Conventional osteosarcoma

Conventional osteosarcomas (COS) are high-grade malignant bone-forming tumors typically arising within the medullary cavity of bone ^1-3.

Epidemiology

Conventional osteosarcoma is the most common subtype of osteosarcoma consisting of approximately 75-80% of all cases ^1-4. It is most frequently seen in the 2^nd  decade and later with a smaller peak in the 5^th decade of life. Men are more commonly affected ¹.

Diagnosis

The diagnosis of conventional osteosarcomas is based on a combination of typical radiographic features and histology ^1,2.

Diagnostic criteria

Diagnostic criteria according to the WHO classification of soft tissue and bone tumors (5th edition) ¹:

• imaging features of a bone tumor

• permeative and destructive growth pattern

• osteoid/bone production by tumor cells

• location within the medullary cavity

The following criteria are desirable:

• high-grade atypia of tumor cells

• frequent atypical mitotic figures

Clinical presentation

The typical clinical presentation includes pain and a growing mass for weeks or months and sometimes restricted motion in the adjacent joint ^1,5. Additional symptoms include erythema and warmth.

A small number of patients will present with a pathological fracture.

Complications

Complications include the following ¹:

• skip lesions and distant metastases (e.g. lung)

• pathological fracture: ~10-15%

Pathology

Conventional osteosarcomas are predominantly intramedullary located osteoid-producing highly aggressive and malignant mesenchymal tumors associated with high mitotic activity and frequent tumor necrosis ^1,2.

Etiology

The exact etiology of osteosarcoma and conventional osteosarcoma is unknown ¹.

However, sporadic conventional osteosarcoma is characterized by chromosomal instability and there are a few rare syndromes with germline mutations in RECQ helicases associated with conventional osteosarcoma ¹.

Location

Conventional osteosarcomas are usually found in the long bones of the extremities but can occur in any bone ¹.

The most frequent locations are as follows ^1,2,6:

• distal femur: ~30%

• proximal tibia: ~15%

• proximal humerus: ~15%

• jaws

• axial skeleton

Within the long bones, the tumors arise usually from the metaphyses ~90%, infrequently from the diaphysis ~9% and only rarely from the epiphysis <1% ¹.

Macroscopic appearance

Macroscopically conventional osteosarcomas are characterized by the following features ¹:

• often a large intramedullary mass of the metaphyseal region

• variable extension into the adjacent epiphysis or diaphysis

• densely solid tan-white/yellow heavily mineralized components

• grey and rubbery non-mineralized cartilaginous parts

• areas of hemorrhage

• areas of tumor necrosis

• cystic change

• eccentric circumferential soft tissue mass in the setting of soft tissue extension

• possible displacement of the periosteum

Microscopic appearance

Microscopically, conventional osteosarcomas display a broad spectrum with the following histological features ¹:

• neoplastic bone formation (essential)

• permeative growth pattern with erosion of preexisting trabeculae

• new bone formation

• severe anaplasia and pleomorphism

• high mitotic activity

 Based on their predominant histological pattern conventional osteosarcomas can be divided into the following subtypes ^1-4,7,8:

• osteoblastic: thin lace-like trabeculae to compact bone formation

• chondroblastic: neoplastic hyaline cartilage merging with neoplastic bone

• fibroblastic: predominantly spindled or less commonly epitheloid cells with extracellular collagen

Immunophenotype

On immunohistochemistry conventional osteosarcomas display a broad profile, but without any specificity. Frequently positive antigens include osteocalcin, osteonectin, osteoprotegerin, SATB2, RUNX2, S100, actin and CD99. Conventional osteosarcomas might be also positive for EMA and keratin ¹.

Usually, tumors are negative for CD31, CD45 and FOS ¹.

Radiographic features

Characteristic imaging features of conventional osteosarcoma include ¹:

• tumor mineralization with an osteoid tumor matrix

• permeative bone destruction

• periosteal displacement with reactive new-bone formation with different patterns

• extraosseous soft tissue extension

The osteoblastic subtype displays a more dense cloud-like mineralization pattern whereas a more lytic radiographic appearance suggests fibroblastic or chondroblastic subtypes with unmineralized tissue components ^8-10.

Plain radiograph

Characteristic appearances of conventional osteosarcoma on plain radiographs include the following ^1,2,8-10:

• osteolytic lesion

• a wide, indistinct transition zone

• non-expansile cortical destruction

• aggressive periosteal reaction (sunburst, onion skin-like, Codman triangle)

• increased soft tissue density 

MRI

MRI shows an aggressive bone-forming tumor with bone destruction and often with soft tissue extension and plays an essential role in assessing local tumor extent, including joint involvement and the detection of skip metastases ^8-10. Whole-body MRI with DWI can be used for the detection of distant skeletal metastases ⁹.

Signal characteristics

• T1: heterogeneous low to intermediate signal

• T2: heterogeneous high signal with low signal areas

• STIR/IMFS: high signal with hemorrhagic and hypointense areas

• T1 C+ (Gd): enhancement of viable tumor and hypointense non-enhancing ossified parts

 It is of note that native T1 weighted images are considered most accurate in predicting medullary involvement or intraosseous tumor extent ^8-12, whereas fluid-sensitive sequences are used for evaluation of soft tissue extension ^9,10. Septonodular or rim enhancement suggests a chondroblastic subtype ^8,9.

Nuclear medicine

FDG-PET shows increased glucose metabolism and is considered sensitive in the detection of distant metastases ^9,10.

Radiology report

The radiological report should include a description of the following:

• form, location and size

• osteoid matrix, growth pattern

• tumor margins and transition zone

• periosteal reaction, cortical erosion, cortical breakthrough

• soft tissue extension and neurovascular involvement

• epiphyseal extension

• joint involvement ⁸:

  • intraarticular mass with disruption of synovial membrane or cartilage

  • joint effusion or its absence

• skip metastases

• distant metastases

Treatment and prognosis

Management consists of wide surgical resection combined with neoadjuvant and postoperative chemotherapy ^1-4 with multiple agents ^1,13-15 traditionally including methotrexate, adriamycin, cisplatin and ifosfamide. Nowadays limb-salvage techniques are often used. Radiation therapy plays a role in the setting of unresectable tumors ¹.

Prognosis hugely depends on metastatic spread at the time of diagnosis, histological response to neoadjuvant chemotherapy, location of the primary tumor, and surgical resection margins. 

Approximately up to 70% of patients with localized disease are long-term survivors. This can increase to >80% in the setting of good response to chemotherapy (defined as ≥90% tumor necrosis) and complete resection with negative margins. On the other hand patients with recurrent or metastatic disease show a low survival rate of <30% and poor response to neoadjuvant therapy as well as incomplete resection are poor prognostic factors as well as proximal extremity or axial skeleton involvement or large tumor size ¹.

Differential diagnosis

Lesions that look similar to conventional osteosarcomas on imaging studies include the following entities ⁴:

• small cell osteosarcoma

• low-grade central osteosarcoma

• chondrosarcoma

• chondroblastoma

• chondromyxoid fibroma

• Ewing sarcoma

• osteoblastoma