See page 272 for diagnosis and treatment.
Continuation of ORP conference from page 271.
Microscopic examination of the biopsy specimen showed a tumor composed in part by a cellular neoplasm with a variety of histologic appearances. In some areas, the tumor contained a prominent, variably cellular chondroid matrix containing markedly atypical cells. The chondroid matrix was surrounded by and blended with highly cellular areas containing fine osteoid matrix deposition (Fig 5, 6). The cells contained within the osteoid matrix were highly atypical, and numerous mitotic figures were identified. In other areas, the tumor was composed of long fascicles of pleomorphic, mitotically active spindled cells devoid of osteoid or chondroid matrices.
Osteosarcoma (high grade; Musculoskeletal Tumor Society and American Joint Committee on Cancer, AJCC, Stage IIB8)
DISCUSSION AND TREATMENT
Osteosarcoma is the most common primary bone sarcoma and the third most common malignant tumor in children, exceeded only by leukemia and lymphoma.11,19 By definition, osteosarcoma is a malignant spindle-cell neoplasm in which the malignant cells form osteoid. It is a relatively rare tumor, with fewer than 1000 new cases per year in the United States, with no racial or ethnic influence on the incidence. There is a male predominance of 1.5:1.11
Osteosarcoma and its variants are categorized by location (intramedullary versus surface), histologic composition (osteoblastic, chondroblastic, fibroblastic), degree of cellular differentiation (high grade versus low grade), the number of foci of involvement (single versus multicentric), and the causation of the neoplasm (primary versus secondary).11,12,23,29 Secondary osteosarcoma is known to arise from conditions such as Paget’s disease and radiation exposure (iatrogenic and accidental). Secondary osteosarcoma is typically seen in the fifth and sixth decades of life. Classic (primary high-grade intramedullary) osteosarcoma is commonly seen during the second decade of life, around the period of the adolescent growth spurt.11,12,29
Classic osteosarcoma typically presents with pain about the lesion, with a characteristic progression of the nature of pain from intermittent to persistent over time.11,30 The patient may describe swelling or a palpable mass. Some patients present with a pathologic fracture secondary to marked weakening of the strength of the bone at the site of the lesion.26
Osteosarcoma typically involves the metaphyseal region of long bones in the appendicular skeleton (80% of cases).11,23 These tumors typically originate in the region of most rapid growth and greatest blood flow, the distal femur in 35% of cases, the proximal tibia (20%), and the proximal humerus (10%) are most commonly involved.11,12,23
The characteristic radiographic features are a destructive lesion about the metaphysis with indistinct borders, periosteal elevation, cortical bone destruction, soft tissue extension, and evidence of ossification. Reactive bone adjacent to the lesion can elevate the periosteum and create a radiographic finding referred to as Codman’s triangle. The periosteal reaction may be dense, multilayered, or even show the characteristic, but not pathognomonic, sunburst appearance, with new bone formation appearing as spicules radiating perpendicularly from the involved cortex.23 The radiographic appearance is highly variable, however, a mixed pattern consisting of both radiolucencies and radiodensities most typically is observed.
The most common route of disease metastasis in patients with osteosarcoma is by hematogenous spread to the lungs and, much less commonly, to bone. Approximately 15% of patients have clinically detectable lung metastases at the time of diagnosis.11,19 Bone metastases are present in less than 5% of patients at time of diagnosis.11 It is necessary to evaluate for the presence of distant disease with the use of bone scintigrams and a CT scan of the chest. For local tumor staging MRI and CT provide complementary information useful in planning surgical resection. Computed tomography is useful in assessing the extent of the bone destruction, periosteal reaction, and matrix composition, while magnetic resonance imaging helps define the intraosseous and extraosseous extent of the tumor.1,20,23 On MRI scans, classic osteosarcoma is observed to be low signal on T1-weighted images. Marrow involvement by the tumor is consequently seen as areas of diminished signal intensity because the neoplasm has replaced the normal marrow fat.1,20 Use of MRI scans to evaluate the tumor extent within the marrow is indispensable, allowing for the evaluation of the presence of skip lesions, and enabling the surgeon to precisely plan the surgical resection.17,20 The T1-weighted MRI scan of the entire involved bone in the sagittal and/or coronal plane before chemotherapy is the most valuable study to determine the intramedullary extent of the tumor. A similar study after chemotherapy then is evaluated to help determine the level of tumor resection.
Other bone lesions that may present with a similar clinical history, examination, and radiographic evaluation, would include primary malignant bone tumors (Ewing’s and lymphoma), benign bone-forming tumors (osteoblastoma), and infection. The histologic evaluation helps differentiate between these when it is correlated with the clinical and radiographic interpretation.
Ewing’s sarcoma is a malignant, small, round-cell tumor, and is the second most common bone tumor in children.11 The radiographic appearance is more permeative than that seen with osteosarcoma, and frequently there is a soft tissue mass out of proportion to the findings seen on plain radiographs. It occurs in the same age range as primary intramedullary osteosarcoma and also presents with pain, swelling, and a mass.30 There is no second age peak as seek with secondary osteosarcomas. Histologically, Ewing’s sarcoma is composed of sheets of monotonous small, round blue cells and is easily distinguished from conventional osteosarcoma. Characteristic cytogenetics [t(11;22)(q24;q12)] and immunohistochemistry (CD-99 immunoreactivity) help confirm the diagnosis.
Another small round blue cell malignancy that can be seen in children and confused with Ewing’s sarcoma is lymphoma. Primary bone lymphoma is rare and accounts for less than 5% of primary bone tumors.6 The median age of 24 patients in a series with long-term followup was 38.5 years. The radiographic findings are variable, but typically suggest an aggressive malignant process. Immunohistochemistry and flow cytometry play a major role in identifying and classifying lymphoma.
Osteoblastoma is a rare, benign, bone-forming tumor, most commonly seen in the posterior elements of the spine. A majority of osteoblastomas show radiographic, pathologic, and clinical features distinct from those seen in osteosarcoma. Generally, the lesions are well-circumscribed radiodense lesions with nonaggressive radiographic features. However, there is a spectrum of disease and radiographic appearance which can be aggressive. Histologically, the lesion is composed of osteoblast-lined osteoid with a benign fibrovascular stroma between the bony trabeculae.9,10 A lack of cellular atypia, mitoses, and necrosis in a majority of osteoblastomas allow them to be distinguished from osteosarcoma.
Osteomyelitis can afflict people of all ages and involve any bone. Radiographic findings are varied, from indolent, focal bone lesions to areas with aggressive osteolysis, cortical destruction and soft tissue extension. In chronic cases or cases involving more virulent organisms, the radiographic changes suggest an aggressive process. A mixed population of acute and chronic inflammatory cells on histologic sections and positive cultures help distinguish the bone destruction attributable to infection from malignancy.23
After complete staging and confirmatory biopsy,21 the current standard of treatment for osteosarcoma includes neoadjuvant chemotherapy (multiagent preoperative chemotherapy) combined with wide surgical resection (limb sparing or ablative), followed by postoperative chemotherapy.7,11,13,14,16,18,22 With multidisciplinary treatment, the current overall survival rate is between 70 and 80% in patients with nonmetastatic osteosarcoma. In the period before chemotherapy, the overall survival was 20%. The administration of chemotherapy in patients with osteosarcoma has led to a dramatic increase in the 5-year survival rate and the rate of limb-salvage surgery.2,15,22,24,25,27,28 Poor prognostic factors include metastatic disease at presentation, poor response to preoperative chemotherapy, and large tumor size.3,4,5,11
Our patient was treated with four cycles of preoperative chemotherapy (ifosfamide, doxorubicin, cisplatinum) followed by wide surgical resection of the distal femur and previous biopsy tract. Coronal-plane sections showed a densely ossified mass that extended from the subchondral plate proximally into the femoral diaphysis, and filled the entire medullary cavity (Fig 7A). No viable tumor cells were identified in any of the histologic sections, indicating a 100% response to neoadjuvant chemotherapy (Fig 7B). An osteoarticular allograft was used to reconstruct the skeletal defect and she maintains excellent, pain-free knee function more than 5 years postoperatively (Fig 8).
1. Abdelwahab IF, Miller TT, Hermann G, et al: Transarticular invasion of joints by bone tumors. Skeletal Radiol 20:279-283, 1991.
2. Bacci G, Ferrari S, Lari S, et al: Osteosarcoma of the limb: Amputation or limb salvage in patients treated by neoadjuvant chemotherapy. J Bone Joint Surg 84B:88-92, 2002.
3. Bacci G, Ferrari S, Mercuri M, et al: Predictive factors for local recurrence in osteosarcoma: 540 patients with extremity tumors followed for minimum 2.5 years after neoadjuvant chemotherapy. Act Orthop Scand 69:230-236, 1998.
4. Bielack SS, Kempf-Bielack B, Delling G, et al: Prognostic factors in high-grade osteosarcoma of the extremities or trunk: An analysis of 1,702 patients treated on neoadjuvant cooperative osteosarcoma study group protocols. J Clin Oncol 20:776-790, 2002.
5. Davis AM, Bell RS, Goodwin PJ: Prognostic factors in osteosarcoma. J Clin Oncol 12:423-431, 1994.
6. de Camargo OP, dos Santos Machado TM, Croci AT, et al: Primary bone lymphoma in 24 patients treated between 1955 and 1999. Clin Orthop 397:271-280, 2002.
7. DiCaprio MR, Friedlaender GE: Malignant bone tumors: Limb sparing versus amputation. J Am Acad Orthop Surg 11:25-37, 2003.
8. Enneking WF, Spanier SS, Goodman MA: A system for the surgical staging of musculoskeletal sarcoma. Clin Orthop 153:106-120, 1980.
9. Frassica FJ, Waltrip RL, Sponseller PD, Ma LD, McCarthy Jr EF: Clinicopathologic features and treatment of osteoid osteoma and osteoblastoma in children and adolescents. Orthop Clin North Am 27:559-574, 1996.
10. Hermann G, Klein MJ, Abdelwahab IF: Osteoblastoma-like osteosarcoma. Clin Radiol 59:105-108, 2004.
11. Gibbs Jr CP, Weber K, Scarborough MT: Malignant bone tumors. J Bone Joint Surg 83A:1728-1745, 2001.
12. Huvos AG: Osteogenic Sarcoma. In Huvos AG (ed). Bone Tumors: Diagnosis, Treatment, and Prognosis. Ed 2. Philadelphia: WB Saunders 85-155, 1991.
13. Kawai A, Muschler G, Lane JM, et al: Prosthetic knee replacement after resection of a malignant tumor of the distal part of the femur. J Bone Joint Surg 80A:636-647, 1998.
14. Lindner NJ, Ramm O, Hillmann A, et al: Limb salvage and outcome of osteosarcoma: The University of Muenster experience. Clin Orthop 358:83-89, 1999.
15. Link MP, Goorin AM, Miser AW, et al: The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. N Engl J Med 314:1600-1606, 1986.
16. Mankin HJ, Gebhardt MC, Jennings LC, et al: Long-term results of allograft replacement in the management of bone tumors. Clin Orthop 324:86-97, 1996.
17. Meyer MS, Spanier SS, Moser M, Scarborough MT: Evaluating marrow margins for resection of osteosarcoma: A modern approach. Clin Orthop 363:170-175, 1999.
18. Meyer WH, Malawer M: Osteosarcoma: Clinical features and evolving surgical and chemotherapeutic strategies. Pediatr Clin North Am 38:317-347, 1991.
19. Meyers PA, Gorlick R: Osteosarcoma. Pediatric Clin North Am 44:973-989, 1997.
20. O’Flanagan SJ, Stack JP, McGee HMJ, Dervan P, Hurson B: Imaging of intramedullary tumour spread in osteosarcoma: A comparison of techniques. J Bone Joint Surg 73B:998-1001, 1991.
21. Peabody TD, Gibbs Jr CP, Simon MA: Evaluation and staging of musculoskeletal neoplasms. J Bone Joint Surg 80A:1204-1218, 1998.
22. Provisor AJ, Ettinger LJ, Nachman JB, et al: Treatment of nonmetastatic osteosarcoma of the extremity with preoperative and postoperative chemotherapy: A report from the Children’s Cancer Group. J Clin Oncol 15:76-84, 1997.
23. Resnick D, Kyriakos M, Greenway GD: Tumor and Tumor-like Lesions of Bone: Imaging and Pathology of Specific Lesions. In: Resnick D (ed). Diagnosis of Bone and Joint Disorders. Vol 6. Ed 3. Philadelphia: WB Saunders 3662-3679, 1995.
24. Rosen G, Caparros B, Huvos AG, et al: Preoperative chemotherapy for osteogenic sarcoma: Selection of postoperative adjuvant chemotherapy based on the response of the primary tumor to preoperative chemotherapy. Cancer 49:1221-1230, 1982.
25. Rougraff B, Simon MA, Kneisl J, et al: Limb salvage compared with amputation for osteosarcoma of the distal femur: A long term oncological, functional, and quality-of-life study. J Bone Joint Surg 76A:649-656, 1994.
26. Scully SP, Ghert MA, Zurakowski D, Thompson RC, Gebhardt MC: Pathologic fracture in osteosarcoma: Prognostic importance and treatment applications. J Bone Joint Surg 84A:49-57, 2002 Erratum J Bone Joint Surg 84A: 622.
27. Sluga M, Windhager R, Lang S, et al: Local and systemic control after ablative and limb salvage surgery in patients with osteosarcoma. Clin Orthop 358:120-127, 1999.
28. Szendroi M, Papai ZS, Koos R, Illes T: Limb-saving surgery, survival, and prognostic factors for osteosarcoma: The Hungarian experience. J Surg Oncol 73:87-94, 2000.
29. Vander Griend RA: Osteosarcoma and its variants. Orthop Clin North Am 27:575-581, 1996.
© 2005 Lippincott Williams & Wilkins, Inc.
30. Widhe B, Widhe T: Initial symptoms and clinical features in osteosarcoma and Ewing sarcoma. J Bone Joint Surg 82A:667-674, 2000.