Sarcomas of Bone

Sarcomas of Bone

Alexandra K. Callan, MD

Jesse L. Roberts, MD

Andrew Park, MD

Dr. Callan or an immediate family member is a member of a speakers’ bureau or has made paid presentations on behalf of Bone Support Inc. Neither of the following authors nor any immediate family member has received anything of value from or has stock or stock options held in a commercial company or institution related directly or indirectly to the subject of this chapter: Dr. Roberts and Dr. Park.


Bone sarcomas are primary malignancies of bone arising from mesenchymal origin. They represent less than 0.2% of malignant tumors overall, with 3,300 cases diagnosed in the United States annually. Although particularly rare in adults, they account for 5% of cancers diagnosed in children younger than 14 years. Osteosarcoma, Ewing sarcoma, chondrosarcoma, adamantinoma, and chordoma are the most common types of bone sarcomas, each with distinct cells of origin. These bone sarcoma subtypes differ with respect to their workup and treatment algorithms. Patients should be followed with physical examination, radiographs of the extremity, and chest radiographs for at least 10 years after surgical resection because of the risk of late local recurrence or metastatic disease.


Osteosarcoma is the most common primary bone cancer. With multidisciplinary treatment including chemotherapy and wide surgical resection, survival rates approach 70% in patients presenting with nonmetastatic disease. Unfortunately, patients with metastatic disease at diagnosis have limited survival of only 20% at 5 years. Survival outcomes have plateaued over the past 40 years, increasing the drive to understand genetic signatures and options for novel therapies.


Although osteosarcoma represents less than 1% of all cancers, it is the most common primary bone cancer in children.1,2,3 Approximately 1,000 new cases of osteosarcoma are diagnosed annually in the United States.4 Osteosarcoma most commonly presents in the second decade of life, corresponding to periods of rapid skeletal growth. A lesser peak of incidence occurs during the seventh and eighth decades of life, when osteosarcoma may arise secondary to prior radiation therapy or conditions such as Paget disease.5 Osteosarcoma has a predilection for the metaphysis of long bones, specifically about the knee (42% in the distal femur, 19% in the proximal tibia) followed by the proximal humerus (10%); however, it can be diagnosed in any bone.5 According to the National Cancer Institute Surveillance, Epidemiology, and End Results Program, primary osteosarcoma in patients younger than 25 years had incidence rates that were slightly higher in males or African-Americans, whereas secondary osteosarcoma was most common in patients older than 60 years with a slight female or Caucasian predominance.3,6


Six subtypes of osteosarcoma were defined in the 2020 World Health Organization Classification: (1) osteosarcoma not otherwise specified, (2) low-grade central osteosarcoma, (3) parosteal osteosarcoma, (4) periosteal osteosarcoma, (5) high-grade surface osteosarcoma, and (6) secondary osteosarcoma. Conventional osteosarcoma, telangiectatic osteosarcoma, and small cell osteosarcoma are included in osteosarcoma not otherwise specified.2 More than 90% of all osteosarcomas are the conventional, high-grade intramedullary variety,2 which has been further subclassified into osteoblastic, chondroblastic, or fibroblastic subtypes. To date, there is no definitive evidence that these subtypes differ in terms of prognosis.12,13 Table 2 presents additional details on incidence, imaging, histology, and outcomes.


Osteosarcoma classically presents as a painful mass in a growing child. The pain is frequently severe at night and can wake the child from sleep. Early symptoms may be ignored, as they are easily attributable to benign conditions such as trauma or growing pains. Most patients eventually present with a firm, painful, nonmobile mass; or much less commonly, a pathologic fracture. Most commonly, patients’ tumors are classified as American Joint Committee on Cancer stage IIB (Table 1).

Evaluation of an osteosarcoma includes plain radiographs of the entire bone, MRI (with and without contrast) of the entire bone, chest CT, whole-body bone scan or PET CT, and biopsy. Laboratory workup may reveal elevated alkaline phosphatase level and lactate dehydrogenase levels. Genetic counseling and testing should be performed if there is any concern for an underlying disorder, and fertility consultation should be considered.14


Plain radiographs reveal increased osteoid production or a radiodense bone lesion with poorly defined margins, often extending beyond the normal cortex. Radiographic signs of an aggressive bone lesion include periosteal reactions such as a sunburst pattern, onion skinning, or Codman triangle. These classic findings represent irregular periosteal bone formation because of rapid growth of the tumor beyond the bone itself (Figure 2).

MRI allows for the detailed assessment of the extent of intramedullary involvement, extramedullary soft-tissue extension, and relationship to nearby anatomic structures. Classically, osteosarcoma is isointense to muscle on T1 sequences, hyperintense on T2 sequences, and enhances with gadolinium contrast (Figure 3).

Chest CT is included in initial staging to identify any pulmonary metastases and serve as a baseline for treatment (Figure 4). Whole-body bone scan with technetium 99 (Tc-99) is the standard of care for evaluation of distant bone metastases (Figure 5). The role of PET CT continues to evolve for staging osteosarcoma, but it is not used routinely at this time.


Osteosarcoma is a malignancy of mesenchymal cell origin characterized by malignant spindle cells that produce osteoid. Histology reveals malignant, light-pink woven osteoid interspersed with ugly, pleomorphic, hyperchromatic spindle cells (Figure 1). Depending on the subtype, microscopic evaluation can reveal various cell types including chondrocytes, fibroblasts, giant cells, or small round blue cells along with malignant osteoid production and pleomorphic spindle cells.

Current Treatment

Although only one-fourth of all newly diagnosed patients have detectable metastases on presentation, all patients are assumed to have micrometastatic disease. This is based on the observation that, in the prechemotherapy era, metastatic disease developed in most patients 3 to 6 months after radical surgical resection of the primary tumor.

Evidence-based practice supports treatment with multiagent chemotherapy and surgical resection.1,13
Standard chemotherapy regimen includes high-dose methotrexate, Adriamycin (doxorubicin), and cisplatin (MAP therapy). Surgery involves a wide surgical resection with the goal of removing all malignant cells and achieving negative margins on pathology. The typical treatment protocol involves 10 weeks of preoperative (neoadjuvant) chemotherapy, surgical resection, and then 20 weeks of postoperative (adjuvant) chemotherapy. This allows for assessment of chemotherapy effect, estimated by histologic necrosis in the tumor, at the time of surgical resection. Tumor necrosis of 90% or higher is considered a favorable response; conversely, necrosis

less than 90% is associated with lower event-free survival rates.13

Limb salvage surgery is possible for nearly 85% of patients with osteosarcoma.15 Even in the setting of pathologic fracture, limb salvage surgery remains feasible for most patients.16 When limb salvage surgery is not possible or reconstruction options are limited, amputations, including rotationplasty, continue to be an important technique for local control. Although limb salvage surgery is associated with greater psychosocial satisfaction, faster rate to ambulation, and less oxygen consumption, it is associated with high complication and revision surgery rates. No long-term differences have been identified between patients undergoing limb salvage surgery versus amputation in terms of overall satisfaction, life success, and functional scores.17

Reconstruction options include endoprostheses, allografts (intercalary or osteoarticular), or allograft prosthetic composites. Each option is tailored to the long-term goals of the patient, taking into account the various risks and benefits. Skeletal immaturity of the patient adds to the complexity of this decision; in children with limited growth remaining, contralateral epiphysiodesis may be considered, whereas for those with significant growth remaining, appropriate reconstruction may necessitate custom growing endoprostheses or rotationplasty (Figure 6).


Five-year survival rate is approximately 76% for patients who present with localized disease, compared with 20% for the 17% of patients presenting with metastatic disease.12 Characteristics associated with a poor prognosis include large tumor size (>8 cm), axial tumor location, pathologic fracture, metastases (skip or distant), necrosis less than 90% at time of resection, local recurrence, older age, and unresectable disease.12 Osteosarcoma outcomes have remained relatively static over the past 40 years, since the advent of current multiagent chemotherapy regimens.18

Emerging Therapies

Newer drug trials have investigated targeted agents such as tyrosine kinase inhibitors and immunotherapies. Currently, several tyrosine kinase inhibitors with anti-angiogenetic targets including sorafenib or regorafenib seem to provide the most promising results for relapsed osteosarcoma.18,19,20 Although overall survival remains similar, progression-free survival was significantly improved with regorafenib in patients with metastatic osteosarcoma.21

Ewing Sarcoma

Ewing sarcoma was first described in 1921 as a series of unusual pediatric bone tumors that lacked bone formation, exhibited a dramatic initial response to radium, and histologically appeared to be of endothelial origin.22 Sixty years later, the most common of the pathognomonic chromosomal translocations of Ewing sarcoma were discovered, corresponding to a single protein responsible for tumorigenesis.23 Current treatment includes chemotherapy for systemic control in addition to surgery and/or radiation therapy for local control. Five-year survival rate is 70% for patients with localized disease but only 30% for patients with metastatic disease on presentation, and this subset makes up 25% of patients overall. Clinical trials are ongoing to determine whether selectively targeting the fusion proteins and their downstream pathways can improve these outcomes.


Representing 3% of all pediatric cancers and 10% of all primary bone cancers, Ewing sarcoma is the second
most common pediatric bone sarcoma (after osteosarcoma) and third most common bone sarcoma overall (after osteosarcoma and chondrosarcoma).24 More than 50% of patients with a diagnosis of Ewing sarcoma are adolescents; there is a 1.5:1 male-to-female predilection, and the disease is more prevalent in Caucasian people. Ten to 15% of patients present with a pathologic fracture.23 Ewing sarcoma most frequently arises in marrow-rich locations of the skeleton, such as the diaphysis of long bones and the pelvis. Primary tumors are most common in the lower extremity (45%), pelvis (20%), upper extremity (13%), and axial skeleton and ribs (13%),25 whereas the most common sites of metastatic disease are the lungs (50%) and bone (25%).26


The Ewing sarcoma family of tumors includes small round cell tumors with common histologic and genetic features. Extraskeletal Ewing sarcoma is one such entity that presents in the soft tissues but arises from the pathognomonic translocations associated with Ewing sarcoma.27,28 A group of sarcomas similar to Ewing sarcoma has been described that share morphologic characteristics with Ewing sarcoma but lack the classic translocation between EWRS1 and the ETS family of transcription factors. The new World Health Organization Classification of Tumors of Soft Tissue and Bone identified four groups of undifferentiated round cell sarcomas: Ewing sarcoma, CIC-rearranged sarcomas, BCOR-altered sarcomas, and sarcomas with EWRS1-non-ETS fusions.29 These rare subtypes have disparate genetic signatures, and few clinical outcomes data are available given their rarity.


Patients with Ewing sarcoma commonly present with several months of pain and swelling; in addition, more than 20% have a fever or other systemic symptoms. Laboratory tests are nonspecific but may show anemia, leukocytosis, elevated erythrocyte sedimentation rate, or elevated serum lactate dehydrogenase. The inflammatory symptoms and laboratory findings are unique, as they do not occur in other bone sarcomas. Finally, bone marrow biopsy may be performed in patients with metastatic disease to evaluate for bone marrow involvement, which is present in up to 5% of all patients with a new diagnosis and 17.5% of patients with metastatic disease.30


Workup begins with plain radiography, then contrast-enhanced MRI of the entire bone. When in a long bone, Ewing sarcoma typically affects the diaphysis or metadiaphysis and appears as an aggressive, permeative intramedullary lesion on plain radiographs. Bone destruction and periostitis may also be seen. Characteristic MRI findings include a lesion that appears hypointense on T1, hyperintense on T2, and avidly enhances; there is a sharp transition in the bone itself, and often a large soft-tissue mass with surrounding edema. MRI can detect skip metastases and is of further value in that it demonstrates the proximity of neurovascular structures to the tumor (Figure 7). Chest CT is performed to evaluate for pulmonary metastases, as Ewing sarcoma most commonly spreads hematogenously to the lungs. Whole-body bone scan was previously the standard of care to screen for skeletal metastases, but [18F]fluorodeoxyglucose positron emission tomography scan is now an alternative.


Ewing sarcoma comprises small round cells with hyperchromatic nuclei and expresses a high degree of CD99 positivity31 (Figure 8). Ewing sarcoma may be definitively diagnosed on fluorescence in situ hybridization or reverse transcription polymerase chain reaction via the detection of rearrangements of EWRS1 on chromosome 22q12 and a member from the ETS transcription factor family. Most commonly, this involves FLI1, but translocations can also involve ERG, E1AF, FEV, ETV1, and ETV4.32 RNA-based next-generation sequencing can be used to confirm the diagnosis if a gene fusion cannot be identified.

Current Treatment

Treatment for Ewing sarcoma requires multidisciplinary care, including either surgery or radiation for local control and multiagent cytotoxic chemotherapy for systemic control. Before the advent of effective chemotherapy protocols, metastatic disease developed and
was fatal in almost all patients despite adequate local control; therefore, patients with Ewing sarcoma are assumed to have subclinical micrometastatic disease on presentation. In the 1970s, the neoadjuvant and adjuvant administration of VAC (vincristine, adriamycin, cyclophosphamide) improved the 5-year survival of localized Ewing sarcoma to 50%, and the addition of ifosfamide and etoposide in the 1980s further improved 5-year survival to 70%.31 Despite these improvements, 5-year survival for patients with metastatic or recurrent Ewing sarcoma is less than 40%, and side effects of chemotherapy include infertility, heart failure, and secondary malignancies such as leukemia.24,33

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May 1, 2023 | Posted by in ORTHOPEDIC | Comments Off on Sarcomas of Bone

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