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NCI/PDQ^® Health professionals: Osteosarcoma and Malignant Fibrous Histiocytoma of Bone Treatment (PDQ®)

National Cancer Institute
Ultima Vez Modificado: 26 de noviembre del 2012

TABLE OF CONTENTS

• General Information About Osteosarcoma and Malignant Fibrous Histiocytoma (MFH) of Bone
  • Prognostic Factors
    • Primary site
    • Tumor size
    • Presence of clinically detectable metastatic disease
    • Adequacy of tumor resection
    • Necrosis following induction or neoadjuvant chemotherapy
    • Additional prognostic factors
  • Syndromes Associated With Osteosarcoma
    • Rothmund-Thomson syndrome
    • Genetic diseases that predispose to osteosarcoma

• Cellular Classification
  • Central (Medullary) Tumors
  • Surface (Peripheral) Tumors

• Staging and Site Information
  • Localized Osteosarcoma
  • Metastatic Osteosarcoma

• Treatment Option Overview

• Localized Osteosarcoma and MFH of Bone
  • Biopsy
  • Surgical Removal of Primary Tumor
  • Chemotherapy
  • Osteosarcoma of the Head and Neck
  • Current Clinical Trials

• Osteosarcoma and MFH of Bone With Metastatic Disease at Diagnosis
  • Lung Metastases Only
  • Bone Only or Bone With Lung Metastasis
  • Current Clinical Trials

• Recurrent Osteosarcoma and MFH of Bone
  • Lung Only Recurrence
  • Recurrence With Bone Metastases Only
  • Local Recurrence
  • Second Recurrence of Osteosarcoma
  • Treatment Options Under Clinical Evaluation for Recurrent Osteosarcoma
    • Current Clinical Trials

• Changes to This Summary (11/26/2012)

• About This PDQ® Summary
  • Purpose of This Summary
  • Reviewers and Updates
  • Levels of Evidence
  • Permission to Use This Summary
  • Disclaimer
  • Contact Us

• Get More Information From NCI

General Information About Osteosarcoma and Malignant Fibrous Histiocytoma (MFH) of Bone

Back Up

Fortunately, cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975. 1 Children and adolescents with cancer should be referred to medical centers that have a multidisciplinary team of cancer specialists with experience treating the cancers that occur during childhood and adolescence. This multidisciplinary team approach incorporates the skills of the primary care physician, an orthopedic surgeon experienced in bone tumors, a pathologist, radiation oncologists, pediatric oncologists, rehabilitation specialists, pediatric nurse specialists, social workers, and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life. (Refer to the PDQ® summaries on Supportive and Palliative Care for specific information about supportive care for children and adolescents with cancer.)

Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics. 2 At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate in these trials is offered to most patients/families. Clinical trials for children and adolescents with cancer are generally designed to compare potentially better therapy with therapy that is currently accepted as standard. Most of the progress made in identifying curative therapies for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI Web site.

Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2002, childhood cancer mortality has decreased by more than 50%. For osteosarcoma, the 5-year survival rate has increased over the same time from 40% to 67% in children and adolescents. 1 Childhood and adolescent cancer survivors require close follow-up because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ® summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)

Osteosarcoma occurs predominantly in adolescents and young adults. Review of data from the Surveillance, Epidemiology and End Results program of the NCI resulted in an estimate of 4.4 per million new cases of osteosarcoma each year in people aged 0 to 24 years. 3 The U.S. Census Bureau estimates that there will be 110 million people in this age range in 2010, resulting in an incidence of roughly 450 cases per year in children and young adults younger than 25 years. Osteosarcoma accounts for approximately 5% of childhood tumors. In children and adolescents, more than 50% of these tumors arise from the long bones around the knee. Osteosarcoma can rarely be observed in soft tissue or visceral organs. There appears to be no difference in presenting symptoms, tumor location, and outcome for younger patients (<12 years) compared with adolescents. 4 5 Two trials conducted in the 1980s were designed to determine if chemotherapy altered the natural history of osteosarcoma following surgical removal of the primary tumor. The outcome of patients in these trials who were treated with surgical removal of the primary tumor recapitulated the historical experience before 1970; more than half of these patients developed metastases within 6 months of diagnosis, and overall, approximately 90% developed recurrent disease within 2 years of diagnosis. 6 Overall survival for patients treated with surgery alone was statistically inferior. 7 The natural history of osteosarcoma has not changed over time, and fewer than 20% of patients with localized resectable primary tumors treated with surgery alone can be expected to survive free of relapse. 6 8 9

Prognostic Factors

Pretreatment factors that influence outcome include site and size of the primary tumor and presence or absence of clinically detectable metastatic disease. 10 After administration of preoperative chemotherapy, surgical resectability and the degree of tumor necrosis influence outcome. In general, prognostic factors in osteosarcoma have not been helpful in identifying patients who might benefit from treatment intensification or who might require less therapy while maintaining an excellent outcome.

Primary site

The site of the primary tumor is a significant prognostic factor for patients with localized disease. Among extremity tumors, distal sites have a more favorable prognosis than proximal sites. Axial skeleton primary tumors are associated with the greatest risk of progression and death, primarily related to the inability to achieve a complete surgical resection.

• Pelvis: Pelvic osteosarcomas make up 7% to 9% of all osteosarcomas; survival rates for patients with pelvic primary tumors are 20% to 47%. 11 12 13 14 Complete surgical resection is associated with positive outcome for osteosarcoma of the pelvis. 11 12
• Craniofacial/head and neck: Within the craniofacial osteosarcoma group, patients with mandibular tumors have a significantly better prognosis than patients with extragnathic tumors. 15 For patients with osteosarcoma of craniofacial bones, complete resection of the primary tumor with negative margins is essential for cure. 16 17 18 There is a better prognosis for patients who have osteosarcoma of the head and neck than for those who have appendicular lesions when treated with surgery alone.

  Despite a relatively high rate of inferior necrosis following neoadjuvant chemotherapy, fewer patients with craniofacial primaries develop systemic metastases than do patients with osteosarcoma originating in the extremities. 19 20 21 This low rate of metastasis may be related to the relatively smaller size and higher incidence of lower grade tumors in osteosarcoma of the head and neck. This low rate of metastasis may be related to the relatively smaller size and higher incidence of lower grade tumors in osteosarcoma of the head and neck.

  While small series have not shown a benefit from adjuvant chemotherapy for patients with osteosarcoma of the head and neck, one meta-analysis concluded that systemic chemotherapy improves the prognosis for these patients. Another large meta-analysis detected no benefit from chemotherapy for patients with osteosarcoma of the head and neck, but suggested that the incorporation of chemotherapy into treatment of patients with high-grade tumors may improve survival. A retrospective analysis identified a trend toward better survival in patients with high-grade osteosarcoma of the mandible and maxilla who received adjuvant chemotherapy. 18 22

  Radiation therapy was found to improve local control, disease-specific survival, and overall survival in a retrospective study of osteosarcoma of the craniofacial bones, which had positive or uncertain margins after surgical resection. 23[[Level of evidence: 3iiALevel of evidence: 3iiA] Radiation-associated craniofacial osteosarcomas are generally high-grade lesions, usually fibroblastic, that tend to recur locally with a high rate of metastasis.] Radiation-associated craniofacial osteosarcomas are generally high-grade lesions, usually fibroblastic, that tend to recur locally with a high rate of metastasis. 24

  In the German series, approximately 25% of patients with craniofacial osteosarcoma had osteosarcoma as a second tumor, and in 8 of these 13 patients, osteosarcoma arose following treatment for retinoblastoma. In this series, there was no difference in outcome for primary or secondary craniofacial osteosarcoma. 15

• Extraskeletal: Osteosarcoma in extraskeletal sites is rare in children and young adults. With current combined-modality therapy, the outcome for patients with extraskeletal osteosarcoma appears to be similar to that for patients with primary tumors of bone. 25

Tumor size

Larger tumors have a worse prognosis than smaller tumors. 10 26 Tumor size has been assessed by the longest single dimension, by the cross-sectional area, or by an estimate of tumor volume; all have correlated with outcome. Serum lactate dehydrogenase (LDH), which also correlates with outcome, is a likely surrogate for tumor volume.

Presence of clinically detectable metastatic disease

Patients with localized disease have a much better prognosis than those with overt metastatic disease. As many as 20% of patients will have radiographically detectable metastases at diagnosis, with the lung being the most common site. 27 The prognosis for patients with metastatic disease appears to be determined largely by the site(s), the number of metastases, and the surgical resectability of the metastatic disease. 28 29

• Site of metastases: Prognosis appears more favorable for patients with fewer pulmonary nodules and for those with unilateral rather than bilateral pulmonary metastases; 28 not all patients with suspected pulmonary metastases at diagnosis have osteosarcoma confirmed at the time of lung resection. In one large series, approximately 25% of patients had exclusively benign lesions removed at the time of surgery. 29
• Number of metastases: Patients with skip metastases (at least two discontinuous lesions in the same bone) have been reported to have inferior prognoses. 30 Analysis of the German Cooperative Osteosarcoma Study experience, however, suggests that skip lesions in the same bone do not confer an inferior prognosis if they are included in planned surgical resection. Skip lesions across a joint have a worse prognosis. 31 Skip metastasis in a bone other than the primary bone should be considered systemic metastasis. Traditionally, metastasis across a joint has been referred to as a skip lesion. Metastasis across a joint might be considered hematogenous spread and it has a worse outcome.

  Patients with multifocal osteosarcoma (defined as multiple bone lesions without a clear primary tumor) have an extremely poor prognosis. 32

• Surgical resectability of metastases: Patients who have complete surgical ablation of the primary and metastatic tumor (when confined to the lung) following chemotherapy may attain long-term survival, though overall event-free survival remains about 20% to 30% for patients with metastatic disease at diagnosis. 28 29 33 34

Adequacy of tumor resection

Resectability of the tumor is a critical prognostic feature because osteosarcoma is relatively resistant to radiation therapy. Complete resection of the primary tumor and any skip lesions with adequate margins is generally considered essential for cure. A retrospective review of patients with craniofacial osteosarcoma performed by the German-Austrian-Swiss osteosarcoma cooperative group reported that incomplete surgical resection was associated with inferior survival probability. 15[Level of evidence: 3iiB] For patients with axial skeletal primaries who either do not have surgery for their primary tumor or who have surgery resulting in positive margins, radiation therapy may improve survival. 11 35 In a European cooperative study, the size of the margin was not significant. However, having both the biopsy and resection at a center with orthopedic oncology experience conferred a better prognosis. 13

Necrosis following induction or neoadjuvant chemotherapy

Most treatment protocols for osteosarcoma use an initial period of systemic chemotherapy prior to definitive resection of the primary tumor (or resection of sites of metastases for patients with metastatic disease). The pathologist assesses necrosis in the resected tumor. Patients with at least 90% necrosis in the primary tumor after induction chemotherapy have a better prognosis than those with less necrosis. 26 Patients with less necrosis (<90%) in the primary tumor following initial chemotherapy have a higher rate of recurrence within the first 2 years compared with patients with a more favorable amount of necrosis (90%). 36 Less necrosis should not be interpreted to mean that chemotherapy has been ineffective; cure rates for patients with little or no necrosis following induction chemotherapy are much higher than cure rates for patients who receive no chemotherapy.

Imaging modalities such as dynamic magnetic resonance imaging (MRI) or positron emission tomography (PET) scanning are under investigation as noninvasive methods to assess response. 37 38 39 40 41 42

Additional prognostic factors

Patients with osteosarcoma as a second malignant neoplasm, including those tumors arising in a radiation field, share the same prognosis as patients with de novo osteosarcoma if they are treated aggressively with complete surgical resection and multiagent chemotherapy. 43 44 45 46 Possible prognostic factors identified for patients with conventional localized high-grade osteosarcoma include the age of the patient, LDH level, alkaline phosphatase level, and histologic subtype. 26 47 48 49 50 51 A number of potential prognostic factors have been identified but have not been tested in large numbers of patients. These include the expression of HER2/c-erbB-2 (there are conflicting data concerning the prognostic significance of this human epidermal growth factor); 52 53 54 tumor cell ploidy; specific chromosomal gains or losses; 55 loss of heterozygosity of the RB gene; 56 57 Loss of heterozygosity of the p53 locus; 58 and increased expression of p-glycoprotein. 59 60 A prospective analysis of p-glycoprotein expression determined by immunohistochemistry failed to identify prognostic significance for newly diagnosed patients with osteosarcoma, although earlier studies suggested that overexpression of p-glycoprotein predicted for poor outcome. 61 In a large series, a delay of 21 days or more from the time of definitive surgery to the resumption of chemotherapy was an adverse prognostic factor. 62 Pathologic fracture at diagnosis or during preoperative chemotherapy does not have adverse prognostic significance. 63

Syndromes Associated With Osteosarcoma

Rothmund-Thomson syndrome

Patients with Rothmund-Thomson syndrome have an increased risk of developing osteosarcoma compared with the general population. They also tend to develop osteosarcoma at a younger age. 64 Rothmund-Thomson syndrome, also called poikiloderma congenitale, is a rare autosomal recessive condition attributed to mutations of the RECQL4 helicase gene on 8q24. It is characterized by distinctive skin findings (e.g., atrophy, telangiectasias, pigmentation), sparse hair, cataracts, small stature, skeletal anomalies, and a significantly increased risk for osteosarcoma. There is no adverse prognostic significance for osteosarcoma in conjunction with Rothmund-Thomson syndrome.

Genetic diseases that predispose to osteosarcoma

Table 1. Genetic Diseases That Predispose to Osteosarcoma^a

^aTable adapted from Kansara and Thomas.

Syndrome	Location	Gene	Function
Bloom syndrome	15q26.1	BLM (RecQL3)	DNA helicase
Diamond-Blackfan anemia		Ribosomal proteins	Ribosome production
Li-Fraumeni syndrome	17p13.1	P53	DNA damage response
Paget disease	18q21-qa22	LOH18CR1	IL-1/TNF signaling; RANK signaling pathway
	5q31
	5q35-qter
Retinoblastoma	13q14.2	RB1	Cell-cycle checkpoint
Rothmund-Thomson syndrome	8q24.3	RTS (RecQL4)	DNA helicase
Werner syndrome	8p12-p11.2	WRN (RecQL2)	DNA helicase; exonuclease activity
65

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Cellular Classification

Back Up

Osteosarcoma is a malignant tumor that is characterized by the direct formation of bone or osteoid tissue by the tumor cells. The World Health Organization's histologic classification 1 of bone tumors separates the osteosarcomas into central (medullary) and surface (peripheral) 2 3 tumors and recognizes a number of subtypes within each group.

Central (Medullary) Tumors

• Conventional central osteosarcomas.
• Telangiectatic osteosarcomas. 4 5
• Intraosseous well-differentiated (low-grade) osteosarcomas.
• Small-cell osteosarcomas.

Surface (Peripheral) Tumors

• Parosteal (juxtacortical) well-differentiated (low-grade) osteosarcomas. 6 7
• Periosteal osteosarcoma: low-grade to intermediate-grade osteosarcomas. 8 9 10
• High-grade surface osteosarcomas. 3 11 12

The most common pathologic subtype is conventional central osteosarcoma, which is characterized by areas of necrosis, atypical mitoses, and malignant osteoid tissue and/or cartilage. The other subtypes are much less common, each occurring at a frequency of less than 5%. Telangiectatic osteosarcoma may be confused radiographically with an aneurysmal bone cyst or giant cell tumor. This variant should be approached as a conventional osteosarcoma. 4 5

Malignant fibrous histiocytoma (MFH) of bone is treated according to osteosarcoma treatment protocols. 13 MFH should be distinguished from angiomatoid fibrous histiocytoma, a low-grade tumor that is usually noninvasive, small, and associated with an excellent outcome with surgery alone. 14 One study suggests similar event-free survival rates for MFH and osteosarcoma. 13

Extraosseous osteosarcoma is a malignant mesenchymal neoplasm without direct attachment to the skeletal system. Previously, treatment for extraosseous osteosarcoma followed soft tissue sarcoma guidelines, 15 though a retrospective analysis of the German Cooperative Osteosarcoma Study identified a favorable outcome for extraosseous osteosarcoma treated with surgery and conventional osteosarcoma therapy. 16

References:

1. Schajowicz F, Sissons HA, Sobin LH: The World Health Organization's histologic classification of bone tumors. A commentary on the second edition. Cancer 75 (5): 1208-14, 1995. [PUBMED Abstract]
2. Antonescu CR, Huvos AG: Low-grade osteogenic sarcoma arising in medullary and surface osseous locations. Am J Clin Pathol 114 (Suppl): S90-103, 2000. [PUBMED Abstract]
3. Kaste SC, Fuller CE, Saharia A, et al.: Pediatric surface osteosarcoma: clinical, pathologic, and radiologic features. Pediatr Blood Cancer 47 (2): 152-62, 2006. [PUBMED Abstract]
4. Bacci G, Ferrari S, Ruggieri P, et al.: Telangiectatic osteosarcoma of the extremity: neoadjuvant chemotherapy in 24 cases. Acta Orthop Scand 72 (2): 167-72, 2001. [PUBMED Abstract]
5. Weiss A, Khoury JD, Hoffer FA, et al.: Telangiectatic osteosarcoma: the St. Jude Children's Research Hospital's experience. Cancer 109 (8): 1627-37, 2007. [PUBMED Abstract]
6. Hoshi M, Matsumoto S, Manabe J, et al.: Oncologic outcome of parosteal osteosarcoma. Int J Clin Oncol 11 (2): 120-6, 2006. [PUBMED Abstract]
7. Han I, Oh JH, Na YG, et al.: Clinical outcome of parosteal osteosarcoma. J Surg Oncol 97 (2): 146-9, 2008. [PUBMED Abstract]
8. Rose PS, Dickey ID, Wenger DE, et al.: Periosteal osteosarcoma: long-term outcome and risk of late recurrence. Clin Orthop Relat Res 453: 314-7, 2006. [PUBMED Abstract]
9. Grimer RJ, Bielack S, Flege S, et al.: Periosteal osteosarcoma--a European review of outcome. Eur J Cancer 41 (18): 2806-11, 2005. [PUBMED Abstract]
10. Cesari M, Alberghini M, Vanel D, et al.: Periosteal osteosarcoma: a single-institution experience. Cancer 117 (8): 1731-5, 2011. [PUBMED Abstract]
11. Okada K, Unni KK, Swee RG, et al.: High grade surface osteosarcoma: a clinicopathologic study of 46 cases. Cancer 85 (5): 1044-54, 1999. [PUBMED Abstract]
12. Staals EL, Bacchini P, Bertoni F: High-grade surface osteosarcoma: a review of 25 cases from the Rizzoli Institute. Cancer 112 (7): 1592-9, 2008. [PUBMED Abstract]
13. Picci P, Bacci G, Ferrari S, et al.: Neoadjuvant chemotherapy in malignant fibrous histiocytoma of bone and in osteosarcoma located in the extremities: analogies and differences between the two tumors. Ann Oncol 8 (11): 1107-15, 1997. [PUBMED Abstract]
14. Daw NC, Billups CA, Pappo AS, et al.: Malignant fibrous histiocytoma and other fibrohistiocytic tumors in pediatric patients: the St. Jude Children's Research Hospital experience. Cancer 97 (11): 2839-47, 2003. [PUBMED Abstract]
15. Wodowski K, Hill DA, Pappo AS, et al.: A chemosensitive pediatric extraosseous osteosarcoma: case report and review of the literature. J Pediatr Hematol Oncol 25 (1): 73-7, 2003. [PUBMED Abstract]
16. Goldstein-Jackson SY, Gosheger G, Delling G, et al.: Extraskeletal osteosarcoma has a favourable prognosis when treated like conventional osteosarcoma. J Cancer Res Clin Oncol 131 (8): 520-6, 2005. [PUBMED Abstract]

Staging and Site Information

Back Up

Historically, the Enneking staging system for skeletal malignancies was widely used. 1 This system inferred the aggressiveness of the primary tumor by the descriptors intracompartmental or extracompartmental. The American Joint Committee on Cancer (AJCC) staging system for malignant bone tumors has updated this staging system, substituting compartmentalization with size (see Table 2). 2 The AJCC classification is as follows:

Table 2. Definitions of TNM Stage I through Stage IV^a

^aReprinted with permission from AJCC: Bone. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 281-90.^bSkip metastases: discontinuous tumors in the primary bone site.

Stage	Tumor Grade	Tumor Size
IA	Low	<8 cm
IB	Low	>8 cm
IIA	High	<8 cm
IIB	High	>8 cm
III	Any tumor grade, skip metastasesb
IV	Any tumor grade, any tumor size, distant metastases

For the purposes of treatment, there are only two stages of high-grade osteosarcoma. Patients without clinically detectable metastatic disease are considered to have localized osteosarcoma. Patients in whom it is possible to detect any site of metastasis at the time of initial presentation by routine clinical studies are considered to have metastatic osteosarcoma.

For patients with confirmed osteosarcoma, in addition to plain x-rays of the primary site that include a single plane view of the entire affected extremity to assess for skip metastasis, pretreatment staging studies should include magnetic resonance imaging (MRI) and/or computed tomography (CT) scan of the primary site. Additional pretreatment staging studies should include bone scan, postero-anterior and lateral chest x-ray, and CT scan of the chest. Positron emission tomography (PET) using fluorine-18-fluorodeoxyglucose is an optional staging modality. 3

Localized Osteosarcoma

Localized tumors are limited to the bone of origin. Patients with skip lesions confined to the bone which includes the primary tumor should be considered to have localized disease if the skip lesions can be included in the planned surgical resection. 4 Approximately one-half of the tumors arise in the femur; of these, 80% are in the distal femur. Other primary sites in descending order of frequency are the proximal tibia, proximal humerus, pelvis, jaw, fibula, and ribs. 5 Compared with osteosarcoma of the appendicular skeleton, osteosarcoma of the head and neck is more likely to be low grade 6 and to arise in older patients.

Metastatic Osteosarcoma

Radiologic evidence of metastatic tumor deposits in the lungs, other bones, or other distant sites is found in approximately 20% of patients at diagnosis, with 85% to 90% of metastatic disease presenting in the lungs. The second most common site of metastasis is another bone. 7 Metastasis to other bones may be solitary or multiple. The syndrome of multifocal osteosarcoma refers to a presentation with multiple foci of osteosarcoma without a clear primary tumor, often with symmetrical metaphyseal involvement. Multifocal osteosarcoma has an extremely grave prognosis. 5

References:

1. Enneking WF: A system of staging musculoskeletal neoplasms. Clin Orthop Relat Res (204): 9-24, 1986. [PUBMED Abstract]
2. Edge SB, Byrd DR, Compton CC, et al., eds.: Bone. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 281-90. [PUBMED Abstract]
3. Meyer JS, Nadel HR, Marina N, et al.: Imaging guidelines for children with Ewing sarcoma and osteosarcoma: a report from the Children's