Neuroblastoma

Neuroblastoma is a rare malignant tumor that primarily affects infants and young children. Derived from fetal nerve cells called neuroblasts, neuroblastomas most commonly develop in the adrenal glands. However, it can also arise in other parts of the sympathetic nervous system, such as the chest, abdomen, or pelvis. Neuroblastoma is notable for its wide range of clinical presentations and outcomes, from spontaneous regression in rare cases to aggressive, metastatic disease in others. Orthopaedic oncologists often become involved in a case of neuroblastoma when it metastasizes to bone, but occasionally the primary mass is in a location where orthopaedic oncologists are involved in the resection.

Epidemiology

Neuroblastoma is rare, with an approximate incidence of 10 cases per 1 million children in the United States, and accounts for approximately 10% of childhood cancers. It has a slight male predominance and typically occurs within the first five years of life. Among infants in their first year, neuroblastoma is the most common extracranial solid tumor, accounting for about 50% of malignant tumors in this age group.

Clinical Features

Neuroblastoma typically presents as a solid mass, with symptoms varying widely depending on the tumor’s size and location. Common manifestations include abdominal pain, decreased appetite, and peripheral neurological deficits. Other symptoms may include fever, weight loss, and proptosis. Notably, some cases are asymptomatic and discovered incidentally during routine examinations or imaging studies. Skeletal lesions are usually due to metastases, presenting with symptoms similar to other metastatic bone lesions, such as pain and swelling.

Laboratory abnormalities often include anemia, which may suggest bone marrow involvement, as well as elevated levels of catecholamines and their metabolites, vanillylmandelic acid (VMA) and homovanillic acid (HVA) in the urine. In rare cases, neuroblastoma can manifest with paraneoplastic syndromes, the most well-known being opsoclonus-myoclonus syndrome, characterized by rapid eye movements, muscle twitching, and ataxia​.

Radiologic Features

Because the primary lesion in neuroblastoma is usually located near the midline in the chest, abdomen, or pelvis, a computed tomography (CT) scan of these areas should be performed. A technetium-99m bone scan can be used to evaluate the presence of bone metastases, and skeletal x-rays can be employed to further elucidate the nature of any lesions found (Figure 1). There currently exist two different staging systems for neuroblastoma: the International Neuroblastoma Staging System (INSS) and the International Neuroblastoma Risk Group Staging System (INRGSS). INSS and INRGSS differ in several important aspects, chiefly that INSS is a post-surgical staging system that relies on surgical findings and the extent of tumor resection, while the INRGSS is a pre-treatment system based on imaging and the presence or absence of Image-Defined Risk Factors (IDRFs). These factors include tumor extension into multiple body compartments or the encasement of major blood vessels. Recognizing the presence of IDRFs is crucial for planning treatment, as they can significantly impact surgical approach and overall prognosis.

Pathology

Neuroblastoma is associated with various molecular and chromosomal abnormalities. Histologically, neural crest tumors can be subclassified as neuroblastoma, ganglioneuroblastoma, or ganglioneuroma, depending on their degree of phenotypic differentiation and specific maturation. Undifferentiated neuroblastoma is composed of small, round blue cells that resemble those seen in Ewing sarcoma. However, unlike Ewing sarcoma, neuroblastoma tumors contain pseudorosettes which are rings of neuroblasts surrounding pink extracellular material known as neuropils (Figure 2). These neuropils are a pathognomonic feature of neuroblastoma histology. Immunohistochemical stains may also be helpful in differentiating this from other round cell tumors. Also, in light of its neural origin,  neuroblastoma usually stains positively for neuron-specific enolase (NSE) and synaptophysin.

Differential Diagnosis

The differential diagnosis for neuroblastoma varies depending on the primary tumor location and presenting symptoms. For abdominal masses, key considerations include Wilms tumor and pediatric rhabdomyosarcoma. Thoracic primaries may be confused with lymphoma or other mediastinal masses. If a skeletal lesion is the initial presentation, neuroblastoma can be initially mistaken for Ewing sarcoma. Accurate diagnosis often requires a combination of imaging studies, pathological examination, and specific biomarkers, such as urinary catecholamines and MYCN amplification status. Gene amplification of MYCN is the oncogenic driver, inducing malignant transformation in neural crest derived cells.

Disease Course: Treatment and Prognosis

The prognosis for patients with neuroblastoma is related to age and specific risk category. Infants typically have a better prognosis than older children. Additionally, three separate risk categories have been identified, with cure rates ranging from approximately 95% for low-risk patients to about 50% for high-risk patients.

Treatment of the primary lesion varies depending on the risk category. Low-risk patients may be treated with surgery alone or, in some cases, with observation. Intermediate-risk patients usually receive a combination of surgery and chemotherapy, whereas high-risk patients typically undergo intensive multimodal therapy, including chemotherapy, surgery, autologous stem cell transplantation, radiation therapy, and immunotherapy.

Key Test Topics

• Neuroblastoma is the most common extracranial solid tumor of childhood.
• Skeletal tumors are usually metastases from midline thoracic or abdominal primary tumors.
• Histology demonstrates a small round blue cell tumor with cells closely mimicking those of Ewing Sarcoma but with the presence of pseudorosettes.