Matt's Story
The Cancer

Seven-year-old Matt is an only child who enjoys playing soccer; he is currently on a team that is competing nationwide. Matt is a generally optimistic child with high aspirations. Both of his parents are extremely supportive of him. Recently, however, they have been concerned about his health. His parents noticed swelling in his upper chest and neck, as well as enlarged lymph nodes. Matt has also been complaining about dizziness, coughing and trouble breathing. All of these symptoms have been affecting his day-to-day activities for the past wee
This information provided us with grounds to run several tests. First, we wanted to find the cause of the enlarged lymph nodes, which could possibly be due to an infection. But, the location of swelling and the symptoms associated with it raised a red flag, indicating it might be the cause for a tumor. Swelling usually occurs when fluid has been built up abnormally in the body.[1] In some cases, if a tumor develops in the chest, it might push against the vena cava, a large vein in the chest that moves blood from the heart to the head and neck. This pushing of the vena cava can cause swelling in the face, neck, arms and upper chest. This can also result in headaches, dizziness, and may also press against the throat or the windpipe and cause coughing and trouble breathing or swallowing.[2] In order to diagnose Matt correctly, we ran a urine test, imaging tests, and biopsies. The urine test is important to detect hormones produced by cancer. Our sympathetic nerve cells usually release hormones called catecholamines, which enter into the blood and are then broken down into smaller pieces that come out with the urine. Neuroblastoma is a specific type of cancer that makes this hormone and can be detected via a urine test. We performed an x-ray to help find out if the specific area is cancerous and how far it might have spread. The biopsy confirms cancer by taking a sample from the tumor through the insertion of a needle into the skin and using a CT scan. All of these test’ results confirmed neuroblastoma.[3] In order to figure out the likely cause of this cancer, we asked Matt’s parents if any of their family has had a history of cancer. Both his parent’s denied. About one to two percent of Neuroblastoma cases are hereditary, so it is common to develop this disease by other means.[4] Unfortunately the ultimate cause of this specific cancer is not known, but may be caused by an infection.

Neuroblastoma is common in children under the age of ten. It is a cancer that occurs in many parts of the body and starts to develop from the tissues of the sympathetic nervous system. The sympathetic nervous system is part of the autonomic nervous system. This nervous system is involved in the fight or flight response that controls internal body functions such as hormones, digestion, heart rate and blood pressure. Most common cases of neuroblastomas may start in the chest and eventually spread to the bones, as well as the lymph nodes.[5]

Every case of neuroblastoma is unique based on the location of the tumor. In Matt’s case, the tumor is located in the chest, which explains his coughing and difficulty breathing. The tumor makes it difficult for the air to pass through the passageways in the chest and lungs making it difficult to breathe. The tumor’s irritation to the air passages is also the cause of the coughing that in turn causes the enlargement of lymph nodes. Lymph nodes are small structures that filter harmful substances. They consist of immune cells that help avoid infection by destroying the germs carried in the lymph fluid. There are multiple lymph nodes in the body that are located in the fingers, legs, and neck, all of which have liquid that flows to the chest. At the chest, the lymph nodes filter everything completely and add the clean fluid into the bloodstream. In Matt’s case, the lymph nodes swell each time they are working to filter out the harmful cells. Now the swollen lymph nodes we are observing in Matt’s neck, are a likely result of his spreading cancer. It is common for cancer to spread from its original site. Usually when cancer cells break apart from the tumor, they travel to different parts of the body through the lymphatic system or the bloodstream. In this case cancer has spread through the lymph system, which in turn has caused Matt’s lymph nodes to swell because they are near the tumor and have to do perform a lot of hard work to get rid of the cancer cells in that specific area. You stated that the lymph nodes are swelling and his cancer is spreading a few times too many.[6]

Neuroblastoma is staged using the international neuroblastoma staging system. Matt’s cancer has not spread to distant parts of the body. The tumor is only spread to nearby lymph nodes in the neck. To be precise, we used the TMN (Tumor- Metastasis-Node) system where the T stands for tumor, M stands for metastasis and N stands for nodes. If there is no cancer in the node, N is assigned the value 0. It there is cancer in nearby nodes; the value is 1 and usually increases depending on how far the cancer has spread. In Matt’s case, the cancer in the nodes is assigned N1. His tumor is located mainly in the upper chest and neck area. According to the International Neuroblastoma Risk Group Staging System, which allows us to stage before surgery through imaging tests and biopsies, Matt is diagnosed with the L2 stage, which means the tumor, has not spread far away from where it started.[7]

Unfortunately this means it will be difficult to remove the tumor solely through surgery. Each stage of neuroblastoma is unique. The treatments will involve a combination of surgery, chemotherapy and radiation. Surgery will allow the surgeon to look for signs of the tumor spreading to other organs. First the surgeon will remove cancer cells near the lymph nodes and then will try to remove the tumor. The rest of the cancer cells left behind by the surgeon will then be removed through radiation or chemotherapy. Surgery may be repeated to remove any leftover cancer cells and check the results of the treatment performed. Like all surgeries, there are risk factors, including problems with anesthesia, excess bleeding, and infection. After the operation is performed, children usually experience pain, but will be facilitated using medicines.[8]

Luckily, Matt’s cancer has not spread in distant places, so it is possible to treat him successfully. Other factors that also affect the prognosis of neuroblastoma depend upon age, tumor histology, and several other markers. We studied the tumor histology by looking at the sample of Matt’s tumor under the microscope and found that there are more normal looking cells compared to cancerous cells, which means there is a better prognosis and a favorable histology. We also looked at serum or blood levels to check for ferritin levels. Ferritin is a chemical involved in normal iron metabolism. Neuroblastoma cells release ferritin, so if ferritin levels are high the prognosis is grim In Matt’s case the ferritin levels are low, which compares with the favorable histology to suggest a satisfactory prognosis.[9]

The Treatment


Matt has been diagnosed with the L2 stage of neuroblastoma in the International Neuroblastoma Risk Group Staging System, which is equivalent to stage 2B in the International Neuroblastoma Staging System. Stage 2B Neuroblastoma indicates that the tumor cannot be removed completely with surgery and that nearby lymph nodes do contain cancer cells. In order to determine the risk group of this stage, we use the Children’s Oncology Group (COG), which uses major prognostic factors discussed in the staging system with a combination of the INSS stage of disease to place the diagnosis into three different risk groups: low, intermediate or high. Matt is considered to be low-risk because he is in the 2B stage, older than one years of age, and has no extra copies of the MCYN gene in his cancer cells. The MCYN gene amplification occurs in 20% of neuroblastoma patients. Luckily we were able to assess for the MCYN gene and have seen no amplification of this gene, which is common with patients diagnosed with the 2B stage of neuroblastoma. [10]

Matt has a tumor in his chest that has spread to the lymph nodes in his neck. Due to the tumor’s position, Matt is having difficulty breathing and it is unsafe for us to immediately treat him with surgery.. We will first need to give him a short course of chemotherapy to shrink the tumor, in order to take control of his symptoms, and then perform surgery to remove the remainder. If chemotherapy is not strong enough, radiation therapy can also be used. [11]

Chemotherapy uses anti-cancer drugs that are injected into the vein. The drugs enter via the bloodstream and go through the body to get rid of cancer cells. This allows for a decrease in size of the tumor in the chest and gets rid of the cancer that has spread to the lymph nodes. Chemotherapy for neuroblastoma includes a combination of drugs. The main chemo drugs used include cyclophosphamide, cisplatin, vincristine, doxorubicin, eptoposide, topotecan and busulfan. For Matt we will be using carboplatin, cyclophosphamide, doxorubicin and eptoposide. Carboplatin, a platinum-containing compound, works by targeting DNA to interfere with DNA repair which slows or stops the growth of cancer cells.[12] Cyclophosphamide works by adding an alkyl group to the guanine base of DNA that then interfered with DNA replication by forming interstrand and intrastrand DNA crosslinks.[13] Doxorubicin is an anthracyclines which is the strongest drug that we will be giving Matt. It works by inserting molecules between the DNA planar DNA bases.[14] Eptoposide, a plant alkaloid, attacks cells during different phases of cell division. It works by forming a three part complex with DNA and topoisomerase II enzyme that helps unwind the DNA and prevents it from re-ligating the DNA strands which is helpful for cancer cells because it leads to apoptosis of those cells.[15] We will give the chemotherapy in cycles, which consists of treatment of a few days in a row, followed by a break period to allow the body to recover. The cycles are typically repeated every three to four weeks. For Matt, we will perform one treatment before the surgery and one after the surgery. Chemotherapy drugs destroy cells that are dividing quickly, such as cancer cells. However, normal cells in the body, such as new blood cells formed in the bone marrow, cells in the lining of the mouth and the intestines, and cells in the hair follicles also divide quickly. Therefore, these cells are also likely to be affected by chemotherapy and this impact can lead to multiple side effects, depending on the type and dose of drugs given during treatment. General side effects include hair loss, loss of appetite, mouth sores, nausea, diarrhea, increased chance of infections, easy bruising, and fatigue. Most of these side effects only last for a short amount of time and tend to go away after treatment. In addition, each drug given during chemo also has its own side effects. Cyclophosphamide can damage the bladder and cause bleeding in the urine. This risk can be lowered by taking this drug with a lot of fluids and a drug called mesena that helps protect the bladder. Doxorubicin may cause heart damage or skin damage if it leaks out of the vein. We will try to reduce this risk as much as possible by giving limited amounts and regularly checking the heart via ultrasound during the treatment. Carboplatin can affect the kidneys and hearing, but the risk will be reduced by giving lots of fluids during the treatment and checking Matt’s hearing through audiograms during or after treatment. Chemotherapy can also have long-term side effects, such as an increased risk of a second cancer forming. This is a serious risk but can be weighed against the importance of treating neuroblastoma. [16]

If chemotherapy is not strong enough to eliminate the cancer cells, we will use radiation therapy. Radiation therapy uses high-energy rays or particles to attack cancer cells. Due to the possible long-term side effects, we will try to stay away from this therapy. But if we do use it, it will be an external beam radiation therapy. The radiation will only be aimed at the tumor. Before treatment starts, the radiation team will take measurements during the imaging tests to determine a proper angle for the radiating beams as well as the proper dosage. Radiation therapy is just like getting an X-Ray, but at a much higher radiation. Matt will be put to sleep and put into a plastic mold, similar to a body cast, to keep him in the same position. The number of radiation treatments is dependent on the tumor situation. During each session, Matt will be lying on a table while the machine will give radiation at a particular angle. Prepping for this therapy will take longer than the actual therapy itself. Matt will not feel any pain during this. The possible side effects for this therapy include mild sunburns, hair loss, and fatigue towards the end of the treatment. Possible long-term side effects include slow growth in normal body tissue, impacts on the heart and the lungs in developing children, and damage to the DNA inside cells, which can gain lead to development of a second cancer. [17]
The surgery will allow the surgeon to look for signs of the tumor spreading to other organs. First the surgeon will remove cancer cells near the lymph nodes and then will try to remove the tumor. The rest of the cancer cells left behind by the surgeon will then be removed through radiation or chemotherapy. Surgery may be repeated to remove any leftover cancer cells and check the results of the treatment performed. Like all surgeries, there are risk factors, including problems with anesthesia, excess bleeding, and infection. After the operation is performed, children usually experience pain, but will be facilitated using medicines.[18]


One of the major disadvantages for children treated for neuroblastoma is the increased risk of a second cancer. Some treatments may cause side effects that occur immediately after. Some occur years later and are known as late effects. Late effects can include mood changes, physical problems or a second cancer. It is extremely important to talk to Matt about second cancers when undergoing treatment. [19]
This treatment will be performed by a team of doctors, including a pediatric surgeon, a radiation oncologist, and an endocrinologist, that will aid in their specialized areas.[20] Each doctor will assist during the treatment when necessary. It is extremely important to follow up with each of the doctors after treatment for better long-term results. Luckily we only needed to perform chemotherapy and surgery with no radiation therapy to successfully treat Matt.



Molecular Basis of Neuroblastoma and Treatment


To better understand Matt’s treatment, we will explain in depth to see the molecular cause of neuroblastoma. Neuroblastoma is an embryonic tumor from cells of the sympathetic nervous system. In general, neuroblastoma like other cancers develops through an accumulation of mutations in critical genes that take charge of cell growth and proliferation (division) or differentiation (development).[21] Mutations in these genes cause cells to grow and divide uncontrollably and eventually form a tumor.[22] Tumor cells require the action of growth factors to proliferate.[23] The first step is the interaction of growth factors and cell signal molecules with different receptors, followed by the activation of other signaling molecules.[24]


In Matt’s case, the genetic mutations are referred to as somatic mutations because they were developed in the past seven years of his life; somatic mutations are also not inherited and are only present in certain cells.[25] Neuroblastoma when not inherited is referred to sporadic neuroblastoma.[26]

Through the biopsy we performed on Matt, we found the ALK and PH0X2B genes to be mutated. The ALK gene has several mutations and is located on chromosome 2.[27] ALK stands for anaplastic lymphoma kinase because this gene provides instructions to make this protein, which is part of family of protein called receptor tyrosine kinase (RTKs).[28] RTKs send signals from the cell surface into the cell through a process called signal transduction. This process starts when a stimulated kinase at the cell surface and attaches to another kinase called dimerization. After dimerization, a phosphate group (group of oxygen and phosphorous atoms) attaches to the kinase called phosphorylation. This process activates the kinase, which is now able to transfer the phosphate group to another protein inside the cell. This activity continues through multiple proteins in a signaling pathway and is responsible for cell proliferation or differentiation. Although the specific function of this protein is unknown, it seems to play an important role in cell proliferation. Mutations in the ALK gene cause an abnormal version of the protein to be turned constantly which leads to abnormal proliferation of the nerve cells that lead to neuroblastoma. [29]

The PHOX2B gene is important for the differentiation and formation of nerve cells. Mutations in this genes interfered with the protein this gene produces in promoting cell differentiation.[30] This mutation results in immature nerve cells to lead to neuroblastoma. Neuroblastoma also leads to infiltration of the bone marrow. Bone marrow is found on he pelvis, ribs and the ends of long bones in the axial skeleton and made up of red marrow and yellow marrow. As we get older, our red marrow is replaced by yellow marrow. When cancer begins to form, abnormal tissue begins to cause immature bone marrow instead of filtering through the normal tissue and developing normal bone marrow.[31]

In order to overcome the neuroblastoma that Matt was diagnosed with, as you know we performed a combination of chemotherapy and surgery. We performed the surgery to remove the tumor near his chest and the cancer spread near his lymph nodes in his neck. Then we performed chemotherapy to remove the remaining cancer cells. For this treatment we used the agents’ carboplatin, doxorubicin, cyclophosphamide and etoposide. At a basic level all of these drugs target the proliferating and differentiating cells and reduce the degree of bone marrow infiltration.
Carboplatin’s molecular mechanism involves increased repair activity of DNA damage, and altered expression of oncogenes and regulatory proteins. Oncogenes are basically the mutated ALK and PHOX2B that cause cells designated for apoptosis to survive and proliferate instead. In addition, the cytotoxicity of carboplatin is controlled through induction of apoptosis and arrest of cell cycle resulting from its interaction with DNA which activates multiple signaling pathways, including those involving p53.[32] Activated p53 binds DNA and activates expression of several genes including microRNA encoding for p21 and hundreds of other down-stream genes. P21 then binds to the G1-S phase CDK complexes which are molecules important for the G1/S phase transition in the cell cycle, inhibiting their activity.[33] The G1 is the fist phase in the cell cycle where the cell grows and the S phase is the second phase in the cell cycle where the DNA replication occurs. When p21 is interlocked with CDK2 the cell cannot continue to the next stage of cell division.[34] A mutant p53 will no longer bind DNA in an effective way, and, as a consequence, the p21 protein will not be available to act as the "stop signal" for cell division.[35]

Cyclophosphamide is part of an alkylating activity and must undergo bio-activation by hepatic cytochrome P450.[36] Hepatic cytochrome P450 belongs to a family of proteins called hemeproteins. These proteins perform multiple functions using a variety of molecules as substrates in enzymatic reactions. They are in general enzymes that are a part of electron transfer chains in a cell. Cyclophosphamide activation is initiated by a cytochrome p450-dependent reaction and metabolically activated in the liver via oxidation by cytochrome P450 enzymes. The activated cyclophosphamide metabolites are then transported into both tumor and healthy cells via the bloodstream.[37]

Doxorubicin interacts with DNA by intercalation and inhibition of macromolecular biosynthesis.[38] This inhibits the progression of the enzyme topoisomerase II, which relaxes supercoils in DNA for transcription. Doxorubicin stabilizes the topoisomerase II complex after it has broken the DNA chain for replication, preventing the DNA double helix from being resealed and thereby stopping the process of replication.[39] Etoposide also targets topoisomerase II.[40] Etoposide poisons the enzyme and induces it to generate DNA breaks that are lethal to the cell. Topoisomerase II-targeted drugs show a limited sequence preference, triggering double-stranded breaks throughout the genome.[41]


Neuroblastoma is a cancer that develops from the tissues of the sympathetic nervous system. Matt has a specific type called the sporadic neuroblastoma, which suggests that it is not inherited. He had tumor in his chest area as well as swollen lymph nodes near in his neck. Matt was diagnosed with the L2 stage of cancer, which means the cancer had not spread to distant places. We found that his ALK and PHOX2B gene were mutated causing abnormal cell proliferation and differentiation. First we performed chemotherapy to reduce the size of the tumor, and then we performed surgery to remove the tumor and the cancer cells that had spread near the lymph nodes. Lastly, we performed chemotherapy with specific drugs that can target the cell signaling pathways involved in cancer cell growth and cell proliferation. Chemotherapy definitely removed the remaining cancer cells in Matt’s body and allowed him to recover fully. Finally, since Matt is a young patient, it is important for him to follow up with the doctors on a regular basis to prevent a second cancer from occurring.

Apercu: To be diagnosed with cancer at such a young age and being able to overcome neuroblastoma with a positive attitude is unbelievable No matter what circumstances life brings you, remember to never let go of the positive attitude.


























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