Hannah+Robin


 * __ The Mystery of Liposarcoma __**
 * Apercu:** //It's amazing that my father was "cured" of not one cancer, but two. But even though his cancers may have been completely destroyed from his body, the thought of recurrence continued to scar him post-operation. As stated by Dr Stephanie Bernik, "cancer is not only a disease of the body, but it is a disease of the mind, often affecting many aspects of the person as a whole" ([|22]). For that reason alone, cancer will forever remain incurable to his mind.//



Part 1: The Story Joseph Robin, known to his family and friends as Joe, is a 62-year-old white male who was diagnosed with an abnormal and rare type of cancer called liposarcoma in 2008. Joe is a father of three, two daughters and a son, and a wife he met when he was working on the job at the hospital. He is a neurologist and has been working for 35 years at his practice along with working for the US Department of Veterans Affairs. In addition to working with veterans, he teaches residency students at the University of Washington, helping them become knowledgeable and successful neurologists. After years in his profession, no one, not even his friends or family, were expecting that a doctor who is highly active in his profession and his physicality, would be diagnosed with a moderately aggressive cancer that was considered life threatening.

Prior to his cancer diagnosis in 2008, in October of 1993, Joe experienced severe abdominal pain and nausea. When he was rushed to the emergency room after profusely vomiting, Joe was informed that he had gallstones and a blocked biliary duct: he needed to have his gallbladder removed. Following a successful surgery, Joe tried to change his eating habits, continue his exercise routines, and build a family with his wife. But as much as Joe adjusted his habits, his body seemed to fight against him. In 2008, Joe noticed that he was urinating more frequently and decided to get his prostate checked. He was quickly diagnosed with prostate cancer. Shortly afterwards, he underwent a radical prostatectomy and had a normal recovery. But following his recovery in July of 2008, he began complaining of some muscle soreness in his right quadricep. Joe believed that the soreness was due to a strained muscle from working out with his trainer. Despite recommended stretching and easing up on certain exercises, it continued to bother him. At the gym where he worked out, Joe consulted with an exercise buddy: an orthopedist. When his friend looked more closely at Joe’s leg, he noticed that his right quadricep was larger then his left. He immediately told Joe that he may have an abnormality and to go get it checked out with a fellow orthopedist. After a biopsy of the lump on his leg, lab results followed, diagnosing Joe with an abnormal type of cancer: a liposarcoma.

In the initial consult, the orthopedist could clearly see Joe’s condition on his leg. The lump was abnormally large and protruded out when palpated, as if it was seeking room to grow. Although the lump was not painful, it was clear that something was wrong. As Joe waited anxiously for results and answers, his wife held his hand in hopes that it would comfort him. Once the doctor returned, he told him he had liposarcoma and that the best procedure would be to surgically remove it and follow up with radiation therapy. Based on it being a moderately aggressive cancer, the prognosis was that he would have a 50% survival rate after five years. But Joe proved to be one of those 50% because it has now been eight years since his operation.

Although extremely rare, liposarcomas represent one of the most common types of fat tissue sarcomas. The transformation of a lipoma into a liposarcoma is exceedingly rare and often doubted by doctors, due to the high rate of lipomas being benign (noncancerous) tumors. But, occasionally, the mass which is presumed to be benign can actually turn out to be a malignant cancerous tumor. Therefore, biopsies or the removal of the tumor must be done for further examination.

Lipomas are a growth of fat cells in a thin, fibrous capsule usually found just below the skin, and normally show up more frequently in men than women. Although lipomas can develop due to genetics, Joe has no family history of getting lipomas that could develop into a liposarcoma, making this an isolated case. Liposarcoma is a malignant tumor, which means that it could spread to other areas of the body, including vital organs. Additionally, this type of tumor can grow anywhere in the body and the common places include the “abdomen, thigh, and behind the knee” ([|2]). There are four types of liposarcomas: well-differentiated, myxoid, pleomorphic, and dedifferentiated liposarcoma. Myxoid is an intermediate to high grade tumor, pleomorphic is the rarest of all subtypes and a high grade tumor, and dedifferentiated occurs when a low grade tumor changes and the newer cells become high grade. But the most common subtype is well-differentiated liposarcoma, which is a “low-grade tumor whose cells look like normal fat cells and grow slowly” ([|1]). Joe had a well-differentiated liposarcoma, and patients with this cancer can survive for years, but recurrence can be a problem ([|1]). These tumors, in particular, “can be removed surgically and the prognosis is often good, but if the tumor is recurrent the threat becomes more challenging as the cancer can spread to other parts of the body and surgery may not be an option” ([|1]). Additionally, radiation has to be used in moderation to avoid side effects.

Joe’s medical history can be inferred as an obstacle that was complex, elaborate, demanding, upsetting, but most of all intriguing. Based off of Joe's medical history, it was hypothesized that there could have been a correlation between his gallbladder removal, prostate cancer, and receiving liposarcoma in his leg. The hypothesis that removing Joe’s gallbladder could have biologically affected cells within his body, increasing his cholesterol, and creating prostate cancer is within possibility. In addition, another hypothesis is that the radiation therapy he received from his prostate cancer could have affected cells near his leg, leading to the growth of his liposarcoma. Although these hypotheses seem obscure, evidence states otherwise.

The gallbladder, located in the upper right abdomen, is the essential storage tank for bile production in one’s liver. After eating, the gallbladder secretes bile into the small intestine to help with absorption and fat digestion. Bile normally contains large amounts of cholesterol, and too much of it could lead to a build-up causing an aggregate of bile that forms into gallstones. Because Joe had his gallbladder removed, means that he could have been at a higher risk of getting plasma cholesterol build up within the bile in his liver. Therefore, from the liver, the high build-up of cholesterol bile could have been trickling into his small intestine through the biliary duct, absorbing into his body, and leading to the development of high-grade prostate cancer ([|5], [|21]). The explanation for this occurrence states, “[that] prostate cancer cells over accumulates cholesterol in their cell membrane, forming lipid rafts, which facilitates pro-carcinogenic cell signaling. Secondly, it was explained that high cholesterol level[s] is vital for carcinogenesis because it activates several signals” ([|5]). With a recent study suggesting that a "10 mg/dL increase in cholesterol was associated with a 9% increase in prostate cancer recurrence", could explain why Joe got prostate cancer (20). Additionally, although not conclusive, database provided by TCGA stated that a "deregulation of cholesterol homeostasis is an important contributing factor to cancer development" (20). Although there is no definitive evidence that Joe received prostate cancer due to a high build-up of cholesterol, some studies suggest there is a correlation, but additional studies need to be examined to link these results in order to concretely resolve this controversy.

In addition to Joe’s cholecystectomy (gallbladder surgery), there is a possibility that the radiation and surgery used for Joe’s prostate cancer could have increased his chance for developing liposarcoma in his leg. Research studies, like one from the American Cancer Society, have shown that radiation given to treat other cancers, like Joe’s prostate cancer, could lead to developing sarcomas. The sarcoma often starts in the area of the body that had been treated with radiation. Even though the radiation therapy was done on his prostate, there could have been a very low chance of it affecting his thigh and leg; this is because radiation exposure accounts for less than 5% of sarcomas ([|3]).

While Joe's medical history is elaborate and complex, there is no definitive answer for why he got liposarcoma in his right extremity. Studies suggest that there are correlations between gallbladder removal, high build-up of cholesterol, and receiving prostate cancer. In addition, the radiation therapy he received on his prostate has a very low chance of increasing sarcomas in the body. The fact of the matter is, Joe received cancer that may or may not have occurred due to his medical procedures, but understanding Joe's previous experiences helps one analyze what could have happened and why. Thus, the origin of cancer will forever be a mystery to us all.

Part 2: The Molecular Analysis Joe’s abnormal growth became a nuisance as it progressively became painful and protruded outward, forcing doctors to take immediate action. Joe’s well-differentiated liposarcoma is a locally aggressive malignant mesenchymal tumor (also known as an atypical fatty tumor) and accounts for about 40-45% of all liposarcomas, representing the largest subgroup of aggressive adipocytic neoplasms (9). Although there are multiple types of liposarcomas, Joe’s is a unique case because his well-differentiated liposarcoma is anatomic to a specific location (i.e his right leg), in comparison to pleomorphic and dedifferentiated liposarcomas. Because well-differentiated liposarcomas respond poorly to systemic chemotherapy, it is essential that doctors understand the molecular basis in order to target certain genes and provide new possibilities for therapies. By understanding the genetics of Joe’s abnormal growth, will not only help the doctors understand which treatments to recommend but also help Joe destroy his irregular tumor.

Well-differentiated liposarcomas are a genetically distinct group of tumors formed in the fat tissue and have been characterized by an amplification of genes on chromosome 12q (7). But all well-differentiated liposarcomas tend to share the same genetic abnormalities, which are represented with the presence of distinctive ring chromosomes. Ring chromosomes are chromosomes that fuse together to form a ring and can be formed in two different ways: by double-strand breaks or telomere dysfunction (see //Figure 1)//. They have been noted to be a consistent cytogenetic feature of well-differentiated liposarcomas (8).Telomeres play an important role in forming ring chromosomes because they cause a large amplification of genes in the 12q region of the chromosome. Telomeres are the disposable buffers that are placed at the ends of chromosomes and become shorter overtime due to cell division. If the telomeres DNA ends shortened too much, it would lead to the detachment of proteins from the chromosome ends ([|10]). Therefore the chromosomes become prone to fusing to other chromosomal ends, ultimately leading to the formation of a ring.

Additionally, the amplification of 12q13-15 chromosomal regions contained copies of important genes such as CDK4 and MDM2. In well-differentiated liposarcomas, both MDM2 and CDK4 oncogenes (cancer genes) are over-expressed (8). CDK4 is part of cell cycle regulation and most notably known to be a part of the cyclin D kinases. Cyclin D kinases play an important role in the cell cycle by regulating the cell cycle to continue to grow and persevere. If CDK4 is highly expressed, along with the cyclin D, this could lead to mutations and an unstable growth cycle, also called //Enabling Growth Suppressors.// On the other hand, MDM2 (or human murine double minute 2) is known for promoting tumor growth by blocking the TP53 suppressor (see //Figure 2)// TP53 is a growth suppressor that can lead to repairing DNA in the cell cycle or apoptosis. By having the oncogene MDM2 block this suppressor (through over expression), leads to exponential cell growth and the Hallmark: //Resisting Cell Death.// As shown in //Figure 2a,// depicts MDM2 regulating the cell cycle normally, but later (//Figure 2b//) MDM2 is over expressed, which, in turn, arrests the cell cycle leading to mutations that can cause cancers like liposarcoma.

Interestingly, according to the COSMIC database, HRAS is the only significant mutated gene, which means that it is the most prevalent mutation in patients that were tested with well-differentiated liposarcoma. HRAS is a protein apart of the transduction-signaling cascade that helps cells grow. If HRAS is mutated, signaling can occur without growth factors and receptors that cause transphosphorylation. This means that the cell can proliferate without relying on outside sources. The mutation is extremely dangerous as it can cause rapid and unstoppable growth. Although it is unclear whether or not Joe had this mutation, research from COSMIC concludes that patients with well-differentiated liposarcoma, like Joe, have the mutated gene in HRAS.

Lastly, in relation to Joe's previous medical procedures and liposarcoma, it was found that TP53 (which is normally blocked due to the over expression of MDM2) is related to the cholesterol pathway in cancer cells. A recent study showed that a loss of TP53 function "unregulated the cholesterol synthesis pathway" (20).Although further investigations need to be done, TP53 has been shown to affect cholesterol homeostasis and could contribute to the progression of other malignancies (20). Based on this study alone, suggests that prostate cancer could have occurred due to the inhibition of TP53, and later creating liposarcoma. With the over-expression of MDM2 that led to the blockage of TP53, could have increased the chances of prostate cancer due to high levels of cholesterol. But not only did it increase prostate cancer, it could have simultaneously increased the chance of liposarcoma. Because Joe's liposarcoma happened a few months after his prostate was removed, makes me hypothesize that the over expression of MDM2 was continuing after the removal of his prostate, leading to the blockage of TP53. In addition, because Joe is known for having high levels of cholesterol, could have also increased his chance for both cancers. Again, although this correlation cannot be concluded, the possibilities are endless.

While Joe may not have had an extreme case of liposarcoma, doctors were concerned about his well-being and how to treat an atypical fatty tumor. Based on the molecular basis of well-differentiated liposarcomas, the best options for Joe are surgery and radiation. Surgical removal will help him get rid of the localized cancer in his leg and radiation will kill the cells that may have survived following surgery.

Part 3: The Treatment The doctor’s molecular analysis of Joe’s bulging tumor helped them predict what treatments to offer him to remove the cancerous intruder. By providing him the treatments that were most affective in killing well-differentiated liposarcoma would remove most, if not all, of the tumor. The doctors offered him the two best options to move forward, which included surgery and radiation therapy. With little to no hesitation, Joe decided to go ahead with the doctor’s recommendations that led to complex procedures and a future of worry, post-operation.

Patients, like Joe, require a lot of medically advanced cancer care because sarcomas are a very rare and multipart cancer. Although Joe had a less invasive cancer, the doctors still took precaution on how to treat him. At Overlake Hospital and Medical Center in Seattle, Joe received appropriate supervision by a multidisciplinary team of surgeons, pathologists, clinical oncologists, and radiation oncologists. With the doctor’s knowledge of Joe’s well-differentiated liposarcoma, led to multiple therapies of lab tests, clinical examinations, CT scans, x-rays, and MRIs of the tumor site, before he got any treatment. Like other sarcoma cases, Joe received these multidisciplinary therapies to minimize his local tumor and limit recurrence, to make sure he had a good postoperative quality of life.

Because the doctors were able to determine that Joe’s cancer was localized, the primary treatment they recommended was surgery. Limb-sparing surgery is the standard surgical approach for most patients with well-differentiated liposarcoma, who have it in the upper and lower extremities. The surgery would include a wide excision with a negative margin, which would incorporate the biopsy site. The categories of surgical margins are: intralesional, marginal, wide, and radial (13). An intralesional surgery passes through the margins of the tumor and directly to the main cavity. In this type of surgery, it may not get the entire tumor. A marginal excision is defined “as a removal of the entire tumor without removing healthy tissue; satellite tumor cells may remain in the reactive tissue” (13). A wide surgical procedure would be the removal of the whole tumor, which includes at least 2 cm margin of normal tissue to make sure there is no local recurrence of the tumor. Lastly, a radical excision (or also known as extra compartmental excision) is the removal of the bone or muscle compartment, to make sure there is a minimal risk of local recurrence. These types of surgeries are adequate enough for any low or high-grade tumor size.

Out of all the surgeries, Joe received a wide surgical procedure in order to minimize local recurrence of his tumor and make sure all cancerous cells were removed. In addition to receiving this drastic procedure, he also had to undergo adjuvant radiation therapy to make sure any remaining cells that were not removed from surgery, were killed. Radiation therapy is often used to reduce the risk of a local recurrence of a cancerous tumor. Even though radiation therapy can happen before a surgical procedure, in Joe’s case it was used post-operatively. The total radiation dose that is generally given to patients can range from 40 to 60 Gy or more, based on the tumor localization, size, and extent of surgery (13). Joe received a radiation of 51 Gy as his tumor was quite enlarged (approximately 10 cm) in his right extremity. Additionally, Joe received external beam radiation therapy, which is delivered from outside the body and focused on the cancer. This type of radiation therapy treats sarcomas and is given daily (approximately 5 days a week) usually for several weeks ([|14]). It is important for treating this type of cancer because the radiation focuses on the tumor and less on the healthy tissue. External beam radiation therapy uses particle beams such as protons or electrons to destroy the cancer cells, using a high energy X-ray beam. The radiotherapy damages the DNA within the cancer cells or creates charged particles “called free radicals that damage the DNA. Then the cancer cells stop growing or die. When the cells die, the body breaks them down and gets rid of any waste substances. Normal cells in the radiotherapy areas may also be damaged, but they can usually repair themselves” ([|15]). For Joe and other cancers alike, radiation has proven to be a powerful tool in preventing the spread of the diseased tissue around the tumor.

Surgery and radiation therapy were the right treatments for Joe’s cancer because they were effective treatments at the time. Although chemotherapy was an option for this type of cancer, Joe did not receive it. For the past few years, chemotherapy has been considered experimental due to tumor recurrence, which is partly why most patients will not accept this type of treatment. Therefore, surgical resections (along with radiation therapies) continue to be the foundation of curative treatments for patients like Joe.

Even though Joe did not receive any other treatments other than surgery and radiation, liposuction could have been another option. A recent study was done on atypical lipomas and found that liposuction was a great way to treat large lipomas that lead to liposarcomas. When the lipoma enlarged to 4cm or more, liposuction was used and was found to have advantages over conventional surgery. Because the entire tumor was removed by liposuction, the prognosis was excellent (16). The cosmetic of the area and morbidity results were far superior to those “anticipated with conventional excisional surgery” (16). Although Joe did not receive this type of treatment, liposuction shows to be an excellent form of removing a fatty tumor.

Additionally, with Joe’s specific molecular mutations has led to analysis of targeted therapies in the field and further investigation into other treatment options. With MDM2 being over expressed in well-differentiated liposarcomas, has increased the investigation of new and improved therapies like Nutlin-based therapy. Nutlin 3A therapy is an MDM2-antagonist that induces apoptosis in cell lines with the amplified MDM2 gene. With the over expression of MDM2 interfering with TP53, means that the cell cannot undergo apoptosis. Therefore, Nutlin has represented a “promising new therapeutic principle for the treatment of a [growing] group of sarcomas” (19). Nutlin 3A has been shown activating P53 in cancer cell lines, inducing apoptosis and cell cycle arrest. With MDM2 over-expressed in the chromosomes of well-differentiated liposarcomas, makes it hard to eradicate and could lead to aggressive variants of the tumor with high malignancy. Based on the study done by Christoph Muller, it was concluded that Nutlin 3A induces apoptosis efficiently enough to a number of liposarcomas that it was predicted to be a new and improved therapeutic agent. Depending on the status of the p53 pathway, “Nutlin acted as a sensitizer to cytyotoxic therapies and protected proliferating normal cells from chemotherapy or radiation associated DNA damage” (19). With the promise of an orally administered efficient drug that is low in toxicity, makes this specific MDM2 inhibitor drug an attractive new treatment option for the increasing range of tumors. With Nutlin 3A being successful in treating sarcoma immunodeficient mice, gave rise to the consideration of clinical trials. Although Joe did not receive this drug, the therapy is another example of the improvement researchers have made in the health field, specifically for destroying cancers like liposarcomas.

While new and improved treatments exist, Joe continued with the doctor’s recommendations of invasive surgery and harsh radiation therapy on his lower right extremity. But little did he know that this would lead to years of challenges he would have to overcome. After Joe’s surgery, he was paralyzed for several weeks on that leg and had to undergo physical therapy to prevent it from getting worse. Additionally, radiation became more and more painful as doctors increased the dose, which changed the coloration and texture of the skin on his leg. Today, due to multiple repetitions of radiation therapy, there is scarring on his right leg, little to no hair, and his skin is thick/dense to the touch.

It has been shown that there is a 9% recurrence rate after a disease free-interval after five years has passed (13). But this did not happen to Joe: he survived both intervals of post-operative follow-ups. Joe received follow-ups through physical examinations, MRI scans, and chest x-rays. Because Joe had a low-grade tumor, it required a follow-up frequency of every 4-6 months post-operation for the first five years, and yearly after five years from diagnosis. With positive check-ups and no cancerous cells detected, Joe became cancer-free several years post-operation.

But even though time has surpassed and it has been several years since Joe has had his cancer, he still continues to get checked once every year, around September, due to stress and fear of recurrence. Although family members continue to tell him time after time again that the cancer is gone, Joe’s fear will forever remain with him as he continues to struggle moving forward from his haunted past.

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