Ewing sarcoma is an aggressive form of childhood cancer. The majority (~75%) arise from bone, with the remainder arising from soft tissues. While the long bones are most commonly affected, Ewing sarcoma can arise in the bones of the orbit as well (Fig. 13.3).

Ewing sarcoma is the second most common primary bone tumor of childhood. Ewing sarcoma is more common in the Caucasian population and has a slight male predominance [10]. The majority of patients (~75%) present with localized disease. The lungs are the most common site of metastases, followed by bone and bone marrow.

Symptoms at presentation depend on the location of the mass. Most patients present with pain or a palpable mass. Fever, weight loss, and night sweats may also be present. Careful assessment of the involved fields, including lymph nodes, is critical for ultimate planning of local control.

With any suspicion of malignancy, a referral to a pediatric oncology center should be considered. Initial imaging and decisions about approach to biopsy/resection are critical, as violation of tissue planes may have implications for staging, treatment, and further local control. Ewing sarcomas are often quite necrotic, so the surgeon must be careful to obtain adequate tissue for histologic and molecular testing.

Imaging of the primary tumor site, usually with MR, allows for a clear assessment of the extent of tumor involvement. Metastatic evaluation should include a non-contrast chest CT, whole-body PET scan, and bilateral bone marrow aspirates and biopsies.

The majority of Ewing sarcomas carry a t(11;22) chromosomal translocation. This results in an EWS-FLI1 gene fusion, which activates a family of transcription factors involved in cellular proliferation and tumorigenesis. Identification of this translocation has become an integral part of the diagnosis of Ewing sarcoma [11], although it has not been convincingly linked to prognosis.

The Children’s Oncology Group defines three risk groups for Ewing sarcoma – patients with localized disease, patients with lung metastases only, and patients with bone and/or other metastases. Various groups have identified male sex, older age, larger tumor size, and histologic response as adverse prognostic signs, although these are not uniformly accepted.

Cytotoxic chemotherapy has significantly improved prognosis for patients with localized Ewing sarcoma. Patients with metastases, unfortunately, continue to fare quite poorly. Effective therapy combines chemotherapy with primary tumor treatment. Primary tumor treatment involves surgical resection, radiation therapy , or a combination of both modalities.

Current chemotherapy for Ewing sarcoma uses a backbone of alternating cycles of vincristine, doxorubicin, and cyclophosphamide with ifosfamide and etoposide. A recent Children’s Oncology Group study showed improved survival when chemotherapy cycles are delivered on an every 2-week cycle as compared to an every 3-week cycle [12].

Primary tumor treatment decisions are quite complex. Complete, en bloc surgical resection with negative margins is preferred. In some circumstances, this is not possible, or the ensuing disability is unacceptable. In those cases, or in those having undergone a surgical resection with positive margins, radiation therapy should be used, with consideration of proton radiotherapy, to spare surrounding tissues as much as possible.

Osteosarcoma is the most common primary tumor of the bone in childhood and represents about 5% of all childhood cancers. Osteosarcoma can occur in any bone in the body, and while orbital presentations are rare, they have been reported. The ability to cure osteosarcoma depends on the ability to achieve a complete resection, so orbital tumors present a particular challenge. The majority of patients present with localized disease. Lungs are the most common site of metastases, when they occur. There are also cases of osteosarcoma metastasizing to the orbital wall (Fig. 13.4).

Osteosarcoma has a bimodal age distribution. There is a peak in adolescence and a second peak in adults greater than 65 years old. Osteosarcoma is more common in the African-American population and has a slight male predominance [13]. Risk factors for the development of osteosarcoma include prior radiation, Li-Fraumeni syndrome, history of retinoblastoma, and Bloom syndrome.

Osteosarcoma typically presents with pain and/or a palpable mass. Systemic symptoms such as fever, weight loss, and night sweats are usually absent. Physical examination often reveals a palpable mass. Nodal involvement is rare.

With any suspicion of malignancy, a referral to a pediatric oncology center should be considered. Initial imaging and decisions about approach to biopsy/resection are critical, as violation of tissue planes may have implications for staging, treatment, and further local control.

Imaging of the primary tumor site is best achieved with MR. Metastatic evaluation includes a CT chest, to assess for pulmonary disease. PET or bone scan is used to evaluate for bony metastases or skip lesions.

The most important prognostic factor in osteosarcoma is the ability to fully resect the primary tumor and metastatic sites. Other adverse prognostic factors include poor histologic response following chemotherapy, male sex, tumor in the axial skeleton, and tumors greater than 10 cm.

Chemotherapy is critical to our ability to cure osteosarcoma, even in those with localized disease, supporting the presence of micrometastases not visible even with modern staging techniques. The long-standing backbone of chemotherapy includes cisplatin, doxorubicin, and methotrexate. This provides cure in about 75% of patients with localized disease. Efforts to intensify therapy have, to date, not yielded an improved outcome. For those with unresectable tumors or unresectable metastases, the prognosis is far worse.

As with all sarcomas, primary tumor treatment is a difficult decision. Osteosarcomas are not radiation sensitive, so we rely solely on surgery to achieve local control. Osteosarcomas can rarely be treated without some long-term disability. The goals of the patient must be seriously considered when proposing options for local control. Although limb salvage techniques have improved significantly over time, for a very active teenager committed to participation in sports, amputation may provide a more acceptable outcome.

Neuroblastoma represents an extraordinarily broad spectrum of disease, from spontaneously regressing tumors to high-risk, widely metastatic disease with a poor prognosis. Improved understanding of molecular and genetic features of these tumors has allowed for more detailed clinical classification.

Neuroblastoma can arise from any site along the sympathetic nervous chain. Metastases can involve the periorbital bones, leading to proptosis and periorbital ecchymoses. Tumors high in the thoracic region or in the neck can also cause a Horner’s syndrome.

Neuroblastoma is the most common extracranial solid tumor of childhood, representing between 8% and 10% of childhood cancers. Neuroblastoma is largely a disease of infants and young children, although diagnosis of an adolescent or young adult is possible.

Clinical presentation varies with the spectrum of disease. Low-risk tumors are often incidentally discovered, while children with high-risk disease are usually ill appearing at presentation. Fevers, bone pain, pallor, and fatigue are common for those with high-risk disease. Orbital metastases can present as “racoon eyes” (Figs. 13.5, 13.6, and 13.7). Genetic analysis of the tumor is critical for risk group assignment. The diagnostic biopsy should be generous, if possible, to ensure adequate specimen. Children presenting with orbital ecchymoses should undergo imaging in search of a primary tumor mass. In the absence of a primary tumor, the orbital lesion may need to be biopsied. There is no role for complete resection, only a diagnostic specimen.

The primary tumor should be imaged with cross-sectional imaging. Metastatic evaluation includes an MIBG scan and bilateral bone marrow aspirates and biopsies. A rare subset of neuroblastomas (~10%) is MIBG non-avid. In this case, a PET scan should be considered to definitively rule out metastases. Urinary catecholamines should also be evaluated.

In an effort to standardize risk group classification, the International Neuroblastoma Risk Group (INRG) was developed. INRG establishes pretreatment risk grouping. Staging via INRG relies on presence of image-defined risk factors (i.e., extent of tumor infiltration, encasement of surrounding vessels, infiltration of adjacent organs, or intraspinal extension). L1 tumors lack image-defined risk factors, while L2 tumors do not. Stage M tumors have spread to other parts of the body. Stage MS includes tumors in children, < 18 months old, with a particular pattern of metastases – skin, liver, and/or bone marrow (<10% bone marrow involvement). In addition to the INRG classification, age of the patient, histology, level of differentiation, ploidy, and presence/absence of MYCN amplification are used to assign a risk group – very low, low, intermediate, or high.

Low- and intermediate-risk tumors are treated with observation, surgery alone, or surgery plus chemotherapy. Treatment of high-risk neuroblastoma is multimodal and includes induction chemotherapy, surgical resection, stem cell transplant, radiation, and immunotherapy. With this intensive approach, long-term survival has reached ~50%. Disease evaluation prior to stem cell transplant determines the approach to “local” control. Patients with persistent sites of MIBG-avid disease, including the orbit, will have those sites irradiated posttransplant.