Osteosarcoma pathophysiology

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2];Associate Editor(s)-in-Chief: Suveenkrishna Pothuru, M.B,B.S. [3]

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Overview

The osteosarcomas may be localized at the end of the long bones (commonly in the metaphysis). Most often osteosarcoma affects the upper end of the tibia, humerus, or lower end of the femur. On gross pathology, areas of bone formation, hemorrhage, fibrosis, and cystic degeneration on cut surface are characteristic findings of osteosarcoma. On microscopic histopathological analysis, presence of osteoid within the tumor, pleomorphic cells, anaplastic cells, and atypical mitoses are characteristic findings of osteosarcoma. Osteosarcoma may be associated with hereditary syndromes such as Li-Fraumeni syndrome and Rothmund-Thomson Syndrome.

Pathophysiology

The osteosarcomas may be localized at the end of the long bones (commonly in the metaphysis). Most often osteosarcoma affects the upper end of the tibia, humerus, or lower end of the femur. Osteosarcomas tend to occur at the sites of bone growth, presumably because proliferation makes osteoblastic cells in this region prone to acquire mutations that could lead to transformation of cells (the RB gene and p53 gene are commonly involved).

Gross Pathology

• Macroscopically, osteosarcomas are solid, hard, and bulky tumors.
• Heterogeneous cut surface demonstrates areas of hemorrhage, fibrosis and cystic degeneration.
• Areas of bone formation are characteristic of osteosarcomas, with the degree of bone formation varying widely.
• The tumor is irregular ("fir-tree" or "sun-burst" appearance on X-ray examination) due to the tumor spicules of calcified bone radiating in right angles. These right angles form what is known as Codman's triangle, which is characteristic but not diagnostic of osteosarcoma. Surrounding tissues are infiltrated.

Osteosarcoma-distal femur-pathology

Microscopic Pathology

• On microscopic histopathological analysis, a characteristic feature of osteosarcoma is presence of osteoid (bone formation) within the tumor.
• Tumor cells are pleomorphic, anaplastic, giant, and display numerous atypical mitoses.
• These cells produce osteoid describing irregular trabeculae (amorphous, eosinophilic/pink) with or without central calcification (hematoxylinophilic/blue, granular) - tumor bone.
• Tumor cells are included in the osteoid matrix. Depending on the features of the tumor cells present (whether they resemble bone cells, cartilage cells or fibroblast cells), the tumor can be sub classified. The presence of immature blood vessels (sarcomatous vessels lacking endothelial cells) favors bloodstream metastasis.

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  Histology of conventional osteosarcoma

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  High-magnification micrograph showing osteoid formation in an osteosarcoma H&E stain

• Characteristic features on microscopic analysis are variable depending on the osteosarcoma subtype:

Subtype	Features on Histopathological Microscopic Analysis
Telangiectatic osteosarcoma	Most osteosarcomas have a small telangiectatic component but in order to be classified as a telangiectatic osteosarcoma the telangiectatic component should comprise more than 90%. Most of the tumor comprises of large blood filled spaces separated by thin bony septations. Microscopically, the tumor consists of vascular sinusoids surrounded by thin septae, osteoid matrix and cells with significant pleomorphism and high mitotic rate.
Low grade osteosarcoma	Histologically it is a low grade tumor which occurs in the medullary canal of long bones. It contains osseous matrix with fibrous stroma and there is variable amount of bone production. Histologic pattern is similar to fibrous dysplasia and low grade parosteal osteosarcoma.
Periosteal osteosarcoma	Periosteal osteosarcoma arise from the inner germinative layer of periosteum. The cytologic grade of this tumor is higher than parosteal osteosarcoma and lower than conventional osteosarcomas. Periosteal osteosarcoma is considered as intermediate grade osteosarcoma (grade 2). It predominantly contains chondroid matrix.
Intracortical osteosarcoma	Intracortical osteosarcoma is a low grade tumor of cortical bones and it typically does not extend into medullary canal and surrounding soft tissue until late stage of the disease. Histologically characterazied as a sclerosing variant of the osteosarcoma. Intracortical osteosarcoma contains osteoid matrix with few fibroblastic foci within and mild degree of cellular atypia.
Parosteal osteosarcoma	Parosteal osteosarcoma originates from the outer fibrous layer of periosteum. They are composed of a dense osteoid component attached to the outer cortex over a narrow zone. It exhibits extensive bone matrix and minimal fibroblastic cellular atypia, and as such is considered to be a low grade tumor.
Extraskeletal osteosarcoma	Microscopically, it is typically a high grade spindle cell malignancy with osteoid and chondroid matrix. The histologic appearance of extraskeletal osteosarcoma resembles malignant fibrous histiocytoma, osteoblastic osteosarcoma and chondroblastic osteosarcoma.

Genetics

Hereditary syndromes of osteosarcoma include:

• RECQL4 gene mutations
• RB1 gene mutations (also implicated in retinoblastoma)
• Li-Fraumeni syndrome
• Rothmund-Thomson Syndrome

These syndromes are extremely rare within the osteosarcoma diagnosis and probably represent less than 0.5% of those diagnosed.

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  This high-power photomicrograph demonstrates the cellular growth pattern. Note that the cells are fusiform and they grow in sheets.

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  This high-power photomicrograph demonstrates the growth pattern and the cell morphology.

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  This is a high-power photomicrograph of the tumor cell morphology and the periosteum (arrow).

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  This high-power photomicrograph of the tumor demonstrates the fusiform morphology of the cells. Note the marked variability in size and staining intensity of the nuclei.

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  This is a high-power photomicrograph of the tumor demonstrating the anaplastic cell morphology.

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  This is a high-power photomicrograph of the tumor demonstrating the anaplastic cell morphology.

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  This is a high-power photomicrograph of the tumor demonstrating the anaplastic cell morphology and multiple mitotic figures (arrows).