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.
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:
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.
Osteosarcoma has a bimodal age distribution. The initial peak is in the 10 to 14 year age group, corresponding to the pubertal growth spurt. This group represents the vast majority of primary osteosarcomas. In the 0 to 14 year age range, the incidence rate of osteosarcoma in all races and genders is 4 cases per year per million people (3.5 to 4.6, 95% confidence interval). This number rises to 5 cases per year per million people (4.6 to 5.6, 95% confidence interval) for the range 0 to 19 year age range. The next observable peak is in adults older than 65, when the appearance of osteosarcoma is more likely to represent secondary cancer resulting from malignant degeneration of Paget disease, sites of bone infarction, etc. The patient’s age has been found to correlate with survival; the poorest survival is among older individuals. Death rates for osteosarcoma have steadily declined by approximately 1.3% per year. The 5-year overall survival rate is about 68%, regardless of sex.
Osteosarcoma accounts for approximately 2.4% of pediatric cancers, making it the eighth most common childhood malignancy. Leukemia is the most common (30%), followed by malignancies of the central nervous system (22.3%), neuroblastoma (7.3%), Wilms tumor (5.6%), Non-Hodgkin lymphoma (4.5%), rhabdomyosarcoma (3.1%) and retinoblastoma (2.8%).
Blacks are the ethnic group most likely to be affected by osteosarcoma, with an incidence rate of 6.8 cases per year per million people. Hispanics are a close second with an incidence rate of 6.5 cases per year per million people. White race individuals experience this malignancy at a rate of 4.6 cases per year per million people.
The incidence of osteosarcoma has historically been reported as higher in males than in females, with an incidence rate of 5.4 cases per year per million males and 4 cases per year per million females, respectively.
Osteosarcoma frequently occurs near the metaphysis of the long bones of the appendicular skeleton. The most common locations include the femur (42%, with 75% of tumors in the distal portion of the bone), the tibia (19%, with 80% of tumors in the proximal portion of the bone), and the humerus (10%, with 90% of tumors in the proximal portion of the bone). Other potential sites include the skull or jaw (8%) and the pelvis (8%). As mentioned previously, osteosarcoma can subdivide into primary and secondary forms:
Osteosarcoma is grossly divided into various subtypes based on its location within the bone then further subdivided by grade.
1. Central (Intramedullary):
2. Surface (Periosteal/Cortical):
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:
National Comprehensive Cancer Network's 2020 Guidelines for Initial Evaluation of Osteosarcoma (Version 1.2020)
1. Clinical history and physical exam (discussed above)
2. Laboratory analysis of Lactate Dehydrogenase (LDH) and Alkaline Phosphatase (ALP) levels
3. Diagnostic imaging of primary tumor site
4. Nuclear Imaging
5. Follow up MRI or CT (both with contrast) of sites of metastasis identified on PET or Bone Scan
6. 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. In recent years, however, research has determined that an open approach correlates with an increased risk of complications such as infection, improper wound healing, and seeding of the site by tumor cells, as previously discussed. As such, core biopsy has replaced the traditional open approach, particularly because of the reduced risk of contamination of the surgical bed with tumor cells but also due to lower cost and decreased recovery time. It is especially crucial for patients with perceived potential for limb-sparing procedures in which as much local tissue should be spared as safely possible. Core needle biopsy is achieved via a single deep stab with a Jamshidi needle through a trocar, which traverses a single tissue plane in a location that will be included in the final resection. Multiple cores are necessary from the representative region of the mass - the soft tissue portion in the periphery of the lesion. The necrotic central region will yield little viable tissue, and the “Codman’s triangle” region will yield only reactive bone. Importantly, recent studies have shown that fine-needle aspiration is not an efficacious approach to biopsy because it does not yield an adequate tissue sample for an accurate diagnosis. Following the biopsy, tissue samples should be analyzed by pathologists in fresh or frozen format for definitive diagnosis, grading, and histological subtyping, all of which will affect medical and surgical treatment strategy.
National Comprehensive Cancer Network's 2020 Guidelines for Management of Osteosarcoma (Version 1.2020)
OSTEO-1 (Low-grade osteosarcoma, no metastasis)
OSTEO-2 (High-grade intramedullary or surface osteosarcoma, no metastasis)
OSTEO-3 (Any grade with metastasis at presentation)
OSTEO-4 (Follow-up & surveillance)
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.
Outcomes of Limb Salvage vs. Amputation
National Comprehensive Cancer Network's 2020 Guidelines of Radiation Therapy for Osteosarcoma (Version 1.2020)
Post-operative radiation treatment for primary tumors:
Radiation treatment for metastatic disease:
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
Recommended chemotherapy regimens for relapsed, refractory or metastatic disease
“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
American Joint Committee on Cancer (AJCC) system for staging of primary bone sarcomas (8th edition)
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.
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.
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. 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.
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.
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.
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.
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.
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.
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.
Symptoms of bone pain, joint pain, and/or palpable mass warrant professional assessment. Patients and their families should be educated on these presenting symptoms as they may potentially be related to an osseous neoplasm.
Patients with osteosarcoma should ideally be under the management of an interprofessional team, including specialists from radiology, pathology, medical/surgical oncology, and orthopedics. Musculoskeletal radiologists and pathologists are essential for the interpretation of imaging findings and tissue samples for definitive diagnosis and establishing a prognosis. Oncologists are crucial team members who provide the appropriate neoadjuvant and adjuvant chemotherapy treatment and assist with long-term surveillance to monitor for local or distant relapse. A pain specialist is usually involved in helping manage the pain. A board-certified oncology pharmacist should work with the oncologist on agent selection and dosing, as well as educate the patient on pain management and available options. Because depression and anxiety are common, a mental health nurse should be involved in counseling both the patient and the family. The oncology nurse should educate the patient and the family about the treatment options, pain management, and support services as well as assist with coordination of care and followup. If the malignancy is advanced, a palliative team should be involved early in the care.
Orthopedic oncologists develop and execute a plan for resection of the tumor, followed by appropriate reconstruction. It is critical to correlate the gross, radiographic, and microscopic findings to establish the correct diagnosis and determine the best course of treatment as osteosarcoma can be highly varied in appearance, imaging features, and histological profile. Following treatment, patients require long term surveillance because of the possibility of tumor recurrence and extra-osseous metastases. An interprofessional team approach is vital if one wants to improve outcomes and improve the quality of life. [Level V]
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