Osteosarcoma pathophysiology
Editor-In-Chief: C. Michael Gibson, M.S., M.D. [2]; Associate Editor(s)-in-Chief: Mohammadmain Rezazadehsaatlou[2].
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Osteosarcoma Microchapters |
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Diagnosis |
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Osteosarcoma pathophysiology On the Web |
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American Roentgen Ray Society Images of Osteosarcoma pathophysiology |
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Risk calculators and risk factors for Osteosarcoma pathophysiology |
Overview
The main cause of osteosarcoma is not well-known, yet. However, a number of risk factors have been identified in this regard. Osteosarcoma can involve any bone but it usually affects the extremities of long bones near metaphyseal growth plates. The most common sites include
- Femur 42% of cases ( the distal femur had around 75% of involvement).
- Tibia 19% of cases ( the proximal tibia had around 80% of involvement).
- Humerus 10% of cases ( the poximal humerus had around 90% of involvement).
- Skull and jaw 8% of cases.
- Pelvis 8% of cases.
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
Traditionally, our knowledge about osteosarcoma has been mostly anatomical but it should be noted that it arises most commonly in the metaphyseal region of long bones, within the medullary cavity, then it involves the bone cortex; consequently a pseudocapsule forms around the penetrating tumor. Osteosarcoma is characterised as a highly cellular tumour consisted of: pleomorphic spindle-shaped cells responsible for the producing an osteoid matrix. However, recent developments in the field of medical sciences and the molecular biology have provided huge insights regarding the molecular pathogenesis of osteosarcoma:
Bone Growth and Tumorigenesis
Previous studies have revealed a positive significant correlation between the osteosarcoma development and the rapid bone growth occurs during puberty. Accordingly the peak age of osteosarcoma development is slightly earlier for female population. And patients affected by the disease are taller compared to the normal population of the same age group. Also, the epiphyseal growth plates of the distal femur and proximal tibia are known to be responsible for the increase in height that occurs during puberty. Meanwhile, the Paget’s disease which is a disorder characterised by both excessive bone formation and breakdown leads to a higher incidence of osteosarcoma among the affected individuals.
Environmental Factors
Environmental Factors known as carcinogens for osteosarcoma include:
- Physical agents
- Chemical agents
- Biological agents
Physical agents
- Meanwhile, the ionising radiation, implicated in only 2% of cases of osteosarcoma, has the best established roll in this regard. Meanwhile, the radiotherapy treatment in children develop a secondary neoplasm, and of these are sarcomas in 5.4% and 25% of cases, respectively.
Chemical agents
The chemical agents responsible for the osteosarcoma formation include:
- methylcholanthrene
- chromium salts
- beryllium oxide
- zinc beryllium silicate
- asbestos
- aniline dyes
Biological agents
Resent investigations suggested a viral origin for osteosarcoma which later got some controversies in this regard. It was stemmed from the detection of simian virus 40 (SV40) in osteosarcoma cells but later it was proposed that may in fact be due to laboratory contamination by plasmids containing SV40 sequences.
Chromosomal Abnormalities
A various amount of chromosomal and genetic syndromes are known to be linked to the osteosarcoma pathophysiology. Specific chromosomal abnormalities are known to be associated with osteosarcoma include: loss of chromosomes 9, 10, 13, and 17 as well as gain of chromosome 1. Meanwhile, a recent studies demonstrated that the amplifications of chromosomes 6p21, 8q24, and 12q14, as well as loss of heterozygosity of 10q21.1, are the most common genomic alterations in osteosarcoma; It should be noted that patients carrying these alleles had a poorer prognosis. Meanwhile, Osteosarcoma had been reported in patients with the below mentioned genetic disorders:
- Bloom syndrome: characterised by genetic defects in the RecQ helicase family
- Rothmund-Thompson syndrome: characterised by genetic defects in the RecQ helicase family
- Werner syndrome: characterised by genetic defects in the RecQ helicase family
- Li-Fraumeni syndrome
- hereditary retinoblastoma.
*DNA-helicases are responsible for the double-stranded DNA prior to replication separation process. Mutations in these genes increases a higher risk of multiple malignancies.
Tumour Suppressor Gene Dysfunction
Any type of exposure to previously-mentioned environmental insults causes a significant damages on the somatic DNA. Due to the tumor-suppressor mechanisms this DNA damage necessarily may not lead to malignant cell line process. These tumor-suppressor mechanisms include:
Repair the DNA damage
Apoptosis
The p53 and retinoblastoma (Rb) genes are the well-known tumor-suppressor genes in cellular system. However, sometimes these tumor suppressor genes may themselves become mutated causing the loss of their protective function effects. Its been reported that the mutations in both the p53 and Rb genes have been proven to be involved in osteosarcoma pathogenesis.
DNA damage → phosphorylate p53 → dissociation from Mdm2
P53 :
The p53 gene mutation found in 50% and 22% all cancers and osteosarcomas respectively. The expression of p53 positively reduced metastatic disease and improved survival for these patients. it is unclear whether p53 mutation or loss may affect tumor behavior. But, using the p53-null SaOS-2 osteosarcoma cell line showed that the adenoviral-mediated gene transfer of wild-type p53 reduced the cell viability and also increased the sensitivity to chemotherapeutic agents in affected cells. for example: Li-Fraumeni syndrome is characterized by an autosomal dominant mutation of p53 leading to the development of multiple cancers such as osteosarcoma.
Retinoblastoma
The Rb gene is critical to cell-cycle control. Inherited mutation of the Rb gene lead to the retinoblastoma syndrome which predisposes a patient to multiple malignancies such as osteosarcoma. The Rb protein controls the cell cycle by binding the transcription factor E2F. E2F usually is held inactive by Rb until the CDK4/cyclin D complex phosphorylates Rb. Mutations of Rb allow for the continuous cycling of cells thus leads to the osteosarcoma occurance. It should be noted that both germ-line and somatic mutations of Rb increases the risk of osteosarcoma.
Transcription Factors
Transcription is the process of forming single-stranded messenger RNA (mRNA) sequences in cell from double-stranded DNA. Transcription factors simplify binding of promoter sequences for specific genes to initiate the process. The transcription is usually tightly regulated and the deregulation may leads to the malignancies like osteosarcoma. Activator protein 1 complex (AP-1) It is a regulator of transcription. AP-1 is comprised of Fos (products of the c-fos) and Jun proteins (c-jun proto-oncogenes). AP-1 controls cell proliferation, differentiation, and also the bone metabolism. Fos and Jun are found to be upregulated in high-grade osteosarcomas than the low-grade and benign osteosarcoma. Myc It is a transcription factor that acts in the nucleus to stimulate both cell growth and division process. Myc amplification has been causes the occurrence and the resistance to chemotherapeutic in osteosarcoma pathogenesis. Also, the down-regulation of Myc increased the therapeutic activity of methotrexate against the osteosarcoma cell.
Growth Factors
Osteosarcoma Cell Proliferation, Apoptosis, and Anchorage-Independent Growth
Cell Adhesion and Migration
Tumor Invasion
Osteoclast Function
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.
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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 https://radiopaedia.org/articles/osteosarcoma
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High-magnification micrograph showing osteoid formation in an osteosarcoma H&E stain https://en.wikipedia.org/wiki/Osteosarcoma
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- Characteristic features on microscopic analysis are variable depending on the osteosarcoma subtype:
| Subtype | Features on Histopathological Microscopic Analysis |
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Genetics
Hereditary syndromes of osteosarcoma include:[3]
- 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. http://peir.path.uab.edu/wiki/IPLab:Lab_7:Osteosarcoma
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This high-power photomicrograph demonstrates the growth pattern and the cell morphology.http://peir.path.uab.edu/wiki/IPLab:Lab_7:Osteosarcoma
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This is a high-power photomicrograph of the tumor cell morphology and the periosteum (arrow). http://peir.path.uab.edu/wiki/IPLab:Lab_7:Osteosarcoma
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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. http://peir.path.uab.edu/wiki/IPLab:Lab_7:Osteosarcoma
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This is a high-power photomicrograph of the tumor demonstrating the anaplastic cell morphology. http://peir.path.uab.edu/wiki/IPLab:Lab_7:Osteosarcoma
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This is a high-power photomicrograph of the tumor demonstrating the anaplastic cell morphology. http://peir.path.uab.edu/wiki/IPLab:Lab_7:Osteosarcoma
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This is a high-power photomicrograph of the tumor demonstrating the anaplastic cell morphology and multiple mitotic figures (arrows). http://peir.path.uab.edu/wiki/IPLab:Lab_7:Osteosarcoma
References
- ↑ Image courtesy of Dr Frank Gaillard. Radiopaedia (original file [1]). [http://radiopaedia.org/licence Creative Commons BY-SA-NC
- ↑ 2.0 2.1 2.2 2.3 2.4 2.5 Osteosarcoma. Dr Yuranga Weerakkody◉ et al. Radiopaedia.org 2015. http://radiopaedia.org/articles/telangiectatic-osteosarcoma
- ↑ Wang LL. Biology of osteogenic sarcoma. Cancer J 11:294-305, 2005.