The most frequent primary tumor of the skeleton

Osteosarcoma. What is it?

Osteosarcoma is a rare type of primary malignant tumor of bone tissue, characterized by the abnormal and uncontrolled growth of immature bone tissue.

There are different forms of it depending on its location, aggressiveness, and the type of cells from which it is composed; however, we can distinguish the most common, extremely aggressive forms called high-grade (classic osteosarcoma) and the less common, less aggressive forms called low-grade.

Classical osteosarcoma primarily affects young individuals, with a peak incidence among adolescents and young adults; although osteosarcoma can develop in any bone in the body, it is most common in the regions of the long bone ends, such as the distal femur, proximal tibia, and proximal humerus.

The origin of osteosarcoma is complex and may be related to genetic and environmental events. Some cases may be associated with inherited genetic mutations, while others may be caused by radiation exposure or previous chemotherapy treatment.

The dominant symptom is prolonged pain, even at rest and often at night; swelling of the affected area may be present, especially in more advanced stages; rarely, osteosarcoma may directly initiate with a pathologic fracture.

Diagnosis of osteosarcoma involves a combination of imaging tests, such as radiographs, computed tomography (CT) scans, and MRIs, to assess the extent of the tumor and involvement of other bone structures. Definitive confirmation is obtained through a bone biopsy, in which a tissue sample is taken and analyzed under a microscope to identify histologic features typical of osteosarcoma.

Treatment of osteosarcoma usually involves a combined approach that includes surgery and chemotherapy. Surgery aims to completely remove the tumor, and in some cases, may require replacement of the removed bone tissue with grafts or prostheses. Chemotherapy is used exclusively in high-grade forms, both before and after surgery, to reduce tumor size, prevent metastatic spread, and destroy any residual tumor cells.

Survival is directly related to tumor grade, presence of metastases, ability to perform extensive excision surgery, and response to chemotherapy.

Despite advances in diagnosis and treatment, osteosarcoma still poses a significant clinical challenge, as it can be resistant to therapy and can spread to the lungs or other parts of the body. Therefore, regular follow-up and long-term monitoring are critical to detect any recurrence early and effectively manage this complex disease.

Research continues to investigate the biology of osteosarcoma and identify new treatment options to improve the prognosis and quality of life for patients with this disease.

Who is affected?

Osteosarcoma mostly affects males, with a ratio of 2 to 1.

Although it can occur at all ages, two peaks of incidence can be identified; a first peak between the second and third decades of life where it occurs with an incidence of about 5.2 cases per million people per year and a second peak, after age 60, where it usually arises as a complication of other diseases, primarily Paget’s disease of the bone.

Thus, we infer a direct correlation between the development of osteosarcoma and the high metabolic activity of bone that can occur either during the period of major skeletal growth or secondary to certain skeletal diseases.

Certain race-related factors would also appear to be implicated in the occurrence of osteosarcoma, being found more in African American males.

What is it caused by?

The origin of osteosarcoma is essentially unknown; this lack of information is partly related to the rarity of the disease, the difficulty of finding sufficient data, and the difficulty of developing in vitro study models.

Several predisposing and risk factors have been identified, although their role is not entirely clear; these factors may be genetic with an influence of about 30% such as mutations in the Rb1 gene and other inherited genetic disorders such as Li-Fraumeni syndrome, Rothmund-Thomson syndrome, Bloom syndrome, and Werner syndrome; acquired factors are expected to be implicated in about 70% of cases and to be related to environmental factors such as radiation, previous use of toxic alkylating agents (mustards, platinum derivatives), radiotherapy or acquired diseases such as, precisely, Paget’s disease.

Thus, several genes have been identified, the mutation of which would appear to be involved in the development of osteosarcoma with direct prognostic value as well, such as TB1, NOTCH1, C-Fos, HER2, C-Myc, FGFR1, PTEN, and several micro-RNA components.

It is not uncommon that a trauma is reported in the history of the affected individual; however, such an event is probably only occasional and is more likely the reason why diagnostic procedures are put in place that detect a preexisting neoplastic pathology that was asymptomatic up to that point.

Clinical features

Among the clinical features, the main and earliest is the pain; this is initially insidious also because it is transient, later it becomes intense, persistent, exacerbates during night rest, and is unresponsive to common painkillers.

Another sign that may be present is tumefaction, which initially may be minimal but becomes increasingly evident as the neoplasm grows. The consistency of this tumefaction is frequently hard-osseous (osteogenic forms), but may be, more rarely, tense-elastic (in osteolytic forms), however it is fixed on the underlying planes. The overlying skin is shiny and taut, with dilatation of the superficial veins.

In osteolytic forms, the onset may be that of a spontaneous fracture of the affected bone (pathologic fracture).

The sites primitively and most commonly affected by osteosarcoma are, in young subjects, the long bones: femur (44%), tibia (17%), humerus (15%), especially at the metaphyseal level; in older patients these anatomical regions are affected in only 14.5% of cases, while the neoplasm develops most frequently at the level of the axillary skeleton (27%), craniofacial bones (13%) and in extra-skeletal sites (11%).

As the disease progresses, tumor cells may acquire the ability to penetrate the circulatory system and reach other sites, at a distance from the site of the primary tumor; thus, so-called metastasis develops, which is the most fearsome complication for patient survival.

Metastases are in most cases pulmonary but become symptomatic, causing respiratory problems, only in advanced stages of the disease. Metastases by the lymphatic route are to be considered quite exceptional.


The diagnosis of osteosarcoma is based on histologic confirmation of a clinical suspicion. For this to occur as expeditiously as possible, close collaboration between the specialists involved is necessary, particularly in the first instance, the clinician, often the orthopedic surgeon, the radiologist, and the anatomopathologist.

Clinical suspicion is derived from the proper consideration of such elements as the patient’s age, site of the lesion, and symptomatology.

Often diriment, for diagnostic purposes, is the radiological aspect.
Osteosarcoma, in fact can have a variable degree of ossification, and this characteristic directly affects the radiological appearance: the higher the level of ossification, the more radiopaque the appearance will be (“white” appearance on RX!!) and the easier the radiographic diagnosis will be.

The earliest radiologic aspects are represented by the presence of an irregular bony neoformation with radiolucent and/or radiopaque areas affecting the cortical over time.

As the tumor passes the cortical, it comes into contact with the periosteum, inducing what is called a “periosteal reaction”; the uplift of the periosteum by the tumor activates its bone deposition, which takes on extremely characteristic aspects with production of bony trabeculae, perpendicular to the bone surface, giving a radiological ‘sunburst’ appearance.

With time, the periosteal reaction itself, is eroded in the most central part by the tumor itself; the most peripheral part, which is still intact, takes on a triangular appearance that forms the radiological sign known as Codman’s triangle.

It should be emphasized that all of these features, which are often diagnostic, can be seen on a classic dual-projection, antero-posterior and latero-lateral radiograph.

Imaging is, therefore, usually completed with a Computed Tomography (CT) scan, both of the affected segment and of the lungs, and with a Nuclear Magnetic Resonance Imaging (MRI) of the limb, with and without contrast medium. The CT scan makes it possible to better highlight all those features present on radiography, such as the type of erosion, the presence of cortical erosion, the periosteal reaction, and to identify any distant metastases; the MRI of the affected segment, makes it possible to assess the intramedullary extension of the sarcoma, and the impairment of soft tissues, especially in the poorly osteogenic forms. Especially MRI, it is important to delineate the boundaries of the disease and identify the cutting margins to excise the tumor.

In the last decade, FDG-PET, a dynamic examination that allows the assessment of tumor metabolism based on the identification of cellular glucose, has taken on fundamental importance; the most aggressive cells, usually cancer cells, in fact consume more glucose, which is highlighted by the examination as it is labeled with a radioactive substance. PET scanning is then used both to search for possible metastases and to assess the tumor’s response to medical therapy.

Arteriography may still be of some use in rare selected cases.

Clinical-radiological suspicion, however clear, must be confirmed by biopsy sampling of pathological tissue and histological examination.

The biopsy is therefore necessary and although it “opens up” the tumor, it gives us information that is essential to be able to start treatment; it must be performed by experienced hands, usually by the same team that will then take charge of treating the tumor, because it must be performed at very specific sites, which can then be removed en bloc with the disease with surgery.


Treatment of osteosarcoma depends on the degree of malignancy.

  • Low-grade osteosarcoma is treated exclusively by surgical excision, removing the tumor with a layer of surrounding healthy tissue (wide margin excision).
  • High-grade osteosarcoma is treated with combination of chemotherapy and surgery.

The classic scheme for limb osteosarcoma involves preoperative chemotherapy, wide margin excision surgery, and postoperative chemotherapy.

The currently most widely used drugs are andriamycin, methotrexate, cis-diaminoplatin, and isophosphamide. Currently, scientific research is attempting to identify and test new chemotherapies targeting specific molecular changes in osteosarcoma.

Response to chemotherapy is assessed by clinical data (such as regression of pain), laboratory data (reduction of alkaline phosphatase), ‘imaging’ data (arrest of growth, ossification and capsule formation, regression of vascularization, reduction of uptake of the radioactive isotope used), and histological assessment of the extent of necrosis of the surgical piece, which must reach a percentage of necrotic tissue greater than 90% to be satisfactory.


The prognosis of osteosarcoma depends on the following factors:

  • histological features of the tumor
  • degree of malignancy
  • radiological characteristics
  • presence or absence of pathological fractures
  • tumor size
  • age and sex of the patient
  • location of the tumor
  • response to chemotherapy when indicated

For the low-grade forms of the limbs the survival is 95% at 5 years, while for the high-grade forms, always of the limbs, the survival varies in the different cases from 60 to 80%, depending mainly on the appearance or not. metastasis and response to chemotherapy. For the forms in other localizations, there are no completely reliable data.