Mayron+Mulugeta

=__The Patient__= Sarah Washington, a single mother of one, and the second eldest of nine siblings, is a lively 53-year-old woman, working two jobs to make ends meet. Although always occupied, she always manages to maintain her outgoing and animated character. She enjoys spending time with friends and traveling to visit family. The hustle and bustle of the holiday season came around as it was her year to host the family festivities. The youthful buzz returned to encompass her in the Christmas spirit and the traditional rounds of games commenced after dinner. Feeling more drained than usual, she opted to sit out of the game. She looked over her shoulder to watch the game that was underway, and her 8-year old nephew sitting in front of her pointed out a small lump in her neck. She discretely brought it to the attention of her older sister who suggested they make an appointment to see the doctor soon. As the holiday season rounded to a close, she returned to her work as a caregiver in two senior homes. Often working two jobs on most days, she found it becoming increasingly difficult to maintain her energy throughout the day. This, along with the thoughts of the small lump constantly racking her brain, she finally went in to the doctor. She had multiple appointments, going back and forth with her sister to accomplish a series of blood tests, a PET scan, and a CT scan. After a biopsy, it was officially declared that she was diagnosed with Stage I follicular thyroid cancer.

=__Diagnosis__= The diagnosis came as disbelief as she had felt that she had been trying to live a healthy and active life, and she had no idea of what this weighted term truly stood for. Did it want her life? Or just to occupy all her efforts and liveliness? Or simply to create a new speed bump in the road of her life? What she did know was that she was a resilient woman that had already experienced her share of journeys. She grew up in the midst of a war, left her home country, and was a single mother. But she was about to embark on a new and different kind of journey. She, as well as her daughter were born and raised in Ethiopia, until she moved to the United States in her thirties. Her daughter had recently finished her graduate school and moved across the country leaving her alone to worry about the diagnosis. She turned to her older sister for guidance as her older sister was previously diagnosed with a benign thyroid nodule and could relate to her initial concern and panic.

=__The Cancer__= Thyroid cancer doesn’t score high on the incidence rankings in comparison to other cancers. Thyroid cancer will have approximately 64,300 new cases in the United States in 2016,(1) which only constitutes a mere 3.7% of all new cancers in the United States (2). This is approximately 25% of the new cases of breast cancer per year (3). There are generally about two to three times more cases of thyroid cancer in women than men (4 ), and 10% of all general thyroid cancer cases have follicular thyroid cancer (5 ). Thyroid cancer may be difficult to diagnose because many general tests do not pick up anything unusually in the thyroid. However one of Sarah’s symptoms was an increase in fatigue. This could result from the growth of the tumor pressing against the trachea, which impedes the oxygen flow to the lungs. This may prevent proper oxygen-rich blood flow to the rest of the body creating bodily weakness and a lack of energy. A common method to check for a thyroid tumor is to examine your neck for nodules (3). This will only work if a cell body has sustained enough cell growth to create a large enough nodule that can be felt through the skin.

Follicular thyroid cancer is not very aggressive and grows slowly as opposed to the more aggressive medullary and anaplastic thyroid cancers. The stages of this cancer run very similar to that of papillary thyroid cancers (figure 1). Stages I and II are considered low-risk with the cancer remaining in the thyroid and being no larger than two centimeters. Stage III is reached when the tumor has reached four centimeters, remains in the thyroid or has begun to spread to lymph nodes or tissues outside of the thyroid. Stage IV is characterized by the spread of tumor cells to nearby tissues, lymph nodes, lungs or bones (6). Follicular thyroid cancer is less likely than papillary thyroid cancer to spread to lymph nodes, however it is more likely to spread to other organs (5). Although alarming, it is not an aggressive cancer and can be stopped before it reaches this state. The size of the nodule however can still impede on the thyroid’s functions such as its ability to regulate breathing, heart rate, metabolism and many other functions. The differentiated cells of thyroid cancers make it slightly more difficult to detect cancerous cells because they may look similar under a microscope. Due to this, other methods must be used to di stinguish cancerous cells.

=__**Progno**____**sis**__= No one looks forward to the day they are diagnosed with cancer, but you can almost see the light at the end of the tunnel when it comes to follicular thyroid cancer. The prognosis for this cancer has a very good outlook when detected early with 90% of patients being cured. The outlook for each individual differs of course, but there are some factors that can decrease the positive outlook such as being older that 45, invasion to other glands or organs, being a male and late diagnosis (7 ). The amount of invasion plays a large role in the outlook of the individual. For example, if the cancerous cells were maintained in the thyroid, the 5-year survival rate is 98%. However, if the cancerous cells are found in distant parts of the body, the 5-year survival rate drops significantly to 54%. Generally, individuals with thyroid cancer do not have shortened lives as 95% of individuals with localized cancer cells have at least a 15-year survival rate (8 ).

In Sarah’s case, an insufficient amount of iodine was not ruled out from being the culprit. Iodine is needed to produce two main hormones that must remain in balance in the thyroid in order to correctly regulate bodily functions. In countries where there is a low iodine intake, thyroid diseases are much more common. The United States has adequate iodine intake, while some regions of Africa, including Ethiopia, have moderate iodine deficiency (9 ). Much of the iodine intake comes from salts, which has decreased the amount of iodine deficient countries, however slow progress is being made in Africa. Further symptoms such as neck pain and trouble swallowing come with an increasing size of the nodule that begins to interfere with ordinary neck movements (10).

=__**The Molecular Basis**__= As Angelina tried to think back and attempt to recall when things started to go downhill, she was missing one major key. Cancers do not merely appear after a single stroke of bad luck, they result from an accumulation of mutations in genes over time. Some gene mutations may be similar in some people, or entirely different in others, however they all may lead to the same cancer. These mutations can arise in oncogenes, tumor suppressors, or can be alterations to pathways, aberrant gene methylation and many more. Follicular thyroid cancer cells are well- differentiated, meaning that they appear to be similar to normal cells when looked at under a microscope. Follicular cells refer to cells in the thyroid gland that secrete hormones such as thyroxine and triiodothyronine, which are responsible for regulating metabolism, heart rate and other essential functions (12). In regards to follicular thyroid cancer, there is not one gene that has been proven to cause cancer when mutated, however there are some genes that are slightly ahead of the pack in terms of prevalence of mutations.

A commonly known mutation in thyroid cancer is to the BRAF gene, which leads to activation of the MAP kinase pathway. The MAP kinase pathway leads to cell proliferation, apoptosis, or cell survival (13). A mutation in BRAF can cause normal cells to become cancerous by overgrowing or not dying when there is cell damage. Ras is another gene that is commonly mutated, which can lead to active MAP kinases, which go on to result in cell proliferation. Ras is also involved in the PI3K/Akt signal cascade. This cascade is found to be commonly amplified in thyroid cancers. In the pathway, Akt goes on to promote cell proliferation and inhibit apoptosis. These mutations are examples of the Hallmark for sustained proliferate cell growth signaling and avoiding cell death (13).

As for tumor suppressors, loss of function of the PTEN gene activates the PI3K/Akt pathway, which leads to cell proliferation, with similar end results as the gain of function mutation of the Ras gene. Aberrant gene methylation can silence genes, including tumor suppressors such as PTEN (14). PTEN normally functions by dephosphorylating PIP3, which suppresses the signaling of the PI3K/Akt pathway (13) as shown in figure 2. When mutated, the PI3K/Akt pathway will not be inhibited, leading to continuous cell growth. This pathway is a complex chain reaction, with the first link being the signal receptor and the final step being cell proliferation. All the links between the two can be mutated and begin the chain reaction from that location, similar to the lining up of dominos. For example, Ras is one of the middle pieces however when it becomes mutated (or gets knocked over) the chain event will occur from that location and eventually lead to cell proliferation at a much quicker rate.



Follicular thyroid cancer does not metastasize often, meaning that it rarely goes on to invade distal tissues. It is not as likely to spread to the lymph nodes, however it could spread to other organs in stage IV. The spreading of the cancer indicates a much more advanced state that makes it more difficult to treat or to remove the tumor. Patients with thyroid cancers have a high ten-year survival rate of 97%, which is very promising in comparison to the 87% ten-year survival rate of breast cancer (16, 17). However when thyroid cancer has spread to other organs, the ten-year survival rate drops drastically to 40%. For patients over the age of 40 with follicular thyroid cancer, about 25% of them will have their cancer spread to other organs. Bone metastasis occurs between 7% and 28% of follicular thyroid patients. Cancerous cells travel to the bones on the hungry search for nutrients as the bones house many growth factors that the cells can thrive on. However, metastasis to the bones results in resistance to the radioactive iodine that is often used for treatment against the cancer (14).

Radioactive iodine is a common method of therapy, however it is seen to work better on patients under 45 years old (14). Poorly differentiated thyroid cancer can also have a decreased ability to be impacted by the radioactive iodine treatment. If this occurs, the metastatic events cannot be targeted. This leaves surgery as an option to get rid of the cancer (15). If neither of these options is available, there may be no way of removing the tumor from what was once an easily curable disease.

=__** Standard of Care **__= Follicular thyroid cancer does not show bias in its standard of care across the board, as it is the same for adults as it is for children (23). Sarah’s stage I cancer calls for surgery to remove the growing tumor, followed by radioactive iodine pills. Surgery is used for cancers that are localized in the thyroid gland, meaning that it has not spread to other areas of the body (19). As no two cancers are the same, the type of surgery also varies on the size of the tumor. Therefore, the size of Sarah’s tumor needed to be determined to see what further steps need to be taken. If the tumor is very small, less than one centimeter in diameter, a unilateral lobectomy can be performed, meaning that one lobe of the thyroid (which can be divided into the left and right lobe) will be removed (19). If the tumor is more than one centimeter, a total thyroidectomy is performed, meaning that the entire thyroid is removed from the body. This is to ensure that the whole of the thyroid cancer is removed. If the tumor is metastatic, a total thyroidectomy is also done along with the removal of cancerous lymph nodes (19).

The removal of the tumor may have seemed like the toughest mountain to climb, but there is still a long way to go. Following surgery, radioactive iodine is given to the patients as a precautionary method to ensure that there are no metastasis or residual tumor left behind (19). Radioactive iodine is taken in a pill form that will eventually end up in the thyroid. This travels to the thyroid the same way iodine would if it were being taken up by the gland. Once at the thyroid, the radiation from the pill will damage the thyroid cells that still remain (20). As it is still radiation on the body, side effects such as nausea, vomiting, or swelling in the areas where the radiation is collected could occur. Signs of side effects are checked for by first giving patients smaller test doses to make sure the treatment will be effective with minimal costs (28).

Patients must then be given thyroid hormone replacement therapy pills after their main treatment for the rest of their life to make up for the necessary function of the hormones that the thyroid used to house (19). Due to this, thyroid cancer can never be something of the past. There is a constant reminder of the mental and physical hardships that they had to endure.

=__** Screening **__= Thyroid cancer is not a cancer that screening is widely recommended for, such as in breast cancer. Screenings are recommended when the disease effects a large portion of people, which thyroid cancer does not, or if there is a better survival rate to finding cancers pre symptomatically, which there is not (24). Screenings can be done at regular check ups and are often done by doctors feeling the thyroid region for any nodules or lumps (figure 3) (21). Nodules would occur if there were an increased body of cells in one region. These lumps of course are not the sole indicators of cancer, and further tests need to be done. These can take the form of an ultrasound or a biopsy, however they are often used together for better results. The ultrasound utilizes sound waves that will bounce off the lumps and reveal how many there are, their sizes, and if they are solid or fluid-filled. When using ultrasounds, solid nodules have an increased likelihood of being cancerous (21). To diagnose the cancer, a small sample must be taken from the module by using a thin needle. To do this more efficiently, the ultrasound is used to guide the hallow needle into the nodule. It is then taken out, collecting some cells. This is repeated in different areas of the nodule and examined under a microscope to determine if they are cancerous (22).



=__** Treatments **__= The current treatments are effective and should not be differentiated by age, as shown by a study done of patients that underwent the standard of care at the University Hospital Groningen in The Netherlands. Their treatment included surgery to remove nearly all or the entire thyroid, followed by radioactive iodine therapy and thyroid hormone replacement therapy. The study found that radioactive iodine does not exhibit additional health costs, however it is not successful in its function for 20% of patients. 7% of patients had reoccurrence of the tumor after complete remission. However the median time was 54 months until remission. This demonstrates the slow progress of thyroid cancers, which may not account for all reoccurrences because the study had an average follow up of 9 years, while reoccurrences can even occur 20 years after treatment (19).

The average age of diagnosis in this study was 34.5 and there was no evidence to prove that patients above the average age had a shorter life expectancy. As a result, there should be no difference in treatment based on age. However what does result in a shorter life expectancy is metastases to lymph nodes and distant organs. It is believed that there is a reduced risk of shorter life expectancy in younger patients with metastatic tumors due to their age. However this study finds that it is not due to age, but the metastatic properties of the cancer. This is often overlooked and efforts should instead be made to find new ways to treat persistent cancers (19).

In general, thyroid cancer treatments have successful outcomes, but improvements can always be made. For example, part of the standard of care includes radioactive iodine to help with the reoccurrence or spread of the cancer. In some cases, radioactive iodine cannot function correctly, leaving patients at an increased risk, or in need of treatments that are not as commonplace. An example of this can arise from a mutation in the BRAF gene that prevents the function of radioactive iodine pills. Drugs are being tested to attempt to target the BRAF pathway to allow cells to uptake radioactive iodine (25).

Without blood vessel growth around tumors, the tumor cannot grow. Mutations to genes such as BRAF and RET/PTC allow for the increase of blood vessel growth. Kinase inhibitors such as sorafenib and lenvatinib block the ability for tumors to grow and can be of great use to patients that are not responding well to standard treatments (26). Many clinical trials are targeted towards patients with recurrent or metastatic thyroid cancers, therefore they are not recommendable for Sarah’s localized tumor. One clinical trial being organized from the University of Michigan could be offered to Sarah if the tumor does not respond to radioactive iodine after surgery. This clinical trial looks at how pioglitazone hydrochloride can inhibit tumor growth by binding to a necessary protein for growth (28). This would assist in slowing down recurrent growth after surgery.

The future for follicular thyroid cancer looks even more promising as more research is being done to target metastatic tumors and hopefully bring up the cure percentage to that of localized tumors. Sarah is now back to work and back to doing the things that she loves. All she has to worry about is maintaining her thyroid hormone replacement therapy.

Aperçu: The causes for follicular thyroid cancer are often out of ones control, however a positive outcome can still be drawn. Although cancer is a daunting term, the consistent standard of care for localized tumors with its high curable rate provides an ease of mind to patients. However do not feel the need to feel forced into this treatment, and do not be afraid to question methods and options presented.

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