Osteosarcoma
Thomas Kühne
Definition – 160 Epidemiology – 160 Location – 160
Etiology and Tumor Genetics – 160 Pathology – 161
Clinical Manifestations – 162 Metastasis – 162
Evaluation – 162 Radiology – 163
Differential Diagnosis – 163 Treatment – 163
Treatment for Relapsed Disease – 164 Prognosis – 164
Complications – 164
Definition
Primary malignant tumor of bone
Origin: primitive mesenchymal stem cell capable of differentiating toward bone (but also fibrous tissue and cartilage)
Osteoid tissue or immature bone production of malignant proliferating mesenchy- mal tumor cells
Represents a heterogeneous group of tumors (Table 13.1.)
Epidemiology
The sixth most common group of malignant tumors in children
Adolescents and young adults: the third most common malignant tumor
The most common bone tumor in children and adolescents (approximately 35% of primary sarcomas of bone)
Rare in the first decade of life (less than 5%)
Approximately 60% of patients are between 10 and 20 years old
Occurs most frequently during the adolescent growth spurt
Bimodal age distribution: the first peak during second decade of life and a small peak (controversial) in patients older than 50 years
Male-to-female ratio is 1.3–1.6:1
Peak incidence in second decade of life is somewhat higher in white males than in males of other races
Location
Skeletal regions affected by greatest growth rate, i.e. distal femoral and proximal tibial metaphyses
Approximately 50% of osteosarcoma in knee region
Humerus is third most frequently involved bone, usually proximal humeral meta- physis and diaphysis
Pelvis, i.e. ilium in approximately 10%
Etiology and Tumor Genetics
Etiology is unknown
Relation between rapid bone growth as in adolescence and development of osteosa- rcoma
Ionizing radiation
Viral cause not proven
Alkylating agents and anthracyclines may be etiologically involved in secondary osteosarcoma
Association with Paget’s disease
Familial osteosarcoma has been reported
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Osteosarcoma following hereditary retinoblastoma or associated with mutations in the retinoblastoma (RB) gene without manifestation of a retinoblastoma are well described. However normal RB alleles are found in most investigated osteosarco-
masFurther evidence of genetic background of osteosarcoma is reflected by TP53 muta- tions (TP53 is a tumor suppressor gene)
Li-Fraumeni syndrome, a familial cancer syndrome, associated with a germline TP53 mutation is strongly associated with osteosarcoma
Pathology
Morphological classification (e.g. osteoblastic, chondroblastic, fibroblastic)
Classification according to growth pattern (e.g. intramedullary osteosarcoma (ori- gin and growth primarily within bone tissue) and surface osteosarcoma (growth at surface of bone with periosteal or parosteal tissue)
There are various classification systems without standardization
Classification is mainly descriptive; there is often a variability of several tissue types, i.e. production of osteoid, anaplastic stroma cells, different amount of bone tissue, small and large round cells, giant cells, normal osteoclasts. There is no clear pheno- typic association with the morphological subtypes
Approximately 50% of bone tumors are malignant
Telangiectatic osteosarcoma
– Rare type osteosarcoma that appears to be a separate entity although similar to conventional osteosarcoma in clinical aspects
Table 13.1. Morphological classification of osteosarcoma
Conventional osteosarcoma Secondary osteosarcoma (retinoblastoma, Paget’s disease,
Osteoblastic irradiation induced, fibrous dysplasia
and others)
Chondroblastic
Fibroblastic Surface osteosarcoma
Small cell parosteal (juxtacortical)
Giant cell periosteal
Epithelioid
Telangiectatic osteosarcoma
Well differentiated ostiosarcoma Multifocal osteosarcoma
– The previously reported poor prognosis being much worse than conventional osteosarcoma has improved and now is no different from conventional
– Management as conventional osteosarcoma
Small-cell osteosarcoma
– May be confused with Ewing sarcoma, but distinguishable by osteoid produc- tion
– Biopsy: adequate tumor sample is required for diagnosis – Management as for conventional osteosarcoma
Clinical Manifestations
The most frequent symptom is pain originating from the involved region often for weeks or even months
Sometimes swelling with local signs of inflammation
Loss of function
Weight loss is unusual and points to metastatic disease if present
Metastasis
At time of diagnosis macrometastases are present in approximately 15–20% of pa- tients, but micrometastases (mainly lungs) much more frequently present
Lung metastases predominate
Rarely skeletal metastases with or without simultaneous lung metastases
Multiple bone metastases may also reflect multifocal osteosarcoma with a poor prog- nosis
Evaluation
Clinical work-up: history, physical examination (pain, location, swelling, signs of inflammation, function)
Radiology: plain radiographs in two planes, magnetic resonance imaging (MRI) of primary site of at least complete involved bone plus adjacent joints (tumor extent in bone and soft tissues); MRI is more appropriate than computed tomography (CT)
scanMetastases: chest X-ray, CT scan of thorax, skeletal radionuclide scan with MRI of hot spots
Assessment of organ functions
Open biopsy of tumor before chemotherapy (preferably performed by the same or- thopedic team involved in future surgery of the patient; close collaboration with pathology and pediatric oncology is the basis for successful management)
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Radiology
High variability
Radiological classification of lytic and sclerotic tumors; both components often present
Tumor matrix may be mineralized resulting in variable dense opacities of different sizes and shapes
Tumor margins may be poorly defined. Destructive growth pattern with lytic and sclerotic areas and normal bone tissue commonly observed
Cortex exhibits frequently destructive growth; the tumor is rarely limited to medul- lary space
Extension into soft tissue common
Periosteal reaction often present with various features, occasionally as radiating stria- tions called “sunburst signs,” or as open triangles overlying the diaphyseal side of the lesion (Codman’s triangle) or in the form of multiple layers (“onion skin”)
Differential diagnosis
May be confused with benign and malignant bone lesions
Callus formation following fracture
Osteogenesis imperfecta (type I)
Acute and chronic osteomyelitis
Osteoblastoma
Aneurysmal bone cyst
Benign and aggressive osteoblastoma
Chondrosarcoma
Malignant fibrous histiocytoma
Giant-cell tumor
Metastatic carcinoma (extremely rare in childhood)
Treatment
Management ideally done using national or international clinical trials
Combined modality treatment essential
Neoadjuvant chemotherapy with standardized evaluation of chemotherapy response of the tumor at the time of definitive surgery followed by risk stratification and postsurgical risk-adapted therapy
Surgery: goal is a wide resection. Limb-saving surgery with allograft or prosthesis.
In situations of unclear surgical resection (questionable wide resection) and in poor chemotherapy responders consideration of amputation
Adjuvant postsurgical chemotherapy according to tumor response to chemotherapy and according to a standardized risk stratification
High-dose chemotherapy with autologous stem-cell transplantation has not been proven to be of value
Osteosarcoma is relatively radioresistant
Treatment of relapsed disease
Prognosis is poor; 5-year post-relapse survival seems to be less than 30%; patients are often heavily pretreated
Complete surgery seems to be the most important prognostic factor
Therapy is not standardized
Prognosis
Results from the German Cooperative Osteosarcoma Study Group (COSS) – Five-year overall survival is approximately 65%
– Five-year overall survival in patients without metastasis at the diagnosis of os- teosarcoma is approximately 70%
– Five-year overall survival in patients with metastasis at the diagnosis of osteosa- rcoma is approximately 30%. Favorable prognostic factors: single metastasis, com- plete surgical resection of tumor
– Patients who respond well to neoadjuvant chemotherapy have a significantly better prognosis than poor responders
– Other important prognostic factors:
Location of primary tumor (osteosarcoma of extremities has a better prognosis than other locations), tumor size, surgical result (patients with incomplete re- section have a worse prognosis)
Complications
According to location of the lesion
Secondary malignancy
Psychological complications (related to diagnosis, location, therapy, body image and functional limitations)
Social problems (costs, school, professional guidance, social contacts, insurability)
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