Soft-Tissue and Bone Sarcomas

Soft-Tissue SarcomasBone SarcomasReferences Sarcomas are a heterogenous group of tumors originating from mesenchymal tissues. According to American Cancer Society estimates, approxiately 8,070 new cases will be diagnosed in 1995, including 6,000 cases of soft-tissue sarcomas and 2,070 cases of bone tumors [1]. Soft-Tissue Sarcomas Soft-tissue sarcomas are extremely rare tumors. They represent 0.7% of adult malignancies [1]; it is estimated that in the United States 6,000 new cases and 3,600 deaths will occur from this disease in 1995 [1]. Soft-tissue sarcomas occur more frequently in children; they represent 6.5% of all cancers in children younger than 15 years of age [1] and are the fifth leading cause of cancer death in this age group. Soft tissues are the extraskeletal tissues of the body that support, connect, and surround other discrete anatomic structures. These tissues contribute more than 50% of the body weight and include muscles and tendons as well as fibrous, adipose, and synovial tissues. Soft-tissue sarcomas represent a histologically heterogeneous group of malignant tumors arising in the soft tissues. The majority of soft-tissue sarcomas are of mesodermal origin, but some sarcomas are derived from the ectoderm (eg, tumors of the connective tissues of the face and tumors composed of neurons). Although sarcomas are often thought to be exclusively mesenchymal in origin, some histologic subtypes (eg, synovial sarcoma and epithelioid sarcoma) share some epithelial features, and it is even speculated that they may be derived from epithelial tissue containing the cytokeratin type of intermediate filament [2]. Epidemiology and Pathogenesis The pathogenesis of soft-tissue sarcomas is not completely understood. Exposure to environmental toxins has been linked with the development of two specific sarcomas: mesothelioma (asbestos [3]) and hepatic angiosarcoma (thorotrast [4] and vinyl chloride [5]). In 1979, a Swedish report linked exposure to phenoxyacetic acids (herbicides) and chlorophenols (wood preservatives)[6] to an increased risk of developing soft-tissue sarcomas, but this was not confirmed in later studies [7–9]. Ionizing radiation has been implicated as a cause of sarcomas arising in soft tissue and bone [10]. The latent period averages approximately 10 years but ranges between 2 and 30 years, and the prognosis is usually poor. The association of lymphedema and lymphangiosarcoma is well recognized, as in Stewart-Treves syndrome [11], and carries a very poor prognosis. Despite anecdotal reports about clusters of sarcomas in some families, there is no clear genetic predisposition except in the Li-Fraumeni syndrome [12]. On the other hand, soft-tissue tumors are thought to occur more frequently in patients with a variety of genetically transmitted diseases, such as the basal cell nevus syndrome, tuberous sclerosis, Werner syndrome, intestinal polyposis, and Gardner's syndrome [13-18]. Sarcomas rarely develop from preexisting benign soft-tissue tumors [19]. The exceptions are neurofibromas in type-I Recklinghausen's disease, which have an increased risk for degeneration into malignant schwannomas. Patients with this disease have a 15% risk of developing neurofibrosarcoma and should be carefully monitored. Recent advances in molecular biology indicate that genetic mutations in mesenchymal stem cells within the soft tissues may be responsible for the development of sarcomas. Alterations in the retinoblastoma gene and p53 gene have been found in a variety of soft-tissue sarcomas [20,21]. Germline mutations of these genes have been identified in familial retinoblastoma cases and in the Li-Fraumeni syndrome [22,23], with soft-tissue sarcomas as manifestations of these disorders. In sarcomas, mutations of p53 have been associated with specific tumor subtypes, high histologic grade, and a poor prognosis [24]. Specific cytogenetic alterations have been associated with some sarcomas and appear to be pathognomonic. For example, t(11;22) is present in 90% of patients with extraskeletal Ewing's sarcomas [25], and 50% of alveolar rhabdomyosarcomas show a t(2;13) translocation [26,27]. Myxoid liposarcomas have been found to have a t(12;16) translocation, clear-cell sarcoma a t(12;22) translocation, extraskeletal myxoid chondrosarcoma a t(9;22) translocation, and synovial sarcoma a t(x;18) translocation [28]. Neuroblastoma has been associated with structural abnormalities of chromosome 1p in 70% to 80% of cases, and these abnormalities appear to confer a poor prognosis [29]. The increasing availability of molecular biology techniques and the identification of specific DNA and RNA gene sequences as expressions of the gene product Myo D1 and oncogenes will help in the diagnosis of sarcomas. Clinical Presentation Soft-tissue sarcomas can occur in any anatomic region of the body because of the ubiquitous nature of connective tissue, but most sarcomas (60%) develop in the extremities. Three times as many sarcomas develop in the legs as in the arms. Other sites include the trunk (31%) and head and neck region (9%). The most common manifestations of sarcomas of the extremity are swelling and pain. Pain is usually mild and occurs later in the course of the disease. Thus, a patient might delay seeking medical attention, and a definitive diagnosis also might be delayed [31]. In children, the majority of soft-tissue sarcomas are rhabdomyosarcomas, arising in 20% of the cases in the extremities, in 37% in the head and neck region, and in 25% in genitourinary sites [32]. Patients with pelvic sarcomas might present with swelling of the leg that simulates primary iliofemoral thrombosis or with pain in the distribution of the femoral or sciatic nerve. Hypoglycemia is rare and is usually associated with large retroperitoneal sarcomas. Evaluation Imaging Techniques: Radiologic evaluation should include a chest x-ray and a computed tomography (CT) scan of the lungs, the most common sites of metastasis [33], and a CT scan or, preferably, a magnetic resonance imaging (MRI) scan of the primary tumor-bearing area. MRI examination of the affected area using T1-weighted images, proton-density-weighted images, and T2-weighted images can maximize the contrast among soft-tissue neoplasm, muscle, fat, and vessels [34] and almost eliminates the need for an arteriogram. If the lesion abuts bone, a bone scan should be obtained to help determine whether there is periosteal invasion or reaction [35]. A positive bone scan does not document bone involvement by the tumor, but it may represent periosteal reaction. The bone scan can serve as a guide to wide resection near the bone or to removal of the periosteum and/or part of the bone in patients treated with surgery alone [36]. Biopsy: The biopsy of soft-tissue sarcomas is an important aspect of disease management. Needle biopsy is the preferred method because it is less invasive, less expensive, and easy to perform; however, a needle biopsy requires expertise in cytopathology for interpretation. Core biopsies can provide enough tissue for morphologic details, electron microscopy, DNA flow cytometry, cytogenetics, immunohistochemistry, and molecular studies, if necessary [37], without compromising the definitive surgery. If an open biopsy must be performed, the biopsy site should be removed at the time of definitive resection. Therefore, it is important for the biopsy incision not to compromise subsequent surgical excision. An excisional biopsy may be used for small or superficial lesions smaller than 2 cm in diameter. The tissues surrounding the tumor form a pseudocapsule that always contains invasive prongs of malignant tissue. Therefore, shelling out soft-tissue sarcomas is never curative. Local recurrence following such procedures occurs in approximately 80% of cases. Pathology There are approximately 70 different histologic types of soft-tissue sarcomas. Most sarcomas are classified according to the normal cell type they mimic, based on the system proposed by Enzinger and Weiss [38]. Even among experienced pathologists, significant disagreement often arises as to the cell of origin of an individual tumor [39]. The relative frequency of the various types of sarcomas differs according to a patient's age. In children, for example, the most common sarcoma is rhabdomyosarcoma, which represents 5% to 8% of all childhood cancers. It occurs primarily in infants and children and has a predilection for the head and neck region, urinary bladder, vagina, prostate, and retroperitoneum. In older children, it can also occur in the extremities. Rhabdomyosarcoma may present as one of four subtypes: embryonal, botryoid, alveolar, and pleomorphic. Immunohistochemistry is very helpful in the differential diagnosis; rhabdomyosarcoma stains positive with antibodies to actin, desmin, myoglobulin, S-100 protein, vimentin, and Myo-D. Electron microscopy can also help by showing the characteristic Z-band pattern of skeletal muscle differentiation [40,41]. Along with the synovial, epithelioid, and clear-cell sarcomas, rhabdomyosarcoma has a higher tendency toward lymphatic dissemination to the regional lymph nodes [42], in contrast to the generally low incidence (5%) of regional lymph-node metastases found in soft-tissue sarcomas [43]. The embryonal subtype is the most frequent and constitutes 75% of all rhabdomyosarcomas. The differential diagnosis of this particular type includes some of the “small-cell tumors,” such as lymphoma, neuroblastoma, oat-cell carcinoma of the lungs, Ewing's sarcoma, small-cell osteosarcoma, and mesenchymal chondrosarcoma. Botryoid sarcoma is a subtype of embryonal sarcoma that has a polypoid or grapelike appearance. This tumor is commonly found in the urogenital tract of infants and children and rarely in the oral and nasal pharynges. The alveolar type-the second most common type of rhabdomyosarcoma-occurs in patients who are 10 to 25 years older and more frequently in the extremities. It is an aggressive tumor and has a poorer prognosis than the embryonal type. Pleomorphic rhabdomyosarcoma is the least common subtype. It occurs in adults, more commonly in the extremities, and should be differentiated from other pleomorphic sarcomas, pleomorphic lymphomas, pleomorphic melanomas, and carcinomas. Here again, electron microscopy and immunohistochemistry are very helpful. In adolescents and young adults, the most common soft-tissue tumors are synovial sarcoma, epithelioid sarcoma, clear-cell sarcoma, and primitive neuroectodermal tumors. Synovial sarcoma occurs usually near the large joints of the lower extremities in patients 15 to 40 years of age and has a slightly higher incidence of lymph-node metastases [44]. Synovial sarcomas frequently calcify, which is rare for soft-tissue tumors; calcification may also occur in extraskeletal osteosarcoma, mesenchymal chondrosarcoma, and myositis ossificans. In adults, the most common sarcoma is malignant fibrous histiocytoma (MFH), which accounts for 10% to 20% of all soft-tissue sarcomas [45]. This type of tumor is believed to be composed of neoplastic fibroblasts with acquired histiocytic features. MFH usually occurs in the thigh and retroperitoneum of adults 40 to 80 years old [46]. In general, the term refers to a high-grade sarcoma, with the exception of myxoid MFH, which is usually regarded as an intermediate-grade sarcoma. Liposarcomas are the second most common adult sarcoma. They usually occur in the deep soft tissue of the extremities and retroperitoneum, rarely in the subcutaneous tissue, and almost never metastasize to the regional lymph nodes [47]. Liposarcomas occur slightly more frequently in men than in women (1.5:1) and can vary in behavior, ranging from low-grade, well-differentiated disease (also called atypical lipomatous tumor) to intermediate-grade myxoid liposarcoma to high-grade pleomorphic liposarcoma. Leiomyosarcomas arise from smooth muscle and can occur anywhere in the body. They commonly arise in the retroperitoneum, where they behave very aggressively. Neurofibrosarcomas originate from the neural sheath. They are frequently associated with Recklinghausen's disease, where patients have a 15% risk of developing neurofibrosarcomas, either de novo or from malignant transformation of preexisting benign soft-tissue tumors. Angiosarcomas include hemangiosarcomas and lymphangiosarcomas, which arise from blood vessels and lymphatic vessels, respectively. Although they are rare, representing only 2% of all soft-tissue sarcomas, they are almost always high-grade tumors, and the 5-year survival rate of patients is only 12% despite multimodality therapy [48]. Alveolar soft-part sarcomas have no benign counterpart. These tumors evolve slowly, with most patients developing metastases that progress gradually over 5 to 15 years before death occurs. Five-year survival rates of 60% are common [49]. This subtype has a higher incidence of brain metastases. Epithelioid sarcomas are very aggressive tumors of unknown origin. They occur almost exclusively in the extremities and have a tendency to spread to noncontiguous areas, including the skin, subcutaneous tissue, fat, bone, and draining lymph nodes, which are the most common sites of metastases for these tumors; the lungs are the second most common sites of metastases [50]. Disease Grade and Staging Sarcomas are classified according to their grade, which represents the most important prognostic factor [51,52]. Grade 1 describes well-differentiated disease, and, at the other extreme, grade 3 refers to poorly differentiated disease. The histopathologic grade of sarcomas is based on the degree of differentiation, cellularity, number of mitoses, pleormorphism, and amount of necrosis. In multivariate analysis, necrosis has been shown to be the best parameter for predicting prognosis [53,54]. The next important prognostic factors are the size and location of the tumor. Sarcomas located in extremities generally have a better prognosis than those not in extremities, probably because they are diagnosed earlier, are more likely to be completely resected, and have a lower risk of dissemination. The staging system of the American Joint Committee on Cancer depends largely on grade and tumor-node-metastasis (TNM) classification (Table 1)[55]. The lungs are the most frequent sites of metastasis (33%), followed by bone (23%) and the liver (15%). Treatment Local Disease: Most soft-tissue sarcomas are treated according to their grade, size, and location, except for Kaposi's sarcoma, extraskeletal Ewing's sarcoma, and rhabdomyosarcoma. In all grades of soft-tissue sarcomas, despite the presence of a pseudocapsule surrounding the tumor, extrusions of tumor extend through the capsule and form micro- and macronodules called satellites. High-grade sarcomas also have a significant incidence (almost 20%) of nodules found in normal tissue beyond the capsule-skip metastases-that are usually confined to the compartment of origin of the tumor. The goal of the treatment of local disease is local control followed by the preservation of optimal function. The surgical margin achieved has a direct influence on the local recurrence rate [38,56-59]. Marginal en bloc excision through the pseudocapsule carries a risk of local recurrence of 70% to 90%. Wide en bloc excision through normal tissue has a local recurrence rate of 20% to 30% for low-grade lesions and as high as 50% for high-grade lesions. Radical resection involving removal of an entire compartment or amputation is associated with a risk of local recurrence of less than 50% but obvious limitations in function. The results of combination radiotherapy (XRT) can influence decisions about proposed surgery. When properly designed XRT is coupled with surgery, narrow surgical margins with XRT have equivalent prognoses to those for wide surgical margins alone, and wide surgical margins coupled with XRT are equivalent to radical surgical margins for local control and survival [60-62]. Limb salvage should be considered when the oncologic margin is not compromised and the functional result is preferable to a prosthesis. Lymph-node dissection is not routinely recommended, even for the histologic types at high risk for lymph-node dissemination, unless clinical findings indicate that it should be performed [38,42,57]. Pre- and postoperative XRT has been used in conjunction with surgery to improve local control of the tumor. If used postoperatively, a dose of 60 to 65 Gy is required to achieve local control [60,63]. If XRT is used preoperatively, the dose required is lower (ie, 50 to 54 Gy), and the radiation field is usually smaller [64]. This is because the postoperative radiation field should include the tumor site and all tissues handled during surgery, including the stab wound and drain tube sites. Also, preoperative XRT usually causes tumor shrinkage, so the tumor is smaller at the time of surgery and has significantly fewer viable cells. Thus, the surgical margins can be safely reduced and the likelihood of reseeding tumor cells during surgery is almost eliminated. The advantages of postoperative radiation include the feasibility of immediate surgery and the avoidance of delay in wound healing caused by prior XRT. A study conducted at The University of Texas M.D. Anderson Cancer Center showed a local failure rate of 22% for patients receiving XRT postoperatively for grades 2 and 3 tumors larger than 5 cm vs a local failure rate of 10% for patients who received preoperative treatment [65]. Comparable results are reported by other investigators [66]. Wound morbidity after surgery and XRT is adversely affected by disease located in the lower extremity, advanced patient age, and a postoperative XRT boost with an interstitial implant, as shown by multivariate analysis [67]. Accelerated fractionation was of borderline significance, whereas high pathologic grade and a resection volume of more than 200 cm³ were significant only on univariate analysis. Preoperative XRT is associated with more wound morbidity than postoperative XRT. Gentle handling of tissues during surgery with adequate hemostasis and drainage, sufficient immobilization, and omission of a postoperative boost XRT dose when possible (ie, negative histologic margins) can reduce wound morbidity [68]. Investigators at the University of California at Los Angeles [69], used intra-arterial chemotherapy with doxorubicin (Adriamycin, Rubex), 30 mg/d for 3 days as a continuous infusion, followed by preoperative XRT and wide resection, in patients with soft-tissue sarcoma. This strategy produced a local recurrence rate of less than 10%, which included an amputation rate of 5%. These results are comparable to those from more conventional surgery and radiation schemes. Retroperitoneal sarcomas pose a complex problem, because complete resection is not often possible due to anatomic constraints [70]. In many cases, partial resection of a major organ is required, and even in completely resected sarcomas, a local recurrence rate of 50% to 70% is common [71]. XRT has been used as adjuvant therapy [72] and in unresectable disease [73]. Harrison et al reported the outcome of Yale University's experience with XRT in retroperitoneal sarcomas. All three patients who underwent a complete excision with negative margins and adjuvant XRT with more than 40 Gy survived free of disease for longer than 5 years. Among the 10 patients who underwent only a biopsy for unresectable retroperitoneal sarcomas, only 4 survived longer than 1 year, and the average radiation dose was 44 Gy. The remaining 6 patients received only an average of 27 Gy and did not survive for 1 year [72]. These results agree with the results reported by Tepper et al from Massachusetts General Hospital [73]. Of the 13 patients who had a primary tumor treated with curative intent, seven patients underwent incomplete surgical resections, three of whom had a relapse of local disease when treated with radiation doses of less than 50 Gy; the four patients with good local disease control received radiation doses varying from 4,990 to 6,070 cGy. Of the three patients with unresectable disease, one treated with 62 Gy had good local control, whereas the other two treated with less than 50 Gy had local relapses. Due to the retrospective nature of the studies and the small number of patients, adjuvant XRT for retroperitoneal sarcomas remains controversial. XRT for unresectable disease, however, does have some potential for local control and palliation. XRT has also been used with good results in the management of desmoid tumors. Desmoid tumors lack the capacity to metastasize, but they aggressively infiltrate locally and can be fatal [74,75]. Abdominal desmoid tumors usually occur in women postpartum [76]. Patients in whom a complete resection is possible have a good prognosis. Extra-abdominal desmoid tumors usually occur in the head and neck area, shoulder girdle, and inguinal region. Wide resection is often difficult or impossible in these areas, and the recurrence rate ranges between 50% and 75% for cases involving close or positive margins [77]. XRT has been used by different investigators as an alternative treatment; it provided good local control in approximately 80% of cases when 60 Gy was given over 6 to 8 weeks [77,78-82]. A review of a 20-year experience at M.D. Anderson Cancer Center using XRT doses of 50 to 76 Gy to treat desmoid tumors revealed no evidence of a dose-control relationship, but a clear dose-complication relationship was seen. Therefore, the current recommended XRT dose at M.D. Anderson is 50 to 55 Gy at 1.8 Gy per fraction [83]. At the time of a patient's initial surgery, XRT is not routinely recommended. A review of the M.D. Anderson experience with chemotherapy for desmoid tumors [84] identified 12 patients so treated; 10 with unresectable primary or recurrent disease and 2 treated preoperatively in an attempt to shrink the tumor and decrease surgical morbidity. Eleven patients received doxorubicin-plus-dacarbazine-based regimens; six of the nine patients whose responses could be evaluated had objective responses (two complete responses [CR] and four partial responses [PR]). With a response rate of more than 60%, chemotherapy is now recommended as primary therapy for inoperable/unresectable tumors. Hormonal therapy with tamoxifen [85], toremifene (Estrinex) [86], and progesterone [87] has been reported to achieve long-term remission of desmoid tumors. Indomethacin and ascorbic acid have been reported to cause regression of some desmoid tumors [88]. In addition, good responses have recently been reported with a combination of methotrexate and oral etoposide (VePesid) [89]. Adjuvant Chemotherapy: Adjuvant chemotherapy is considered standard therapy for rhabdomyosarcomas [32] and extraskeletal Ewing's sarcoma [90]. These two tumors are highly responsive to systemic chemotherapy, have a high incidence of systemic micrometastases, and are associated with a 5-year disease-free survival rate of less than 20%. The role of adjuvant chemotherapy in all other soft-tissue sarcomas remains controversial. The most active single agents for soft-tissue-sarcomas are ifosfamide (Ifex, 30%)[91], doxorubicin (26%)[92], dactinomycin (Cosmegen, 17%)[93], and dacarbazine (16%)[94]. The combination of dacarbazine and doxorubicin resulted in a response rate of 42% [95] and has been found to be superior to doxorubicin alone [96,97]. There was a dose-response relationship for doxorubicin, with regimens including doses of greater than 70 mg/m² having higher response rates than regimens using lower doses [84]; significantly less cardiotoxicity was seen when doxorubicin was administered as a prolonged infusion [99,100]. Ifosfamide (with mesna [Mesnex] for urothelial protection) resulted in a response rate of 25% to 30% in patients who did not respond to doxorubicin-based regimens [101-103]. A dose-response relationship was documented for ifosfamide in subsequent trials [103-104]. Several prospective, randomized studies were conducted to evaluate the role of adjuvant chemotherapy in localized soft-tissue sarcomas (Table 2)[105-116]. Several studies show a statistically significant improvement in disease-free survival; however, only one study (Bordeaux) showed a statistically significant difference in the rate of overall survival in favor of the adjuvant chemotherapy group. Despite criticism of the use of single-agent suboptimal-dose doxorubicin as adjuvant treatment in most of these cases and the inclusion of low-risk patients in some of the studies, results of a recent meta-analysis of 11 published prospective, randomized, adjuvant studies (that took into account only published information) revealed a disease-free survival advantage (68% vs 53%, P < .00001) and an overall survival advantage (81% vs 71%, P = .0005) for adjuvant chemotherapy for soft-tissue sarcomas [117]. A preferred approach is to provide preoperative chemotherapy to patients in a high-risk subset. This would help to identify patients who are more likely to benefit from aggressive systemic treatment while sparing the “nonresponders” from the morbidity of prolonged chemotherapy. Recurrent Disease: The two most common types of disease recurrence are local recurrence and hematogenous spread that most commonly involves the lungs. Local recurrence should be treated with aggressive surgical resection or as a high-risk primary tumor, with preoperative chemotherapy followed by local therapy depending on the clinical situation. Eighty percent of local recurrences occur in the first 2 years after initial surgery, and all recurrences develop by 3 years [118]. Patients with isolated local recurrences have a 5-year survival rate of 45% to 85% when treated with aggressive local therapy [119,120]. Resection of pulmonary metastases is indicated for patients with favorable prognostic factors-a tumor-doubling time of longer than 40 days, a disease-free interval of more than 1 year, fewer than three nodules, unilateral disease, and MFH tumor histology (rather than other histologies [121-123])-yielding a 5-year survival rate of 10% to 30%, with little morbidity and very low mortality. For patients with less favorable prognostic factors, chemotherapy is the only available treatment option, although CR rates range between 10% and 15% and only one third of patients achieve long-term disease-free survival. Doxorubicin and ifosfamide are the most active single agents, with response rates ranging from 15% to 40%. The combination of ifosfamide and doxorubicin with or without dacarbazine yielded variable results, with a CR rate of 5% to 10% and a PR rate of 25% to 48% [124-129]. Two prospective, randomized, cooperative group trials indicated better overall response rates with the ifosfamide/doxorubicin combination with or without dacarbazine but no significant improvement in CR rate or survival time [130,131]. Attempts to use high-dose chemotherapy with or without total-body irradiation (TBI) have been disappointing. Responses were of short duration, and substantial treatment-related morbidity and mortality without improvement in the survival rate were seen [132,133]. The use of growth factors, such as granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) allows intensification of the chemotherapeutic regimens and reduces the morbidity related to neutropenia. The multilineage growth factor PIXY 321 (a fusion protein of GM-CSF and interleukin-3) or thrombopoietin with G-CSF or GM-CSF may allow an increase in the dose intensity by counteracting dose-limiting thrombocytopenia, which currently remains a significant consideration. Bone Sarcomas Bone sarcomas account for 0.2% of all primary cancers in adults and approximately 5% of childhood malignancies. It is estimated that 2,070 new cases will be diagnosed in the United States in 1995 and that 1,280 deaths will be caused by bone sarcomas in the same year [1]. Bone sarcomas are classified according to the tissue of origin: I, bone-forming tumors; II, cartilage-forming tumors; III, giant-cell tumors; IV, mesenchymal tumors; and V, vascular tumors [134]. The four most common types of bone sarcomas are osteosarcoma, chondrosarcoma, MFH of bone, and Ewing's sarcoma. A team at a specialized center, including an orthopedic surgeon with experience with bone tumors, a radiologist, an experienced pathologist, and a medical oncologist, is essential for the appropriate management of these tumors. As in the case of soft-tissue sarcomas, careful preoperative evaluation is necessary for patients with bone sarcomas. Evaluation Imaging Techniques: Staging requires plain films and CT scans of the involved area and the lungs. CT scanning of the area, including the entire bone and adjacent joint, helps to determine intraosseous and extraosseous extension [135]. CT scans of the lungs are required to evaluate for metastatic disease because the lungs are the most common sites of metastasis via hematogenous spread [136]. Bone scans can detect bone metastases and occasional multicentric primary lesions [137,138] or skip metastases [139]. MRI films of the area are very helpful in evaluating the extent of bone-marrow involvement and in detecting skip lesions. MRI can also help to evaluate a positive bone scan when findings on the corresponding plain radiograph are normal [140,141]. Some authors believe that MRI is the best single technique to use for preoperative evaluation [142], whereas others prefer a baseline CT scan for better bony details and a preoperative MRI scan for surgical planning. As in the case of soft-tissue sarcomas, arteriograms are rarely necessary for surgical planning for bone sarcomas. However, they are very helpful in assessing the vasculature of the tumor preoperatively [143] and in determining chemotherapy response that manifests as a decrease in vascularity of the tumor [144]. After careful staging, a biopsy is performed, preferably by the same physician who will be involved in the patient's definitive treatment. The same principles apply for biopsy of bone sarcomas as for biopsy of soft-tissue sarcomas. The biopsy site should be removed during definitive resection. Biopsy: Trephine or core biopsy under fluoroscopic visualization is recommended and in most cases (as with 89% of patients with suspected osteosarcoma at M D. Anderson [145]) yields adequate material for diagnosis. Needle biopsy has the advantage of less tissue contamination than open biopsy. If the lesion extends to the extraosseous soft tissues, a biopsy of these components should be obtained. Intraosseous lesions require perforation of the cortex. In blastic lesions, tissue should be obtained from the least dense area [146]. Staging of Bone Tumors A surgical staging system proposed by the Musculoskeletal Tumor Society in 1980 is used for bone sarcomas (Table 3)[147]. The system is based on the fact that bone sarcomas, regardless of their histologic type, behave similarly according to grade (G), location (T), and lymph-node involvement or distant metastases (M). Bone tumors metastasize almost exclusively through hematogenous spread, with pulmonary metastases usually occurring first followed by bony involvement [148]. Lymphatic involvement occurs rarely; it is found in 10% of cases at autopsy [136] and in 3% of patients with osteosarcoma undergoing amputation. Lymphatic involvement is considered a poor prognostic sign [148]. Osteosarcoma Epidemiology and Clinical Presentation: Osteosarcoma is the most common primary malignant bone tumor. It affects men more than women (ratio, 1.5:1)[1]. There is a bimodal age distribution; the first peak occurs during childhood and adolescence and the second peak occurs during the sixth decade of life. It is a high-grade, malignant, spindle-cell tumor of the bone characterized by the production of osteoid by the malignant spindle-cell stroma [149]. Genetic alterations of the retinoblastoma (Rb) gene have been identified in cases of osteosarcoma [150] in patients with hereditary retinoblastoma, who carry a risk for osteosarcoma of 7% in radiation ports and in nonirradiated long bones [151], as well as in patients with sporadic osteosarcoma [152]. Loss of heterozygosity (LOH) and DNA alterations of the Rb gene in sporadic osteosarcomas indicate a poor prognosis [153]. During childhood and adolescence, 80% to 90% of osteosarcomas occur in a lower limb [154]. The disease's peak incidence during childhood/adolescence and the predominance of the distal femur and proximal tibia as first sites of presentation in that age group indicate that osteosarcoma is associated with rapid growth of weight-bearing long bones. In patients older than 40 years, the skull, pelvis, and mandible are frequent sites of osteosarcoma presentation. People with Paget's disease have a 10-fold risk of developing bone cancer [155]. Other conditions associated with an increased risk for bone sarcoma are hereditary multiple exostoses, enchondromatosis (Ollier's disease), enchondromatosis with skin hemangiomas (Maffucci's syndrome), polyostotic fibrous dysplasia, and osteogenesis imperfecta [156]. Ionizing radiation is the only environmental agent known to cause bone tumors. People who were exposed to radium and patients receiving radiation therapy are at increased risk for osteosarcoma [157]. Such risk is expected to decrease with the use of megavoltage therapy, which is not absorbed by bone as much as orthovoltage therapy is. Fifty percent of all osteosarcomas occur in the knee joint area; the proximal humerus is the next most common site, with 25% of the cases. The axial skeleton is rarely involved [154]. The most common presenting symptom is pain, with a firm, palpable, soft-tissue mass fixed to the underlying bone with slight tenderness. There is no erythema or effusion in the adjacent joint, and range of motion is normal. Fewer than 1% of patients will have a pathologic fracture. There are different types of osteosarcoma. Radiologically, the classic osteosarcoma may present as a lesion that can range from nearly normal to extremely dense or even involve complete destruction of the bone. In one series, purely lytic osteosarcoma was described in nearly 14% of patients [158]. Radiographically, purely lytic disease cannot be distinguished from a telangiectatic osteosarcoma, giant-cell tumor, aneurysmal bone cyst, or MFH of bone. The periosteal reaction classically described as “sunburst” is an important diagnostic feature; this is characteristically irregular and interrupted, which distinguishes malignancy from other benign conditions. A soft-tissue mass immediately adjacent to the bone lesion is usually present. Histologically, 75% of all osteosarcomas fall in the conventional category, which includes osteoblastic, chondroblastic, and fibroblastic subtypes. The survival rate is similar for all subtypes [159]. In patients treated with surgery alone, the size of the tumor, the age of the patient, and the degree of malignancy did not correlate with the survival rate [159]. The most significant variable was anatomic site; patients with pelvic and axial lesions had lower survival rates than patients with tumors of the extremities, probably because of incomplete resection in the former group. The preoperative serum alkaline phosphatase level has been reported as a significant prognostic factor of survival time [160]. Tumor ploidy also has been shown to be a significant prognostic factor. Disease-free survival and overall survival times are significantly longer in patients with near-diploid cell lines [161]. However, a recent review of the published data on prognostic factors in the postadjuvant-chemotherapy era assessed age, anatomic location, tumor size, and tumor necrosis following neoadjuvant chemotherapy; only tumor necrosis maintained its significance as a predictor of disease-free survival in multivariate models [162]. Treatment of Localized Disease: Prior to the 1970s, treatment of localized osteosarcoma consisted of amputation one joint above the tumor-containing bone or transmedullary amputation, with an overall survival rate of 5% to 20% at 2 years [163]. Pulmonary metastases usually occurred within 9 months and were responsible for the patient's death at 18 to 24 months after diagnosis [164]. The introduction of effective chemotherapeutic agents-high-dose methotrexate with leucovorin rescue [165], doxorubicin [166], cisplatin (Platinol)[167], and the alkylating agents ifosfamide [168] and high-dose cyclophosphamide (Cytoxan, Neosar)[169]-allowed a change in the approach to treatment of osteosarcomas. The beneficial role of adjuvant chemotherapy in patients with osteosarcoma is now proven. A large multi-institutional study showed a 2-year disease-free survival rate of 66% for patients treated with surgery and adjuvant postoperative chemotherapy vs a 2-year disease-free survival rate of less than 20% for patients treated with surgery alone [170]. Moreover, the introduction of neoadjuvant chemotherapy allowed more conservative limb-salvage surgery in 50% to 80% of patients without compromising a patient's chance of survival by delaying surgery [171]. Currently, limb-salvage surgery is preferred for a significant number of patients with osteosarcoma and other high-grade sarcomas. The risk of local recurrence (less than 5%) was shown to be the same or lower than that of patients treated with amputation in a carefully selected group of patients [172]. Contraindications for limb-salvage surgery include major neurovascular involvement, an inappropriate biopsy site, infection, a pathologic fracture with spread of tumor cells via hematoma, extensive muscle involvement, and immature skeletal age, especially for anticipated significant discrepancies in leg length. The latter is far less critical now with the development of expandable prostheses, but limb-sparing surgery is still usually not an option for children younger than 10 years old [173]. A number of trials have evaluated the role of chemotherapy administered either preoperatively or postoperatively. Most of the chemotherapeutic regimens included combinations of doxorubicin, high-dose methotrexate, cyclophosphamide, cisplatin, and ifosfamide. Relapse-free survival rates of 48% to 77% have been reported with different regimens. The effectiveness of high-dose methotrexate, however, has not been universally accepted. Response rates ranging from 0% and 80% have been reported [174-178]; a dose-response relationship has been proposed [179]. A study from the National Cancer Institute (NCI) evaluated the relationship of dose intensity to more than 90% tumor necrosis following neoadjuvant chemotherapy and suggested that large, highly concentrated doses of doxorubicin contribute to a favorable outcome in cases of Ewing's sarcoma and osteosarcoma. Cisplatin and high-dose methotrexate also revealed significant activity [180]. Doxorubicin and cisplatin-based adjuvant chemotherapy are now accepted as standard therapy for osteosarcoma in many institutions. The role of chemotherapy prior to surgery (neoadjuvant) vs its role postoperatively (adjuvant) has not yet been established in a randomized trial. The rationale for neoadjuvant chemotherapy has been to institute early systemic therapy against micrometastases, to increase the chances for successful limb-salvage surgery, to decrease the risk of viable tumor cells being spread at the time of surgery, and, very importantly, to tailor treatment individually according to the patient's response. Several systems have been proposed for grading the tumor response to neoadjuvant chemotherapy, all of which are based on the degree of cellularity and necrosis in the resected specimen [181,182]. Only grade 4 response, as determined by Huvos et al (absence of viable tumor within the entire specimen)[181], and more than 90% tumor necrosis, by the M.D. Anderson criteria [182], predicted continuous disease-free survival [183]. Both intra-arterial (IA) and intravenous (IV) chemotherapy have been administered preoperatively. A randomized trial using IA vs IV cisplatin combined with systemic doxorubicin and high-dose methotrexate showed a significantly higher histologic response (more than 90% tumor necrosis) in the group treated with IA cisplatin. No differences in the percentage of clinical/radiologic response or in the percentage of limb-salvage procedures performed were seen, and no differences in local or systemic side effects were observed [184]. IA cisplatin was compared with high-dose IV methotrexate at M.D. Anderson, and IA cisplatin was found to be more efficacious [185]. It should be noted that the IA technique requires excellent angiographic support facilities and experienced personnel to minimize complications. At the present time, preoperative chemotherapy is standard at M.D. Anderson, with four cycles of systemic doxorubicin administered as a continuous infusion followed by cisplatin, preferably given IA where feasible, followed by limb-salvage surgery and the tailoring of postoperative therapy based on the tumor's response. Therapy is switched to ifosfamide and high-dose methotrexate for patients with less than 90% tumor necrosis. Patients with more than 90% tumor necrosis receive another six cycles of doxorubicin, with dacarbazine replacing cisplatin due to dose-limiting peripheral neuropathy. Mature data from patients treated between 1980 and 1982 (cisplatin, 120 mg/m²) have shown that patients with complete responses at the time of surgery had a 5-year continuous disease-free survival rate of 86%, compared with 13% for patients with partial and/or poor responses [183,186]. Patients treated later with intensified cisplatin (160 mg/m²) showed a slight improvement in the overall survival rate, although this difference was not statistically significant. A significant improvement in the overall survival rate was observed for patients with less than 90% tumor necrosis (33%)[187]. Late relapses, although rare, can occur; 1 of 37 patients treated at M.D. Anderson between 1980 and 1982 had a recurrence of disease more than 6 years after surgery. Therefore, careful long-term follow-up and reports of mature data are very important. Recent studies [187a,187b] with muramyltripeptide phosphatidylethanolamine (MTP-PE), a synthetic, lipophilic analog of muramyldipeptide (MDP), the smallest component of a mycobacterium capable of stimulating the immune system, have shown that liposomes containing MTP-PE localize to the pulmonary microvasculature, resulting in activation of pulmonary macrophages. Animal studies revealed the efficacy of MTP-PE in canine osteosarcoma models [188]. A phase II study in humans documented histologic changes in the characteristics of the pulmonary nodules that recurred after treatment with MTP-PE [189]; peripheral fibrosis and inflammatory-cell infiltration with neovascularization were demonstrated as well as a change from high- to low-grade lesions after therapy. These changes indicated a potential role for MTP-PE in conjunction with surgery and chemotherapy in the treatment of osteosarcomas. A phase II trial of L-MTP-PE administered to patients with osteosarcoma who had pulmonary metastases that either developed during adjuvant chemotherapy or persisted despite chemotherapy showed a significant prolongation of disease-free survival in the patients who received treatment for 24 weeks [190]. Treatment of Metastatic Disease: Metastatic osteosarcoma is a treatable and potentially curable disease when combined modality therapy is administered. The most frequent sites of metastasis are the lungs. Whether pulmonary metastasis is present at diagnosis or occurs after the primary tumor is treated, if the lungs are the only sites of metastatic disease, it should be resected aggressively. A 5-year postthoracotomy survival rate of nearly 40% has been reported by Putnam et al [191], and similar results were reported by Skinner et al for patients treated with combined-modality therapy [192]. The number of nodules on preoperative lung tomograms, the disease-free interval, the resectability of the tumor, and the number of metastases resected at thoracotomy are prognostic factors influencing survival [191]. The completeness of the surgical resection is crucial to prolonged survival [193]. Variables such as preoperative chemotherapy vs immediate surgery, serum lactic dehydrogenase (LDH) level, alkaline phosphatase level, or the site of primary tumor did not affect the survival of patients who presented with metastatic disease [194]. Patients with unresectable metastatic disease have a poor prognosis. Ifosfamide (with mesna for urothelial protection), alone or in combination with etoposide, has shown activity in up to one third of patients with recurrent osteosarcoma [194,195]. XRT was used as primary therapy for osteosarcoma in the 1950s and early 1960s, without good results [196]. High doses of radiation were required to sterilize only a small subset of tumors and were associated with significant necrosis of normal tissue. Preoperative XRT did not offer any survival advantage either compared with surgery alone [197]. XRT has been used successfully in facial lesions; when followed by wide surgical excision, XRT promotes a 5-year survival rate of 73%, compared with 35% to 45% with surgery alone [198]. For palliation of metastatic bone sarcomas and unresectable lesions in axial sites or the pelvis, XRT is useful, especially when combined with IA or IV radiosensitizers (5-bromodeoxyuridine or idoxuridine) [199,200]. Variants of Osteosarcoma Parosteal and periosteal osteosarcomas are the most common variants of osteosarcoma. Parosteal osteosarcoma accounts for 4% of all osteosarcomas [201]. It usually occurs in older people, with a slightly higher incidence in women. The distal femur is involved in 75% of cases. Parosteal osteosarcoma arises from the cortex of bone. It presents as a mass that is occasionally associated with pain and grows slowly over months or years with late metastases. Overall survival rates range between 75% and 85% [201,202]. Radiographically, parosteal osteosarcoma is characterized by a large, dense, lobulated mass broadly attached to the underlying bone without involvement of the medullary canal. However, such involvement can be present without being radiographically apparent. Parosteal osteosarcoma is treated surgically with wide excision alone. Dedifferentiated parosteal osteosarcoma and high-grade surface osteosarcoma have a much poorer prognosis and are treated with chemotherapy and surgery. Periosteal osteosarcoma originates in the cortex, usually of the tibial shaft. A characteristic, small, radiolucent lesion, evidence of bone spicules on a plain radiograph, and a Codman's triangle are hallmarks of this disease [203]. Pathologically, periosteal osteosarcoma is usually a high-grade chondroblastic osteosarcoma. Treatment recommendations follow the same concepts as those for high-grade classic osteosarcoma. Chondrosarcoma of Bone Chondrosarcoma is the second most common primary malignant spindle-cell tumor of the bone, characterized by cartilaginous neoplastic tissue without direct osteoid formation. Occasionally, bone formation occurs from differentiated cartilage. There are five types of chondrosarcoma: central (arising within the bone), peripheral (arising from the bone surface), mesenchymal, dedifferentiated, and clear cell [204]. The most common variants are central and peripheral chondrosarcomas, which may arise as primary tumors or may be secondary to underlying benign neoplasms (multiple osteochondromas or enchondromas)[205-207]. Chondrosarcomas usually present in patients older than 40 years of age. The most common sites are the pelvis (30%), femur (20%), and shoulder girdle (15%). Chondrosarcomas usually reach a significant size before symptoms, such as a palpable mass with pain or pressure and occasionally urinary symptoms (sometimes noted with pelvic tumors), are noted. Chondrosarcomas are pathologically classified as grade I to grade III tumors. High-grade (grade III) tumors have the worst prognosis, with a risk of metastasis of 75% [208]. Surgical removal of the tumor is the treatment for chondrosarcoma. There is no effective chemotherapy for the central and peripheral types of the disease. Dedifferentiated chondrosarcoma, on the other hand, does respond to standard chemotherapy used against osteosarcoma, and such treatment should be employed. Few reports document the efficacy of XRT in chondrosarcomas [209-211]. Five-year local control rates ranged between 45% and 82% and were directly related to the histology of the tumor. A review of a 15-year XRT experience with chondrosarcoma of bone at M.D. Anderson revealed that none of the four patients treated with a combination of neutron- and photon-beam XRT had disease recurrence locally [211]. One of the seven patients treated with conventional radiotherapy alone experienced local disease recurrence, suggesting a benefit from the mixed-beam technique [211]. Clear-cell chondrosarcoma is the rarest type. This tumor grows slowly and locally recurs with some malignant potential. It is often confused with chondroblastoma. Treatment is wide surgical excision; systemic therapy is not required, and metastases occur only after multiple local recurrences [212]. Mesenchymal chondrosarcoma is a rare, aggressive tumor that affects younger patients. It shows a predilection for flat bones and has high metastatic potential. Treatment is wide surgical excision with adjuvant chemotherapy. XRT is used when the tumor cannot be completely excised [213,214]. Malignant Fibrous Histiocytoma of Bone MFH is a high-grade tumor in bone as well as in soft tissues. It usually occurs during adulthood and commonly involves the metaphyseal ends of long bones, especially those of the knee joint [215]. MFH presents as a lytic, metaphyseal lesion with marked cortical disruption, minimal cortical or periosteal reaction, and no evidence of bone formation. Pathologic fractures are common [216]. The patient's alkaline phosphatase level is normal. MFH of bone disseminates rapidly to lung tissue, and lymph-node metastases have been reported in up to one third of cases with lung metastases [217]. Although data are limited, it seems that MFH of bone is sensitive to chemotherapy [218-220]. In one study, patients treated with surgery and chemotherapy had a disease-free survival rate of 59%, compared with only 5% of patients treated with surgery alone [218]. In a recently updated study, 7 of 15 patients with MFH of bone treated with neoadjuvant chemotherapy at M.D. Anderson showed more than 90% tumor necrosis. The median continuous disease-free survival for patients who achieved more than 90% tumor necrosis was 43 months, compared with only 7 months for patients with less than 90% tumor necrosis (P < .05). A trend for better overall survival was documented (66 months vs 20 months, respectively), although it was not statistically significant [221]. MFH of bone should be treated as is osteosarcoma, with chemotherapy and surgery. Ewing's Sarcoma Ewing's sarcoma (ES) is a rare tumor that usually occurs in bone and presents most frequently during the second decade of life; it is an unusual occurrence before 5 or after 30 years of age. In patients up to 13 years old, ES occurs with equal frequency in girls and boys; after age 13, the disease is more common in males. ES is extremely rare in African and American blacks and Chinese populations but constitutes 12% of malignant primary tumors of bone in white persons. It was originally thought to arise from endothelial cells [222], but mesenchymal, myeloid, reticular, pericystic, neuroepithelial, and primitive multipotential cells have been suspected to be the cells of origin [223]. The most widely accepted belief is that ES is of neuroectodermal origin [224]. ES is an undifferentiated, small, round-cell tumor that may be confused with other small, round, blue-cell tumors of childhood, among them small-cell osteosarcoma, mesenchymal and myxoid chondrosarcoma, rhabdomyosarcoma, lymphoma, neuroblastoma, and peripheral neuroepithelioma. A careful review of light microscopy studies by an experienced pathologist is extremely important for the diagnosis of ES. Morphologic features may be indistinguishable from those of the peripheral primitive neuroectodermal tumors (pPNETs). Immunocytochemical staining is often positive for neuron-specific enolase (NSE)[225], although others believe that NSE is specific for pPNET and might be used to distinguish between the two entities [226]. The monoclonal antibody 5C11 has been reported to react exclusively with ES and not with pPNET [227], whereas expression of the MIC2 gene has been reported in both entities [228]. Electron microscopy studies may also assist the diagnosis, revealing dense core granules, neurites, neurotubules, and neurofilaments in prominent Golgi's complexes [229]. A chromosomal translocation t(11;22)(q24;q12) is a characteristic abnormality of ES [230,231], but it has also been reported in pPNET [232]. ES is associated with skeletal abnormalities (such as enchondroma and aneurysmal bone cyst) and genitourinary anomalies (hypospadias and duplicate collecting system). Clinical Presentation, Prognostic Factors, and Staging: ES can affect any bone, although it most commonly presents in the femur and pelvis. The axial skeleton is often involved. In the long bones, ES usually localizes in the diaphysis, with frequent extension through the bone cortex into the soft tissues. It presents as a rapidly enlarging mass causing poorly localized pain. Constitutional symptoms, such as fatigue, weight loss, and fever, may be present, especially in metastatic disease. Leukocytosis and an elevated erythrocyte sedimentation rate (ESR) may mimic osteomyelitis. Metastases are present at the time of initial diagnosis in 15% to 50% of cases. The lungs are the most common sites of metastasis at presentation or relapse, followed by bone and bone-marrow sites. Metastases to the central nervous system occur in fewer than 1% of patients [222]. Diagnostic and staging evaluations should include plain radiographs of the involved area and the lungs, CT or MRI scans of the primary tumor, a CT scan of the lungs, a bone scan, and bone-marrow biopsy and aspirate studies. There is no uniformly accepted staging system for ES, but a TNM system seems appropriate. Lymph-node (N) involvement is rare. Central location of the tumor, systemic symptoms at diagnosis, elevated pretreatment LDH levels [233], the presence of a gross extraosseous extension of the primary tumor [234], metastatic disease at diagnosis [235], and less-than-complete response to preoperative chemotherapy [236] are poor prognostic factors. Treatment: ES is considered a systemic disease; even when a tumor is apparently localized, approximately 90% of the cases include occult metastatic disease. Before treatment with chemotherapy was available, local control was achieved in 50% to 85% of patients by means of surgery or radiation doses of more than 40 Gy to 50 Gy. However, only 10% of these patients survived for 5 years. Death was usually caused by distant metastatic disease [237,238]. Because XRT can establish good local control of Ewing's sarcoma [222], the role of surgery has historically been limited to diagnostic biopsy and primary control of an expendable bone, such as a rib or clavicle [239]. Surgery can also be used to treat the primary tumor when XRT would jeopardize function. However, the higher rate of local control achieved with surgery or surgery plus XRT, compared with XRT alone [240], and the desire for prevention of long-term side effects of XRT (growth failure, normal tissue damage, and development of second malignancies [241,242]) may broaden the indications for surgery. The advent of chemotherapy significantly improved the disease-free survival rate (50% to 60%) at 2 to 3 years, compared with such rates when XRT or surgery was used alone [243-249]. The most active single agents are cyclophosphamide (50%)[250], doxorubicin (40%) [251], vincristine (Oncovin, 30%)[252], dactinomycin (33%), etoposide (30%), and high-dose melphalan (Alkeran, 80%)[253]. Adjuvant chemotherapy is now accepted as standard therapy for ES. The combination of vincristine, dactinomycin, and cyclophosphamide has been evaluated alone or with doxorubicin or bilateral pulmonary XRT in a large intergroup study [254]. According to this study, the addition of doxorubicin significantly improved relapse-free survival and overall survival. A dose-intensity relationship exists between doxorubicin and ES [180]. A high-dose, intermittent method of chemotherapy delivery using the four drugs listed yielded significantly better disease-free survival (68%) and overall survival (77%) rates than a moderate-dose, continuous method (48% and 53%, respectively)[255]. The high-dose, intermittent schedule also improved the relapse-free survival and overall survival rates of patients with ES of the pelvic or sacral bones, a group with a generally poor outcome [256]. The combination of ifosfamide and etoposide has also shown activity in newly diagnosed [257] and previously treated [258] cases of ES, with response rates of 96% and 50% to 60%, respectively. Longer follow-up is needed to assess the duration of these responses and their effect on survival rates. The prognosis for patients with recurrent or metastatic disease is poor. Combination chemotherapy using doxorubicin, vincristine, cyclophosphamide, and dactinomycin has been the basis of treatment. Methotrexate, bleomycin (Blenoxane), and fluorouracil have been incorporated into some protocols [244,259-261], with 5-year survival rates in the 30% range. XRT to the sites of metastatic disease (bone or soft tissue) in a dose of 45 to 50 Gy can be considered for palliation. 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