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Thyroid Cancer—Risks and Causes

Oncology & Hematology Review, 2014;10(2):144–51 DOI:


The incidence of thyroid cancer has almost doubled in recent years and over 60,000 people will be diagnosed in the US in 2015. While the prognosis for most such patients is excellent, a significant proportion die of thyroid cancer from local tumor progression and above all from metastases. Here we review the different types of thyroid cancers and their molecular changes with a special emphasis on the currently known susceptibility and precipitating factors. With the recent clinical introduction of tyrosine kinase inhibitors for the treatment of metastatic thyroid cancer it is clear that a simple cure is not at hand and further understanding of the molecular mechanisms of these tumors is urgently needed.

Keywords: Thyroid, cancer, follicular, papillary, anaplastic, mutations, gene fusions, susceptibility genes, radioiodine, TSH, autoimmunity, nodules, EMT
Disclosure: Simon Bonnefond, MD, and Terry F Davies, MD, FRCP, FACE have no conflicts of interest to declare. No funding was received in the publication of this article.
Received: August 22, 2014 Accepted: October 08, 2014
Correspondence: Terry F Davies, Box 1055, Mount Sinai Medical Center, 1 Gustave L Levy Place, New York, NY 10029, US. E:

Thyroid cancer is the most common endocrine cancer, representing about 1 % of all malignancies diagnosed worldwide, with approximately 600,000 men and women alive in the US who have a history of cancer of the thyroid ( cts/html/thyro.html). Despite its prevalence, the mortality from thyroid cancer remains relatively low at ~0.5 per 100,000 population per year as a result of the availability of effective therapies for most types of the disease. The exception to this is the anaplastic subtype, which is ranked among the most deadly of all human cancers.

While the incidence of many cancers has remained stable or even decreased in recent years, thyroid cancer incidence has significantly increased with an annual percentage change of 6.4 % for males and females in the US over the period 1997–2010 ( cts/html/thyro.html) (see Figure 1A). There is variation between countries that could be explained by differences in environmental exposure, genetic factors, or access to healthcare (see Figure 1B). It is estimated that 60,000 men and women (15,000 men and 45,000 women) will be diagnosed with the disease in 2014 and almost 2,000 will die. The reasons for this increased incidence are controversial and most likely multifactorial. Increased detection of preclinical stage tumors of small size would appear to be an obvious cause with the introduction and widespread use of thyroid sonography and increased use of aspiration biopsies of small tumor as suggested by Davies and Welch.1,2This explanation for earlier diagnosis and identification of small tumors is supported by the lack of increase in thyroid cancer mortality. But many experts claim that the rising incidence of thyroid cancer cannot be explained by improvements in screening and detection,3–5 as an increase has occurred in large tumors especially papillary thyroid cancer but no significant change for the follicular, medullary, or anaplastic histotypes.1,5 A true increase could be the result of a change in exposure to an unidentified risk factor in the environment or in our lifestyle. To date, ionizing radiation is the best-established risk factor for thyroid cancer, as a result of data obtained from nuclear incidents such as the Chernobyl radioiodine releases and from Hiroshima and Nagasaki. Many studies have focused on other possible risk factors, which we will review.

Patients die of thyroid cancer from local tumor progression and above all from metastases. Epithelial to mesenchymal transition (EMT) is thought to play a major role in tumor genesis/invasion and spread of metastases in many cancers including thyroid cancer. The relationship between cancer cells, EMT, and cancer stem cells (CSCs) is poorly understood although it has been shown that certain epithelial cancer cells that pass through EMT acquire CSC properties including thyroid cancer cells.6,7 Determining the mechanisms by which known risk factors such as EMT initiation could potentially lead to the development of new specific targets for thyroid cancer.

The goal of this review, therefore, is to summarize the risk factors and susceptibilities for thyroid cancer in order to lead to the development of new and more-effective therapeutic targets. Moreover, detailed examination of population-level risk factors can help identify and support prevention efforts to reduce the disease burden.

The Different Types of Thyroid Cancer
Thyroid cancers are still categorized by their histologic appearance and their natural history (see Table 1). The two most common forms of differentiated thyroid cancer are the papillary and follicular types. The papillary form tends not to metastasize outside the neck compared with follicular thyroid cancers, which have a propensity to spread further. This histologic differentiation is now supported by molecular studies (see below). The vast majority of thyroid tumors arise from thyroid follicular epithelial cells but the 3–5 % of medullary cancers originate from the C cells, which secrete calcitonin and are outside the purview of this review.

The well-differentiated thyroid cancers often have an indolent clinical course with low morbidity and mortality. With some exceptions, these are among the most curable of cancers and, as a consequence, patients are sometimes ill advised that thyroid cancer is not a serious problem. Although anaplastic thyroid cancer (ATC), which is highly aggressive and accounts for ~50 % of all thyroid cancer-related deaths, remains uncommon, more malignant forms of differentiated thyroid cancer exist, such as the tall cell variant of papillary thyroid cancer8 and the Hurtle cell follicular cancers,9,10 which can be difficult to treat.

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Keywords: Thyroid, cancer, follicular, papillary, anaplastic, mutations, gene fusions, susceptibility genes, radioiodine, TSH, autoimmunity, nodules, EMT