Primary bone cancer in the pediatric population

By Meghen B. Browning, MD, and Dave M. King, MD

This table shows percent of representation among pediatric malignancies and overall percent survival.

Cancer in children represents only 2 percent of cancer in the western world. However, it still affects about 12,500 children per year in the U.S. Childhood cancer survival continues to improve, with approximately 80 percent of all children diagnosed with cancer surviving disease-free at five years postdiagnosis¹.

Primary bone malignancies have proved to be more difficult to cure than many other pediatric tumors. (See Table 1 for a listing of common pediatric tumors.) Osteosarcoma, the most common primary pediatric bone tumor, makes up about 5 percent of all pediatric cancer and has a five-year disease-free survival of about 65 percent. The Ewing's sarcoma family of tumors makes up about 4 percent of all pediatric cancer, with a five-year disease-free survival of about 55 percent. 

A review of these two most common pediatric primary bone cancers demonstrates some of the challenges encountered with these tumors and some areas where improvements in care can be made.

Osteosarcoma

Case illustration:
A 15-year-old male presented with a three-month history of knee pain. He was referred to physical therapy for a presumed sports injury. His pain did not improve. An X-ray showed a sclerotic lesion with marked periosteal reaction, localized to the distal femur. Core needle biopsy showed osteosarcoma. Staging (MRI of the involved extremity, CT of the lungs and total body bone scan) showed localized disease. He was treated with neoadjuvant chemotherapy. At the time of limb-salvage surgery, he was found to have 70 percent tumor necrosis. He completed adjuvant chemotherapy but relapsed with multiple lung nodules four months off therapy. He received further therapy on an experimental protocol, followed by surgical resection of his lung nodules.

Primary bone sarcomas are diagnosed in about 1,500 patients per year in the U.S., the majority of whom are younger than 25 years old. Osteosarcoma is the most common primary malignancy of bone in pediatrics, being diagnosed in 500 to 1,000 people per year. Seventy-five percent of osteosarcoma occurs in patients between the ages of 10 and 20. It has a 1.5:1 male:female preponderance¹. The most typical presenting complaint is pain, with the second being a palpable mass. The average duration of symptoms prior to diagnosis is more than three months. Osteosarcoma is associated with mutations of the retinoblastoma gene in a minority of patients. It may be seen as a secondary bone tumor in radiated or otherwise-damaged bone, but this is much more common in older adults. 

Figure 1: Radiograph showing a poorly-demarcated tumor. Tumor shows significant periosteal reaction and ossification of a large soft-tissue component. Cortical destruction also is seen.

Radiographs of osteosarcoma may show lytic lesions or mixed bone destruction and formation. Cortical destruction and soft tissue ossification are classic. Ninety percent of osteosarcoma is metaphyseal. The most common sites, in descending order, are distal femur, proximal tibia and proximal humerus². (See Figure 1.)

The primary prognostic factor for osteosarcoma is disease extent – a solitary bone lesion predicts a five-year disease-free survival of about 65 percent; a bone lesion with lung metastases leads to a five-year disease-free survival of 20 to 30 percent; multiple bony lesions confer a disease-free survival of less than 5 percent^3-7. Osteosarcoma tends to metastasize only to other bones and to lung, although it also rarely metastasizes to lymph nodes and other sites. In addition to extent of disease, another important prognostic factor is response to therapy. About half of patients achieve good tumor necrosis with neoadjuvant chemotherapy, which is given after biopsy but prior to definitive surgery. Good tumor necrosis is defined as greater than 90 percent of the tumor volume being necrotic. Patients with single bony lesions and good tumor necrosis have a five-year disease-free survival of up to 85 percent8. The prognostic implications of biologic factors such as HER-2 expression are not yet established^9-11. Patients with recurrent disease have a survival rate of up to 20 percent, but only if their recurrence is surgically resectable^12-13. Radiation has only a palliative role in osteosarcoma.

Ewing's sarcoma

Case illustration:
An 8-year-old male presented with a one-month history of leg/ankle pain. Radiographs showed a lytic lesion with a pathologic fracture. A percutaneous biopsy was per-formed and showed Ewing's sarcoma of the distal tibia. On further staging, the distal fibula also was involved. Chest/abdomen/pelvis CTs, a bone scan and a PET/CT were otherwise negative. Bone marrows also were negative. He was casted and received neoadjuvant chemotherapy with good clinical response. His surgical procedure was complicated by the need to resect the biopsy tract in addition to the involved bone. He completed adjuvant chemotherapy and remains in remission.

Ewing's sarcoma is the second most common primary bone malignancy in children. It may occur as a primary bone tumor with or without an associated soft tissue mass or as a soft tissue mass with or without bone involvement. It is one of the "small, round, blue-cell tumors." Eighty percent of all Ewing's sarcoma cases occur in patients between the ages of 5 and 25 years. Like osteosarcoma, it commonly presents with pain and/or mass and has a 1.5:1 male preponderance¹. Ewing's sarcoma is more likely than osteosarcoma to have systemic symptoms such as fever or weight loss and also is more likely to metastasize to lymph nodes, bone marrow or other sites. However, it most commonly metastasizes to, or recurs in, the lungs. 

Figure 2: Radiograph of a Ewing's sarcoma of the fibula.Cortical disruption is prominent. Exuberant periosteal reaction is seen. The lesion is poorly demarcated.

The most common bony sites of Ewing's sarcoma are pelvis, femur, humerus, tibia/fibula and rib¹⁴. Ewing's sarcoma classically occurs as a diaphyseal lesion, although metaphyseal lesions are statistically more common. It often is associated with a large, nonossified soft tissue mass. Like osteosarcoma, the lesions are destructive, show periosteal reaction and are poorly marginated. (See Figure 2.)

The primary prognostic factor for Ewing's sarcoma is extent of disease. Five-year disease-free survival overall is about 55 percent, although cohorts with good tumor necrosis to neoadjuvant chemotherapy reach 90 percent in some studies^15-18. Response to therapy is slightly less well-established for Ewing's sarcoma than for osteosarcoma, but it is becoming more predictive as more data accrues^19-24. Local tumor control may be achieved with either surgery or radiation. More recent studies have demonstrated slight increases in survival and slight decreases in local recurrence rates with surgery^{22, 25-26}.

Pelvic sites carry a worse prognosis and typically present later and with bulkier disease²⁵. Metastatic disease at diagnosis confers a poor prognosis, with less than 20 percent survival²⁷. The presence of typical (11;22) translocation has less  prognostic significance than presence of metastases²⁸. Recurrent Ewing's sarcoma has a dismal prognosis, although patients who have late recurrences with limited, pulmonary-only nodules can have improved survival rates^{16, 29-31}. 

Multidisciplinary, coordinated care

The two cases detailed above demonstrate some pitfalls in the care of patients with primary bone tumors. Pediatric solid tumors in general, including bone tumors, often are diagnosed after considerable delay. Cancer in the pediatric population is rare. This makes the index of suspicion low. However, 1 in every 600 children in the U.S. will develop cancer before age 15, and that rate is increasing¹. (See Table 2.) Factors that may help differentiate a bone tumor from another process include progressive pain, pain that does not improve with rest, association of a soft tissue mass and symptoms that persist for more than a few weeks. If in doubt, bone malignancies almost always are visible on plain X-rays.

Appropriate biopsy of a tumor is crucial to both outcome and treatment options. There currently are about 20 studies open to children and young adults with sarcomas. Most of these studies require that sufficient biopsy material be obtained for samples to be sent out for research purposes in addition to that used for diagnostic purposes. Pathologists who are unaccustomed to assessing pediatric tumors also may require more tissue than they might for more familiar cancers. Because pediatric tumors have been studied in cooperative groups for several decades, there is additional prognostic information that may be available through specialized studies of biopsy material, if sufficient sample is available. Even more critically, sarcoma therapy (as well as some other therapies) requires treatment of the biopsy tract in order to achieve the best outcome. Contamination of uninvolved tissue from poorly placed or poorly planned biopsies may require additional surgery or adjuvant radiation. Either of these may result in poorer cosmetic and/or functional outcome. When feasible, the surgeon who will perform the resection also should perform the biopsy to avoid these pitfalls. This approach has been shown to statistically improve outcome^32-33.

Treatment of pediatric bone sarcomas typically consists of a few weeks of multiagent chemotherapy to achieve initial tumor shrinkage. This is known as neoadjuvant chemotherapy, and the response to it helps predict outcome. Patients then receive local control, consisting of either resection of their tumor and/or radiation of any sites of tumor that are visible by scans. This is followed by further multiagent chemotherapy, known as adjuvant chemotherapy. Many supportive care techniques are available to help patients tolerate their chemotherapy.

Resection of primary bone tumors requires extraordinarily specialized care. In the modern era, limb-salvage resections have equal survival outcomes to amputation³⁴. Thus, a surgeon experienced in such cases can make an enormous difference for a patient's functional outcome. Appropriate choice of internal prosthetics and allografts for bone reconstitution, along with specialized reattachment of tendons and careful attention to vascular supply, can even allow sports participation for many bone tumor patients. Orthopedic oncology surgeons are specially fellowship trained in these surgeries, and they often work as a team with plastic surgeons to appropriately replace major bone and soft tissue defects.

Multidisciplinary clinics add the dimension of coordinated care for patients with complex medical issues. In a multidisciplinary oncology clinic, patients may be able to consult with their medical oncologist and their surgical oncologist simultaneously. Such centers may offer more-specialized providers with increased expertise in relatively rare problems such as pediatric sarcomas. Providers with narrower job descriptions may have more resources to offer patients enrollment on investigational protocols and to stay up-to-date on the latest therapies. Grouping patients and health care providers in this way maximizes access to research and fosters collaboration between basic science and clinical research teams. Multidisciplinary teams often are available to offer follow-up assistance  for the complex issues that face survivors of pediatric bone cancers.