Pediatric Solid Tumors

Epidemiology

Osteosarcoma, a malignant neoplasm derived from primitive mesenchymal cells and characterized by the presence of osteoid-producing spindle cell stroma, is the most common malignant bone tumor in the pediatric age group. Osteosarcoma ranks 10th among all newly reported pediatric cancers in the United States, accounting for close to 3% of all neoplasms in children and adolescents. The estimated annual incidence is 4.9 cases per 1 million population among white children and adolescents and 5.7 per 1 million population among African American children and adolescents. Most osteosarcomas occur during the first 2 decades of life, a period characterized by rapid skeletal growth. Boys are affected more commonly than girls. Several observations support the association between skeletal growth velocity and osteosarcoma. First, patients with osteosarcoma tend to be taller than their counterparts without this disease. Second, osteosarcoma develops at an earlier age in female patients than in male patients, perhaps because of differences in the timing of onset of puberty and the growth spurt.

Tumor Biology

Unlike osteosarcoma in adults, in whom more than 25% of tumors are associated with preexisting pathologic osseous conditions such as Paget disease or fibrous dysplasia, most pediatric osteosarcomas arise spontaneously in areas of bone without any abnormality. Irradiation is the best-characterized etiologic factor contributing to the development of secondary osteosarcoma. In a study involving 91 patients with second malignant bone sarcomas, osteosarcoma accounted for 72 cases, 52 (72%) of these tumors arising within previously irradiated fields. The median time for development of the secondary tumor was 9.6 years after irradiation. Osteosarcoma as a second malignancy is often associated with retinoblastoma; osteosarcoma is the most common malignancy in survivors of retinoblastoma, both in the irradiated and the nonirradiated areas, and it accounts for 25% to 40% of all second neoplasms in this population. One-half to two-thirds of osteosarcomas occur in the irradiated fields of the skull and face, one-third of tumors develop in the extremities, and fewer than 10% occur in the trunk. Osteosarcoma is also a very frequent malignancy in individuals with germline TP53 mutations (Li-Fraumeni syndrome)and in patients with REC helicase-associated disorders (Rothmund-Thomson, Werner, and Bloom syndromes).

Consistent with the association of osteosarcoma with retinoblastoma survivors and Li-Fraumeni syndromes, alterations in components of the cell-cycle control system appear to characterize the ontogeny of osteosarcoma. Studies using next-generation sequencing technologies show multiple somatic chromosomal lesions, including structural variations and copy number alterations. The single nucleotide variations exhibit a pattern of localized hypermutation (“kataegis”) in 50% of the tumors. Alterations in the p53 pathway are present in all tumors, and mutations in RB1 , ATRX , and DLG2 genes are noted in 29% to 53% of cases. The central role of those alterations in the pathogenesis of osteosarcoma is demonstrated in the animal models; genetically engineered mice based on osteoblast-restricted deletion of p53 and pRb develop short-latency high-grade osteosarcoma that reproduces many of the defining features of human osteosarcoma, including cytogenetic complexity and comparable gene expression signatures, histology, and metastatic behavior. Finally, pathway analysis and shRNA studies indicate that the PI3K/mammalian target of rapamycin (mTOR) pathway could represent a central vulnerability for therapeutic exploitation.

Pathology

Osteosarcoma is characterized by the presence of spindle cell stroma that produces osteoid. Conventional osteosarcoma can be subdivided histologically into three major groups depending on the predominant cell type. Approximately 50% of tumors are categorized as osteoblastic because the predominant extracellular element is osteoid, but 25% are chondroblastic , with a prominent cartilaginous component. Approximately 25% have a herringbone pattern similar to that observed in fibrosarcoma and are therefore called fibroblastic . No significant differences in overall outcome are apparent among these three histologic subtypes. In one report, however, patients with fibroblastic histology showed better histologic response and better overall outcome than were observed for patients with osteoblastic or chondroblastic histology.

Clinical Manifestations

Pain is the most common symptom in children and adolescents with osteosarcoma. Onset of pain often is insidious, and the pain usually involves the area affected by tumor. Severe pain of sudden onset commonly is associated with pathologic fracture. Swelling around the affected bone is the second most common clinical finding. The tumor may be easily palpable when located in areas such as the anterior surface of the femur but may manifest only as leg edema when occurring in difficult-to-appreciate areas such as the popliteal fossa. A painful limp that increases with weight bearing is the third most common symptom. Systemic signs and symptoms such as fever and weight loss are uncommon.

Osteosarcoma most commonly involves the long bones, most tumors occurring around the knee. The most frequent sites of involvement are the distal part of the femur, the proximal portion of the tibia, and the proximal part of the humerus. The axial skeleton, including the pelvis, is rarely affected in children (<10% of cases) but more frequently is involved in patients older than 60 years. Overt macroscopic metastatic disease occurs in 20% of cases and carries a grave prognosis.

Laboratory and Radiologic Evaluation

Laboratory evaluation often is unrevealing. Elevations of serum lactate dehydrogenase (LDH) and alkaline phosphatase levels are the most common laboratory abnormalities. The latter appears to correlate with osteoblastic activity and thus has proved useful in monitoring response to therapy.

Radiologic evaluation of a patient with osteosarcoma must include assessment of the primary site as well as a search for distant metastatic lesions. Plain radiography is the most effective method of detection of bone tumors. The main limitation of plain radiography is accurate delineation of local tumor extent. Characteristic radiologic findings in osteosarcoma commonly include a metaphyseal permeative lesion with periosteal new bone formation and destruction of preexisting cortical bone. A soft tissue mass is present in more than 90% of cases. Other radiologic signs commonly associated with osteosarcoma include cumulus cloudlike density and the presence of Codman triangle ( Fig. 92.1A ). A baseline chest radiograph should be obtained to search for distant metastatic lesions. Angiography usually is reserved for patients who receive intraarterial chemotherapy or for those who need optimal vessel visualization before limb salvage.

Computed tomography (CT) of the primary tumor is accurate in assessment of degree of tumor calcification and ossification, which are important in assessment of response to therapy. Chest CT always should be performed at the time of diagnosis for documentation of metastatic disease. Findings by magnetic resonance imaging (MRI) offer the best estimate of intramedullary tumor extension, joint and vascular involvement, detection of “skip” metastatic lesions, and delineation of the soft tissue component ( Fig. 92.1B ). The blood supply and vascularity of the tumor can be better appreciated with administration of gadopentetate dimeglumine, or gadolinium-diethylenetriamine pentaacetic acid (Gd-DTPA), a paramagnetic contrast material. MRI is helpful in assessing response to chemotherapy, as evidenced by changes in signal intensity on T ₂ -weighted images and alterations in the enhancement of tumor tissue after administration of Gd-DTPA ( Fig. 92.2 ). Dynamic contrast-enhanced MRI (DEMRI) is a valuable method for assessing microcirculation in osteosarcoma. DEMRI can be used to evaluate changes in regional contrast access during chemotherapy. The findings appear to correlate accurately with histologic response and outcome, allowing early identification of patients at risk for recurrence. Radionuclide bone scans with technetium-99m ( ^99m Tc)–labeled bone-seeking phosphate compounds are particularly useful in detection of metastatic bone lesions. Fluorodeoxyglucose–positron emission tomography (FDG-PET) is also a useful tool in diagnosis and response assessment.

Biopsy of the primary tumor should be done carefully, preferably by the surgeon who will ultimately perform the definitive operation. In performance of biopsy of a suspected bone tumor, the following basic principles should be observed: (1) avoidance of transverse incisions, which can make subsequent surgery difficult; (2) avoidance of contamination of multiple compartments and hematoma formation because successful limb-sparing procedures can be jeopardized; and (3) if feasible, biopsy of the soft tissue component only.

Osteosarcoma Subtypes

In addition to conventional osteosarcoma, a small proportion of patients are seen with clinical subtypes that are characterized by distinct clinical, radiologic, and histologic characteristics.

Prognostic Factors

The most important adverse prognostic factor in patients with osteosarcoma is the presence of metastatic disease. In addition, primary tumor location is associated with outcome. Children with primary tumors of the tibia and distal femur appear to have a more favorable prognosis than those with axial primary tumors. This finding highlights the importance of complete surgical resection in the management of this malignant disease. For patients with localized disease, factors associated with poor prognosis include measures of tumor burden, such as tumor size, and levels of alkaline phosphatase and LDH, as well as more biological measures, such as poor histologic response to preoperative chemotherapy, hyperdiploidy, and increased expression of P-glycoprotein or Ki-67. The percentage of tumor necrosis after preoperative chemotherapy is the most consistent and important factor associated with outcome in children and adolescents with localized osteosarcoma. A favorable response (>90% tumor necrosis) correlates with excellent overall survival (OS) rate. Patients who have less than 90% tumor necrosis are considered poor responders, for whom the prognosis usually is poor. Because of this strong correlation between degree of histologic response to preoperative chemotherapy and outcome, noninvasive methods such as DEMRI, used for monitoring tumor response, can be used to evaluate changes in regional contrast access during chemotherapy. Finally, a proportion of patients with extremity osteosarcoma are seen with a pathologic fracture, or a pathologic fracture develops after institution of therapy. This has been considered a poor prognostic factor and an indication for immediate amputation. It is possible, however, that with the use of preoperative chemotherapy and judicious use of limb-sparing techniques, a selected group of patients with pathologic fracture may still do well without amputation.

Treatment

Optimal management of osteosarcoma consists of multiple-agent chemotherapy and local control measures, including amputation or limb-sparing surgical procedures. Box 92.1 outlines the standard approach to management of osteosarcoma used at most institutions. Before the development of limb-sparing procedures, amputation was the standard surgical method used for curative treatment of osteosarcoma. Amputation now generally is reserved for primary tumors deemed unresectable. Limb function after below-the-knee amputation usually is excellent. Over the past several years, the role of limb-sparing procedures has increased dramatically. As a result of refinements in neoadjuvant chemotherapy, bioengineering, and imaging techniques, it is estimated that as many as 80% of patients with osteosarcoma will eventually be candidates for limb-sparing procedures. The criteria for limb-sparing procedures include (1) absence of major neurovascular involvement by tumor, (2) feasibility of wide surgical excision to include a normal muscle cuff in all directions and en bloc removal of all biopsy sites, (3) resection of the adjacent joint and capsule, (4) adequate motor reconstruction with regional muscle transfer, and (5) adequate soft tissue coverage. In the past, immature skeletal age and primary tumor of the humerus were relative contraindications; however, new expandable prosthetic devices may help overcome this problem. More recent improvements have been concentrated on achieving noninvasive extension of prostheses. One such method is the Phenix technology (Repiphysis). The basic principle involves storage of energy in a spring maintained in compressed form by a locking system. Prosthetic lengthening is performed through exposure to an external electromagnetic field that pilots the locking system and allows controlled release of the spring energy ( Fig. 92.3 ). Prosthetic expansion of several millimeters can be achieved with each procedure, and the total duration of the procedure is less than 30 seconds ( Fig. 92.4 ). Thus limb-sparing procedures are considered feasible in the care of most children and adolescents with osteosarcoma; when these procedures are appropriately performed, the risk of local recurrence is low (<5%). Long-term functional outcome, however, must be carefully compared with that obtained with amputation alone. Complications of limb-sparing surgery include infection, nonunion, fracture, and unstable joints.

Before the introduction of adjuvant chemotherapy, fatal metastatic disease developed in more than 80% of patients with osteosarcoma. Trials of single-agent chemotherapy began in the 1960s and early 1970s and established, in a nonrandomized manner, a role for the use of chemotherapy in the management of osteosarcoma. Responses with single-agent high-dose methotrexate or doxorubicin occurred in 20% to 40% of patients with metastatic disease. Since then, different combinations of platinum compounds, doxorubicin, and high-dose methotrexate have formed the basis of standard chemotherapy regimens that lead to cure in 50% to 75% of patients with nonmetastatic disease ( Table 92.1 ).

For more than 2 decades, therapy for nonmetastatic osteosarcoma has followed the basic guidelines of the T-10 protocol, and most of the current treatment strategies have evolved from lessons learned with it. The T-10 protocol and its variants consist of a multiple-agent regimen of high-dose methotrexate, doxorubicin, cisplatin, and a combination of bleomycin, cyclophosphamide, and dactinomycin. When the T-10 protocol guidelines are used, the 5-year actuarial event-free survival (EFS) rate may approach 70%. These results are not always reproducible, however, and multiinstitutional US and European studies conducted according to similar guidelines have shown lower EFS rates, usually 50% to 60%. The lack of reproducibility of the results of the original study may be attributed in part to the complexity of the treatment. In a study performed by the European Osteosarcoma Intergroup, patients were randomly assigned to receive the T-10 protocol or a much simpler treatment of 6 courses of a combination of cisplatin and doxorubicin. Only half of the patients in the T-10 protocol–like group completed all scheduled therapy, but 94% of the patients in the short-treatment group received the 6 courses of chemotherapy. The results for both treatment groups were identical, suggesting that a simple, two-drug regimen of cisplatin and doxorubicin can cure more than half of patients with nonmetastatic osteosarcoma.

A major contribution of the T-10 protocol and its predecessor T-7 is that the histologic response to neoadjuvant chemotherapy has been identified as the most important prognostic factor in the care of patients with nonmetastatic disease. Intensification of postoperative or preoperative chemotherapy with cisplatin, doxorubicin, and ifosfamide, however, has not improved outcome. To increase the proportion of good histologic responders, some researchers have investigated intraarterial administration of cisplatin. In the context of an aggressive, multiple-agent treatment, however, intraarterial infusion of cisplatin does not offer any significant advantages.

In recent years, ifosfamide has been incorporated into therapeutic regimens for osteosarcoma. After early reports showed that ifosfamide as a single agent achieved response rates of 10% to 60% in patients with advanced or treatment-refractory osteosarcoma, some investigators began to use the agent in salvage therapy regimens for poor responders. More recently, ifosfamide has been incorporated into frontline therapy in many regimens. However, whether incorporating the agent into standard treatment will improve the cure rate is unknown.

In the cooperative POG-Children's Cancer Group (CCG) Intergroup INT0133 trial, patients with localized osteosarcoma received treatment with a standard methotrexate–cisplatin–doxorubicin regimen and underwent a double randomization. The first randomization was to receive ifosfamide; the second randomization was to receive MTP (muramyl tripeptide), a derivative of the Bacillus Calmette-Guérin (BCG) cell wall that is known to stimulate the immune system, with the objective of decreasing pulmonary failures. Therefore four regimens were compared. The addition of ifosfamide or MTP alone to the standard regimen did not seem to provide any benefit. However, the addition of both ifosfamide and MTP-PE (muramyl tripeptide phosphatidylethanolamine) resulted in a significantly better EFS compared with the other three regimens. When the long-term outcome of the same cohort of patients was analyzed, patients who received MTP had improved OS (although not improved EFS) compared with those who did not. The significance of these findings is unclear.

The combination of ifosfamide and etoposide appears to be more effective than ifosfamide alone in patients with advanced or refractory osteosarcoma. In patients with refractory osteosarcoma, some of whom had previously received ifosfamide, the combination of ifosfamide and etoposide achieved response rates of 15% to 48%. Response rates of 59% have also been reported in patients with untreated metastatic osteosarcoma receiving this combination.

These results have led to the increasing use of this combination for the salvage of patients with poor histologic responses; however, evidence is lacking for improved outcome in this group of patients. The recently reported European-American Osteosarcoma (EURAMOS) trial for patients with localized osteosarcoma used a MAP (high-dose methotrexate, Adriamycin, cisplatin) backbone and randomized patients with good response (<10% viable tumor after 2 MAP cycles) to the addition of interferon alpha 2b, and patients with poor response (≥10% viable tumor) to the addition of ifosfamide and etoposide. Neither intervention resulted in improved outcomes over the standard MAP; the 3-year EFS estimates for good responders were 75% and 77% for MAP and MAP plus interferon alpha 2b, respectively, and the 3-year EFS estimates for poor responders were 55% and 53% for MAP and MAP plus ifosfamide and etoposide, respectively.

Methotrexate is the classical antifolate and blocks the action of dihydrofolate reductase. Methotrexate was among the first drugs reported to have an antitumor effect in osteosarcoma, and it has been a major component of the osteosarcoma treatment ever since. Furthermore, there is evidence that suggests that the pharmacokinetics of this agent may influence outcome, although this influence is minor in the context of more intensive multiagent protocols. However, the role of methotrexate appears to be limited to the administration of high doses (usually 12 g/m ² ) because the administration of lower doses appears to have a lesser therapeutic effect. The administration of high-dose methotrexate requires close monitoring of serum levels, which cannot be performed in many institutions, particularly those of developing countries, and extensive supportive measures, including hyperhydration, urine alkalinization, and leucovorin rescue, which must be adjusted to the methotrexate serum levels. The development of acute renal failure, mediated by the perception of methotrexate and its metabolites in the renal tubules, is a potentially life-threatening complication. Even among patients receiving all available monitoring and supportive care, the rate of severe nephrotoxicity is 2%, and the mortality rate is 4.4%. Dialysis methods have limited effectiveness in removing methotrexate compared with the rapid reductions in plasma concentrations that can be achieved with carboxypeptidase G2. Studies have shown the possibility of obtaining comparable outcomes without the use of methotrexate, provided intensification of platinum, ifosfamide, and doxorubicin is performed.

Cisplatin is one of the most active agents against osteosarcoma. The toxicity of this agent is substantial and includes hearing loss and renal impairment that can be permanent for some patients. Substitution of carboplatin for cisplatin was investigated at St. Jude Children's Research Hospital. In the context of a multiple-agent chemotherapeutic approach with high-dose methotrexate, ifosfamide, and doxorubicin, use of carboplatin resulted in a 3-year EFS rate of 72%, an outcome comparable with that obtained with cisplatin-based therapy but with less long-term toxicity. Incorporation of carboplatin in future osteosarcoma trials needs further evaluation, however, because in some reports, carboplatin as a single agent has been found to have poor antitumor effect in the treatment of metastatic disease.

Approximately 20% of patients with osteosarcoma have clinically detectable metastatic disease at diagnosis, and their outcome usually is very poor. Optimal treatment for these patients entails a very aggressive multimodality approach that combines intensive preoperative and postoperative chemotherapy with resection of both the primary tumor and metastatic lesions. When these guidelines are followed, contemporary protocols that incorporate ifosfamide or the combination of ifosfamide and etoposide, along with high-dose methotrexate, doxorubicin, and cisplatin, result in 2- to 5-year progression-free survival rates of 25% to 45%.

For patients with recurrent osteosarcoma, a very aggressive surgical approach is recommended; the 5-year postrelapse survival rate for patients in whom a complete resection of all macroscopic disease can be achieved is close to 40%. In a small number of patients (3% to 5%), metachronous osteosarcoma can develop after primary treatment. This condition has been associated with the presence of germline TP53 (Li-Fraumeni) or RB1 gene mutations. These second primaries usually develop within 3 years from initial diagnosis, and with systemic chemotherapy and surgery, 30% to 40% of these patients can be cured.

Lung metastasis develops in most patients in whom therapy fails. The ability to control pulmonary micrometastatic disease after completion of therapy would certainly result in a significant improvement in outcome. In an animal model, administration of liposome-encapsulated muramyl tripeptide phosphatidylethanolamine (L-MTP-PE) resulted in activation of pulmonary macrophages and eradication of pulmonary micrometastatic lesions. However, as indicated earlier, the clinical impact of the addition of this agent in the frontline of osteosarcoma therapy is not well defined. Other strategies under evaluation include administration of aerosolized granulocyte-macrophage colony-stimulating factor, although available data seem to indicate lack of effect of such approach.

Finally, administration of high doses of the bone-seeking radio-pharmaceutical samarium-153 ethylenediamine tetramethylene phosphonate ( ¹⁵³ Sm-EDTMP) may provide good pain palliation with minimal nonhematologic toxicity for patients with local recurrences or bone metastasis of osteosarcoma, and its role may be expanding.

Epidemiology

The term Ewing sarcoma family tumors (ESFTs) defines a group of small, round cell neoplasms of neuroectodermal origin that manifest as a continuum of neurogenic differentiation. On this continuum, Ewing sarcoma of bone represents the least differentiated (most primitive) form of neuroectodermal tumors, and peripheral neuroepithelioma represents the most differentiated form. Ewing sarcoma is the second most common malignant bone tumor in children and adolescents. The estimated incidence among white children and adolescents (0 to 19 years old) is 2.95 cases per 1 million population. The tumor is rare in the nonwhite population; its incidence is 3.44 per million white children and adolescents compared with 0.65 in African Americans, and it also shows a lower incidence in Hispanics compared with non-Hispanics (2.60 versus 3.03, respectively). Males are predominantly affected in most series; most cases are diagnosed during the second decade of life. The location of the tumor varies. Although most Ewing sarcomas arise in bone, a significant proportion arise in soft tissue. The most common locations for this tumor are the chest wall, pelvis, and extremities, but any bone can be involved.

Tumor Biology

The histogenesis of Ewing sarcoma has been a source of controversy since the first description of the tumor in 1921. Various hypotheses have been proposed in an attempt to identify the possible cell of origin in Ewing sarcoma. Among these, cells of endothelial, pericytic, myeloid, mesenchymal, and neuroectodermal origin have been suggested. The existence of either a mesenchymal stem cell or an early primitive neuroectodermal cell that has retained its ability for multilineage differentiation is the currently accepted hypothesis. It is now well accepted that ESFTs constitute a single group of neurally derived neoplasms that share unique immunocytochemical, cytogenetic, and molecular markers.

Nearly all ESFTs have a reciprocal translocation that involves the EWS gene in chromosome 22q12. The t(11;22) is the most commonly observed translocation (85% to 95% of cases) and juxtaposes the DNA-binding domain of the human homologue of the murine Fli1 gene in chromosome 11 with the 5′ end of EWS in chromosome 22 ( Fig. 92.5 ). The most common fusions occur between exon 7 of EWS and exon 6 of FLI1 (type 1; 55% to 60% of cases) and between exon 7 of EWS and exon 5 of FLI1 (type 2; 25% of cases). The t(11;22) appears to play a pivotal role in development of ESFTs because the EWS-FLI1 fusion transcript can transform NIH 3T3 cells. As many as 10% of ESFTs contain an alternative translocation between chromosomes 21 and 22. This translocation fuses the ERG gene on chromosome 21 and the EWS gene on chromosome 22, producing an ERG-EWS fusion transcript. Finally, rare cases of ESFT contain a t(7;22)(p22;q12) that fuses the ETV1 and EWS genes. The mechanism by which these fusion transcripts become tumorigenic is poorly understood, although it has been postulated that this chimeric transcript can transcriptionally deregulate members of the manic fringe family of genes, which are instrumental in somatic development. The IGF1/IGF1R pathway is actively involved in the cell transformation and inhibition of apoptosis induced by EWS-FLI1 . Next-generation sequencing studies have reported a more comprehensive description of the genomic landscape of these tumors. In these studies, ESFT has demonstrated to have low number of single-nucleotide and structural variants. However, chromosome 1q gain and chromosome 16q loss appear to be associated with worse prognosis, and single nucleotide variants and structural variants correlate with age at diagnosis and survival. The most frequent coding variants occur in STAG2 , TP53 , and in epigenetic regulators, and coexistence of STAG2 and TP53 mutations is associated with highly aggressive tumors.

Pathology

Microscopic examination shows that Ewing sarcoma is the prototypical small, round, blue cell tumor of childhood. Ewing sarcoma is characterized by the presence of a dimorphic pattern of densely packed cells with variable amounts of large clear cytoplasm. Individual cells have an ellipsoid nucleus without distinct cytoplasmic outlines. The cells are primitive, show a paucity of organelles, and often contain large amounts of intracellular glycogen. Various microscopic patterns, including the diffuse, lobular, organoid, and filigree patterns, have been described. Immunocytochemical analysis shows vimentin and CD99 reactivity. The latter monoclonal antibody specifically recognizes the cell surface antigen ^p30/p32 MIC-2, which normally is expressed as a component of the T-cell receptor complex. When overt neural differentiation is present, the term peripheral neuroectodermal tumor or peripheral neuroepithelioma is used. In such cases, the cells are round with more abundant cytoplasm but do not show mature neural elements, such as nerve bundles and mats of neuropile. The term extraosseous Ewing sarcoma has been reserved for neoplasms that cannot be differentiated from Ewing sarcoma at light microscopic examination but arise exclusively in soft tissue. Patients with this histologic variety accounted for 5% of all subjects in the Intergroup Rhabdomyosarcoma Study, although extraosseous tumors are now managed in the same manner as for classic Ewing sarcoma of bone. Despite these histologic distinctions, Ewing sarcoma of bone, extraosseous Ewing sarcoma, primitive neuroectodermal tumors, and peripheral neuroepithelioma are unified by the presence of the same oncogenic events and should therefore be considered the same neoplasm and managed in a similar manner. The advent of molecular diagnostic techniques has allowed development of sensitive tests, such as reverse transcriptase-polymerase chain reaction (RT-PCR) analysis, which is accurate in detection of EWS-FLI1 and EWS-ERG fusion transcripts at levels well below those commonly found with routine cytogenetic studies. RT-PCR assay is a useful adjunct in the diagnosis of Ewing sarcoma, particularly in differentiation from other soft tissue small, round cell tumors, such as rhabdomyosarcoma.

Clinical Manifestations

Ewing sarcoma commonly manifests during the second decade of life (median age, 13 years) with localized pain and a visible palpable mass. Fewer than 3% of cases occur in children younger than age 3 years. Boys are more commonly affected than girls. Pathologic fractures may be present in as many as 15% of children and adolescents before diagnosis. Back pain, extremity weakness, or altered sensation should raise suspicion for the presence of primary or metastatic disease. Systemic manifestations such as fever are more frequent than in osteosarcoma. Almost half of patients have signs and symptoms referable to the primary tumor for more than 3 months before the diagnosis is made. Ewing sarcoma has a tendency to involve the shaft of long tubular bones, pelvis, and ribs, but almost every bone can be affected. More than 50% of the tumors arise from axial bones, the pelvis being the most commonly involved (25%); one-third of the tumors originate in the lower extremities and fewer than 10% in the upper extremities. Chest wall Ewing sarcoma is known as Askin tumor ( Fig. 92.6 ). Approximately 20% to 25% of patients with this tumor have metastatic disease when they are seen for evaluation. The most common sites of metastatic disease are in the lungs followed by the bones and bone marrow. Metastatic disease appears to be associated with older age and with large tumor or pelvic primaries.

Laboratory and Radiologic Evaluation

Patients with suspected Ewing sarcoma should be thoroughly evaluated to define the extent of local disease and the presence of metastatic lesions. Initial laboratory studies include complete blood cell count and erythrocyte sedimentation rate; measurement of serum electrolytes; LDH assay; renal and liver function tests; determination of alkaline phosphatase, calcium, phosphorus, and magnesium levels; and coagulation profile. In Ewing sarcoma, elevation of erythrocyte sedimentation rate and of serum LDH is not uncommon. Bone marrow aspiration and biopsy should be performed, and evaluation with molecular techniques such as RT-PCR is recommended. Important imaging studies are chest radiography, plain radiography of primary and metastatic sites, bone scintigraphy, CT of the chest, and MRI of the primary site with T ₁ - and T ₂ -weighted sequences, as well as DEMRI.

In Ewing sarcoma, plain radiographs typically show a diaphyseal destructive lesion with a laminated periosteal reaction and large soft tissue mass ( Fig. 92.7A ). St. Jude Children's Research Hospital favors MRI over CT for defining the intramedullary component of the primary tumor and the extent of soft tissue mass ( Fig. 92.7B ). In contrast with the situation in osteosarcoma, DEMRI findings are not a reliable prognostic indicator. Newer techniques such as positron emission tomography (PET) appear to be useful in noninvasive evaluation of response to chemotherapy.

Prognostic Factors

A variety of initial clinical features have been correlated with outcome of therapy for Ewing sarcoma. Several groups have analyzed factors that are prognostically important in Ewing sarcoma. The results confirmed the classic clinical features associated with poor prognosis, such as metastatic disease, older age, large tumor size, and trunk and pelvic primary sites. However, with refinement in the multidisciplinary approach to this disease that entails newer and more intensive chemotherapeutic regimens and superior local control measures, some of these classic prognostic factors are being redefined.

Although large tumor size classically has been associated with worse prognosis, this feature may be less important with more aggressive treatment. For example, in the first Cooperative Ewing Sarcoma Study (CESS-81), tumors larger than 100 cm ³ were associated with worse outcome. With treatment improvements, the tumor size associated with worse prognosis has increased to 200 cm.

Tumor location also seems to be losing its prognostic significance with newer treatments, although pelvic and axial tumor locations classically were associated with worse outcome in the early studies. differences in outcome were minimal in subsequent studies. The first POG–CCG Ewing sarcoma trial (POG-8850/CCG-7881), an investigation of the effect of addition of ifosfamide and etoposide to the standard VACD regimen (vincristine, actinomycin D, cyclophosphamide, and doxorubicin), showed that addition of the drug pair abrogated the negative prognostic implications of large tumor size (>8 cm in diameter) and pelvic location. Of note, the benefit of addition of ifosfamide and etoposide was not seen in patients older than 18 years.

A newer prognostic factor is degree of histologic response to chemotherapy. European studies consistently have shown the prognostic value of histologic response, the significance of which stands across protocols and appears to be independent of the drugs used. Patients with good histologic responses had a significantly better outcome than those with poor responses in the consecutive REN-1, -2, and -3 trials in Italy and in the CESS-81 and CESS-86 trials in Germany. Because ESFTs manifest a continuum of neuroectodermal differentiation, the histologic diversity may reflect different biological behaviors. Evidence is lacking, however, for correlation of degree of neuroectodermal differentiation with prognosis. The most important prognostic factor remains the presence of metastatic disease at diagnosis. Advances in management of ESFTs have resulted in only very modest improvement in outcome among patients with metastatic lesions. Even among patients with metastatic disease, heterogeneity is common. With an appropriately intensive treatment that includes bilateral lung irradiation, the European Intergroup Cooperative Ewing Sarcoma Studies (EICESSs) have shown that patients with isolated metastatic lesions in the lung may have a better prognosis, albeit still inferior to that for patients with localized disease. Patients with extrapulmonary metastasis have a worse prognosis.

With the use of molecular techniques in the staging of ESFTs, it is evident that a significant proportion of patients with localized disease (20% to 30%) have micrometastatic disease in the bone marrow detected by polymerase chain reaction (PCR) assay. In patients with lung metastasis and those with bone metastasis, this proportion is 40% and 90%, respectively. Although clinical stage remains the most powerful prognostic indicator in patients with ESFT, detection of minimal disease in the bone marrow by RT-PCR has been associated with metastatic disease and appears to connote a more adverse clinical outcome in a subset of patients with apparently localized disease. The utility of detecting circulating neoplastic cells by RT-PCR in patients with ESFT is less clear.

Treatment

Before the introduction of systemic chemotherapy, fewer than 20% of children with Ewing sarcoma treated with either surgery or radiation therapy alone were expected to be long-term survivors. In the past 3 decades, major advances have been made in the management of Ewing sarcoma. These advances derive largely from cooperative trials ( Table 92.2 ). The first studies conducted by the Intergroup Ewing Sarcoma Study (IESS) showed the importance of adjuvant chemotherapy that included a combination of alkylating agents and anthracyclines (IESS-I and IESS-II). Thereafter, conventional management of Ewing sarcoma included local control measures in combination with administration of VACD. More recently, incorporation of ifosfamide (VAID [vincristine, actinomycin D, ifosfamide, doxorubicin]) has resulted in modest benefit for patients with high-risk features. Combined administration of ifosfamide and etoposide (IE) has been shown to be very active in patients with Ewing sarcoma who have not received previous treatment. Two randomized studies were conducted to investigate the effect of adding etoposide to VACD or VAID regimens. In EICESS-92, patients with localized high-risk disease (tumor diameter >200 cm ³ ) receiving VAID did not seem to benefit from the addition of etoposide. The first POG–CCG Ewing sarcoma trial (POG-8850/CCG-7881) was an investigation of incorporation of the IE combination in frontline management of ESFTs. Patients were randomly assigned to receive VACD with or without IE; patients receiving IE plus VACD appeared to have a more favorable outcome.

Incorporation of granulocyte colony-stimulating factor (G-CSF) into treatment regimens for many types of cancer has allowed modest dose intensification of multiple-agent chemotherapy by either increasing the total dose per cycle or shortening the time between treatments. For ESFTs, this strategy is based on use of high cumulative doses of alkylating agents and topoisomerase-II inhibitors. When these general treatment guidelines are followed, the disease-free survival rate for patients with localized, low-risk disease approaches 70% to 75%, and the OS rate for this group of patients may be greater than 80%.

The importance of dose intensification in the management of ESFT was evaluated in the second POG–CCG Ewing sarcoma trial (POG-9354/CCG-7942). In that trial, patients were randomly assigned to receive alternating courses of vincristine, doxorubicin, and cyclophosphamide with IE over either 48 or 30 weeks. The early results of that randomized trial demonstrated no difference in outcome between the standard and the dose-intensified treatment groups. An alternative to increasing dose intensity is decreasing the intervals between cycles while maintaining the same dose per cycle with the use of granulocyte colony-stimulating factor. In the United States, this is the approach taken by the Children's Oncology Group (COG) in the recently completed AEWS-0031 study, in which patients were randomly assigned to receive alternating cycles of VCD (vincristine, cyclophosphamide, doxorubicin) and IE every 3 weeks or 2 weeks, which results in 33% dose intensification. The administration of chemotherapy every 2 weeks resulted in a significantly better event free survival (73% versus 65%). This dose-compressed approach is currently considered the standard of care in the United States. Although it cannot be delivered without the use of G-CSF, it is otherwise feasible and does not result in more toxicity than the 3-week regimen.

Despite improvement, the prognosis for patients with metastatic disease continues to be very poor, and only 20% to 25% survive. Several institutions have used treatment intensification, by which very high doses of different agents are administered in a short time. In the case of ESFTs, this is a very attractive alternative because ESFTs are highly sensitive to alkylating agents, which have a steep dose–response curve. Although most patients with ESFTs treated in this manner may exhibit good clinical and histologic responses, the final results are not better than those obtained with conventional therapy.

Use of protocols that include intensification of alkylators and topoisomerase II inhibitors has resulted in a significant increase in the incidence of treatment-related leukemia—specifically, acute myelogenous leukemia (AML)—and myelodysplastic syndrome (t-AML/MDS) ( Box 92.2 ). This therapeutic strategy appears to be strongly leukemogenic, and patients are at increased risk for both alkylator-related and etoposide-related t-AML/MDS. This increased risk of t-AML/MDS appears to be related to both the increase in the total cumulative doses and dose intensification. The role of hematopoietic growth factors in this complication is unknown.

New drugs and new drug combinations continue to be investigated in the care of patients with Ewing sarcoma. Although phases I and II studies of topotecan and irinotecan as single agents have shown little or no activity in patients with refractory disease, recent studies suggest that their combination with alkylating agents may be more promising. Phase II studies of the combination of topotecan (0.75 mg/m ² per day for 5 days) and cyclophosphamide (250 mg/m ² per day for 5 days) resulted in responses in 36% of patients with recurrent disease and in 56% of patients with untreated metastatic disease. After demonstrating the feasibility of the incorporation of this combination in the frontline treatment of ESFTs, given in alternating cycles with VCD and IE, the COG is currently exploring the impact of this addition in a randomized manner. Also recently, the combination of irinotecan on a protracted schedule (10–20 mg/m ² per day for 5 days in 2 consecutive weeks) with temozolomide (100 mg/m ² per day for 5 days) has shown excellent response rates.

The use of monoclonal antibodies against IGF-1R has been explored in three phase I/II studies; in this population of patients with refractory disease, responses were seen in 10% to 20% of the patients. The COG is currently exploring the impact of the use of a monoclonal antibody against IGF-1R in combination with chemotherapy in the frontline management of patients with metastatic disease in a randomized trial.

Advances in management of ESFTs have resulted in only modest improvement in outcome among patients with metastatic disease. With appropriately intensive treatment that includes bilateral lung irradiation, however, the prognosis for patients with isolated lung metastasis may be better than for patients with extrapulmonary metastasis. For patients with bone and bone marrow metastasis therefore more intense therapies may have a role. ESFTs are very sensitive to alkylators, a group of agents with a very steep dose–response curve, which provides the basis for the use of consolidation with myeloablative therapy and autologous hematopoietic stem cell transplantation (HSCT). The results of treatment with megatherapy and HSCT for patients with high-risk ESFTs must be analyzed with caution because of the lack of randomized studies and the heterogeneity of patients and treatments. Results of most retrospective European and American studies do not seem to support the use of this approach, although there could be a role for consolidation with high-dose chemotherapy and autologous HSCT in patients with relapsed disease that show response to salvage chemotherapy. The European Euro-EWING 99 trial explored the use of consolidation with high-dose busulfan-melphalan for patients with primary disseminated ESFT; the event-free and OS rates at 3 years were 27% and 34%, respectively, suggesting that patients with primary disseminated ESFT may survive using this approach.

Improvement in outcome among patients with ESFT also must be attributed to improvement in local control, which is largely related to advances in radiation therapy and better surgical approaches. Advances in systemic therapy by means of incorporation of new drugs and treatment intensification also appear to contribute to better local control. With current multimodality intensive protocols, rates of local recurrence have decreased significantly, and little difference in efficacy has been observed between surgery and radiation therapy for local control. Surgery continues to offer slightly better results, but this observation is biased by the fact that small lesions are more likely to be managed surgically. For unresectable tumors or in case of gross residual disease, recommended doses are 55 to 60 Gy. Doses of 40 to 45 Gy are used for microscopic disease. The risk of secondary sarcoma after radiation therapy is not negligible. This risk is dose dependent, but use of lower doses of radiation therapy has been associated with higher local recurrence rates.

Epidemiology

Neuroblastoma is the most common extracranial solid tumor of childhood, accounting for 8% to 10% of all pediatric cancers. The incidence of neuroblastoma varies in different regions of the world, with a greater prevalence in developed countries. In the United States, the annual incidence is approximately 8.2 new cases per 1 million children per year with 650 newly diagnosed cases. The median age at diagnosis is approximately 18 months. It is the most common cancer of infancy. Most (85%) of the cases are diagnosed by the age of 5 years; it is extremely rare in children older than 10 years. Familial cases occur, and a small number are inherited in an autosomal dominant manner (5%). Studies have linked germline mutations in the anaplastic lymphoma kinase (ALK) gene or in the PHOX2B gene to familial neuroblastoma. Genome-wide association studies suggest a number of germline genetic variants that may predispose to sporadic neuroblastomas. Neuroblastoma also has been found in patients with neurofibromatosis, Hirschsprung disease, Beckwith-Wiedemann syndrome, fetal hydantoin syndrome, and central hypoventilation syndrome. Microscopic neuroblast nodules are found in the adrenal glands of 2% to 3% of infants who die of nonmalignant causes before 3 months of age. It is uncertain whether these nodules represent spontaneous regression of congenital neuroblastoma or maturation of the tumor into asymptomatic benign tumors. Use of prenatal ultrasonography can coincidentally detect in utero cases as early as 31 weeks' gestation.

Mass screening programs for detection of neuroblastoma in early infancy with assays for urinary catecholamine metabolites have been conducted in Japan, Germany, and the United States. In general, patients with neuroblastoma detected in these programs have early stage disease and enjoy an otherwise excellent outcome. Mass screening, however, has not resulted in a reduction in deaths from neuroblastoma. In addition, early detection has not changed outcome among patients with tumors that have biological features associated with a poor prognosis.

Ethnic disparities have been identified with African American and Native American patients frequently presenting with high-risk features and poor outcomes.

Tumor Biology

Neuroblastoma originates in neural crest cells of the sympathetic nervous system and, not unexpectedly, secretes a variety of neurogenically derived substances, including catecholamines, neuron-specific enolase (NSE), and ferritin. Urinary excretion of abnormally high levels of catecholamine metabolites occurs in 75% to 90% of patients and is related to the degree of tumor differentiation. The metabolites most often measured in evaluation of suspected neuroblastoma are urinary vanillylmandelic acid and homovanillic acid. Levels of these catecholamines are sensitive indicators of disease status. At diagnosis, other biological markers, such as NSE, serum ferritin, and ganglioside G _D2 , are present in high concentration in the serum of most patients with neuroblastoma. None of these biological markers is specific, but their presence at diagnosis may be associated with the extent of disease.

Cytogenetic studies of neuroblastoma have demonstrated segmental chromosomal abnormalities in most cases. The most common cytogenetic abnormalities in neuroblastoma are double-minute chromatin bodies (DMs), homogeneously staining regions (HSRs), and nonrandom deletion or loss of heterozygosity (LOH) of the short arm of chromosome 1p36 and 11q. DMs and HSRs both represent cytogenetic manifestations of amplified sequences of the MYCN cellular oncogene. Amplified MYCN (>10 copies per cell) is a feature in approximately 40% of neuroblastomas. It is associated with the presence of advanced disease at diagnosis and poor outcome, even in patients who have early stage disease or who come to medical attention in infancy. The DNA content of the tumor (ploidy) has been shown to correlate with therapeutic outcome and survival among infants with this tumor. Infants with hyperdiploid tumors (DNA index >1.0) have a more favorable outcome than those with diploid tumors (DNA index, 1.0). Results suggest that the presence of either MYCN amplification or diploid cellular DNA tumor content identifies whether an infant has a poor prognosis with current therapeutic regimens, independent of stage. For children older than 24 months with disseminated disease, however, the DNA content of the tumor does not appear to have prognostic importance. Recent studies suggest that additional cytogenetic imprints, such as LOH at 1p36 and 11q23, confer an aggressive phenotype. Activating mutations in the tyrosine kinase domain of the anaplastic lymphoma kinase (i) oncogene have recently been noted to account for most cases of hereditary neuroblastoma and may be somatically acquired in 5% to 10% of neuroblastoma.

Pathology

Neuroblastoma is one of the small, round, blue cell tumors of childhood. It originates from neural crest cells from within the sympathetic nervous system. In 1999, the International Neuroblastoma Pathology Classification (INPC) was established to standardize the terminology and criteria for the prognostic evaluation of the morphologic features of neuroblastic tumors in an age-linked framework. The INPC categorizes neuroblastic tumors into favorable and unfavorable histology based on the degree of neuroblastic differentiation, Schwannian stroma content, mitosis-karyorrhexis index, and age at diagnosis. The INPC distinguishes four histologic categories: neuroblastoma (Schwannian stroma poor), ganglioneuroblastoma intermixed (Schwannian stroma rich), ganglioneuroma (Schwannian stroma-dominant), and ganglioneuroblastoma nodular (composite Schwannian stroma-rich/stroma dominant and stroma poor) ( Fig. 92.8 ).

These subgroups appear to recapitulate stages in the normal differentiation of neural crest stem cells. For example, neuroblastoma is the most primitive entity and is characterized by diffuse growth of undifferentiated neuroblastic cell nests irregularly separated by thin fibrovascular septa (see Fig. 92.8A ). By contrast, benign ganglioneuroma consists of mature ganglion cells embedded in bulky stroma composed of Schwann cell sheets enveloping neuritic processes and perineural and endoneural elements (see Fig. 92.8C ). Between these two extremes is the transitional form known as ganglioneuroblastoma (see Fig. 92.8B ). These transitional forms have been subclassified into intermixed and nodular diffuse ganglioneuroblastoma. Composite (nodular) tumor is a ganglioneuroma that contains one or more discrete nodules of pure neuroblastoma. Intermixed (diffuse) tumor contains a mixture of primitive and differentiating neuroblasts with bizarre, immature, and mature ganglion cells. Patients frequently have tumors with mixtures of these cell types, and evidence supports the clinical observation that neuroblastoma can sometimes mature into benign ganglioneuroma. Spontaneous regression and therapy-induced maturation can occur.

Clinical Manifestations

The clinical manifestations of neuroblastoma are varied. Nonspecific constitutional signs and symptoms, such as fever, general malaise, and pain, are frequent initial features. The most common sites of primary tumors are the abdomen (adrenal gland or paraspinal ganglia) and the thorax (usually the posterior mediastinum). In infants, the distribution is slightly different in that a higher proportion of primary tumors occur in the thoracic cavity than is the case in older children. Common manifestations include a hard, painless mass in the neck; a localized intrathoracic mass found incidentally on a chest radiograph; and a palpable abdominal mass, according to the location of the tumor. A palpable abdominal mass can result from an enlarging primary adrenal or retroperitoneal tumor or from hepatomegaly secondary to tumor metastasis. Children may appear chronically ill and irritable and have periorbital ecchymosis, scalp nodules, and bone pain from widespread metastasis to the bone marrow or bone ( Fig. 92.9 ; see also Fig. 92.8D ). Lower-limb paresis secondary to epidural extension of a primary paraspinal tumor growing through the intervertebral foramen can cause signs of spinal cord compression. Intermittent abdominal pain, malaise, failure to gain weight, and recurrent, unexplained fever may be present for prolonged periods before neuroblastoma is diagnosed.

Seventy-five percent of patients with neuroblastoma have metastatic disease at the time of diagnosis. The most common sites of metastasis are lymph nodes (local or distant), bone marrow, liver, skin, orbit, and bone (facial bones, skull, appendicular skeleton). Nearly half of patients have widespread skeletal metastasis at diagnosis. The bones of the skull and orbit frequently are affected, so proptosis, ecchymosis, and masses beneath the scalp are frequent findings (see Fig. 92.9A ). Lung metastatic lesions are extremely uncommon when the patient is first diagnosed but can be seen after autologous HSCT. Horner syndrome (ipsilateral miosis, ptosis, and anhidrosis) may be present in patients with lesions originating in the cervical or upper thoracic sympathetic ganglia. Less frequent is the syndrome of opsomyoclonus and ataxia, manifested as acute cerebellar encephalopathy, truncal ataxia, and rapid and random conjugate eye movements (so-called dancing eyes , dancing feet ). The pathophysiological mechanism of this syndrome is unknown, but metabolic and immunologic causes have been invoked. A syndrome of chronic watery diarrhea also may occur in patients with neuroblastoma. Increased serum levels of vasoactive intestinal peptide, which lead to increased intestinal motility and secretions, have been found in some cases.

Laboratory and Radiologic Evaluation

When neuroblastoma is suspected, evaluation should be performed to establish the diagnosis, determine the extent of disease, and obtain tumor material for molecular and genetic analyses. The physical examination should include special attention to look for blood pressure abnormalities, asymmetrical pupil size, facial sweating, lower limb weakness and other signs of spinal cord compression, and evidence of increased intracranial pressure. In addition, during the clinical examination, the size of palpable masses, enlarged lymph nodes, cutaneous lesions, and the liver should be carefully documented.

Laboratory studies include complete blood cell count, renal and liver function studies, coagulation screen, urinalysis, and measurement of urine catecholamines. Serum often is obtained for LDH, NSE, ferritin, and ganglioside G _D2 determinations because the results may be helpful in prognosis.

Staging of neuroblastoma requires radiologic studies and marrow aspiration and biopsy to determine the extent of local disease and distant spread. The minimal evaluation for metastatic disease includes radionuclide skeletal scintigraphy and bone marrow aspiration. CT generally has replaced intravenous pyelography, arteriography, and inferior vena cavography ( Fig. 92.10 ). Ultrasonographic studies of the abdomen and pelvis may be useful in evaluation of mass lesions and the degree of compression of vital structures causing secondary complications. MRI may further improve the accuracy of determination of the anatomic extent of disease, especially in evaluation of tumors impinging on the spinal cord and assessment for the presence of hepatic metastasis. CT- or MRI-based myelography is necessary in evaluation of all patients with neurologic evidence of cord involvement. Neuroblastoma is a tumor derived from the sympathetic nervous system, thus neuroblastoma cells typically express the norepinephrine transporter which mediates active intracellular uptake of radiolabeled m -iodobenzylguanidine (MIBG) in approximately 90% of patients. Scans performed with radionuclides such MIBG may be more accurate and sensitive for detection of nonosseous as well as osseous disease. Newer modalities such as FDG-PET combined with CT scanning may provide additional value in the management and diagnosis of MIBG-negative neuroblastoma, and in visualization of hepatic metastases and soft tissue lesions not readily visualized with MIBG scan (see Fig. 92.9B and C ). When tumor material is obtained, it should be submitted for determination of DNA content (tumor cell ploidy), detection of MYCN genomic amplification, and cytogenetic analysis and should be preserved for additional genomics evaluation.

The differential diagnosis suggested by the early manifestations of the tumor is broad because the initial signs and symptoms can be so vague. The presence of an abdominal mass may suggest Wilms tumor, hydronephrotic kidney, enlarged spleen or liver, lymphoma, germ cell tumor, and mesenteric cyst. Compression of vital structures in the neck and mediastinum can cause superior vena cava syndrome indistinguishable from that caused by other tumors. Persistent diarrhea suggests the presence of a malabsorptive state. Arterial hypertension may be attributed to intrinsic renal disease or pheochromocytoma. Bone pain can simulate rheumatic fever, rheumatoid arthritis, osteomyelitis, and acute leukemia. When initial signs are attributable to widespread lymphatic metastasis, a broad range of possibilities in the differential diagnosis, including primary tumor of the lymphoreticular system, storage disease, acute infection, and primary hematologic disorder, must be considered.

The diagnosis of neuroblastoma is established by pathologic evaluation of tumor tissue obtained at biopsy or by documentation of bone marrow involvement at bone marrow trephine biopsy or aspiration with the presence of characteristic clumps or syncytia of tumor cells, together with increased urine or serum levels of catecholamines or metabolites. If the histologic diagnosis is equivocal, genetic features characteristic of neuroblastoma, such as deletion of 1p or MYCN genomic amplification, support the diagnosis.

Several staging systems have been used to classify disease extent. The Evans and POG staging systems historically were the most widely used in the United States before 1999. To facilitate comparison of clinical studies, the International Neuroblastoma Staging System (INSS), which is based on clinical and surgical evaluations, was developed by consensus of major pediatric oncology groups in the United States, Europe, and Japan. The INSS differentiates among INSS stages 1, 2A, 2B, 3, 4, and 4S based on surgical excision, lymph node involvement, and metastatic sites ( Table 92.3 ). Because the INSS is a surgically based staging system, the stage for patients with locoregional disease can vary based on degree of surgical resection. It is noteworthy that patients with localized disease who will not undergo surgery cannot be adequately staged. For these reasons, the International Neuroblastoma Risk Group (INRG) Task Force developed a new pretreatment staging system in 2005 based on clinical criteria and specific image-defined risk factors. Required imaging modalities include either CT or MRI, as well as MIBG scintigraphy. The International Neuroblastoma Risk Group Staging System (INRGSS) differentiates among L1, L2, M, and MS stage. The INRGSS differs from the INSS in that the INRGSS is based on preoperative imaging characteristics and not on surgical resection. The age for the INRGSS MS stage is set at 547 days (18 months) compared with 12 months in the INSS 4S stage. Table 92.4 compares INSS and INRGSS. The INRGSS not only allows preoperative staging but also permits reassessment during treatment.