Grossly, neuroblastomas are large, lobulated, and soft; they may appear to be pseudoencapsulated. The cut surface is gray-red, and multiple hemorrhagic areas are frequently present. Microscopically, the tumor is composed of small cells with scanty cytoplasm. The nuclei are round to polygonal with a salt-and-pepper chromatin pattern. Characteristically, a circular grouping or pseudorosette formation of cells appears around a fine fibrillar network (Fig. 196-1). The background of the tumor may contain varying amounts of neuropil. Occasional large cells with ganglionic differentiation may be seen. Foci of calcification are commonly present. Rarely, as reported by
Stowens and Lin,¹²⁵ abundant intracytoplasmic neuromelanin (pigmented neuroblastomas) is present.

Ultrastructurally, Taxy¹³⁰ has described fine intracytoplasmic neurofilaments, dense-core neurosecretory granules, and abundant extracellular neurofibrillary material.

Mediastinal neuroblastomas are seen most often in children <1 year of age, but the tumor may occur in adolescents. Fifty percent are seen in children <1 year of age, and almost 90% are seen within the first 10 years of life.

These intrathoracic neuroblastomas account for approximately 15% to 20% of all neuroblastomas seen in the pediatric age group. Patients with mediastinal neuroblastomas may be asymptomatic and have only an incidental radiographic finding, but generally most patients are symptomatic with local and constitutional findings. Chest pain, Horner’s syndrome, paraplegia, cough, dyspnea, and dysphagia are not uncommon. Heterochromic iridis, fever, malaise, and failure to thrive can be present. As the result of production of catecholamines, sweating, flushing, or an admixture of both may develop. Diarrhea and abdominal distention may be observed and is probably due to the production vasoactive intestinal peptide. The more common complaints observed at the Children’s Memorial Hospital have been Horner’s syndrome, paraplegia, and flushing and sweating. Some infants also present with acute cerebellar ataxia with opsoclonus and chaotic nystagmus, the so-called dancing eyes originally described by Solomon and Chutorian¹²² and Altman and Baehner.⁵ Jones and associates⁵⁸ believe that this syndrome is caused by an autoimmune mechanism. This symptom complex is seen in patients with more mature neuroblastomas and usually occurs in infants under 1 year of age. In 60% of infants with this syndrome, the neuroblastoma is located in the thorax, and most lesions are either stage 1 or 2 (Table 196-5). Stage 4 and 4S disease may occur in association with thoracic neuroblastomas, as with primary neuroblastomas elsewhere in the body. Distant metastases to liver or bone can occur, although thoracic neuroblastomas rarely present with metastatic involvement.

In addition to elevated plasma and urine levels of catecholamines, VMA, and HVA, elevated serum ferritin and lactate dehydrogenase levels may be present.

Bar-Ziv and Nogrady¹¹ describe the radiographic features of a paravertebral neuroblastoma as a ghost-like mass with indistinct borders (Fig. 196-2). These investigators described scattered calcifications in more
than 70% of these tumors, the uncalcified ones being more commonly seen in infants <1 year of age. Reed and associates¹⁰¹ found the incidence of calcification to be much less, but it is our impression that the incidence of calcification is greater than 50%. Rib erosions and rib displacement are common. A high incidence of intervertebral foramen enlargement and intraspinal canal extension is also present, occurring in two-thirds of the patients reported by Bar-Ziv and Nogrady.¹¹ Reed and associates¹⁰¹ reported lower incidences of these bony changes.

Slovis and colleagues¹²¹ demonstrated that a chest radiograph is 100% sensitive in establishing a diagnosis of neuroblastoma. Magnetic resonance imaging (MRI) is the best imaging modality for detecting nodal involvement, intraspinal extension, and chest wall involvement (Fig. 196-3). A bone scan is needed to detect remote disease.

The International Neuroblastoma Staging System (INSS) (Table 196-5) has replaced all other previously used staging systems and has been implemented worldwide.

Several clinical and biological prognostic factors have been identified in children with neuroblastoma (Table 196-6). Many of these prognostic factors play a role in treatment protocols. Stage of disease is the most important prognostic factor, and age at diagnosis is the only other independent prognostic indicator. Tumor markers predictive of poor outcome include serum ferritin (>142 ng/mL), serum lactic dehydrogenase (>1,500 IU/L), and serum neuron-specific enolase (>100 ng/mL).

Shimada and colleagues¹¹⁶ classified neuroblastoma histology as favorable or unfavorable depending on the degree of neuroblast differentiation, stromal content, mitosis–karyorrhexis index, and age at diagnosis (Table 196-7). Joshi and associates⁵⁹ modified this system using mitotic ratio (i.e., number of mitoses per 10 high power fields) and the presence of calcification in the tumor (Table 196-8).

Amplification of the N-myc oncogene is associated with advanced-stage disease and rapid tumor progression, as described by Seeger¹¹² and Brodeur¹⁷ and their associates. The relevance of N-myc amplification in low-stage or 4S disease is debated. Other biological prognostic factors include tumor cell ploidy; deletion or loss of heterozygosity of the short arm of chromosome 1; levels of expression of TrkA, TrkB, and TrkC (neutrophin receptors); levels of expression of multidrug resistance–associated protein; tumor vascularity; and expression of pCD44, a cell surface receptor.

In general, thoracic neuroblastomas have a favorable biological profile: low lactic dehydrogenase level, low serum ferritin level, DNA index = 1, and N-myc nonamplification. In the comprehensive review by Morris and colleagues,⁹⁰ the biological variables measured for children with thoracic neuroblastoma did not completely explain the higher survival rates in this group when compared with the nonthoracic site (Figs. 196-4, 196-5, 196-6).

Clinical risk groups have been devised to classify patients with neuroblastoma and direct therapy. These risk groups are based on INSS stage, age, N-myc number, tumor cell ploidy, and tumor histology using Shimada criteria (Table 196-9).

Low-risk patients (INSS 1 and 2) and infants with 4S disease and favorable biology (normal N-myc copy number, hyperdiploid DNA index, and favorable histology) should be treated with complete surgical resection. Regional lymph nodes, especially the posterior mediastinal node groups, should be excised.

In patients with intraspinal extension, vertebral body involvement, or both, the cooperation of a neurosurgeon or an orthopedic spinal specialist is essential for evaluation and preoperative planning. Hoover and colleagues⁵³ reported that recovery from neurologic deficits was not altered by laminectomy when chemotherapy or surgery was used. In their study comparing patients with and without laminectomy, there was a higher incidence of subsequent spinal deformities in those treated with laminectomy. Biopsy followed by chemotherapy may be the best preoperative strategy, as intraspinal extension may disappear and avoid the need for laminectomy.

Intermediate-risk patients (INSS 3 and 4) who lack N-myc amplification and infants with 4S tumor (normal N-myc copy number, diploid DNA content, or unfavorable histology) are treated with a combination of surgery and multiagent chemotherapy. Few patients with thoracic neuroblastoma fit into this risk group.

The indications for and timing of surgery for patients in the high-risk group are controversial. Initial surgical resection of large tumors is seldom recommended. Multimodal therapies include myeloablative chemotherapy or chemoradiation therapy followed by autologous bone marrow transplantation. Kletzel and associates⁶⁷ reported improved survival statistics for patients with high-risk neuroblastoma.

Thoracoscopy is being used with increasing frequency for diagnostic biopsy and complete surgical resection of thoracic
neurogenic tumors. Petty and colleagues⁹⁹ compared open thoracotomy with thoracoscopy in a small group of patients and found similar results in terms of local control and disease-free interval. Thoracoscopy allowed shorter length of hospital stay. DeCou and associates³⁰ reported excellent results in a small series of patients who underwent primary gross total resection with the thoracoscopic approach. All were stage I and most had favorable histology. None were N-myc–amplified.

Ganglioneuromas are frequently large, firm, well-circumscribed, encapsulated tumors arising in a paravertebral sulcus in a child, adolescent, or adult. The tumor is usually attached to a sympathetic or intercostal nerve trunk. Extension
into the spinal canal can occur but is uncommon. On cut section, the tumor is yellowish to gray; Marchevsky and Kaneko⁷⁹ state that it frequently has a whorled, trabeculated surface that may simulate a leiomyoma. Microscopic examination reveals mature ganglion cells, singly and in nests, in a stroma composed of Schwann cells and fibrous tissue (Fig. 196-9). Areas of degeneration are evident within the tumor. Calcification may or may not be present in these areas. The ganglion cells are large, and their cytoplasm may contain various inclusions. Ultrastructurally, dense-core vesicles have been identified by Bender and Ghatak¹³ and Yokoyama and associates¹⁴² as well as others.

Clinically, the patient may be asymptomatic, but patients with large lesions may present with cough, dyspnea, dysphagia, Horner’s syndrome, and, occasionally, chest pain. Heterochromia iridis was reported by McRae
and Shaw⁸³ to be the result of sympathetic injury by the tumor involving the superior cervical ganglion. The age distribution is not dissimilar to that observed in patients with ganglioneuro- blastomas (see Table 196-3). Elevated levels of VMA and HVA are observed infrequently. Chronic diarrhea also has been reported in association with these tumors by Mendelsohn⁸⁴ and Trump¹³³ and their associates. This is thought to be caused by the presence of vasoactive intestinal peptide, which can be localized to the cytoplasm of the ganglion cells by means of immunoperoxidase techniques.

The tumor presents as a solid, well-defined, ovoid or lobulated mass in one of the paravertebral sulci (Fig. 196-10). Stippled calcification was observed by Bar-Ziv and Nogrady¹¹ in 50% of the patients studied. Rib erosion, when observed, is uncommon and subtle in nature. Extension into the spinal canal is uncommon but can occur, as noted by Bar-Ziv and Nogrady¹¹ and Davidson and associates.²⁸ Thus, computed tomographic (CT) or MRI scanning is always indicated (Fig. 196-11).

Surgical excision is the treatment of choice and is curative. Marchevsky and Kaneko⁷⁸ report that occasionally a regional lymph node may contain metastatic ganglioneuroma. Enzinger and Weiss³⁵ believe these to be residual foci of neuroblastomas that have matured into benign ganglioneuromas; subsequent recurrence of the disease is not seen in these patients.