Osteosarcoma

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohammadmain Rezazadehsaatlou[2].

Bone cancer is a malignant (cancerous) tumor of the bone that destroys normal bone tissue. Osteosarcoma is the most common type of malignant bone cancer, accounting for 35% of primary bone malignancies. It is a malignant tumor that is characterized by the direct formation of bone or osteoid tissue by the tumor cells. Malignant tumors that begin in bone tissue are called primary bone cancer. Osteosarcoma may be classified according to the World Health Organization’s histologic classification of bone tumors into three groups. The osteosarcomas may be localized at the end of the long bones (commonly in the metaphysis). Most often it 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. There are no established causes for osteosarcoma. The common risk factors in the development of osteosarcoma are radiation to bones, alkylating antineoplastic agents, Paget disease, multiple hereditary osteochondromas, fibrous dysplasia, Bloom syndrome, Rothmund-Thomson syndrome, and Li-Fraumeni syndrome. Common complications of osteosarcoma include pathologic fracture and metastasis. The most common symptoms of osteosarcoma include bone pain that may be worse at night, swelling, and redness at the site of the tumor. On x-ray, osteosarcoma is characterized by medullary and cortical bone destruction, periosteal reaction, tumor matrix calcification, and soft tissue mass. On MRI, osteosarcoma is characterized by intermediate intensity of soft tissue and low signal intensity of ossified components on T1. High signal intensity of soft tissue and low signal intensity of ossified components on T2. The predominant therapy for osteosarcoma is neoadjuvant chemotherapy (chemotherapy given before surgery) followed by surgical resection. The most common drugs used to treat osteosarcoma are cisplatin, doxorubicin and high-dose methotrexate.

Osteosarcoma is known as the most common bone malignant tumor. Osteosarcoma is an ancient disease and is not completely understood, yet. Nobody knows when and who discovered osteosarcoma, but recent Paleontology discoveries revealed that osteosarcoma has a long story on planet earth. Recent discoverers in Germany revealed a 240 million-year-old highly malignant tumor in the fossilized leg bone of a stem turtle. It is been found that osteosarcoma is the earliest case of human cancer which was found on the 1.7 million-year-old fossil of an early ancestor of mankind in Swartkrans cave in South Africa. In 1990, a thousand-year-old mummy of a woman in her mid-30s of age had with a malignant tumor in her upper-left arm which that mass had grown so large that it might burst through her skin while she was still alive.

Osteosarcoma (OS) is a rare bone cancer that affects both adolescents and young adults. Osteosarcoma was classified as primary and secondary. Later the World Health Organization sub-typed as intramedullary/central and surface osteosarcoma with a number of sub-types under each group.

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 characterized as a highly cellular tumor consisted of pleomorphic spindle-shaped cells responsible for producing an osteoid matrix. However, recent developments in the field of medical sciences and molecular biology have provided huge insights regarding the molecular pathogenesis of osteosarcoma.

There are no established causes for osteosarcoma. However, some studies show that an increased level of c-fos proto-oncogene expression can lead to osteosarcoma.

Osteosarcoma must be differentiated from other diseases such as any type of bone lesions caused by infection and/or tumors. Features such as the eccentric location of the tumor in the metaphyseal portion of the bone and the skeletal location help to distinguish osteosarcoma from Ewing sarcoma. Bone metastases from other primary tumors, less frequent in the young than in adult patients, should also be considered.

Osteosarcoma is the most common nonhematologic primary malignant bone neoplasm causing 35% of primary bone malignancies and occurs at any age, it usually affects patients in the second and third decade of life with a peak incidence between 13 and 16 years of age. It is the 8th leading cancer in children under age 15, comprising 2.4% of all malignancies in pediatric patients and about 20% of all primary bone cancers. The overall incidence of osteosarcoma in the U.S. population under 24 years of age is estimated at 0.44 cases for 100,000 individuals. Osteosarcoma is slightly more common in males than in females. Primary osteosarcoma typically occurs in young patients (10-20 years) with 75% occurring before the age of 20. Secondary osteosarcoma occurs in elderly patients.

Common risk factors in the development of osteosarcoma are radiation to bones, alkylating antineoplastic agents, Paget disease, multiple hereditary osteochondromas, fibrous dysplasia, Bloom syndrome, Rothmund-Thomson syndrome, and Li-Fraumeni syndrome.

According to the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for osteosarcoma.

Common complications of osteosarcoma include pathologic fracture and metastasis. Pre-treatment factors that influence the outcome of the osteosarcoma are primary tumor site, size of the primary tumor, and site of metastasis. After the administration of preoperative chemotherapy, factors that influence the outcome of the osteosarcoma are the adequacy of tumor resection and necrosis following induction or neoadjuvant chemotherapy. The 5-year survival rate of osteosarcoma after adequate therapy is approximately 60-80%.

According to the American Joint Committee on Cancer (AJCC), there are four stages of osteosarcoma based on the size of the primary tumor, metastasis, the involvement of lymph nodes, and grade of the tumor. For the purpose of treatment, there are only two stages of high-grade osteosarcoma: localized osteosarcoma and metastatic osteosarcoma

The most common symptoms of osteosarcoma include bone pain that may worsen at night, swelling, and redness at the site of the tumor. The affected bone is not as strong as normal bones and may fracture with minor trauma (a pathological fracture).

Physical examination findings will depend on the location of the osteosarcoma. Common physical examination findings of osteosarcoma are localized swelling and tenderness at the site of the tumor.

Laboratory tests for osteosarcoma include complete blood count (CBC), serum alkaline phosphatase and lactate dehydrogenase.

Biopsy of osteosarcoma is important for confirming the diagnosis and for determining the histologic subtype. Biopsy may be performed percutaneously with either a fine-needle, or a wide-bore needle, or through a formal incision.

On x-ray, osteosarcomais characterized by medullary and cortical bone destruction, periosteal reaction, tumor matrix calcification, and soft tissue mass.

CT scan in osteosarcoma may be helpful in biopsy and staging. CT scan adds little to plain radiography and MRI in direct assessment of the tumor.

On MRI, osteosarcoma is characterized by an intermediate intensity of soft tissue and low signal intensity of ossified components on T1. The high signal intensity of soft tissue and low signal intensity of ossified components on T2. Considerable contrast enhancement of solid components on T1 contrast.

Bone scan in osteosarcoma is used to observe abnormal areas of bone and metastasis.

A bone scan in osteosarcomais used to observe abnormal areas of bone and metastasis.

The predominant therapy for osteosarcoma is neoadjuvant chemotherapy (chemotherapy given before surgery) followed by surgical resection. The most common drugs used to treat osteosarcoma are cisplatin, doxorubicin and high-dose methotrexate. Ifosfamide can be used as an adjuvant treatment if the necrosis rate is low. Samarium is a radioactive drug that targets areas where bone cells are growing, such as tumor cells in the bone. It helps relieve bone pain.

The mainstay of therapy for osteosarcoma is surgical resection. Rather than using the standard staging system, a simpler system is often used when planning treatment for osteosarcoma. This system divides osteosarcomas into 2 groups: localized osteosarcoma and metastatic osteosarcoma.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohammadmain Rezazadehsaatlou[2].

Osteosarcoma is known as the most common bone malignant tumor. Osteosarcoma is an ancient disease and is not completely understood, yet. Nobody knows when and who discovered osteosarcoma, but recent Paleontology discoveries revealed that osteosarcoma has a long story in planet earth. Recent discoverers in Germany revealed a 240 million-year-old highly malignant tumor in the fossilized leg bone of a stem turtle. Its been found that osteosarcoma is the earliest case of human cancer which was found on the 1.7 million-year-old fossil of an early ancestor of mankind in Swartkrans cave in South Africa. In 1990, a thousand-year-old mummy of a woman in her mid-30s of age had with a malignant tumor in her upper-left arm which that mass had grown so large that it might burst through her skin while she was still alive.

• In 1805, a French surgeon Alexis Boyer was first described the term osteosarcoma.^{[1][2][3][4][5][6]}
• In 1847, Guillaume Dupuytren had a true description and natural history of the process.
• In 1854, Hermann Lebert was the first histologic description of bone tumors.
• In 1867, Rudolf Virchow created a classification of bone tumors based on histology based on the work of the Hermann Lebert in 1854.
• In 1879, Samuel Gross, had some recommendations regarding the main definition of osteosarcoma.
• In 1909, Ernest Codman, described many of the features that osteosarcomas demonstrate on X-rays, including the periosteal elevation which continues to be known as Codman’s Triangle.
• In the years after World War II, advances in general and surgical implants orthopedic techniques made this opportunity to perform increasingly complex reconstructions following bone tumor removal. Despite this, the survival rates associated with osteosarcomas remained low.
• In the 1970s, the modern age of osteosarcoma treatment really began with the discovery and the usage of the chemotherapeutic agents. Thus, we can see a major jump in the survival rates from about 30 % to almost 70 % during this period of time.
• Unfortunately, despite major technological advances in medical and orthopedic sciences in the past 40 years, the survival rates for osteosarcoma have reached a plateau over that period of time.
• Consequently, this issue lead to start an area of intense research regarding the osteosarcoma and related diagnostic and therapeutic methods to help mankind in this regard.
• In 2009, William Enneking in the History of Orthopedic Oncology in the United States, provides a detailed account of the history of osteosarcoma.

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohammadmain Rezazadehsaatlou[2].

Osteosarcoma (OS) is a rare bone cancer which affects both adolescents and young adults. Osteosarcoma was classified as primary and secondary. Later the the World Health Organization sub-typed as intramedullary/central and surface osteosarcoma with a number of sub-types under each group.

• Osteosarcoma (OS) may be classified into several subtypes based on World Health Organization and are as follows:^{[1][2][3][4][4][5][1][6][7]}

Classification of osteosarcoma

Primary osteosarcoma	Conventional–intramedullary/central high grade (most common) further sub-typed as:	Osteoblastic (50%) Chondroblastic (25%) Fibroblastic (25%)
Secondary osteosarcoma	Unusual forms of osteosarcoma given below are viewed as subtypes of conventional osteosarcoma because their biological behavior is similar.	Osteoblastic osteosarcoma-sclerosing type Osteosarcoma resembling osteosarcoma Chondromyxoid fibroma‑like osteosarcoma Chondroblastoma-like osteosarcoma Clear-cell osteosarcoma Malignant fibrous histiocytoma‑like osteosarcoma Giant cell rich osteosarcoma–Epithelioid osteosarcoma

Osteosarcoma (Primary) subtypes within central and surface tumours

subtypes	Osteosarcoma
CENTRAL (MEDULLARY)	A. Conventional high-grade central osteosarcoma (80%) B. Telangiectatic osteosarcoma (4%) C. Intraosseous well-differentiated (low-grade) osteosarcoma (1-2%) D. Small cell osteosarcoma (1-2%)
SURFACE (PERIPHERAL)	a. Parosteal (juxtacortical) well-differentiated (low-grade) osteosarcoma(4-6%) b. Periosteal osteosarcoma– low- to intermediate-grade osteosarcoma(<4%) c. High-grade surface osteosarcoma(1%)

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohammadmain Rezazadehsaatlou[2].

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 proximal humerus had around 90% of involvement).
• Skull and jaw 8% of cases.
• Pelvis 8% of cases.

• Traditionally, our knowledge about osteosarcoma has been mostly anatomical but it should be noted that osteosarcoma arises most commonly in the metaphyseal region of long bones, especially 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 tumor 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^{[1][2][3][4][5]}:

• Impaired expression of growth factors leads to the accelerated proliferation of cells. Most important growth factor include:^{[6][7][8][9][10]}
  • Transforming growth factor (TGF)
  • Insulin-like growth factor (IGF)
  • Connective tissue growth factor (CTGF)
  • Parathyroid hormone (PTH)

• These proteins are a large family of dimeric proteins and they influence a wide variety of cell process such as differentiation, proliferation, apoptosis, and matrix production.
• Bone morphogenic proteins (BMPs) build a large component of the TGF-β families.
• Expression of the TGF-β1 is significantly higher in high-grade osteosarcomas.
• Recent studies revealed an association between increased susceptibility and metastasis of osteosarcoma with TGFR1 variants, TGFBR1*6A, and Int7G24A.

• IGF-I and IGF-II are growth factors usually overexpressed by osteosarcomas.
• IGF families bind corresponding receptors such as IGF-1R, causing the activation of the PI3K and MAPK transduction pathways.
• Consequently they supports the cell proliferation and inhibition of apoptosis. Meanwhile, the Lentivirus-mediated snRNA targeting IGF-R1 increases the chemosensitivity and the anti-tumor response of osteosarcoma cells to docetaxel and cisplatin.

• CTGF related to a number of proteins in the CCN family (CTGF/Cyr61/Cef10/NOVH).
• CTGF act through the integrin signaling pathways.
• Like TGF-β which was mentioned before the CTGF has a diverse range of functions which includes the following:
  • Adhesion
  • Migration
  • Proliferation
  • Survival
  • Angiogenesis
  • Differentiation

• Parathyroid hormone (PTH), and its related peptide (PTHrP) and receptor (PTHR1) play important roles in the progression and metastasis of osteosarcoma.
• PTHrP associated with tumor metastasis and hypercalcemia.
• PTHrP leads to chemoresistance by downregulated expression of proapoptotic Bax and PUMA and upregulated anti-apoptotic Bcl-2 and Bcl-xl and by blocking signaling via the p53, death-receptor and mitochondrial pathways of apoptosis.

• A various amount of chromosomal and genetic syndromes are known to be linked to the osteosarcoma pathophysiology.^{[11][12][13][14][15]}
• Specific chromosomal abnormalities are known to be associated with osteosarcoma include: loss of chromosome 9, chromosome 10, chromosome 13, and chromosome 17 as well as gain of chromosome 1.
• Meanwhile, a recent studies demonstrated that the amplifications of chromosome 6p21, chromosome 8q24, and chromosome 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 the replication separation process. Mutations in these genes increase higher risk of multiple malignancies.

• Genes involved in the pathogenesis of osteosarcomas include:

• Transcription is the process of forming single-stranded messenger RNA (mRNA) sequences in cell from double-stranded DNA. ^{[16][17][18][19]}
• 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.

• 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 bone metabolism.
• Fos and Jun are found to be upregulated in high-grade osteosarcomas than the low-grade and benign osteosarcoma.

• 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.

• Osteosarcoma is a highly metastatic tumor, and pulmonary metastases and known as the common cause of death. ^{[20][21][22][23]}
• The metastatic sequence involves the detachment of osteosarcoma cells from the primary tumor, adhesion to the extracellular matrix, local migration and invasion through stromal tissue, intravasation, and extravasation.
• The ability of osteosarcoma cells to metastasise by such a pathway completely depended on the complex cell-cell and cell-matrix interactions.

• Osteosarcoma invasion of bone relies on interactions between the bone matrix, osteosarcoma cells, osteoblasts, and osteoclasts.^{[24][25][26][27]}
• In response to the hypoxic and acidotic conditions the osteosarcoma cells release molecules such as: endothelin-1 (ET-1), VEGF and PDGF.
• Endothelin-1 (ET-1), VEGF, and PDGF factors have predominantly osteoblast-stimulatory functions.
• The PTHrP as an important GF and the IL-11 also act on osteoblasts enhancing the expression of receptor activator of nuclear factor κB ligand (RANKL).
• RANKL is a key mediator of osteoclast differentiation and activity. The activated osteoclasts release proteases to resorb the non mineralised components of bone.
• Consequently, the osteoclast pathways (differentiation, maturation, and activation) have potential as therapeutic effect.
• For example: Inhibition of bone resorption at the tumor-bone interface reduces the osteosarcoma local invasion.

• Previous studies have revealed a positive significant correlation between the osteosarcoma development and the rapid bone growth occurs during puberty.^{[28][29][30][31][32][33][34][35][36][37][38]}
• 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 characterized by both excessive bone formation and breakdown leads to a higher incidence of osteosarcoma among the affected individuals.

• Environmental factors known as carcinogens for osteosarcoma include:

1. Physical agents
2. Chemical agents
3. Biological 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.

• The chemical agents responsible for the osteosarcoma formation include:
  • Methylcholanthrene
  • Chromium salts
  • Beryllium oxide
  • Zinc beryllium silicate
  • Asbestos
  • Aniline dyes

• Recent 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.

• Any type of exposure to previously-mentioned environmental insults causes a significant damages on the somatic DNA.^[39][40][41]
• Due to the tumor-suppressor mechanisms this DNA damage necessarily may not lead to malignant cell line process.
• These tumor-suppressor mechanisms include:

• 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.
• It’s 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

• 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.

• 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 germline and somatic mutations of Rb increases the risk of osteosarcoma.

• Tumour angiogenesis is essential for sustained osteosarcoma growth and metastasis.^{[48][49][50][51]}
• The most common sites for osteosarcoma spread include: Metastasis to the lungs and bone also relies on the formation and maintenance of blood vessels.
• A hypoxic and acidotic microenvironment exists at the proliferated osteosarcoma area.
• While the osteosarcoma is a relatively vascular tumor, angiogenesis is regulated by the balance between pro-angiogenic and antiangiogenic factors.
• Antiangiogenic proteins such as thrombospondin 1, TGF-β, troponin I, pigment epithelial-derived factor (PEDF), and reversion-inducing cysteine rich protein with Kazal motifs (RECK) are downregulated in osteosarcoma.

• Invasion of the surrounding tissues by osteosarcoma also involves degradation of the extracellular matrix using the Matrix metalloproteinases (MMPs).^{[20][52][53][17]}

• MMPs are a family of zinc-dependent endopeptidases that are involved in a range of physiological processes including inflammation, wound healing, embryogenesis, and fracture healing.
• In normal healthy tissues, MMPs are regulated by natural inhibitors such as tissue inhibitors of MMPs (TIMPs), RECK, and α2 macroglobulin. but in the malignancies such as osteosarcoma, the MMPs break down extracellular collagens, facilitating both tumor and endothelial cell invasion.
• The urokinase plasminogen activator (uPA) system an other osteosarcoma invasion regulator interacting with MMPs.
• Accordingly, the downregulation of uPAR in an in vivo osteosarcoma model resulted in reduced primary tumor growth and fewer metastases.

• Malignant cells such as osteosarcoma cells are mostly resistant to apoptosis.^{[54][55][56][57]}
• Apoptosis consists of initiation phase and execution phase. Both intrinsic and extrinsic pathways regulate the initiation phase.
• The intrinsic pathway relies on increased mitochondrial permeability while extrinsic pathway is known as a death receptor-initiated pathway.
• Osteosarcoma cells are resistant to anoikis and proliferate despite deranged cell-cell and cell-matrix attachments.
• This resistance to anoikis called anchorage-independent growth (AIG).

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohammadmain Rezazadehsaatlou[2].

There are no established exact causes for osteosarcoma. But physicians and medical researchers suggest that the the DNA mutations (either inherited or acquired after birth) inside the bone cellular system can be responsible for the occurrence of OS.

Common causes of osteosarcoma may include:

• There is limited understanding about the exact etiology of osteosarcoma.^{[1][2][3][4][5][6]}.

• The peak age during puberty seems to have an important relationship between rapid bone growth and the development and progression of OS.
• Commonly osteosarcoma occur at an earlier age in girls than boys.
• Osteosarcoma have also been associated with the previous history of radiation, the use of diagnostic radiocontrast agent s such as:
  • Intravenous radium 224
  • Thorotrast
  • Exposure to alkylating agents

Less common causes of osteosarcoma include:

• On the other hand, the conditions associated with an increased risk of development of osteosarcoma include:
  • Paget’s disease
  • Solitary or multiple osteochondroma
  • Solitary enchondroma or enchondromatosis (Ollier’s disease)
  • Multiple hereditary exostoses
  • Fibrous dysplasia
  • Chronic osteomyelitis
  • Sites of bone infractions and sites of metallic implants

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohammadmain Rezazadehsaatlou[2].

Osteosarcoma must be differentiated from other diseases such as: any type of bone lesions caused by infection and/or tumors. Features such as the eccentric location of the tumor in the metaphyseal portion of the bone and the skeletal location help to distinguish osteosarcoma from Ewing sarcoma. Bone metastases from other primary tumours, less frequent in the young than in adult patients, should also be considered.

Osteosarcoma must be differentiated from:Osteomyelitis, Pediatric Osteomyelitis, Rhabdomyosarcoma, Pediatric Rhabdomyosarcoma, Chondrosarcoma, Metastases from other malignancies, Fibrous dysplasia, Giant cell tumors, Ewing’s sarcoma, Malignant fibrous histiocytoma, Lymphoma Osteoblastoma, Aneurysmal bone cyst, Fibrosarcoma and Cortical desmoid.

Disease	History/demography	Symptoms			Physical examination		Diagnosis
		Palpable mass	Pain	Others	Mass tenderness	Others	Genetics	Imaging	Histology
Rhabdomyosarcoma[1][2][3][4]	Most common soft tissue cancer among children and adolescents The third most common extracranial solid tumors Two-third of all cases happen under 6 years old	+	+	Skin changes Respiratory difficulties Vomitting Hematuria	+/-	Fever Erythematous skin Proptosis Ophthalmoplegia Dysconjugate gaze	Loss of heterozygosity of 11p15. Mutations in: TP53 NRAS KRAS HRAS PIK3CA CTNNB1 FGFR4 Translocations in PAX3 or PAX7 genes with FOXO1	CT scan: Soft tissue density Enhancement with contrast Bone destruction Ultrasound: Well-defined and irregular mass Low to medium echogenicity MRI: T1: Low to intermediate intensity Hemorrhage areas are present in alveolar rhabdomyosarcoma T2: Hyperintense Prominent flow voids are present in extremity lesions of rhabdomyosarcoma T1 C+(Gd): Enhancement	An appearance of round blue cell tumors Myogenesis pathway has various types of differentiation Positive immunohistochemical results for: myoglobin actin desmin Myogenin
Wilms tumor[5][6][7][8][9]	Also called nephroblastoma The most common childhood abdominal malignancy Average age of 3.5 years old	+	+	Hematuria Respiratory symptoms ( due to lung metastases)	+/-	Fever Hypertension/ hypotension	Present mutations of: WT1 P53 FWT1 FWT2 11p15.5 loci	Ultrasound: The best initial diagnostic study. Distinguish tumor mass from other causes of renal swelling like hydronephrosis. Doppler ultrasonography can help to detect invasion of renal vein and IVC by the tumor. CT scan: Heterogeneous soft-tissue density mass Areas of calcification and fat density regions Lymph node metastasis Surrounding organs invasion Thrombus in renal vein or inferior vena cava	Arises from mesodermal precursors of the renal parenchyma Well-circumscribed/ macrolobulated lesion Hemorrhage/ central necrosis may be present It is comprised of 3 types of cells: Stromal Epithelial Blastemal The stroma may include: Striated muscle cartilage bone Fat tissue Fibrous tissue.
Ewing sarcoma[10][11][12][13]	Include ewing sarcoma, askin tumor, and peripheral neuroectodermal tumors primitive The second most common childhood malignant primary bone tumors Usually arises in the long bones of the extremities Common age between 10-20 years old	+	+	Weight loss Fatigue	+	Fever Pathologic fractures Petechiae/ purpura	Reciprocal translocation between chromosomes 11 and 22	Radiographic of region: Poorly marginated destructive lesion Permeative or “moth-eaten” appearance CT scan: Cortical destruction Demonstrate soft tissue disease MRI: Considered as a preferred diagnostic study Better shows tumor size/ intraosseous/extraosseous extent	Small/ round/ blue cell tumors May be undifferentiated or differentiated Regular sized primitive appearing cells
Pediatric neuroblastoma [14][15][16][17]	Most common extracranial solid tumor of infancy Arising from pluripotent sympathetic cells Age distribution: < 1 years old ( 40%) 1-2 years old (35%) > 2 years old (25%)	+ (Abdominal)	+	Constipation Weakness Diarrhea	+(Abdominal)	Proptosis Periorbital ecchymosis Horner syndrome Opsoclonus myoclonus syndrome	Chromosome 1p deletion N-myc amplification	CT scan: Heterogeneous mass Calcification Necrotic areas MRI: T1: heterogeneous mass T2: Heterogeneous/ hyperintense Cystic/ necrotic areas C+ (Gd): Heterogeneous mass	Well defined/ infiltrative mass Homer wright rosettes Secretion of vanillylmandelic acid (VMA) and homovanillic acid (HVA)
Pediatric pheochromocytoma[18][19][20][21]	Rare catecholamine-secreting tumor Occur in both children and adults Average age of 11 years old Associated with neurofibromatosis, von Hippel-Lindau disease, tuberous sclerosis, sturge-weber syndrome, and multiple endocrine neoplasia (MEN) syndromes	–	+/-	Headache Sweating Weakness Convulsion	–	Hypertension Tachycardia Pallor face	Genetic mutation in: NF1 RET VHL SDHD SDHC EGLN1 EGLN2 KIF1B SDHAF2 TMEM127 SDHA IDH1 SDHB MAX HIF2A FH	Ultrasound: Different appearance from solid to mixed cystic or solid to cystic CT scan: Large and heterogenous Calcification Necrosis Cystic changes MRI (in extra adrenal tumors): T1: Heterogenous enhancement Hypointense T2: Hyperintense T1 C+ (Gd): Heterogenous enhancement	Zellballen pattern on microscopy Well-defined clusters Eosinophilic cytoplasm Positive stains for: Chromogranin for zellballlen cells Neurospecific enolase markers for neuronal cells S-100 protein for sustentacular cells
Pediatric osteosarcoma[22][23][24]	The second most common primary bone tumor The third most common tumor among adolescents Can be primary or secondary Primary osteosarcoma occurs in age of 10-20 years old Secondary osteosarcoma occurs in older patients and is secondary to paget disease and bone infarcts Accompanied with positive history of trauma	+	+	Soft tissue swelling Fracture Night sweating	+	Mass swelling Fever Arthritis Decreased joint range of motion Lymphadenopathy	Alteration in retinoblastoma gene (Rb)	Radiography: Osteolytic/ osteoblastic feature Periosteum reaction Calcification or ossification CT scan: Primary lesion and chest CT are required Demonstrate tumor location and extension MRI: Exact assessment of tumor extension Involving joint to joint findings	Contain various cellular pleomorphism and mitoses Poorly trabecular bone formation Fibrocystic and chondroblastic features
Pediatric liposarcoma[25][26][27][28]	Considered as a nonrhabdomyosarcoma soft tissue sarcomas One of the least frequent tumors during childhood Rarely seen in adolescents and age of < 8 years old Average age is 50 years among adults Occur mostly in lower extremities, retroperitoneal region, and shoulder	+	+/-	Weight loss Fatigue	–	N/A	Amplification of 12q13–15 region in MDM2 and CDK4 genes Translocation of t (12;16) (q13;p11.2) in myxoid liposarcoma	CT scan: Inhomogenous fatty structure Tumor mineralization Cortical bone erosion Calcification Infiltration to mediastinum MRI: Adipose content mass Thin irregular septa Hemorrhage Necrosis areas	Divided into following subtypes: Well-differentiated Dedifferentiated, Myxoid/ round cell Pleomorphic Common findings: Lipoblasts presence Cytoplasmic lipid vacuoles Chromatin spikes
Pediatric acute myelocytic leukemia[29][30][31][32]	Replacement of normal bone marrow cells with abnormal cells Myeloblast is malignant cell Wide distribution among childhood to adults Survival rate of 60% Common in down syndrome	+/- ( Abdominal mass, mediastinal mass)	+ (bone pain, joint pain)	Bleeding Infectious	+/-	Lymphadenopathy Hepatosplenomegaly Bruising Petechiae Pallor face Anemia Fever	Genetic translocations include: t (8;21) t (3;21) t (15;17)	Radiography: Chest radiography: Diagnosis of mediastinal mass Extremities radiography: Metaphyseal bands Lytic lesions New periosteal bone formation Pathologic fractures CT scan/ MRI: Thickening/ edema of the bowel wall in presence of abdominal pain or bowel infection Detection of early sinusitis Intracranial hemorrhage in presence of neurological symptoms Radionuclide imaging: Detection of occult infection	Hyperplastic bone marrow with leukemia cells replacement Megaloblastic feature Decrease in normal hematopoietic cell
Pediatric acute lymphoblastic leukemia[33][34]	The most common malignancy among children Few cases may associated with down syndrome, wiskott- aldrich syndrome, and ataxia-telangiectasia Peak age of 2-5 years old Previous history of cancer/ drug exposure Bone marrow replaced with malignant lymphoblasts	+/-( Extramedullary mass in abdomen/ head/ neck)	+/- (Musculoskeletal pain)	Weakness Fatigue Weight loss Bleeding	–	Fever Lymphadenopathy Hepatosplenomegaly Pallor Papilledema Nuchal rigidity Cranial nerve palsy Dyspnea	Chromosomal translocations: t (9;22) t (12;21) t (5;14) t (1;19)	Radiography: Chest x ray: Nodular mass Central lymphadenopathy Bone x ray: Radiolucent metaphyseal bands Coarse trabeculation Periosteal reaction Osteopenia Brain MRI: Leukoencephalopathy Glial cell hyperplasia Meningitis	Divided into 3 subgroups: L1: Small lymphoblast cells Scant cytoplasm Invisible nucleoli L2: Larger lymphoblast cells Abundant cytoplasm Prominent nucleoli L3: Large lymphoblast cells Deep cytoplasmic basophilia Similar to Burkitt lymphoma
Pediatric non-hodgkin lymphoma[35][36][37]	Cancer derives from lymphocytes Diverse age of incidence Associated with autoimmune disorders, previous cancer therapy, and infection	+	–	Lymph node swelling Weight loss Anorexia Abdominal pain Nausea/ vomiting	+ (Chest tenderness)	Fever Hepatosplenomegaly Lymphadenopathy Seizure Petechiae	MLL2 MEF2B EZH2 EP300 KMT2D CDKN2A	Radiography: Chest x ray: Central lymphadenopathy Pleural effusion Pericardial effusion CT scan: Presence of enlarged lymph node in chest, abdomen, and pelvis Ultrasound: Hepatosplenomegaly	Histology findings of non-hodgkin lymphoma depend on: Cell differentiation Cell lineage Location of cell origin

Disease	Bone involvement	Bone pain	Fever	Fractures	Mechanism	ALK level	Diagnosis
Osteoblastoma	Single	Yes	No	Yes	Neoplasm	High	Radiology and biopsy
Osteosarcoma	Single	Yes	No	Yes	Neoplasm	Normal	Radiology and biopsy
Osteoid osteoma	Single	Yes	No	Yes	Neoplasm	High	Radiology and biopsy
Aneurysmal bone cyst	Single	Yes	No	No	Neoplasm	High	Radiology and biopsy
Stress fracture	Multiple	Yes	No	Yes	Stress	Normal	Radiology
Osteomyelitis	Single	Yes	Yes	No	Infection	Normal	Radiology and biopsy
Brodie’s abscess	Single	Yes	Yes	No	Infection	Normal	Radiology and biopsy

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohammadmain Rezazadehsaatlou[2].

Osteosarcoma is the most common nonhematologic primary malignant bone neoplasm causing 35% of primary bone malignancies and occurs at any age, it usually affects patients in the second and third decade of life with a peak incidence between 13 and 16 years of age. It is the 8^th leading cancer in children under age 15, comprising 2.4% of all malignancies in pediatric patients and about 20% of all primary bone cancers. The overall incidence of osteosarcoma in U.S. population under 24 years of age are estimated at 0.44 cases for 100,000 individuals. Osteosarcoma is slightly more common in males than in females. Primary osteosarcoma typically occurs in young patients (10-20 years) with 75% occurring before the age of 20. Secondary osteosarcoma occurs in elderly patients.

• Osteosarcoma is the most common type of malignant bone cancer, accounting for 35% of primary bone malignancies. in other words: the annual incidence of osteosarcoma is 2-3 per million in the general population.^[1][2][3][4]
• Osteosarcoma incidence is less than 1 case per million in children under the age of 5 years.
• 2 cases per million at the age of 5-9 years.
• 7 cases per million at the age of 10-14 years and peaks at 8-11 cases per million at the age of 15-19 years.
• The new cases of osteosarcoma are reported each year in the U.S are around 1,000 cases.
• Osteosarcoma is the 8^th leading cancer in children under age 15, comprising 2.4% of all malignancies in pediatric patients and about 20% of all primary bone cancers.
• A second peak in incidence occurs in the elderly, usually associated with an underlying bone pathology such as Paget’s disease, medullary infarct, or prior irradiation.

• The overall incidence of osteosarcoma in U.S population vary between 1 and 5 cases per million per year, with approximately 400 to 1000 new cases diagnosed every year (4.8 cases per million persons < 20 y).^[5]
• The incidence of osteosarcoma in Europe is similar with that in the US.

• The overall 5-year survival rate for patients with osteosarcoma who were diagnosed between 1974 and 1994 was 63% (59% for male patients, 70% for female patients).

• Osteosarcoma originates more frequently in the metaphyseal region of tubular long bones, with 42% occurring in the femur, 19% in the tibia, 10% in the humerus, 8% in the skull and jaw, and another 8% in the pelvis.

• Osteosarcoma is slightly more common in males with a reported male-to-female ratio of around 1.5:1 to 2:1.

• The incidence of osteosarcoma increases with age:
  • In patients younger than 5 years diagnosed in about 1% of cases.
  • In patients aged 5-9 years, diagnosed in about 2.6 cases for African Americans and 2.1 cases for caucasians per million population.
  • In patients aged 10-14 years, diagnosed in about 8.3 cases for African Americans and 7 cases for caucasians per million population.
  • In patients aged 15-19 years, diagnosed in about 8.9 cases for African Americans and 8.2 cases for caucasians per million population.

• Osteosarcoma is slightly higher in african americans than in caucasians.
• The annual incidence in african american population 5.2 cases per million population younger than 20 years.
• The annual incidence in caucasians population 4.6 cases per million population younger than 20 years.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohammadmain Rezazadehsaatlou[2]

Common risk factors in the development of osteosarcoma are radiation to bones, alkylating antineoplastic agents, Paget disease, multiple hereditary osteochondromas, fibrous dysplasia, Bloom syndrome,Rothmund-Thomson syndrome, and Li-Fraumeni syndrome.

• The most common risk factors for osteosarcoma include:^[1][2][3][4]
  • Teenage growth spurts
  • Being tall
  • Previous treatment with radiation for another cancer, especially at a young age or with high doses of radiation.
  • Drugs: past treatment with anticancer drugs called alkylating antineoplastic agents.

• Presence of certain benign (noncancerous) bone diseases, such as:

1. Paget disease of bone
2. Multiple hereditary osteochondromas
3. Fibrous dysplasia
4. Enchondromatosis

• Less common risk factors in the development of osteosarcoma include:

1. Bloom syndrome
2. Diamond-Blackfan anemia
3. Familial adenomatous polyposis
4. Li-Fraumeni syndrome
5. Hereditary retinoblastoma
6. Rothmund-Thomson syndrome
7. Werner syndrome

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohammadmain Rezazadehsaatlou[2].

According to the the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for osteosarcoma.

According to the the U.S. Preventive Service Task Force (USPSTF), there is insufficient evidence to recommend routine screening for osteosarcoma.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Mohammadmain Rezazadehsaatlou[2].

• Prognosis is separated into three groups.

• Stage I osteosarcoma is rare and includes parosteal osteosarcoma or low-grade central osteosarcoma. It has an excellent prognosis (>90%) with wide resection.

• Stage IIb prognosis depends on the site of the tumor (proximal tibia, femur, pelvis, etc.) size of the tumor mass (in cm.), the degree of necrosis from neoadjuvant chemotherapy (beforeoperation chemotherapy), and pathological factors like the degree of p-glycoprotein, whether your tumor is cxcr4-positive.^[1] Her2-positive as these can lead to distant metastases to the lung. Longer time to metastases, more than 12 months or 24 months and the number of metastases and resectability of them lead to the best prognosis with metastatic osteosarcoma. It is better to have fewer metastases than longer time to metastases. Those with a longer length of time(>24months) and few nodules (2 or fewer) have the best prognosis with a 2-year survival after the metastases of 50% 5-year of 40% and 10 year 20%. If metastases are both local and regional the prognosis is different unfortunately.

• Initial Presentation of stage III osteosarcoma with lung metastates depends on the resectability of the primary tumor and lung nodules, degree of necrosis of the primary tumor, and maybe the number of metastases. Overall prognosis is 30% or greater depending.

 complications and prognosis