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General Aspects of Osteosarcoma.- The Epidemiology of Osteosarcoma.- The Etiology of Osteosarcoma.- Imaging Assessment of Osteosarcoma in Childhood and Adolescence: Diagnosis, Staging, and Evaluating Response to Chemotherapy.- Osteosarcoma Multidisciplinary Approach to the Management from the Pathologist's Perspective.- Conditions that Mimic Osteosarcoma.- Treatment.- Surgical Management of Primary Osteosarcoma.- The Role of Radiotherapy in Oseosarcoma.- Osteosarcoma Lung Metastases Detection and Principles of Multimodal Therapy.- Surgical Treatment of Pulmonary Metastases from Osteosarcoma in Pediatric and Adolescent Patients.- Non-Surgical Treatment of Pulmonary and Extra-pulmonary Metastases.- Review of the Past, Impact on the Future.- Adjuvant Chemotherapy in Osteosarcoma.- Osteosarcoma: Review of the Past, Impact on the Future. The American Experience.- Osteosarcoma: The European Osteosarcoma Intergroup (EOI) Perspective.- The Treatment of Nonmetastatic High Grade Osteosarcoma of the Extremity: Review of the Italian Rizzoli Experience. Impact on the Future.- Osteosarcoma: The COSS Experience.- Treatment of Osteosarcoma. The Scandinavian Sarcoma Group Experience.- Childhood Osteosarcoma: Multimodal Therapy in a Single-Institution Turkish Series.- International Collaboration is Feasible in Trials for Rare Conditions: The EURAMOS Experience.- Pediatric and Adult Osteosarcoma: Comparisons and Contrasts in Presentation and Therapy.- Supportive Care and Quality of Life.- The Role of Physical Therapy and Occupational Therapy in the Rehabilitation of Pediatric and Adolescent Patients with Osteosarcoma.- Caring for Children and Adolescents with Osteosarcoma: A Nursing Perspective.- Prosthetics for Pediatric and Adolescent Amputees.- Functional, Psychosocial and Professional Outcomes in Long-Term Survivors of Lower-Extremity Osteosarcomas: Amputation Versus Limb Salvage.- Research and Investigation: New and Innovative Strategies.- Bridging the Gap Between Experimental Animals and Humans in Osteosarcoma.- Is There a Role for Immunotherapy in Osteosarcoma?.- Molecular Classification of Osteosarcoma.- Current Concepts on the Molecular Biology of Osteosarcoma.- How the NOTCH Pathway Contributes to the Ability of Osteosarcoma Cells to Metastasize.- The Role of Fas/FasL in the Metastatic Potential of Osteosarcoma and Targeting this Pathway for the Treatment of Osteosarcoma Lung Metastases.- Bone Marrow Micrometastases Studied by an Immunomagnetic Isolation Procedure in Extremity Localized Non-metastatic Osteosarcoma Patients.- Strategies to Explore New Approaches in the Investigation and Treatment of Osteosarcoma.- History of Orthopedic Oncology in the United States.

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

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.

As the number of osteosarcoma survivors increases, the impact of quality of life and function needs to be addressed. Limb salvage is the preferred treatment when patients have treatment options; yet, the questionable long-term durability and complications of prostheses, combined with ambiguous function, leave some doubt regarding the best clinical and surgical options. Comparisons between limb salvage patients, amputees and controls also require further investigation. Amputation would leave the patients with a lifelong requirement for an external prosthetic leg associated with an overall limited walking distance. While artificial limbs are much more sophisticated than those used in the past, phantom limb sensations remain a substantial and unpredictable problem in the amputee. Complications such as stump overgrowth, bleeding, and infection, also require further elucidation. Limb salvage surgery using endoprosthesis, allografts or reconstruction is performed in approximately 85% of patients affected by osteosarcoma located in the middle and/or distal femur. One drawback in limb-salvage surgery in the long-term survivor is that endoprostheses have a limited life span with long-term prosthetic failure. The inherent high rate of reoperation remains a serious problem. Replacing a damaged, infected or severely worn-out arthroplastic joint or its intramedullary stem is difficult, especially in the long-stem cemented endoprostheses used in the 1980s. Limb lengthening procedures in patients who have not reached maturity must also be addressed. Periprosthetic infections, compared to other indications for joint reconstruction, were found to be more frequent in patients treated for neoplastic conditions and their outcome can be devastating, resulting in total loss of joint function, amputation, and systemic complications. Quality of life in terms of function, psychological outcome and endpoint achievements such as marriage and employment apparently do not differ significantly between amputee and nonamputee osteosarcoma survivors. Amputee patients nonetheless appear to have made satisfactory adjustments to their deficits with or without a functional external prosthesis. It also appeared that amputee patients had a similar psychological and quality of life outcome as limb salvage patients. There was no evidence of excessive anxiety or depression or deficits in self-esteem compared with the normal population or matched controls. A number of long-term survivors also achieved high ranking in the professional and commercial work place. These positive aspects should be recognized and emphasized to patients and their parents when discussing the outcome.

Osteosarcoma is the most common malignant bone tumor affecting children and adolescents. The biological behavior is consistent with the premise that pulmonary micrometastases are present at diagnosis in the majority of patients. These are silent and undetected on imaging studies. They usually surface six to twelve months following amputation of the primary tumor and if untreated are responsible for the patients demise. Until the 1970s the tumor was generally considered to be chemoresistant. However, in the early 1970’s, two chemotherapeutic agents were found to be active in osteosarcoma. These comprised Adriamycin (doxorubicin) and high-dose Methotrexate with Citrovorin factor rescue (Leucovorin rescue). The administration of high-dose Methotrexate following amputation alone or in combination with other agents yielded a cure rate of 40-65 percent. This was attributed to the destruction of the pulmonary micrometastases. The improved survival due chemotherapy did not go unchallenged. The Mayo Clinic adduced data to suggest that there had been a “natural improvement” in the cure rate over several years and that it should not necessarily be assumed that chemotherapy, particularly high-dose Methotrexate, was responsible for the improvement. The veracity of historical controls and the efficacy of high dose Methotrexate were also disputed by additional claims from the Mayo Clinic. Principal among these was recent advances in diagnostic techniques i.e. CT lung and radionuclide bone scans.

A variety of conditions may mimic osteosarcoma. The differential ­diagnosis includes benign and malignant tumors, infection and inflammatory processes arising from the musculoskeletal system. An accurate clinical history, imaging studies, and pathological evaluation are essential to establish the exact diagnosis. This chapter describes many of the conditions which may mimic the diagnosis of ­osteosarcoma. For convenience, the conditions are divided into several categories.

Osteosarcoma is a primary malignant tumor of the bone in which proliferating neoplastic cells produce osteoid and/or bone, if only in small amounts. This histological principle defines a tumor that usually affects young males more frequently than females, and disproportionately involves the long bones of the appendicular skeleton. These tumors are generally locally aggressive and tend to produce early, lethal systemic metastases. However, osteosarcoma is not a single disease but a family of neoplasms, sharing the single histological finding of osseous matrix production in association with malignant cells.

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 of radiotherapy.

This communication will review therapeutic and toxic effects of intraarterial cis-diamminedichloroplatinum-II (CDP) in the treatment of the primary tumor and will discuss controversial issues [1,2,3].

The majority of children who present with osteosarcoma have pulmonary metastases at the time of diagnosis. Despite surgical resection of the primary tumor and aggressive adjuvant chemotherapy, the 2-year metastasis-free survival (MFS) is approximately 66%. The implication of this observation is that these patients harbor “drug-resistant” tumor cells. Therapy failure can be explained by an inherent drug resistance of some metastatic cells in the lung, by an inability to deliver sufficient quantities of drug to the metastatic cells because of side effects, or by the metastatic cells being located in an area where chemotherapy cannot reach them. New forms of therapy are therefore clearly needed if we are to make a further impact in the treatment of osteosarcoma.

Adrenal cortical carcinoma is a rare neoplasm in infancy. Most cases present with Cushing’s syndrome, hirsuitism, precocious puberty, or rarely inappropriate ADH secretion. Associated congenital anomalies and concurrent central nervous system and hepatic tumors have also been documented. Occasionally, the tumor may be non-functioning. Three cases have been seen at the M.D. Anderson Hospital and Tumor Institute with a variety of presentations and outcome.

During the past decade, major advances have been reported in the treatment of osteosarcoma [1–9]. These derive principally from the application of chemotherapy in the management of the primary tumor, as an adjuvant to prevent pulmonary metastases, and in multidisciplinary strategies to eradicate established disease. These developments, however, have not been without controversy [10–13]. The latter emerged principally from a comparison of the results of the new investigations with historical controls. This communication will outline the impact of chemotherapy in osteosarcoma and examine the controversial issues.

The Bone Tumor Center of the "Istituto Ortopedico Rizzoli" was established in 1955 with the aim of Studying and treating the musculoskeletal tumors. Between 1959 and 2006, 1245 patients with high grade nonmetastatic osteosarcoma of the extremity were treated at our Institute. Most of them were enrolled in study protocols. In the "prechemotherapy era", the cure rate was 11%, with an amputation rate of 90%. Our first experience with adjuvant chemotherapy was in 1972. A total of 223 patients received adjuvant chemotherapy, with a disease-free survival (DFS) ranging froth 45% to 53%, according to the chemotherapy protocol used. With the introduction of neoadjuvant chemotherapy, the resection rate increased and reached 94%, when high dose fosfamide was added to standard doses of methotrexate, cisplatin. and adriamycin. In the last few years, the results of treatment of nonmetastatic osteosarcoma of the extremity have reached a plateau (64% five-year DFS), and strategies of dose intensification are not able to improve the prognosis. Not only new active drugs, but also different approaches to the disease, are needed. In this regard, we are now investigating tumor microenvironment-targeted agents and chemotherapy protocols based on prospective biological stratification of patients. Collaborative projects with international groups and institutions are crucial for this rare disease.