Courtesy: Dr Manish Agarwal, Hinduja Hospital, Mumbai, India

Definition

• Osteosarcoma is a primary malignant bone tumor in which neoplastic cells produce osteoid matrix.

• This feature differentiates it from other tumors such as Ewing sarcoma, which does not produce osteoid.

• It is the most common primary malignant bone tumor of non-hematopoietic origin.

• Among all primary malignant bone tumors, it is the second most common overall, after multiple myeloma.

• Diagnosis must always be confirmed through biopsy followed by histopathological examination.

Histopathological Characteristics

• Tumor cells are located directly adjacent to osteoid matrix.

• No intervening normal osteoblast layer is present between the tumor cells and osteoid.

• Additional microscopic components may include:

  • Cartilage

  • Fibrous tissue

  • Vascular spaces

  • Sheets of small round cells

• These features indicate a high-grade malignant tumor.

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Classification of Osteosarcoma

Primary Osteosarcoma

Primary osteosarcoma is divided into two major groups.

Intramedullary Osteosarcoma (about 95 percent)

• High grade

  • Osteoblastic

  • Chondroblastic

  • Fibroblastic

  • Other variants

• Low grade (rare)

Surface Osteosarcoma (about 5 percent)

• Parosteal osteosarcoma

• Periosteal osteosarcoma

• High grade surface osteosarcoma

• Dedifferentiated parosteal osteosarcoma

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Conventional Osteosarcoma

Incidence

• Approximately 3 to 5 cases per million population in individuals aged zero to twenty four years.

• Accounts for 3 to 5 percent of childhood cancers.

Age Distribution

• Most common between 10 and 25 years of age.

Sex Distribution

• Male to female ratio is approximately 1.4 to 1.

Common Site

• The region around the knee joint is the most frequent location, particularly the distal femur and proximal tibia.

Second Age Peak

• A second peak occurs between 60 and 75 years in Western populations.

• This is usually due to secondary osteosarcoma, often associated with Paget disease of bone.

• This pattern is less commonly seen in India and other Asian countries.

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Histological Subtypes

Common histological variants include:

• Osteoblastic osteosarcoma

• Chondroblastic osteosarcoma

• Fibroblastic osteosarcoma

• Telangiectatic osteosarcoma

• Small round cell osteosarcoma

• Giant cell–rich osteosarcoma

Clinical Significance

• These subtypes generally do not significantly alter prognosis.

• However, they may sometimes create diagnostic confusion.

Special Variant

Telangiectatic osteosarcoma

• Appears as a purely lytic lesion on imaging.

• Can resemble an aneurysmal bone cyst.

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Histological Grading

High Grade Osteosarcoma

• Composed of pleomorphic malignant cells.

• Cells have large hyperchromatic nuclei.

• Frequent mitotic figures are present.

Low Grade Osteosarcoma

• Characterized by:

  • Fewer pleomorphic cells

  • Low mitotic activity

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Low Grade Intramedullary Osteosarcoma

• Rare tumor.

• Slow growing.

• Has the potential to dedifferentiate into a high grade tumor.

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Surface Osteosarcoma

Surface osteosarcomas arise from the outer surface of bone and represent approximately five percent of all osteosarcomas.

Parosteal Osteosarcoma

• Originates adjacent to the external surface of bone.

• Most commonly located on the posterior aspect of the distal femur.

• Usually low grade.

Periosteal Osteosarcoma

• Arises from the periosteum.

Radiological Features

• Marked periosteal reaction

• Codman triangle

• Onion skin appearance

• Hair-on-end pattern

• Scalloping of the cortex

• Linear streaks perpendicular to bone surface representing tumor growth along vascular channels

Histology

• Predominantly well differentiated cartilage with minimal osteoid production.

• Can resemble chondrosarcoma, which forms an important differential diagnosis.

Grade

• Usually low to intermediate grade.

High Grade Surface Osteosarcoma

• Rapidly growing tumor.

• Histology resembles conventional high grade intramedullary osteosarcoma.

• Treatment approach is similar to conventional osteosarcoma.

Dedifferentiated Parosteal Osteosarcoma

• Develops when a long-standing low grade parosteal osteosarcoma transforms into a high grade tumor.

• Associated with poor prognosis.

• Often less responsive to chemotherapy.

• Treatment involves chemotherapy and wide surgical excision.

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Secondary Osteosarcoma

Secondary osteosarcoma develops in bone affected by a preexisting disorder, including:

• Paget disease of bone

• Bone infarction

• Fibrous dysplasia

• Previous radiation exposure

Clinical Characteristics

• Rare in young individuals.

• Accounts for more than half of osteosarcoma cases in patients older than sixty years.

• These tumors are usually high grade and have a poor prognosis.

• They tend to respond poorly to adjuvant therapy.

• More common in Western populations than in Asian populations.

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Extraskeletal Osteosarcoma

• A high grade soft tissue sarcoma that produces bone or osteoid but does not arise from bone.

• Managed similarly to other high grade soft tissue sarcomas.

Treatment

• Wide surgical excision

• Radiotherapy

Chemotherapy has not consistently shown clear benefit in these tumors.

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Etiology and Risk Factors

The exact cause of osteosarcoma remains unclear.

Known risk factors include:

• Germline mutations involving:

  • Tumor protein p53 gene

  • Retinoblastoma gene

• Radiation exposure

• Preexisting bone disorders

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Initial Patient Assessment

The first step in evaluation is determining whether the limb is:

• Salvageable

• Borderline salvageable

• Not salvageable

This assessment guides the treatment plan.

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Imaging Evaluation

Plain Radiograph

Typical findings include:

• Metaphyseal osteoblastic lesion

• Sunburst periosteal reaction

• Hair-on-end pattern

• Codman triangle

• Ill defined permeative margins

• Soft tissue extension

Other radiological appearances may include:

• Purely lytic lesions

• Moth-eaten bone destruction

• Diaphyseal involvement

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Magnetic Resonance Imaging

Magnetic resonance imaging is essential for:

• Assessing extent of the tumor within bone

• Detecting soft tissue involvement

• Evaluating neurovascular bundle involvement

• Assessing joint involvement

• Identifying skip lesions

• Planning the biopsy site

• Local staging

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Staging Investigations

Standard staging includes:

• Magnetic resonance imaging of the affected bone

• Chest radiograph

• Computed tomography of the chest

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Chest Radiograph

• Used to identify pulmonary metastases.

• Can detect nodules larger than approximately eight millimeters.

Computed Tomography of Chest

• Detects pulmonary metastases as small as two millimeters.

• A standard multislice spiral computed tomography scan is usually adequate.

Positron Emission Tomography with Computed Tomography

• May help detect rare metastatic sites such as lymph nodes.

• Useful for evaluating response to treatment.

• Not yet included in all standard treatment guidelines.

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Biopsy

• Histological confirmation is mandatory before initiating treatment.

• Core needle biopsy is generally preferred.

• If the biopsy was performed elsewhere, slide review is recommended.

• Open biopsy should be avoided, unless performed by the surgical team responsible for definitive treatment.

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Treatment Strategy

The standard treatment approach involves:

1. Neoadjuvant chemotherapy

2. Wide surgical resection or amputation

3. Adjuvant chemotherapy

4. Resection of pulmonary metastases, when present and surgically removable

Survival Improvement

• Surgery alone historically produced very poor survival rates.

• Combined chemotherapy and surgery significantly improved outcomes.

Current outcomes:

• Two year survival: approximately fifty to eighty percent

• Five year survival: approximately sixty to seventy percent

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Chemotherapy Regimens

Commonly used agents include:

• High dose methotrexate

• Doxorubicin

• Cisplatin

• Ifosfamide

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Neoadjuvant Chemotherapy

Benefits include:

• Control of micrometastatic disease

• Time for custom prosthesis preparation

• Improved tumor demarcation for limb salvage surgery

Typical treatment course:

• Total of six to nine cycles

• Two to five cycles before surgery

Advantages

• Reduces tumor vascularity

• Sterilizes satellite tumor cells

• Thickens the pseudocapsule around the tumor

• Facilitates healing of pathological fractures

Toxicity Considerations

• Methotrexate may cause acute toxicity.

• Ifosfamide may cause permanent infertility.

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Prognostic Assessment

The histological response to chemotherapy is the most important prognostic indicator.

Tumor necrosis grading after chemotherapy:

• Grade one: minimal or no necrosis

• Grade two: more than ten percent viable tumor

• Grade three: more than ninety percent tumor necrosis

• Grade four: complete tumor necrosis with no viable tumor

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Surgical Management

Surgery is mandatory, regardless of chemotherapy response.

Unlike Ewing sarcoma, osteosarcoma is relatively resistant to radiotherapy.

Resectable metastatic lesions should also be surgically removed.

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Decision Factors in Treatment

Management decisions depend on:

• Presence or absence of metastasis

• Feasibility of limb salvage

• Financial and social factors, including cost of chemotherapy and prosthetic reconstruction

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Amputation

Required in approximately ten to fifteen percent of cases.

Indications include:

• Very large tumors

• Previous unplanned surgery

• Improper or contaminated biopsy

• Extensive soft tissue involvement

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Limb Salvage Surgery

Prerequisites include:

• Ability to achieve wide surgical margins

• Availability of chemotherapy treatment

• Adequate financial resources

Recommended Surgical Margins

• Approximately three centimeters of normal bone margin

• At least one healthy muscle layer around the tumor

• Natural barriers such as:

  • Growth plate

  • Periosteum

  • Thick fascia

A marginal margin near neurovascular structures may occasionally be accepted.

Prosthesis Considerations

• Rotating hinge prostheses with hydroxyapatite coated collars show better long term survival than fixed hinge prostheses.

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Limb Salvage in Children

The major issue is limb length discrepancy.

Solutions include:

• Expandable or growing prostheses, which can be lengthened as the child grows.

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Rotationplasty

A reconstructive procedure in which:

• The limb is rotated 180 degrees.

• The ankle joint functions as a new knee joint.

Advantages

• Durable and mobile joint function

• Better gait compared with above knee amputation

• Compensation for limb length discrepancy

• Children adapt well to the prosthesis

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Outcomes

Survival

• Non metastatic disease: 60 to 70 percent survival

• Metastatic disease: 20 to 30 percent survival

Recurrence Pattern

• About 85 percent of relapses occur within the first three years.

• Approximately 95 percent occur within the first five years.

Failure Pattern

• Local recurrence rate is less than ten percent.

• Most treatment failures occur due to lung metastases.