Best Practice & Research Clinical Endocrinology & Metabolism
5Molecular pathology of thyroid cancer: diagnostic and clinical implications
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).
References (120)
- et al.
Intragenic mutations in thyroid cancer
Endocrinology and Metabolism Clinics of North America
(2008 Jun) Thyroid carcinoma: molecular pathways and therapeutic targets
Modern Pathology
(2008 May)The GDNF/RET signaling pathway and human diseases
Cytokine & Growth Factor Reviews
(2001 Dec)- et al.
The ins and outs of Raf kinases
Trends in Biochemical Sciences
(1994 Nov) - et al.
The Raf/MEK/ERK pathway: new concepts of activation
Biologie cellulaire
(2001 Sep) - et al.
Biochemical analysis of MEK activation in NIH3T3 fibroblasts. Identification of B-Raf and other activators
The Journal of Biological Chemistry
(1995 Mar 31) - et al.
Oncogenic B-Raf mutations: crystal clear at last
Cancer Cell
(2004 Apr) - et al.
Follicular thyroid tumors with the PAX8-PPARgamma1 rearrangement display characteristic genetic alterations
The American Journal of Pathology
(2005 Jul) - et al.
Oncogenic RAS induces accelerated transition through G2/M and promotes defects in the G2 DNA damage and mitotic spindle checkpoints
The Journal of Biological Chemistry
(2006 Feb 17) - et al.
Mitochondrial DNA somatic mutations (point mutations and large deletions) and mitochondrial DNA variants in human thyroid pathology: a study with emphasis on Hurthle cell tumors
The American Journal of Pathology
(2002 May)
Mutant PIK3CA promotes cell growth and invasion of human cancer cells
Cancer Cell
Thyroid pathologic findings in patients with Cowden disease
Annals of Diagnostic Pathology
Dysregulation of the phosphatidylinositol 3-kinase pathway in thyroid neoplasia
Endocrinology and Metabolism Clinics of North America
Differential nuclear and cytoplasmic expression of PTEN in normal thyroid tissue, and benign and malignant epithelial thyroid tumors
The American Journal of Pathology
The many ways of Wnt in cancer
Current Opinion in Genetics & Development
Beta-catenin dysregulation in thyroid neoplasms: down-regulation, aberrant nuclear expression, and CTNNB1 exon 3 mutations are markers for aggressive tumor phenotypes and poor prognosis
The American Journal of Pathology
Increasing incidence of thyroid cancer in the United States, 1973–2002
JAMA: The Journal of the American Medical Association
Molecular mechanisms of RET activation in human cancer
Annals of the New York Academy of Sciences
Characterization of a multicomponent receptor for GDNF
Nature
Distinct pattern of ret oncogene rearrangements in morphological variants of radiation-induced and sporadic thyroid papillary carcinomas in children
Cancer Research
RET/PTC oncogene activation is an early event in thyroid carcinogenesis
Oncogene
Distinct multiple RET/PTC gene rearrangements in multifocal papillary thyroid neoplasia
The Journal of Clinical Endocrinology and Metabolism
Targeted expression of the ret/PTC1 oncogene induces papillary thyroid carcinomas
Endocrinology
Development of thyroid papillary carcinomas secondary to tissue- specific expression of the RET/PTC1 oncogene in transgenic mice
Oncogene
The RET/PTC3 oncogene: metastatic solid-type papillary carcinomas in murine thyroids
Cancer Research
In vitro irradiation is able to cause RET oncogene rearrangement
Cancer Research
Continued expression of a tissue specific activated oncogene in the early steps of radiation-induced human thyroid carcinogenesis
Oncogene
RET rearrangements in post-Chernobyl papillary thyroid carcinomas with a short latency analysed by interphase FISH
British Journal of Cancer
Prevalence of RET/PTC rearrangements in thyroid papillary carcinomas: effects of the detection methods and genetic heterogeneity
The Journal of Clinical Endocrinology and Metabolism
RET activation and clinicopathologic features in poorly differentiated thyroid tumors
The Journal of Clinical Endocrinology and Metabolism
Correlation between genetic alterations and microscopic features, clinical manifestations, and prognostic characteristics of thyroid papillary carcinomas
The American Journal of Surgical Pathology
Molecular profiling of poorly differentiated and anaplastic thyroid cancers by mass spectrometry with a thyroid cancer-specific platform reveals distinct patterns of oncogenic activation
American Thyroid Association
Characterization of intracellular signals via tyrosine 1062 in RET activated by glial cell line-derived neurotrophic factor
Oncogene
High prevalence of BRAF mutations in thyroid cancer: genetic evidence for constitutive activation of the RET/PTC-RAS-BRAF signaling pathway in papillary thyroid carcinoma
Cancer Research
Alternative mutations of BRAF, RET and NTRK1 are associated with similar but distinct gene expression patterns in papillary thyroid cancer
Oncogene
BRAF mutations and RET/PTC rearrangements are alternative events in the etiopathogenesis of PTC
Oncogene
Detection of activated ras oncogenes in human thyroid carcinomas
Oncogene
Point mutations of ras oncogenes are an early event in thyroid tumorigenesis
Molecular Endocrinology (Baltimore, Md.)
Molecular profile and clinical-pathologic features of the follicular variant of papillary thyroid carcinoma. An unusually high prevalence of ras mutations
American Journal of Clinical Pathology
BRAF mediates RET/PTC-induced mitogen-activated protein kinase activation in thyroid cells: functional support for requirement of the RET/PTC-RAS-BRAF pathway in papillary thyroid carcinogenesis
Endocrinology
Oncogenic AKAP9–BRAF fusion is a novel mechanism of MAPK pathway activation in thyroid cancer
The Journal of Clinical Investigation
BRAF mutation in thyroid cancer
Endocrine-Related Cancer
BRAF mutations are associated with some histological types of papillary thyroid carcinoma
The Journal of Pathology
BRAF mutations in thyroid tumors are restricted to papillary carcinomas and anaplastic or poorly differentiated carcinomas arising from papillary carcinomas
The Journal of Clinical Endocrinology and Metabolism
BRAF mutations in papillary carcinomas of the thyroid
Oncogene
Clinical implication of hot spot BRAF mutation, V599E, in papillary thyroid cancers
The Journal of Clinical Endocrinology and Metabolism
High prevalence of BRAF gene mutation in papillary thyroid carcinomas and thyroid tumor cell lines
Cancer Research
BRAF mutation in papillary thyroid carcinoma
Journal of the National Cancer Institute
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