Neuroblastoma is the most common solid, extracranial malignant tumor in children, accounting for 8% to 10% of all childhood cancers (4,5,6). Most children with neuroblastoma are between 1 and 5 years of age, with a median age at diagnosis of 22 months. Neuroblastomas may arise in the adrenal medulla or anywhere along the sympathetic ganglion chain. Up to 75% of neuroblastomas arise in the abdomen, and two-thirds of these lesions arise in the adrenal medulla. The remaining abdominal and pelvic tumors usually originate in the paravertebral sympathetic ganglia or presacral area. Occasionally, an abdominal tumor arises in the organ of Zuckerkandl. On cut-section, neuroblastoma is usually well demarcated, although it lacks a capsule, and it commonly contains areas of necrosis, hemorrhage, cystic degeneration, and calcification. Microscopically, the tumor is composed of small, darkly straining, round cells that are characteristically arranged in rosettes. Average tumor size is 8 cm at the time of presentation.

The most common clinical presentation of abdominal neuroblastomas is an abdominal mass. Other presenting features include skeletal pain; neurologic abnormalities, such as nystagmus, ataxia, opsoclonus, and paraparesis; ophthalmic signs, including proptosis and periorbital ecchymoses; and gastrointestinal complaints, such as diarrhea, anorexia, and vomiting. These signs and symptoms usually are related to metastatic spread of the tumor, intraspinal invasion, or the production of various hormones. Approximately 90% of patients with neuroblastoma have increased serum or urinary levels of catecholamines or their metabolites, particularly vanillylmandelic acid (VMA) and homovanillic acid (HVA). Between 60% and 70% of children have metastatic disease at time of diagnosis. Common sites of metastases are distant lymph nodes, cortical bone, bone marrow, liver, and skin. Neuroblastoma has been associated with neurofibromatosis type I and with aganglionosis of the colon.

Two paraneoplastic syndromes have been described in association with neuroblastoma. One is myoclonic encephalopathy of infancy, which includes the triad of cerebellar ataxia, myoclonus, and opsomyoclonus. The precise cause of this syndrome is unknown, but it has been postulated that an immune response to the primary tumor leads to production of antineural antibodies that cross-react with cerebellar tissue. The second syndrome consists of intractable watery diarrhea and hypokalemia caused by excess production of vasoactive intestinal peptides.

The International Neuroblastoma Staging System (INSS), based on the combination of clinical, radiographic, and surgical findings, is the system used most often to stage neuroblastoma (see Table 9.1). Distribution of stages based the INSS is approximately I, 20%; II, 10%; III, 15%; IV, 50%; and IV-S, 4% (5).

The treatment of neuroblastoma varies with the stage of the tumor. Patients with tumors that are localized to one side of the midline or cross the midline without encasement of major vessels undergo primary surgical resection. Chemotherapy is the treatment of choice in patients with unresectable disease. The use of radiation therapy is limited to patients with localized disease that cannot be resected and does not regress completely with chemotherapy. Once unresectable tumors decrease sufficiently in volume, delayed surgical resection is performed. Infants with IV-S disease may not be treated, as spontaneous regression sometimes occurs in these patients.

The principal determinants of prognosis are the stage and site of the tumor and the age of the patient. Tumors with lower stages, those arising at extra-abdominal sites, and tumors occurring in children under 1 year of age have a more favorable prognosis. Stage is a particularly important factor. Two-year survival ranges from 80% with disease limited to the adrenal to less than 5% for disease with skeletal metastases. Thoracic tumors also have a better overall survival rate than abdominal tumors. Several biological markers of tumor tissue also influence survival rate. Favorable factors include triploid karyotypes, well-differentiated stroma, an unamplified N-myc oncogene, and absence of abnormalities of chromosome 1. Unfavorable prognostic signs are a “diploid” (decreased DNA) karyotype, N-myc amplification (more than 10 copy numbers), and allelic loss of chromosome 1p.

Ganglioneuroblastoma is a malignant tumor containing both primitive and differentiated cells. Ganglioneuroma is a benign completely differentiated tumor composed of mature ganglion cells. Ganglioneuroblastoma and ganglioneuroma tend to occur later in the first decade of life or in the second decade of life. They have imaging findings similar to those of
neuroblastoma (6). The diagnosis is made histologically by the degree of cellular maturation and differentiation.

Pheochromocytoma is a functionally active neoplasm of the adrenal medulla that causes catecholamine overproduction. Most pheochromocytomas originate in the adrenal medulla, but up to 30% may arise in extraadrenal sites, mainly the paravertebral sympathetic chain, paraaortic bodies, and bladder wall. When this tumor originates outside of the adrenal glands, it is termed a paraganglioma. Most pheochromocytomas in children are benign.

Clinical features suggestive of the diagnosis are paroxysmal hypertensive episodes, headache, tachycardia, palpitation, diaphoresis, and pallor. Patients with bladder wall paragangliomas may present with micturition syncope. There is an increased incidence of pheochromocytomas in patients with multiple endocrine neoplasia type 2 (medullary thyroid carcinoma and parathyroid disease), and in patients with neurofibromatosis and von Hippel-Lindau disease. Multiple or bilateral tumors are more likely in these syndromes. The diagnosis of pheochromocytoma is usually established by biochemical testing, which demonstrates elevated urinary or serum catecholamines levels or elevated urine metanephrine or vanillylmandelic acid levels.

Localization of pheochromocytomas is accomplished with CT, MRI, or ¹²³I- or ¹³¹I-labeled MIBG. Total body scanning with MIBG is especially useful in patients with multifocal tumors or metastatic disease.

Pheochromocytomas are usually large (>2 cm in diameter), sharply marginated lesions (1,2,3,4,11) (Fig. 9.10). Smaller tumors commonly have a homogeneous matrix, whereas larger tumors are often heterogeneous. Calcifications are present in about 15% of tumors. The tumors are predominantly soft-tissue attenuation on CT, hypointense to liver on T1-weighted images, and markedly hyperintense to liver and fat on T2-weighted and fat-suppressed images. Moderate to marked heterogenous enhancement after intravenous administration of contrast medium or gadolinium is typical. Signs of malignancy, such as local invasion, lymph node enlargement and distant metastases, may also be seen. The imaging appearance of pheochromocytoma is not specific and differentiation from other adrenal tumors requires biochemical studies.

Adrenal carcinoma is a rare highly malignant neoplasm of the adrenal cortex. The tumor commonly causes virilism in girls and pseudoprecocious puberty in boys. Cushing syndrome, feminization, and hyperaldosteronism are less common presentations. Mean patient age at diagnosis is 9 years. The tumor may invade the inferior vena cava and spread to regional lymph nodes. Distant metastases are to lung, liver, and lymph nodes. Biochemical criteria for diagnosis of a virilizing tumor are elevated levels of urinary 17-ketosteroids and normal to mildly elevated urinary cortisol levels.

Adrenal carcinomas are readily detected by sonography, CT, and MRI. They have an imaging appearance similar to that of neuroblastoma. Most often they are seen as large masses, measuring more than 5 cm in diameter, at the time of presentation. Central areas of necrosis are common. Calcification is found in 25% to 40% of tumors (Fig. 9.11). They are echogenic on sonography, soft-tissue attenuation on CT, hypointense to liver on T1-weighted images, and hyperintense to liver on T2-weighted and fat-suppressed images. Adrenal carcinoma enhances after administration of intravenous contrast medium and gadolinium.

Adrenal adenomas usually are functional and result in the overproduction of adrenocorticotropic hormone or aldosterone, resulting in Cushing syndrome and Conn syndrome, respectively. Clinical features of Cushing syndrome include obesity, muscle wasting, virilism, hypertension, and elevated 24-hour urinary cortisol and 17-hydroxycorticoids. Clinical manifestations of primary aldosteronism or Conn syndrome include muscle weakness, hypertension, and hypokalemia. Occasionally, adenomas are nonfunctioning and present as abdominal masses.

Adenomas are usually smooth, homogeneous, round or oval masses ranging between 2 and 5 cm in diameter. They are echogenic at sonography. At CT, they can have soft-tissue attenuation or a lower density because of their relatively high lipid content, and they show little if any enhancement after intravenous contrast administration (Fig. 9.12). On MRI, the signal intensity of adenomas is equal to that of liver on T1-weighted images, equal or slightly greater than liver on T2-weighted images, and less than liver on fat-suppressed images. Enhancement is minimal to moderate after administration of gadolinium compounds.

Congenital adrenal hyperplasia results in excess production of androgens or cortisol secondary to an enzymatic defect in steroid synthesis. Most cases are due to 21-hydroxylase deficiency. The remaining cases are usually due to errors in production of 11β-hydroxylase and 3β-hydroxysteroid dehydrogenase. Clinical manifestations of 21-hydroxylase deficiency are virilism in girls, premature masculization in boys, and advanced somatic development in both sexes. The adrenal glands may be normal-sized or enlarged. They usually maintain their triangular configuration. The margins of the gland may be smooth or nodular. A wrinkled “cerebriform” pattern also has been described in neonates (17) (Fig. 9.13).

Adrenal hemorrhage is more common in neonates than in older children. In neonates, hemorrhage is usually secondary to birth trauma or perinatal anoxia, but it has been seen in the setting of overwhelming septicemia and anticoagulation therapy. A palpable abdominal mass, jaundice, and anemia are the common clinical manifestations. Adrenal insufficiency does not develop, because the major insult is to the regressing fetal cortex rather than to the adult cortex.

Ultrasonography is the examination of choice in neonates suspected of having adrenal hemorrhage. Hemorrhage typically replaces the entire gland, producing a round or triangular suprarenal mass (Fig. 9.14). Less commonly, it is limited to a part of one limb, appearing as a focal mass adjacent to a normal portion of the gland. Acute hemorrhage is usually homogeneous and may be iso- or hyperechoic relative to surrounding tissues. Within several days, the hemorrhage becomes heterogeneous as the blood lyses and coalesces. During the next several weeks, this mass involutes and disappears, often leaving a residual focus of calcification (Fig. 9.15).

The primary differential diagnostic problem is the rare case of congenital neuroblastoma that presents as a complex or cystic mass with little evidence of metastatic disease. In general, masses due to adrenal hemorrhage decrease in size within 1 to 2 weeks and eventually disappear in several weeks, whereas the size of a neuroblastoma is unlikely to decrease. Since neonatal neuroblastoma has a relatively good prognosis and delayed diagnosis is not harmful, serial imaging, usually with sonography, is an acceptable method of separating the two lesions if clinical and laboratory data are not diagnostic. Elevated levels of urine catecholamines or their metabolites, which occur in about 90% of patients with neuroblastoma, also increase diagnostic specificity.

In infants and older children, adrenal hemorrhage usually occurs in the setting of abdominal trauma, but it also can be seen in the setting of overwhelming sepsis, especially that caused by Neisseria meningitidis, hypotension, anticoagulation therapy, and liver transplantation.