Radiation+and+Thyroid+Cancer

=**What is the Relationship Between Radiation and Thyroid Cancer?**= By: Analisa Goossens and Nicole Mattson

=Introduction=

**The Thyroid:**


The thyroid gland is a butterfly-shaped hormonal gland that plays an important role in metabolism, growth, and maturation of the body. It is located in the front part of the neck just beneath the Adam’s Apple (also known as the thyroid cartilage) Figure 1 1. The tissue of the thyroid is composed of small individual lobules joined together by thin sheets of connective tissue 1. The lobules contain small vesicles called follicles that store droplets of the thyroids hormones Figure 2 1.



There are two main types of cells that make up the thyroid: follicular cells and C cells. Follicular cells use iodine to synthesize thyroid hormones triiodinethyronine (T3) and tetraiodinethryonine (thyroxine or T4) which increase basal metabolic rate 1. The other main type of cells, C cells (or parafollicular cells), synthesize the hormone calcitonin, which regulates calcium use and bone metabolism 2. The immune system cells, known as lymphocytes, are less common but are also found in the thyroid 2.

**Common Problems Associated with the Thyroid:**
Problems associated with the thyroid generally involve abnormal amounts of hormone production, enlargement of gland, or presence of nodules. A condition known as hyperthyroidism occurs when T3 and T4 hormones are overly expressed, resulting in rapid or irregular heartbeat, nervousness, insomnia, hunger, weight loss, and hot flushes/sweating 2. On the other hand, if not enough hormones are produced, a condition known as hypothyroidism, the result will be a loss of energy, gain in weight, fatigue, slow pulse, dry skin, sensitivity to cold, and even depression 1. These hormones are regulated by the pituitary gland in the brain, which produces the thyroid-stimulating hormone 2. Other problems that may occur to the thyroid involve the enlargement of the gland or the formation of nodules in the gland. Most of the time the enlargement of the thyroid caused by hormonal imbalance (also known as a goiter) is not cancerous, however 1 in 20 thyroid nodules, or lumps in the thyroid gland, are cancerous 2. Different thyroid cancers can also develop, with different forms of the cancer arising from the different types of cells found in the gland.

**Types of Thyroid Cancer:**
Thyroid cancer is not just a one size fits all type of thing, there are multiple forms of thyroid cancer and each are different from the other. The most common types of thyroid cancer are papillary and follicular carcinomas. Other rare but prominent types would be sporadic and familial medullary thyroid carcinoma. These four types will be the focus of this project but it is important to know that other types also exist; those include anaplastic carcinoma, Hurthle cell carcinoma, thyroid lymphoma, and thyroid sarcoma.
 * Papillary carcinoma: The most common type of thyroid cancer, about 8 out of 10 cases. It usually only develops in one lobe of the thyroid, grows very slowly, and frequently spreads to the lymph nodes located in the neck. If caught early it is very easily treated.
 * Follicular carcinoma: The next most common type, about 1 out of every 10 cases. It is believed that low iodine diets are a risk factor for this type. Although this type will not spread to the lymph nodes, it can metastasize in the lung, liver, or bones. It is not as easily treated as papillary carcinoma.
 * Medullary Thyroid carcinoma (MTC): A mutation in the C cells is the cause of this cancer. It can easily metastasize in the surrounding lymph nodes, lungs, and liver before the tumor is even discovered. The C cells do not absorb radioactive iodine, making it extremely difficult to detect the cancer in this manner, however, a blood test can detect the over production of calcitonin and carcinoembryonic antigens that result from cancer.
 * Sporadic MTC: Accounts for about 8 out of 10 cases of MTC and occurs due to random mutations in older adults, affecting only one lobe.
 * Familial MTC: Inherited throughout generations of a family, occurs early in childhood. Often times the cancer affects both lobes and spreads easily to other parts of the body.

=Causes of Thyroid Cancer=

====We know that radiation causes DNA damage, which can lead to the development of cancer. From this, the specific effect of radiation on the development of thyroid cancers was researched. The effect of various forms of radiation that could be contributing to thyroid cancer was reviewed to understand what is known so far and to analyze the relationship between them.====

**Chernobyl:**
In 1986, there was a nuclear power plant meltdown in Chernobyl that caused large amounts of radioactive iodine (Iodine-131) to be released into the surrounding areas. The increased amounts of iodine, specifically radioactive iodine, resulted in an increase in the incidents of thyroid cancer. I-131 was leaked into the nearby areas and infused into the ground and plants; grass that was infused with I-131 were eaten by cows who then produced radioactive milk. That radioactive milk was then drunk by children and young adults of the surrounding area. This is where the problem begins. The thyroid, as described above, is the organ that uses iodine to synthesize certain hormones; so when the I-131 milk was ingested by the children and young adults, the iodine was transported to the thyroid where the radioactivity took its toll.

The children of the affected areas did not get thyroid cancer overnight; thyroid cancer-just like any other cancer- takes multiple steps in order to become a full blown neoplasm. The data in Table 1. shows that it wasn't until after the meltdown, that the rates of thyroid cancer increased. Each year after the meltdown, the number of incidents increased slowly from only 6 cases in 3 years between 1986-1989 then rapidly to 114 cases in 3 years from 1990-1992. This data suggests that it would have taken more than one glass of milk enriched with radioactive iodine to caused the cancer. Milk might not be the only contributing factor either; the iodine could have been in the air or other foods, however, milk is the most plausible source because most of the cases of thyroid cancer occur in children; and children drink milk more often than older adults do. The radioactive iodine that was released into the surrounding areas affected much of the population, with children and young adults being the most affected by the iodine released.

In a separate study conducted by Dr. Yoshisada Shibata, a distinct increase in the incidence of thyroid cancer was observed in children born before the meltdown; a 7.5 fold increase from those born after the meltdown. There could be many explanations for this, one being that after the meltdown everyone evacuated the area, therefore they were not in close proximity to the radioactive material. For those children born before the meltdown, they were immediately affected by the radioactive iodine released into the area, as they were drinking the radioactive milk.  What this data suggests, is that an individual needs to be in direct contact with the radiation in order to be affected by it. This subtlety is probably due to the fact that Iodine has a relatively short half life, which is approximately 8 days. With such a short half life, the original idea of radioactive milk seems implausible, but it still accounts for the data presented. Being born after the meltdown reduced your risk of getting thyroid cancer because most of the radioactive iodine had degraded.  The iodine that was released into the air does not exactly correlate to the rising incidents of thyroid cancer in Belarus and Ukraine. There could have just been an increase in the incidence due to better screening and diagnostic tests, but Jacob Radiol presents the data seen in Table 2 which proves that it was the iodine that caused the thyroid cancers, specifically papillary carcinoma, in Belarus and Ukraine. Knowing that papillary carcinoma is known to be caused from high levels of iodine, it makes sense that the incidence of this type is high in Belarus and Ukraine and not other areas. In specific the incidence of papillary carcinoma is 24 fold greater than follicular carcinoma, and 73 fold greater than medullary carcinomas. This confirms the idea that radioactive iodine was the cause of the increased thyroid cancers. Also, Radiol shows that papillary carcinoma has highest and follicular and medullary carcinomas have the lowest incidence as compared to other countries. This suggests that there are more cases of this type of cancer in Belarus and Ukraine because of the iodine that was released. If the nuclear meltdown did not occur then one would see a more even distribution on thyroid cancers in Belarus and Ukraine. The iodine indeed did cause the cases of thyroid cancer to increase, particularly cases of papillary carcinoma.
 * Who was affected:**[[image:islaslab/made3.JPG width="408" height="236" align="right" caption="Figure 3. Percentage of children with thyroid cancer. Manipulated data from "15 Years After Chernobyl: New Evidence of Thyroid Cancer" by Dr. Yoshisada Shibata."]]

 **Therapeutic Radiation:**

 Thyroid cancer cannot only be acquired by mass radiation exposure events such as Chernobyl, but it can also be caused by more common forms of radiation. Therapeutic radiation treatments have been shown to cause thyroid cancer, particularly when the procedures are performed during childhood. Therapeutic radiations were used to treat lymphomas, Hodgkin’s, tonsil cancers, and even acne in the 1950's, but was soon discovered to increase the risk of thyroid cancer. The affect of therapeutic radiation was first observed through rats, when researchers found that rat thyrocytes subjected to therapeutic radiation had significant clonal DNA damage. Once it was confirmed through the rats experiment that the radiation of the head and neck was causing thyrocyte DNA damage, the differences between radiation-induced and sporadic carcinomas were studied through profiling the genetic mutations of papillary thyroid carcinomas in humans.  The most common mutations in papillary carcinomas of the thyroid include //ras// gene mutations, //RET/PTC// translocations, and //BRAF// mutations. Genes identified in the //ras// gene family code for proteins that are involved in signaling pathways, cell growth, and apoptosis. The next gene, //RET/PTC,// codes for a RET protein that, when stimulated by growth factors, is involved in a signaling cascade leading to the division, maturation, and specialization of the cell. The third gene listed, //BRAF//, codes for a protein that is part of the RAS/MAPK signaling pathway. This pathway regulates cell proliferation, differentiation, and apoptosis, and is essential for human development before birth. Interestingly, when childhood radiation-induced and sporadic papillary carcinomas mutations were compared, it was found that the radiation-induced papillary carcinomas had a lower frequency of the BRAF mutations but higher rates of loss of heterozygosity. Unfortunately, no explanation was determined as to how or why these differences occur. However, w hile the use of these therapeutic radiation procedures are becoming less common, it is still important to be aware of the risks of any radiation exposure.

 **Dental X-rays:**  Another form of clinical radiation that was looked at in relation to thyroid cancer was the radiation emitted by dental x-rays. A case-control study was performed using a population in Kuwait, a country with a relatively high incidence of thyroid cancer, to determine the correlation between thyroid cancer and dental x-rays. Cases were identified as patients who were residents of Kuwait with primary thyroid cancer and who were alive and entered into the cancer registry via the International Classification of Disease for Oncology. The population controls were then selected from local primary health clinics and were individually matched to a case.   The data was collected through medical records and a questionnaire which included medical histories of any type of diagnostic x-rays (including dental x-ray) and the number of exposures, reproductive history, family history, diet, and any other sociodemographic characteristics. A dose response pattern for the number of dental x-ray exposures was analyzed as well as an odds ratio. The study found that patients with thyroid cancer were two times more likely to have been exposed to dental x-rays that those without thyroid cancer (Table 3) 11 .The dose response pattern indicated an increase risk of thyroid cancer with an increase in number of exposures to dental x-ray (Table 3).  While the p values are low enough to deem the data significant, in studies such as this case-control study, there can be many biases that come into play such as recall bias, in which the patient with the disease may know more about there medical history that those without the disease because of their health situation. Moreover, it is very difficult to be completely certain of causality, therefore the study can conclude that dental x-rays can only be considered a risk factor of thyroid cancer. Nonetheless, perhaps merely identifying risk factors and becoming aware of them in our present environment could contribute to lowering incidence rates and mortality rates of thyroid cancer.  **Germline** :

<span style="font-family: Arial,Helvetica,sans-serif;"> Thyroid cancer is not just a cancer of damage and repair induced mutation, it can also be inherited. It is a more rare form of cancer, but still prevalent. The inherited thyroid cancer is a medullary thyroid carcinoma. <span style="font-family: Arial,Helvetica,sans-serif;"> Familial medullary thyroid carcinoma (FMTC) is a sub class of Multiple Endocrine Neoplasia Type 2 (MEN2), a rare hereditary disorder that affects the thyroid. The gene that is mostly associated with FMTC is the RET gene found on chromosome 10, a transmembrane tyrosine kinase involved in the glial-derived neurotrophic pathway. The common mutations associated with FMTC occur in cysteine rich areas in the extra cellular domain of the protein. Mutating one of the cysteines prevents crucial disulphide bridges from forming. Without the ionic bonds, the signal transductase pathway is constitutively turned on because the protein can now form a dimmer without binding to a signal. This gain of function is bad for the cell because now the cell constantly receives a signal to proliferate, thus resulting in a tumor. <span style="font-family: Arial,Helvetica,sans-serif;"> The upside to this uncontrolled cell division is that it is easily detected in early age. The increased amounts of C cells increases the production of calcitonin and those increased levels can be detected by a blood test. A genetic screen to determine the exact location of the mutation is conducted in order to decided the type of treatment that should be given to patients with FMTC. The breakdown is as follows: <span style="font-family: Arial,Helvetica,sans-serif;"> 1) A complete thyroidectomy if there is a mutation in codons 883, 918, or 922. <span style="font-family: Arial,Helvetica,sans-serif;"> 2) A complete thyroidectomy before the age of 5 if there is a mutation in codons 611, 618, 620 or 634. <span style="font-family: Arial,Helvetica,sans-serif;"> 3) A thyroidectomy can be conducted if the clinician recommends it, but is not necessary if there is a mutation in codons 609, 768, 790, 791, 804 or 891. <span style="font-family: Arial,Helvetica,sans-serif;"> Mutations in any of those codons leads to aggressive types of thyroid cancer because the ability of the kinase to form dimmers increases. Other mutations do occur in the intracellular domain, but those are not well studied. <span style="font-family: Arial,Helvetica,sans-serif;"> Before the discovery of correlation between the RET gene and MTC, there was no easy way to diagnosis the thyroid neoplasm. By knowing which gene is affected, the diagnostic abilities have strengthened, which is crucial to increasing the survival rate of patients diagnosed with any MTC. Genetic screens have allowed clinicians to see exactly which codon is mutated and decided how the treat the patient. Also, clinicians have the ability to screen at risk patients for which prospective treatments can be given.

=An Increasing Issue=

<span style="font-family: Arial,Helvetica,sans-serif;">Although studies have pinpointed a few risk factors and causes of thyroid cancer, there is still much that is unknown about this particular disease. This uncertainty has become an even greater issue as incidence of thyroid cancers increase over the years. For example, the question remains whether the increase in incidence is mainly due to more and more people actually acquiring the cancer or due to an increase in detection of previously undetected tumors with the use of more modern diagnostic technology such as fine needle aspiration biopsy and ultrasound. Researchers looking into this issue are leaning more towards the idea that the increase is accredited to modern technology’s ability to detect smaller tumors. <span style="font-family: Arial,Helvetica,sans-serif;"> Figure 4. shows that there has only been a significant increase in papillary cancer, the slower and less aggressive of the thyroid cancers, and smaller tumors. In the past, it was common to find these small tumors while performing autopsies on patients who had never complained of symptoms of thyroid cancer during their life, supporting the idea that detection has merely become more advanced. Furthermore, if there were a true increase in incidence, we should see an increase in incidence of all thyroid cancer types and sizes, which is not the case, as also demonstrated by Figure 4. <span style="font-family: Arial,Helvetica,sans-serif;"> On the other hand, the idea of a true increase in people acquiring these tumors cannot be completely ruled out. Generally, if there is a true increase in a disease, there should be an increase in exposures to risk factors. Since the decline in use of therapeutic radiation, researchers say that the exposures to risk factors has decrease, and therefore we should not see an increase in true incidence. However, looking into the causes and risk factors of thyroid cancer, such as radiation, it is clear that there is still much unknown about what causes the disease and thus it cannot be said that there is no other factor out there that is causing the increasing numbers. <span style="font-family: Arial,Helvetica,sans-serif;"> The problem that we are seeing today with this cause uncertainty is overdiagnosis. Patients with small thyroid cancers that are now just being detected by better technology are undergoing procedures, such as thyroidectomies, to rid themselves of the tumors even though they may never become symptomatic in their lifetime. Risks that accompany such procedures such as the thyroidectomy include compromised voice quality and hypoparathyroidism, in which the thyroid gland does not produce enough parathyroid hormone, leading to low blood calcium levels, abdominal pain, cataracts, muscle cramps, brittle nails, dry hair, and even seizures. While the risks involved with these procedures may not be fatal, it is a large price to pay for an unnecessary procedure.

=Conclusion=

<span style="font-family: Arial,Helvetica,sans-serif;">With the rapid increase in incidents of thyroid cancer it seems shocking that more information isn't readily available. What can be done to alleviate the problem? <span style="font-family: Arial,Helvetica,sans-serif;"> Over diagnosis is an issue with all cancers, this one is no exception. If the increase in incidence is correlated with more sensitive diagnostic tests a change needs to be made in the test. But that may be near impossible to do, so as with breast cancer insitu, doctors may recommend a continued monitoring of the tumors instead of more aggressive treatments. Being told that there is a tumor in your throat is shocking to a patient, even if they are assured it is not cancer. By developing a better plan of action in response to more sensitive tests, the incidence will not go down, but there will be a more appropriate treatment. Moreover, in order to avoid overdiagnosis, research should be done to determine how to test for which tumors will become symptomatic and which will not. <span style="font-family: Arial,Helvetica,sans-serif;"> On the other hand, if radiation is truly causing an increase in the incidents of thyroid cancer a better understanding of when, where, and how patients are coming into contact with sufficiently harmful radiation should be investigated. It is also important to identify how radiation affects the specific oncogenes. For instance, we know that BRAF mutation are less common in radiation-induced carcinomas, but why? What is it about this gene that makes it more susceptible to sporadic mutations? Does a certain does or form of radiation always affect the same gene? <span style="font-family: Arial,Helvetica,sans-serif;"> It seems that the majority of thyroid cancers are caused from mutations in the RET, BRAF, and RAS genes, knowing that is helpful, but perhaps knowing how radiation causes those problems and why could help doctors understand a specific patient's mutation. Along the same lines, a very clear and detailed log should be kept regarding a patients radiation exposure to help with casualty analysis if a cancer should occur. Furthermore, keeping a better log about on how much radiation a patient is exposed will also give hints as to what radiation dose can be tolerated before cancer occurs and what type of radiation seems to be causing cancer. <span style="font-family: Arial,Helvetica,sans-serif;"> Overall, a more clear and detailed explanation needs to be drawn between thyroid cancer and radiation. Making clear distinct connections may be a difficult task but it will help in finding an overall cure for thyroid cancer.