Andy Lin, Krrish Ladha, Lauren Park, Saawariya Shahriar
Discussion
Choosing to research Neuroblastoma was driven by curiosity about the complexities of pediatric cancers and the urgent need for improved treatment options. Neuroblastoma presents an intricate challenge as its underlying genetic mutations and wide-ranging clinical manifestations make it a compelling subject for study. The combination of scientific intrigue and a desire to advance medical knowledge fueled our decision to focus on Neuroblastoma. As one of the most aggressive and dangerous cancers, by writing this article, we aimed to inform patients and the public about the effects and impacts of Neuroblastoma on human life. The idea of knowing that people live their lives without knowing the implications of such a cancer fueled our decision to write this article.
Abstract
Neuroblastoma is a malignant tumor that commonly impacts young children. It derives from nerve tissues (neuroblasts) and develops in the adrenal gland. It occurs when genetic changes cause undeveloped neuroblasts to proliferate uncontrollably. During this process, due to the irregular growth of immature nerve tissues, a genetic mutation causes the cells to grow and divide. The genetic mutations work by altering the cell cycle of regulatory genes, causing the rapid growth of abnormal cells that lead to the formation of a tumor. This article aims to provide information on mutations linked to Neuroblastoma and a comprehensive overview of Neuroblastoma, including its impact, prognosis on humans, and treatment opportunities. The purpose of this article is to inform patients, the general public, and healthcare professionals about the effects and implications of treating mutations linked with Neuroblastoma, as well as the importance of early detection. In doing so, people will better understand Neuroblastoma and consider funding further research to formulate safer treatments.
Table of Contents
Discussion ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 2
Abstract •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 2
Introduction ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••4
Diagnosis •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 4-5
Medical Professions ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 5-6
Treatments ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••6-7
Genetic Mutations Regarding Neuroblastoma ••••••••••••••••••••••••••••••••••••••••••••7
- ALK Gene Mutations •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 7-8
- MYCN Amplifications ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 8-9
- PHOX2B Gene Mutations ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 9-10
Statistics •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••10-11
Impact •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••11
Conclusion •••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••• 12
Work Cited ••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••••13-15
Introduction
Neuroblastoma is a pediatric cancer that predominantly impacts young children. It originates in early, underdeveloped nerve cells called neuroblasts. Neuroblastoma develops from the uncontrollable growth of underdeveloped nerve cells, leading to cancer cells that form a tumor. The National Library of Medicine states, “It is classified as an embryonal neuroendocrine tumor, originating from neural crest progenitor cells.” As a result, they can occur anywhere along the sympathetic nervous cells, including the sympathetic ganglia. The prognosis of Neuroblastoma varies from low-risk patients to intermediate and high. Children with low risks are usually classified into the stage I or II range, children with intermediate-risk are classified as stage II to III, sometimes IIII, and high-risk patients are stages III and IIII. Understanding the effect of mutations in Neuroblastoma is necessary to advance treatment opportunities and the diagnosis of Neuroblastoma.
Diagnosis
As the most common cancer in infants, Neuroblastoma diagnosis may start as early as in unborn babies through prenatal ultrasound, also known as fetal or pregnancy ultrasounds. Through the use of a transducer, a device that converts one form of energy to another, high frequency sound waves ricochet off of structures and reproductive organs in the carrier and the baby to produce soft-tissue images onto a screen. The images can provide a thorough understanding of the health and growth of the fetus, and a multitude of scans may be administered to determine formation of tumors and their impact to tissues in their periphery. For instance, MRI scans soft tissues through the use of a magnet and radio waves. An X-ray scans a specific region (with less detailed images), whereas a CT scan involves injection of a dye into the child’s vein in order to create many X-rays. Moreover, a Methyliodobenzylguanine (MIBG) scan incorporates the use of a scanner for imaging and a safe radiotracer known as 123-iodinated MIBG that specifically tracks for neuroblastoma cells 90% of the time. When neuroblastoma tumors are resistant to the MIBG compound, a PET scan, a nuclear medicine scan that searches for active neuroblastoma cells, is administered in place. Aside from scanning, blood tests, urine tests, and biopsies may be used to further confirm diagnosis. Through a blood test, hormone levels and substances in the blood are detected to ensure no abnormalities or potential signs of cancer are present. Similarly, the urine test determines the levels of chemicals in the child, with caution being issued for results outside normal ranges. However, with the use of a biopsy, a tissue sample is scrutinized under a microscope and undergoes various tests to check for chromosomal alterations of the tumor cells to prescribe an accurate risk category and treatment plan. Biopsies come in the form of testing the bone marrow too. By directly testing the bone, bone marrow, and blood, detection for signs of cancer is precise.
Medical Professions
A multi-professional team of surgeons, oncologists, and radiologists are required to diagnose and treat neuroblastoma. This team of medical professionals oversees multiple regiments, including the care plan, its diagnosis, and the course of treatment. This diverse team of medical experts is essential for developing and managing the procedure and complex mutations. Furthermore, since Neuroblastoma is a condition that affects children, a medical professional that specializes in pediatrics would be necessary for any surgical procedures.
The Attending Physician, or Pediatric Oncologist, provides specialty care, supervises the care team, and directs a care plan for the patient. An advanced practice provider (APP) nurse helps diagnose patients and prepares them for the next doctor. The APP may interpret imaging studies to help diagnose the cancer through MRIs, CT scans, and ultrasounds. An oncologist overviews the APP’s diagnosis, and if necessary, the oncologist will issue more tests. A pathologist may also examine samples from the patient to diagnose the tumor's characteristics so that the method of surgery will be more effective for each case. Following the diagnosis, the oncologist will then develop a treatment plan that includes surgery, chemotherapy, radiation treatment, immunotherapy, and more. A Radiation Oncologist may help with treatment, as they specialize in radiation therapy to kill cancer cells. Additionally, pharmacists prepare medications for patients, ensuring that the medicine is safe for pediatric patients. Throughout this medical process of diagnosing, treatment, and recovery, various nurses as well as physician assistants will work closely with both patients and oncologists to administer treatment and provide patient comfort.
To become a Pediatric Oncologist or Radiation Oncologist, however, takes time. To become a Pediatric Oncologist, one needs four years of college, four years of medical school, three years of pediatric residency, and three years of hematology/oncology fellowship. To become a Radiation Oncologist, one needs four years of college, four years of medical school, one year of general medical training, and four years of training in residency for radiation oncology. So, in turn, one must have unwavering dedication to become one, otherwise essential time would have been lost. It is until one is in their thirties before claiming the title and practicing such craft. Though, with such a vital and costly role, they are held up to decent salaries. On average, Pediatric Oncologists make $170,000 annually and Radiation Oncologists make $400,000 annually.
Medical Professionals are also needed in areas outside of the hospital. Neuroblastoma may result in harmful long-term effects following treatment, such as hearing loss, scoliosis, and issues with the nervous system (American Cancer Society). In severe cases where the physical aspects of a patient are affected, a physical therapist may assist with restoring lost mobility function so that the patient may resume daily activities with minimal discomfort. Psychologists may also provide emotional support for both patients and their family members with the emotional impact of their diagnosis. Genetic Counselors may provide information regarding the genetic aspects of Neuroblastoma, especially if there is a family history relating to this disease. Throughout treatment, nutritionists or dietitians can help patients maintain proper nutrition, ensuring that treatment goes well.
Treatments
Neuroblastoma is categorized on three levels: low-risk, intermediate-risk, and high risk. By understanding the severity through diagnosis, respective treatment will be given. For low-risk children, there is a possibility of tumors dissipating without treatment especially if the child is under 6 months old, but however, surgery, an incision to remove most to all of the tumor, is still a common method of removal. In fact, chemotherapy, drugs injected into the veins in order to preclude the multiplying of cancer cells but some healthy cells too (and often several weeks or months long depending on severity), may also be issued if risk of malignancy is there. With intermediate-risk patients, the initial process starts with surgery to remove the tumor and any potential cancer cells that spread into the lymph nodes. Nevertheless, chemotherapy may be administered prior to the surgery to shrink the tumor and ensure a better surgery, but having chemotherapy post-surgery works just as well. In addition to high doses of chemotherapy and surgery, high-risk patients may undergo stem cell transplantation, radiation, immunotherapy, and medication. Stem cell transplants help reconstruct the immune system of healthy stem cells after succumbing to high-dose chemotherapy. This process requires the child’s stem cells to be extracted from the bloodstream from the bone marrow and frozen until after the chemotherapy doses to then inject back to the child's bloodstream, which will make its way to the bone marrow and supplant the dead stem cells from the treatment. Radiation, like chemotherapy, stops the multiplication of cancerous cells while harming healthy cells in the area. However, radiation is only used in the most severe cases to attempt to prevent the cancer from returning after treatment. And so, immunotherapy is provided to combat cancerous cells that still remain after radiation and chemotherapy. Through immunotherapy, the child is injected with antibodies in the vein that detect GD2 proteins on the cellular surface of neuroblastoma cells, which when attached to, triggers a signal to the body to destroy the neuroblastoma cells. Furthermore, medication such as 13-cis-retinoic acid and difluoromethylornithine (DFMO) is provided for several months to further ensure the impeding growth of cancer cells by restricting blood flow to the tumor. In turn, the growth of the tumor and how far cancerous cells have traveled depicts the treatment and its duration.
Genetic Mutations Regarding Neuroblastoma
Various genetic mutations contribute to heterogeneity of Neuroblastoma, influencing factors such as the behavior of the tumor, treatment method, and response to treatment. Mutations may occur in different genes which mainly affect cell growth and development, leading to the uncertain effect Neuroblastoma may have on the patient. Understanding these genetic alterations is of utmost importance for prognosticating and treatment.
ALK Gene Mutations
Found on chromosome 2, the ALK Gene’s purpose is to provide instruction for the creation of a protein known as ALK receptor tyrosine kinase. This protein is part of a broader family known as Receptor Tyrosine Kinases (RTKs), which “transmits signals from the cell surface into the cell.” (National Library of Medicine). A function known as phosphorylation usually activates the RTKs, which then through another process, which activates the cell, completing the signal-like transmitting process. These signals used through the RTKs are a principal method in various cellular processes. The ALK RTK’s function is known to benefit and regulate the proliferation of nerve cells during human development, hence its close relation to Neuroblastoma, which mainly affects children 5 and younger.
The most common health cases regarding the ALK gene are Neuroblastoma and Lung Cancer. A buildup of mutations in many critical genes allows cells to grow at an alarming rate, forming a tumor. ALK mutations are most likely classified into two types: Point mutations and amplification. Point mutations is the more common of the two classifications, where a nucleotide of the DNA of the ALK gene changes. Amplification happens when there is an abundance of the ALK protein, leading to an abundance of cells, which then forms a tumor. Furthermore, most cases of ALK mutations are somatic, meaning that genetic changes occur during one’s lifetime, presented in certain cells, and cannot be inherited. There are only a few number of Neuroblastoma cases in which the ALK gene has been inherited from a parent. One of the most common mutations of the ALK gene is when the amino acid glutamine at position 1275 (R1275Q) replaces the amino acid arginine. Mutated ALK RTKs may also no longer need stimulation from an outside cell to start the transmission process, so in conclusion, this signaling pathway is consistently in action, leading to a buildup of nerve cells, resulting in a tumor. A study from the National Library of Medicine shows that Therapeutic Targeting, a method to combat Neuroblastoma through means of different types of therapy such as radiation therapy and chemotherapy, is very effective for 20% of Neuroblastoma patients (Pastorino). There is currently limited research done on treatment methods for the ALK gene in Neuroblastoma, and research is needed for a more solid method.
MYCN Amplification
MYCN, more commonly referred to as N-MYC in scientific literature, is an oncogene located on chromosome 2 in the human body. As a member of the MYC Family, MYCN plays a crucial role in regulating cellular processes associated with cellular expansion and proliferation. According to MedlinePlus, “When mutated, oncogenes have the potential to cause normal cells to become cancerous.” Mutation (MYCN Amplification) occurs within the gene because of uncontrollable proliferation. This happens when the cancerous effect on the tightly regulated cellular homeostasis within the MYCN gene causes improper cell progression. MYCN Amplification is a mutation that is associated with neuroblastoma. This genetic mutation is commonly linked to the aggressive stages of neuroblastoma (malignant brain tumor) and has a severe prognosis. This cancerous mutation primarily impacts young children and is very dangerous.
Neuroblastoma is the most common health case regarding the gene MYCN and its genetic mutation MYCN Amplification. Mutations play a significant role in the pathogenesis of neuroblastoma. The genetic mutation (MYCN Amplification) is considered to have the most significant impact and influence on neuroblastoma, causing a faster and more aggressive growth of the tumor with resistance to standard treatment. Those with neuroblastoma associated with the mutation MYCN Amplification have a significantly low prognosis. Furthermore, through the loss of chromosomal regions (1p and 11p), the elimination of the suppressor genes promotes further genetic instability by contributing to the disease.
PHOX2B Gene Mutations
The PHOX2B Gene’s function is to provide instruction on human development before birth, found on chromosome 4. Supporting the formation of nerve cells, the PHOX2B protein also regulates the rate at which nerve cells mature and carry out specific tasks. This protein is mainly active while the patient is still an embryo, creating cells which develop into tissues and organs. These cells are known as Nerve Crest Cells, which is part of the autonomic nervous system, controlling aspects such as breathing and heart rate.
Similar to the ALK gene mutation, the PHOX2B gene mutation correlates to two health conditions, Congenital central hypoventilation syndrome and Neuroblastoma. Nearly all mutations in the PHOX2B gene occur when an amino acid changes in the PHOX2B protein. Furthermore, an addition or deletion of nucleotides in the amino acid may interfere in the PHO2BX protein’s role in neuron differentiation, which leads to an excess of Nerve Crest cells and results in Neuroblastoma. Various cases of Neuroblastoma show that patients with the PHOX2B mutation also have a case of Hirschsprung disease due to the gene variations that affect nervous system and tissues that develop from the Neural Crest (National Library of Medicine). Treatment wise, the PHOX2B gene is especially significant in cases of familial Neuroblastoma, so genetic testing is often recommended to find the most effective treatment outlets.
Statistics
Survival Rate
In Neuroblastoma cases, a 5-year survival rate is often used. This refers to “the percentage of children who live at least 5 years after their cancer is cured, and the rates vary among the risk level of the Neuroblastoma. According to the American Childhood Cancer Organization, “low risk” has a five-year prognosis and “high risk has a five-year survival rate of 40-50%.” There are also prognosis factors, with a survival rate higher than 95%.” “Intermediate risk” has a five-year survival rate of 90-95%.”, where the child’s age may contribute to their chance of survival. The chart shown on the left, conducted by a research group in the Netherlands shows that 16% of patients under 18 months are diagnosed with Stage 4S Neuroblastoma, 26% are Stage 4, 17% are Stage 3, and 41% are Stage 1 or 2. For patients above or equal to the age of 18 months, 1% are Stage 4S, 76% are Stage 4, 9% are Stage 3, and 17% are stage 1 or 2 (Tas). It is evident that patients who are equal or above 18 months are 47% more likely to be diagnosed with Stage 4 Neuroblastoma, and 24% less likely to be diagnosed with Stage 1 or 2 Neuroblastoma. Based on these findings, it can be concluded that the patients who are diagnosed with Neuroblastoma 18 months and older are more likely to be diagnosed
with a more severe stage of Neuroblastoma than patients younger than 18 months. Another finding regarding Neuroblastoma survival rates at BMC Pediatrics claims that patients with an abundance of MYCN genes, or MYCN gene amplification, have their tumors grow more quickly and respond less effectively to treatment, resulting in a lower survival rate. Using TARGET and GEO datasets, the researches at BMC Pediatrics show that in the TARGET dataset, unamplified MYCN Genes have a survival rate of over 80% even after the patient is over 5 years old, and while the survival rate of patients with the amplified MYCN gene is only over 60% after the patient is over 5 years old. The GEO dataset conveys the same info, and while the unamplified MYCN gene still maintains a survival rate of over 80%, the amplified gene has a rate barely over 20%. The difference between the survival rates of the amplified gene may be very apparent, however the underlying claim is still intact: the amplified MYCN gene has a lower survival rate for patients than for patients with the unamplified MYCN gene.
Impacts
Neuroblastoma affects the body in several significant ways due to its impact on nerve cells and the dangerous nature. Neuroblastoma tumors can both grow and spread quickly around body parts, including lymph nodes, bone marrow, liver, bones, and skin. If the cancer spreads to the bone marrow it disrupts the production of blood cells which can lead to anemia, infections, and even bleeding problems in children. The spreading can interrupt organ functions and cause more conflict around the body. Even if the cancer is cured, neuroblastoma can leave a patient with long-term effects that highly impacts their bodies. Most of the long term effects depend on which type of treatment a child went through, where the tumor was on their body, and the age of the child when treated. For example children that were given multiple types of treatment, e.g.: surgery, radiation, chemotherapy, immunotherapy, etcetera have a higher chance of having serious long-term side effects. Cell mutations that occur in neuroblastoma is one of the reasons why children might face life-changing issues even after treatment. Depending on the treatment and other factors, late effects after neuroblastoma treatment might include: Hearing loss, scoliosis, thyroid problems, problems with growth and development, infertility, conflict in the nervous system, second cancers, psychological issues, etc.. Overall, the impacts of neuroblastoma on the body are extreme, affecting organs and overall health. To reduce the risk of the long-term effects after the treatment, it is very important for the guardians of the children to take them to the doctors for check ups.
Conclusion
Neuroblastoma remains a challenge in pediatric oncology, distinguished by its complex biology. Although significant strides have been made in understanding and treating neuroblastoma, there is still much more to be done. While advances in diagnostic technologies and treatment strategies have improved the prognosis for some patients, the disease’s heterogeneity necessitates a more nuanced approach. Personalized treatment plans require much research and clinical trials, which are essential to addressing the unique characteristics of each case. In order to enhance survival rates and reduce long-term effects, early detection of cancer or tumors should be carried out in a timely manner.
Continued investment in research is an undeniable, beneficial aspect to determine the underlying mechanisms of neuroblastoma and developing targeted therapies. Efforts should focus on expanding knowledge of the disease on a molecular level, refining treatment protocols, and exploring novel therapeutic approaches. Collaborative research implementing academic institutions, healthcare providers, and patient advocacy groups will be fundamental to driving this process.
On the macro level, raising awareness for neuroblastoma is equally important. Public education campaigns can inform people about the symptoms and the need for early detection, whereas fundraising initiatives can provide necessary resources for research. Moreover, partaking in media and community organizations amplify these efforts, ensuring that neuroblastoma receives necessary attention to foster further research and improve patient-case results. Through uniting and advocating for further research, significant steps in fighting against neuroblastoma will be fulfilled, and new hope will be offered to those affected by this challenging disease.
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