MelissaZimel, MD

Osteosarcoma is a malignant bone tumor that produces osteoid, the organic matrix of bone. Approximately 85% of all osteosarcomas form de novo in the bone, and are designated primary osteosarcomas. The remaining 15%, the secondary osteosarcomas, arise from malignant transformation of bone affected by prior radiation, Paget’s disease, infarction, and other disorders.

Approximately 90% of all primary osteosarcomas are designated “conventional” and are found inthe intramedullary region of the metaphysis of long bones. There are four common histologic conventional osteosarcoma subtypes, identified by the matrix they produce. Osteoblastic osteosarcoma, representing about 50% of cases, is characterized by a bundant osteoid. The fibroblastic and chondroblastic subtypes, each seen in about 25% of cases, have a spindle cell stroma and cartilaginous matrix, respectively. The rare telangiectatic osteosarcomas are noted by a vascular matrix that contains scant osteoid.

Non-conventional osteosarcomas include parosteal, periosteal and high-grade surface osteosarcoma osteosarcomas, which, as their names suggest, are not intramedullary lesions. Non-conventional osteosarcomas are found in some what older patients, and in thecase of parosteal osteosarcoma, for one, have a better prognosis.

Epidemiology

Osteosarcoma is the most common primary malignant tumor of bone, but is rare compared toother non-musculoskeletal cancers. In the United States, there are about 1,000 new cases of osteosarcoma seen each year. (Breast, lung and prostate cancers, by contrast, are each seen at least 200 times more frequently.) Males areaffected more than females, in a ratio of 1.4:1. There is bimodal age distribution, with approximately 70% of patients between 10 to 18 years of age, with most cases coincident with the growth spurt of puberty. Parosteal and periosteal osteosarcomas are found in patients slightly older than those with conventional osteosarcoma.

Primary osteosarcoma may arise in any bone but usually develops in the extremities, at sites of rapid bone turnover. The distal femur accounts for 30% of all cases, followed by the proximal tibia (15%) and proximal humerus (15%). The metaphysis (90%) is the most common site within the bone. Osteosarcoma may also develop in the jaw, pelvis, and spine, but this is more likely in older individuals. Periosteal osteosarcoma has a predilection for the diaphysis of the femur.

Approximately 30% of cases of osteosarcoma are found in individuals over 40 years old, and are almost always secondary osteosarcomas. Secondary osteosarcomas can be found all over the skeleton. The lifetime risk of osteosarcoma in patients with known Paget’s disease is 1%, with a peak incidence in the seventh decade, accounting for half of all osteosarcoma cases in patients over 60 years old. Approximately 5% of osteosarcomas are associated with prior treatment for another malignancy. Radiation treatment is the main risk, though, chemotherapy, especially with concurrent radiation may be responsible as well.

Clinical Features

Osteosarcoma usually presents as an enlarging painful mass. Pain may be worse at night. Given the age of the typical patient, the symptoms produced by the tumor may beinitially misattributed to a sports injury or “growing pains.” The overlying skin may be warm, erythematous, and edematous with engorged veins. Large tumors may limit the ability to walk or restrict joint range of motion. In rare cases, patient present with a pathologic fracture. (Pathologic fracture is associated particularly with telangiectatic osteosarcoma.)

Metastases, most often to the lungs, are clinically detectable at the time of presentationin approximately 20% of patients. Extensive lung involvement can cause dyspnea, though this symptom, and indeed systemic complaints of any type, are rare.

Micro-metastases should be presumed present even in patients without lung nodules detected onchest computed tomography. Because occult spread can be presumed, neoadjuvant chemotherapy, namely treatment given before operating on the tumor itself, is often recommended.

In patients with prior radiation or Paget’s disease, the clinical presentation is also characterized by new onset pain or swelling. Thorough history taking is critical to establishing a diagnosis of secondary osteosarcoma.

There are no laboratory tests for osteosarcoma. Serum alkaline phosphatase and lactate dehydrogenase levels can be measured at the time of presentation, both toassess disease burden and to provide a baseline for measuring response to treatment.

Radiologic Features

Radiograph sreveal a poorly defined, destructive mass measuring 5 cm or less, arising inthe metaphysis or diaphysis. Osteosarcoma may appear lytic, blastic, or both. Aggressive periosteal reactions are common, sunburst or onion-skinning patterns, with or without a Codman’s triangle, are seen. The cortex is attenuated, and anextraosseous soft-tissue mass may be seen.

Magnetic resonance imaging (MRI) will show a mass centered in the bone that destroys the overlying cortex and has an associated soft-tissue mass, with surrounding soft-tissue and bony edema. The periosteum will be elevated from the bone, covering themass. Most commonly, osteosarcoma will not cross the physis. However, a whole bone MRI is necessary to evaluate for so-called skip metastases within the same bone. Intra-articular spread is rare, but a large effusion should raise concern for its occurrence.

Because osteosarcomas are highly active metabolically, radionuclide bone scans have hotspots demonstrating the up take within the lesion itself. The primary utility of such scans, though, is not for characterizing the primary lesion (which is readily seen on plain radiographs) but rather to detect metastases.

Telangiectatic osteosarcoma may appear primarily lytic on radiographs with internal fluid-fluid levels seen on T2 MRI sequences. They are nicknamed “bag of blood” with very little to no bone formation whatsoever. Because of the lack of bone formation, these tumors can be mistaken for benign aneurysmal bone cysts. Destructive, lytic femur lesions with enhancing solid tissue on post-gadolinium sequences and fluid-fluid levels should raise concern for telangiectatic osteosarcoma.

Osteosarcoma can be found on the surface of the bone in rare instances. A parosteal osteosarcomaemanates from the outer layer of periosteum, whereas a periosteal osteosarcoma arises from the inner layer, closer to the cortex of the bone.

Metastaticlesions, especially in the lungs, may also appear calcified. Following administration of neoadjuvant chemotherapy, the tumor may appear more ossifiedon radiographs and show less enhancement and necrosis on MRI. These findings are thought to represent a positive response to chemotherapy.

There should be high suspicion for secondary osteosarcoma when aggressive appearing bony lesions arise in previously irradiated bone or known lesions of Paget’sdisease. Secondary osteosarcoma will have a similar appearance as primary osteosarcoma (i.e., a destructive mass with extraosseous extension), but the underlying bone will be abnormal from the pre-existing conditions.

Pathology

Conventional osteosarcoma has a wide range of morphology. Critical to the diagnosis of osteosarcomais the identification of neoplastic bone and malignant spindle cell stroma. Malignant stromal cells are characterized by pleiomorphism, mitoses, and atypia. This atypia can be described as epithelioid, plasmacytoid, fusiform, small andround, or spindled, thus leading to sub-classifications of tumors based on this feature.

Conventional osteosarcoma commonly contains varying amounts of neoplastic cartilage and fibroblastic components. Based on their predominant matrix, they are subdivided into osteoblastic, chondroblastic, fibroblastic and telangiectatic. Raresubtypes also include giant cell-rich, osteoblastoma-like, epithelioid, clearcell, and chondroblastoma-like.

In osteoblastic osteosarcoma, the neoplastic bone is the principle matrix. In chondroblastic osteosarcoma, the neoplastic cartilage is usually hyaline but maybe myxoid. The chondrocytes within the matrix are severely a typical. In fibroblastic osteosarcoma, the malignant cells are spindled and demonstrate severe cytological atypia.

Conventional osteosarcoma has complex, highly aneuploid karyotypes with multiple numerical and structural chromosomal aberrations. The malignant osteoblasts stain positively for the nuclear stain SATB2.

Differential Diagnosis

• Ewingsarcoma
• Other bones arcomas, such as fibrosarcoma
• Lymphoma
• Osteomyelitis

Disease Course: Treatment and Prognosis

The diagnosis of osteosarcoma is usually established by conventional imaging, though all patients should have their diagnosis confirmed by a biopsy. This biopsy can be performed as an open procedure or percutaneously. The biopsy should be performed by an orthopedic oncologist or by a radiologist who has discussed needle placement with the surgeon who will perform the definitive surgicalresection. It is critical minimize the contamination of healthy tissue by tumor cells.

Whole body imaging is needed for initial staging. The staging system of the Musculoskeletal Tumor Society (also known as the Enneking classification) is commonly used. The Musculoskeletal Tumor Society system considers any tumor with known metastases to be Stage III. Among those without known metastases, tumors with low grade histology are StageI and high grade are Stage II. Stage I and Stage II are further sub-classified as either intra- or extra-compartmental, based on whether the tumor has extended beyond its anatomical confines, e.g., the bone or fascial plane. The full staging system, accordingly is as follows:

• StageIA: low-grade, no metastasis, intra-compartmental
• StageIB: low-grade, no metastasis, extra-compartmental
• StageIIA: high-grade, no metastasis, intra-compartmental
• StageIIB: high-grade, no metastasis, extra-compartmental
• StageIII: metastasis is present, independent of grade

Pediatric patients with osteosarcoma are given neoadjuvant chemotherapy with adriamycin, cisplatin, and high-dose methotrexate for 11 weeks. For adult patients, cisplatin and adriamycin are given. High-dose methotrexate is less commonly administered.

After acourse of neoadjuvant chemotherapy, amputation or limb-salvage surgery is then under taken. The only strict indication for amputation is a tumor that completely surrounds the nearby neurovascular bundle.

Limb-salvage surgery aims to save the use and appearance of the limb by removing only the tumor and retaining the normal tissue distal to it. Because a large amount of bone ordinarily must be removed to completely excise the tumor, some form of reconstruction is necessary. (If the tumor is found in a non-load-bearing bone, such as the fibular or clavicle, resection alone suffices.) Complete distal femoral replacements, proximal tibia replacements, and proximal humerus replacements are commonly used. Allografts and vascularized fibula free flapsare options too.

A rotationplasty may be suggested for very young patients with osteosarcoma of the distal femur who would otherwise face an above-the-knee amputation. In a rotation plastyprocedure, the distal femur and proximal tibia is removed, with distal tibiaretained. This bone is then rotated 180 degrees and attached to the distal femur. With this rotation and reattachment, the native ankle joint, now transposed, can serve as an active hinge where the knee once was. This allows for a more functional prosthesis.

Two to three weeks following surgery, once the surgical wounds have healed, adjuvant chemotherapyis restarted. The choice of chemotherapeutic agents is based on the response to the initial neoadjuvant chemotherapy. Ideally, 90% or more of the specimen removedat surgery should be necrotic. A poorer response suggests that different agents may be needed.

The lungs are the most common site of metastatic disease. Lung metastases are more likely to present in patients with axial-located or large tumors, and those with a longer history of symptoms. Spread to lymph nodes or other bones can occur, albeit much less commonly. Any clinically detectable metastatic disease should be removed (ina so-called metastasectomy procedure).

Radiation is used only to palliate patients with metastatic disease not amenable to surgery. Osteosarcoma, in general, is resistant to radiation.

The current 5-year survival rate for all patients with non-metastatic osteosarcoma is approximately 70%. Among those patients who respond well to neoadjuvant chemotherapy (definedas 90% necrosis of the specimen removed at surgery), complete local resection of the tumor is associated with a 5-year survival rate greater than 80%. Patients presenting with overt metastatic disease have a 10-year survival rate of about 25%. Poor prognosis is associated with a tumor originating in the axial skeleton, large tumor volume, metastatic disease at diagnosis, and poor response to preoperative chemotherapy.

Osteosarcoma associated with Paget’s disease has a poor prognosis, with a 5-year survival rate of 10%. Radiation-induced osteosarcoma has an estimated 5-year survival of 42-58%.

Commonly Tested on Exam

1. Recognizeclinical and radiographic findings
2. Treatment protocols
3. Recognize secondary osteosarcoma

Acknowledgements

AmirQorbani, MD – histology photos and description.

Controversies and frontiers

JB: need lebiopsy ok? Genetics? Mention small cell?

Needed figures

• X-ray of osteosarcoma, showing periosteal reactions sunburst or onion-skinning patterns, Codman’s triangle
• Magnetic resonance imaging of tumor with skip lesion?
• bone scan
• path slides showing histologic conventional osteosarcoma subtypes (osteoblastic, fibroblastic, chondroblastic and telangiectatic)
• imaging of non-conventional osteosarcomas include parosteal, periosteal
• surgical treatment, including prostheses and rotationplasty