Che,+Andrea


 * ** Esophageal Cancer: Adenocarcinoma ** ||

**The Cancer**

__ Introducing the Patient: __ My grandmother lived in a rural area in Changzhou, China. She raised five children, including my father, her third child. Life was tough for them, but they appreciated it every day. Until one day, my grandmother felt pain in her chest when she was swallowing. As the pain enhanced, she checked in at a local hospital and was diagnosed with stage III adenocarcinoma of the esophagus. That year, she was forty-six. Because I never met my grandmother, I only know her from my father. As my father described, my grandmother never smoked cigarettes or drank alcohol. Smoking, not only a risk factor of lung cancer, is also a major risk factor of esophageal cancer. People who smoke more than a pack of cigarettes a day double their chances of developing adenocarcinoma compared to nonsmokers. A combination of smoking and drinking raises the risk. Despite her healthy lifestyle, she passed away two years after her diagnosis, and never had a chance to enjoy old age.

__ Risk Factors: __ What were the risk factors that led to esophageal cancer in my grandmother? My grandmother was diagnosed with a late stage adenocarcinoma, one of the two major types of esophageal cancer, which starts in the gland cells. Gland cells are not normally found in the esophagus, and interestingly, these gland cells found a way to replace squamous cells, which are the surface lining of the hollow organs including the esophagus. My grandmother had Barrett’s esophagus, which is a high risk factor that leads to adenocarcinoma. Barrett’s esophagus is caused by a continuous reflux of stomach acid into the gastroesophageal junction, located between the esophagus and the stomach. The squamous cells, which do not tolerate the acid are damaged and replaced by gland cells. The gland cells form linings in stomach and the small intestine, and they are resistant to stomach acid. However, as reflux continuous, the gland cells in the lower end of the esophagus begin to become pre-cancerous cells. Then, those pre-cancerous cells go through series of mutations that allow them to proliferate and become a tumor that blocks the pathway to the stomach. If the esophagus has narrowed to one-half of its normal size, it will lead to dysphasia, which makes swallowing difficult and painful. Research has shown that many people with risk factors never developed esophageal cancer, whereas other people may not have any risk factors, but still developed esophageal cancer. If esophageal cancer is diagnosed in earlier stages, a patient can recover. Unfortunately, it is often diagnosed in later stages. At stages IV, usually cancer can be treated but cannot be cured because invasive cancer cells have travelled to other sites in the body.



__ Statistics: __ China is one of the main countries that have the highest number of incidences for esophageal cancer. Esophageal cancer occurs 20 to 30 times more frequently in China than in the U.S.. Every year, about 300,000 people die worldwide due to this type of cancer, and half of these deaths occur in China. The general trend of people who have esophageal cancer shows the chance of developing esophageal cancer increases with age. In China, the average age an individual is diagnosed with esophageal cancer is 40; on the other hand, in the U.S., usually people are diagnosed around age 55. The average life expectancy for patients with esophageal cancer is five years. With stage I (T1) esophageal cancer, the cancer is localized, and 39.6% of the patients survive over 5 years after diagnosis. With stage II (T2) esophageal cancer, the cancer usually spreads to regional lymph nodes, and 21.1% of the patients survive over 5 years. With stage III (T3) esophageal cancer, the cancer grows beyond the esophagus, and 21.1% of the patients survive over 5 years. With stage IV (T4) esophageal cancer, the cancer spreads to other parts of the body, and only 3.8% of the patients survive over 5 years. Compared to other cancers, esophageal cancer only represents 1.1% of new cancer cases in the U.S., but it is more aggressive in terms of survival rate compared to other cancers. There were about 18,170 new cases, and 15,450 deaths in 2014. Esophageal cancer is most frequently found in age 65-74, and the highest percent of deaths is also found in this age group. From 2007-2011, there were 1.7 new cases per 100,000 persons in white women, and 1.0 of new cases per 100,000 persons in asian women.

__ Follow-up with the Patient: __ Back in the late 1930s and early 1940s, technology in hospitals was not advanced enough to perform treatments or even find which mutated genes were the causes of cancer, especially in the rural area that my grandmother lived. She also knew that it would be hopeless to go to the hospital because nobody with this type of cancer ever came out from the hospital once they went in. During my grandmother’s generation, my family was poor. With the responsibility of taking care of five children, she decided not to add more burdens to the family.

** Molecular Basis of Esophageal Cancer **

__ FLG gene: __ Cancer is a multi-step process. Accumulated mutations occur and make otherwise healthy cells to grow uncontrollably. In esophageal adenocarcinoma, eighteen percent of the patients have mutated FLG gene. Collected data shows that mutation of a combination of two or three genes could lead to esophageal adenocarcinoma, but some patients with only one mutated FLG gene have developed esophageal cancer as well . FLG gene encodes for the intermediate filament-associated protein that aggregates keratin intermediate filaments in mammalian epidermis. Many students would ask, “how does this keratin intermediate filaments relate to esophageal cancer?” It turns out that ninety-five percent of the cells in the epidermis in esophagus are keratinocytes. Keratinocytes are epidermal cells that produce keratin. Keratinocyte stem cells are located in the basal layer of the epidermis. As these cells divide and differentiate, they move upwards to the epidermis, and eventually, they would be the outer most layer of the epidermis, called the stratum corneum. Stratum corneum layer is composed of dead cells creating a tougher outer layer of protection. The stratum granulosum layer is right below the stratum corneum. When stratum granulosum cells differentiate into stratum corneum cells, they produce FLG; FLG functions to aggregate keratin filaments, resulting in the cornified cells, which have a critical role as barrier function. Stratum corneum cells are the first line of defense between the body and the environment in the esophagus. Those cells also serve as a chemical immune role as immunomodulaters in response to injury. People who have normal FLG gene that creates healthy stratum corneum cells would be less likely to develop Barrett’s esophagus. As reflux of stomach acid happens, the stratum corneum cells, which do not tolerate the acid are damaged and replaced by gland cells. The gland cells are found in the linings of stomach and the small intestine are resistant to stomach acid. However, as reflux continuous overtime, the gland cells in the lower end of the esophagus begin to become pre-cancerous cells. Healthy FLG gene would produce stratum corneum cells at a constant rate and continuously being replaced by new stratum corneum cells. The replacement of injured stratum corneum cells caused by reflux would be faster than the rate of being damaged. The Barrett’s esophagus would be less likely to develop in people with normal FLG gene, which also decrease the chance of developing esophageal adenocarcinoma. On the other hand, when FLG gene expression is turned off due to loss-of-function mutation, new stratum corneum cells would not be made to protect the esophagus. If FLG gene is mutated, stratum granulosum cells cannot be certified into stratum corneum cells. Lack of FLG gene would also affect the natural moisturizing factor (NMF) once served by stratum corneum cells. Normally, stratum corneum cells have functions such as maintaining hydration, barrier homeostasis, and desquamation. Because FLG gene does not function, epidermal cells would be too dry and stratum corneum layer would shed, exposing the stratum granulosum cells, which cannot serve the functions of stratum corneum cells.

__ Growth Factors: __ Without stratum corneum cells in the esophagus patients who have mutated FLG gene, one way we can help these patients is by upregulating growth factors. During the development of epidermal cells from basal cells, several growth factors are in control of inducing basal cells division and growth. Transforming growth factor alpha (TGFα) is an autocrine growth factor that stimulates the division of basal cells. When TGFα is unregulated, growth factor binds to autocrine receptor and sustain the proliferative signaling. This would result in constant division of basal cells, and eventually into stratum corneum cells. Keratinocytes growth factor (FGF7) is a paracrine growth factor that regulates proliferation of basal cells. When FGF7 is unregulated, basal cells would force neighboring cells to release growth factors. With a constant supply of growth factors, basal cells would be in constant cell proliferation. Both TGFα and FGF7 could potentially be one of the hallmarks of cancer, sustaining proliferative signaling, but if we are able to control them, they could counter act the negative effect caused by FLG gene. The growth factors are natural substance capable of stimulating cellular growth. TGFαgrowth factor could bind to autocrine receptor and sustain the proliferative signaling to make stratum corneum cells. The same method would work for FGF7. Even though there is no treatment that target the mutated FLG gene yet, there are other treatment options that are in use.


 * Treatment **

__ Treatment Options: __ Specific sequence of treatments is given to different stages of esophageal cancer. For stage III adenocarcinoma patients, like my grandmother, there are many treatment options. Stage III cancer has usually spread beyond the esophagus to nearby tissue, but has not travelled to distant parts yet. If my grandmother had lived in the 21st century and could be treated, I would first recommend her to have chemoradiation, then surgery, and finally some supportive care.

__Prepare for Treatments: __ The most important preparation that my grandmother should do before she could get treatments is to obtain another eating method. The most visible sign of her cancer, according to my father, was that she lost a significant amount of weight. She was malnourished because the pain it caused to swallow. Having an adequate amount of nutrition makes her stronger before treatment. Because the esophagus is the only tube where food passes through from throat to the stomach, another eating method should be introduced before the treatment. To do that, a J-tube is inserted through a cut in her abdomen and into the small intestine. This feeding tube avoids the esophagus and directly delivers food and medication for her to absorb.

__ Chemoradiation Therapy: __ The standard treatment option for stage III adenocarcinoma is chemoradiation followed by surgery. My grandmother’s tumor stage is T3 and N+. T3 means the tumor is in the outer layer of the esophagus, and N+ means the cancer has spread to nearby lymph nodes. Exactly how many lymph nodes contain cancer is unknown until surgery. Chemoradiation is a treatment that combines chemotherapy with radiation therapy. Chemotherapy uses chemical substances to treat cancer, where as radiation therapy uses high-energy rays to damage and kill cancer cells. Chemoradiation is used first to reduce tumor size. Radiation alone with drugs such as paclitaxel and carboplatin are commonly used. Paclitaxel is an antimitotic agent; it blocks cell growth by stopping cell division and may kill cancer cells. Carboplatin interferes the functions of DNA and prevents cancer cells from dividing. Trastuzumab is a drug that targets the HER2 receptor, blocks down stream signaling, and inhibits cell proliferation. In a clinical trail study on patients with HER2-overexpressing adenocarcinoma, some patients are treated with trastuzumab and chemotherapy, and others are treated with chemotherapy alone. The result shows a median survival of 6 weeks higher in patients received trastuzumab and chemotherapy. I would add trastuzuma as a part of the chempradiation therapy to target HER2-overexpressing. Would there be a difference if I choose radiation therapy for my grandmother? Another randomized trail of chemoradiation versus radiation therapy alone showed a better result in chemoradiation. The 5-year survival rate of chemoradiation is 27% and for radiation therapy, it is 0%. Other trail has shown that chemoradiaiton provide a better 2-year survival rate than radiation therapy alone. Despite the better survival rate, chemoradiation results in side affect such as leukopenia, neutropenia, anorexia, and fatigue. After chemoradiation treatment, if the tumor starts to shrink, then esophagectomy is used to surgically remove a part or the entire esophagus. Not all patients who are treated with chemoradiation are this lucky; some tumors can even grow larger, and become metastasized. In this situation, not much can be done.

__ Ecophagectomy: __ My grandmother is lucky, and her tumor size shrank, and she is ready for surgery. The goal of surgery is to remove all the cancer from her body. To be confident of doing this, usually some normal-looking tissue around the cancer called the margin, is removed as well. Esophagectomy is performed, and the lower part of the esophagus should be removed alone with nearby lymph nodes. The rest of the normal esophagus can be surgically reattached to the stomach. Since removing the lower part of the esophagus also removes the lower esophageal sphincter (LES), an artificial LES can be replaced to prevent future gastric reflux. The magnetic sphincter is a new antireflux method that was proved by Food and Drug Administration in 2012. In this method, a small ring of magnet balls is placed around the esophagus on top of the stomach. When no food is coming through, the magnets are next to each other, and prevent gastric juice from reflux into the esophagus. When food comes, the diameter of the ring becomes larger due to the pressure of the contraction wave in the esophageal body, and food passes through. This device is still new, and it can cause problems. In 1000 patients who have implanted with magnetic sphincter, 56 patients had trouble swallowing and needed endoscopic dilations, 34 patients had reoperations. Nissen Fundoplicatio is another method of strengthening the LES. In the surgery, the upper part of the stomach is used to warp around the LES. It increases the pressure and prevents gastric reflux. I would not recommend this to my grandmother because she just had her lower esophagus removed reconnected to the stomach. I would not stress her body with another complicated and time-consuming surgery. Putting a magnetic sphincter on her would be the better option. After her esophagus recovers, the J-tube can be removed.

__ Supportive Care: __ Cancer and the treatments can cause unpleasant symptoms, and the goal of supportive care is to relieve discomfort. It can be given at any stage of cancer. When supportive care becomes the main care for advanced cancer, it is called palliative care, which only helps patients to feel better. One of the most common symptoms of esophageal cancer is dysphagia, difficulty swallowing. Treatments like endoscopic treatments, stents, radiation therapy, and surgery can be used to dilate the narrowed esophagus. Bleeding caused by tearing of the esophagus can be stopped by surgery and endoscopic treatments.

__ Conclusion: __ Every year, esophageal cancer is affecting 300,000 people worldwide. This type of cancer once affected my grandmother. Because every person would have different mutated genes, and picking the most suitable treatment method is critical. After treated my grandmother with chemoradiation and esphagectomy, her cancer was under control. Unfortunately, her cancer came back from cancer cells in some of her infected lymph nodes. At least, her treatment prolonged her life by three years. Scientists are making efforts trying to find more efficient treatments for esophageal cancer patients. Today, as technology advances, many treatment options such as chemoradiation and esophagectomy, which were not available in the late 1990s, are now in common use in China and around the world. Due to the efforts made to help these patients, the survival rate is gradually increasing. However, there are still a lot to learn about the genes that cause this cancer. Researchers around the world are taking actions to discover more about the FLG gene and other mutated genes relate to esophageal cancer. It is our hope that one day, they will develop chemotherapy or even targeted therapy to help esophageal cancer patients.

__ Apercu: __ It is important to have regular check-up in the hospital for any potential cancer causing diseases that may lead to cancers. Even though some type of cancers are unnoticeable until they cause pain, still do not give up getting treatments because there are so many treatment options available.

__ References: __