Paul+Kozel

= Rare, but not to me... =

Apercu
If there was one word to describe abdominal pleomorphic liposarcomas, that word would be rare. One in three million people worldwide get diagnosed with pleomorphic liposarcomas in the abdomen each year. Lack of cases means lack of research, so not a lot of facts are known about this type of cancer. Despite the rarity of this cancer, this cancer is not rare to me. Three months ago, my uncle was diagnosed with an abdominal pleomorphic liposarcoma. He is currently undergoing treatment for this cancer and even though the odds have been against him, everything has been successful so far. This research paper has helped me to help him understand what he is going through, what challenges he may face in the future, and what decisions he will have to make later in the course of his care.

The Case
About two months ago, one of my patients presented to me with abdominal pain. He had been having the abdominal pain for about two months now. The patient is a white 48-year-old male with a history of colonic diverticulitis, thus the pain was cause for concern as the diverticulitis could worsen. Diverticulitis is the formation of pouches (diverticula) on the outside surface of the colon. Patients usually complain of left abdominal pain, which is consistent with what my patient presented with. I ordered a CT scan to check the diverticulitis, and much to my surprise, the radiology report came back, which showed a large, well-circumscribed mass in the left retroperitoneal space (Figure 1). I believed the mass was a cancerous tumor, likely liposarcoma. When the patient was diagnosed with the diverticulitis, about 10 months prior, there was a CT scan taken which did not show any distinguishable signs of cancer or tumors. However, comparing this recent CT (2/9/2016) to the old CT (4/29/2015), there was a subtle small mass in the left perinephric space, as shown in figure 1.

We scheduled surgery two days later, where the tumor and the patient’s left kidney were removed. The mass weighed 1857 grams, about 4 pounds, and measured about 16 centimeters (Figure 2). The pathology report showed the mass was indeed a pleomorphic liposarcoma, which had invaded into the cortex of the left kidney. There also appeared to be a noncancerous cyst on the kidney that was removed. I referred the patient to a specialist in Liposarcomas at MD Anderson Cancer Center in Houston, Texas. There, the specialist ran a series of tests, which included more CT scans, which were negative for metastases. For now, the cancer is not an immediate problem for the patient, therefore chemotherapy is not being pursued at this time. The patient was also advised that the cancer was stage II and even though no metastases at this time, there is a 70-80% chance that the cancer will return.

What exactly is a liposarcoma? A liposarcoma is a type of soft-tissue sarcoma, which affects fat tissue cells. Sarcomas, cancer of nonepithelial cells, themselves are rare, accounting for about one percent of all cancer diagnoses in the United States each year and Liposarcomas account for about ten to eighteen percent of all the sarcoma diagnoses (1). There are about 2.5 cases of liposarcoma reported per every one million people (2). Liposarcomas usually present in adult patients, usually between the ages of 40 and 60, and are more common in males than females. My patient fits both of these criteria. Patients usually do not know a tumor is growing because the cancer presents as a slow-growing, painless mass. Most patients will feel a hard bump following a trauma to the affected area. My patient did not report any trauma to the area and did not report and hard bump in his abdomen area.

There are four different subtypes of liposarcomas: well-differentiated, dedifferentiated, myxoid, and pleomorphic. The liposarcoma in this patient is pleomorphic, which is the rarest type of liposarcoma, about five to ten percent of all liposarcomas (1). Pleomorphic sarcomas also have a high rate of metastasis. This type of liposarcoma is the most aggressive form too and grows rapidly, unlike many of the other more common forms. The other types are low to intermediate grade tumors, whereas pleomorphic is a high grade tumor. High grade just means it is more rapidly growing and has a higher chance of metastasizing. This explains the rapid growth time of the tumor in my patient, which was ten months.

There is currently no known cause of liposarcomas. There are many ongoing research studies to link causes with certain factors. There has been observed mutations in the p53 in about 60% of liposarcoma patients. My patient currently has not been tested for genetic markers, but patients with this cancer have had complex aberrations in their chromosomes. The only known correlation for the cause is trauma to the area of the tumor and a hard, palpable lump that does not go away, which my patient has not reported. The patient does not smoke and is not a heavy drinker. He is about six feet, five-inches and weighs 190 pounds. History of cancer does not run in the family and in previous generations. This leads me to think that the cause of the cancer was pure chance caused by some mutation in some gene. There is also no association with liposarcomas and race. The mortality rates for liposarcomas vary depending on the subtype. Pleomorphic liposarcomas have the worst survival rate of liposarcoma subtypes with 56% of patients surviving five years after diagnosis and 39% of patients living ten years after diagnosis (1).

The Science
One of the major challenges in my patient’s case was diagnosing the type of tumor. Pleomorphic liposarcomas (PLS) present unique diagnostic challenges as they share many common characteristics with other pleomorphic sarcomas or dedifferentiated liposarcomas. Since the patient, in this case presented with a tumor in the retroperitoneal space, which is highly uncommon in PLS, we look to the molecular properties of this cancer to distinguish pleomorphic liposarcoma from other types of liposarcomas and other pleomorphic type sarcomas.

A major distinguishing characteristic in PLS is a complex karyotype, or the map of the chromosomes. The karyotypes of patients diagnosed with PLS possess “gross chromosomal aberrations,” as shown in Figure 3 (3, 4). The chromosomes are often so complex that identifying specific rearrangements is extremely difficult.



Aberrations, or abnormal findings, include ring chromosomes and giant marker chromosomes, typically found in chromosome 11 or 15. Ring chromosomes are chromosomes whose ends have fused together to form a ring instead of the typical line. A marker chromosome is an abnormal chromosome that is present where no part of the chromosome can be identified (3, 5-6). In figure 3, the chromosome labeled “mar” is the marker chromosome. Pleomorphic sarcomas, dedifferentiated liposarcomas, and well-differentiated all have chromosomal aberrations, such as ring chromosomes and giant marker chromosomes (Figure 4). However, pleomorphic liposarcomas have the most complex aberrations, often times the exact aberrations and mutated sequences are too mutated to identify (7).



A revealing characteristic that distinguishes PLS from the other three subtypes is the gene MDM2, a gene that regulates the tumor suppressor gene TP53 (3). In well-differentiated, myxoid (not as much), and dedifferentiated liposarcomas, there is an overexpression of the MDM2 gene. This is caused by the amplification of the regions on chromosome 12q14-15, which encode for MDM2 (7). Figure 5 shows the interaction of MDM2 and TP53 (8).



Image A shows a normally functioning cell where p53 senses cell damage and induces cell death. MDM2 inhibits p53, therefore regulating p53 so that it is only on when it needs to be. Image B shows what happens in a cancerous cell with an overexpression of MDM2. When MDM2 is overexpressed, p53 is inhibited so much so that it is almost nonexistent, which means cells will not die and keep growing (9). PLS tumors do not show this amplification of MDM2. PLS do show a mutation in p53 in sixty percent of the studied cases (10). There are observed mutations in chromosome seventeen, which contains the information for p53 (6). The same effect occurs where p53 is not functional, therefore causing uncontrollable cell growth. Since the p53 gene is one of the most mutated genes in cancer cells, this is not particularly helpful in distinguishing PLS from other sarcoma types, however this may be an area of further research in the process for finding targeted drug therapies for PLS.

When you break down the word liposarcoma, you get the prefix “lipo,” meaning fat, and the word sarcoma, which is a cancer of non-epithelial origin. Fat cells are call adipocytes and the precursor cells for adipocytes are called lipoblasts (11). The presence of these lipoblasts distinguishes PLS from other types of pleomorphic sarcomas. In PLS, these lipoblasts are found to be mutated and have a unique appearance from lipoblasts in other types of liposarcomas and because of this, the presence of these lipoblasts is an extremely useful marker in making a diagnose of PLS (12).

Research has found an amplification on chromosome 5 that contains information for the protein delta-catenin (6). Delta catenin is found at cell-to-cell junctions and has shown to help cells stick to each other. Over expression of delta-catenin is associated with the down-regulation and loss of function of E-catenin protein. E-catenin is a metastasis suppressor gene and, like delta-catenin, mediates cell-cell adhesion (12). One important characteristic of PLS is the high metastasis rate associated with the cancer, occurring in thirty to fifty percent of patients, and often metastases to the lung (13). This makes this cancer very aggressive and the tumor is considered a high-grade tumor based on this. If patients with liposarcomas over-express delta-catenin, which down-regulates the E-catenin, then the cancer cells have lost the ability to stick to each other and then can spread (metastasize) throughout the body. Since PLS is the only liposarcoma with such a high metastasis rate, the over expression of is most likely delta-catenin is unique to PLS, and therefore we can use this to help narrow down our diagnosis.

It is difficult to make an accurate diagnosis of PLS because of the shared characteristics between other pleomorphic sarcomas and other liposarcomas. Often times to make a diagnosis, physicians must look for the molecular and genetic markers that I have mentioned and must use process of elimination to come to the conclusion of PLS. The lack of specific molecular markers and recurring gene mutations in PLS makes it difficult to treat with chemotherapy. More research into the treatment of PLS along with more clinical trials will lead to more breakthroughs and new discoveries of the molecular basis of PLS.

The Treatment
After a series of CT scans and MRI’s to evaluate the tumor in my patient, I must determine if the tumor is resectable via surgery. Typically, if the tumor has not metastasized, or is not stage IV, then the liposarcoma can be resected. Since retroperitoneal liposarcomas are sometimes deep in the abdomen, a biopsy is often done after the tumor has been surgically removed (14). My patient presented with a large mass, roughly sixteen centimeters long, so we decided that immediate surgery was the best option. The mass appeared to be well defined in the CT, which means the mass could be easily resected in one piece. Since the tumor invaded the cortex of the left kidney, the kidney also had to be removed. Overall, the resected mass measured 24 x 18 x 13 centimeters and weighed 1857 grams total. The resected mass was sent to the lab to have tests done to obtain an accurate diagnose of what kind of tumor this was.

During surgery the edge of the tumors were covered with ink. This area is called the margin and is examined by the pathologist when the tumor is sent to the lab. The ideal case is that this area will be clear of cancerous cells, also called negative margins, which means the surgical team removed all the cancer. If the pathologist finds cancerous cells, this is referred to as positive margins and the surgical team may have to go back and resect some more of the tumor (15). Radiation therapy can be used as adjuvant therapy and can be used in place of the second surgery to remove the rest of the cancerous cells (14).

My patient had a successful surgery and the tumor had negative margins. Follow-up chest and abdomen CT scans showed no signs of metastasis, which means the primary surgery treatment removed all the cancer. My patient did remain in the Intensive Care Unit for five days post-surgery to recover from the nephrectomy, or kidney removal. Since there were no signs of cancer in my patient, we decided against adjuvant therapy. There is no need for it at this time and chemotherapy and/or radiation could harm my patient since he only has one kidney now. I was worried that my patient’s body would not be able to filter out the toxins from the chemotherapy; it is best for his body to adjust to functioning with one kidney. For the time being, I have referred my patient to a liposarcoma specialist at MD Anderson Comprehensive Cancer Center at the University of Texas where he will check in every six to eight weeks and will get physical exams and CT scans to check for metastases.

Normally in pleomorphic liposarcoma patients, adjuvant therapy is only used for metastatic disease. At this time, my patient has a localized disease, but that is not to say that the disease could become metastatic in the future. Standard of care does not recommend postoperative radiation therapy or chemotherapy unless there are positive margins. At that time, radiation, chemotherapy, or re-resection is recommend, but varies on the patient and the tumor. If the primary tumor metastasizes or reoccurs, then it can be resected again, if it can be resected, or radiation or chemotherapy can be used to attempt to decrease the tumor size or control any symptoms (14).

If my patient’s tumor was to metastasize, which pleomorphic liposarcomas are known to do, then I would recommend adjuvant therapy, probably in the form of radiation therapy. Radiation is the first step for pleomorphic liposarcomas as there are currently no targeted drugs to treat this disease because of the lack of known recurring genes (14). Right now, Doxorubicin is the most common drug given to pleomorphic liposarcoma patients for chemotherapy (14). Doxorubicin binds between DNA base pairs and prevents DNA replication and protein synthesis from occurring (16). This is especially useful in pleomorphic liposarcomas as there are no known recurring gene mutations to target and these chromosomes are complex. This drug will stop the replication of the DNA in the mutated chromosomes, causing the flow of bad information to cease. On average, about forty percent of the Doxorubicin dosage that is given to patients is excreted in the urine within five days after the treatment (16). This shows that the Doxorubicin does pass through the kidneys and the removal of my patient’s kidney could cause the drug to not be excreted properly, possibly causing harm to my patient.

There are several ongoing clinical trials in developing targeted therapies to treat pleomorphic liposarcomas. One major study is studying the use of the drug Pazopanib (17). While Doxorubicin stops the DNA replication in cancer cells, Pazopanib inhibits protein tyrosine kinases, which reduces angiogenesis, which ultimately reduces tumor growth (18). This is a promising development as Pazopanib can be used in combination with Doxorubicin as they do not counteract each other and reduce tumor growth by two different methods. Both these drugs are systemic treatments and therefore can have many side effects, such as nausea, headaches, and weight loss (19, 20). Doxorubicin has a high toxicity level and so there is current research experimenting on combination drug treatments to lower the toxicity of Doxorubicin (16,19). One such study is combining Doxorubicin with Dexrazoxane (21). Dexrazoxane has immunosuppressive properties and in combination with Doxorubicin, provides cardiac protection to eliminate the toxic affects of the cancer drug (22). In the future, as more genetic and molecular research is done on liposarcomas, more recurring gene mutations will be found that are specific to pleomorphic liposarcomas. Once these mutations have been identified, specific targeted drugs can be produced. Until we have these targeted drugs and have more knowledge on the molecular basis of this cancer, I would not recommend chemotherapy. The adverse effects of the drug treatment are too great for my patient right now. I would still recommend radiation therapy as the major form of adjuvant therapy after the surgery.

The outcome for pleomorphic liposarcomas all depends on if the disease becomes metastatic. If the cancer metastasizes, the chances for survival dramatically decreases, evident in Figure 6. For localized diseases with no metastases, the five-year chance of survival is about 61%, where the five-year survival chances for patients with a metastatic disease is 0%. Remember that the pleomorphic subtype is the most aggressive form, which is accurate with this data that shows a 0% five-year survival rate for patients with a metastatic tumor.

The standard of care for pleomorphic liposarcomas is surgical resection. Radiation therapy is not useful as a primary treatment since the size of these tumors are often massive (the average being eleven centimeters). Chemotherapy is not useful as there are no specific targeted drugs that are effective towards these tumors. Radiation and chemotherapy are used as adjuvant therapies after surgical resection, or in the case of metastases. Even with these treatments, if the disease metastasizes, the outcome for these patients is not good.

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