Osteosarcoma: An Evolving Understanding of a Complex Disease

John H. Alexander, MD; Odion T. Binitie, MD; G. Douglas Letson, MD; David M. Joyce, MD

Disclosures

J Am Acad Orthop Surg. 2021;29(20):e993-e1004. 

In This Article

Patient Evaluation

History and Physical Examination

Patients typically present with nonspecific symptoms, including pain, swelling, and sometimes a palpable mass. Pain at rest or at night is classically described in patients with tumor-related bone pain. The presentation and time to diagnosis of osteosarcoma can be variable and are dependent on the location of the primary tumor; in particular, pelvic osteosarcoma is often associated with a notable delay in diagnosis. Finally, patients may present with a pathologic fracture, requiring orthopaedic providers to thoughtfully evaluate fractures associated with minor trauma, antecedent pain, or preexisting bone lesions to prevent inappropriate management.

Site-specific Imaging

The initial workup of any suspicious bone lesion begins with orthogonal radiographs of the entire bone. In many cases, the diagnosis of osteosarcoma can be made with high certainty based on plain radiographs alone. Conventional intramedullary high-grade osteosarcoma is classically described as a permeative, nongeographic lesion in the metadiaphyseal region of the long bones with varying degrees of cloud-like mineralization. Frequently, an extraosseous soft-tissue mass is present, leading to the formation of a Codman triangle (Figure 1) and a sunburst periosteal reaction. Radiographic features may vary considerably based on patient age and histologic subtype. In particular, older patients and the telangiectatic osteosarcoma subtype may present as primarily lytic lesions with minimal or no osseous matrix (Figure 2).

Figure 1.

Radiographs demonstrating conventional intramedullary osteosarcoma. A, AP radiograph of a skeletally immature patient demonstrates a permeative, destructive, bone-forming lesion in the metadiaphyseal region of the left distal femur. A large extraosseous soft-tissue implant with a classic periosteal reaction is present. B, Technetium-99 bone scan demonstrates focal radiotracer uptake in the distal femur. C, A coronal T1 MRI image demonstrates a low-signal intensity intramedullary bone lesion with a large extraosseous soft-tissue mass. The extent of intramedullary involvement is clearly defined on this sequence. D, Finally, a coronal T1 fat-saturated gadolinium-enhanced MRI image defines the extraosseous extent of the tumor, periosteal reaction, and areas of central necrosis. E, AP postoperative radiographs after resection and reconstruction with a noninvasive growing prosthesis.

Figure 2.

Radiographs demonstrating telangiectatic osteosarcoma. Unfortunately, telangiectatic osteosarcoma can mimic aneurysmal bone cysts because of their similar lytic and expansile radiographic appearance, which may lead to delays in diagnosis. This young, skeletally immature patient initially presented with a pathologic fracture through a suspected aneurysm bone cyst which can be appreciated on (A) AP shoulder radiographs. B, Several months later, her tumor continued to grow and nearly completely destroyed her entire proximal humerus. There is a small amount of cloud-like, dense ossification within the mass distally evident on this radiograph. C, Coronal T1 and (D) axial T1 fat-saturated gadolinium-enhanced images demonstrate a large, lobular mass within the proximal humerus with fluid-fluid levels present (white arrow). These fluid-filled, cystic regions can make resection with negative soft-tissue margins difficult.

A complete magnetic resonance imaging (MRI) series with and without contrast of the entire involved compartment, including T1, T2/short tau inversion recovery, and fat-suppressed contrast-enhanced sequences in the axial, coronal, and sagittal planes is widely accepted as the preferred imaging modality to evaluate the intramedullary and extraosseous extent and detect skip metastases (synchronous foci of tumor occurring in the same bone, but anatomically separated from the primary lesion). Skip metastases occur in approximately 1.4% of patients and are associated with worse OS compared with localized disease.[3]

In addition, MRI facilitates the evaluation of the tumor's relationship to critical structures including major nerves, blood vessels, and the physis in pediatric patients. The T1-weighted coronal and sagittal sequences are reliable for predicting the extent of intramedullary involvement when correlated with pathologic specimens and are crucial for planning the appropriate resection level. Short tau inversion recovery sequences aid in identifying the extent of peritumoral edema. Contrast-enhanced, fat-saturated, T1-weighted sequences are helpful when defining the extent of any extraosseous soft-tissue mass and neurovascular involvement. Finally, the axial T1 sequences are particularly useful for planning surgical approaches and defining anatomic relationships with critical neurovascular structures.

Staging

Because of the propensity of osteosarcoma to metastasize to the lungs and less commonly to other skeletal and visceral sites, the presence of distant disease is best evaluated with a CT of the chest to screen for pulmonary disease. Metastatic pulmonary nodules tend to be calcified, ≥6 mm, and peripherally located, although up to 14% of metastases may have an atypical appearance.[4]

A technetium-99 whole-body bone scan has traditionally been the standard test to identify distant skeletal metastases. However, the use of [18]F-fluorodeoxyglucose positron emission tomography-CT ([18]F-FDG-PET-CT) has garnered notable interest in recent years. PET-CT has superior sensitivity in identifying distant disease compared with bone scintigraphy, an advantage most evident in skeletally immature patients with physiologically active physes.[5] The utilization of 18F-FDG-PET-CT to risk stratify patients and predict histologic response to neoadjuvant chemotherapy is currently under investigation. The current National Comprehensive Cancer Network guidelines recommend either a whole-body bone scan or head-to-toe PET-CT for initial screening, followed by MRI or CT with contrast of any sites that are concerning for skeletal metastases.

Staging Classifications

The most common classification systems used to stage osteosarcoma are the Enneking Staging System and the American Joint Committee on Cancer staging system (Table 1). The Enneking system includes an assessment of tumor grade, the presence or absence of extraosseous extension, and the presence or absence of metastatic disease. The American Joint Committee on Cancer staging system for bone sarcomas takes into account additional factors, including location, size (≤ or >8 cm), grade, and the presence of skip, pulmonary, regional lymph node, and/or extrapulmonary sites of metastatic disease. With the recently updated version of the American Joint Committee on Cancer staging system, the eighth edition, the histologic grading system changed from four to three grades and anatomic location is now differentiated. Specifically, separate criteria are used for defining the primary tumor based on appendicular, spine, and pelvis locations, acknowledging their unique anatomic considerations and prognostic value[6] (Table 1, Supplemental Digital Content, https://links.lww.com/JAAOS/A674).

Ancillary Tests

Although the diagnosis of osteosarcoma is not contingent on serum laboratory tests, a baseline complete blood count and comprehensive metabolic panel are obtained before initiating systemic treatment, with attention paid to serum calcium levels and renal and liver function. In addition, elevated serum lactate dehydrogenase and alkaline phosphatase are associated with decreased event-free survival (EFS) and should be assessed at diagnosis.[7–9]

Osteosarcoma chemotherapy regimens are associated with toxicities that can cause lifelong disability; therefore, baseline testing is required before starting chemotherapy. These include an echocardiogram due to the small, but notable risk of cardiomyopathy in patients receiving doxorubicin, and an audiogram because of the relatively high risk of hearing loss associated with platinum-based chemotherapeutics.

Biopsy

Biopsies of suspected malignant bone tumors should be done at an institution capable of performing the definitive resection as biopsies done elsewhere are associated with a higher rate of local recurrence (LR) and a need for more ablative procedures.[10]

Traditionally, an open biopsy approach has been advocated to obtain a histologic diagnosis; however, recent evidence suggests that core needle biopsies are accurate and reliable.[11] At the time of definitive resection, the biopsy tract must be excised because residual viable tumor cells may be present along the biopsy tract. Thus, image-guided biopsies necessitate a discussion between the orthopaedic oncologist and the interventional radiologist regarding the location of the planned incision for definitive resection. Alternatively, a core needle biopsy of a suspected osteosarcoma can be done in the operating room, which ensures appropriate biopsy placement and allows for frozen section to confirm that diagnostic tissue has been obtained.

Biopsy tissue should be assessed by a musculoskeletal pathologist familiar with sarcoma pathology. The specific histologic diagnosis is based on cell morphology, matrix production, degree of cellular pleomorphism and anaplasia, presence and number of mitotic figures, and molecular aberrations[12] (Figure 3). This histologic diagnosis is then correlated with patient demographics and the radiologic appearance of the tumor to determine a final diagnosis[7,12–24] (Table 2, Supplemental Digital Content, https://links.lww.com/JAAOS/A675; Figures 1 to 14, Supplemental Digital Content [1: https://links.lww.com/JAAOS/A676; 2: https://links.lww.com/JAAOS/A677; 3: https://links.lww.com/JAAOS/A678; 4: https://links.lww.com/JAAOS/A679; 5: https://links.lww.com/JAAOS/A680; 6: https://links.lww.com/JAAOS/A681; 7: https://links.lww.com/JAAOS/A682; 8: https://links.lww.com/JAAOS/A683; 9: https://links.lww.com/JAAOS/A684; 10: https://links.lww.com/JAAOS/A685; 11: https://links.lww.com/JAAOS/A686; 12: https://links.lww.com/JAAOS/A687; 13: https://links.lww.com/JAAOS/A688; 14: https://links.lww.com/JAAOS/A689]).

Figure 3.

Illustrations showing conventional intramedullary osteosarcoma may present with a variety of histologic subtypes. The most common being osteogenic, chondrogenic, and fibroblastic. A, The prototypic morphology of osteosarcoma is osteoblastic and is seen in varying proportions. It may vary from densely sclerotic areas to fine lace-like osteoid deposited between anaplastic tumor cells. Osteoid matrix ranges from pink dense glassy collagenous appearance to more basophilic (purplish) dense mineralized matrix. Atypical, pleomorphic tumor cells embedded within or surrounded by osteoid matrix in different proportions and different densities can be appreciated; less mature osteoid is characterized by pink and lace-like thin strands between cells. Some of the malignant cells lie within lacunar formations of reminiscent of osteocytes in lamellar bone formation. B, Chondroblastic osteosarcoma showing a dominant pink to bluish-gray areas of cartilaginous matrix (center right) and evident osteoblastic components embedded in-field (center left). Neoplastic chondroblastic osteosarcoma elements within lacunae and abundant cartilaginous matrix with areas of ossification are evident by the pinkish hue (central and top right areas). This is in contrast to the adjacent mineralized osteoid matrix to the right. C, Fibroblastic osteosarcoma with long sweeping and intersecting fascicles of spindle cells with focal variable cytologic atypical appearance of fibroblastic cells. Dark hyperchromatic elongated nuclei with prominent nucleoli are present. Possible glassy osteoid matrix formation is noted; similar to telangiectatic osteosarcoma, fibroblastic osteosarcoma sometimes has very focal and limited osteoid matrix formation. Slides courtesy for Hector Monforte, MD of Johns Hopkins All Children's Hospital, St. Petersburg, FL.

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