Symptom-Based Diagnosis in Pediatrics (CHOP Morning Report) 1st Ed.

CASE 16-6

Two-Year-Old Boy

JEANINE RONAN

HISTORY OF PRESENT ILLNESS

A 2-year-old boy with a medical history of asthma initially presented to the emergency department with a fever, cough, and difficulty breathing. The toddler also complained intermittently of back pain. At this time, the physical examination was remarkable only for cervical adenopathy and mild diffuse expiratory wheeze. He was treated with albuterol by metered-dose inhaler and discharged home. One week later, the patient returned to the hospital with an unsteady gait for 2 days. At the time of presentation, he was refusing to walk. He continued to have fevers over the past few days. His activity level was drastically diminished. In addition, he appeared to have focal pain over his lower back. There was no discomfort over any of his extremities. There was no history of trauma. There was no weight loss, night sweats, emesis, or diarrhea.

MEDICAL HISTORY

The boy’s birth history was complicated by meconium aspiration syndrome requiring mechanical ventilation for 1 week. He has a history of asthma. He has had several exacerbations treated as an outpatient with albuterol via meter dose inhaler and spacer. He has never received corticosteroids, required hospitalization, or been on daily controller therapy. The family history was unremarkable.

PHYSICAL EXAMINATION

T 38.5°C; RR 24/min; HR 111 bpm; BP 120/70 mmHg; Weight 25th percentile

In general, he appeared comfortable lying with his parents but expressed significant discontent when asked to sit or stand. There was no lymphadenopathy. The heart and lungs were normal. There was no splenomegaly or hepatomegaly. There was mild focal tenderness over the lumbosacral spine with palpation. He was able to flex and extend both lower extremities without difficulty. Deep tendon reflexes were 2+ and symmetric. Cranial nerves appeared intact. His motor strength was symmetrical in all extremities. Sensation appeared intact. There were no cerebellar signs.

DIAGNOSTIC STUDIES

A complete blood cell count of the boy revealed a WBC of 5500 cells/mm3 (65% segmented neutrophils, 33% lymphocytes), a hemoglobin of 11.2 g/dL, and a platelet count of 225 000 cells/mm3. The sedimentation rate was elevated at 70 mm/h. The C-reactive protein level was also elevated at 8.5 mg/dL. The lactate dehydrogenase level was high at 2276 U/L (normal range, 470-900 U/L).

COURSE OF ILLNESS

The patient was hospitalized to evaluate for possible vertebral osteomyelitis and diskitis. Given the focal findings on examination, magnetic resonance imaging (MRI) of the lumbar spine was performed (Figure 16-5). The MRI suggested another diagnostic entity and biopsy of the lesion confirmed the final diagnosis.

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FIGURE 16-5. MRI of the spine.

DISCUSSION CASE 16-6

DIFFERENTIAL DIAGNOSIS

In this case, the initial concern was to evaluate the patient for possible osteomyelitis and diskitis. When this toddler presented with fever, refusal to walk, and elevated markers of inflammation, an infectious etiology must be considered. The most common cause of vertebral osteomyelitis is Staphylococcus aureus. Less common causes include group A StreptococcusStreptococcus pneumoniae, and enteric Gram-negative rods. Tuberculosis can cause vertebral osteomyelitis. Malignancies should also be considered in this setting. Leukemia and lymphoma often present with nonspecific findings including fever, weight loss, malaise, and refusal to walk. Bone tumors including osteosarcoma or Ewings sarcoma are other possible etiologies. Metastatic neuroblastoma often presents with bone pain and fever. Neuroblastoma can also present with local effects, including an isolated thoracic or abdominal mass.

DIAGNOSIS

The MRI (Figure 16-5) demonstrated a heterogeneous bone marrow signal with marked contrast enhancement of approximately 1 cm in the anterior aspect of the vertebral body. The lesion did not extend into or disrupt the disk space. There was no associated soft tissue edema or abscess. These MRI findings were not consistent with osteomyelitis. When there is an infectious cause, soft tissue edema and disk space involvement should be seen. Given these concerns, biopsies of the vertebral lesion and bone marrow were performed. The pathology results showed metastatic neuroblastoma. Further radiologic studies, including computed tomography of the head, abdomen, and chest, were unable to determine a primary lesion. The patient received chemotherapy for stage 4 neuroblastoma.

Neuroblastoma is an embryonal tumor derived from the neural crest cells that form sympathetic ganglia and adrenal medulla. As in this case, the diagnosis is suspected based on history and radiographic findings, but confirmed by pathology. Histologically, neuroblastoma typically is made up of areas of calcification and hemorrhage surrounding small round cells with cytoplasmic granules. The cells may form together into shapes like rosettes, which are called Homer Wright rosettes.

INCIDENCE AND EPIDEMIOLOGY

Neuroblastoma, the most common extracranial solid tumor of childhood, accounts for about 10% of all childhood cancers. There are about 500 new cases in the United States every year. Most cases are diagnosed before 4 years of age with the median age of 17 months at the time of diagnosis. Most tumors (80%) are located below the diaphragm and approximately 50% of all neuroblastoma tumors arise from the adrenal gland.

CLINICAL PRESENTATION

Neuroblastoma presents in a wide variety of ways depending on the tumor location and extent of disease. It can arise throughout the body from developing tissues of the sympathetic nervous symptoms. Tumors can develop in the adrenal medulla or paraspinal ganglia, and in the neck, chest, abdomen, and pelvis. A thoracic mass may be seen as a hard, painless lump in the neck or chest, or may present with signs of superior vena cava syndrome due to compression from large mediastinal tumors. In some cases, a young child may present with an enlarging abdominal mass. Depending on location, the patient may be asymptomatic, and show signs of bowel obstruction, or liver involvement. If compression occurs on renal vasculature due to an enlarging adrenal tumor, the patient may develop hypertension. If the tumor involves cells from the sympathetic ganglia, a paraspinal mass may be present. These patients may experience back pain and nerve compression resulting in bladder or bowel dysfunction or gait disturbance. If cervical sympathetic ganglia are involved, a unilateral Horner syndrome (ptosis, miosis, anhidrosis) may be seen. Common sites of metastatic disease include regional lymph nodes and bone marrow and liver via the hematopoietic system.

There are some unique presentations with neuroblastoma. A paraneoplastic syndrome, called opsoclonus-myoclonus or “dancing eyes,” may develop. This involves jerky and chaotic eye movements and myoclonic jerks. If this is detected, it is important to look for the primary source of the tumor. In most cases, the opsoclonus and myoclonus improve with treatment. However, some patients continue to have issues even after eradication of the tumor. Occasionally, metastases may deposit in the periorbital region causing proptosis and periorbital ecchymosis. This finding resembles “raccoon eyes.” Excess catecholamine secretion from the tumor leads to other systemic signs including flushing, tachycardia, hypertension, and diarrhea.

DIAGNOSTIC APPROACH

The first step to the diagnostic approach is to consider the possibility of neuroblastoma. Consider the diagnosis in patients with nonspecific systemic signs and bone pain. Physical examination findings may involve a palpable abdominal mass and lymphadenopathy. It is also important to pay attention to the patient’s blood pressure.

Complete blood count. Pancytopenia suggests bone marrow involvement.

Urinary catecholamines. In more than 90% of cases, urine catecholamines, such as homovanillic acid (HVA) and vanillylmandelic acid (VMA), will be elevated. These should be collected via a 24-h urine collection since random “spot” samples may yield false-positive results.

Bone marrow biopsy. Bone marrow aspirates are necessary to determine metastatic involvement of the bone marrow.

Radiologic studies. Skeletal radiographs should be performed to detect metastatic bone lesions. Computed tomography of the chest, abdomen, and pelvis should be performed to detect the primary site and possible metastatic sites of involvement. Meta-iodobenzylguanidine (MIBG) scintography is very helpful in determining the extent of the disease. It is taken up by the sympathetic neurons in 90%-95% of patients with neuroblastoma. This study can be used with the initial diagnosis and as a means to monitor treatment.

TREATMENT

As with many oncologic diseases, the treatment and prognosis is determined based on the patient’s stage at presentation. The International Neuroblastoma Staging System (INSS) was developed based on clinical, radiographic, and surgical evaluation of children with neuroblastoma. Stage 1 represents localized tumor with complete gross excision. Stage 2 refers to localized disease with ipsilateral lymph node involvement. When patients present with localized disease (stage 1 and most stage 2), surgical removal of the tumor is usually curative. Stage 3 occurs when disease crosses the midline and there is contralateral lymph node involvement. Stage 4 refers to any primary tumor with dissemination to distant lymph nodes, bone, bone marrow, liver, skin, or other organs (except as defined for stage 4S). Stage 4S refers to localized primary tumor with dissemination limited to skin, liver, or bone marrow in infants younger than 1 year. Patients with stage 4S disease are frequently classified into the low-risk category. However, this classification has had its limitations in its ability to address the appropriate therapy for patients who fall between the extremes. The International Neuroblastoma Risk Group (INRG) has developed a new system based on the prognostic risk factors associated with the tumor, including patient age, tumor stage, tumor differentiation, DNA ploidy, and amplification of the MYC-N oncogene. This further classification system will hopefully be able to better define therapy with the best chance for cure. For more favorable prognostic factors, ways to reduce toxicity may be identified. For more aggressive tumors, intensification of the chemotherapy can be evaluated.

Treatment for patients with high-risk neuroblastoma includes an induction phase of remission, consolidation phase, and a maintenance phase. Autologous hematopoietic stem cell transplant after myeloablative chemotherapy has been shown to improve the disease-free survival. Aggressive induction therapy is imperative as 50%-60% of high-risk patients will have a relapse and currently there are no curative salvage treatment plans. Isotretinoin has been shown to differentiate neuroblastoma cell lines and is now part of standard therapy. Future developments are investigating ways to treat children with high-risk neuroblastoma including the possibility of131 I-labeled MIBG. Patients with low-risk neuroblastoma (asymptomatic stages 2a or 2b) have excellent survival rates after surgery alone; overall survival is 97% and event-free survival (absence of progressive disease, relapse, secondary malignancy, or death from any cause) is approximately 90%. Chemotherapy may be restricted to the minority of patients with low-risk neuroblastoma such as older children with stages 2b disease and those with unfavorable tumor histology or diploid tumors.

Survival rates exceed 98% in those children categorized as low risk and approaches 90%-95% in those children categorized as intermediate risk. Unfortunately, those considered high risk have a survival rate of only 40%-50%.

SUGGESTED READINGS

1. Castleberry RP. Biology and treatment of neuroblastoma. Pediatr Clin N Am. 1997;44:919-937.

2. Strother DR, London WB, Schmidt ML, et al. Outcome after surgery alone or with restricted use of chemotherapy for patients with low-risk neuroblastoma: results of Children’s Oncology Group study P9641. J Clin Oncol. 2012;30:1842-1848.

3. Behrman RE, Kliegman RM, Arvin AM. Nelson Textbook of Pediatrics. Philadelphia: W.B. Saunders Company; 1996.

4. Maris J. Recent advances in neuroblastoma. N Engl J Med. 2010;362:2202-2011.