Neuroblastoma

Cancer is second only to accidents as the cause of death in children. Although neuroblastomas account for only about 8 percent of all tumors in children, they are responsible for 11 percent of cancer-related deaths in this group. [1] The annual incidence of neuroblastoma is 8.7 cases per 1 million in white children and 7.4 cases per 1 million in black children. These numbers represent approximately 500 newly diagnosed cases each year in the United States. Neuroblastomas are rare in children older than 14 years of age; 50 percent of these tumors occur in children under age two and 75 percent occur in children under age four.

Pathology

Neuroblastoma arises from the sympathetic nervous system, which is derived from neural crest cells. The tumor occurs in the abdomen in 50 to 75 percent of cases; two-thirds of these tumors originate from the adrenal glands and one-third originate elsewhere in the abdomen. Abdominal neuroblastomas are often centrally located, enveloping the aorta and splanchnic arteries. Other sites of involvement are the chest (i.e., mediastinum), neck, pelvis and head (including intracranial tumors). The primary site is unknown in approximately 10 percent of patients.

First described by Virchow in 1864 as an abdominal "glioma," neuroblastoma microscopically consists of small, round cells and may be difficult to differentiate by routine light microscopy from leukemia, lymphoma, Ewing's sarcoma or rhabdomyosarcoma. Neuroblastoma is frequently metastatic at the time of diagnosis; lymph nodes, bone, bone marrow and liver are common sites of spread. Pulmonary, renal, subcutaneous and brain metastatic lesions are relatively less common. Staging

Clinical staging of neuroblastoma is outlined in Table 1.2 Approximately 11 percent of tumors are stage I at presentation, 13 percent are stage II, 10 percent are stage Ill, 56 percent are stage IV and 9 percent are stage IV-S.[.sup.3] A clinicopathologic staging system has also been developed (Table 2). [4]

The overall two-year survival rate of patients with neuroblastoma is approximately 30 to 35 percent. [5] However, the child's age and the stage of the disease at the time of diagnosis are two important clinical factors in determining prognosis and treatment. More than 90 percent of patients with stage I disease remain tumor-free. [6] In children who have stage IV disease and are older than one year, the cure rate with current therapy is less than 20 percent. [7] However, in infants younger than one year of age with stage IV disease, disease-free survival is 50 percent or greater. [1] Patients with stage IV-S disease have a survival rate that exceeds 75 percent, with minimal therapy.

Because of the relative rarity of the disease, the primary care physician may diagnose neuroblastoma only once or twice. The following case illustrates the salient features of the clinical presentation, diagnosis and treatment of neuroblastoma.

Illustrative Case

A three-and-one-half-year-old girl was brought to her physician with a history of progressive abdominal pain and low-grade fever (to 38 degrees C for two to three weeks. She had been in normal health previously. When the episodes of abdominal pain first occurred, the child awakened at night with intense pain that lasted briefly. During the week prior to admission, the pain occurred up to seven times a night and also began to occur during the daytime. Her parents noted a persistent low-grade fever.

On physical examination one week prior to admission, her oral temperature was 37.9 degrees C (100.2 degrees F), and she was found to have right otitis media. Other data, including urinalysis, were normal. Amoxicillin, 250 mg orally four times daily for ten days, was prescribed for the otitis media.

The child was again seen three days later because of increasing abdominal pain. Physical examination was unrevealing; urine culture results were negative. Flat and upright abdominal radiographs demonstrated considerable stool in the colon. The abdominal pain persisted, necessitating hospital admission.

On examination in the hospital, the patient occasionally cried out because of the abdominal pain. Her oral temperature was 39.1 degrees C (102.4 degrees F); pulse, 130 beats per minute; blood pressure, 90/50 mm Hg, and respiratory rate, 32 per minute. Significant findings included resolving right otitis media and a slightly distended abdomen with no areas of tenderness, rebound or organomegaly. However, fullness in the upper abdomen was noted.

Abdominal radiographs again demonstrated a large amount of residual stool. Relevant laboratory data included: hemoglobin, 10.3 g per dL (103 g per L); mean corpuscular volume, 83.5 [micro]M[.sup.3] ($3.5 fL); leukocyte count, 11,600 per MM[.sup.3] (11.6 x 10[.sup.9] per L); platelet count, 577,000 per MM3 (577 x 10[.sup.9] per L), and erythrocyte sedimentation rate, 97 mm in one hour (Westergren method).

Ultrasonography of the abdomen revealed a large retroperitoneal mass that did not appear to involve the kidneys. The mass showed evidence of calcification and had the appearance of a neuroblastoma. Twenty-four-hour urinary excretion of vanillylmandelic acid (VMA), homovanillic acid (HVA) and cystathionine was measured. Bone marrow biopsy and aspirate studies, radionuclide bone scan, skeletal bone survey and magnetic resonance imaging (MRI) of the abdomen were also performed prior to surgical evaluation.

MRI of the abdomen demonstrated a 5.3 x 6.0 x 9.0-cm mass that appeared to originate from the right adrenal gland (Figure 1). The mass involved several vessels, including the right renal vein, and caused marked deviation in the course of the inferior vena cava. No extension of the tumor into the spinal canal was apparent.

The 24-hour urinary excretion of VMA was increased (29 fig per mg of creatinine [ normal: 0 to 13 [micro]g per mg 1), as was the 24-hour HVA (58 [micro]g per mg of creatinine [normal: 0 to 13.5 [micro]g per mg]). The VMA/HVA ratio was 0.5.

The bone marrow aspirate revealed decreased erythropoiesis and granulopoiesis with involvement by metastatic neuroblastoma (Figure2). The radionuclide bone scan documented multiple areas of increased uptake, consistent with widespread metastasis involving the skull, thoracic and lumbar spine, ribs, left humerus and femur, and right tibia. However, a radiographic bone survey did not demonstrate evidence of metastasis.

Because of the widespread metastasis, the tumor was classified as stage IV. Surgical resection was thought to be impossible because of the involvement of the abdominal vessels. A right atrial catheter was placed, and on the fourth hospital day, chemotherapy was begun with dacarbazine (DTIC), cyclophosphamide (Cytoxan) and vincristine.

Clinical Presentation

Because neuroblastoma may originate wherever sympathetic nervous system tissue exists, there are many manifestations of the disease (Table 3). Most neuroblastomas arise in the abdomen and are widely metastatic at the time of diagnosis. Thus, the symptoms may be nonspecific. Patients may present with fever, abdominal pain or distention, an abdominal mass, weight loss, anemia, bone pain, or proptosis and periorbital ecchymoses. Less commonly, the cervical sympathetic ganglia may be involved, producing Horner's syndrome. If the ophthalmic sympathetic nerve is involved, heterochromia iridis (irides of different colors) may be noted. Unilateral nasal obstruction may result from disease in the olfactory bulb.

Some patients present with hypertension. [9] Rarely, patients have chronic, intractable diarrhea secondary to the production of vasoactive intestinal peptide by the tumor. [10] The triad of opsocionus, myoclonus and truncal ataxia without an increase in intracranial pressure (acute myoclonic encephalopathy) is a rare syndrome associated with neuroblastoma. [11] The cause of this syndrome remains unclear, but one theory suggests that it is an auto-immune phenomenon in which an antibody cross-reacts with the cerebellum.

The illustrative case is typical of metastatic neuroblastoma. Abdominal pain is a frequent presenting symptom in patients with neuroblastoma originating in the abdomen, and fever is often seen in patients with metastatic disease. Pallor, another typical presenting sign, was also present in our patient, and evaluation revealed normocytic normochromic anemia. Especially in symptomatic patients, normocytic normochromic anemia should be investigated with bone marrow examination; in the illustrative case, the involvement by neuroblastoma was documented by the bone marrow biopsy.

A neuroblastoma that originates as an extraspinal mass may extend directly through an intervertebral foramen and produce spinal cord compression. Spinal cord compression by neuroblastoma (dumbbell or hourglass tumor) is an oncologic emergency and necessitates immediate laminectomy.

Prognosis

As previously mentioned, the patient's age and tumor stage at the time of diagnosis are the two most important prognostic factors. In addition, most neuroblastomas produce and secrete catecholamines; their major metabolites are VMA and HVA (Figure 3). Urinary excretion of these metabolites is increased in most children with neuroblastoma. A VMA/HVA ratio of at least 1.5 carries a more favorable prognosis than a lower ratio does. Persistence or reappearance of increased urinary catecholamine excretion is evidence of active malignant disease. A recent study by Alvarado and associates [12] suggests that the plasma level of dopa, a catecholamine precursor, may also be an indicator of the patient's prognosis.

Seeger and colleagues [13] discovered that amplification of the oncogene N-myc within the tumor is associated with a worse prognosis. When the neuroblastoma had one copy of N-myc, 18-month survival was 70 percent; when there were three to ten copies, 18-month survival was 30 percent; with more than ten copies, 18-month survival was 5 percent. Amplification of N-myc was more evident in tumors of higher stage. For each stage, an increase in the copy number of N-myc was associated with a worsening of the outcome.

Other factors, such as VMA/HVA ratio, lymph node involvement, serum ferritin level and site of origin, are also important prognostically. Shimada and colleagues [14] recently described a clinicopathologic classification to define the prognosis in patients with neuroblastoma.

Diagnostic Evaluation

Table 4 outlines the diagnostic studies usually included in the work-up of patients with neuroblastoma.

For the patient with an abdominal mass, ultrasonography is a useful initial study for evaluation and diagnosis. Neuroblastoma usually can be distinguished from Wilms' tumor because of its extrarenal development. The sensitivity of computed tomography (CT) of the abdomen is almost 100 percent for detecting neuroblastoma, and this imaging technique can be used to stage the disease at the same time. CT metrizamide myelography delineates any spinal cord lesions present. MRI provides definition of the extent of the disease and evaluation of disease within the spinal canal. Other imaging procedures required in the diagnostic evaluation include chest radiographs, radionuclide bone scan and metastatic radiographic bone survey.

Useful diagnostic laboratory tests include a complete blood cell count with differential, liver function tests, serum ferritin measurement, bone marrow aspiration and biopsy, and urinary VMA and HVA determinations. N-myc amplification may be helpful in identifying patients with a poor prognosis, especially those patients with an otherwise low stage of disease.

Treatment

Operative resection, when possible, remains the initial treatment of choice for localized neuroblastoma. Unfortunately, the anatomic aspects of the tumor often preclude resection. For stage Il tumors, either radiotherapy or chemotherapy may be used; however, neither therapy offers any additional benefit after surgery. Advanced tumors are usually treated with combination chemotherapy, such as DTIC, doxorubicin (Adriamycin), cisplatin (Platinol), cyclophosphamide, VM-26 (also called teniposide) and vincristine. Unfortunately, no agent or combination of agents has been found to improve survival rates significantly. 5 Aggressive chemotherapy followed by bone marrow transplantation may significantly improve disease-free survival in patients with advanced tumor. [15]

An initially good clinical response to chemotherapy is typical for patients with stage IV neuroblastoma. The response is frequently incomplete, however, and a cure is rarely achieved with standard therapy. New chemotherapeutic induction regimens for stage III and stage IV neuroblastoma need to be developed. Recently, two combinations-teniposide plus cisplatin and ifosfamide plus etoposide have shown promise as a means of improving the initial response rate.

Stage IV-S disease is defined as metastatic disease confined to the liver, skin or bone marrow (or any combination of the three) with no radiologic evidence of skeletal involvement and with a small primary tumor. This form of the disease usually occurs in children under 12 months of age and is associated with a more favorable outcome. Many stage IV-S tumors regress spontaneously. [2] Radiation therapy or chemotherapy, or both, may benefit patients with progressive stage IV-S disease. Similarly, limited radiotherapy or chemotherapy may be required for patients with stage IV-S disease and massive tumor and impaired organ function. However, it must be remembered that complications of therapy are important causes of death in patients with stage IV-S neuroblastoma.

Neuroblastoma is highly responsive to radiation therapy, although the role of radiation therapy is not well defined. [16] Radiation therapy has been used in progressive stage IV-S disease and for the treatment of bone pain, spinal cord compression, proptosis or bladder obstruction. Radiation therapy may also be used to shrink a large tumor, making it more amenable to surgical treatment.

Final Comment

Neuroblastoma may be considered a relatively common tumor of childhood. Because the symptoms may be nonspecific initially, the clinician must be aware of the many manifestations of neuroblastoma. Referral to and treatment by a pediatric oncologist are important once the diagnosis is suspected.

ACKNOWLEDGMENT: The authors thank Bruce H. Kaufman, M.D., for his thoughtful review of this manuscript and for his role in the care of this patient.

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COPYRIGHT 1990 American Academy of Family Physicians
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