Causes of Thyroid Cancer

Thyroid cancer is rare, accounting for less than 1% of all malignancies, but the incidence of thyroid cancer is increasing, with 2553 new cases in Australia in 2013 (619 cases in Victoria in 2015). Usually the cause is not known, however there are a number of risk factors for thyroid cancer being present in a thyroid nodule:

• history of neck irradiation
• age younger than 20 years and older than 50 years
• low or high iodine intake
• history of change in voice
• history of previous benign thyroid disease
• family history of thyroid cancer or MEN syndrome
• syndromes – Gardner’s, Cowden’s and familial adenomatous polyposis (FAP)
• examination findings: large, fixed nodule or lymph nodes

Certain studies have shown that the risk of thyroid cancer decreases with greater alcohol intake (> or =2 drinks per day), which suggests a potential protective role for alcohol consumption in thyroid cancer.

Radiation

The relationship between radiation and thyroid cancer has been recognised since the 1950s. External beam radiotherapy was often given in the early to mid 20^th century as treatment for enlargement of the tonsils, adenoids, thymus and lymph nodes in the neck, and even for skin conditions such as acne and tinea capitis. It has been well documented that radiation to the neck given to children in this way results years later in the development of thyroid cancers.

Nuclear fallout from the atomic bombing of Japan in 1945 and accidents such as Chernobyl in 1986 resulted in an increased incidence of thyroid cancer in the affected population. Two thirds of radiation induced tumours are benign, and one third malignant, most of which (70-95%) are papillary cancers.

The relative risk increases for 5-10 years after exposure, peaks at 15-20 years and decreases over subsequent years, but can still be apparent at 40 years. High dose radiation can also induce cancers in the thyroid even when exposure to radiation has been elsewhere in the body from the neck, such as in treatment for Hodgkins lymphoma, cervical cancer or childhood abdominal tumours.

The younger the age of exposure the higher the risk, as radiation has greater effects during periods of rapid cell proliferation such as in the developing thyroid gland.

Radioiodine (131I) treatment of thyrotoxicosis however, is not associated with a significant increase in thyroid cancer.

TSH levels

Higher TSH levels, even within the normal range, have been associated with a greater risk of thyroid malignancy. The relationship between TSH and papillary thyroid cancer (PTC) was analysed in a recent large study from Pisa, which showed that TSH levels were significantly higher in PTC patients than in patients with benign thyroid nodular disease or with a clinical diagnosis of multinodular goitre and single/isolated nodule. A significant age-dependent development of thyroid autonomy (TSH <0.4 µU/ml) was observed in patients with benign thyroid disease, but not in those with PTC, diagnosed both on cytology and histology.

In patients with MNG, the frequency of thyroid autonomy was higher and the risk of PTC was lower compared to those with single nodules. In all patients, the presence of thyroid auto-antibodies  (TAb) was associated with a significant increase of TSH. However, both in TAb positive and TAb negative patients TSH levels were significantly higher in PTC than in benign thyroid disease. There seems to be a direct relationship between TSH levels and risk of PTC in patients with nodular thyroid diseases. Thyroid autonomy conceivably protects against the risk of PTC, while thyroid autoimmunity does not play a significant role.

Genetic

Common genetic alterations found in human papillary thyroid cancer are RET/PTC rearrangements, the BRAF V600E mutation and PAX8/PPARγ mutations. A mutation of the BRAF oncogene is the most common genetic alteration found in papillary thyroid carcinoma (PTC) and is associated with extrathyroidal extension, lymph node metastasis, and tumor recurrence. RAS mutations have a role in both papillary and follicular thyroid cancer development (Table 1).

Table 1: Common genetic abnormalities in thyroid tumours: frequency and histological & clinical associations

Medullary cancer of the thyroid may arise as a familial condition due to a variety of germline mutations on chromosome 10 in the RET gene, occurring as part of the MEN syndrome.

Familial

It has been estimated that between 3 and 6% of thyroid cancer can be explained by familial factors. Over 90% of familial thyroid cancers are PTC and there has been a 4-10-fold increase in the incidence of PTC reported in relatives of patients with PTC.

If a parent has a PTC, this increases the risk 3 times, but a sibling with PTC increases the risk to 6 times the rest of the population.

There are a variety of familial associations with well-differentiated thyroid carcinoma, grouped under the heading of familial non-medullary thyroid cancer (FNMTC). Hereditary non-medullary thyroid cancer may occur as a minor component of familial cancer syndromes (familial adenomatous polyposis, Gardner's syndrome, Cowden's disease, Carney's complex type 1, Werner's syndrome, and papillary renal neoplasia) or as a primary feature (familial non-medullary thyroid cancer [FNMTC]).

Epidemiologic and clinical kindred studies have demonstrated that FNMTC is a unique clinical entity. Most studies suggest that FNMTC is associated with more aggressive disease than sporadic cases, with higher rates of multicentric tumors, lymph node metastasis, extrathyroidal invasion, and shorter disease-free survival. A hereditary predisposition to non-medullary thyroid cancer is well established, but the susceptibility genes for isolated FNMTC have not been identified.

A rare familial predisposition has been identified for papillary thyroid cancer (PTC) with a strong association with multinodular goitre (MNG). This condition of familial PTC (FPTC) involving abnormalities on chromosome 14 has an autosomal dominant inheritance, with a peak of diagnosis in the third decade of life, a female to male ratio of 2:1, and a slightly more aggressive course than sporadic PTC. A family history of younger PTC or MNG patients, especially with multifocal, invasive or metastasising tumours should raise the suspicion of FPTC. Associations have also been studied between PTC and certain types of renal cell carcinoma.

A variety of other mutations can increase the incidence of thyroid cancer: mutation in the APC gene on chromosome 5 in familial adenomatous polyposis (FAP) is associated with PTC (5-10-fold increase), while the PTEN genetic mutations on chromosome 10, resulting in the multiple hamartoma formation of Cowden’s syndrome, are associated with FTC.  Other oncogenes, like the RAS genes and growth factors, can stimulate tumour growth when activated, and mutations in tumour suppressor genes like p53 may be important in the initiation of thyroid tumour growth and progression.

Iodine

Follicular cancer rarely occurs in Iceland where, due to high dietary intake of fish, there is high iodide intake. In contrast, in areas of low iodide intake (mountainous regions such as the Alps, Andes and Himalayas) follicular cancer has a high incidence, due to chronic TSH stimulation of the thyroid.

Iodising salt and bread as a public health measure to combat iodine deficiency does not change the incidence of thyroid cancer, but increases the proportion of papillary cancers and reduces the incidence of follicular cancer. The overall incidence of thyroid cancers remains virtually the same, only the mix of types is different. In Australia iodine deficiency is rare and supplements are generally not needed, and may in fact be harmful if taken in excess quantities.

Thyroiditis

Fig.1: MALT lymphoma of thyroidPapillary cancers may arise more often in patients with a long-term severe inflammation of their thyroid (thyroiditis).

The vast majority of primary thyroid lymphomas almost always arise in the background of chronic lymphocytic thyroiditis (Hashimoto’s thyroiditis) (Fig. 1).

Some thyroid lymphomas arising in this background of lymphocytic thyroiditis are part of the mucosal-associated lymphoid tissue system (MALT). Indeed, up to 69% of thyroid lymphomas have been demonstrated to be of MALT origin and thyroid lymphomas are noted to occur in association with gastrointestinal MALTomas.