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Sarcoma of Soft Tissue and Bone
Written by , Shreyaskumar R. Patel, Robert S. Benjamin Craig's Doctors at MDACC

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Sarcomas Of Soft Tissue And Bone

Shreyaskumar R. Patel, Robert S. Benjamin

[Copyright © 1998, 1999, 2000 by The McGraw-Hill Companies, Inc. Reproduced with permission of The McGraw-Hill Companies.]


Sarcomas are rare mesenchymal neoplasms that arise in bone and soft tissues. They constitute less than 1 percent of all malignancies. Most of these tumors are mesodermal in origin, although a few are derived from neuroectoderm, and they are biologically distinct from the more common epithelial malignancies. Sarcomas affect all age groups; 15 percent are found in children younger than age 15, and 40 percent occur after age 55. Sarcomas are one of the most common solid tumors of childhood and are the fifth most common cause of cancer deaths in children. Sarcomas may be divided into two groups, those derived from bone and those derived from soft tissues.

Soft Tissue Sarcomas

Soft tissues include muscles, tendons, fat, fibrous tissue, synovial tissue, vessels, and nerves. Approximately 60 percent of soft-tissue sarcomas arise in the extremities, with the lower extremities involved three times as often as the upper extremities. Thirty percent arise in the trunk, the retroperitoneum accounting for 40 percent of all trunk lesions. The remaining 10 percent arise in the head and neck.


Approximately 6400 new cases of soft tissue sarcomas occurred in the United States in 1996. The annual age-adjusted incidence is approximately 2 per 100,000 population, but the incidence varies with age and with the types of neoplasms included in the definition. Soft tissue sarcomas constitute 0.7 percent of all cancers in the general population and 6.5 percent of all malignancies in children.


Malignant transformation of a benign soft tissue tumor is extremely rare, with the exception that malignant peripheral nerve sheath tumors (neurofibrosarcoma, malignant schwannoma) can arise from neurofibromas in patients with neurofibromatosis. Several etiologic factors have been implicated in the pathogenesis of soft tissue sarcomas.

Environmental Factors Trauma or previous injury is rarely involved, but sarcomas can arise in scar tissue resulting from a prior operation, burn, fracture, or foreign body implantation. Chemical carcinogens such as polycyclic hydrocarbons, asbestos, and dioxin may be involved in the pathogenesis.

Iatrogenic Factors Sarcomas in bone or soft tissues occur in cancer patients who are treated with radiation and survive at least 5 years. The tumor nearly always arises in the irradiated field. The risk increases with time.

Viruses The association of Kaposi's sarcoma (KS) with human immunodeficiency virus (HIV) type 1 has led to studies of the role of viruses in the pathogenesis of KS. Herpesvirus-like DNA sequences have been documented in AIDS-associated KS, classic KS, and KS in HIV-negative homosexual men, leading to the hypothesis that this new herpes virus [human herpes virus (HHV8)] may be the common etiologic factor for all three variants of KS.

Immunologic Factors Congenital or acquired immunodeficiency, including therapeutic immunosuppression, is associated with or influences sarcoma development.

Genetic Factors Li-Fraumeni syndrome is a familial cancer syndrome in which affected individuals have germ-line abnormalities of the tumor suppressor gene p53 and an increased incidence of soft tissue sarcomas and other malignancies, including breast cancer, osteosarcoma, brain tumors, leukemia, and adrenal carcinoma (Chap. 84). Neurofibromatosis 1 (NF-1, peripheral form, von Recklinghausen's disease) is characterized by multiple neurofibromas and café au lait spots. Neurofibromas occasionally undergo malignant degeneration to become malignant peripheral nerve sheath tumors. The gene for NF-1 is located in the pericentromeric region of chromosome 17 and encodes neurofibromin, a tumor suppressor protein with GTPase-activating activity that inhibits Ras function (Chap. 375). Germ-line mutation of the Rb-1 locus (chromosome 13q14) in patients with inherited retinoblastoma is associated with the development of osteosarcoma in those who survive the retinoblastoma and of soft tissue sarcomas unrelated to radiation therapy. Other soft tissue tumors, including desmoid tumors, lipomas, leiomyomas, neuroblastomas, and paragangliomas, occasionally show a familial predisposition.

Insulin-like growth factor (IGF) type 2 is produced by some sarcomas and is thought to act both as an autocrine growth factor and as a motility factor that promotes metastatic spread. Antibodies to IGF-1 receptors block the stimulation of growth by IGF-2 in vitro but do not affect IGF-2-induced motility. If secreted in large amounts, IGF-2 may produce hypoglycemia (see Chaps. 102 and 335).


Approximately 20 different types of sarcomas are recognized on the basis of the pattern of differentiation toward normal tissue. For example, rhabdomyosarcoma shows evidence of skeletal muscle fibers with cross-striations; leiomyosarcomas contain interlacing fascicles of spindle cells representing smooth muscle features; liposarcomas contain adipocytes; and angiosarcomas contain a rich network of blood vessels. When precise characterization of the type is not possible, the tumors are called unclassified sarcomas. All of the primary bone sarcomas also can arise from soft tissues (e.g., extraskeletal osteosarcoma, extraskeletal Ewing's sarcoma, and extraskeletal chondrosarcoma). The entity malignant fibrous histiocytoma includes a large number of tumors previously classified as fibrosarcomas or as pleiomorphic variants of other sarcomas and is characterized by a mixture of spindle (fibrous) cells and round (histiocytic) cells arranged in a storiform pattern with frequent giant cells and areas of pleiomorphism.

For purposes of treatment, most soft tissue sarcomas can be lumped together, with the choice of treatment depending mainly on the stage of disease. However, some aspects of the natural history require that specific histologic diagnoses be considered in planning treatment and follow-up. For example, the term liposarcoma indicates histogenesis from adipose tissue but gives no indication of biologic behavior. Pleiomorphic liposarcomas and dedifferentiated liposarcomas behave like other high-grade sarcomas; in contrast, well-differentiated liposarcomas (better termed atypical lipomatous tumors) lack metastatic potential, and myxoid liposarcomas metastasize infrequently but, when they do, have a predilection for unusual metastatic sites containing fat, such as the retroperitoneum, mediastinum, and subcutaneous tissue. Rhabdomyosarcomas, Ewing's sarcoma, and other small cell sarcomas tend to be more aggressive, even when small, and are more responsive to chemotherapeutic agents than the more typical soft tissue sarcomas.


The most common presentation is an asymptomatic mass. Mechanical symptoms referable to pressure, traction, or entrapment of nerves or muscles may be present, especially with large tumors. All new and persistent or growing masses should be biopsied, either by a cutting needle (core-needle biopsy) or preferably by a small incision, placed so that it can be encompassed in the subsequent excision without compromising a definitive resection. Sarcomas tend to metastasize through the blood rather than the lymphatic system. Consequently, the incidence of lymph node metastases is low (5 percent) for most of these tumors, although it is higher (17 percent) for certain tumors--e.g., synovial and epithelioid sarcomas, clear-cell sarcoma (melanoma of the soft parts), angiosarcoma, and rhabdomyosarcoma. The pulmonary parenchyma is the most common site of metastases in the vast majority of sarcomas. Exceptions are leiomyosarcomas arising in the gastrointestinal tract, which metastasize to the liver; myxoid liposarcomas, which seek fatty tissue: and clear-cell sarcomas, which may metastasize to bones. Central nervous system metastases are rare, except in the case of alveolar soft tissue sarcoma.

Radiographic Evaluation Imaging of the primary tumor is best accomplished by plain radiographs and magnetic resonance imaging (MRI) for tumors of the extremities or head and neck and by computed tomography (CT) for tumors of the chest, abdomen, or retroperitoneal cavity. A radiograph and CT scan of the chest are important for the detection of lung metastases. Other imaging studies may be indicated, depending on the symptoms, signs, or histology.

Staging Systems

The histologic grade and size of the primary tumor are the most important prognostic factors. Tumors are staged according to two systems, the American Joint Commission on Cancer (AJCC) staging system and the Musculoskeletal Tumor Society staging system.

Ajcc Staging System The primary determinant of stage is tumor histologic grade. Grade 1 (well-differentiated) tumors are stage I; grade 2 (moderately well differentiated) tumors are stage II; and grade 3 (poorly differentiated) tumors are stage III. These stage designations are qualified further on the basis of tumor size as either A (tumor diameter <5 cm) or B (tumor diameter 5 cm). Tumors with lymph node metastases are stage IVA, and those with distant metastases are stage IVB.

Musculoskeletal Tumor Society Staging System This system is based on grade and compartmental localization. A Roman numeral reflects the tumor grade: stage I is low-grade, stage II is high-grade, and stage III includes tumors of any grade that have lymph node or distant metastases. In addition, the tumor is given a letter reflecting its compartmental localization. Tumors designated A are intracompartmental (i.e., confined to the same soft tissue compartment as the initial tumor), and tumors designated B are extracompartmental (i.e. extending into the adjacent soft tissue compartment or into bone). Thus, a stage IA tumor is a low-grade tumor confined to its compartment of origin, whereas a stage IB tumor is a low-grade tumor that extends outside its original compartment.


Prognosis is related to the stage, with 5-year survival rates averaging 75 percent for AJCC stage I, 55 percent for stage II, and 29 percent for stage III. The 5-year survival rate for stage IV disease is <20 percent, but a small number of patients in this category can be cured. Most patients with stage IV disease die within 6-12 months, but there is great variability in survival, and patients may live with slowly progressive disease for many years.


Surgery Soft tissue sarcomas tend to grow along fascial planes in the path of least resistance. As a result, the surrounding soft tissues are compressed to form a pseudocapsule that gives the sarcoma the appearance of a well-encapsulated lesion. This is invariably deceptive, because "shelling out" or marginal excision of such lesions results in a 50 to 90 percent probability of local recurrence. Radical excision with a negative margin, incorporating the biopsy site, is the standard surgical procedure for local disease. The adjuvant use of radiation therapy and/or chemotherapy improves the local control rate and permits the use of limb-sparing surgery with a local control rate comparable to that achieved by radical excisions and amputations. The National Institutes of Health consensus conference in 1984 recommended limb-sparing surgery in conjunction with adjuvant irradiation and/or chemotherapy as effective therapy for local control except when negative margins are not obtainable, when the risks of radiation are prohibitive, or when neurovascular structures are involved so that resection will result in serious functional consequences to the limb. When appropriately performed, conservative limb-sparing procedures result in local failure rates of only 10 to 15 percent.

Radiation Therapy External beam radiation therapy is an adjuvant to limb-sparing surgery for improved local control. Preoperative administration of radiation therapy allows the use of smaller fields and smaller doses but results in a higher rate of wound complications. When radiation therapy is given postoperatively, the field of radiation must be larger, as the entire surgical bed must be encompassed, and the dose must be higher to compensate for hypoxia in the operated field. Brachytherapy or interstitial therapy, in which the radiation source is inserted into the tumor bed, is thought to be comparable in efficacy and also less time consuming and less expensive. Intraoperative irradiation has not been studied thoroughly.

Adjuvant Chemotherapy The role of adjuvant chemotherapy is controversial except for Ewing's sarcoma and rhabdomyosarcoma, where it is standard. Doxorubicin-based combination chemotherapy improves disease-free survival but has less effect on overall survival. Nevertheless, meta-analysis indicates that there is a significant decrease in the risk of disease recurrence (either local or distant) and death for patients with high-grade extremity sarcomas who are treated with adjuvant chemotherapy. This approach is considered reasonable for high-risk primary tumors. An alternative approach is to treat such patients preoperatively with chemotherapy; the subset of patients who respond continue adjuvant therapy postoperatively, and the nonresponders can be spared the toxicity of systemic therapy to which they are unlikely to respond. Neither strategy has been proved superior.

Advanced Disease Metastatic soft tissue sarcomas are largely incurable, but up to 20 percent of patients who are rendered free of clinical evidence of disease become long-term survivors. The therapeutic intent, therefore, is to produce a complete remission with chemotherapy and/or surgery. Surgical resection of metastases, whenever possible, is an integral part of the management. Some patients benefit from repeated surgical excision of metastases. Despite their histologic heterogeneity, the sensitivity to chemotherapy of most soft tissue sarcomas is poor. The two most active chemotherapeutic agents are doxorubicin and ifosfamide, an analogue of cyclophosphamide. There is a steep dose-response relationship for these drugs in sarcomas. Dacarbazine (DTIC) has modest activity as a single agent but has better activity in combination with doxorubicin. Vincristine, etoposide, and dactinomycin are effective in Ewing's sarcoma and rhabdomyosarcoma, especially in children. Chondrosarcomas and leiomyosarcomas arising from the gastrointestinal tract are unresponsive to standard chemotherapeutic drugs.

Dose-intensive regimens (i.e., ones involving higher and more frequent doses) of doxorubicin and ifosfamide-based combinations, with growth factor support to ameliorate myelosuppression, may improve the rates of complete and partial response. Myeloablative doses of chemotherapy in combination with bone marrow transplantation have not been successful.

Incidence And Epidemiology

Bone sarcomas are rarer than soft tissue sarcomas; they accounted for only 0.2 percent of all new malignancies and approximately 2500 new cases in the United States in 1996. Several benign bone lesions have the potential for malignant transformation. Enchondromas and osteochondromas can transform into chondrosarcoma; and fibrous dysplasia, bone infarcts, and Paget's disease of bone can transform into either malignant fibrous histiocytoma or osteosarcoma.


Benign Tumors The common benign bone tumors include enchondroma, osteochondroma, chondroblastoma, and chondromyxoid fibroma, all of cartilaginous origin; osteoid osteoma and osteoblastoma, of bone origin; fibroma and desmoplastic fibroma, of fibrous tissue origin; hemangioma, of vascular origin; and giant cell tumor, of unknown origin.

Malignant Tumors The most common malignant tumors of bone are plasma cell tumors (see Chap. 114). The four most common malignant tumors of nonhematopoietic origin are osteosarcoma, chondrosarcoma, Ewing's sarcoma, and malignant fibrous histiocytoma. Rare malignant tumors include chordoma (of notochordal origin), malignant giant cell tumor and adamantinoma (of unknown origin), and hemangioendothelioma (of vascular origin). Sarcomas of bone are staged according to the Musculoskeletal Tumor Society staging system outlined above.


Osteosarcoma, accounting for almost 45 percent of all bone sarcomas, is a spindle cell neoplasm that produces osteoid (unmineralized bone) or bone. About 60 percent of all osteosarcomas occur in children and adolescents in the second decade of life, and about 10 percent occur in the third decade of life. Osteosarcomas in the fifth and sixth decades of life are frequently secondary to either radiation therapy or transformation in a preexisting benign condition, such as Paget's disease. Males are affected 1.5 to 2 times as often as females. Osteosarcoma has a predilection for metaphyses of long bones, and the most common sites of involvement are the distal femur, proximal tibia, and proximal humerus. The classification of osteosarcoma is complex, but 75 percent of osteosarcomas fall in the "conventional or classic" category, which include osteoblastic, chondroblastic, and fibroblastic osteosarcomas. The remaining 25 percent are classified as "variants" on the basis of (1) clinical characteristics, as in the case of osteosarcoma of the jaw, postradiation osteosarcoma, or Paget's osteosarcoma; (2) morphologic characteristics, as in the case of telangiectatic osteosarcoma, small cell osteosarcoma, or malignant fibrous histiocytoma; or (3) location, as in parosteal or periosteal osteosarcoma. Diagnosis usually requires a synthesis of clinical, radiologic, and pathologic features. Patients typically present with pain and swelling of the affected area. A plain radiograph reveals a destructive lesion with a moth-eaten appearance, a spiculated periosteal reaction (sunburst appearance), and a cuff of periosteal new bone formation at the margin of the soft tissue mass (Codman's triangle). A CT scan of the primary tumor is best for defining bone destruction and the pattern of calcification, whereas MRI is better for defining intramedullary and soft tissue extension. A chest radiograph and CT scan are used to detect lung metastases. Metastases to the bony skeleton should be imaged by a bone scan. Almost all osteosarcomas are hypervascular. Angiography is not helpful for diagnosis, but it is the most sensitive test for assessing the response to preoperative chemotherapy. Pathologic diagnosis is established either with a core-needle biopsy, where feasible, or with an open biopsy with an appropriately placed incision that does not compromise future limb-sparing resection. Most osteosarcomas are high-grade. The most important prognostic factor for long-term survival is response to chemotherapy. The 2-year survival of historical controls treated with surgery alone is <20 percent. The efficacy of adjuvant chemotherapy is better defined in osteosarcoma than in soft tissue sarcoma. Prospective, randomized trials have shown that adjuvant chemotherapy improves survival. The current state of the art, therefore, is preoperative chemotherapy followed by limb-sparing surgery (which can be accomplished in >80 percent of patients) followed by postoperative chemotherapy. The effective drugs are doxorubicin, ifosfamide, cisplatin, and high-dose methotrexate with leucovorin rescue. The various combinations of these agents that have been used have all been about equally successful. With the current management strategy, long-term survival rates in extremity osteosarcoma range from 60 to 70 percent. Osteosarcoma is radioresistant; radiation therapy has no role in the routine management. Malignant fibrous histiocytoma is considered a part of the spectrum of osteosarcoma and is managed similarly.


Chondrosarcoma, which constitutes approximately 20 to 25 percent of all bone sarcomas, is a tumor of adulthood and old age with a peak incidence in the fourth to sixth decades of life. It has a predilection for the flat bones, especially the shoulder and pelvic girdles, but can also affect the diaphyseal portions of long bones. Chondrosarcomas can arise de novo or as a malignant transformation of an enchondroma or, rarely, of the cartilaginous cap of an osteochondroma. Chondrosarcomas have an indolent natural history and typically present as pain and swelling. Radiographically, the lesion may have a lobular appearance with mottled or punctate or annular calcification of the cartilaginous matrix. It is difficult to distinguish low-grade chondrosarcoma from benign lesions by x-ray or histologic examination. The diagnosis is therefore influenced by clinical history and physical examination. A new onset of pain, signs of inflammation, and progressive increase in the size of the mass suggest malignancy. The histologic classification is complex, but most tumors fall within the conventional or classic category. Like other bone sarcomas, high-grade chondrosarcomas spread to the lungs. Most chondrosarcomas are resistant to standard sarcoma chemotherapy, and surgical resection of primary or recurrent tumors, including pulmonary metastases, is the mainstay of therapy. There are two histologic variants for which this rule does not hold, however. Dedifferentiated chondrosarcoma is a low-grade tumor that dedifferentiates into a high-grade osteosarcoma or a malignant fibrous histiocytoma, a tumor that responds to chemotherapy. Mesenchymal chondrosarcoma, a rare variant composed of a small-cell element, also is responsive to systemic chemotherapy and is treated like Ewing's sarcoma.

Ewing's Sarcoma

Ewing's sarcoma, which constitutes approximately 10 to 15 percent of all bone sarcomas, is common in adolescence and has a peak incidence in the second decade of life. It typically involves the diaphyseal region of long bones and also has an affinity for flat bones. The plain radiograph may show a characteristic "onion-peel" periosteal reaction with a generous soft tissue mass, which is better demonstrated by CT or MRI. This mass is composed of sheets of monotonous, small, round, blue cells and can be confused with lymphoma, embryonal rhabdomyosarcoma, and small cell carcinoma. The presence of p30/32, the product of the mic-2 gene (which maps to the pseudoautosomal region of the X and Y chromosomes) is a cell-surface marker for Ewing's sarcoma [and other members of a family of tumors called peripheral primitive neuroectodermal tumors (PNETs)]. Most PNETs arise in soft tissues; they include peripheral neuroepithelioma, Askin's tumor (chest wall), and esthesioneuroblastoma. Glycogen-filled cytoplasm detected by immunohistochemical staining with periodic acid-Schiff is also characteristic of Ewing's sarcoma cells. The classic cytogenetic abnormality associated with this disease (and other PNETs) is a reciprocal translocation of the long arms of chromosomes 11 and 22, t(11;22), which creates a chimeric gene product of unknown function with components from the fli-1 gene on chromosome 11 and ews on 22. This disease is very aggressive, and it is therefore considered a systemic disease. Common sites of metastases are lung, bones, and bone marrow. Systemic chemotherapy is the mainstay of therapy, often being used before surgery. Several chemotherapeutic drugs are active, including doxorubicin, cyclophosphamide or ifosfamide, etoposide, vincristine, and dactinomycin. Local treatment for the primary tumor includes surgical resection, usually with limb salvage or radiation therapy. Patients with lesions below the elbow and below the mid-calf have a 5-year survival of 80 percent with effective treatment. Ewing's sarcoma is a curable tumor, even in the presence of obvious metastatic disease, especially in children less than 11 years old. High-dose chemotherapy with hematopoietic support can cure a substantial fraction of patients with metastatic disease.

Tumors Metastatic to Bone

Bone is a common site of metastasis for carcinomas of the prostate, breast, lung, kidney, bladder, and thyroid and for lymphomas and sarcomas. Prostate, breast and lung primaries account for 80 percent of all bone metastases. Metastatic tumors of bone are more common than primary bone tumors. Tumors usually spread to bone hematogenously, but local invasion from soft tissue masses also occurs. In descending order of frequency, the sites most often involved are the vertebrae, proximal femur, pelvis, ribs, sternum, proximal humerus, and skull. Bone metastases may be asymptomatic or may produce pain, swelling, symptoms of encroachment on a nerve root or the spinal cord, pathologic fracture, or myelophthisis (replacement of the marrow). Symptoms of hypercalcemia may be noted in cases of bony destruction.

Pain is the most frequent symptom. It usually develops gradually over weeks, is usually localized, and often is more severe at night. When patients with back pain develop neurologic signs or symptoms, emergency evaluation for spinal cord compression is indicated (see Chap. 104). Bone metastases exert a major adverse effect on quality of life in cancer patients.

Cancer in the bone may produce osteolysis, osteogenesis, or both. Osteolytic lesions result when the tumor produces substances that can directly elicit bone resorption (vitamin D-like steroids, prostaglandins, or parathyroid hormone-related peptide) or cytokines that can induce the formation of osteoclasts (interleukin 1 and tumor necrosis factor). Osteoblastic lesions result when the tumor produces cytokines that activate osteoblasts. In general, purely osteolytic lesions are best detected by plain radiography, but they may not be apparent until they are larger than 1 cm. These lesions are more commonly associated with hypercalcemia and with the excretion of hydroxyproline-containing peptides indicative of matrix destruction. When osteoblastic activity is prominent, the lesions may be readily detected using radionuclide bone scanning (which is sensitive to new bone formation), and the radiographic appearance may show increased bone density or sclerosis. Osteoblastic lesions are associated with higher serum levels of alkaline phosphatase, and, if extensive, may produce hypocalcemia. Although some tumors may produce mainly osteolytic lesions (e.g., kidney cancer) and others mainly osteoblastic lesions (e.g., prostate cancer), most metastatic lesions produce both types of lesion and may go through stages where one or the other predominates.

In older patients, particularly women, it may be necessary to distinguish metastatic disease of the spine from osteoporosis. In osteoporosis, the cortical bone may be preserved, whereas cortical bone destruction is usually noted with metastatic cancer.

Treatment of metastatic bone disease depends on the underlying malignancy and the symptoms. Some metastatic bone tumors are curable (lymphoma, Hodgkin's disease), and others are treated with palliative intent. Pain may be relieved by local radiation therapy. Hormonally responsive tumors are responsive to hormone inhibition (antiandrogens for prostate cancer, antiestrogens for breast cancer). Strontium 89 is a bone-seeking radionuclide that can exert antitumor effects and relieve symptoms. Bisphosphonates such as pamidronate may relieve pain and inhibit bone resorption. When the integrity of a weight-bearing bone is threatened by an expanding metastatic lesion that is refractory to radiation therapy, prophylactic internal fixation is indicated. Overall survival is related to the prognosis of the underlying tumor. Bone pain at the end of life is particularly common; an adequate pain relief regimen including sufficient amounts of narcotic analgesics is required. The management of hypercalcemia is discussed in Chap. 354.


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New Bibliographic References

  1. Fizazi K et al: Ewing's family of tumors in adults: Multivariate analysis of survival and long-term results of multimodality therapy in 182 patients. J Clin Oncol 16:3736, 1998 [PMID 9850016]
  2. Kawai A et al: SYT-SSX gene fusion as a determinant of morphology and prognosis in synovial sarcoma. N Engl J Med 338:153, 1998 [PMID 9428816]
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