Erika Newman
Ihab Halaweish
Presentation
A 17-month-old male is brought by his parents to the emergency department with complaints of irritability, reduced appetite, and loose stools for the past 2 weeks. In addition, they note that his abdomen appears larger and more firm than usual. He is an otherwise healthy toddler who has been growing appropriately and meeting all milestones. He has had no unexplained fevers, weight loss, or abnormal skin lesions. The physical examination is significant for hypertension, abdominal distension, and a palpable abdominal mass in the left upper quadrant. A plain abdominal film shows displacement of the stomach medially and the left diaphragm superiorly. An abdominal ultrasound was obtained revealing a retroperitoneal mass.
Differential Diagnosis
The differential diagnosis of neuroblastoma (NB) is broad and varies according to the location of the mass. Suprarenal and retroperitoneal masses include NB, Wilms tumor, undifferentiated soft tissue sarcoma, and lymphoma. Metastatic disease in the bone marrow must be distinguished from lymphoma, osteosarcoma, Ewing’s sarcoma, and primitive neuroectodermal tumors. NB is the most common tumor in infants and the most common extracranial malignancy in children, accounting for up to 8% to 10% of all childhood malignancies. Further imaging to characterize the nature of the mass is typically needed.
Workup
In addition to a complete abdominal and pelvic examination, including an evaluation for hypertension, the workup of NB involves a series of radiographic and chemical studies. A plain radiograph of the affected area may reveal stippled calcification within the tumor, common with NB. In children, ultrasound is typically the first imaging modality for solid masses and may reveal a lobulated mass of mixed echogenicity. Computed tomography (CT) with intravenous contrast can provide valuable information regarding the resectability of the mass as detailed by its relationship with surrounding structures and blood vessels. Large thoracic and abdominal tumors that encase any major blood vessels, encroach the spinal canal, or cross the midline are unresectable at diagnosis. CT may also help to define the extent of metastasis. Magnetic resonance imaging (MRI) will determine whether spinal extradural tumor extension has occurred. Bone scans and long bone plain radiographs will determine the presence of bone cortex metastasis. Iodine-123-labeled metaiodobenzylguanidine (MIBG) is metabolized by the medullary cells of the adrenal gland, and is useful in assessing primary tumors and metastatic disease. Bone marrow aspirates may show neuroblastic metastatic foci. A bone marrow biopsy of both iliac crests is often required in cases of negative bone marrow aspirates for adequate staging. Laboratory testing for the urine catecholamines homovanillic acid (HVA) and vanillylmandelic acid (VMA), which may be elevated in up to 95% of patients, is useful as tumor markers. In this case, a CT of the orbits, chest, abdomen, and pelvis reveals a large mass extending from the diaphragm to the pelvis (Figure 1). There is also an infraorbital mass and lytic lesions in the right mandible, fifth rib, right humerus, iliac crest, and pubic ramus. MIBG shows enhancement in similar areas. Biopsy of the abdominal mass shows a small round blue-cell tumor consistent with NB. Cytogenetic analysis reveals MYC-N amplification and detection of loss of heterozygosity for chromosome 1p.
FIGURE 1 • Retroperitoneal NB that crosses the midline and encases the abdominal aorta and mesenteric vessels.
Discussion
NB is an embryonal cancer of the peripheral sympathetic nervous system with signs and symptoms reflecting the tumor site and extent of disease. Over 50% of cases occur in children <2 years and 90% of cases are diagnosed by 8 years of age. There are approximately 650 new cases in the United States each year. The majority of NB arises in the retroperitoneum (75%) with 50% in the adrenal gland and 25% in the abdominal and pelvic paravertebral ganglia. The remaining cases are at the paravertebral ganglia in either cervical or thoracic locations (Figure 2). More than half of patients present with metastases to the long bones and skull, bone marrow, liver, lymph nodes, and skin.
FIGURE 2 • Thoracic NB in the posterior upper mediastinum.
NB arises from cells of the neural crest that form the adrenal medulla and sympathetic ganglia. The genetic event that triggers the pathogenesis of NB is most likely related to a series of prenatal and perinatal mutational events. NB exhibits extreme clinical heterogeneity from spontaneous regression in newborns to aggressive and metastatic disease in school-age children. There are several karyotypic abnormalities including chromosomal deletions, translocations, and gene amplifications that have been shown to affect prognosis. Aneuploidy of tumor DNA occurs and carries a favorable prognosis, whereas amplification of the N-myc oncogene (>10 copies) adversely correlates with prognosis independent of clinical stage in up to 30% of patients. Gain of 17q and deletion of the short arm of chromosome 1 (1p deletion) are also associated with poor prognosis.
The clinical presentation of NB is insidious with vague symptomatology. Pain, due to primary or metastatic disease, is the most common symptom. Nonspecific symptoms include malaise, fever, sweating, weight loss, and growth retardation. Neurologic symptoms are less common and include Horner’s syndrome due to invasion of superior cervical ganglion and paralysis due to spinal cord and nerve root compression. Opsomyoclonus syndrome is a paraneoplastic syndrome of autoimmune origin characterized by ataxia, opsoclonus (“dancing eyes”), myoclonus, and dementia. Orbital metastases with orbital proptosis, and periorbital ecchymoses (“raccoon eyes”) are uncommon.
The diagnosis of NB is established from tumor tissue obtained by biopsy. Diagnosis can also be established by the presence of tumor cells in a bone marrow aspirate or biopsy. Histologically, immature neuroblasts appear as sheets of dark-blue nuclei with scanty cytoplasm in a delicate vascular stroma. Further differentiated masses contain ganglion cells with a more abundant stroma. Using the Shimada index, NB can be grouped into favorable or unfavorable histology on the basis of immunohistochemistry.
HVA and VMA in urine samples are elevated in 95% of cases and help establish the diagnosis. Evaluation of local disease is accomplished by ultrasound, CT, and MRI. During the workup for metastatic disease, bone scan has traditionally been used to detect cortical bone involvement and bone marrow aspirates or biopsies are used to establish marrow disease. MIBG can be used to evaluate the extent of bone or metastatic disease.
Diagnosis and Treatment
Patient stratification is important in guiding therapeutic options. The International Neuroblastoma Staging System (INSS) is the most widely accepted staging system and is the current standard for clinical trials (Table 1). INSS takes into account the resectability of the tumor and the lymph nodal status.
TABLE 1. International Neuroblastoma Staging System
The Children’s Oncology Group (COG) has further developed a stratification system based on INSS stage, age, N-myc status, and Shimada histology that classifies patients into low risk, intermediate risk, and high risk. This provides the most accurate assessment and directs therapy for optimal outcomes.
Treatment modalities used in the management of NB are surgery, chemotherapy, and radiation therapy. In low-risk patients with stage 1 or 2 disease, surgery alone may be sufficient. Achieving complete macroscopic clearance is not essential as minor residual disease is usually stable with cure rates of >90% without further therapy. Chemotherapy is indicated in the event of relapse, or in the presence of N-mycamplification with unfavorable histology.
In children with intermediate-risk disease and stage 3 or 4 disease, initial chemotherapy with chemotherapeutic agents such as cyclophosphamide, vincristine, dacarbazine, doxorubicin, cisplatin, and teniposide is mandatory, followed by surgical resection of the primary tumor. Radiation therapy is used for tumors with incomplete response to chemotherapy.
Treatment of children with high-risk disease includes induction with high-dose chemotherapy. In the event of response, resection of the primary tumor is attempted with administration of radiotherapy to the primary tumor bed. This is followed by myeloablative chemotherapy and stem cell rescue. Postchemotherapy treatment with 13-cis-retinoic to control minimal residual disease has been shown to improve outcomes in this group.
In some children with stage 4S disease without N-myc amplification, no treatment is necessary and the disease resolves spontaneously. Early treatment with chemotherapy or low-dose radiotherapy is required in the face of large tumors or hepatomegaly with mechanical obstruction, respiratory compromise, or liver dysfunction.
Surgical Approach
If the tumor appears resectable, without metastases, surgical resection is indicated with the goal of complete resection. Epidural anesthesia is often considered and provides excellent pain control in the postoperative period. For abdominal tumors, a full inspection of the liver with biopsy of any suspicious lesions and a sampling of lymph nodes are warranted for adequate staging and treatment planning. A minimum of 6 to 9 nodes should be obtained from the para-aortic region (hiatus to the bifurcation). The same principles apply to tumors in the cervical and thoracic regions, though sampling of contralateral nodes is not required. During thoracotomy for thoracic tumors or laparotomy for abdominal/pelvic masses arising from the sympathetic ganglia, it may be impossible to avoid leaving small amounts of gross or microscopic residual disease along the nerve roots at the foramina. The areas are marked with titanium clips for postoperative monitoring. A small amount of residual disease with negative lymph nodes could still result in stage IIa disease with good prognosis.
For tumors with vascular encasement encountered intraoperatively, the tumor rarely invades into the tunica media of major blood vessels. The key principle is to identify major blood vessels early before they enter the tumor and then proceed with a careful and meticulous dissection is performed outside of the subadventitial plane with the scalpel.
Successful thoracic NB resection via a thorascopic approach has been utilized. The technique is useful for small (<6 cm), stage I lesions with favorable histology, and has been found to have similar local control and disease-free survival when compared to open thoracotomy.
Special Intraoperative Considerations
The most important factors of survival in NB are age at the time of diagnosis, N-MYC status, and stage (Table 2). The current trend is to intensify therapy in the high-risk group and minimize therapy in low-and intermediate-risk patients. Current clinical trials are aimed at reducing toxic therapies in the intermediate-risk patients.
TABLE 2.
Case Conclusion
The patient’s first chemotherapy course was complicated by the development of a right eye ptosis with sixth cranial nerve palsy and significant fluid retention that all resolved within the month. He tolerated subsequent cycles of chemotherapy without further events. He then underwent resection of the primary tumor, including dissection off of the right common iliac artery. His final stratification was stage IV, high risk. He went on to myeloablative chemotherapy and rescue bone marrow transplantation with complete response. He remains disease free at 6 months post therapy.
TAKEHOME POINTS
· NB is the most common tumor in infants and the most common extracranial solid neoplasm in all children.
· Low-risk disease may be cured with surgical resection alone.
· Current trials are focused on reducing chemotherapy and toxicity in intermediate-risk patients.
· N-myc amplification is associated with poor prognosis independent of patient age and tumor stage in up to 30% of patients.
· Complete surgical excision is the goal of operative therapy though effort should be made to preserve adjacent organs and the spinal canal.
SUGGESTED READINGS
Maris JM. Recent advances in neuroblastoma. N Engl J Med. 2010;362(23):2202–2211.
Maris JM, Hogarty DM, Bagatell R, et al. Neuroblastoma. Lancet. 2007;369:2106–2120.
O’neill JA. Principles of Pediatric Surgery. 2nd ed. St Louis, MO: Mosby, 2003.
Park JR. Neuroblastoma: biology, prognosis, and treatment. Pediatr Clin North Am. 2008;55(1):97–120.