Most common primary malignant neoplasm of bone.

Primary mesenchymal tumor characterized by production of osteoid by malignant cells.

Approximately 900 new cases a year in the United States.

Peak incidence of 4.4 cases/100,000 per year in adolescent and young adults in the United States.

There is a male to female ratio of 1.4 to 1 in younger patients and the proportion of axial tumor sites increases with age.

In younger patients, most osteosarcoma‘s arise in extremities.

Represents approximately 3.4% of all childhood cancers and 56% of malignant bone tumors (gurney JG et al).

Most common primary malignant tumor of childhood.

Occurs mainly in teenagers and young adults.

Most cases occur in children and young adults 10 to 30 years of age, with a peak incidence during the adolescent growth spurt.

Bimodal distribution within initial peak in the late adolescent and young adult, with the second peak during or after the sixth decade.

While adolescent and young adult are categorized as primary lesions, one third to one half of adult tumors are secondary, resulting from malignant transformation of Paget’s disease of bone, or less commonly from another benign bone lesion.

Male to female ratio 1.43:1.

Incidence peaks earlier in females.

Most common in the long bones, especially around the knee.

In young individuals arises most often in the metaphyses of long bones, such as the distal femur, proximal tibia, and proximal humerus.

Risk factors for the occurrence of osteosarcoma include: previous radiation therapy,  Paget disease of the bone, and germline genetic abnormalities associated with Li-Fraumeni syndrome, Werner syndrome, Bloom syndrome, and hereditary retinoblastoma.

Genetic susceptibility occurs in patients with families with the Li-Fraumeni syndrome (TP53 mutation) or Hereditary retinoblastoma (RB1).

Increased risk of osteosarcoma is a feature of rare genetic syndromes caused by defects in DNA helicases  and ribosomal proteins.

Pathogenic germline mutations are present in approximately 1/4 of patients.

MDM2 amplification is presenting grade in 85% of cases.

Approximately 10 to 15% of patients present with metastatic disease, primarily to the lung.

Pelvic osteosarcoma accounts for 5-10% of all osteosarcomas.

Majority of cases occur in adolescence with a second incidence peak in the seventh and eighth decades.

In the second age peak more than 50% of cases arise secondary to pre-existing conditions such as Paget’s disease and previous radiation.

Often considered a secondary neoplasm in elderly related to a sarcomatous transformation of Paget disease of bone or some other benign bone lesion.

In the elderly tumors occur more commonly in axial locations and in areas previously irradiated, or that underlying bone abnormalities.

In the older population up to 40% of such tumors present in the pelvis.

Within the pelvis the ilium is the most common location of osteosarcoma, followed by the acetabulum and then the ischium.

The most common tumor sites are those with the most extensive longitudinal bone growth: the knee (distal femur and proximal tibia) and the shoulder (proximal humerus).

A second peak of about 10% of cases, occurs in persons over the age of 60 years and is often associated with Paget’s disease of the bone and is probably a distinct biologic process.

Pelvic osteosarcoma often involves multiple parts of the pelvis, and iliac tumors often infiltrate the sacrum.

Represents less than 1% of all cancers in the U.S.

Patients are found to be significantly taller than those in the general population.

Incidence is highest among Asians/Pacific Islanders, followed by blacks, Hispanics, whites, and American Indian/Alaskan natives.

Paget’s disease associated with osteosarcoma more frequent among males, 1.58:1.

The incidence of malignant transformation of Paget’s disease is approximately 1%.

Osteosarcomas arising from Paget’s disease have a poor prognosis, with no recent improvements in treatment or survival.

Five-year survival for localized extremity osteosarcoma approaches 70% but for pelvic lesions is approximately 30%.

Five-year survival is only 20% among patients presenting with metastases or recurrent disease.

Survival rates have not improved during the last three decades.

Pelvic osteosarcoma has an inferior survival compared to extremity osteosarcoma because of larger tumor volume at presentation, difficulty in achieving adequate surgical margins, higher likelihood of metastases at presentation, less adequate preoperative chemotherapy effect, and presence of microscopic tumor emboli in large blood vessels.

Both Paget’s disease and osteosarcoma demonstrate a loss in heterozygosity, involving to varying degrees, of the distal end of chromosome 18 (McNairm JD et al).

Genetic predisposition to developing osteosarcoma seen with: hereditary retinoblastoma, Li-Fraumeni syndrome, Rothmund-Thomson syndrome, and Bloom and Werner syndrome.

In carriers of the germline mutation of RB gene osteosarcoma second most common malignancy after retinoblastoma (Gurney JD et al).

Incidence of osteosarcoma in carriers of the RB gene mutation 500 times greater than in the general population.

70% of patients with OS demonstrate an overt RB gene mutation (Feugeas O et al).

Second most common malignancy in Li-Fraumeni syndrome, with a 12% incidence (Siddiqui R et al).

Approximately 70% of cases demonstrate a p53 tumor suppressor gene mutation on chromosome 17p13, suggesting that this defect is part of the Li-Frameni syndrome.

Overall the number of OS cases associated with a germline p53 mutation is low, and in the pediatric population it involves approximately 3% of cases ( MacIntyre JF).

Over two thirds over two thirds of cases are associated with mutations in the RB and p53 genes.

Rothmund-Thomson syndrome, also known as poikiloderma congenitale, a genomic instability syndrome with RECQL4 gene mutations in 70% of cases and osteogenic sarcoma develops in up to 32% of patients ( Wang LL et al).

The second peak between ages 1685 has an incidence of 4.2 per million and is more common in women, with the greater it incidents among blacks 4.6 per million followed by whites 3.7 per million.

Telangiectasia, characterized by multiple dilated blood filled cavities with sarcomatous cells, present in 2-12% of cases.

Risk factors include the use of ionizing radiation in the treatment of childhood solid cancers.

Of 108 secondary sarcomas in children surviving childhood malignancies this lesion was the second most common cancer occurring in 31 of 100 tumors ( Henderson TO et al).

The incidence of osteosarcoma as a second cancer is 10%.

Of the head and neck represent about 0.5-8.1% of osteosarcomas.

Of the head and neck usually occur secondary to radiation and chemotherapy given for other malignancies.

5-year survival for patients with localized disease up to 70%.

Prognosis in children with metastatic disease 5-year survival 50%, but only 20% for event free survival.

Patients present with localized pain and swelling of the affected site.

Most patients present with recurrent symptoms of bone pain, often leading to radiographic studies that suggest osteosarcoma.

Most frequent sites of involvement include the metaphyseal bone of the distal femur, proximal tibia, and the proximal humerus. But

While pain is often a reported preceding event, no evidence exists to support an association he trained trauma and the development of osteosarcoma.

Pain is initially related to activity but subsequently occurs at rest and at night.

The median time from onset of symptoms to diagnosis is four months.

Rarely patients may present with pathologic fracture.

Systemic manifestations of fever and weight loss are very rare.

Alkaline phosphatase may be elevated in 40% of cases and LDH in 30% of cases.

Patients with normal alkaline phosphatase levels have improved five-year disease free survival rates of 67% versus 54%, and a longer time to disease recurrence 25% versus 18 months ( Clark JC et al).

Extreme elevations of LVH suggests that poor outcome (Bacci G et al).

Approximately 10 to 20% of patients present with gross metastatic disease and approximately 80% of patients have microscopic metastases, which are subclinical or undetectable with present imaging techniques.

Metastases are typically hematogenous, with the most common site being the lungs followed by other bones.

Skip metastases may represent local regional disease, distinct from distant metastases.

Skip metastases is associated with a poor prognosis.

Patients with metastases to a single site have a better prognosis than patients with multiple organ involvement.

Patients with more than 8 lung metastases have a poorer outlook than patients with fewer lesions because they are less likely to have all their lesions resected completely.

Bone metastases associated with a poor prognosis.

Metastases detected at the time of presentation reduces long-term outcomes from 70% to less than 20%.

Metastases to the lung has a better prognosis than bone metastases or skip metastases.

Patients with lung metastases and fewer then three metastatic nodules and unilateral disease may have a survival advantage related to the ability to resect these lesions.

Cells with little or no Fas expression form lung metastases while cells with high expression do not have lung metastases.

Patients with more than 1-2 bone metastases have a very poor prognosis.

High alkaline phosphatase levels reflect bone tumor volume and growth kinetics.

High alkaline phosphatase levels suggest a worse prognosis because of the existence of a more aggressive and bulky tumor.

Adverse prognostic factors include proximal extremity tumor site, large tumor volume, elevated serum alkaline phosphatase or LDH levels and older age.

Multifocal osteosarcoma a rare variant of osteosarcoma with involvement of two or more sites in the axial appendicular skeleton.

Patients who have progressive disease while undergoing systemic therapy or have recurrent disease have less than 20% rate of long-term survival.

Plain x-ray studies reveal mixed radiodense and lytic lesions arising eccentrically from a metaphaseal bone.

Plain X-rays may demonstrate tumor extension into soft tissues, cortical destruction and P2242y are still reactions.

Typical x-ray findings of periosteal reaction is manifest as a sunburst pattern.

Codman’s triangle, refers to an elevation of the periosteum to the tumor’s periphery, a classic but nonspecific feature of osteosarcoma.

Mineralizes is in a centrifugal manner, while myositis ossificans, a benign lesion ossifies in a centrietal fashion.

MRI evaluation of the bone is performed to assess extent of disease and to identify skip metastases.

CT scan of the thorax is performed to evaluate lung metastases.

Bone scans are performed to evaluate involvement of other bony sites.

PET scan evaluation is presently being studied.

Biopsy should be an incisional one or utilize a core needle technique, and is required for diagnosis.

An incisional type biopsy provides the largest amount of tissue and has the greatest likelihood of diagnostic success, approximately 96%.

Diagnosis is made by biopsy.

The site of incisional biopsy is important, as that site ultimately will need to be resected en bloc following diagnosis.

Core needle biopsies for malignant bone tumors yield diagnostic accuracy that ranges from 74-88%.

Fine needle aspiration is not an acceptable biopsy technique since it provides too little sample for accurate diagnosis.

Staging utilizes the Musculo-skeletal Tumor Society scheme (Ennecking WF).

Staging includes grading of tumors as low or high grade, intra-compartmental or extra-compartmental and metastatic.

Most patients present with stage IIBdisease, characterized by high-grade histologic features with extension through the bone cortex into the periosteum and no metastases.

Most tumors are high-grade and/or 8 cm or less in diameter without metastases: stage IIA.

Surgical management includes complete removal of the tumor with previously placed biopsy tract, drain, or potentially contaminated tissues.

Surgical resection requires a wide excision to ensure complete resection of disease.

Curative treatment of high-grade osteosarcoma consists of chemotherapy and surgery with multi modality management for high-grade, localized osreosarcoma the disease free survival probability goes from less than 20% to grade and 60%.

Chemotherapy is generally delivered before and after surgery, although preoperative chemotherapy does not improve survival as long as chemotherapy is administered after surgery.

Preoperative chemotherapy, however ,allows the assessment of histological response which helps predict survival.

Drugs with anti-tumor activity in osteosarcoma include doxorubicin, cisplatin, high-dose methotrexate, and ifosfamide.

Amputation or dysarticulation may be required, although more conservative management that allows limb salvage and reconstruction must be considered.

Clear margins are the first goal of surgery.

Most current treatment protocols for localized disease include preoperative chemotherapy to facilitate local surgical treatment and allow assessment of histological response, although there is no evidence to support this technique.

In determining the extent of surgery the optimal oncological outcome takes priority over functional outcomes.

Because most lesions arise within the the metaphysis and do not extend into the joint, intra-articular resections are frequent.

With intra-articular involvement, resection requires extra-articular surgery.

With very small lesions partial resection of the metaphysis may be considered.

With lesions that are diaphyseal in nature, resection of the involved bone can be done while sparing adjacent joints.

Intra-articular resections can be reconstructed with allograft bone, which can be harvested with tendons and/or ligaments to provide improved tissue repair and joint function.

Allograft bone is not viable and does not fully re-vascularize such that reconstruction is subject to fractures, non-unions and infection.

Reconstruction with fractures or infection can lead to nonunion and 11-27% of cases, with higher rates seen with associated chemotherapy administration ( Hornicek FJ et al).

Reconstruction is associated with infection in approximately 15% of cases and fracture up to 27% of cases (Mankin HJ et al, Brigman BE et al).

Intra-articular resections also may use endoprosthetic joint replacements or prostheses for reconstruction.

Allograft-prosthetic composites may also be used for reconstruction.

For skeletal immature patients expandable prostheses are available.

Amputation may be a preferred procedure for patients who want to maintain athletic lifestyles, have a lower risk of recurrence, and is associated with fewer additional surgeries.

Factors associated with a poor outcome for the presence of metastasis and axial skeletal location.

Metastatic disease is to be aggressively resected to completely remove all known sites of disease, as such apprach confers survival benefit, and potential for cure (Kempf-Bielack B et al).

Surgical resection of lung lesions require open thoracotomy for manual examination since imaging does not detect small lesions, and contralateral exploration is required to ensure that the other lung does not have subclinical metastases.

With the addition of chemotherapy perioperatively for osteogenic sarcoma the five-year overall survival has improved 60-70% for localized disease.

Chemotherapy alone can result in durable remissions, but the disease eventually relapses in patients who do not undergo resection.

Chemotherapy for osteogenic sarcoma relies on for active drugs-doxorubicin, cisplatin, high-dose methotrexate, and ifosfamide.

Treatment of high grade localized osteosarcoma of the extremity consists of neoadjuvant chemotherapy followed by limb sparing surgical resection and subsequent adjuvant chemotherapy.

Neoadjuvant therapy provides the opportunity to assess the efficacy of chemotherapy by examining the amount of treatment induced necrosis in the resected specimen.

After 10 to 12 weeks of standard therapy about 55% of patients have a good response with a five-year survival rate of about 75%.

Patients with a poor response, the five-year survival is about 45%.

While neoadjuvant therapy is standard treatment, a randomized study comparing pre-surgical chemotherapy with immediate surgery followed by adjuvant chemotherapy showed no significant difference in outcome.

In the above studies long-term overall survival rates are greater than 60% and limb salvage is greater than 80% of patients.

Doxorubicin and methotrexate chemotherapy results in relapse free survival rates of up to 60%-70%.

Standard treatment consists of cisplatin, doxorubicin and high-dose methotrexate.

Neoadjuvant or induction chemotherapy generally administered for a period of 10 weeks prior to surgical resection.

Following surgical resection, and wound healing maintenance chemotherapy is given for 29 weeks.

The above treatment plan achieves long-term surival in 60-70% of patients with localized disease, but only 20-30% of those with metastatic disease.

For patients with recurrent disease ifosfamide associated with 30-40% response rates.

No targetable molecular genetic abnormalities available.

May respond to pembrolizumab.

Pre-treatment factors associated with poor outcome are the presence of metastases and axial skeletal location.

Post treatment factors contributing to poor survival include incomplete surgical resection and poor response to chemotherapy.

For patients who present with metastatic disease treatment consists of localized treatments and the use of adjuvant chemotherapy and subsequent resection of the primary tumor and also to metastatic disease whenever possible.

The surgical removal of all evident disease is associated with improved overall survival.

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