Jaroslaw T. Hepel and Timothy J. Kinsella
Primary malignant tumors of bone are rare neoplasms accounting for <0.2% of all cancers. In 2010, an estimated 2,650 new cases and 1,460 related deaths were expected.1 Osteosarcoma, chondrosarcoma, and Ewing sarcoma are the most common, comprising 35%, 30%, and 16% of cases, respectively. Other rare entities include malignant fibrous histiocytoma, fibrosarcoma, and chordoma. Ewing sarcoma is discussed in detail in Chapter 88. Osteosarcoma and the other malignant bone tumors will be discussed here.
OSTEOSARCOMA
Epidemiology
Osteosarcoma is a rare primary malignant tumor of bone, accounting for approximately 750 to 900 new cases in the United States annually. Despite its rarity, osteosarcoma is the fifth-most-common malignancy and the most common malignant bone tumor in children and adolescents.2,3 It has a bimodal age distribution, with peak incidence in early adolescence and another smaller peak in adults older than 65 years of age.4 In childhood, osteosarcoma typically occurs sporadically, whereas in adulthood it is more commonly associated with sarcomatous degeneration of Paget’s disease or other benign bone lesions. There is a slight male predilection, with a ratio of 1.2:1.2
Pathogenesis and Risk Factors
The etiology of osteosarcoma is unknown, but there is a suggestion of a relationship with rapid bone growth. The peak incidence of osteosarcoma occurs during the adolescent growth spurt; this peak is earlier in girls corresponding to their earlier bone development. The most frequent sites of involvement correspond to the areas of greatest increase in bone length—the metaphysis of the distal femur, proximal tibia, and proximal humerus. It has been suggested that an aberration in the natural process of bone growth leads to osteosarcoma, but the specific etiology has not been elucidated. Unlike other pediatric tumors, no characteristic translocation or genetic abnormality has been defined for osteosarcoma.
Several risk factors have been associated with osteosarcoma. Development of osteosarcoma after radiation therapy exposure in childhood has been reported. The mean latency period is generally >10 years.5–7 Similarly, chemotherapy, especially alkylating agents, has been implicated with secondary osteosarcoma.7 Benign bone lesions, particularly Paget’s disease, have also been associated with osteosarcoma. Paget’s disease of bone is a focal skeletal disorder characterized by accelerated bone turnover. Sarcomatous transformation is usually seen in long-standing Paget’s and occurs in only 0.7% to 1% of cases.8 Other benign bone lesions have also been associated with risk of osteosarcoma, including chronic osteomyelitis, multiple hereditary exostoses, fibrous dysplasia, osteochondromas, enchondromas, sites of bone infarcts, and sites of metallic implants.9 Several genetic conditions have been linked to an increase risk of osteosarcoma. Retinoblastoma is associated with an increased risk of secondary tumors, more than half of which are soft-tissue sarcomas and osteosarcomas.10 Li–Fraumeni syndrome is associated with a spectrum of malignancies, including breast, adrenocortical, brain, leukemia, and sarcomas, including osteosarcoma. Li–Fraumeni syndrome involves a germline inactivation of p53, a key cell cycle regulatory gene.11 Rothmund–Thomson, Bloom, and Werner syndromes have also been associated with osteosarcoma.12
Clinical Presentation
Most patients present with localized pain in the affected bone. Pain is usually of several months duration and may wax and wane. There may be associated soft-tissue swelling or a palpable mass. Some patients present with pathologic fracture. Osteosarcoma has a predilection for involvement of the metaphysis of long bones. The most common site of involvement is the knee (distal femur or proximal tibia), followed by the proximal humerus, mid and proximal femur, and then other bones.13 Although most patients have micrometastatic disease at the time of presentation, only 10% to 20% of patients present with clinical evident macrometastases. The lung is the most common site of metastatic involvement, followed by bone.14
Diagnostic Evaluation
Plain x-ray of the affected bone classically demonstrates destruction of the normal trabecular bone with lytic and/or sclerotic lesions, osteoid formation under the periosteum (Codman’s triangle), and variable ossification of the associated soft tissue mass (Fig. 82.1). Magnetic resonance imaging (MRI) of the affected bone is essential to fully delineate the extent of the lesion, evaluate any soft-tissue component, and evaluate for involvement of joint, nerves, and vasculature (Fig. 82.2). The entire affected bone should be imaged to evaluate for the presence of skip lesions. Skip metastases are well recognized in osteosarcoma but occur infrequently, with <5% incidence.15,16 Systemic staging should include a computed tomography (CT) scan of the chest and radionuclide bone scan to evaluate for pulmonary and bone metastases, respectively. Positron emission tomography (PET) scan can be used as an alternative for systemic staging but may have less sensitivity than CT and bone scan.17,18 PET scan has also been used to assess response to preoperative chemotherapy.19
Biopsy of the tumor should be performed to confirm the diagnosis and to differentiate from other bone lesions. Similar to soft-tissue sarcomas, the biopsy should be performed at a center with expertise in bone tumors and should be carried out by or in conjunction with the orthopedic surgeon who will be performing future definitive surgery in order to not jeopardize subsequent treatment, particularly a limb-preserving procedure.
FIGURE 82.1. A: Plain radiograph of a distal femur osteosarcoma showing a lytic region and Codman’s triangle in the medial distal femur. B: Magnetic resonance image scan of the same lesion.
FIGURE 82.2. Plain radiograph of a sclerotic pelvic osteosarcoma.
TABLE 82.1 STAGING OF OSTEOSARCOMA
Staging Systems
There are two staging systems commonly used for osteosarcoma (Table 82.1). The Musculoskeletal Tumor Society (MSTS) staging system is a surgical staging system stratifying tumors by grade and subdividing by local extent.20The American Joint Committee on Cancer system is less often used.21
Pathology
Osteosarcoma is characterized by the presence of malignant sarcomatous stroma with associated osteoid (immature bone) production.22 Osteosarcoma is believed to arise from mesenchymal stem cells with the capacity to have fibrous tissue, cartilage, and bone differentiation. Thus, osteosarcoma shares many features with chondrosarcomas and fibrosarcomas. However, only osteosarcoma produces woven bone matrix, a key element for diagnosis.
Osteosarcoma is classified into two main categories: conventional (intramedullary) and surface.23 The conventional type accounts for 90% of osteosarcomas and is associated with the typical presentation in adolescence. The majority of conventional osteosarcomas are high-grade tumors. Conventional osteosarcoma is further subdivided into osteoblastic, chondroblastic, fibroblastic, and mixed subtypes. Other, less common histologic variants of conventional osteosarcoma include small cell, telangiectatic, malignant fibrous histiocytoma, and multifocal. Multifocal osteosarcoma typically carries a worse prognosis.
Surface osteosarcoma is subdivided into parosteal, periosteal, and high-grade surface.24,25 Parosteal variant is considered to be a low-grade tumor with a low metastatic potential. Periosteal variant is intermediate in grade, with an intermediate rate of developing metastases, between parosteal and conventional osteosarcoma, about 20%. A rare variant, extraosseous osteosarcoma, arises in soft tissues and is generally associated with prior radiation exposure.26
Treatment
Chemotherapy plays a critical role in the management of most patients with osteosarcoma. Although only 10% to 20% of patients present with overt metastatic disease, the vast majority of patients harbor subclinical metastatic disease at the time of presentation. Before effective chemotherapy, 80% to 90% of patients subsequently developed distant metastases and died of their disease despite achieving local disease control.27 The typical treatment sequence for intermediate- and high-grade osteosarcoma is neoadjuvant chemotherapy, followed by surgery with a limb-sparing procedure if possible, and then followed by further adjuvant chemotherapy. With this approach, 60% to 70% of patients without overt metastases at diagnosis are expected to be long-term survivors.28 Those with isolated lung metastases have an overall survival of 35% to 40%, whereas those with more extensive metastatic disease at diagnosis have <20% likelihood of long-term survival. For the less common low-grade tumors such as parosteal osteosarcoma, treatment with surgery alone is appropriate because the risk of developing metastases is low. These patients have an 80% to 90% likelihood of long-term survival.29
Surgery
The mainstay of surgical management is the complete en bloc resection of tumor. The extent and functional implications of surgery have dramatically evolved over time, with an emphasis on more conservative, limb-sparing resections with maintenance of function rather than amputation. Neoadjuvant chemotherapy has played an important role in this evolution.
For extremity lesions, limb preservation is preferred and can be accomplished in the majority of cases. Retrospective studies have shown equivalent results of limb-sparing surgery and amputation as long as adequate margins can be achieved.30–32 Contraindications to limb-sparing surgery include nerve or vascular encasement, presence of large, biopsy-related hematoma, and pathologic fracture. Some data suggest that pathologic fracture does not increase the risk of local recurrence after limb-sparing surgery as previously believed.33,34 Reconstructive options include use of allografts, endoprostheses, and occasionally rotationplasty.
Axial tumors, although much less common, pose a particular challenge because achieving complete surgical resection can be difficult. As a result, these lesions have a worse prognosis compared to extremity tumors. Pelvic tumors typically require a hemipelvectomy for en bloc resection. Some patients can undergo resection of the hemipelvis with preservation of the extremity (internal hemipelvectomy). This has a better functional outcome compared to an external hemipelvectomy, also referred to as a hindquarter amputation. Adjuvant radiation has been used to improve outcomes in patients with incomplete resections of pelvic tumors. Spinal tumors are also particularly difficult to resect with negative margins. Typically, an en bloc resection with vertebrectomy is performed, combined with mechanical stabilization. Postoperative radiation therapy can be used when negative margins cannot be obtained, particularly when there is microscopic dural involvement.
Chemotherapy
In the absence of chemotherapy, 80% to 90% of patients will subsequently develop distant metastases.27 Chemotherapy thus plays an important role for all patients with intermediate- and high-grade tumors. Level I evidence for the benefit of chemotherapy was established by two randomized trials in the 1980s. Eilber et al.35 reported on 59 patients with nonmetastatic osteosarcoma randomized to surgery followed by observation versus adjuvant chemotherapy. Disease-free survival at 2 years was 55% with chemotherapy and 20% with observation (p < .01). Overall survival was also superior at 2 years: 80% versus 48% with and without chemotherapy, respectively (p < .01). Link et al.36reported similar results in a group of 36 patients with nonmetastatic, high-grade osteosarcoma randomized to observation versus adjuvant chemotherapy after primary surgery. Disease-free survival at 2 years was 66% with chemotherapy and 17% with observation (p < .001).
The concept of neoadjuvant chemotherapy arose in conjunction with evolving surgical techniques striving for limb-preserving procedures and improved functional outcomes. This led to a randomized clinical trial by the Pediatric Oncology Group (POG).37 POG 8651 randomized patients with nonmetastatic, high-grade osteosarcoma to neoadjuvant chemotherapy followed by surgery or surgery followed by the same chemotherapy. The 5-year relapse-free survival was not statistically different between the two groups (65% vs. 61%, respectively), nor was the rate of limb salvage (55% vs. 50%, respectively). Although this trial did not show improved outcomes with neoadjuvant chemotherapy, it did show equivalence and established a benchmark for comparison with future trials. Neoadjuvant chemotherapy is favored by most centers, with the belief that the likelihood of limb-sparing surgery and, ultimately, functional outcome can be improved with this approach. Furthermore, the response to neoadjuvant chemotherapy has been shown to be prognostic.38 This allows for the stratification of patients for more intensive postoperative treatment.
The optimal choice of chemotherapy and administration schedule remains a subject of active research. The Memorial Sloan-Kettering Cancer Center T10 regimen is frequently used for nonprotocol patients and consists of high-dose methotrexate, doxorubicin, bleomycin, cyclophosphamide, and actinomycin D.39 Patients are being accrued to EURAMOS I (AOST 0331), an international collaborative group trial sponsored by European and American Osteosarcoma Study Group, as well as by other groups, including the Children’s Oncology Group.40 This trial is evaluating the benefit of additional chemotherapy after preoperative and postoperative chemotherapy consisting of methotrexate, doxorubicin, and cisplatin. Patients with a poor response to preoperative chemotherapy are randomized to the addition of ifosfamide and etoposide, whereas those with a good response to preoperative chemotherapy are randomized to the addition of interferon.
Radiation
Historically, radiation has been used for the treatment of osteosarcoma; however, high local failure rates with the use of radiation alone, improved surgical techniques, allowing for limb preservation, and effective use of chemotherapy limits the use of radiation therapy for osteosarcoma today. With a combined approach of chemotherapy and surgery with negative margins, local control rates of 90% to 98% have been reported.30–32,41
Patients who have tumor resection with inadequate or positive margins or who have unresectable tumors, however, have high rates of local recurrence. The Cooperative Osteosarcoma Study Group (COSS) performed a multivariate analysis of 1,702 patients and found that poor response to neoadjuvant chemotherapy and incomplete surgical resection predicted negatively for overall survival.42 Picci et al.43 also reported that local recurrence was higher for limb-salvage surgery if wide, negative margins were not achieved. Furthermore, high recurrence rates have been reported in locations where complete surgery is usually not possible, including a recurrence rate of 70% in the pelvis, 68% in the spine, and 50% in the skull regions.44–46 Radiation can potentially improve local control in these patients. Therefore, indications for integration of radiation therapy with other treatment modalities currently include incompletely resected tumors with positive margins and unresectable tumors or for palliation of symptoms.
Radiation Therapy Techniques
As with other sarcomas, proper patient position at the time of simulation and treatment is essential to achieve optimal tumor coverage and normal-tissue sparing. Customized immobilization devices may need to be constructed to achieve optimal positioning that is reproducible on a daily basis. Three-dimensional treatment planning with the aid of presurgical and postsurgical imaging is used to define gross tumor volumes and areas of subclinical disease. Typically, a 2-cm margin is used for axial tumors, which can be extended to 4 to 5 cm for extremity tumors. These margins can be restricted at natural tissue and fascial boundaries. The radiation technique used, either three-dimensional conformal or intensity-modulated radiation therapy, should be tailored to the individual patient. Dose to uninvolved organs should be minimized to prevent late organ dysfunction, as should the integral dose to minimize risk of secondary malignancy.
A prescription dose of 60 Gy in 2-Gy fractions is typically used for microscopically involved margins, whereas 66 Gy is used for macroscopic residual disease and 70 Gy is used for inoperable tumors. Chemotherapy should not be interrupted to deliver local radiation therapy. Radiation can be given concurrently but is usually delivered after chemotherapy due to increased acute toxicity with concurrent administration.
Intraoperative radiation therapy has been used to deliver dose directly to close or involved surgical margins.47,48 Proton particle therapy has been used in an attempt to escalate radiation dose, particularly in unresectable tumors.49,50 Radionuclide therapy with rhenium,51 strontium,52 and samarium53 has been used for palliation of extensive bone metastases with good effects.
Results of Radiation Therapy
In the prechemotherapy era, Cade54 pioneered a technique of radiotherapy with delayed amputation in patients who did not develop distant metastases. The primary tumor was controlled in some patients who refused amputation. However, the overall results were poor, with most patients dying of metastatic disease. The incorporation of chemotherapy with optimal surgery has resulted in significantly improved outcomes, obviating the need for radiation therapy for most patients. Dincbas et al.55 evaluated the addition of preoperative radiation therapy to chemotherapy followed by limb-sparing surgery. They reported on a series of 46 patients, most of whom received 35 Gy in 10 fractions. Local control and overall survival rates at 5 years were 97.5% and 48.4%, respectively. Although the results were excellent, it is not clear whether preoperative radiation therapy improved outcomes, given that the rate of local control with chemotherapy follow by surgery in the absence of adjuvant radiation is high, as previously summarized.
For patients who have incomplete tumor resection or unresectable tumors, the risk of local recurrence/progression is high. These patients, therefore, can potentially benefit from radiation therapy. Machak et al.56 reported on a series of 187 patients with nonmetastatic osteosarcoma treated with induction chemotherapy. Of these, 31 patients refused surgery and were treated with radiation to a mean dose of 60 Gy. Local control was related to response to induction chemotherapy. There were no local recurrences in 11 patients who had a good response to chemotherapy. However, local progression-free survival was 31% at 3 years and 0% at 5 years for nonresponders. Schwarz et al.57reported on an analysis of 100 patients treated with radiation therapy in the COSS registry. Local control and overall survival for the whole group were 30% and 36%, respectively, at 5 years. Local control was significantly better when surgery was combined with radiation compared to radiation alone: 48% vs. 22%, respectively (p = .002). Local control was also higher for primary tumors compared with recurrent tumors: 40% vs. 17%, respectively. DeLaney et al.50 reported on the Massachusetts General Hospital (MGH) experience. Forty-one patients with osteosarcoma underwent radiation for close or positive margins or for unresectable disease. Anatomic sites included 17 skull, 8 extremity, 8 spine, 7 pelvis, and 1 trunk. Patients received a median dose of 66 Gy (10–80 Gy), with about half of patients receiving a portion of their treatment with protons. The overall local control rate was 68% at 5 years. Local control was similar between patients who underwent a gross total resection or subtotal resection but was significantly better than for those who underwent biopsy only: 78% versus 78% versus 40% at 5 years, respectively (p < .01).
Overall, it appears that radiation is most effective when the tumor burden is small, with the best results achieved in patients who have a good response to chemotherapy or are able to undergo gross total or subtotal tumor resection. Total dose may also be an important factor. Gaitán-Yanguas58 showed a dose–response relationship for osteosarcoma, with no lesions controlled at doses ≤30 Gy and all lesions controlled at doses of >90 Gy. The best clinical results were reported in the MGH series.50 A median dose of 66 Gy was used, and half of the patients received proton therapy as part of their treatment. The unique dose–depth properties of proton radiation therapy allows for dose escalation while maintaining normal-tissue sparing. This approach may explain the improved outcomes reported. However, this study did fail to show a dose–response relationship.
Whole-Lung Irradiation
Whole-lung irradiation has been shown to be beneficial in several other pediatric tumors with a propensity for lung metastases. This led to the rationale that this treatment may improve outcomes in osteosarcoma, which has a high propensity for metastases and for which the lung is the most common site of spread. Two initial small randomized trials in the prechemotherapy era showed a trend for improved disease-free and overall survival for whole-lung irradiation.59,60 This led to the EORTC-20781/SIOP-03 phase III trial, which randomized 240 patients to three arms: chemotherapy, whole-lung irradiation, or both.61 The whole-lung dose was 20 Gy. The 4-year disease-free survival and overall survival were 43% and 24%, respectively, with no difference between the arms. Therefore, with the recognition of the other advantages of systemic therapy, whole-lung irradiation has fallen out of favor.62
TABLE 82.2 SELECTED STUDIES OF BASE-OF-SKULL CHORDOMA AND CHONDROSARCOMA
TABLE 82.3 SELECTED STUDIES OF SACRAL/SPINE CHORDOMA AND CHONDROSARCOMA
Surveillance and Sequelae of Treatment
Surveillance for recurrence should include imaging of the primary site with CT or MRI and chest imaging. Late complications are largely related to chemotherapy and surgical interventions. Limb functional outcomes are related to location of tumor and type of resection and reconstruction performed. Complications related to radiation therapy include joint fibrosis with decreased range of motion, bone weakening and fracture, loss of allograft, and secondary malignancy.50 Careful consideration of radiation technique and physical rehabilitative therapy are essential to minimizing late functional impairment.
CHONDROSARCOMA
Epidemiology
Chondrosarcoma is characterized by a neoplastic process with associated cartilage matrix production that is devoid of osteoid, a characteristic of osteosarcoma. It is the second-most-common primary bone tumor, accounting for approximately 30% of cases.63 Chondrosarcoma may arise at any age but typically occurs in middle-aged and older adults.64
Pathogenesis and Risk Factors
The etiology of chondrosarcoma is not fully understood. It is usually sporadic but can also develop from malignant transformation of benign cartilaginous lesions—osteochondromas and enchondromas. Osteochondroma is a cartilage-capped bony projection arising on the external surface of bones. It is usually located on long bones, particularly around the knee. Multiple osteochondromas are associated with hereditary multiple exostoses, an autosomal dominant syndrome. Malignant transformation occurs in 5% of patients with either solitary or multiple osteochondromas.65,66 Enchondroma is a benign cartilaginous tumor developing in the marrow cavity of bone. Multiple enchondromas, or enchondromatosis, are usually associated with congenital disorders such as Ollier disease or Maffucci syndrome. Malignant transformation of solitary enchondromas is extremely rare, but the risk with enchondromatosis is as high as 25% to 30%.66,67
Clinical Presentation and Diagnostic Evaluation
Patients typically present with localized pain in the affected bone with or without associated soft-tissue swelling or a palpable mass. Plain radiograph is obtained for initial evaluation, but CT and MRI are essential to characterize the lesion(s) and determine the full extent of disease.
Tissue biopsy of the tumor is necessary to confirm the diagnosis and to differentiate it from other malignant bone tumors. Biopsy should be aimed at the most aggressive portion as determined by imaging. This can help avoid biopsy a portion of a benign precursor lesion. It also helps avoid less aggressive surgical approaches used for low-grade lesions if a high-grade component is present.68
The rate of metastatic disease for chondrosarcoma is very dependent on tumor grade. Low-grade lesions have a <10% risk of metastases, intermediate-grade lesions have a 10% to 50% risk, and high-grade lesion have a 50% to 70% risk.69,70 The lungs are the main site of metastases. Staging evaluation thus should include a chest CT for intermediate- and high-grade lesions.
Staging Systems
As with osteosarcoma, both the MSTS staging system and the American Joint Committee on Cancer staging system can be used (Table 82.1). MSTS is used more often.20,21
Pathology
Chondrosarcoma pathologically is divided into conventional, which comprises 85% to 90% of cases, and other, uncommon variants. Conventional chondrosarcoma is further subdivided into central, peripheral, and periosteal.71,72Central chondrosarcoma is the most common type, accounting for 75% of all chondrosarcomas. Most are sporadic, but as many as 40% may arise for underlying enchondromas. Most commonly the proximal femur, pelvis, and proximal humerus are involved.73 Peripheral chondrosarcoma by definition arises from a pre-existing osteochondroma. The long bones, pelvis, and shoulder girdle are most commonly affected.66 Periosteal chondrosarcoma arises from the surface of bone and is rare. It usually affects adults at a younger age, in their 20s and 30s, and tends to have a good prognosis.74 Nonconventional chondrosarcoma variants include clear cell, dedifferentiated, myxoid, and mesenchymal. Clinical behavior of chondrosarcoma is highly dependent on histologic grade.69,75,76
FIGURE 82.3. Base-of-skull chordoma. Fifty-year-old patient who presented with several months of headaches and visual field deficits. T1-weighted, postgadolinium sagittal magnetic resonance imaging of the head depicts a chordoma (arrow) arising from the clivus (asterisk) with mass effect and posterior displacement of the brainstem.
FIGURE 82.4. Sacral chordoma. Forty-five-year-old patient who presented with 1 year of low back pain radiating to the coccyx. T2-weighted sagittal magnetic resonance imaging of the pelvis depicts a 5-cm chordoma involving the inferior sacrum up to the level of S2.
Treatment
Histologic grade and tumor location are important determinates of treatment approach. Surgical excision is the primary treatment modality for chondrosarcoma. For low-grade tumors, which constitute the vast majority of chondrosarcomas, surgical resection alone is sufficient to achieve a high rate of disease control. For low-grade central tumors, intralesional excision or curettage is the preferred method of resection. This can be combined with local adjuvant chemical treatment or cryotherapy. These approaches result in good local control rates and minimize the morbidity of more extensive surgical resection.77–80 The best outcomes are obtained with small tumors located in the extremities. Larger tumors, tumors with intra-articular or soft-tissue involvement, and axial or pelvic tumors have higher local recurrence rates with these more conservative treatments and are better treated with wide excision.81,82For the less common intermediate- and high-grade tumors, wide en bloc excision is the optimal surgical approach.76 Radiation therapy is indicated for incompletely resected high-grade or locally recurrent tumors and tumors that are unresectable. Chemotherapy is generally not very effective for chondrosarcoma, especially for the most prevalent conventional type. There is no established adjuvant chemotherapy regime for these patients. There is some suggestion that dedifferentiated and mesenchymal chondrosarcomas may potentially benefit from chemotherapy, but phase III randomized data are lacking in these rare tumors.83–85
Radiation
As with osteosarcoma, no level 1 evidence exists for radiation therapy in chondrosarcoma. Based on first principles and results of published case series, radiation therapy is indicated to improve on high local failure rates after incomplete resection of high-risk tumors. These indications include intermediate- to high-grade tumors, locally recurrent tumors, and tumors in locations where surgical resection is challenging or limited. Definitive radiation can also be used for unresectable tumors. Doses of 50 Gy preoperatively and 60 to 66 Gy postoperatively for close or positive margins are typically used. Doses of ≥70 Gy are needed for definitive treatment.
Results of Radiation Therapy
Although chondrosarcoma was traditionally considered to be a “radioresistant” tumor, modern series have shown good outcomes with radiation therapy. Goda et al.86 presented the Princess Margaret Hospital experience of combined surgery and radiation therapy for high-risk extracranial chondrosarcoma. They reported on 60 patients with a median follow-up of 75 months and showed local control rates of 100%, 94%, and 42% for R0, R1, and R2 resected patients, respectively. Ten-year overall survival was 86%. Definitive radiation therapy has also been used for locations where complete surgical resection is difficult to achieve, that is, the spine and base of skull.87–90 In these locations, en bloc resection is generally not possible, and even piecemeal resection is often not complete. Proton radiation therapy has been used in this setting. The unique depth–dose properties of protons allows for dose escalation while sparing neighboring critical structures. A large series was reported from Massachusetts General Hospital consisting of 200 patients with base-of-skull chondrosarcoma treated using a combination of photon and proton radiation therapy.91 With median dose of 72 cobalt-gray-equivalent (CGE), they reported a 10-year local control rate of 98%. Similar local control rates have been reported by other institutions using various conformal radiation methods to achieve a high tumor dose, including protons, fractionated stereotactic photon, and carbon ions.92–95 Tables 82.2 and 82.3 summarize the results of selected studies of radiation therapy for chondrosarcoma involving the base of skull and the spine, respectively.
Surveillance and Sequelae of Treatment
Functional assessment, rehabilitation, and physical therapy are important to minimize the long-term morbidity of surgery and/or radiation therapy. Surveillance for recurrence should include history and physical exam, CT or MRI imaging of the primary area, and chest imaging on a periodic basis. Follow-up should continue for a minimum of 10 years because late recurrences are more commonly observed with chondrosarcoma than with other sarcomas.105
CHORDOMA
Epidemiology
Chordoma is a rare, malignant neoplasm arising from the remnant of the primitive notochord. Chordoma accounts for 1% to 4% of primary bone tumors, with an annual incidence in the United States of 0.08 cases per 100,000.106Median age at presentation is 60 years, but base-of-skull location typically present at a younger age, usually in the third to fourth decade of life.
Pathogenesis
In normal embryologic development, the notochord regresses as the embryo matures. Remnants can be found anywhere along the tract of the notochord from the base of skull to the sacrum. The largest foci remain at the cranial and caudal ends. This corresponds well with the anatomic distribution of chordoma, with half arising in the sacrococcygeal region and one-third at the base of skull, typically the clivus.106 The rest occur in the vertebral bodies of the spine. Chordomas in other locations are exceedingly rare.107
Clinical Presentation and Diagnostic Evaluation
Chordomas are slow-growing but locally destructive tumors. They typically present with pain at the affected area that may be of long-standing duration. Neurologic symptoms based on location are frequent. Base-of-skull tumors can present with cranial nerve deficits, particularly cranial nerve 3 or 6 palsies (Fig. 82.3). Hydrocephalus and sensorimotor deficits can also occur. In the sacral region, sacral nerve roots can be affected, resulting in bowel or bladder dysfunction. Diagnostic evaluation includes CT and MRI to characterize the extent of the primary tumor and involvement or neighboring neural structures (Fig. 82.4). Biopsy should be performed to establish the pathologic diagnosis.
Chordomas have a low metastatic potential, but metastases may occur in as many as 10% to 40% of patients.108–112 These typically occur late in the disease course and can involve lung, bone, liver, lymph nodes, or soft tissues. Metastatic deposits tend to be slow growing, and control of local disease progression remains the major therapeutic challenge in most patients.112
Pathology
Chordomas are classified histologically into conventional (classic), chondroid, and dedifferentiated. The majority are conventional. Chondroid chordoma accounts for 5% to 15% and tends to have a better prognosis. Dedifferentiated chordoma account for <5% of chordomas but are more aggressive, faster growing, and more likely to metastasize.113 Chordoma can be histologically difficult to differentiate from low-grade chondrosarcoma. The latter has a better prognosis, so the distinction is prognostically important. A careful pathologic review by a pathologist experienced in these tumors is recommended.114
Treatment
Although chordoma has the potential to metastasize, the dominant failure pattern is local recurrence, and this typically dictates morbidity and mortality for these patients. Salvage after local recurrence can achieve disease control for a period of time, but the ultimate outcomes tends to be poor. Thus, aggressive upfront treatment affords the best potential for cure.
Surgery has been the primary approach for these tumors. Complete en bloc resection with negative margins has been reported to achieve local control in 70% to 80% of patients.115 However, when negative margins cannot be achieved, the failure rate is >70%.115,116 Unfortunately, less than half of sacral tumors and even fewer base-of-skull tumors are amenable to complete resection. Aggressive surgery can also result in significant morbidity. Base-of-skull resection can result in cranial nerve deficits.117 Resection of sacral chordomas can result in bowel and bladder dysfunction when S2 or S3 nerve roots are injured or sacrificed.118,119
Chordomas are considered relatively “radioresistant” tumors, and so doses of >66 Gy are required. These doses have traditionally been difficult to achieve with conventional external beam techniques, given the location of these tumors abutting sensitive neural structures. Given the advantages of the physical dose properties of the Bragg peak of charged particles, these tumors were treated early in the advent of this technology. Thus far, the best results in the treatment of chordomas have been achieved with a combination of surgery and high-dose proton radiation therapy. Local control rates of 54% to 90% have been reported.92,93,96,97,100,101
Chemotherapy has long been known to be inactive in chordoma, and thus chemotherapy has not played a role in the definitive management of these patients. Recently, expression of Platelet-derived growth factor and epidermal growth factor receptors on these tumors and antitumor activity of targeted therapies against these receptors have been described, renewing interest in systemic treatment.120,121 Imatinib, cetuximab, and gefitinib have been used, but clinical experience is limited.122,123
Results of Radiation therapy
For base-of-skull chordomas, one of the largest experiences has been reported from Massachusetts General Hospital.112 A crude local control of 69% was achieved in 204 patients treated using proton radiation therapy to a dose of 66.6 to 79.2 CGE. Reports of using heavier charged particle have shown similar outcomes.98 With improvement in technology, dose escalation using conventional photons has also been achieved using intensity-modulated radiation therapy, fractionated stereotactic radiation therapy, and stereotactic radiosurgery techniques.92–94,97–99 The outcomes with these approaches have been comparable to those reported for proton techniques. Table 82.2 summarizes the results of selected published studies for base-of-skull chordomas.
For sacral chordomas, the published literature is less robust but has shown similar results. DeLaney et al.100 reported local control in 90% of 29 patients with sacral chordoma at a median follow-up of 4 years. Five-year actuarial local control was 100% for primary treatment versus 56% for salvage. There was no statistical difference based on extent of resection. Table 82.3 summarizes the results of published studies for spine sarcomas, including chordoma.
Sequelae of Radiation Therapy
Due to the high dose required for treatment of chordomas and the proximity of sensitive structures, late complications are not infrequent, and patients need to be followed and monitored closely. For base-of-skull chordoma, hypopituitarism, memory impairment, cranial nerve injury, sensory neural hearing loss, and central nervous system necrosis have been reported.88,92,110 For sacral chordoma, sacral nerve root injury, erectile dysfunction, rectal bleeding, and sacral insufficiency factures have been reported.100
RARE MALIGNANT BONE TUMORS
Fibrosarcoma of bone is a very rare tumor, accounting for <5% of all primary bone tumors.124 It is a malignant neoplasm of mesenchymal origin characterized by predominance of fibroblasts without tumor osteoid or cartilage production. It has a predilection for long bones and has a high metastatic potential. It is treated with complete surgical resection and often with adjuvant or neoadjuvant chemotherapy. Radiation therapy can be used for incompletely resected or unresectable tumors.
Malignant fibrous histiocytoma of bone also accounts for <5% of bone tumors.124 It is characterized by a mixture of spindle-shaped fibroblastic cells in a storiform pattern and admixed with mononuclear cells with histiocytic morphology and anaplastic giant cells without tumor osteoid or cartilage production. The mainstay of treatment is complete surgical resection. Like osteosarcoma, it has a high rate of metastases. Malignant fibrous histiocytoma of bone is typically treated similarly to osteosarcoma and has been shown to benefit from chemotherapy.125
SELECTED REFERENCES
A full list of references for this chapter is available online.
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