Osteosarcoma

Osteosarcoma, the most common bone malignancy in children and adolescents, often presents with an aggressive mixed lytic-sclerotic lesion, aggressive periosteal reaction and a soft tissue component containing osteoid, typically around the knee.

Description

Osteosarcoma is a highly malignant primary bone tumour characterised by the production of osteoid or immature bone by malignant cells. It is the most common primary malignancy of bone excluding myeloma and lymphoma.

Pathogenesis

The exact pathogenesis of osteosarcoma remains unclear, though it involves a complex interplay of genetic, environmental, and possibly hormonal factors. Commonly implicated genes include TP53, RB1, and genes involved in the RECQL4 pathway. There’s an association with Paget’s disease and irradiated bone.

Epidemiology, Risk Factors & Associations

• Osteosarcoma is the most common primary malignant bone tumour in children and adolescents, with a peak incidence at around 15-19 years of age (nearly 60% of cases occur in the 10-20 year age range). There is a smaller second peak in older adults (>65 years)
• Males are slightly more frequently affected than females (ratio 1.5:1)
• Certain genetic syndromes are associated with an increased risk, including Li-Fraumeni syndrome, Rothmund-Thomson syndrome, and hereditary retinoblastoma.
• Paget’s disease of bone (1% develop osteosarcoma)
• Osteomyelitis
• Ossify fibroma
• Giant cell tumour
• Fibrous dysplasia
• Radiation exposure is a significant risk factor, with osteosarcoma risk rising 5-20 years after exposure. The risk further increases with higher radiation doses.
• Alkylating chemotherapy agents have also been associated with an increased risk of osteosarcoma.

Clinical Features

• Pain and swelling, often in the metaphysis of long bones (most commonly around the knee)
• May arise in the craniofacial bones (< 10%), usually presenting with rapidly enlarging and panful mandible or maxilla
• Systemic symptoms like fever and weight loss can be present
• Pathological fractures can occur

Complications

• Metastatic disease: Most commonly to the lungs and other bones
• Local invasion causing nerve damage, joint involvement, and impaired mobility

Subtypes

• Conventional Osteosarcoma: This is the most common type, accounting for approximately 75-80% of all osteosarcomas. It most commonly arises in the metaphysis of long bones, particularly around the knee. Histologically, conventional osteosarcoma can be subclassified into osteoblastic, chondroblastic, and fibroblastic types, depending on the predominant malignant cell. Regardless of the subtype, this osteosarcoma typically presents as a mixed lytic and sclerotic lesion with an aggressive periosteal reaction.
• Surface osteosarcoma:
  • Parosteal Osteosarcoma: Parosteal osteosarcoma is a low-grade malignant variant that typically arises from the outer fibrous layer of the periosteum of long bones, particularly the posterior aspect of the distal femur. It often presents as a large, lobulated mass attached to the cortex with a broad base. Histologically, it’s characterised by a slow indolent course, with well-differentiated trabeculae of woven bone within a fibrous stroma. There’s often minimal cellular atypia, but higher grade areas can occur. It’s most ocmmon in 3rd and 4th decades.
  • Periosteal Osteosarcoma: Periosteal osteosarcoma is a rare, intermediate-grade variant that also arises from the inner germinative cambium layer of periosteum of long bones. It is most commonly found on the lower end of the femur and upper end of the tibia. Radiographically, it often presents as a saucer-shaped lesion attached to the cortex with a broad base. Histologically, it typically demonstrates a chondroblastic phenotype with malignant cartilage capped by a layer of malignant osteoid.
  • High-grade Surface Osteosarcoma: High-grade surface osteosarcoma is an extremely rare variant that arises from the surface of bones without medullary involvement. Like other osteosarcomas, it often affects the long bones but can occur anywhere. Its clinical and radiological features are often similar to those of conventional high-grade intramedullary osteosarcoma. Histologically, it’s characterised by high-grade malignant cells producing osteoid on the bone surface. Despite the surface origin, it has a poor prognosis, similar to conventional osteosarcoma.
• Telangiectatic Osteosarcoma: Telangiectatic osteosarcoma is a rare variant of osteosarcoma, which accounts for less than 5% of all osteosarcomas. It most commonly affects the metaphyses of long bones, particularly the femur and tibia. On imaging, it often presents as a large, lytic, and expansile lesion with a thin rim of reactive bone and possible fluid-fluid levels. Histologically, it’s characterised by large blood-filled cystic spaces, hence the term ‘telangiectatic,’ lined by malignant osteoid-producing cells. Prognosis is similar to conventional osteosarcoma when treated with comparable modalities. Telangiectatic osteosarcoma does not often appear as aggressive as conventional osteosarcoma

Pathological Features

Histopathology

• Gross: Large destructive, tan-white, gritty, haemorrhagic and cystic masses
• Microscopic: Characterised by hyperchromatic, pleomorphic, mitotically active anaplastic cells producing osteoid and immature bone and demonstrating a lacelike pattern – osteoblastic, chondroblastic or fibroblastic. Histologic appearance of parosteal osteosarcoma is often misdiagnosed as fibrous dysplasia

Radiological Features

General Features

Osteosarcoma typically presents as an aggressive bone lesion at the metaphysis of long bones, often near the knee:

• Distal femur (40% of cases)
• Proximal tibia (20%)
• Proximal humerus (10%)

Uncommon locations include the craniofacial bones, of which the most common sites of involvement include:

• Mandible
• Alveolar ridge
• Antral area of the maxilla

Characteristic imaging features include:

• Osteoid matrix: The production of osteoid or immature bone by the tumour is a hallmark feature of osteosarcoma, which can be identified on radiographs as a dense (less dense than bone), amorphous, cloud-like area of abnormal bone within the tumour.
• Aggressive periosteal reaction:
  • Sunburst appearance or hair-on-end sign due to perpendicular periosteal spicules of new bone formation extending into the surrounding soft tissue.
  • Codman’s Triangle refers to the elevation of periosteum away from the cortex, forming a triangle with the cortex and raised periosteum. It’s a result of rapid tumour growth.
• Soft tissue component: A soft tissue mass and cortical break through is often seen in conjunction with the bone lesion, reflecting the aggressive nature of this tumour. This can often be best appreciated on cross-sectional imaging like MRI or CT.
• Solitary, metaphyseal (site of bone growth), mixed lytic and sclerotic lesions, with a permeative or moth-eaten appearance with wide zone of transition
• Telangiectatic osteosarcoma: Fluid-fluid levels
• Skip metastases may be present: Non-contiguous lesions in same or adjacent bone.

XR

• Permeative moth-eaten destructive lesion eccentrically located in the metaphysics or metadiaphysis with osteoid matrix.
• Wide zone of transition with no sclerotic margin.
• Osteoid matrix
• An associated soft tissue mass may be visible, often with new bone formation.
• Lung metastases may be ossified

CT

• Reveal the presence of osteoid matrix mineralisation and the extent of bony destruction and soft tissue extension.
• Soft tissue mass may demonstrate osteoid matrix and low attenuation necrosis
• Contrast is not recommended as it tends to obscure bone matrix

MRI

T1 best for intramedullary extent. Fluid-sensitive sequences and C+ best for soft tissue mass

• T1: Osteoid matrix appears as low signal. Nonosteoid regions are isointense to muscle.
• T2: High signal intensity due to tumour heterogeneity (necrosis, haemorrhage). Petritumoural oedema.
• T1 C+: Intense enhancement of marrow and soft tissue mass
• DWI/ADC: Restricted diffusion may be seen in the solid tumour components.

NM

• PET FDG: Shows high uptake due to increased metabolic activity of the tumour.
• Bone Scintigraphy (Tc-99m MDP): Shows increased uptake (“hot spot”) at the tumour site. Useful for screening for multicentric disease and metastases.

Grading and Staging

Staging is based on the Enneking surgical staging system for malignant tumours, which takes into account the grade (G1-G2), local extent (T1-T2), and presence or absence of metastases (M0-M1).

Differential Diagnosis

• Ewing Sarcoma: Usually occurs in the diaphysis of long bones rather than the metaphysis. It’s also more prevalent in the younger population and typically presents as an aggressive lytic lesion with associated periosteal reaction. On a pathological level, it lacks the production of osteoid seen in osteosarcoma, and it is characterised by uniform small round blue cells. In terms of genetic alterations, Ewing sarcoma often presents with a t(11;22) translocation, which is not seen in osteosarcoma. Radiologically demonstrates a characteristic onion skin periosteal reaction (less often the sunburst appearance).
• Chondrosarcoma: Chondrosarcoma usually presents in older adults, in contrast to osteosarcoma’s predominance in the teenage population. Radiologically, it appears as a lytic lesion with calcified chondroid matrix and endosteal scalloping, which differentiates it from osteosarcoma. Pathologically, it features malignant cartilage formation instead of the osteoid matrix seen in osteosarcoma.
• Metastasis: Bone metastases can often mimic the appearance of primary bone tumours like osteosarcoma. However, they usually occur in older adults and most commonly in the spine, in contrast to osteosarcoma’s predilection for the metaphysis of long bones. Multiple bone lesions are often suggestive of metastasis rather than primary bone tumours. In terms of pathology, the type of cells seen microscopically will typically resemble the primary tumour of origin rather than the osteoblastic cells seen in osteosarcoma.
• Primary Lymphoma: Extends into the soft tissue without causing bony destruction.

Management

Management typically involves neoadjuvant chemotherapy, followed by wide surgical resection, then adjuvant chemotherapy. Limb-sparing surgery is preferred when possible. It’s imperative to collaborate with orthopaedic oncologists, medical oncologists, and radiologists for optimal patient care. Prognosis depends on the response to chemotherapy, tumour size, and the presence of metastatic disease.