Irritability, leg pain, and more in a long month of a boy's short life

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His records convey that it's been a long and difficult four weeks of "decreased ambulation and increased irritability" for your new patient, a 3-year-old boy, that has led to his referral to the general pediatric service of your hospital for evaluation. You promptly walk through available details: His mother reported that he had a "stomach virus" at the onset of symptoms, which lasted approximately two days. Axillary temperature during that time rose as high as 100° F, and he had episodes of vomiting without associated diarrhea. The rest of the family experienced similar symptoms. The boy was seen by his pediatrician, who offered a diagnosis of a viral syndrome and instructed the parents to administer ibuprofen for relief.

But the child grew progressively irritable, and then began to refuse to bear weight on either leg. Placed in a standing position by his parents, he would moan in pain as he attempted to walk. He continued to use his arms without difficulty, and to be talkative and interactive with his family—so long as he was seated.

The boy was taken again to the pediatrician, who ordered a complete blood count that revealed anemia but judged him otherwise healthy. Electrolytes were normal. The boy was placed on iron supplementation because of suspected iron deficiency anemia. His pain on walking subsided initially afterward, but later returned intermittently without associated symptoms or predisposing factors.

An unsettling turn

One week after symptoms first developed, the boy experienced two separate episodes of stiffening of the upper arms and legs, each lasting approximately two minutes, without associated clonus or nystagmus. He did not lose consciousness, and there was no postictal period. He was taken to the emergency room after the second episode, where a computed tomography (CT) scan of the head was negative. He was referred to the neurology clinic for further evaluation.

The neurologist who evaluated the child the following week found him active and walking well. The neurol- ogist did not attribute these episodes to seizure activity; given the boy's otherwise normal development, he did not think further neurologic evaluation was warranted at that moment.

Over the next two weeks, he still refused intermittently to bear weight on his legs. He then developed swelling of the left knee without associated warmth or erythema. He was again brought to the ER, where he was found to be afebrile. A radiograph of the left knee was negative. He was sent home for follow-up by his pediatrician.

The following day, the pediatrician noted that the swelling in the knee had resolved but that the boy had drainage from the right ear and an axillary temperature of 102.2° F. Oral amoxicillin-clavulanate and ofloxacin ear drops were prescribed for suspected otitis media.

And then some

That evening, the boy developed bilateral periorbital edema of both upper eyelids. For the third time, he was brought to the ER. He was treated with diphenhydramine for a suspected allergic reaction and sent home.

The eyelid edema did not improve, however, and the boy was, once again, refusing to bear weight on his legs. That prompted the referral to your institution.

Having digested this substantial history, you examine your patient. He is afebrile and tachycardic, with a pulse of 137 beats/min. Blood pressure and respiratory rate are normal. Weight for age is at the 25th percentile; his mother comments that she has noted that her son's appetite has diminished over the past week. Height for age is also at the 25th percentile. Head circumference is 52.5 cm—above the 95th percentile for age. You learn that the child was given a diagnosis of familial macrocephaly in infancy and that head circumference has not increased in association with the current illness.

The patient repeatedly falls asleep during your exam, but becomes quite irritable when you attempt to manipulate his legs. You note bilateral eyelid edema, a violaceous hue to the upper eyelids, and ptosis of the left eyelid. There is no proptosis. The right ear is draining clear fluid in the external auditory canal; you see erythema and decreased mobility of the tympanic membrane. The left ear appears normal. You palpate multiple nontender, mobile, anterior cervical lymph nodes, all less than one centimeter in diameter.

On auscultation of the heart, there is a Grade I/VI systolic murmur at the left sternal border, without radiation. Lungs are clear bilaterally. The abdomen is soft and nontender, but the abdomen is distended with a fluid wave, indicating ascites. Bowel sounds are normoactive. The liver is palpable approximately 2.5 cm below the right costal margin, but you are unable to palpate the spleen.

Examination of the lower extrem- ities reveals painful range of motion at 30º flexion of the hips; the pain is exaggerated on internal rotation, with the left side more affected than the right. The patient is unable to rise from a seated position; once placed in the standing position and coaxed to walk, he appears to have an antalgic gait that is not wide-based. He has normal range of motion in the knees and ankles bilaterally, and in his upper extremities.

On neurologic exam, the pupils are normal, facies are symmetric, and the tongue is midline. You consider the possibility that the ptosis of the left eyelid is secondary to the edema. Sensation is intact throughout. Reflexes are normal. Strength in his right lower extremity is 4/5; in the left lower extremity, 3+/5.

You order a number of laboratory tests, including a complete blood count, which reveals a normal white blood cell count of 7.3 x 10³/µL, with 63% segmented neutrophils, 6% bands, and 27% lymphocytes. Hemoglobin (8.3 g/dL) and hematocrit (24.9%) are both decreased; the mean corpuscular volume (MCV) and platelet count are normal.

Tests of alanine aminotransferase, alkaline phosphatase, and bilirubin are within normal limits, but aspartate aminotransferase is mildly elevated at 69 U/L (normal, 6 to 56 U/L). Blood urea nitrogen (13 mg/dL) is mildly elevated for age; creatinine (0.3 mg/dL) is normal. Albumin is 3.2 g/dL. Serum electrolytes, including calcium, magnesium, and phosphorus, are all within normal limits. Lactate dehydrogenase is elevated at 2,337 U/L (normal, 425 to 975 U/L); uric acid is normal. Creatine phosphokinase is normal.

The erythrocyte sedimentation rate (>150 mm/h) and C-reactive protein (27.50 mg/dL) are both extremely elevated. Chest and abdominal radiographs are both negative.

You face a confusing picture of weight loss, intermittent refusal to bear weight, and facial findings. What can tie these manifestations together? One suspicion comes to the forefront, and you order one more test that you think may help determine the underlying cause of this child's perplexing findings.

An unfortunate answer

It is a suspicion of malignancy that is still nagging you. So you order a technetium bone scan for the following morning. The scan reveals a large right adrenal mass with several areas of hypermetabolic bone activity in the ribs and, bilaterally, in the upper and lower extremities and the base of the orbits. The presumptive diagnosis? Stage 4 neuroblastoma with diffuse bony metastases. A CT scan of the abdomen reveals that the tumor originated in the right adrenal gland.

Bilateral bone marrow biopsy and aspiration of the iliac crest and intralesional biopsy of the adrenal mass confirm the suspected diagnosis. Urinary catecholamine levels are elevated, further clinching the diagnosis.

The patient is started on chemotherapy for an aggressive tumor with metastases. Almost five months later, he undergoes adrenalectomy. Six months later to the day, he receives an autologous bone marrow transplant.

Faces of a common foe

Neuroblastoma is a malignant neoplasm of neural crest origin and, therefore, a tumor of the peripheral nervous system. Because neural crest cells differentiate into tissues that form the sympathetic nervous system, the tumor can arise in any spinal sympathetic ganglia and in chromaffin cells of the adrenal medulla.¹

Presenting signs and symptoms of neuroblastoma reflect the location of both primary and disseminated disease. No wonder, therefore, that neuroblastoma, with its potential for so many sites of origin and metastasis, has more diverse patterns of presentation than any other tumor—making the diagnosis a challenge. A number of paraneoplastic syndromes also complicate the picture.²

Constitutional signs, such as fever, weight loss, and irritability, are often the presenting manifestations of neuroblastoma but are also often too vague to lead directly to the diagnosis. Several unique syndromes have, however, been associated with neuroblastoma in particular.

Pepper syndrome is characterized by hepatomegaly, the manifestation of tumor spread to the liver. Infants and young children may demonstrate the opsoclonus-myoclonus syndrome, in which the child exhibits myoclonic jerks of the extremities and random eye movements.³

Bluish skin nodules from subcutaneous spread are seen only in patients (usually infants) with a tumor that has a favorable prognosis.⁴

Young children with bony metastatic disease at the time of diagnosis typically exhibit malaise, low-grade fever, irritability, and a limp, as happened to be the case with your patient. This spectrum of complaints is known as Hutchinson's syndrome.³

A classic presentation of neuroblastoma in young children is that of proptosis and periorbital ecchymoses—so-called raccoon eyes—associated with metastatic disease to the retrobulbar and orbital tissues and, similarly, with a much less favorable prognosis than other presentations.⁵ The ocular findings in your patient are, in fact, the manifestation of orbital metastasis.

Intractable, watery, secretory diarrhea is a manifestation of a paraneoplastic syndrome known as Kerner-Morrison syndrome.¹

Diagnosis

The varied clinical manifestations of neuroblastoma often make the diagnosis a challenging one. Findings on the physical exam may direct the clinician toward a list of differential diagnoses, but other studies are required to establish the diagnosis definitively. To address these dilemmas, the International Neuroblastoma Staging System (INSS) working committee has revised diagnostic criteria, first in 1988 and again in 1993. The INSS established minimal required testing to identify the primary tumor and any local or disseminated disease.

CT or magnetic resonance imaging (MRI) must be performed to determine the location of the primary tumor, and a metaiodobenzylguanidine (MIBG) scan is recommended if available.^1,5

Common sites of metastasis are bone, bone marrow, liver, and skin, by hematogenous dissemination. Rarely does neuroblastoma metastasize to the lungs. To detect sites of bony metastasis, bilateral bone marrow biopsy and aspiration are necessary, as are a bone scan and skeletal survey to detect cortical lesions. CT or MRI of the abdomen must be performed to evaluate for liver metastasis, and a chest radiograph must be taken to evaluate thoracic involvement.⁵

According to INSS criteria, the diagnosis is confirmed if a pathologic diagnosis is made from a tissue biopsy of the tumor or bone marrow biopsy material contains tumor cells and levels of urinary catecholamines are increased.¹

Staging

Once the diagnosis is established, most neuroblastomas require some form of surgical excision. The sur- gical specimen, along with the results of the required studies just discussed, help determine the stage of disease.

The clinical behavior of neuroblastoma can, like its presentation, vary widely: from spontaneous regression to extremely aggressive widespread dissemination. Stages 1, 2A and 2B represent unilateral disease that does not cross the midline. Stage 3 disease has crossed the midline. Stage 4 disease involves distant dissemination to the common sites already discussed. There is also the noteworthy Stage 4S, which carries a much more favorable prognosis than the bleak outcome often associated with metastastic disease.

Treatment

Management of neuroblastoma is multifaceted. Most patients require surgery at some point during treatment—either as a tool for resection or an aid in staging, or to take a second look at the effectiveness of other treatments.⁵

Neuroblastomas are radiosensitive tumors; some treatment regimens therefore incorporate radiation therapy—for example, to control a localized tumor that cannot be resected or to treat a tumor that is not fully responsive to chemotherapy. Radiotherapy is sometimes implemented in cases of Stage 4S disease or as a palliative treatment in a child whose disease is terminally advanced.

Chemotherapy, however, is the cornerstone of therapy. Several agents are used in combination to promote synergy and prevent resistance.

Autologous bone marrow transplantation is attempted in cases of Stage 4 disease, with its often extremely poor prognosis. Even though this modality has been used for just longer than a decade, it appears to, overall, offer improved survival compared to standard therapy.

Prognosis and outcome

Prognosis for patients with neuroblastoma is mainly determined by age and stage of disease at presentation. Most patients who have Stage 1, 2, or 4S disease have a three-year survival rate that ranges from 75% to 90%. Infants with Stage 3 disease have a cure rate of 80% to 90%, whereas many with Stage 4 disease have a cure rate of 60% to 75%.¹

Patients older than 1 year of age do not fare as well: Those with Stage 3 disease have a three-year survival rate of 50%; those with Stage 4 disease, only 15%.

None of the treatment regimens reviewed earlier has made a significant positive impact on outcome in children whose disease is advanced at presentation—the group into which this patient falls. Nevertheless, he is doing well post-transplantation—at home with his family, eagerly planning his fourth birthday party.

Research on potential therapeutic modalities is ongoing, and gene therapy is a possibility on the distant horizon if a gene for neuroblastoma can be identified. When that promise can become reality, children who, like this boy, have advanced disease will plan and enjoy many more birthday parties for themselves.

REFERENCES

1. Castleberry R: Biology and treatment of neuroblastoma. Pediatr Clin North Am 1997;44:919

2. Chauvenet A, Wofford M: Cures in childhood cancer. Pediatr Rev 1990;11:311

3. Hero B, Simon T, Horz S, et al: Metastatic neuroblastoma in infancy: What does the pattern of metastases contribute to prognosis? Med Pediatr Oncol 2000;35:683

4. Altman AJ, Quinn JJ: Cancer in infancy: A special challenge. Contemp Pediatr 1995;12(2):39

5. Alexander F: Neuroblastoma. Urol Clin North Am 2000;27:383

DR. NELSON is chief resident in the department of pediatrics at the Children's Hospital of Louisiana State University Health Sciences Center, New Orleans.

DR. EY is retired from the position of professor of clinical pediatrics and director of the pediatric residency program at Louisiana State University Health Sciences Center that he held when the manuscript of this article was written.

DR. SIBERRY is an assistant professor of pediatrics in the divisions of general pediatric and adolescent medicine and pediatric infectious diseases at The Johns Hopkins Hospital, Baltimore.