Neuroblastoma

Overview

Neuroblastoma is a tumor that begins in the early nerve cells known as neuroblasts. Normally, these immature nerve cells develop into functioning nerve cells. However, in neuroblastoma, they develop uncontrolled and transform into cancer cells, forming a solid tumor.

Neuroblastoma begins in the adrenal gland tissue. These triangle glands, which lie on top of the kidneys, produce hormones that regulate heart rate, blood pressure, and other vital physiological processes. Neuroblastoma can also begin in other parts of the body containing clusters of nerve cells, such as the abdomen, chest, or neck. Cancer can travel via the blood and begin to metastasis in other regions of the body, including the lymph nodes, bones, lungs, and liver.

Childhood Neuroblastoma

Neuroblastoma (NB) is the most common extracranial pediatric tumor. It is a kind of embryonal neuroendocrine tumor that develops from neural crest progenitor cells. As a result, it can develop anywhere in the sympathetic nervous system, including the superior cervical, paraspinal, and celiac ganglia, with the adrenal glands accounting for the bulk of cases.

Because of the wide variety of clinical signs and symptoms, clinical signs and symptoms at presentation might range from a benign palpable lump with distension to serious sickness from extensive tumor dissemination. Although overall gains in five-year event-free survival have been reported, subgroup-specific mortality analysis has indicated a discrepancy between high cure rates for the more benign low-risk forms and no improvement in the high-risk types. As a result, there is a tremendous drive for the development of tailored medicines in the intensive management of high-risk patients.

Neuroblastoma cancer

The origin and migratory pattern of neuroblasts during fetal development explains the several anatomic locations where these tumors appear; tumor location changes with age. Tumors can form in the abdomen (40 percent adrenal, 25 percent paraspinal ganglia) or at other locations (15 percent thoracic, 5 percent pelvic, 3 percent cervical tumors, 12 percent miscellaneous). Infants are more likely to appear with thoracic and cervical tumors, but older children are more likely to present with abdominal tumors.

The majority of patients report with tumor-related signs and symptoms, while tiny tumors have been found due to the widespread use of prenatal ultrasonography. Large abdominal tumors frequently cause an increase in abdominal girth as well as other local symptoms (eg, pain). Paraspinal dumbbell tumors can invade the spinal canal, impact on the spinal cord, and cause neurological impairment.

The most important prognostic markers are the tumor's stage at the time of diagnosis and the patient's age. Although patients with localized tumors (regardless of age) have an excellent outcome (80-90 percent 3-year event-free survival rate), patients with metastatic disease who are older than 18 months fare poorly. In general, more than half of patients have metastatic disease at the time of diagnosis, 20-25 percent have localized disease, 15% have regional extension, and roughly 7% have disseminated disease restricted to the skin, liver, and bone marrow throughout infancy.

Epidemiology

Neuroblastoma is the most frequent sympathetic nervous system tumor (97%) and the most common childhood cancer, with a median age of diagnosis of 17 months. It is responsible for 15% of pediatric cancer mortality. In the United States, the yearly incidence of neuroblastoma is around 650 instances, i.e., 10.2 per million children (65 per million babies), with minimal variation (0.4 percent) over time. 

Etiology

Neuroblastoma has no recognized etiology, and no particular environmental exposure or risk factors have been found.

Because of the disease's early beginning, researchers have concentrated on events before conception and during pregnancy.

Medication, hormones, birth features, congenital malformations, past spontaneous abortion or fetal death, alcohol or cigarette use, and paternal occupational exposures are among the factors explored for which data is limited or inconsistent.

The great majority of neuroblastoma cases are sporadic, having no family history of the disease. However, 1-2 percent of newly diagnosed individuals have a neuroblastoma family history. Patients with familial neuroblastoma frequently appear at a younger age or with several primary tumors.

Neuroblastoma has been related to various illnesses associated with aberrant neural crest tissue development, such as Hirschsprung disease or central congenital hypoventilation syndrome. A genetic abnormality in these uncommon family instances of neuroblastoma was discovered by a genome-wide examination of the tumors. A germline mutation in PHOX2B has been linked to cases of neuroblastoma that occur alongside other congenital neural crest abnormalities. This gene is a homeobox gene that regulates the development of the autonomic nervous system.

ALK mutations in the germline have been detected in familial neuroblastoma cases that are not related with other congenital diseases of neural crest development. These mutations primarily arise in the kinase domain, resulting in ALK signaling activation. Efforts are being made to explore the prevalence of ALK mutations across all subtypes of neuroblastoma, however preliminary evidence suggests that somatic ALK gene mutations are also present in certain cases of sporadic neuroblastoma.

Pathophysiology

Many biochemical indicators of neuroblastoma have been identified, the most prominent of which being MYCN. This oncogene is overexpressed in roughly 25% of neuroblastoma patients. The gene is also typically detected in advanced cancer patients. Patients who carry the MYCN gene have a higher risk of cancer development and poor outcomes. Expression of the H-Ras gene, on the other hand, is linked to early-stage illness.

The DNA index is also used to evaluate therapy response. Those with a DNA index greater than one had a better response to doxorubicin and cyclophosphamide than those with a lower index. Other biological indicators associated with poor prognosis include a lack of glycoprotein CD 44 expression and high levels of telomerase RNA. Elevated levels of LDH, serum ferritin, and serum neuron-specific enolase are also associated with a bad prognosis.

Nearly 90% of patients had elevated levels of vanillyl mandelic acid and homovanillic acid in their urine. Mass screening using urine catecholamines has been found to reduce fatalities from high-risk neuroblastomas in Japan.

Neuroblastomas can form in the adrenal gland (the most common location), the paraspinal ganglia, and, less frequently, the thoracic, pelvis, and cervical locations. Infants are more likely to appear with neck or thoracic masses, but older children are more likely to show with stomach masses.

The symptoms are mostly caused by the lesion's bulk, which increases abdominal girth and produces discomfort. Neurological impairments can occur as a result of spinal canal lesions.

Neuroblastoma symptoms

More than 90% of patients exhibit measurable amounts of homovanillic acid (HVA) and/or vanillylmandelic acid (VMA) in their urine. In Japan, Quebec, and Europe, mass screening trials employing urine catecholamines in neonates and babies have showed the capacity to detect neuroblastoma before it becomes clinically evident. However, the majority of the cancers discovered are in newborns with a fair prognosis. None of these studies demonstrate that mass screening reduces fatalities from high-risk neuroblastoma.

Markers associated with a poor prognosis include:

1. Elevated ferritin levels,
2. Elevated serum lactate dehydrogenase (LDH) levels, and 
3. Elevated serum neuron-specific enolase (NSE) levels. 

However, as additional relevant biomarkers have been discovered, these indicators have become less essential (ie, chromosomal and molecular markers). In reality, ferritin was left out of the most current version of the International Neuroblastoma Risk Category Classification System because it was not shown to make a difference in prognosis in the high-risk group.

Because neural crest cells may be found in a variety of locations, neuroblastoma can manifest in the neck, chest, abdomen, or pelvis. Patients frequently arrive with a solid abdominal mass, with the adrenal medulla being the most common source of genesis. Aside from a neck mass, superior cervical ganglia involvement can cause (ptosis, miosis, anhydrosis). If the tumor affects the spinal cord, there may be cord compression or paralysis.

At presentation, tumor activity might range from spontaneous retreat to broad spreading. With over half of all neuroblastoma patients having hematogenous spread at diagnosis, the illness can include the bone and bone marrow (56 percent and 71%, respectively), followed by lymph nodes (31%), and the lungs .

Fever, weight loss, and exhaustion are non-specific clinical symptoms. As a result, signs and symptoms, which can vary from an asymptomatic palpable mass to severe critical disease, are very diverse and reliant on characteristics currently associated with prognosis.

Hypertension is uncommon and is frequently induced by renal artery compression rather than catecholamine excess. Chronic diarrhea caused by vasoactive intestinal peptide secretion might be the first symptom.

Pain and a limp may be evident when the bone is affected. Furthermore, bone metastases might manifest as pathological fractures. Horner syndrome can occur as a result of thoracic lesions.

In rare situations, the patient may have myoclonus and opsoclonus. These individuals have illness that is confined and has a decent prognosis. The neurological deficiency, on the other hand, might be debilitating.

At the time of diagnosis, half of the patients have localized illness, whereas the other three-fifths have regional lymph node spread.

Metastasis can develop through the hematogenous and/or lymphatic pathways, seeding bone marrow, liver, and bone. The orbits are frequently affected, resulting in periorbital edema and proptosis 

When the disease spreads to the skin, individuals acquire blue subcutaneous nodules, a condition known as blueberry muffin syndrome. Surprisingly, this is linked to a better prognosis and the likelihood of spontaneous tumor regression.

Neuroblastoma has the propensity to release catecholamines because to its neuroendocrine features, resulting in early-onset hypertension and tachycardia. Paraneoplastic syndromes may also occur in patients. Intractable diarrhea with electrolyte problems caused by the production of vasoactive intestinal peptide (VIP), encephalomyelitis, or sensory neuropathy are some examples.

Diagnosis

The index of suspicion must be strong based on clinical presentation. Basic blood work (complete blood count, serum electrolytes, liver function tests) and a chest radiograph, which may indicate calcifications or a posterior mediastinal mass, should be performed as part of the first diagnostic testing.

Increased levels of catecholamines or catecholamine metabolites in the urine or serum will be seen as further diagnostic findings (dopamine, vanillylmandelic acid, and homovanillic acid). Nonspecific biomarkers such as lactate dehydrogenase (>1500 U/ml), ferritin (>142 ng/ml), and neuron-specific enolase (>100 ng/ml) may be raised in patients, which may be related with advanced stage and/or recurrence.

Preliminary imaging with MRI is preferred for high resolution and surgical excision planning. Because of its similarity to norepinephrine, sympathetic neuronal absorption of mIBG (metaiodobenzylguanidine) can be used to define the extent of neuroblastoma metastasis with a high degree of precision and quality. Bone marrow samples are necessary to complete tumor staging. Notable paraneoplastic diseases connected with neuroblastoma include opsoclonus-myoclonus syndrome and persistent secretory diarrhea caused by VIP production.

• To screen for calcifications and metastatic lesions, a CT scan of the abdomen and chest is advised.

• If cord compression and Horner syndrome are suspected, a spine MRI is indicated.
• Skeletal examinations may aid in determining the existence of metastatic lesions.
• A baseline ECG and echocardiography are required. Before beginning cisplatinum treatment, a baseline hearing test is advised.

Management

Chemotherapy, surgical excision, and/or radiation are the mainstays of treatment. However, many aggressive neuroblastomas have gained resistance to chemotherapeutic treatments, making recurrence quite likely.

Because tumor location, grade, and stage vary at diagnosis, treatment options include simple observation, surgical resection, chemotherapy, radiation therapy, stem cell transplantation, and immunotherapy. Low-risk NB patients have circumscribed tumors, with some (infants) having a high proclivity for spontaneous tumor regression. Children with little tumors (less than 5 cm) can thus be monitored using imaging every six to twelve weeks to check tumor progression, avoiding surgery in the newborn infant entirely.

The intermediate-risk category has metastasis that is localized, i.e., to a lymph node or bone marrow (in infants). They are normally treated only with chemotherapy and, if possible, surgical resection.

The high-risk category has the poorest prognosis and is characterized by extensive metastatic illness to the bone marrow, bone, lungs, and liver. They are given induction chemotherapy to minimize tumor burden in both the primary and metastatic sites, followed by maximum surgical resection, myeloablative chemotherapy, and stem-cell transplantation. Patients are then maintained with a mix of maintenance chemotherapy and immunotherapy.

Dinutuximab, a monoclonal antibody that binds to a carbohydrate molecule (GD2) on the surface of many neuroblastoma cells, is being utilized as an immunotherapy medicine in the treatment of neuroblastoma. Dinutuximab therapy has been shown to increase the two-year event-free survival rate of high-risk neuroblastoma patients from 46% to 66%.

Surgery is critical in the treatment of neuroblastoma. Surgery can provide a cure for limited sickness. Surgery is sometimes required to establish a diagnosis. Debulking surgery is frequently performed as a follow-up to chemotherapy.

Differential Diagnosis

• Dermoid cyst
• Ewings sarcoma
• Germ cell tumour
• Hepatoblastoma
• Infantile fibromatosis
• Infection
• Lymphoma
• Rhabdomyosarcoma
• Small round cell sarcoma
• Wilm’s syndrome

Staging

In the United States, neuroblastomas are staged using the International Neuroblastoma Staging System (INSS), which is based on surgical resection.

Stage 1:

• A localized lesion with complete gross excision. There may be microscopic residual disease
• Ipsilateral lymph nodes are negative for cancer

Stage 2:

• Localized tumor with obvious gross tumor not completely excised
• Ipsilateral lymph nodes are negative for cancer

Stage 2B:

• Localized tumor with complete gross excision but ipsilateral lymph nodes are positive for tumor
• Enlarged contralateral lymph nodes are negative for cancer

Stage 3:

• Unresectable cancer that has crossed the midline, there is regional lymph node involvement
• A localized unilateral lesion with positive contralateral lymph nodes

Stage 4:

• Any primary lesion that has spread to distant lymph nodes, liver, bone marrow or skin

Stage 4s:

• Localized primary tumor with spread limited to liver, skin or bone marrow
• Limited to infants

Neuroblastoma survival rates

Determinants of response and outcome include the following:

• The outcome is determined by the tumor's stage, age, and several biologic characteristics.
• Similarly, the patient may have genetic polymorphisms that affect medication absorption, distribution, metabolism, and excretion.

The following treatment strategies are available to treat patients with recurrent neuroblastoma:

• A local recurrence in a patient with early-stage illness normally has a fair prognosis, and patients are routinely treated with conventional chemotherapy, surgery, and/or radiation if needed.
• Patients who arrive with disseminated illness have a significant recurrence rate and a poor prognosis.
• Various phase I/II agents are often available for individuals with recurrent illness in this situation.

The following response criteria are used to evaluate the efficacy of therapy:

• Complete clinical response - A reduction of more than 90% in the main tumor and metastatic disease (if any), no new lesions, and healing of bone lesions.
• A partial clinical response is defined as a reduction of 50% or less (sum of the products of the largest perpendicular diameters) in the main tumor and metastatic illness (if any), the absence of new lesions, and the healing of bone lesions.
• Minor response - A decrease of more than 25% and less than 50% (sum of the products of the largest perpendicular diameters) of the main tumor and metastatic disease (if any), no new lesions, and healing of bone lesions.
• No response - A reduction of less than 25% (the sum of the products of the largest perpendicular diameters) in the original tumor or metastatic disease (if any), with no new lesions.
• Progressive disease is defined as a rise of more than 25% (sum of the products of the largest perpendicular diameters) in the original tumor or all metastatic lesions (if any), as well as the formation of new lesions.

Conclusion 

Neuroblastoma is an uncommon abdominal tumor that affects children under the age of five. However, if the tumor is not detected in time, it is deadly. As a result, neuroblastoma is best diagnosed and treated by an interprofessional team that includes a pediatrician, a pediatric surgeon, an oncologist, a radiation therapist, social workers, a pharmacist, a dietician, and specialty care nurses. Because young kids have unique needs, it is critical to establish a staff devoted to pediatric malignancies. Because all cancer therapies might restrict development, a dietician should be included in the care from the start.

The tumor can appear anywhere along the sympathetic chain and is often misdiagnosed as a Wilms tumor. Oncologic pharmacists help with chemotherapy formulation, screen for drug-drug interactions, and educate families and patients.

Oncology nurse practitioners and nurses play an important role in patient treatment and family education. Some children may acquire neurological abnormalities that limit motor function, necessitating occupational therapy. A pleasant atmosphere is critical for the youngster to flourish in this challenging scenario. To better their care, team members should interact honestly with one another.

The survival of these individuals has improved marginally over the last decade for early-stage lesions, but it is catastrophic for late-stage lesions. As a result, there is a tremendous drive for the development of tailored medicines in the intensive management of high-risk patients.