Chapter 47: Soft Tissue and Bone Sarcomas and Bone Metastases

Sarcomas are rare (<1% of all malignancies) mesenchymal neoplasms that arise in bone and soft tissues. These tumors are usually of mesodermal 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% are found in children <15 years of age, and 40% occur after age 55 years. 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 tissues include muscles, tendons, fat, fibrous tissue, synovial tissue, vessels, and nerves. Approximately 60% 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% of all trunk lesions. The remaining 10% arise in the head and neck.

INCIDENCE

Approximately 11,410 new cases of soft tissue sarcomas occurred in the United States in 2013. The annual age-adjusted incidence is 3 per 100,000 population, but the incidence varies with age. Soft tissue sarcomas constitute 0.7% of all cancers in the general population and 6.5% of all cancers in children.

EPIDEMIOLOGY

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 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 patients who are treated with radiation therapy. The tumor nearly always arises in the irradiated field. The risk increases with time.

Viruses

Kaposi’s sarcoma (KS) in patients with HIV type 1, classic KS, and KS in HIV-negative homosexual men is caused by human herpesvirus (HHV) 8. No other sarcomas are associated with viruses.

Immunologic factors

Congenital or acquired immunodeficiency, including therapeutic immunosuppression, increases the risk of ­sarcoma.

GENETIC CONSIDERATIONS

Li-Fraumeni syndrome is a familial cancer syndrome in which affected individuals have germline abnormalities of the tumor-suppressor gene p53 and an increased incidence of soft tissue sarcomas and other malignancies, including breast cancer, osteosarcoma, brain tumor, leukemia, and adrenal carcinoma (Chap. 25). 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 guanosine 5′-triphosphate (GTP)ase-activating activity that inhibits Ras function (Chap. 48). Germline 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.

Ninety percent of synovial sarcomas contain a characteristic chromosomal translocation t(X;18)(p11;q11) involving a nuclear transcription factor on chromosome 18 called SYT and two breakpoints on X. Patients with translocations to the second X breakpoint (SSX2) may have longer survival than those with translocations involving SSX1.

Insulin-like growth factor (IGF) type II is produced by some sarcomas and may act as an autocrine growth factor and as a motility factor that promotes metastatic spread. IGF-II stimulates growth through IGF-I receptors, but its effects on motility are through different receptors. If secreted in large amounts, IGF-II may produce hypoglycemia (Chap. 54).

CLASSIFICATION

Approximately 20 different groups 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 resembling smooth muscle; and liposarcomas contain adipocytes. When precise characterization of the group is not possible, the tumors are called unclassified sarcomas. All of the primary bone sarcomas can also arise from soft tissues (e.g., extraskeletal osteosarcoma). The entity malignant fibrous histiocytoma (MFH) includes many tumors previously classified as fibrosarcomas or as pleomorphic 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 pleomorphism. As immunohistochemical suggestion of differentiation, particularly myogenic differentiation, may be found in a significant fraction of these patients, many are now characterized as poorly differentiated leiomyosarcomas, and the terms undifferentiated pleomorphic sarcoma (UPS) and myxofibrosarcoma are replacing MFH and myxoid MFH.

For purposes of treatment, most soft tissue sarcomas can be considered together. However, some specific tumors have distinct features. For example, liposarcoma can have a spectrum of behaviors. Pleomorphic 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, they 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 and are more responsive to chemotherapy than other soft tissue sarcomas.

Gastrointestinal stromal cell tumors (GISTs), previously classified as gastrointestinal leiomyosarcomas, are now recognized as a distinct entity within soft tissue sarcomas. Its cell of origin resembles the interstitial cell of Cajal, which controls peristalsis. The majority of malignant GISTs have activating mutations of the c-kit gene that result in ligand-independent phosphorylation and activation of the KIT receptor tyrosine kinase, leading to tumorigenesis. Approximately 5–10% of tumors will have a mutation in the platelet-derived growth factor receptor α (PDGFRA). GISTs that are wild type for both KIT and PDGFRA mutations may show mutations in SDH B, C, or D and may be driven by the IGF-I pathway.

DIAGNOSIS

The most common presentation is an asymptomatic mass. Mechanical symptoms referable to pressure, traction, or entrapment of nerves or muscles may be present. All new and persistent or growing masses should be biopsied, either by a cutting needle (core-needle biopsy) or by a small incision, placed so that it can be encompassed in the subsequent excision without compromising a definitive resection. Lymph node metastases occur in 5%, except in synovial and epithelioid sarcomas, clear-cell sarcoma (melanoma of the soft parts), angiosarcoma, and rhabdomyosarcoma, where nodal spread may be seen in 17%. The pulmonary parenchyma is the most common site of metastases. Exceptions are GISTs, 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 alveolar soft part sarcoma.

Radiographic evaluation

Imaging of the primary tumor is best with 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 AND PROGNOSIS

The histologic grade, relationship to fascial planes, and size of the primary tumor are the most important prognostic factors. The current American Joint Committee on Cancer (AJCC) staging system is shown in Table 47-1. Prognosis is related to the stage. Cure is common in the absence of metastatic disease, but a small number of patients with metastases can also be cured. Most patients with stage IV disease die within 12 months, but some patients may live with slowly progressive disease for many years.

TREATMENT

INCIDENCE AND EPIDEMIOLOGY

Bone sarcomas are rarer than soft tissue sarcomas; they accounted for only 0.2% of all new malignancies and 2890 new cases in the United States in 2013. Several benign bone lesions have the potential for malignant transformation. Enchondromas and osteochondromas can transform into chondrosarcoma; fibrous dysplasia, bone infarcts, and Paget’s disease of bone can transform into either UPS or osteosarcoma.

CLASSIFICATION

Benign tumors

The common benign bone tumors include enchondroma, osteochondroma, chondroblastoma, and chondromyxoid fibroma, of cartilage 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 (Chap. 18). The four most common malignant nonhematopoietic bone tumors are osteosarcoma, chondrosarcoma, Ewing’s sarcoma, and UPS. Rare malignant tumors include chordoma (of notochordal origin), malignant giant-cell tumor and adamantinoma (of unknown origin), and hemangioendothelioma (of vascular origin).

Musculoskeletal tumor society staging system

Sarcomas of bone are staged according to the Musculoskeletal Tumor Society staging system 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). The tumor-node-metastasis (TNM) staging system is shown in Table 47-2.

OSTEOSARCOMA

Osteosarcoma, accounting for almost 45% of all bone sarcomas, is a spindle cell neoplasm that produces osteoid (unmineralized bone) or bone. Approximately 60% of all osteosarcomas occur in children and adolescents in the second decade of life, and approximately 10% 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 1.5–2 times as often as females. Osteosarcoma has a predilection for metaphyses of long bones; the most common sites of involvement are the distal femur, proximal tibia, and proximal humerus. The classification of osteosarcoma is complex, but 75% of osteosarcomas fall into the “classic” category, which include osteoblastic, chondroblastic, and fibroblastic osteosarcomas. The remaining 25% 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 epithelioid osteosarcoma; 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 or by fluorodeoxyglucose positron emission tomography (FDG-PET). 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. Preoperative chemotherapy followed by limb-sparing surgery (which can be accomplished in >80% of patients) followed by postoperative chemotherapy is standard management. 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. Long-term survival rates in extremity osteosarcoma range from 60 to 80%. Osteosarcoma is radioresistant; radiation therapy has no role in the routine management. UPS is considered a part of the spectrum of osteosarcoma and is managed similarly.

CHONDROSARCOMA

Chondrosarcoma, which constitutes ~20–25% 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 classic category. Like other bone sarcomas, high-grade chondrosarcomas spread to the lungs. Most chondrosarcomas are resistant to chemotherapy, and surgical resection of primary or recurrent tumors, including pulmonary metastases, is the mainstay of therapy. This rule does not hold for two histologic variants. Dedifferentiated chondrosarcoma has a high-grade osteosarcoma or a malignant fibrous histiocytoma component 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 ~10–15% 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 the Ewing’s family of tumors, sometimes called PNETs). Most PNETs arise in soft tissues; they include peripheral neuroepithelioma, Askin’s tumor (chest wall), and esthesioneuroblastoma. Glycogen-filled cytoplasm detected by 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. Doxorubicin, cyclophosphamide or ifosfamide, etoposide, vincristine, and dactinomycin are active drugs. Topotecan or irinotecan in combination with an alkylating agent is often used in relapsed patients. Targeted therapy with an anti-IGF-I receptor antibody in combination with an inhibitor of mammalian target of rapamycin (mTOR) appears to have promising activity in refractory cases. 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 rate of 80% with effective treatment. Ewing’s sarcoma at first presentation is a curable tumor, even in the presence of obvious metastatic disease, especially in children <11 years old.

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% 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, nerve root or spinal cord compression, 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 (Chap. 56). 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 >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