The most frequent primary tumor of the skeleton

Osteosarcoma. What is it?

Osteosarcoma is the most frequent primary tumor of the skeleton.

Often with a high degree of malignancy, it consists of mesenchymal cells that produce a bone matrix that may or may not be calcified and / or immature bone.

It mainly affects the bones of the limbs, especially the lower ones, with 50% of cases localized in the knee area. The dominant symptom is prolonged pain, even at rest and often at night.

Diagnosis is complex and requires the integration of orthopedic specialists, radiologists and pathologists with specific experience. Patient survival is linked to the response to therapy and the presence or absence of distant localizations (metastases), which usually affect the lungs.

Who is affected?

It generally affects males more than females, with a 2/1 ratio.

The age of onset of osteosarcoma is quite variable but in 61% of cases, it occurs between the first and second decade of life (up to 20 years). Only 10% of all osteogenetic sarcomas affect individuals over the age of 60 and in such cases they are almost always secondary to other pathologies.

It is reasonable to derive from these data a connection between the development of osteosarcoma and the rapid skeletal growth that occurs during the adolescent period.

What is it caused by?

Osteosarcoma can originate with no apparent cause, or be secondary to other skeletal diseases (cases that often develop late in life). It is not uncommon for bone trauma to be reported in the history of the affected person. Probably this event is not the cause of the tumor development, but it represents the reason for which diagnostic procedures are put in place that detect a pre-existing neoplastic pathology, up to that moment asymptomatic.

There are increasingly convincing data that link osteosarcoma with genetic defects: in particular, an association with familial retinoblastoma has been found in which the tumor suppressor gene located on chromosome 13 is deleted. Osteosarcoma genotype is very complex.

Many gene alterations have been identified that could lead, in the future, to identifying possible therapeutic targets. Finally, the reported function of the SV40 virus in the onset of osteosarcoma is still controversial.

Conditions predisposing the onset of secondary osteosarcoma can be:

  • Exuberant calluses in fracture repair in subjects with osteogenesis imperfecta
  • Fibrous dysplasia
  • Paget’s disease of the bone
  • Previous exposure to ionizing radiation.

Clinical features

Among the clinical features, the main and earliest is pain; this is initially insidious also because it is transient, subsequently, it becomes intense, persistent, exacerbates during the night’s rest and is not very sensitive to common painkillers.

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

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

The primary sites and most 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 only in 14.5% of cases, while the neoplasm develops more frequently in the axial skeleton (27%), in the craniofacial bones (13%) and in extra-skeletal sites (11%)

The distant localizations (metastases), which represent the most fearful complication, are often pulmonary.


The first factor to be taken into consideration for the purpose of a correct and rapid diagnosis of osteosarcoma is that of close collaboration between the specialists involved, in particular the clinician, often the orthopedist, the radiologist, and the pathologist. In the clinical setting, elements such as the age of onset of the tumor, its location, and symptoms must be taken into consideration.

Decisive for the purpose of diagnosis are often the radiological and radiographic aspects in relation to which it must be said that osteosarcoma can show a variable degree of ossification. The higher the level of ossification, the easier the radiographic diagnosis through the detection of radiopacity. The earliest radiological aspects are represented by the presence of an irregular bone neoformation with radiolucent and / or radiopaque areas that over time affects the cortex. This involvement is evident with its erosion and overcoming with consequent involvement of the surrounding soft tissues.

Frequently there is a periosteal reaction with the production of bone trabeculae, perpendicular to the bone surface, which give a radiological appearance to ‘sun rays’. During the production of these trabeculae, the periosteum detaches towards the outside, delimiting a triangular space which constitutes the radiological sign known as ‘Codman’s triangle’.

It should be emphasized that all these characteristics, often diagnostic, can be highlighted with a classic radiograph in several projections.

Other useful imaging techniques are computed tomography (CT) and nuclear magnetic resonance (NMR) with and without contrast. The first is useful in highlighting the intramedullary extension of the sarcoma, in revealing the presence of metastases and finally in evaluating the neurovascular compromise of the joints and cortical bone. The second, on the other hand, allows us to specify the size of the tumor as well as its intramedullary extension and the involvement of soft tissues, especially in the poorly osteogenic forms.

These modern imaging techniques represent a useful guide to perform selective surgical resections and, when possible, not excessively demolitive.

Arteriography may still be of some use, in selected rare cases, while data is being acquired for a possible diagnostic validation of PET. The diagnosis of overt osteosarcoma does not usually present major difficulties both from a clinical, radiological and histological point of view, although the determination of the histotype on the biopsy material is not always easy. The essential histological aspect is the presence of bone matrix directly in contact with neoplastic cells with malignant characteristics; in the absence of frank matrix deposition, diagnosis can be difficult.


Treatment of osteosarcoma with a high degree of malignancy is based on pre and post-operative chemotherapy and surgery of the primary tumor and metastases. The drugs currently most used are andriamycin, methotrexate, cis-diaminoplatin, and isophosphamide. Currently, scientific research is attempting to identify and experiment with new chemotherapies aimed at specific molecular alterations of osteosarcoma.

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

In the low-grade forms of malignancy, a wide-margin surgery is sufficient and there is no indication for other therapies.


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.