Continuing Education Activity

Neuroblastoma (NB) is the most frequently-occurring extracranial childhood tumor. It is classified as an embryonal neuroendocrine tumor, originating from neural crest progenitor cells. Hence, it can occur anywhere along the sympathetic nervous system, including the superior cervical, paraspinal, and celiac ganglia; the majority arise in the adrenal glands. Due to the high variability in its presentation, clinical signs and symptoms at presentation can range from benign palpable mass with distension to major illness from substantial tumor spread. This activity reviews the cause, pathophysiology, and presentation of neuroblastoma and highlights the role of the interprofessional team in its management.

Objectives:

• Describe the pathophysiology of neuroblastoma.
• Review the presentation of neuroblastoma.
• Summarize the treatment options for neuroblastoma.
• Explain modalities to improve care coordination among interprofessional team members in order to improve outcomes for patients affected by neuroblastoma.

Introduction

Neuroblastoma (NB) is the most frequently-occurring extracranial childhood tumor. It is classified as an embryonal neuroendocrine tumor, originating from neural crest progenitor cells.[1] Hence, it can occur anywhere along the sympathetic nervous system, including the superior cervical, paraspinal, and celiac ganglia; the majority arise in the adrenal glands.[2] Due to the high variability in its presentation, clinical signs and symptoms at presentation can range from a benign palpable mass with distension to major illness from substantial tumor spread. Although overall increases in five-year event-free survival have been reported, subgroup-specific analysis of mortality has revealed discordance between the high cure rates for the more benign low-risk forms and little improvement in the high-risk groups.[3][4] Thus, the impetus for the development of targeted therapeutics in the intensive management of high-risk groups is strong.

Etiology

Risk factors for the acquisition of mutations in key genes leading to neuroblastoma have yet to be identified, although exposures during conception and pregnancy are a topic of investigation. Neuroblastoma can develop either sporadically or be transmitted in the germline. Most familial cases of neuroblastoma occur due to the inheritance of highly penetrant mutations in either the ALK or PHOX2B genes.[2] [5] A small subset of familial NB demonstrates autosomal dominant inheritance.[6] Although up to 15% of sporadic cases of neuroblastoma arise from mutations in ALK, more common transforming mutations involve polymorphisms in BARD1 (2q35), LIN28B (6q16.3), or FLJ22536 (6p22.3). Cytogenetic aberrations can further include loss of chromosome 1p and 11q, copy number variation in 1q21, and gain of 17q.[1][7][8][9] Notably, amplification of MYCN oncogene is seen in approximately 25% of patients and is associated with the poorest prognosis; 17q gain and 1p loss correlate with MYCN amplification.[1][10]

Epidemiology

Neuroblastoma is the most common tumor of the sympathetic nervous system (97%) and the most common malignancy of infancy with a median age of diagnosis of 17 months.[11] It accounts for 15% of pediatric cancer-related deaths.[12] The annual incidence of neuroblastoma in the United States is approximately 650 cases, i.e., 10.2 per million children (65 per million infants), with little change (0.4%) over time.[2] While an overall improvement in five-year mortality has been noted between 1975 through 2005, subgroup-specific mortality paints a different picture.

Pathophysiology

Many biological markers of neuroblastoma have been discovered, of which the most important is MYCN. This oncogene is overexpressed in nearly 25% of patients with neuroblastoma. The gene is also commonly found in patients with advanced cancer. Patients with the MYCN gene tend to have rapid progression of cancer and poor outcomes. On the other hand, expression of the H-Ras gene is associated with low stage disease.

The DNA index is also used to assess response to treatment. Those with a DNA index of more than 1 tend to show a good response to doxorubicin and cyclophosphamide compared to those with an index of less than 1. Other biological markers linked to poor prognosis include lack of expression of glycoprotein CD 44 and elevated levels of telomerase RNA. Other markers linked to poor prognosis include elevated levels of LDH, serum ferritin, and serum neuron-specific enolase.

Close to 90% of patients have elevations in vanillyl mandelic acid and homovanillic acid in the urine. In Japan, mass screening using urinary catecholamines has been shown to lower deaths from high-risk neuroblastomas.

Neuroblastomas can develop in the adrenal gland (most common), paraspinal ganglia, and less often in the thorax, pelvis, and cervical areas. Infants commonly present with neck or thoracic masses, whereas older children tend to present with abdominal masses.

The symptoms are chiefly due to the mass of the lesion, which increases abdominal girth and causes pain. Lesions in the spinal canal can present with neurological deficits.

Histopathology

Histopathology will reveal small round blue cells with clustering of cells in the connective tissue and the presence of pseudorosettes. These pseudorosettes are only seen in 10%-15% of cases.

History and Physical

Given the wide areas populated by neural crest cells, neuroblastoma can present in the neck, chest, abdomen, or pelvis. With the most frequent site of origin being the adrenal medulla, patients often present with a solid abdominal mass. With the involvement of the superior cervical ganglia, aside from a neck mass, Horner syndrome (ptosis, miosis, anhydrosis) can be observed. If the tumor involves the spinal cord, cord compression, or paralysis may be seen. Furthermore, tumor behavior can range from spontaneous regression to widespread dissemination at presentation. With over half of all neuroblastoma patients having hematogenous spread at diagnosis, the disease can involve the bone and bone marrow (56% and 71%, respectively), followed by lymph nodes (31%), and lungs (3%). Non-specific clinical signs include fever, weight loss, and fatigue. Thus, signs and symptoms, which can range from an asymptomatic palpable mass to significant critical illness, are highly variable and dependent upon factors now linked with prognosis.

Hypertension is rare and is often caused by compression of the renal artery rather than the catecholamine excess.

Chronic diarrhea due to the secretion of vasoactive intestinal peptide may be the initial presentation.

When the bone is involved, pain and a limp may be present. In addition, bone metastases may present with pathological fractures.

Thoracic lesions may present with Horner syndrome.

In rare cases, the patient may present with myoclonus and opsoclonus. These patients tend to have localized disease and good outcomes. However, the neurological deficit can be disabling.

Evaluation

Clinical Evaluation

Diagnostic evaluation relies not only on a careful history and physical, but also on biochemical, histologic, and radiographic analyses. Laboratory studies should include the following:

• CBC
• Renal function
• Liver function
• Electrolytes
• LDH

Histologic confirmation is required to establish a diagnosis of neuroblastoma. Histologically, small round pale blue cells, known as Homer-Wright pseudorosettes, can be seen; these are similarly seen in Wilm's tumor and Ewing sarcoma, leading to their common group categorization as small blue cell tumors.[1] If a biopsy sample is tumor-positive, DNA ploidy and MYCN gene status are further evaluated. Since neuroblastoma cells originate from neural crest cells destined to differentiate into sympathetic peripheral neurons, cells often produce catecholamines; break-down products of these catecholamines are homovanillic acid (HVA) and vanillylmandelic acid (VMA). Thus, in over 90% of neuroblastoma, elevation in these catecholamine breakdown products in urine is diagnostic.[13]

Preliminary imaging is preferentially conducted with MRI for good resolution and surgical excision planning. Further exploiting sympathetic neuronal uptake of mIBG (metaiodobenzylguanidine), due to its analogous nature to norepinephrine, the extent of neuroblastoma metastasis can be delineated with an mIBG scan with high accuracy and quality.[14] To complete tumor staging, bone marrow biopsies are required.[1] Of note, common paraneoplastic conditions associated with neuroblastoma include opsoclonus-myoclonus syndrome and intractable secretory diarrhea due to vasoactive intestinal peptide (VIP) secretion.[15][16]

CT scan of the abdomen and chest are recommended to look for calcifications and metastatic lesions.

MRI is the spine is required if cord compression and Horner syndrome are suspected.

Skeletal surveys may help assess the presence of metastatic lesions.

Baseline ECG and echocardiogram are necessary. Baseline hearing is recommended before initiating cisplatinum treatment.

Treatment / Management

Given the heterogeneity in tumor location, grade, and stage at diagnosis, treatment modalities include simple observation, surgical resection, chemotherapy, radiation therapy, stem cell transplantation, and immunotherapy. Patients with low-risk NB have localized tumors, some (infants) with a high propensity for spontaneous tumor regression.[17] Thus, children with small tumors (less than 5 cm) can be observed with imaging done every six to 12 weeks to monitor tumor growth, thus avoiding surgery in the young infant altogether.[1]

For larger, localized tumors, in patients' past infancy, surgical resection is pursued. For patients younger than 18 months of age, the observational approach is currently under international investigation by COG (NCT02176967) and SIOPEN (NCT01728155) cooperative groups. For children who present with symptoms, limited chemotherapy is given without surgical palliation or radiation therapy.[1]

The intermediate-risk group presents with localized metastasis, i.e., to the lymph node or bone marrow (in infants). They are usually managed with chemotherapy alone and possible surgical resection if able.[18]

The high-risk group has the worst prognosis and presents with widespread metastatic disease to the bone marrow, bone, lungs, and liver. They receive induction chemotherapy to reduce tumor burden at both the primary and metastatic locations, followed by maximal surgical resection, followed by myeloablative chemotherapy and stem-cell transplantation. After that, patients are managed on a combination of maintenance chemotherapy and immunotherapy.[19] A monoclonal antibody, dinutuximab that attaches to a carbohydrate molecule (GD2) on the surface of many neuroblastoma cells, is being used as an immunotherapy drug for neuroblastoma treatment. Dinutuximab treatment is reported to improve the two-year event-free survival of high-risk neuroblastoma patients from 46% to 66%.[20]

Surgery plays a vital role in the treatment of neuroblastoma. For localized disease, one can obtain a cure with surgery. Sometimes surgery is needed to establish a diagnosis. Second look surgery after chemotherapy is often done for debulking purposes.

Differential Diagnosis

• Dermoid cyst

• Ewings sarcoma

• Germ cell tumour

• Hepatoblastoma

• Infantile fibromatosis

• Infection

• Lymphoma

• Rhabdomyosarcoma

• Small round cell sarcoma

• Wilm’s syndrome

Staging

The International Neuroblastoma Staging System (INSS) based on surgical resection is used to stage neuroblastomas in the United States.

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

Subgroup Classification

The widespread variability in neuroblastoma tumor behavior is linked to multiple factors now linked with patient prognosis. Classic prognostic categorization by Children’s Oncology Group (COG) divides patients into four groups based on patient age, post-surgical stage, MYCN amplification, histology, and DNA ploidy [3]:

1. Low risk: localized tumor only, greater than 90% survival
2. Intermediate risk: localized tumor with regional extension and/or metastases to bone and bone marrow, 90% to 95% survival
3. High risk: widely disseminated disease (excluding infants), 40% to 50% survival
4. Tumor stage 4S: widely disseminated disease in infants, greater than 90% survival due to spontaneous regression of the tumor.

However, COG classification of neuroblastoma has differed from the European SIOPEN and other cooperative groups. In 2004, the International Neuroblastoma Risk Group (INRG), a task force of pediatric neuroblastoma experts worldwide, met with the primary aim of developing a consensus approach to neuroblastoma risk stratification pre-treatment.[21] Using patient age, tumor stage, tumor grade, and differentiation, tumor histology, MYCN amplification, cytogenetic aberrations in 11q, and DNA ploidy, the group defined 16 pre-treatment groups broadly divisible into four prognostic subgroups based on five-year event-free survival (EFS):

1. Very low risk: five-year event-free survival (EFS) greater than 85%
2. Low risk: five-year EFS 75% to 85%
3. Intermediate risk: five-year EFS 50% to 75%
4. High risk: five-year EFS less than 50%

Over 50% of newly diagnosed neuroblastoma are very-low or low-risk.[21] Negative prognostic markers include age older than 18 months, metastasis at diagnosis, and presence of MYCN amplification, 1p loss, 11q loss, 17q gain, or DNA copy number alterations.[1][21]

Enhancing Healthcare Team Outcomes

Neuroblastoma is a rare abdominal tumor in young children. However, if the diagnosis is missed, the tumor is fatal. Hence, the diagnosis and treatment of neuroblastoma are best managed by an interprofessional team that includes a pediatrician, a pediatric surgeon, oncologist, radiation therapist, social workers, pharmacist, dietitian, and specialty care nurses. A team dedicated to childhood cancers is vital as these patients have special needs. All cancer treatments can stunt growth, and hence, a dietitian should be involved early in the care.

The tumor may occur anywhere along the sympathetic chain and can be mistaken for a Wilms tumor. Oncologic pharmacists assist in the formulation of chemotherapy, check for drug-drug interactions, and provide family and patient education. Oncology nurse practitioners and nurses play a vital role in patient care and the education of the family. Occupation therapy is necessary as some children may develop neurological deficits that may impair motor function. A positive environment is essential to ensure that the child thrives in this difficult situation. Team members should openly communicate with each other to improve their care. [Level 5]

Over the past decade, the survival of these patients has slightly improved for early-stage lesions, but for late stages, the survival is abysmal. Thus, the impetus for the development of targeted therapeutics in the intensive management of high-risk groups is strong.[22][23]