Chapter 67 Pediatric Sarcomas of Bone
Etiology and Epidemiology
The incidence of Ewing’s sarcoma is approximately 2.8 cases per million in children younger than 15 years of age.1 Generally, the disease occurs in the teenage years during the adolescent growth spurt.2 The age of onset is variable, however; approximately 30% of cases occur in the first decade of life and 10% occur in the third decade. More males than females are affected. There is a predilection for whites, in whom the disease is more frequent than Asians. It rarely occurs in black children.
The cause of Ewing’s sarcoma is unknown, and it does not appear to be induced by any known agents.
Osteosarcoma also is primarily a disease of adolescents and young adults; a different type of osteosarcoma linked to Paget’s disease occurs in older adults. This section focuses on osteosarcoma in the younger age-group. There is limited understanding of the etiology of osteosarcoma. The peak incidence coincides with a period of rapid bone growth, suggesting that a correlation exists between this phenomenon and the evolution of osteosarcoma. Furthermore, osteosarcoma is known to be induced by radiation therapy, particularly in children with retinoblastoma or other genetic abnormalities.3
Biologic Characteristics and Molecular Biology
The histogenesis of Ewing’s sarcoma has been controversial. The tumor was first described as an endothelioma of bone. It is now thought to be of neural origin, specifically from postganglionic, parasympathetic, primordial cells.4,5 Previously, extraosseous Ewing’s sarcoma and malignant peripheral neuroectodermal tumor (PNET) were considered separate entities from Ewing’s sarcoma of bone and were treated differently; they are now believed to be from the same family of tumors, however.5 This is confirmed by their similar characteristics. Both exhibit identical chromosomal translocations, t11:22 (q24;q12), and more than 85% of patients share a common surface antigen, MIC2.6–8 Ewing’s sarcoma, atypical Ewing’s sarcoma, and PNET of bone exist in the spectrum within this family, from the most undifferentiated tumors to those with neural differentiation. PNET can be differentiated from Ewing’s sarcoma by the presence of a globular growth pattern, neuron-specific enolase (NSE) positivity, and Homer Wright rosettes.
Osteosarcoma is associated with inactivation of the retinoblastoma tumor suppressor gene (13q14), which occurs in approximately one-third of cases.9 Other genetic abnormalities include translocations, gene amplification, and abnormal TP53 function.10,11
Pathology and Pathway of Spread
Ewing’s sarcoma is an undifferentiated blue round cell tumor usually of the bone. Its pathologic appearance is a monomorphic pattern of densely packed, small, round, malignant cells with hyperchromatic nuclei and varying amounts of cytoplasm.12 Immunohistochemical studies reveal cell-surface glycoprotein p30/32 MIC2 (CD 99) and vimentin, HBA-71, and β2-microglobulin positivity. Occasionally, cytokeratin and neuron-specific enolase (NSE) are positive. These studies can help differentiate Ewing’s sarcoma from other small round cell malignant tumors of childhood. Approximately 87% of cases within the family of Ewing’s tumor are Ewing’s sarcoma of bone.13 The remainder are peripheral primitive neuroectodermal tumors (PNETs) or extraosseous Ewing’s sarcoma.
About 75 % percent of patients with Ewing’s sarcoma present with localized disease at diagnosis (Fig. 67-1). Approximately 80% of children experience distant metastases if treated with only local therapy, however. This suggests that in the majority of cases, there are unidentifiable micrometastases present at diagnosis. The most common site of metastasis is the lung, followed by bone. Other distant sites include bone marrow, soft tissues, and, rarely, the liver or central nervous system (see Fig. 67-1).
Osteosarcoma is derived from bone-forming mesenchyme, and is described as a malignant sarcomatous stroma associated with the production of osteoid bone, its defining histopathologic feature.12 The most common types in the pediatric population are the conventional osteosarcomas, including osteoblastic, chondroblastic, and fibroblastic types. Each type has varying amounts of osteoid formation and a different predominant component. There is no difference in outcome or treatment recommendations among these different types. Other types of less common osteosarcomas include telangiectatic, small cell, juxtacortical, periosteal, and high-grade surface sarcomas.
Approximately 90% of children with osteosarcoma present with localized disease at diagnosis (Fig. 67-2). However, if only the primary tumor is treated, about 90% will experience metastatic disease.12
Clinical Manifestations, Patient Evaluation, and Staging
Ewing’s sarcoma patients present in general with localized pain, swelling, and a palpable mass. The most common primary tumor sites are illustrated in Figure 67-1. In Ewing’s sarcoma, plain radiographs show a lytic, destructive lesion, most typically of the diaphysis, with or without a soft tissue mass. Codman’s triangle may form from the elevated periosteal reaction. An “onion skin” effect, derived from the development of parallel, multilaminar, periosteal reactions, is typically seen.
Osteosarcoma patients present with similar signs and symptoms, in general, localized pain, swelling, and a palpable mass. The frequency with which osteosarcoma occurs within the different regions of the body is illustrated in Figure 67-2. Plain radiographs of patients with osteosarcoma typically show sclerotic or lytic lesions of the metaphysis. The elevated periosteal reaction may cause Codman’s triangle to form. In osteosarcoma, periosteal new bone formation may be present, with the blastic component showing a bony sunburst pattern.
The evaluation for Ewing’s sarcoma and osteosarcoma patients is similar.14 A complete history and physical examination are performed, with particular attention to the duration of symptoms, the presence of pain, difficulty of function, neurologic symptoms, and the location and size of the mass. Studies commonly obtained to evaluate the extent of disease include routine blood work, urine analysis, bone scanning, plain radiographs, and computed tomography (CT) scanning or magnetic resonance imaging (MRI) of the primary region. A chest CT scan should be obtained to rule out lung metastases. If the chest radiograph is negative and the CT scan is positive for subtle anomalies, an excision may be needed for accurate staging and treatment recommendations. If available, a fluorodeoxyglucose (FDG) PET scan should be performed. An electrocardiogram and echocardiogram are included in the evaluation before chemotherapy is initiated. In the case of Ewing’s sarcoma, a bone marrow biopsy is obtained. A summary of staging and follow up investigations is given in Table 67-1.
TABLE 67-1 Staging Investigations at Diagnosis in Osteosarcoma and Ewing’s Sarcoma
| Investigation | Diagnosis | Follow-up |
|---|---|---|
| Radiograph in two planes, whole bone with adjacent joints | + | + |
| MRI and/or CT, affected bone(s) and adjacent joints | + | + |
| Biopsy: material for histologic and molecular biologic testing | + | |
| Thoracic CT (lung window) | + | + |
| Bone marrow biopsy and aspirates (in Ewing’s sarcoma): microscopy (molecular biology still investigational) | + | |
| Whole-body technetium-99 m bone scan | + | + |
| FDG-PET scan | + + | + + |
CT, Computed tomography; FDG-PET, fluorine-18 fluorodeoxyglucose positron emission tomography; MRI, magnetic resonance imaging; +, mandatory; ++, indicated, if available.
In osteosarcoma, available staging systems are those of the Musculoskeletal Tumor Society and, lately, of the International Union Against Cancer and American Joint Committee on Cancer (UICC/AJCC).15,16
The prognosis for patients with Ewing’s sarcoma is dependent on a number of factors, the most important of which is the presence or absence of metastatic disease. Other prognostic factors include the site of the lesion and its size.17 Furthermore, the histologic response to chemotherapy is an extremely good predictor of outcome.
The prognostic features of osteosarcoma are similar, namely, the presence or absence of metastatic disease, the tumor location and size, whether complete resection of the primary tumor was possible, and the response to adjuvant chemotherapy.18–21
Treatment of Ewing’s Sarcoma
Primary Therapy
Historically, patients with Ewing’s sarcoma received treatment to the primary lesion only; cure rates were less than 20%. In the early 1960s, single-institution studies began to show an improved outcome with the addition of adjuvant chemotherapy.22–24 Today, the standard treatment consists of local therapy and neoadjuvant and adjuvant polychemotherapy. Local therapy consists of surgery or radiotherapy, or a combination of both. Concerning systemic therapy, a number of randomized trials have been performed to assess the value of different drug combinations.
The first Intergroup Ewing Sarcoma Study (IESS) investigated the use of polychemotherapy from 1973 until 1978. Patients received radiation therapy to the primary lesion and were randomized among three adjuvant chemotherapy treatment arms: vincristine, actinomycin D, and cyclophosphamide (VAC); VAC plus doxorubicin (trade name Adriamycin, so the regimen is known as VACA); or VAC plus bilateral pulmonary radiation therapy.25 This study showed a significant improvement in all parameters with the addition of doxorubicin. Furthermore, VAC plus bilateral lung irradiation, although less effective than VACA, showed superior results to VAC alone. As a consequence of these results, doxorubicin was considered to be an essential drug in further trials. The importance of doxorubicin and also of high-intensity initial treatment was further highlighted by a systematic meta-analysis of clinical trials by Smith and colleagues.26 In addition to the standard VACA regime, an additional benefit of the use of ifosfamide and etoposide has been discussed.
The third large intergoup study, INT-0091, investigated the addition of etoposide and ifosfamide to VACA; at 5 years, data showed a statistically significant benefit from the addition of these two drugs.27 In the European Cooperative Intergroup Ewing Sarcoma Study EICESS-92, the value of the single agents was evaluated. In standard-risk patients (localized disease and tumor volume of <100 mL), VACA was randomized against VAIA (ifosfamide instead of cyclophosphamide). There was no significant difference in event-free survival rates between the groups. In high-risk patients (larger tumors or metastatic disease), VAIA was randomized against VAIA plus etoposide; again, no significant difference in event-free survival rates was observed, but a marginal benefit was demonstrated for patients with large localized disease with the use of etoposide.28 In 2008, the American Children’s Oncology Group (COG) study AEWS0031, comparing three-weekly doses versus two-weekly doses of vincristine, doxorubicin, cyclophosphamide, ifosfamide-etoposide (VDC-IE), showed an impressive 10% 3-year event-free survival benefit for two-weekly doses of chemotherapy, a regimen that is becoming standard in the United States.29 A further treatment intensification strategy is the use of high-dose chemotherapy with autologous hematopoietic stem cell rescue. Because of its toxicity, this treatment is mainly used for very high risk patients. In the ongoing Euro-EWING 99 trial, in patients who respond poorly as shown by histologic testing, the use of high-dose chemotherapy with busulfan is randomized against conventional therapy or, in metastatic patients with lung metastases only, against conventional chemotherapy and whole-lung irradiation with 15 Gy or 18 Gy, depending on the age of the patient.
A summary of results of different phase III trials is given in Table 67-2.
Advanced Disease and Palliation
Children with metastatic Ewing’s disease at diagnosis continue to have a poor outcome despite the use of aggressive multiagent chemotherapy. The current overall approach in these patients is to intensify adjuvant and neoadjuvant chemotherapy. High-dose chemotherapy using busulfan or etoposide or treosulfan, and melphalan, is used for patients with bone metastases. Radiation therapy and, sometimes, surgery are used to treat the primary disease and sites of bone metastases. In patients with lung metastases only, the use of whole-lung irradiation has shown favorable results in the CESS and EICESS trials.30 Radiation therapy can be used as a palliative local measure in patients in whom curative management fails.
Local Therapy
Local therapy is an essential modality in the treatment of Ewing’s sarcoma. With systemic therapy alone, cure cannot be obtained. The modality of local therapy with best local control rates and functional outcome has been a matter of debate for some time. Essentially, local therapy can be given with surgery alone or radiotherapy alone, or a combination of both, either as preoperative or postoperative radiotherapy. To date, there have been no randomized trials comparing local therapy modalities, and no such trial is to be expected in the near future. From retrospective analyses of several groups, the impression has been that local control is improved when surgery is performed.31–34
