usually large, markedly invasive, and consist of admixtures of spindle, epithelioid and pleomorphic

Beta-catenin and the APC pathway in thyroid cancer

The β-catenin protein, encoded by CTNNB1, functions in both cell adhesion and transcription. In normal cells, β-catenin is mostly bound to cell membrane cadherins at adherens junctions, thus fulfilling its essential role in cell adhesion, and remaining sequestered from the nucleus and its growth-promoting role.95 Also β-catenin is a critical component of the Wnt signaling pathway, which is crucial during embryonal development and is also activated in various human cancers. The cellular

Use of molecular genetic information for preoperative diagnosis

As some of the most prevalent thyroid oncogenes are found exclusively (i.e. BRAF, RET/PTC) or with high frequency (RAS, PAX8–PPARγ) in malignant tumors, several groups have explored whether screening for mutations improves the diagnostic accuracy of cytopathology after fine-needle aspiration of thyroid nodules.101, 102, 103, 104, 105, 106 Although molecular diagnostics is controversial in this setting107, the preponderance of the evidence suggests that it could become a useful adjunct to

Acknowledgements

This work was supported in part through NIH-CA50706 and CA72597, a Translational and Integrative Medicine Research Grant from MSKCC and the Margot Rosenberg Pulitzer Foundation (JAF).

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