Danielle+Willkom

= Neuroblastoma: Finn’s Diagnosis =

When asked, Finn’s parents would talk endlessly about how their four year old child was truly a miracle from God. Any one who had the pleasure of meeting Finn would find the biggest smile on his face, as he is always laughing and in the best of moods. This four year old truly had the ability to turn your day around.

One week, it became a recurring theme that Finn would refuse to eat his dinner, claiming he was already full. Too tired to argue, Finn’s mother prepared him for a bath, and noticed a large lump on his abdomen and swelling in his legs. Because it was likely that Finn had gotten hit with a basketball at camp, the swelling in his legs was not so alarming. However, his lack of appetite and the lump on his abdomen raised some red flags. Finn was immediately rushed to the hospital. Finn’s parents discussed his symptoms and how long they had lasted, then an abdominal x-ray was performed. The x-ray revealed a tumor growing in Finn’s abdomen, which resulted in his lack of appetite for the past week (1).

Blood and urine tests were conducted in order to properly diagnose Finn. Both tests have the ability to detect whether or not the tumor is secreting hormones. Finn’s results revealed hormones called catecholamines, which are normally released by the sympathetic nerve cells. Unfortunately, neuroblastoma cells release catecholamines, which suggested that this cancer may be the source of Finn’s troubles. While the symptoms and test results continued to lean towards the possibility of neuroblastoma, a biopsy was performed in order to come to a conclusion. A needle biopsy could confirm the presence of a cancer by removing a small sample of the tumor with a thin, hollow needle. The results confirmed neuroblastoma (2).

Neuroblastoma often occurs in children under the age of five, as it is a cancer that forms in specific types of immature, or developing, cells. It starts in neuroblasts of the sympathetic nervous system, thus providing a wide range for the cells’ native habitat (3). In most cases, the cancer forms in the adrenal glands or chest. Screening for the cancer, at ages as young as six months old, can detect tumors that are not normally diagnosed because the cancer cells eventually die for no reason or the tumor goes away on its own. On the other hand, tumors can begin to rapidly grow and metastasize by the time it is diagnosed (4).

Although the tumor was confirmed to be a result of neuroblastoma, an imaging test was performed in order to find out if the cancer had metastasized, or if the swelling in Finn’s legs was simply a result of an accident from basketball. Tumors have the ability to affect other parts of the body that do not contain cancer cells. Unfortunately, Finn’s neuroblastoma tumor in the abdomen invaded and clogged the lymph vessels. The obstruction prevented fluids from circulating back to the heart, and resulted in the swelling in his legs (5).

About one to two percent of neuroblastoma cases are a result of gene mutations passed down from a parent (6). However, the majority of neuroblastoma cases, such as Finn’s, are not hereditary. Studies have shown that some gene changes that happen early in the child’s development have lead to neuroblastoma. Some may be inherited, a result of random events that occur inside the cell, or have an unknown outside cause. There are no lifestyle or environmental factors that are known to lead to this cancer. Ultimately, it remains unclear what exactly causes neuroblastoma (7).

The International Neuroblastoma Risk Group Staging System allows doctors to use the results of imaging tests and biopsies to determine a patient’s prognosis. According to the staging system, Finn is diagnosed with L2 stage. This means that the tumor has not spread far from the abdomen, but it does contain at least one image-defined risk factor (IDRF). IDRFs are factors that increase the possibility that the tumor will be difficult to remove through surgery. An example of an IDRF is if the tumor grew into a vital organ or around important blood vessels (8). Specific markers, such as stage, age, gene status, DNA ploidy, and tumor histology provide a better prediction for which treatments will work, and whether or not the tumor will return after treatment. The markers allow patients to be placed in either low-risk, intermediate-risk, or high-risk neuroblastoma. Those with low risk disease are often treated with surgery alone, while those with intermediate risk disease are treated with both surgery and chemotherapy. Several intensive treatments are used for those with high risk disease (9).

The 5-year survival rate for children younger than one year old is 90%, while the survival rate for those aged one to four years old is 68% (10). Finn’s tumor histology was examined under the microscope, and the tumor revealed to contain more cancerous cells than normal-looking cells, thus resulting in an unfavorable histology and poorer prognosis (8). Despite the unfavorable histology, it is important to remember that the tumor has not spread far from its primary site of origin, such as the other side of the body. Surgery may completely remove the tumor, but because Finn was diagnosed at an older age, and the cancer had invaded his lymph vessels by the time he was diagnosed, a more intensive treatment may be considered in order to provide a better prognosis. While, at this point, Finn’s parents are unsure as to what will be best for him, one thing is for sure: they cannot bear to see that radiant smile leave Finn’s face.

= The Molecular Basis = While the cause of neuroblastoma is unknown, several gene changes have been found to correspond to a patient’s response to treatment and poorer prognosis. “Neuroblastoma develops when normal fetal neuroblasts fail to become mature nerve cells or adrenal medulla cells. Instead, they continue to grow and divide” (7). The cell growth and proliferation remains in young children and forms tumors. By the time of diagnosis, the cells have no hope of maturing into nerve cells, and instead grow and metastasize. The neuroblasts’ stunted growth and failure to mature is a result of chromosome aberrations.

Abnormalities in DNA caused by cancer can turn oncogenes on or suppressor genes off. Oncogenes assist cell growth and division, while tumor suppressor genes hinder cell division and prompt cell death when necessary. Such abnormalities in DNA can be inherited, though only one to two percent of neuroblastoma cases have been passed down from a parent (7). The ALK oncogene is the most commonly mutated gene held responsible for most cases of hereditary neuroblastoma (7). ALK creates a protein called anaplastic lymphoma kinase, whose specific protein function is unknown. Mutations in the ALK gene create an abnormal anaplastic lymphoma kinase that is incessantly activated. This activation can result in the proliferation of immature nerve cells (11).

Sporadic neuroblastoma refers to neuroblastoma that results from genetic changes acquired during a person’s lifetime (11). In other words, these genetic changes are not hereditary. Despite the uncertainty of what gene changes specifically cause sporadicneuroblastoma, some gene changes have been found to determine the severity of the disease. Finn’s biopsy revealed that his MYCN genes were overexpressed. Amplification of the MYCN gene is currently “the best characterized genetic marker of risk in neuroblastoma” (12). Although MYCN amplification is more associated with more aggressive cases of neuroblastoma, it has been found that low-stage diseases with this gene amplification are also associated with rapid progression and poorer prognosis (13). MYCN amplification is found in about twenty-five percent of neuroblastoma cases (11).

The MYCN gene codes for a protein that is believed to play a significant role in the formation of tissues and organs during embryonic development. Specifically, the gene plays a key role in the normal development of the nervous system (14). Because this gene is an oncogene, it has the ability to disrupt the regulation of cell growth, division, and death when mutated. Finn’s tumor had a prolonged latency and “showed recurrent chromosomal copy number abnormalities” (12). Such results reveal that both genetic mutations and misexpressed MYCN gave rise to his neuroblast transformation. The loss of tumor suppressors, such as TP53, resulted in additional mutations. Such mutations, in addition to misexpression of MYCN, allowed the cancer cells in Finn’s tumor to proliferate, then penetrate and clog the lymph vessels.



Finn’s MYCN-amplified neuroblastoma demonstrates several hallmarks through its power to evade growth suppressors and activate invasion and metastasis. MYCN plays multiple roles in malignancy, including the ability to inhibit the TP53 tumor suppressor (12). TP53 uses signals from DNA damage, oxygen levels, and precursor pools to stop the cell cycle, specifically the G-1 phase, which is an important period committed to cell proliferation (12). The cancer cells in Finn’s tumor had found a way to circumvent TP53’s power to regulate cell growth. The inactivation of the TP53 tumor suppressor ultimately prevented cell death and allowed the cancer cells to proliferate. In Finn’s case, the neuroblasts that failed to mature were unable to experience cell death, and instead continued to grow and divide.

<span style="font-family: 'Times New Roman',Times,serif;">In addition to MYCN’s ability to inhibit TP53, it promotes the transcription of focal adhesion kinase (FAK). Specific integrin signals are needed during the process of tumor growth to metastasis. Such signals “enable cancer cells to detach from neighbouring cells, re-orientate their polarity during migration, and survive and proliferate in foreign microenvironments” (15). The promotion of FAK allowed the epithelial tumor cells (which line the cavities of the body) in Finn’s abdomen to transform into mesenchymal stem cells, which unlike epithelial cells, are able to migrate throughout the surrounding tissue and rest of the body. This process resulted in metastasis and the invasion of the cancer to the lymph vessels. Because FAK can be repressed by TP53, both MYCN and TP53 compete to regulate the FAK levels. In Finn’s case, MYCN won.

<span style="font-family: 'Times New Roman',Times,serif;">The Treatment
<span style="font-family: 'Times New Roman',Times,serif;">The standard treatment for patients with neuroblastoma is heavily dependent on the age of the child, the size and position of the tumor, metastasis, and several other prognostic markers such as MYCN status (16). Treatment also varies significantly on the risk of relapse (17). About 50% of children with high-risk disease suffer a relapse, while relapses only occur 5 to 15% of the time for those with intermediate or low-risk disease (17). Children with low-risk disease, usually under the age of 18 months, do not need intensive treatment to cure the neuroblastoma. Some children who are diagnosed at such a young age have surgery as their only treatment, or do not need treatment at all, because the neuroblastoma can mature and go away on its own (18). On the other hand, those with intermediate-risk disease are treated with both surgery and chemotherapy, while those with high-risk disease need a combination of several intensive treatments, such as chemotherapy, surgery, and radiation (9). Finn’s neuroblastoma has invaded the lymph vessels in the abdomen, but has not spread to distant parts of the body, thus placing him at intermediate-risk disease. Because he was diagnosed with L2 stage, and the cancer has spread to the lymph vessels, it is not guaranteed that the tumor in Finn’s abdomen can be removed with surgery. Additionally, Finn’s MYCN amplification indicates a more aggressive neuroblastoma. Thus, Finn will undergo neoadjuvant chemotherapy, where drugs will first be administered in hopes of shrinking the tumor to a point that will allow removal through surgery. The treatment after chemotherapy will then be determined based on the efficacy of the drugs on Finn’s tumor.

<span style="font-family: 'Times New Roman',Times,serif;">The standard chemotherapy regimen for patients with intermediate-risk disease is a combination of carboplatin, cyclophosphamide, doxorubicin, and etoposide (18). The drugs enter the bloodstream, then destroy the cancer cells in multiple cycles before surgery (19). One cycle can last a few days in a row, then time off is needed in order for the body to recover. The cycles are repeated every 3 to 4 weeks, and the overall length of treatment depends on the risk group (19). Following every few cycles of chemotherapy, radiology, bone marrow, blood, and urine tests are conducted to determine how the child’s tumor is responding to the therapy (20).

<span style="font-family: 'Times New Roman',Times,serif;">Children with neuroblastoma that has spread to distant parts of the body, or who are high-risk with MYCN amplification, are given high-dose chemotherapy with stem cell support after an initial treatment of chemotherapy (16). High doses of chemotherapy have the ability to target any remaining neuroblastoma cells that were not removed through the initial round of chemotherapy, but can also wipe out the the body’s bone marrow, where blood cells are made (16). Thus, stem cells are “collected from the child through a drip before high dose chemo is given”, then the stem cells are frozen and stored (16). The stem cells are then given back to the child’s bloodstream through an IV, where they can return to the bone marrow and grow and develop into mature blood cells (16).

<span style="font-family: 'Times New Roman',Times,serif;">While surgery or chemotherapy, either alone or together as a combination therapy, remain as the standard treatments for children with neuroblastoma, experiments with monoclonal antibodies are becoming more common. Since March of 2015, the monoclonal antibody dinutuximab has been routinely used as a first-line therapy for children with high-risk neuroblastoma (21). Because children with high-risk disease need more intensive treatments, the dinutuximab monoclonal antibody has been approved as a part of a multimodality therapy, whether it be combined with surgery, chemotherapy, or radiation. “A monoclonal antibody is a laboratory-produced molecule that is carefully engineered to attach to specific defects in cancer cells” (22). The monoclonal antibodies are able to imitate the natural antibodies produced by the body (22). Dinutuximab is an antibody that was engineered to recognize and bind to GD2, which is a molecule that is highly expressed on the surface of a variety of tumors. Specifically, it is most commonly expressed on neuroblastoma tumors (22). GD2’s expression in normal tissues is highly restricted to the cerebellum and peripheral nerves (23). The binding of dinutuximab to GD2 causes antibody-dependent cellular cytotoxicity (ADCC). The ADCC mechanism takes place when the antibody, dinutuximab, attaches to the target cell and releases other cells such as lymphocytes and macrophages where GD2 resides (24). The binding of the antibody to GD2 initiates an immune response that can kill the cancerous cells. The 5-year survival rate for high-risk neuroblastoma remains below 40%, with the majority of the patients either suffering relapse, or immediate resistance to the initial therapy (25). Hence, immunotherapy and antibodies that target GD2 are becoming a main strategy against high-risk neuroblastoma.

<span style="font-family: 'Times New Roman',Times,serif;">Although anti-GD2 antibodies have been increasingly common in clinical trials, several side effects raise questions as to whether this is the best treatment. Before FDA approval in 2015, a clinical trial for dinutuximab was conducted by the Children’s Oncology Group in 2011 (21). Nearly 20% of the patients in the trial discontinued treatment due to severe side effects. The approval of dinutuximab “fulfills a critical need by providing a treatment option that can prolong survival in children with high-risk neuroblastoma”, but are the adverse reactions always worth it (26)? Of the many side effects seen in the clinical trials, the more severe are neuropathy, which is a nerve problem that causes pain, numbness, tingling, swelling, or muscle weakness in different parts of the body, and capillary leak syndrome, which is a massive leakage of plasma and other blood components from blood vessels into neighboring body cavities and muscles (21). However, after FDA approval, the safety and efficacy of dinutuximab was once again evaluated, and 226 high-risk pediatric patients whose tumors shrunk after chemotherapy were treated with the antibody. 63% of the participants were alive and free of tumor growth or recurrence after three years of treatment assignment (26).

<span style="font-family: 'Times New Roman',Times,serif;">Despite the fact that Finn was diagnosed with intermediate-risk disease, his MYCN amplification makes it necessary for him to be treated as if he had high-risk neuroblastoma. The MYCN amplification indicates high chances of rapid progression and poorer prognosis, despite his intermediate-risk diagnosis. Thus, after chemotherapy, Finn will be treated with dinutuximab. Because the initial round of chemotherapy had successfully shrunk Finn’s tumor, the possible side effects Finn might experience with dinutuximab are worth the efficacy of the antibody on his MYCN-amplified tumor. At only four years old, Finn has a bright future ahead of him. Although his smile may fade for the time he will be under intensive treatment, the amount of time he will be tumor-free far surpasses it.

<span style="display: block; font-family: 'Times New Roman',Times,serif; text-align: center;">Aperçu:
<span style="display: block; font-family: 'Times New Roman',Times,serif; text-align: center;">While the amplification of MYCN genes reveal the severity of one’s case, what actually causes the neuroblastoma remains unknown. One may think that the lack of knowledge as to what gave rise to the cancer leaves us tied up in the dark. Having a young child suffer without knowing what could have caused it can be incredibly difficult. However, it is important to note that the MYCN-amplified neuroblastoma allows us to provide the child with a successful treatment particular to the hallmarks the cancer has.

= <span style="font-family: 'Times New Roman',Times,serif;">References = <span style="font-family: 'Times New Roman',Times,serif;">(1) “Signs and Symptoms of Neuroblastoma.” American Cancer Society. American Cancer Society, Inc., 14 Mar. 2014. Web. 13 Apr. 2016. <http://www.cancer.org/cancer/neuroblastoma/detailedguide/neuroblastoma-signs-and-symptoms>. <span style="font-family: 'Times New Roman',Times,serif;">(2) “How Is Neuroblastoma Diagnosed?” American Cancer Society. American Cancer Society, Inc., 14 Mar. 2014. Web. 13 Apr. 2016. <http://www.cancer.org/cancer/neuroblastoma/detailedguide/neuroblastoma-diagnosis>. <span style="font-family: 'Times New Roman',Times,serif;">(3) “What Is Neuroblastoma?” American Cancer Society. American Cancer Society, Inc., 14 Mar. 2014. Web. 13 Apr. 2016. <http://www.cancer.org/cancer/neuroblastoma/detailedguide/neuroblastoma-what-is-neuroblastoma>. <span style="font-family: 'Times New Roman',Times,serif;">(4) “Can Neuroblastoma Be Found Early?” American Cancer Society. American Cancer Society, Inc., 14 Mar. 2014. Web. 13 Apr. 2016. <http://www.cancer.org/cancer/neuroblastoma/detailedguide/neuroblastoma-detection>. <span style="font-family: 'Times New Roman',Times,serif;">(5) Lanciano, Peter. “Neuroblastoma and Neuroblastoma Treatment.” Neuroblastoma. Neotropix, 2008. Web. 13 Apr. 2016. <http://www.neotropix.com/neuroblastoma.htm>. <span style="font-family: 'Times New Roman',Times,serif;">(6) “Hereditary Neuroblastoma.” St. Jude Children's Research Hospital. N.p., n.d. Web. 13 Apr. 2016. <https://www.stjude.org/disease/hereditary-neuroblastoma.html>. <span style="font-family: 'Times New Roman',Times,serif;">(7) “Do We Know What Causes Neuroblastoma?” American Cancer Society. American Cancer Society, Inc., 14 Mar. 2014. Web. 13 Apr. 2016. <http://www.cancer.org/cancer/neuroblastoma/detailedguide/neuroblastoma-what-causes>. <span style="font-family: 'Times New Roman',Times,serif;">(8) “How Is Neuroblastoma Staged?” American Cancer Society. American Cancer Society, Inc., 14 Mar. 2014. Web. 13 Apr. 2016. <http://www.cancer.org/cancer/neuroblastoma/detailedguide/neuroblastoma-staging>. <span style="font-family: 'Times New Roman',Times,serif;">(9) “Neuroblastoma - Childhood: Stages and Groups | Cancer.Net.” Cancer.Net. American Society of Clinical Oncology, 25 June 2012. Web. 13 Apr. 2016. <http://www.cancer.net/cancer-types/neuroblastoma-childhood/stages-and-groups>. <span style="font-family: 'Times New Roman',Times,serif;">(10) “Neuroblastoma Treatment.” National Cancer Institute. N.p., 14 Jan. 2016. Web. 13 Apr. 2016. <http://www.cancer.gov/types/neuroblastoma/hp/neuroblastoma-treatment-pdq>. <span style="font-family: 'Times New Roman',Times,serif;">(11) "Neuroblastoma." Genetics Home Reference. U.S. National Library of Medicine, Mar. 2011. Web. 8 May 2016. <https://ghr.nlm.nih.gov/condition/neuroblastoma#genes>. <span style="font-family: 'Times New Roman',Times,serif;">(12) Huang, Miller, and William A. Weiss. “Neuroblastoma and MYCN.” Cold Spring Harbor perspectives in medicine 3.10 (2013): a014415. PMC. Web. 28 Apr. 2016 <http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3784814/> <span style="font-family: 'Times New Roman',Times,serif;">(13) Robertson, Sally. "What Is Neuroblastoma?" News-Medical.net. AZoM.com Limited, 02 Dec. 2009. Web. 8 May 2016. <http://www.news-medical.net/health/What-is-Neuroblastoma.aspx>. <span style="font-family: 'Times New Roman',Times,serif;">(14) "MYCN." Genetics Home Reference. U.S. National Library of Medicine, Mar. 2011. Web. 8 May 2016. <https://ghr.nlm.nih.gov/gene/MYCN>. <span style="font-family: 'Times New Roman',Times,serif;">(15) Guo, Wenjun, and Filippo G. Giancotti. "Integrin signalling during tumour progression." Nature reviews Molecular cell biology 5.10 (2004): 816-826. <http://www.nature.com/nrm/journal/v5/n10/full/nrm1490.html> <span style="font-family: 'Times New Roman',Times,serif;">(16) "Neuroblastoma in Children." Macmillan Cancer Support. Macmillan Cancer Support, 1 Jan. 2013. Web. <http://www.macmillan.org.uk/cancerinformation/cancertypes/childrenscancers/typesofchildrenscancers/neuroblastoma.aspx>. <span style="font-family: 'Times New Roman',Times,serif;">(17) "Neuroblastoma in Children - In Treatment." CureSearch for Children’s Cancer. CureSearch, n.d. Web. 30 May 2016. <http://curesearch.org/Neuroblastoma-In-Treatment>. <span style="font-family: 'Times New Roman',Times,serif;">(18) "Treatment of Neuroblastoma by Risk Group." American Cancer Society. American Cancer Society, Inc., 14 Mar. 2014. Web. <http://www.cancer.org/cancer/neuroblastoma/detailedguide/neuroblastoma-treating-by-risk-group>. <span style="font-family: 'Times New Roman',Times,serif;">(19) "Chemotherapy for Neuroblastoma." American Cancer Society. American Cancer Society, Inc., 14 Mar. 2014. Web. <http://www.cancer.org/cancer/neuroblastoma/detailedguide/neuroblastoma-treating-chemotherapy>. <span style="font-family: 'Times New Roman',Times,serif;">(20) "In Treatment for Neuroblastoma." Children's Oncology Group. The Children's Oncology Group, n.d. Web. <https://childrensoncologygroup.org/index.php/in-treatment-for-neuroblastoma>. <span style="font-family: 'Times New Roman',Times,serif;">(21) "FDA Approves First Therapy for High-Risk Neuroblastoma." NIH: National Cancer Institute. National Cancer Institute, n.d. Web. <http://www.cancer.gov/news-events/cancer-currents-blog/2015/dinutuximab-neuroblastoma>. <span style="font-family: 'Times New Roman',Times,serif;">(22) "Cancer." Monoclonal Antibody Drugs for Cancer: How They Work. Mayo Foundation for Medical Education and Research, n.d. Web. <[]>. <span style="font-family: 'Times New Roman',Times,serif;">(23) Ahmed, Mahiuddin, and Nai-Kong V. Cheung. "Engineering anti-GD2 monoclonal antibodies for cancer immunotherapy." FEBS letters 588.2 (2014): 288-297. Web. <http://onlinelibrary.wiley.com/doi/10.1016/j.febslet.2013.11.030/full>. <span style="font-family: 'Times New Roman',Times,serif;">(24) Mody, Rajen. "What Is the Mechanism of Action for Dinutuximab?" Journal of the Advanced Practitioner in Oncology. Harborside Press, LLC, n.d. Web. 30 May 2016. <http://www.advancedpractitioner.com/tips/rajen-mody-clip-36.aspx>. <span style="font-family: 'Times New Roman',Times,serif;">(25) Mora, Jaume. "Dinutuximab for the treatment of pediatric patients with high-risk neuroblastoma." Expert review of clinical pharmacology 9.5 (2016): 647-653. Web. <[]>. <span style="font-family: 'Times New Roman',Times,serif;">(26) "FDA Approves First Therapy for High-risk Neuroblastoma." U.S. Food and Drug Administration. U.S. Food and Drug Administration, 10 Mar. 2015. Web. <[]>.