Osteosarcoma – Causes, Symptoms, Diagnosis, Treatment

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Osteosarcoma (OS) is an osteoid-producing malignancy of mesenchymal origins. This high-grade tumor is the most common primary malignancy of bone and is often fatal in both children and adults. While primary bone cancers represent less than 0.2% of all cancers [], according to the National Cancer Institute SEER (Surveillance, Epidemiology, and End Results) program, their frequency has been increasing by 0.3% per year over the last decade []. While OS occurs most frequently in patients between 5 years of age and early adulthood, incidence peaks again in the older (>65) populations and has been associated with pre-existing Paget’s disease and prior radiation therapy []. Collectively, the metaphysis of the lower long bones, specifically the distal femur and proximal tibia, are the most commonly involved primary sites, with patients over 25 displaying a greater variety of bony locations [].

Osteosarcoma is the most common primary pediatric bone malignancy, derived from primitive bone-forming (osteoid producing) mesenchymal cells. It occurs in primary (no underlying bone pathology) and secondary forms (underlying pathology which has undergone malignant degeneration/conversion), accounting for approximately 20% of all primary bone tumors. Osteosarcoma is highly heterogeneous in its manifestation, which permits division into several subtypes according to the degree of differentiation, location within the bone, and histological variation. These subtypes vary in imaging appearance, demographics, and biological behavior. With the ceaseless work of numerous medical, surgical, and scientific professionals, treatment options and survivability have vastly improved in recent years.

Types of Osteosarcoma

Osteosarcoma is a malignant tumor that is characterized by the direct formation of bone or osteoid tissue by the tumor cells. The World Health Organization’s histologic classification [] of bone tumors separates the osteosarcomas into central (medullary) and surface (peripheral) tumors [,] and recognizes a number of subtypes within each group.

Central (Medullary) Tumors
  • Conventional central osteosarcomas. The most common pathologic subtype is conventional central osteosarcoma, which is characterized by areas of necrosis, atypical mitoses, and malignant osteoid tissue and/or cartilage. The other subtypes are much less common, each occurring at a frequency of less than 5%.
  • Telangiectatic osteosarcomas.[,] Telangiectatic osteosarcoma may be confused radiographically with an aneurysmal bone cyst or giant cell tumor. This variant should be approached as a conventional osteosarcoma.[,]
  • Intraosseous well-differentiated (low-grade) osteosarcomas.
  • Small-cell osteosarcomas.
Surface (Peripheral) Tumors
  • Parosteal (juxtacortical) well-differentiated (low-grade) osteosarcomas.[,]
  • Periosteal osteosarcomas. Low-grade to intermediate-grade osteosarcomas.[]
  • High-grade surface osteosarcomas.[,,]
Parosteal and Periosteal Osteosarcoma

Parosteal osteosarcoma – is defined as a lesion arising from the surface of the bone with a well-differentiated appearance on imaging and low-grade histological features.[] The most common site for parosteal osteosarcoma is the posterior distal femur. Parosteal osteosarcoma occurs more often in older patients than does conventional high-grade osteosarcoma and is most common in patients aged 20 to 30 years. Parosteal osteosarcoma can be treated successfully with wide excision of the primary tumor alone.[,]

Periosteal osteosarcoma – typically appears as a broad-based soft tissue mass with extrinsic erosion of the underlying bony cortex.[] Pathology shows an intermediate grade of differentiation. In a series of 119 patients, metastasis was reported in 17 patients.[] Wide resection is essential. A single-institution retrospective review identified 29 patients with periosteal osteosarcoma.[] The 5-year disease-free survival rate was 83%. The authors could not make a definitive statement regarding the benefits of adjuvant chemotherapy. Another single-institution retrospective review identified 33 patients with periosteal osteosarcoma.[]

  • Conventional (“classic”) – The most prevalent subtype, comprising 80% of all osteosarcomas. Classically high-grade, arising from the intramedullary canal. Spindle to polyhedral cell shape malignant mesenchymal cells is seen. Cell nuclei are pleomorphic with occasional mitotic figures. Extracellular matrix production can be osteoblastic, osteoclastic, or fibroblastic; however, a combination is common.
  • Telangiectatic – <4% of osteosarcomas. Dilated hemorrhagic sinusoids are seen with small amounts of osteoid. These cavities mimic the appearance of an aneurysmal bone cyst, with the presence of high-grade sarcoma cells distinguishing the tumor.
  • Low-grade – <2% of osteosarcomas. Well-differentiated cells are seen embedded in the osseous matrix and fibrous stroma, with small amounts of osteoid.
  • Small cell – 1.5% of osteosarcomas. Numerous small round malignant cells are seen within an osteoid matrix. Small cell sarcoma can resemble Ewing sarcoma; however, the production of osteoid and sporadic spindling of cells are distinguishing features.
  • Parosteal – 1-6% of osteosarcomas. Slow growing, arising from the outer surface of the metaphysis. Low-grade, with a well-differentiated, mostly cartilaginous matrix with minimal osteoid.
  • Periosteal – 1-2% of osteosarcomas. More aggressive than parosteal osteosarcoma, with intermediate-grade tumors showing increased cell atypia. Mostly cartilaginous matrix with minimal osteoid.
  • High-grade – <1% of osteosarcomas. Histologically like conventional osteosarcoma, showing high-grade spindle shape cells with nuclear pleomorphism.

Chondrosarcomas are characterized by the production of hyaline cartilage to form a cartilaginous matrix. Lobules of cartilage are seen with significant variation in dimension. Cell nuclei show pleomorphism with chondrocytes varying in size and shape. Conventional chondrosarcoma accounts for over 85% of all chondrosarcomas. It can be further subcategorized into primary central (developing within the medullary canal), or secondary peripheral (developing from the surface of the bone secondary to pre-existing enchondroma or osteochondroma). Histologically both primary central and secondary peripheral are alike. Grading is an essential process to allow the prediction of clinical behavior.

  • Grade I: Low-grade lesions, lowly cellular, with a predominantly cartilaginous matrix and small dense nuclei. Distinguishing grade I chondrosarcoma and benign enchondroma can be difficult, both radiologically and histologically.
  • Grade II: Reduced cartilaginous matrix and moderately cellular. Nuclei are enlarged and hyperchromatic, with increased atypia. Mitoses may be seen.
  • Grade III: High-grade lesions, highly cellular, with increased cellular atypia showing vesicular and enlarged nuclei. Cartilaginous matrix is rare or absent, with myxoid material evident. Mitoses are more readily identified.

Several rare subtypes of chondrosarcoma are also identified. Dedifferentiated chondrosarcoma is characterized by low-grade chondrosarcoma next to a dedifferentiated high-grade lesion, with a sharp transition between the two. The tumor is extremely aggressive. Mesenchymal chondrosarcoma is a high-grade tumor occurring in either bone or soft tissue. Undifferentiated small round cells are seen, with varying amounts of a cartilaginous matrix. Clear cell chondrosarcoma is a low-grade tumor, with cells showing clear, vacuolated cytoplasm. Areas of hemorrhage and cyst formation are seen.

Ewing Sarcoma

Ewing sarcoma is a high-grade aggressive sarcoma and belongs to the group of small round cell tumors. Monomorphic small cells are seen in sheets, with round nuclei and finely dispersed chromatin, with nucleoli usually not identifiable. Frequently necrosis is seen, with remaining viable cells arranged perivascularly. Cell membranes express the glycoprotein CD99, with immunohistochemistry showing that >95% of Ewing sarcomas have extensive membranous expression. CD99 expression is not specific to Ewing sarcoma, and other markers are also used for diagnosis.

Other Types of PBC

Chordoma, adamantinoma, and giant cell tumors of bone are typically low-grade locally invasive tumors. Undifferentiated pleomorphic sarcoma and fibrosarcoma are aggressive malignant tumors, with generally poor prognosis.

Extraosseous Osteosarcoma

Extraosseous osteosarcoma is a malignant mesenchymal neoplasm without direct attachment to the skeletal system. Previously, treatment for extraosseous osteosarcoma followed soft tissue sarcoma guidelines,[] although a retrospective analysis of the cooperative German-Austrian-Swiss osteosarcoma study group identified a favorable outcome for extraosseous osteosarcoma treated with surgery and conventional osteosarcoma therapy.[]

Undifferentiated Pleomorphic Sarcoma (UPS) of Bone

UPS of bone should be distinguished from angiomatoid fibrous histiocytoma, a low-grade tumor that is usually noninvasive, small, and associated with an excellent outcome using surgery alone.[] One study suggests similar event-free survival rates for UPS and osteosarcoma.[]

Causes of Osteosarcoma

Although the quality of life of patients affected by osteosarcoma has significantly improved over the last few decades, its etiology remains obscure. Studies aiming to determine the causes of osteosarcoma have classically focused on multiple factors, including genetics, epidemiology, and the environment.

The highly complex karyotypes typical of osteosarcoma tumor cytology have created challenges regarding the thorough characterization of recurrent chromosomal mutations. However, research has identified several genetic aberrations in cases of primary osteosarcoma:

  • Genetic factors are linked – Germline abnormalities in hereditary cancer predisposition syndromes have an increased risk of later developing bone cancer, through downregulation of tumor suppressor genes or upregulation of oncogenes. TP53 tumor suppressor gene is often altered in Li-Fraumeni syndrome, with patients at an increased risk of developing osteosarcoma. Similarly, a mutation in the Rb1 gene leading to hereditary retinoblastoma is linked to osteosarcoma. Werner and Rothmund-Thomson syndromes are also linked to an increased risk of developing osteosarcoma. Previous treatment for cancer with radiotherapy is linked to an increased risk of developing PBC in later life, particularly when exposed to ionizing radiation in childhood.
  • Several benign conditions – show the potential to progress to PBC. Paget disease of the bone is a condition characterized by a disorder of bone metabolism, particularly osteoclastic function. These patients are at an increased risk of developing osteosarcoma; however, it is a rare complication. Enchondromas and osteochondromas are benign cartilaginous neoplasms that can later develop into malignant chondrosarcoma.
  • Hereditary retinoblastoma – an autosomal dominant condition caused by germline mutations in the RB1 gene, causes bilateral retinoblastoma at an average presenting age of 1 year. Retinoblastoma characteristically presents as an absence of the “red reflex” in the eye or eyes of the affected child. This disorder imparts an increased risk of osteosarcoma later in life.
  • Li-Fraumeni syndrome – an autosomal dominant disorder due to mutations in the p53 tumor suppressor gene, has been found in up to 3% of children with osteosarcoma. Patients with this disorder are also at a high risk of developing several additional types of cancer at a very early age.
  • Rothmund-Thompson syndrome – an autosomal recessive syndrome due to a mutation in the RECQL4 gene, conveys a predisposition to osteosarcoma as well as a characteristic infantile rash, dysplastic osseous structures, alopecia, premature cataracts, and chronic gastrointestinal distress.
  • Bloom syndrome – an autosomal recessive disorder caused by mutations in the BLM gene, a gene responsible for maintaining DNA stability during replication. In addition to a predisposition to osteosarcoma and other cancers, these patients may also present with UV-induced rashes, short stature, and sparse subcutaneous fat.
  • Werner Syndrome – an autosomal recessive disorder, also known as adult progeria, is characterized by premature aging, bilateral cataracts, osteoporosis, short stature, scleroderma-like skin changes, and a predilection for osteosarcoma. A faulty WRN gene is responsible.
  • Familial cases where the deletion of chromosome 13q14 inactivates the retinoblastoma gene is associated with a high risk of osteosarcoma development.
  • Bone dysplasias, including Paget’s disease of bone, fibrous dysplasia, enchondromatosis, and hereditary multiple exostoses, increase the risk of osteosarcoma.
  • Li–Fraumeni syndrome (germline TP53 mutation) is a predisposing factor for osteosarcoma development.
  • Rothmund–Thomson syndrome (i.e. autosomal recessive association of congenital bone defects, hair and skin dysplasias, hypogonadism, and cataracts) is associated with increased risk of this disease.
  • Large doses of Sr-90 emission from nuclear reactors, nicknamed bone seeker increases the risk of bone cancer and leukemia in animals, and is presumed to do so in people.[rx]

Research has identified associations with secondary osteosarcoma in patients with Paget disease, electrical burns, trauma, exposure to beryllium, exposure to alkylating agents, FBJ virus, osteochondromatosis, enchondromatosis, fibrous dysplasia, orthopedic prosthetics as well as bone infarction and infection. Additionally, osteosarcoma reportedly correlates with exposure to ionizing radiation, radium, and archaic contrast agents such as Thorotrast.

Associate Causes

  • Age – Middle-age patients (over 40 years old) have considerably worse survival rates than younger adults even after the exclusion of secondary forms of osteosarcoma. Several studies have determined that patients over the age of 40 were more apt to have involvement of the axial skeleton and metastatic lesions on presentation, which correlate with poorer outcomes (as described below). Older patients (older than 60 years) fare the worst, typically due to refusal of chemotherapy and radical surgery.
  • Gender – Men reportedly demonstrate less response to chemotherapy, a higher propensity for recurrence, and a four-fold increase in morbidity. Conversely, female sex correlated with a higher percentage of chemo-related tumor necrosis as well as greater overall survival.
  • Biomarker levels – Serum alkaline phosphatase, a biomarker associated with bone turnover, has been found in elevated levels in patients with osteosarcoma. However, it is crucial to consider the age of the patient when interpreting ALP levels as intrinsically higher values are typical in younger age groups. Research has documented high levels in association with less disease-free survival. However, serum alkaline phosphatase levels may be normal at the time of diagnosis in nearly half of patients, particularly in cases where a tumor features minimal osteoid deposition.[9] Lactate dehydrogenase (LDH) is also a useful biomarker. Significantly higher serum LDH levels have been observed in patients with metastasis on initial presentation than patients with local disease alone.
  • Tumor location – Patients with tumors located in the axial skeleton tend to fare worse compared to those diagnosed in the appendicular skeleton. A difference of up to 10 years of survival exists between groups. Furthermore, patients with femoral tumors often do much worse than patients with lesions located in the distal tibia.
  • Tumor burden –Larger/bulky tumors, as one may expect, carry worse prognoses than smaller lesions. One study found that the morbidity likelihood is 3.4 times higher in larger masses (over 15 cm). When tumor volume exceeds 200 mL, patients are significantly less likely to have successful limb salvage; they also demonstrate a poorer response to chemotherapy and a greater likelihood of recurrence. Unsurprisingly, the chance of death is significantly higher in patients with evidence of metastasis on presentation.
  • Histology – The role of histology in response to chemotherapy and survival outcome is modest. Fibroblastic differentiation is generally considered to be favorable histology. This histologic profile is associated with improved chemotherapy-related tumor necrosis as well as a lower risk of death than alternative histologic subtypes. Chondroid predominant tumor histology correlates with poorer outcomes.
  • Preoperative chemotherapeutic response – Survival outcome is dependent upon several factors, but the most important predictor of success is the degree of chemotherapy-induced tumor necrosis; Necrosis of 90% or more of the tumor is associated with an excellent prognosis.
  • Pathological fracture – Osteosarcoma patients have an increased risk of local recurrence and a decreased rate of survival if a pathological fracture is a feature of the initial presentation. Pathological fractures sustained during preoperative chemotherapy have been found to have a decreased rate of survival compared with patients without therapy-associated pathologic fracture.
  • Body Mass Index – High BMI has correlations with reduced overall survival.


Many patients first complain of pain that may be worse at night, maybe intermittent and of varying intensity and may have been occurring for some time. Teenagers who are active in sports often complain of pain in the lower femur, or immediately below the knee. If the tumor is large, it can present as overt localized swelling. Sometimes a sudden fracture is the first symptom because the affected bone is not as strong as normal bone and may fracture abnormally with minor trauma. In cases of more deep-seated tumors that are not as close to the skin, such as those originating in the pelvis, localized swelling may not be apparent

Signs and symptoms of osteosarcoma may include, among others:

  • Swelling near a bone
  • Bone or joint pain
  • Bone injury or bone break for no clear reason
  • Swelling or lumps around bones or the ends of bones
  • Bone or joint pain or soreness. This pain may come and go for months.
  • Broken bones without a clear reason
  • Pain at night
  • Pain after exercise
  • Limpin
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Diagnosis of Osteosarcoma


Osteosarcoma is grossly divided into various subtypes based on its location within the bone then further subdivided by grade.

1. Central (Intramedullary)

  • High-grade central

    • Conventional – “classic” appearance; cells are spindle-like to polyhedral in shape; nuclei are variable in appearance, and cells undergoing mitosis are readily identifiable. Matrix production by the tumor cells may be osseous (“osteoblastic”), cartilaginous (“chondroblastic”), or fibrous (“fibroblastic”) but a combination of the three often presents. Osteoid matrix must be identified somewhere in the lesion, even if only in a minuscule amount. In the case of osteoblastic osteosarcoma, there may be excessive osteoid matrix production such that the tumor is described as “sclerosing” in appearance.

      • Osteoblastoma-like – histologically resembles osteoblastoma but features more cellular atypia and local aggressiveness, and osteoid matrix production
      • Chondroblastoma-like – histological resembles chondroblastoma but features more cellular atypia, local aggressiveness, and osteoid matrix production
      • Chondromyxoid fibroma-like – histological resembles chondromyxoid fibroma but features more cellular atypia, local aggressiveness and osteoid matrix production
      • Malignant fibrous histiocytoma-like – histologically resembles malignant fibrous histiocytoma but features more cellular atypia, local aggressiveness and osteoid matrix production
      • Epithelioid – features cells which are so poorly differentiated that it may be hard to distinguish histologically whether the lesion is a sarcoma (connective tissue origin) or a carcinoma (epithelial origin)
      • Giant cell – features benign multinucleated osteoclast-like giant cells
      • Clear cell – features numerous cells with clear or ground-glass cytoplasm and vacuoles
    • Telangiectatic – comprised of numerous blood-filled sinusoids such that the tumor mimics the histology of an aneurysmal bone cyst; the presence of pleomorphic/atypical nuclei will distinguish the malignancy
    • Small cell – considered to be a histological combination of Ewing sarcoma/PNET and osteosarcoma, features numerous small round cells. A minuscule volume of an osteoid matrix will distinguish this as a variant of osteosarcoma
  •  Low-grade central

    • Fibrous dysplasia–like – features a large volume of osseous matrix embedded in a small amount of fibrous stroma
    • Desmoplastic fibroma–like – features a very small volume of osseous matrix embedded in a large amount of fibrous stroma

2. Surface (Periosteal/Cortical)

  • Low-grade surface 

    • Parosteal – found on the outer periosteal surface of the bone, features ribbons of osseous trabeculae oriented in parallel, primarily composed of a chondroid matrix with only a minuscule amount of osteoid matrix
  •  Intermediate-grade surface 

    • Periosteal – found between cortex and the inner periosteal surface of the bone, features ribbons of osseous trabeculae oriented in parallel, primarily composed of a chondroid matrix with only a minuscule amount of osteoid matrix, more nuclear atypia than the parosteal variant
  •  High-grade surface 

    • High-grade surface – histological identical to high grade/conventional/central variant, varies only in location (being confined the surface of the bone) which is thought to represent dedifferentiated parosteal osteosarcoma

3. Extraskeletal

  • Low-grade 

    • Histologically identical to low-grade surface/parosteal variant and low-grade central variant varies only in geography, potentially appearing at any extraskeletal location in the body, including the soft tissues of the thigh, buttocks, upper extremities or retroperitoneum.
  • High-grade 

    • Histological identical to high grade/conventional/central variant differs only in geography, being found at any extraskeletal location in the body

History and Physical

Symptoms of osteosarcoma may be present for a significant amount of time, sometimes weeks to months, before patients seek evaluation. Most commonly, the presenting symptom is bone pain, particularly with activity. Parents are often concerned that their child has incurred a sprain, arthritis, or growing pains. There may or may not be a reported history of traumatic musculoskeletal injury.

Pathologic fractures are not a common mainstay of osteosarcoma, except for the telangiectatic type of osteosarcoma, which is associated with pathologic fractures. The resulting pain may manifest as a limp. A swelling or lump may or may not be reported, depending on tumor size and location. Systemic symptoms, such as those seen in lymphoma (fever, night sweats, etc.), are rare.

Respiratory symptoms are rare and, when present, indicate extensive lung involvement. Additional symptoms are unusual because metastases to other sites are extremely rare.

Physical examination findings are typically focused around the location of the primary tumor and may include:

  • A palpable mass which may be tender and warm with or without an overlying pulsation or bruit, though these signs are nonspecific
  • Joint involvement with decreased range of motion
  • Local or regional lymphadenopathy (unusual)
  • Respiratory findings with metastatic forms


    National Comprehensive Cancer Network’s 2020 Guidelines for Initial Evaluation of Osteosarcoma (Version 1.2020)

    Clinical history and physical exam
    • Laboratory blood testsSpecific laboratory blood tests are not used in the diagnosis of PBC; however, they form part of the patient workup. In patients undergoing chemotherapy, baseline urea, creatinine, and liver function tests allow baseline assessment of renal and hepatic function. Biochemical markers alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) offer some prognostic value, and levels can be monitored in follow up to assess for disease recurrence.
    Laboratory analysis of Lactate Dehydrogenase (LDH) and Alkaline Phosphatase (ALP) levels
    • Biochemical markers such as serum alkaline phosphatase (ALP) and lactate dehydrogenases (LDH) are assessed in the initial workup because they provide evidence for diagnosis and prognosis. ALP levels will be high due to the increased osteoblastic activity associated with osteosarcoma. Extremely high levels have been linked to heavy tumor burden and are generally considered a poor prognostic indicator. It is important to evaluate the levels of the biomarkers later in the treatment process as well, as levels may decrease with success therapy or rise with residual disease or recurrence.
    Diagnostic imaging of primary tumor site 
    • Radiographs – although MRI is the gold standard for diagnostic imaging of osteosarcoma, radiographs are generally the first study obtained when a potential bone mass is identified on the physical exam. A conventional radiograph of osteosarcoma may demonstrate:

      • Medullary and cortical bone destruction
      • Permeative or moth-eaten cortex
      • “Sunburst” configuration (due to aggressive periostitis)
      • “Codman’s triangle” configuration (due to elevation of the periosteum away from the bone)
      • Ill-defined “fluffy” or “cloud-like” osseous lesion
      • Soft-tissue mass
      • Calcification of osteoid matrix produced by the tumor

        • Osteolytic, osteoblastic, or mixed changes.
        • A moth-eaten appearance, suggesting bone destruction secondary to a rapidly expanding tumor within a bone, commonly seen in Ewing sarcoma and telangiectatic osteosarcoma
        • A permeative appearance, suggesting tumor progressing through bone, with an ill-defined zone between tumor and healthy bone, often seen in small cell tumors, including Ewing sarcoma
        • “Onion skinning,” with the tumor lifting partially-formed periosteal bone, classically seen in Ewing sarcoma.
        • “Codman triangle,” with periosteum lifted off bone and osteoid laid down.
        • “Sunburst” appearance, with vertical osteoid calcification due to significant periostitis.
    • Magnetic Resonance Imaging – after identifying a suspicious lesion on a radiograph, MRI may be necessary for further characterization. MRI is an indispensable tool for defining the extent of a tumor inside and outside the bone. The entirety of the involved bone, as well as one joint above and one joint below the tumor, should be included in the study so that “skip” lesions are not missed. MRI can accurately and precisely delineate (1) degree of tumor in the adjacent soft tissues, (2) joint involvement, (3) whether or not the tumor crosses the physis, (4) proximity to the nearest neurovascular bundle. Nearly every aspect of treatment is assessable with MRI, from pre-surgical assessment for limb-sparing resection to the degree of chemotherapy response in the form of tumor necrosis, shrinkage, and improved capsulation. Traditional sequences acquired in MRI of osteosarcoma may demonstrate the following:

      • T1 Weighted Images

        • Non-ossified soft tissue component: intermediate signal intensity
        • Osteoid components: low signal intensity
        • Peritumoral edema: intermediate signal intensity
        • Scattered foci of hemorrhage: variable signal intensity based on chronicity
      • T2 Weighted Images

        • Non-ossified soft tissue component: high signal intensity
        • Osteoid components: low signal intensity
        • Peritumoral edema: high signal intensity
    • Computed Tomography – the role of CT is primarily to assist with biopsy planning and disease staging. CT may not significantly contribute to direct assessment of the tumor after radiography and MRI unless the osseous lesion in question is predominantly lytic. In the case of lytic lesions, small amounts of mineralized material may be unobservable on both plain film and MRI. CT of the chest, however, is the modality of choice for evaluation of metastasis. 
    Nuclear Imaging
    • Positron Emission Tomography – PET is a nuclear medicine imaging modality that detects highly metabolic lesions. It is an essential tool that is useful for determining tumor extent and searching for subtle lesions after identifying a suspicious mass on initial diagnostic imaging. Later in the treatment process, PET is valuable for the detection of recurrence.
    • Radionuclide Bone Scan – Tc99 methylenediphosphonate (Tc99 MDP) bone scan is an effective and readily available imaging modality for detecting bony metastasis. It is a less expensive but less specific alternative to PET imaging.
    • Follow up MRI or CT (both with contrast) of sites of metastasis identified on PET or Bone Scan
    •  Fertility consultation – may be a consideration (chemotherapy and radiation therapy may affect fertility).
    • Biopsy of Osteosarcoma – After the physical exam, laboratory analysis, and diagnostic imaging confirm the presence of a lesion consistent with osteosarcoma, a biopsy is necessary. The final surgical procedure must include resection of the biopsy tract, which should be tattooed for easy identification, to avoid recurrence due to potential seeding of this tract with cancer cells.  Ideally, the surgeon who undertakes the biopsy should be the same individual who completes the resection, so they are familiar with the path and extent of the biopsy. An open approach to biopsy was previously considered to be the best option owing to a high rate of accuracy.
    • Computed tomography (CT) – CT scan is used when the diagnosis remains unclear following MRI, or MRI is contraindicated. It remains the modality of choice in pelvic PBC and for planning reconstructive surgery. Patients with confirmed PBC require staging, and although many centers still perform chest radiographs, a CT chest is the gold standard for assessing metastatic pulmonary disease.
    • Whole-body bone scintigraphy (bone scan) – Whole-body bone scintigraphy is a nuclear medicine study that utilizes Technetium-99m as an active agent, highlighting areas of osteoblastic activity. It allows the detection of malignancy and is useful in diagnosing metastatic disease.
    • Positron emission tomography (PET) – PET scan is a nuclear medicine study that utilizes the high metabolic rate of tumor cells, measuring the uptake of injected radiolabeled F-18 fluoro-deoxy-glucose (FDG). PET scan is in some centers for initial staging of PBC, and studies have suggested it as a modality for follow up when used in combination with CT scan.
    • Tissue biopsy – Biopsy of the lesion is needed for definitive diagnosis, allowing for histopathological assessment and tumor grading. Biopsy should be performed in conjunction with the operating surgical team, ideally in a specialist bone cancer center. It requires meticulous planning, with suboptimal biopsy impacting on definitive surgical treatment options. Imaging should be performed before a biopsy, aiding in approach planning and preventing tissue disruption that could make radiological assessment more difficult. Percutaneous, incisional, or excisional techniques are used. Ultrasound, x-ray, and CT scans allow precise guidance. The tract should be well marked, allowing for excision at the time of surgery, and a specialist bone cancer pathologist should assess samples.
    • Bone scan – A procedure to check if there are rapidly dividing cells, such as cancer cells, in the bone. A very small amount of radioactive material is injected into a vein and travels through the bloodstream. The radioactive material collects in the bones with cancer and is detected by a scanner.

    Treatment of Osteosarcoma

    National Comprehensive Cancer Network’s 2020 Guidelines for Management of Osteosarcoma (Version 1.2020)

    OSTEO-1 (Low-grade osteosarcoma, no metastasis)
    • Intramedullary and surface

      • Wide excision alone (no neoadjuvant chemotherapy)

        • If postsurgical pathology demonstrates low-grade features, then no adjuvant chemotherapy
        • If postsurgical pathology demonstrates high-grade features, consider adjuvant chemotherapy
    • Periosteal

      • Neoadjuvant chemotherapy then perform a wide excision

        • If postsurgical pathology demonstrates is consistent with biopsy (low grade features only) then no adjuvant chemotherapy
        • If postsurgical pathology demonstrates high-grade features, consider adjuvant chemotherapy
     OSTEO-2 (High-grade intramedullary or surface osteosarcoma, no metastasis)
    • Neoadjuvant chemotherapy then restage the lesion

      • If restaging suggests the lesion is resectable, then perform a wide excision

        • Positive margins

          • If there was a good response to preoperative neoadjuvant chemotherapy (less than10% viable tumor on postsurgical pathology), then continue the same neoadjuvant chemotherapy regimen and consider additional surgical resection +/- radiation therapy
          • If there was an inadequate response to preoperative neoadjuvant chemotherapy (greater than 10% viable tumor on postsurgical pathology), then continue the same neoadjuvant chemotherapy regimen or consider a new regimen and consider additional surgical resection +/- radiation therapy
        • Negative margins

          • If there was a good response to preoperative neoadjuvant chemotherapy (less than 10% viable tumor on postsurgical pathology), then continue the same neoadjuvant chemotherapy regimen. No further resection is required.
          • If there was an inadequate response to preoperative neoadjuvant chemotherapy (greater than 10% viable tumor on postsurgical pathology), then continue the same neoadjuvant chemotherapy regimen or consider a new regimen. No further resection is required.
      • If restaging suggests the lesion is unresectable, then continue chemotherapy and consider radiation therapy
    OSTEO-3 (Any grade with metastasis at presentation)
    • If metastases are resectable (pulmonary, visceral or skeletal), then perform metastasectomy and follow OSTEO-2 guidelines
    • If metastases are unresectable, then consider chemotherapy and radiation therapy, after which the primary site requires reassessment for local control
     OSTEO-4 (Follow-up & surveillance)
    • Surveillance schedule

      • Every three months for post-op years 1 and 2
      • Every four months in post-op year 3
      • Every six months in post-op years 4 and 5
      • Yearly for post-op years six and beyond
    • Surveillance visit should include

      • Physical exam with assessment of function
      • Imaging of post-op site and chest

        • Consider PET/CT or Bone scan
      • CBC +/- additional laboratory tests as clinically indicated (e.g., alkaline phosphatase levels)
    • If a relapse is detected, the following are the guidelines to follow:

      • Chemotherapy +/- resection (if possible)

        • Response to these treatments should have an evaluation via:

          • Radiographs of the original tumor site
          • CT or MRI (both with contrast) of the site of relapse
          • CT of the chest to assess for pulmonary lesions
        • Good response to treatment:

          • Surveillance (restart OSTEO-4 guidelines)
        • Poor response/progression of the disease:

          • Resection (if possible)
          • Clinical Trial
          • Palliative Radiation
          • Best supportive care
    Extraskeletal osteosarcoma
    • Follow the National Comprehensive Cancer Network’s guidelines for the treatment of soft tissue sarcoma.


    Preoperative chemotherapy
    • Almost all patients receive intravenous preoperative chemotherapy as initial treatment. However, a standard chemotherapy regimen has not been determined. Current chemotherapy protocols include combinations of the following agents: high-dose methotrexate, doxorubicin, cyclophosphamide, cisplatin, ifosfamide, etoposide, and carboplatin.[]
    Evidence (preoperative chemotherapy)
    • A meta-analysis of protocols for the treatment of osteosarcoma concluded that regimens containing three active chemotherapy agents were superior to regimens containing two active agents.[]

      • The meta-analysis also concluded that regimens with four active agents were not superior to regimens with three active agents.
      • The meta-analysis suggested that three-drug regimens that did not include high-dose methotrexate were inferior to three-drug regimens that did include high-dose methotrexate.
    • An Italian study used regimens containing fewer courses of high-dose methotrexate and observed a lower probability for EFS than did earlier studies that used regimens containing more courses of high-dose methotrexate.[]
    • The Children’s Oncology Group (COG) performed a prospective randomized trial in newly diagnosed children and young adults with localized osteosarcoma. All patients received cisplatin, doxorubicin, and high-dose methotrexate. One-half of the patients were randomly assigned to receive ifosfamide. In a second randomization, one-half of the patients were assigned to receive the biological compound muramyl tripeptide-phosphatidyl ethanolamine encapsulated in liposomes (L-MTP-PE) beginning after definitive surgical resection.[]

      • The addition of ifosfamide did not improve outcome.
      • The addition of L-MTP-PE produced improvement in the EFS rate, which did not meet the conventional test for statistical significance (P = .08), and a significant improvement in the OS rate (78% vs. 70%; P = .03).
      • There has been speculation regarding the potential contribution of postrelapse treatment, although there were no differences in the postrelapse surgical approaches in the relapsed patients. The appropriate role of L-MTP-PE in the treatment of osteosarcoma remains under discussion.[]
    • The COG performed a series of pilot studies in patients with newly diagnosed localized osteosarcoma.[]

      1. In pilot study 1, patients with lower degrees of necrosis after three-drug initial therapy received subsequent therapy with a higher cumulative dose of doxorubicin of 600 mg/m2.
      2. In pilot study 2, all patients received four-drug initial chemotherapy with cisplatin, doxorubicin, high-dose methotrexate, and ifosfamide. Patients with lower degrees of necrosis received subsequent chemotherapy with a higher cumulative dose of doxorubicin of 600 mg/m2.
      3. In pilot study 3, all patients received the same four-drug initial chemotherapy as pilot study 2. Patients with lower degrees of necrosis received higher doses of ifosfamide with the addition of etoposide in subsequent therapy.
      • Outcomes for all three pilot studies were similar to each other and to historical controls.
      • All patients received dexrazoxane before each dose of doxorubicin. The addition of dexrazoxane did not appear to decrease the rate of good necrosis after initial therapy or EFS.
      • Left ventricular fractional shortening, as measured by echocardiography, was minimally affected at 78 weeks from study entry.
      • There was no evidence for an increased risk of secondary leukemia.
    Postoperative chemotherapy

    Historically, the extent of tumor necrosis was used in some clinical trials to determine postoperative chemotherapy. In general, if tumor necrosis exceeded 90%, the preoperative chemotherapy regimen was continued. If tumor necrosis was less than 90%, some groups incorporated drugs not previously utilized in the preoperative therapy.

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    Patients with less necrosis after initial chemotherapy have a prognosis that is inferior to the prognosis for patients with more necrosis. The prognosis is still substantially better than the prognosis for patients treated with surgery alone and no adjuvant chemotherapy. Based on the following evidence, it is inappropriate to conclude that patients with less necrosis have not responded to chemotherapy and that adjuvant chemotherapy should be withheld for these patients. Chemotherapy after definitive surgery should include the agents used in the initial phase of treatment unless there is clear and unequivocal progressive disease during the initial phase of therapy.

    Evidence (postoperative chemotherapy):

    • In an early experience, the German cooperative osteosarcoma group performed a trial in which the chemotherapy regimen for patients with poor necrosis was changed after initial treatment.[] The agents used before surgery were discontinued and other agents were substituted.

      • The results were substantially poorer for these patients than for patients who continued to receive the same agents.
    • A limited-institution pilot trial tested the strategy of discontinuing the agents used in the initial phase of therapy for patients with poorer necrosis; postoperative therapy consisted of melphalan with autologous stem cell reconstitution.[]

      • The 5-year EFS rate for this group was 28%, which was lower than the EFS rates observed in many large series in which agents were continued despite a lesser degree of necrosis.
    • Addition of cisplatin.

      • The approach to incorporate drugs not previously used for preoperative therapy was based on early reports from Memorial Sloan Kettering Cancer Center (MSKCC) that suggested that adding cisplatin to postoperative chemotherapy improved the outcome for patients with less than 90% tumor necrosis.[] With longer follow-up, the outcome for patients with less than 90% tumor necrosis treated at MSKCC was the same whether they did or did not receive cisplatin in the postoperative phase of treatment.[]
      • Subsequent trials performed by other groups failed to demonstrate improved EFS when drugs not included in the preoperative regimen were added to postoperative therapy.[,]
    • Addition of interferon or high-dose therapy.

      1. The international European and American Osteosarcoma Study (EURAMOS) group consortium was formed to conduct a large prospective, randomized trial to help determine whether modifying the chemotherapy regimen on the basis of the degree of necrosis would improve EFS. All patients received initial therapy with cisplatin, doxorubicin, and high-dose methotrexate (MAP). Patients with more than 90% necrosis were randomly assigned to continue the same chemotherapy after surgery or to receive the same chemotherapy with the addition of interferon.[]

        • The addition of interferon did not improve the probability of EFS.
      2. In the same EURAMOS trial, patients with less than 90% necrosis were randomly assigned to continue the same chemotherapy or to receive the same chemotherapy with the addition of high-dose ifosfamide and etoposide (MAPIE).[]

        • With a median follow-up of over 61 months, the EFS did not differ between the two groups.
        • The intensification of treatment in the MAPIE group resulted in greater toxicity than did the treatment in the standard MAP arm.

    Radiation therapy

    If complete surgical resection is not feasible or if surgical margins are inadequate, radiation therapy may improve the local control rate.[,]; []Radiation therapy should be considered in patients with osteosarcoma of the head and neck who have positive or uncertain resection margins.[]

    Evidence (radiation therapy for local control)

    1. While it is accepted that the standard approach is primary surgical resection, a retrospective analysis of a small group of highly selective patients reported long-term EFS with external-beam radiation therapy for local control in some patients.[]
    2. Investigators from a single institution reported on 28 children and young adults with osteosarcoma who were treated with radiation therapy for local control. Sixteen patients received radiation therapy during the primary treatment course, and 12 patients received radiation therapy as part of retrieval therapy after recurrence.[]
      • For patients who received radiation therapy during primary treatment, the cumulative incidence of local failure at 5 years was 25%.
      • For patients with recurrent disease, the cumulative incidence of local failure at 5 years was 44%.
      • Local tumor progression was observed in 3 of 13 patients (23%) who were treated with adjuvant radiation therapy after resection, while three of six patients (50%) who received definitive radiation therapy as a sole modality of local control experienced local progression.

    Target Therapy

    The following chemotherapy and targeted therapy agents have been studied to treat recurrent osteosarcoma and UPS of bone:

    • Ifosfamide alone with mesna uroprotection, or in combination with etoposide – Ifosfamide alone with mesna uroprotection, or in combination with etoposide, has been active in as many as one-third of patients with recurrent osteosarcoma who have not previously received this drug.[]
    • Gemcitabine and docetaxel – A nonrandomized comparison of two doses of gemcitabine, both given with docetaxel, suggested that a higher dose of gemcitabine (900 mg/m2) was associated with a better response rate and longer survival than was a lower dose of gemcitabine (675 mg/m2) for recurrent or refractory osteosarcoma.[]The combination of gemcitabine (at a dose of 900 mg/m2) and docetaxel has also been reported to have activity in some studies that included patients with unresectable disease.[]; []
    • Cyclophosphamide and etoposide – Cyclophosphamide and etoposide have been shown to have activity in recurrent osteosarcoma.[]
    • Sorafenib – The Italian Sarcoma Group reported rare objective responses and disease stabilization with sorafenib in patients with recurrent osteosarcoma.[]
    • Sorafenib and everolimus – The Italian Sarcoma Group also reported the outcome of patients with metastatic recurrent osteosarcoma treated with the combination of sorafenib and everolimus. They observed two partial responses and two minor responses in 38 patients; 17 of 38 patients were progression-free at 6 months from study entry but toxicity was greater than with sorafenib monotherapy.[]
    • Mifamurtide – is used after a patient has had surgery to remove the tumor and together with chemotherapy to kill remaining cancer cells to reduce the risk of cancer recurrence. Also, the option to have rotationplasty after the tumor is taken out exists.[22]
    • Standard therapy – is a combination of limb-salvage orthopedic surgery when possible (or amputation in some cases) and a combination of high-dose methotrexate with leucovorin rescue, intra-arterial cisplatin, adriamycin, ifosfamide with mesna, BCD (bleomycin, cyclophosphamide, dactinomycin), etoposide, and muramyl tripeptide.[rx] Rotationplasty may be used. Ifosfamide can be used as an adjuvant treatment if the necrosis rate is low.
    • Filgrastim or pegfilgrastim – help with white blood cell counts and neutrophil counts. Blood transfusions and epoetin alfa help with anemia. Computational analysis on a panel of Osteosarcoma cell lines identified new shared and specific therapeutic targets (proteomic and genetic) in Osteosarcoma, while phenotypes showed an increased role of tumor microenvironments.[rx]
    • Regorafenib. Two prospective, randomized, double-blind trials have evaluated the role of regorafenib in the treatment of metastatic recurrent osteosarcoma. Both studies used the approved treatment regimen of 160 mg by mouth daily for 21 days followed by 7 days without treatment. The French trial randomly assigned patients 2:1 between regorafenib and placebo and allowed crossover for patients assigned to placebo.[] Seventeen of 26 patients (65%; one-sided 95% CI, 47%) in the regorafenib group did not have disease progression at 8 weeks, compared with 0 of 12 patients in the placebo group. The Sarcoma Alliance for Research Collaboration (SARC) group randomly assigned adult patients 1:1 between regorafenib and placebo.[] Median progression-free survival was significantly improved with regorafenib versus placebo: 3.6 months (95% CI, 2.0–7.6 months) versus 1.7 months (95% CI, 1.2–1.8 months), respectively (hazard ratio, 0.42; 95% CI, 0.21–0.85; P = .017).
    • Monoclonal antibody therapy – is a cancer treatment that uses antibodies made in the laboratory, from a single type of immune system cell. These antibodies can identify substances on cancer cells or normal substances that may help cancer cells grow. The antibodies attach to the substances and kill the cancer cells, block their growth, or keep them from spreading. Monoclonal antibodies are given by infusion. They may be used alone or to carry drugs, toxins, or radioactive material directly to cancer cells. Denosumab and dinutuximab are monoclonal antibodies being studied for the treatment of recurrent osteosarcoma.
    • Mammalian target of rapamycin (mTOR) inhibitors block – a protein called mTOR, which may keep cancer cells from growing and prevent the growth of new blood vessels that tumors need to grow. Everolimus is an mTOR inhibitor used to treat recurrent osteosarcoma.
    • High-dose samarium Sm 153-ethylenediamine tetramethylene phosphonic acid (153Sm-EDTMP) – coupled with peripheral blood stem cell support may provide significant pain palliation in patients with bone metastases.[] Toxicity of 153Sm-EDTMP is primarily hematologic.[]
    • High-dose Methotrexate with Leucovorin Rescue – Methotrexate works by binding stoichiometrically and irreversibly to dihydrofolate reductase, inhibiting the formation of tetrahydrofolate and preventing the synthesis of thymidylate causing cell death []. Leucovorin is the antidote to methotrexate and serves to replenish tetrahydrofolate stores depleted by methotrexate. This regimen (MTX-L), a mainstay in OS chemotherapy, was established by Jaffe et al. and is comprised of IV doses of 10-12.5 g/m2 over 4-6h with leucovorin rescue starting 24h after the onset of methotrexate infusion [,]. When used in combination therapy, the interval between doses of MTX-L is generally 21-28 days. Doxorubicin is typically administered 8-10 days after the initial dose of MTX-L. When administered as a single adjuvant agent following surgical resection of the primary tumor, MTX-L resulted in a 40% disease-free survival. However, when combined with other agents as pre- and post-operative therapy, disease-free survival rates of 65-75% were achieved [,,]. Methotrexate has been shown to potentiate the effects of radiation therapy [].
    • Leucovorin – is administered according to algorithms available in most institutions. Most protocols include an IV dose of 10 mg after completion of the methotrexate infusion followed by subsequent doses every 6 h until the MTX level falls below 0.1 μmol/L; this typically requires 72h and 12 doses.
    • Doxorubicin – Doxorubicin is used in most OS combination chemotherapy regimens and has been called the single most effective agent [,]. Doxorubicin is an anthracyline chemotherapeutic which functions by intercalating into DNA, inducing single- and double-strand breaks. Initial studies using doxorubicin in patients with pulmonary metastases resulted in response rates of 35-40%, including the complete disappearance of lung lesions in some patients and an overall 40% reduction in tumor volume [,]. Similar to methotrexate, doxorubicin can potentiate the therapeutic effects of radiation therapy, albeit with occasional complications of erythema and ulceration of skin when used intra-arterially; these adverse effects can preclude limb-salvage procedures [,,].
    • Cisplatin – Cisplatin (cis-diamminedichloroplatinum II) is a platinum-containing chemotherapeutic that, although lacking an alkyl group, is also classified as an alkylating agent. It is thought to function by binding and crosslinking DNA, interfering with transcription and DNA replication []. Cisplatin can be administered intravenously or intra-arterially. Initial studies in patients with unresectable or metastatic OS demonstrated responses of 30-50% when administered intravenously as a single agent or in combination with doxorubicin [,]. Surprisingly, response rates were as high as 60-90% when administered intra-arterially as a single agent for primary tumor treatment [,,]. Intra-arterial administration increases local cytotoxic concentrations, thereby improving tumor penetration [,]. Studies at the University of Texas MD Anderson Cancer Center utilized a regimen consisting of 120 mg/m2 of cisplatin intra-arterially over 4h with 95 mg/m2 doxorubicin concurrently administered over 24h in a series of four preoperative courses administered at 4-week intervals. Although tumoricidal effects are achieved more rapidly with intra-arterial therapy, similar cytotoxic effects can be achieved with intravenous therapy administered in several courses []. Toxicities of cisplatin include auditory and renal dysfunction [,,]. Hearing impairment may occur in approximately 40% of patients []. Patients can also develop peripheral neuropathies. Another platinum-containing chemotherapeutic agent, carboplatin, has been used in combination with other chemotherapeutics and will be discussed later in this review [,,,,].
    • Oxazaphosphorines – Alkylating agents of the oxazaphosphorine family used in treating OS include cyclophosphamide and ifosfamide. Alkylating agents function by adding alkyl groups to guanine nucleotides, inducing DNA damage and resulting in cytotoxicity. Furthermore, the addition of etoposide, a topoisomerase inhibitor that interferes with DNA structural changes during the normal cell cycle, to cyclophosphamide may synergize in treating both primary and metastatic OS. The administration of regimens containing ifosfamide and etoposide (IE) to poor responders to chemotherapy demonstrated outcome improvements similar to those of good responders [,]. Intensification of IE chemotherapy in patients with limited tumor necrosis following first-line therapy is currently being evaluated in a clinical trial [,]. Alkylating agents are not cross-resistant, and patients who experience relapse after treatment with one alkylating agent may achieve responses when using another [,,].


    Surgery to remove the entire tumor will be done when possible. Chemotherapy may be given before surgery to make the tumor smaller. This is called neoadjuvant chemotherapy. Chemotherapy is given so less bone tissue needs to be removed and there are fewer problems after surgery.

    The following types of surgery may be done:

    • Wide local excision – Surgery to remove cancer and some healthy tissue around it.
    • Limb-sparing surgery – Removal of the tumor in a limb (arm or leg) without amputation, so the use and appearance of the limb is saved. Most patients with osteosarcoma in a limb can be treated with limb-sparing surgery. The tumor is removed by wide local excision. Tissue and bone that are removed may be replaced with a graft using tissue and bone taken from another part of the patient’s body, or with an implant such as artificial bone. If a fracture is found at the time of diagnosis or during chemotherapy before surgery, limb-sparing surgery may still be possible in some cases. If the surgeon is not able to remove all of the tumor and enough healthy tissue around it, an amputation may be done.
    • Amputation – Surgery to remove part or all of an arm or leg. This may be done when it is not possible to remove all of the tumors in limb-sparing surgery. The patient may be fitted with a prosthesis (artificial limb) after amputation.
    • Rotationplasty – Surgery to remove the tumor and the knee joint. The part of the leg that remains below the knee is then attached to the part of the leg that remains above the knee, with the foot facing backward and the ankle acting as a knee. A prosthesis may then be attached to the foot.

    The goal of surgical management of osteosarcoma is complete excision of the lesion, which typically takes place via resection with wide margins. Two main approaches exist to accomplish this objective: limb salvage and amputation.

    Limb Salvage
    • The vast majority of patients (about 85 to 90%) with osteosarcoma undergo limb salvage. Limb salvage involves the removal of a tumor from a limb without the removal of the entire limb itself. This process occurs in two main steps: initial resection and subsequent reconstruction. Resection is essential for the elimination of the disease. As previously mentioned, the surgical excision of the mass should also include the biopsy site/tract, with a minimum margin of 2 cm, to avoid recurrence of disease from tumor cells, which may have escaped during tissue sampling. Radiological imaging performed during the initial evaluation should be reviewed preoperatively to determine the volume of bone that requires removal. Ideally, the mass and reactive zone surrounding it should not be disturbed, such that the entirety of dissection occurs through normal healthy tissues, which typically includes an additional 6 to 7 cm of adjacent normal bone. Computer-generated anatomical reconstructions are very useful for this purpose, particularly in tumors of the flat bone of the pelvis and sacrum, where excessive resection of bone can create postoperative problems with structural stability.
    • Because osteosarcoma is the most common primary osseous malignancy in the pediatric population, surgery presents a unique set of challenges. To achieve clear margins, excision may necessitate physeal resection, which can lead to growth disturbances as the child matures. In the past, a tumor that traversed the growth plate was considered to be an indication for amputation because there was no available means to restore function. With the advent of options that “grow” or expand with the patient (discussed below), masses that cross the growth plate are no longer considered a contraindication to limb salvage.
    • Another difficulty that surgeons encounter in the quest for limb salvage is a mass which encompasses a joint; this is a common challenge due to the predilection of osteosarcoma for the knee. However, a combination of resection and tissue regeneration (discussed below) have helped to over this obstacle such that joint involvement is no longer considered a contraindication to limb salvage.
    • After resection, reconstruction can begin. The purpose of reconstruction is the restoration of function to the affected limb. In the case of non-weight bearing bones like the fibula or clavicle, reconstruction is unnecessary because the excision of these structures does not impart functional deficit. Reconstruction of weight-bearing bones, as one might imagine, is an arduous task. One of the greatest challenges facing surgeons is a recapitulation of large swaths of missing bone. In recent years, several options have become available. These options fall into three main classes: allograft/autograft bone reconstruction, metallic (endoprosthesis) reconstruction, and tissue regeneration reconstruction.
    Allograft/Autograft Bone Reconstruction
    • Allograft bone replacement utilizes bones collected in the postmortem period from organ donors. As with an organ donation, potential donors undergo screening for communicable diseases. Once surgically grafted into the osteosarcoma patient, the native bone will grow into the allograft bone and heal. Rejection is rare because very few donor cells remain within the donated bone, and bone itself is a relatively inert material. As one might imagine, the most serious complication that may arise with allograft reconstruction is the failure of fusion between patient bone and allograft bone. Infection and fracture are also important complications that require internal fixation or removal, respectively. A hybrid reconstructive device is available in the form of an allograft prosthetic composite (APC), which combines an allograft bone fragment with a metallic prosthesis. APC arthroplasty is useful for the reconstruction of weight-bearing joints such as the knee or hip. This device combines the easier reinsertion of a biological graft with the instant weight-bearing ability of a prosthetic.
    • In centers without access to a donor bone bank, resected malignant bone can be irradiated (or less frequently, pasteurized or treated with liquid nitrogen) and reimplanted, resulting in a perfect match for the osseous defect at the surgical site. This process is known as autografting, and it can be very cost-effective. However, there are only limited indications for autografting, as donor bone for allograft is relatively easy to procure.
    Metallic Prosthetics
    • Metallic prosthetics have revolutionized surgical reconstruction. So-called “mega prostheses” provide for the replacement of large segments of the bone and the joint that connects them. A decade ago, most of these devices had to be custom made but today, “off the shelf” options are available for immediate implantation. Some of these prostheses are expandable “growing” implants that permit interval lengthening. These are particularly efficacious in skeletally immature individuals. Because the growth plates of the affected segment of bone often get resected, the prosthesis can be elongated by 1 to 2 cm at a time, so the length of the previously diseased limb correlates with the contralateral healthy limb.
    Tissue Regeneration
    • Tissue regeneration for reconstruction following resection of osteosarcoma is a relatively new field. In general, this process utilizes a combination of a patient’s own cells, purified intrinsic growth factors, and synthetic, scaffold-like matrix materials to induce autologous tissue regeneration. Until this emerging technology is more widely available, procedures such as the Ilizarov technique or spatial frame method utilize external fixation devices to promote the growth of long bones up to 1 millimeter per day (about 1 inch per month).
    • Amputation –  previously considered the gold standard for surgical management of osteosarcoma, is reserved only for non-resectable masses with contamination of myotendinous and neurovascular that make limb salvage impossible. Amputation may be performed as a standalone treatment or in conjunction with rotationplasty.
    • Rotationplasty  – is a procedure that involves resection of the lower extremity to the level of the distal femur. Resection is followed by a 180-degree rotation of the lower extremity with subsequent reattachment at the distal femur, essentially transforming the ankle into a “knee” joint such that the plantar flexors (soleus and gastrocnemius) get converted to knee extensors. The procedure has been shown to provide surprisingly favorable functionality. However, its unusual appearance has been known to cause psychological distress in some patients.
    • Outcomes of Limb Salvage vs. Amputation – A few studies have demonstrated a slight increase in the rate of recurrence in patients with limb salvage when compared to amputees. Still, the overall rate of survival in patients who recur is comparable. Interestingly, though, several studies report higher survival rates in patients who have undergone limb salvage versus amputation. The vast majority of clinicians who treat osteosarcoma now favor limb salvage over amputation.

    Radiation Oncology

    National Comprehensive Cancer Network’s 2020 Guidelines of Radiation Therapy for Osteosarcoma (Version 1.2020)

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    Post-operative radiation treatment for primary tumors:

    • Resectable tumors: Post-operative radiation therapy with 55 Gy plus 9 to 13 Gy boost for residual microscopic or gross disease (64-68 total dose)
    • Unresectable tumors: 60 to 70 Gy (the total dose is dependent on tolerance on normal tissue)

    Radiation treatment for metastatic disease

    • Samarium 153-EDTMP
    • Stereotactic radiosurgery (SRS)

    Medical Oncology

    Before the advent of chemotherapy, the survival rates for patients with high-grade osteosarcoma were abysmal despite the removal of all visible disease via amputation; this indicated the presence of undetectable micrometastases, typically to the lungs. Chemotherapy, in conjunction with surgical resection, has addressed the presence of micrometastases and significantly improved survival rates.

    National Comprehensive Cancer Network’s 2020 Recommendations for Chemotherapy Agents & Regimens for Treatment of Osteosarcoma (Version 1.2020)

    Recommended neoadjuvant/adjuvant chemotherapy regimens for initial-occurrence 

    • Cisplatin and doxorubicin (Category 1)
    • MAP (high-dose methotrexate, cisplatin, and doxorubicin) (Category 1)
    • Doxorubicin, cisplatin, ifosfamide, and high-dose methotrexate

    Recommended chemotherapy regimens for relapsed, refractory or metastatic disease

    • Regorafenib (Category 1)
    • Ifosfamide (high dose) +/- etoposide
    • Sorafenib
    • Sorafenib and everolimus

    “Category 1” recommendations are those based upon high-level evidence, with uniform NCCN consensus that the intervention is appropriate. This designation represents the highest level of clinical confidence in efficacy.


    Two popular systems exist for the staging of bone tumors. The Musculoskeletal Tumor Society’s Enneking system is used primarily by orthopedic surgeons because it takes into account the anatomic location of the tumor: intracompartmental (completely contained within the bone) vs. extracompartmental (extension outside of the bone). The alternative system described by the American Joint Committee on Cancer does not take anatomic location into account. However, it does account for the size of the tumor, which research has recognized as having significant prognostic value for predicting response to treatment and overall survival. Specifically, larger lesions have a propensity to metastasize, so these patients may benefit from chemotherapeutic intervention, making the AJCC system more popular with oncologists.

    Musculoskeletal Tumor Society/Enneking system for staging of malignant musculoskeletal tumors
    • Stage IA: Low grade, Intracompartmental tumor location, no metastasis
    • Stage IB: Low grade, Extracompartmental tumor location, no metastasis
    • Stage IIA: High grade, Intracompartmental tumor location, no metastasis
    • Stage IIB: High grade, Extracompartmental tumor location, no metastasis
    • Stage III: Any grade, Any location, Metastasis present
    American Joint Committee on Cancer (AJCC) system for staging of primary bone sarcomas (8th edition)
    • Stage IA: Low grade, less than 8 cm tumor size, No spread to regional lymph nodes, No distant metastasis
    • Stage IB: Low grade, greater than 8 cm tumor size or skip lesions, No spread to regional lymph nodes, No distant metastasis
    • Stage IIA: High grade, greater than 8 cm tumor size, No spread to regional lymph nodes, No distant metastasis
    • Stage IIB: High grade, less than 8 cm tumor size, No spread to regional lymph nodes, No distant metastasis
    • Stage III: High grade, Discontinuous tumor involvement/”skip” lesions, No regional lymph nodes, No distant metastasis
    • Stage IVA: Any grade, Any size, No regional lymph node spread, Lung metastasis
    • Stage IVB: Any grade, Any size, Regional lymph node spread, Lung or extrapulmonary metastasis
    TNM system – American Joint Committee on Cancer (AJCC):

    This refers to the extent of tumor (T), spread to local lymph nodes (N), metastatic spread (M), and histological grade (G).

    Stage IA (T1 N0 M0 G1/GX)

    • ≤8cm in size, with no lymph node or metastatic spread. Low grade.

    Stage IB (T2 N0 M0 G1/GX, or T3 N0 M0 G1/GX)

    • >8cm in size (T2), with no lymph node or metastatic spread. Low grade.
    • Cancer at more than one location in the same bone (T3), with no lymph node or metastatic spread. Low grade.

    Stage IIA (T1 N0 M0 G2/G3)

    • ≤8cm in size, with no lymph node or metastatic spread. High grade.

    Stage IIB (T2 N0 M0 G2/G3):

    • >8cm in size, with no lymph node or metastatic spread. High grade

    Stage III (T3 N0 M0 G2/G3):

    • Cancer at more than one location in the same bone, with no lymph node or metastatic spread. High grade.

    Stage IVA (Any T N0 M1a Any G):

    • Any size and maybe in more than one location in the same bone, with no lymph node involvement. Metastatic spread to the lungs (M1a). Any grade.

    Stage IVB (Any T, N1, Any M, Any G, or Any T, Any N, M1b, Any G):

    • Any size and maybe in more than one location in the same bone. It has spread to local lymph nodes (N1). It may or may not have metastasized to distant organs. Any grade.
    • Any size and maybe in more than one location in the same bone. It may or may not have spread to local lymph nodes. Metastatic spread to distant sites like other bones, liver, or brain (M1b). Any grade.
    Enneking system

    Refers to the histological grade (G), the extent of the tumor in relation to the anatomical compartments of the body (T), and metastatic spread (M)

    Stage IA (G1 T1 M0)

    • Low grade, intra-compartmental, no metastasis.

    Stage IB (G1 T2 M0)

    • Low grade, extra-compartmental, no metastasis.

    Stage IIA (G2 T1 M0)

    • High grade, intra-compartmental, no metastasis.

    Stage IIB (G2 T2 M0)

    • High grade, extra-compartmental, no metastasis.

    Stage III (Any G, Any T, M1)

    • Any grade, any location, regional, or distant metastatic spread.

    Recently Completed Clinical Trials for OS Therapies

    Clinical TrialPhase
    Agent(s) TestedMechanism of Agent(s)
    Carboplatin/Ifosfamide Window
    Therapy for Osteosarcoma: OS91
    IICarboplatin, Ifos-
    Carboplatin: Platinum-
    containing chemotherapeu-
    tic, Ifosfamide: Alkylating
    regimen demonstrated similar re-
    sponse rates to cisplatin-containing
    therapies with lower toxicity
    Frontline treatment of localized
    osteosarcoma without
    methotrexate: OS99 Trial
    IICarboplatin, Ifos-
    Methotrexate: Dihydrofo-
    late reductase inhibitor
    regimen demonstrated similar re-
    sponse rates to both cisplatin-
    containing or methotrexate-
    containing regimens
    Addition of pamidronate to chemo-
    therapy for the treatment of os-
    IPamidronateBisphosphonatePamidronate was safely incorporated
    into OS chemotherapy regimens
    without altering efficacy and may
    improve durability of reconstruction
    The Addition of Muramyl Tripep-
    tide to Chemotherapy Improves
    Overall Survival: Intergroup Study
    IIILiposomal mu-
    ramyl tripeptide
    ethanolamine (L-
    Non-specific immune
    modulator activates pul-
    monary inflammatory cells
    Addition of ifosfamide to cis-
    platin/doxorubicin and MTX did not
    improve EFS or overall survival;
    addition of L-MTP-PE significantly
    improved overall survival with a
    trend toward improved EFS
    Addition of muramyl tripeptide to
    chemotherapy for patients with
    newly diagnosed metastatic OS
    IIILiposomal mu-
    ramyl tripeptide
    ethanolamine (L-
    Non-specific immune
    modulator activates pul-
    monary inflammatory cells
    Addition of L-MTP-PE did not
    demonstrate improvement in out-
    comes among patients with metas-
    tatic OS
    Inhaled GM-CSF for First Pulmo-
    nary Recurrence of Osteosarcoma:
    Effects on Disease-Free Survival
    and Immunomodulation
    Macrophage Col-
    ony Stimulating
    Factor (GM-CSF)
    Immunostimulatory protein
    secreted by WBCs aug-
    ments proliferation and
    function of WBCs
    Inhalation of GM-CSF was feasible
    with low toxicity, but no detectable
    immunostimulatory effects or im-
    proved outcomes were demonstrated
    Phase II Trial of Trastuzumab in
    Combination With Cytotoxic
    Chemotherapy for Treatment of
    Metastatic Osteosarcoma With
    HER2R Overexpression
    IITrastuzumabHumanized monoclonal
    antibody to human epider-
    mal growth factor receptor
    2 (HER2)
    Addition of trastuzumab to cytotoxic
    chemotherapy in patients with
    HER2-positive OS did not improve
    patient outcomes. Trastuzumab was
    safely administered without short-
    term cardiotoxicity


    Tumor-specific Complications

    Complications of the tumor itself include pathological fractures. These may occur at presentation or during preoperative chemotherapy. As mentioned above, patients in both these scenarios have poorer outcomes than those without pathological fractures.

    Biopsy-related Complications

    When devising an approach to biopsy a lesion concerning for osteosarcoma (or any sarcoma, for that matter), careful planning of the biopsy approach is necessary to lower the potential for tumor cells to seed the biopsy tract and surrounding tissues. A biopsy tract that extends across multiple compartments may necessitate a larger field of resection, which increases the risk of treatment-related complications.

    Treatment-related Complications
    • Chemotherapy side effects

      • When utilizing chemotherapy, the majority of the major side effects occur during the treatment process. Nausea, malaise, alopecia, anemia, and anorexia are possible but usually resolve shortly after completion of the chemotherapy cycle. There are, however, some long-term side effects, which may include cardiotoxicity, pulmonary toxicity, and gradual hearing loss. There are reports of later development of a secondary malignancy.
    •  Radiation side effects

      • Radiation is known to impart superficial side effects, including skin dryness, itching, peeling, and uncommonly, burns. Menstrual changes, erectile dysfunction, and infertility are all reported adverse events in cases of pelvic radiation. When the chest and abdomen are involved in radiation treatment, diarrhea, incontinence, rectal bleeding, nausea, vomiting, dry mouth, dysphagia, pneumonitis, and fibrosis are possible. Much like chemotherapy, there is a small risk of late development of a secondary malignancy.
    •  Periprosthetic infection

      • Prostheses-related infections are a relatively frequent complication (approximately 10% of limb salvage surgeries) most often due to lengthy surgery time, repeated surgery at the same site, and immunosuppression secondary to chemotherapy. First-line treatment of these periprosthetic infections typically involves one or more debridement procedures with both local and systemic antibiotic therapy (systemic and local antibiotic cement beads). If these efforts are ineffective, the implant requires removal, followed by debridement and wash out. A cement spacer impregnated with an antibiotic generally gets placed before the insertion of a new prosthesis. Ultimately, amputation may be necessary for a number of these patients.
    • Implant failure

      • The most common reason for reconstruction failure is the mechanical breakdown of the mega prosthesis. Mechanical failure necessitates the replacement of the prosthetic. The tibia is the most frequent site of mechanical failure.
    • Fracture/non-union of allograft/autograft

      • Fracture/non-union of allograft/autograft reconstruction is a relatively infrequent complication, but it does occur. Chemotherapy, radiation, and extracorporeal treatment of autograft bone have been reported to increase the risk of these complications. Refractory cases may necessitate metallic implant placement or amputation.

    Tumor-related complications:

    • Pathological fracture
    • Tumor recurrence
    • Distant metastasis

    Treatment-related complications

    • Surgery

      • Surgical site or periprosthetic infection
      • Implant failure
      • Non-union/fracture of biological implant
    • Chemotherapy

      • Short-term side effects include malaise, anemia, nausea, vomiting, and alopecia.
      • Long-term side effects include cardiotoxicity, renal toxicity, hearing loss, and an increased risk of developing a secondary malignancy.
    • Radiotherapy

      • Side effects following radiation therapy are site-dependent, affecting the skin, pelvic organs, gastrointestinal tract, and lungs.
      • Long-term, there is a small increased risk of developing a secondary malignancy.


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