Osteosarcoma derives from primitive bone-forming mesenchymal cells and is the most common primary bone malignancy. The incidence rates and 95% confidence intervals of osteosarcoma for all races and both sexes are 4.0 (3.5-4.6) for the range 0-14 years and 5.0 (4.6-5.6) for the range 0-19 years per year per million persons. Among childhood cancers, osteosarcoma occurs eighth in general incidence and in the following order: leukemia (30%), brain and other nervous system cancers (22.3%), neuroblastoma (7.3%), Wilms tumor (5.6%), Non-Hodgkin lymphoma (4.5%), rhabdomyosarcoma (3.1%), retinoblastoma (2.8%), osteosarcoma (2.4%), and Ewing sarcoma (1.4%). The incidence rates of childhood and adolescent osteosarcoma with 95% confidence intervals areas follows: Blacks, 6.8/year/million; Hispanics, 6.5/year/million; and Caucasians, 4.6/year/million. Osteosarcoma has a bimodal age distribution, having the first peak during adolescence and the second peak in older adulthood. The first peak is in the 10-14-year-old age group, coinciding with the pubertal growth spurt. This suggests a close relationship between the adolescent growth spurt and osteosarcoma. The second osteosarcoma peak is in adults older than 65 years of age; it is more likely to represent a second malignancy, frequently related to Paget's disease. The incidence of osteosarcoma has always been considered to be higher in males than in females, occurring at a rate of 5.4 per million persons per year in males vs. 4.0 per million in females, with a higher incidence in blacks (6.8 per million persons per year) and Hispanics (6.5 per million), than in whites (4.6 per million). Osteosarcoma commonly occurs in the long bones of the extremities near the metaphyseal growth plates. The most common sites are the femur (42%, with 75% of tumors in the distal femur), the tibia (19%, with 80% of tumors in the proximal tibia), and the humerus (10%, with 90% of tumors in the proximal humerus). Other likely locations are the skull or jaw (8%) and the pelvis (8%). Cancer deaths due to bone and joint malignant neoplasms represent 8.9% of all childhood and adolescent cancer deaths. Death rates for osteosarcoma have been declining by about 1.3% per year. The overall 5-year survival rate for osteosarcoma is 68%, without significant gender difference. The age of the patient is correlated with the survival, with the poorest survival among older patients. Complete surgical excision is important to ensure an optimum outcome. Tumor staging, presence of metastases, local recurrence, chemotherapy regimen, anatomic location, size of the tumor, and percentage of tumor cells destroyed after neoadjuvant chemotherapy have effects on the outcome.
Major advances have been achieved in the treatment of osteosarcoma with the discovery of several chemotherapeutic agents that were active in the disease. These agents comprise high-dose methotrexate with leucovorin rescue, Adriamycin, cisplatin, ifosfamide and cyclophosphamide. The agents were integrated into various regimens and administered in an effort to destroy silent pulmonary micrometastases which are considered to be present in at least 80% of patients at the time of diagnosis. Their efficacy in achieving this goal was realized and their use was further extended to the application of preoperative (neoadjuvant) chemotherapy to destroy the primary tumor and achieve safe surgical resections. Disease free survival was escalated from <20% prior to the introduction of effective chemotherapy to 55-75% and overall survival to 85%. Further, the opportunity to perform limb salvage was expanded to 80% of patients. Of interest also was an attempt in one series to treat the primary tumor exclusively with chemotherapy, and abrogation of surgery. Adding to these advances, varieties of subsequently discovered agents are currently undergoing investigations in patients who have relapsed and/or failed conventional therapy. The agents include Gemcitabine, Docetaxel, novel antifolate compounds, and a liposome formulation of adriamycin (Doxil). A biological agent, muramyl tripeptide phosphatidyl ethanolamine (MTPPE) was also recently investigated in a 2x2 factorial design to determine its efficacy in combination with chemotherapy (methotrexate, cisplatin, Adriamycin and ifosfamide).In circumstances where the tumor was considered inoperable, chemotherapy and radiotherapy were advocated for local control. High dose methotrexate, Adriamycin and cisplatin and Gemcitabine interact with radiation therapy and potentiate its therapeutic effect. This combination is also particularly useful in palliation. Occasionally, the combination of radiation and chemotherapy may render a tumor suitable for surgical ablation. Samarium153, a radio active agent, is also used as palliative therapy for bone metastases.However, despite the advances achieved with the multidisciplinary application of chemotherapy, radiotherapy and surgical ablation of the primary tumor over the past 3(1/2) decades, the improved cure rate reported initially has not altered. Particularly vexing is the problem of rescuing patients who develop pulmonary metastases after receiving seemingly effective multidisciplinary treatment. Approximately 15-25% of such patients only are rendered free of disease with the reintroduction of chemotherapy and resection of metastases. Extrapulmonary metastases and multifocal osteosarcoma also constitute a major problem. The arsenal of available agents to treat such patients has not made any substantial impact in improving their survival. New chemotherapeutic agents are urgently required to improve treatment and outcome. Additional strategies to be considered are targeted tumor therapy, anti tumor angiogenesis, biotherapy and therapy based upon ...
Studies to determine the etiology of osteosarcoma involve epidemiologic and environmental factors and genetic impairments. Factors related to patient characteristics include age, gender, ethnicity, growth and height, genetic and familial factors, and preexisting bone abnormalities. Rapidly proliferating cells may be particularly susceptible to oncogenic agents and mitotic errors which lead to neoplastic transformation. Genetic aberrations that accompany osteosarcoma have received increasing recognition as an important factor in its etiology. Osteosarcoma tumor cells exhibit karyotypes with a high degree of complexity which has made it difficult to determine whether any recurrent chromosomal aberrations characterize osteosarcoma. Although extremely rare, osteosarcoma has occasionally been observed in several members of the same family. No other clinical abnormalities in the proband or the affected members were reported. Pathologic examination of the tumors revealed no unusual features. Genetic testing was not available in most of these reports. The patients generally responded to conventional therapy. A genetic predisposition to osteosarcoma is found in patients with hereditary retinoblastoma, characterized by mutation of the retinoblastoma gene RB1 on chromosome 13q14. The Rothmund-Thomson syndrome is an autosomal recessive disorder with a heterogeneous clinical profile. Patients may have a few or multiple clinical features including skin rash, small stature, skeletal dysplasias, sparse or absent scalp hair, eyebrows or eyelashes, juvenile cataracts, and gastrointestinal disturbance including chronic emesis and diarrhea; its molecular basis is the mutation in the RECQL4 gene in a subset of cases. The Li-Fraumeni syndrome is an autosomal dominant disorder characterized by a high risk of developing osteosarcoma and has been found in up to 3% of children with osteosarcoma. It is associated with a germline mutation of the p53, a suppressor gene. The following three criteria must be met for a diagnosis of Li-Fraumeni syndrome: (1) A proband diagnosed with sarcoma when younger than 45 years; (2) A first-degree relative with any cancer diagnosed when younger than 45 years; (3) Another first- or second-degree relative of the same genetic lineage with any cancer diagnosed when younger than 45 years or sarcoma diagnosed at any age. A second recessive p53 oncogene on chromosome 17p13.1 may also play a role in the development and progression of osteosarcoma. Osteosarcoma has also been associated with solitary or multiple osteochondroma, solitary enchondroma or enchondromatosis (Ollier's disease), multiple hereditary exostoses, fibrous dysplasia, chronic osteomyelitis, sites of bone infarcts, sites of metallic prostheses and sites of prior internal fixation. Ionizing radiation is a well-documented etiologic factor. Osteosarcoma has also been associated with the use of intravenous radium and Thorotrast. Exposure to alkylating agents may also contribute to its development ,and it is apparently independent of the administration ...
The predominant sites of viable and nonviable tumor were determined in the primary lesions of 50 patients with osteosarcoma after initial treatment with preoperative chemotherapy. The degree of tumor destruction was classified as good, fair, and poor and a map of the sites revealing viable and nonviable tumor was constructed. The study revealed several preferential sites where viable tumor was likely to persist: soft tissues, cortex, subcortex, ligaments, and areas in contact with cartilage (growth plate and/or articular cartilage). Localized areas of hemorrhage and necrosis, designated "lacunae," were noted within the tumor. They were frequently surrounded by bundles of viable tumor and appeared to correlate with open surgical biopsies. Factors responsible for this phenomenon and the persistence of viable tumor are discussed. The findings have important implications in the design of surgical treatment and in the use of needle biopsies to determine the effects of preoperative treatment.
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