MALIGNANT TUMORS OF BONE, SARCOMAS, AND OTHER SOFT TISSUE NEOPLASMS
Primary bone tumours arise from cells that are normal components of bone tissues and that have the potential to metastasize. They are relatively uncommon malignancies (accounting for 0.2% of all neoplasms in the Surveillance, Epidemiology, and End Results [SEER] database, with 1.8 new cases per 100,000 population per year). Malignant bone tumours must be distinguished from a variety of more common benign bone lesions, such as osteochondromas and enchondromas.
Patients with primary malignant and benign bone tumours present with pain, swelling, and occasionally pathologic fracture of the involved bone. If radiologic studies suggest a malignant primary bone tumour, an orthopaedic oncologist should be consulted before carrying out a biopsy because improper biopsy technique may compromise subsequent surgical care, particularly limb-sparing surgery. Staging of patients with bone tumours generally requires computed tomography (CT) scans of the chest, abdomen, and pelvis to evaluate whether metastatic disease is present. Characterization of the primary bone tumour may benefit from magnetic resonance imaging (MRI) assessment of soft tissue extension or CT scan assessment of cortical bone involvement, or both.
Myeloma is the most common primary bone malignancy.
Osteosarcoma is the most common malignant sarcoma of bone, representing about 35% of cases. It has a bimodal age distribution with the highest incidence in patients younger than 20 years of age, most likely related to the normal rapid bone growth that occurs during adolescence. In this age group, most tumours arise in the metaphyseal areas of the long bones of the extremities, particularly around the knee. Males are affected more commonly than females at a ratio of 3 : 2. A second peak of incidence occurs in adults older than 60 years. The sites of origin in these older patients are somewhat more heterogeneous, with craniofacial and pelvic bones each accounting for 20% of tumours. Osteosarcomas are classified based on location, cell type, and tumour grade. All osteosarcomas contain varying amounts of osteoid, with most also containing some cartilage and fibrous tissue. Radiographically, osteosarcomas usually present as mixed osteoblastic and osteolytic lesions, although pure forms of either appearance can occur. Periosteal elevation (Codman’s triangle), cortical destruction, and tumour extension into soft tissue are common on plain radiographs or MRI.
The incidence of osteosarcoma is increased in families that carry germline deletions of retinoblastoma ( RB ), TP53 (Li-Fraumeni), or RecQ DNA helicase (Rothman-Thompson, Werner, or Bloom syndrome) genes. Consistent with these observations, although most younger patients with osteosarcomas have no apparent predisposing factor or family history of bone tumours, alterations in the TP53 and RB genes of such sporadic tumours occur in 40% and 60% of patients, respectively. In older patients, a variety of conditions may predispose to osteosarcoma, most convincingly antecedent Paget disease or prior radiation therapy.
Osteosarcoma is a highly proliferative neoplasm that metastasizes rapidly, most often by hematogenous spread; the most common site of metastasis is the lung. Despite aggressive surgical resection of the primary bone tumour, the incidence of recurrence with metastatic disease is high in the absence of systemic treatment, consistent with the concept that most patients present with clinically inapparent micrometastatic disease. The development of effective systemic chemotherapy with doxorubicin and cisplatin, with or without methotrexate, has had a profoundly positive effect on treatment outcome, with 5-year disease-free survival rates exceeding 65% in patients younger than 40 years with nonmetastatic extremity tumours. However, subsequent progress has been less striking. Most patients are managed with initial neoadjuvant chemotherapy, delayed resection of the primary tumour, and then further postoperative chemotherapy. Serum alkaline phosphatase levels, often elevated in patients with osteosarcoma, can be used to monitor disease status.
Modern surgical techniques have allowed resection of most extremity osteosarcomas without amputation. Although resection of lung metastases can be curative in about 20% of selected patients, detection of radiographically-apparent metastatic disease at presentation significantly worsens prognosis. Long-term disease control in older adults with osteosarcoma is substantially lower than in younger patients, with a 5-year overall survival rate of 22% in one series of patients older than 65 years, most likely because of fundamental differences in the underlying molecular pathophysiology of tumours in older adults. Although osteosarcoma is generally considered to be relatively radiation resistant, radiation can play a palliative role in selected patients.
Chondrosarcoma is a malignant tumour characterized by hyaline cartilage differentiation; it is the second most common sarcoma of bone, representing 25% of bone sarcomas. The peak incidence is in the fifth to seventh decades of life. The most common primary sites are in the pelvis, proximal femur, and proximal humerus. Patients present with long-standing complaints of swelling, pain, or both. Radiographically, chondrosarcoma usually appears as a mixed lytic and sclerotic lesion. MRI provides the optimal modality for determining the extent of marrow replacement by conventional intramedullary chondrosarcoma. Distinguishing low-grade chondrosarcomas from benign central enchondromas can be difficult; location in the axial skeleton and size larger than 5 cm favours malignancy.
Up to 15% of chondrosarcomas arise from preexisting peripheral osteochondromas and, similar to their benign counterparts, harbour mutations in the exostosin (EXT) gene. The remaining 85% of chondrosarcomas arise in a central location, some in preexisting enchondromas. Chondrosarcomas are divided into three grades, with higher grade tumours characterized by greater cellularity and cellular atypia. In one series, 61% of patients had grade 1 tumours; only 4% of such patients developed metastases. In contrast, 36% of patients had grade 2, and 3% grade 3 tumours; among this combined group, 29% developed metastases.
Unlike osteosarcoma and Ewing sarcoma, chondrosarcomas generally grow slowly, metastasize less commonly, and have an excellent prognosis after adequate surgical resection. Although chondrosarcomas are considered relatively radiation resistant, radiation therapy may provide palliation for patients with large or recurrent, unresectable central chondrosarcomas.
Ewing sarcoma and primitive neuroectodermal tumours (PNET) are a family of small round cell sarcomas that represent 16% of primary bone sarcomas. The molecular hallmark of Ewing sarcoma is the translocation between the Ewing sarcoma protein (EWS) and an ETS (E26 transformation-specific or E-twenty-six) family transcription factor. In 85% of cases, the t(11;22) (q24;q12) translocation between EWSR1 and FLI1 is detected, although other fusion genes have also been described.
As with osteosarcoma, the peak incidence occurs during the second decade of life, but unlike osteosarcoma, the incidence of Ewing sarcoma is unimodal, being distinctly unusual in older adults and in nonwhites. Ewing sarcoma tends to arise in the diaphyseal region of long bones, in the pelvis, or in the ribs. Ewing tumours are characterized radiologically by a permeative or “moth-eaten” appearance of the affected bone, with a multilayered “onion-skin” periosteal reaction. MRI studies frequently document a significant soft tissue mass associated with the bone lesion. Unlike other sarcomas of bone, Ewing sarcoma may present with symptoms of an inflammatory systemic illness, with intermittent fevers, anaemia, leukocytosis, and an increased sedimentation rate.
Eighty-five percent of Ewing’s family sarcomas contain a t(11;22)(9q24;q12) chromosomal translocation that juxtaposes the EWS gene on chromosome 22 with FLI1, an ETS family transcription factor. Another 15% contain a variant in which EWS is juxtaposed to ERG, another ETS family member on chromosome band 21q22. Because Ewing sarcoma resembles other small round cell tumours microscopically, reverse transcription–polymerase chain reaction and fluorescent in situ hybridization studies that document such translocations play a critical role in confirming the diagnosis. Ewing sarcoma/PNET cells characteristically express the CD99/MIC2 cell membrane glycoprotein.
Patients with localized disease treated with multimodality therapy can achieve a 5-year event-free survival rate of 70%, but the 5-year overall survival rate of patients who present with overt bone or bone marrow metastatic disease at diagnosis is less than 20%. The development of effective systemic chemotherapy regimens has substantially improved long-term control of Ewing sarcoma. After completion of staging procedures, patients are treated with neoadjuvant chemotherapy. One highly active regimen alternates cycles of vincristine, doxorubicin, and cyclophosphamide with ifosfamide and etoposide. After 3 months of chemotherapy, the primary tumour is resected, radiated, or both, depending on the location and extent of the primary tumour. Chemotherapy is then resumed for a total of up to 1 year of treatment. Using such an approach, the mean 5-year event-free survival rate for patients who present with nonmetastatic disease is 73%. Insulin-like growth factor-1 receptor antagonists have demonstrated clinical activity in recent clinical trials for chemotherapy-refractory disease.
Tumors metastatic to bone are important causes of cancer-related morbidity. Effective prevention and treatment of skeleton-related metastases are important parts of clinical care for many cancer patients. The most common tumours that metastasize to bone are breast cancer in women and prostate cancer in men followed by cancers of the lung, kidney, gastrointestinal tract, and thyroid.
Bone metastases typically present with localized or referred pain and less commonly as a new bone fracture. Plain radiographs may demonstrate blastic or lytic lesions. Although bone metastases from prostate cancer are often blastic and multiple myeloma usually lytic, most other tumours have a mixed appearance. In patients with one documented bone metastasis or in patients with widely metastatic disease and bone pain, a radiologic survey can identify bone metastases that may ultimately place the patient at risk for a pathologic fracture. Radionuclide bone scans are useful to delineate the extent of bone metastases and in following response to therapy. However, a negative study result must be interpreted cautiously because tumours that are potentially purely lytic (particularly multiple myeloma) may not be detectable by bone scan. In such tumours, a plain skeletal survey or CT or MRI scan is preferable. Routine screening for bone metastases is not indicated for cancer patients with no symptoms or signs of bone involvement.
In the absence of fracture or impending fracture, painful bone metastases are treated with external-beam radiation therapy. In patients with numerous bone metastases, systemic chemotherapy or endocrine therapy can play an important palliative role. Pathologic fractures or imminent fractures are generally managed by operative internal fixation.
In patients with breast cancer, prostate cancer, and multiple myeloma, bisphosphonate therapy increases the time to a first skeletal event. Bisphosphonate therapy also appears to prolong survival in patients with metastatic breast cancer. The optimal schedule and duration of administration of bisphosphonates to maximize benefit and minimize potential complications remain to be established.
Sarcomas are tumours of mesenchymal origin that make up approximately 1% of human cancers. They are a heterogeneous group of malignant neoplasms of connective tissues, including bone and soft tissue, comprising more than 50 histologic subtypes. Mesenchymal cells (derived from mesoderm), as well as neural crest cells (from ectoderm), give rise to connective tissues and provide critical functions such as support and nourishment to neural tissues. When growth, differentiation, or survival of these cells is aberrant, tumours arise, and this is the family of neoplasms to which sarcomas belong. Sarcomas include a vast array of tumour types related to muscle, stromal tissue, adipose tissue, blood and lymphatic vessels, nerves and nerve sheaths, cartilage, bone, and other fibrous tissues.
Although very rare in adults, true sarcomas represent a disproportionately large number of cancers in the paediatric population (≈15% of paediatric cancers). The overall incidence of sarcomas of soft tissue and bone is approximately 15,000 cases per year in the United States. The prevalence of sarcomas significantly exceeds the incidence because sarcomas can be cured with expert multidisciplinary care. Hence, the initial evaluation and management of patients suspected of having sarcomas should be performed by an experienced team with relevant expertise and interdisciplinary capabilities (including expertise in sarcoma pathology, surgical specialization, and radiotherapeutic experience and judgment, as well as access to the latest systemic therapeutic agents).
Certain patients are at high risk of developing sarcomas, most notably individuals in families with Li-Fraumeni syndrome and those with neurofibromatosis (at risk for malignant peripheral nerve sheath tumours and gastrointestinal stromal tumours [GISTs]) or familial polyposis (at risk for intra-abdominal desmoid tumours). Other risk factors include exposure to radiation (including radiation therapy for other cancers, such as patients with prior irradiated breast cancer or survivors of retinoblastoma). Chemical carcinogens can also increase the risk of sarcoma development, such as the increased incidence of sarcomas in Vietnam veterans exposed to Agent Orange or the greatly increased risk of hepatic angiosarcomas associated with occupational exposure to polyvinyl chloride. However, the vast majority of sarcomas appear to be sporadic, with no evident inciting risk factors.
Sarcomas and other connective tissue neoplasms are a heterogeneous mixture of diseases with a wide range of clinical behaviours and outcomes. Some soft tissue neoplasms, such as localized tenosynovial giant cell tumours, can be cured by expert resection, but more advanced tumours of this type (referred to as pigmented villonodular tenosynovitis) often lead to debilitating amputations or even death because of metastatic disease. Expert pathological review is necessary for the diagnosis of specific sarcoma subtypes; unfortunately, interobserver variability can impair even the most elegant diagnostic categories, such as those promulgated by the World Health Organization. Increasingly, knowledge of the molecular pathways that drive sarcomas has provided more objective diagnostic tools, including novel immunohistochemical staining patterns and genetic markers. In general, sarcomas may exhibit differentiation patterns consistent with defined connective tissues (e.g., well-differentiated liposarcoma may appear as only slightly bizarre fat cells under the microscope), or they may be unclassifiable. In any case, as diagnostic tools have evolved, it has become possible to place poorly differentiated tumours more accurately into certain histopathologic categories based on the expression of lineage-related proteins (e.g., smooth muscle actin expression may help categorize tumours as leiomyosarcomas) or on the basis of genomic markers (e.g., overexpression of chromosome 12 material or the MDM2 gene locus is most consistent with a dedifferentiated liposarcoma). Recent studies have revealed that mesenchymal-to-epithelial transition (MET) may be operative in sarcomas, and MET may be an important basic biological and clinical process in tumours of mesenchymal original in general.
Given the variety of sarcoma subtypes, it is understandable that the clinical course of these diseases can range from rapidly evolving and immediately life-threatening to indolent lesions that can take decades to evolve (e.g., atypical lipomatous tumours, also known as well-differentiated liposarcomas). Most patients with sarcomas present with a mass, often nontender, with a history of abnormal growth over time. For extremity tumours of soft tissues, it is important to note that many benign tumours (e.g., lipomas) cannot be easily distinguished from more worrisome neoplasms or even from frankly malignant sarcomas. Therefore, it is important to include sarcoma in the differential diagnosis of any mass.
The initial biopsy or surgical approach to a sarcomatous lesion is often the most important, and a poorly oriented biopsy or a suboptimal surgical procedure can make the difference between cure with full limb function and disease recurrence with the need for amputation or mutilating surgical re-resection. The National Comprehensive Cancer Network has developed expert consensus guidelines for clinical practice that emphasize the importance of expert management from the moment a suspected sarcoma presents. The initial diagnosis includes appropriate imaging studies of relevant anatomic areas, including plain radiographs, CT, or MRI to define the anatomic area of the mass and surrounding tissue, as well as systemic staging because sarcomas can spread in well-defined patterns to distal sites such as the lung or liver. The decision to proceed to diagnostic biopsy, with optimal orientation, is an important one, and for certain lesions, forgoing incisional biopsy and proceeding directly to expert surgical excision may be justified. The most important consideration is to make the correct diagnosis, and there must be sufficient amounts of properly prepared and expertly oriented tissues for optimal diagnostic analysis. In certain tumours with pathognomonic molecular markers (e.g., the translocation between chromosomes X and 18 that characterizes synovial sarcoma or the balanced translocation between chromosomes 12 and 16 that defines myxoid and round cell liposarcoma), molecular analyses such as fluorescence in situ hybridization may help make the diagnosis. New molecular subtypes of sarcoma enter the pathology literature frequently; these new diagnostic categories may lead to the use of novel, molecularly targeted therapies. Nowhere has this been more evident than in the rapid evolution of effective therapy against the major pathobiologic cause of GISTs (see below).
The diagnosis of a soft tissue sarcoma is made by evaluating biopsy material in a clinical context, which includes understanding the tumour’s anatomic location and imaging characteristics. Such contextual diagnostics are critical to understanding whether a lesion may represent a primary sarcoma or whether it may be the first presentation of metastases from an occult primary tumour located elsewhere. Given the broad spectrum of sarcomas, the diagnostic considerations are quite far reaching, especially because many benign pathophysiologic conditions can mimic sarcomas.
The most important element of treatment is expert multidisciplinary care. The range of options is too broad to categorize simply, and the specific details of each patient’s anatomy, comorbidities, functional status, and personal preferences must be taken into account when defining treatment options and management plans. Therefore, the care of virtually all sarcoma patients should be managed by an expert multidisciplinary team with expertise in advanced surgical or orthopaedic oncology techniques, radiation therapy, reconstructive surgery, physical therapy and rehabilitation medicine, systemic therapies such as conventional cytotoxic chemotherapy, hormonal therapy, and modern molecularly targeted therapy with agents such as kinase inhibitors, and psychosocial support and specialized nursing care. Therefore, appropriate referral to obtain expert opinion and to define the diagnostic and treatment options for patients with suspected sarcomas is recommended.
For most localized masses for which sarcoma is in the differential diagnosis, the first step is to obtain the correct diagnosis in a manner that does not compromise patient outcome or function. The need for biopsy must be considered first because some small, localized sarcomas are best approached through definitive surgical excision following careful staging and expert review of imaging studies. For suspected sarcomas in deeper locations, such as within muscle compartments, or for large visceral lesions, biopsy may be necessary to ascertain that the process is in fact a sarcoma, as well as to fully characterize the histopathologic subtype. This may make the difference between initial management with chemotherapy, as might be appropriate for a highly chemosensitive disease, versus surgery, which might be appropriate for a less chemosensitive disease such as dedifferentiated liposarcoma. Expert opinion varies regarding the utility and timing of adjuncts to surgical resection, such as radiation therapy or systemic cytotoxic chemotherapy.
In general, expert surgical resection is the first-line of therapy for localized sarcomas. Preoperative systemic chemotherapy may be appropriate for some rhabdomyosarcomas. Many expert teams favour preoperative radiation therapy for certain sarcomas; irradiation of a large primary tumour can deliver smaller doses to surrounding normal tissues preoperatively compared with postoperatively, but this is a matter of personal preference. A randomized trial of preoperative versus postoperative radiation therapy for large sarcomas of the extremity was performed in Canada, and outcomes were similar, with subtle differences: patients who received preoperative radiation had a higher incidence of serious postoperative wound complications, but the long-term functional outcomes were slightly more favourable.
Many sarcoma centres disagree about the relative value of cytotoxic chemotherapy, although there is no doubt that chemotherapy has greatly improved disease control rates and cure rates of certain subtypes of aggressive sarcomas such as rhabdomyosarcoma. For other forms of sarcoma originating in bone (e.g., chondrosarcoma) or soft tissue (e.g., leiomyosarcoma, synovial sarcoma), there is no strong evidence that systemic chemotherapy increases cure rates or long-term clinical outcomes, although there may be some improvement in local disease control and recurrence-free survival. This has led to discordant expert opinion: many experts believe that the risks and toxicities of aggressive chemotherapy justify the benefit of longer disease-free survival, but others believe that such toxicities are not reasonable without a major improvement in overall survival. Limited series of postoperative adjuvant therapy are often contradictory owing to the relatively small patient groups under study, as well as divergent patient selection factors, such as the inclusion of those with a lower risk of recurrence or death from metastatic disease. Inclusion of a sizable percentage of sarcoma patients with low-risk disease no doubt dilutes the results of even a reasonably effective therapy and runs the risk of making the study result negative.
It is also critical to recognize that treatment may differ radically depending on the histologic diagnosis. The best example of this is GIST, a form of sarcoma that, in more than 95% of cases, is driven by aberrant tyrosine kinase signalling. Routine systemic chemotherapy is completely ineffectual against this disease; however, tyrosine kinase inhibitor therapy (e.g., with imatinib mesylate or sunitinib malate) produces dramatic tumour regressions and tumour control in more than 85% of patients. Fortunately, pathologists are increasingly able to recognize this disease histopathologically, and immunohistochemistry to detect CD117 (the Kit receptor tyrosine kinase) and DOG1 (a membrane antigen that is reasonably specific for GIST), as well as tumour genotyping via molecular genetics have significantly increased the accuracy of GIST diagnosis in the past decade. Imatinib has been approved by the Food and Drug Administration to decrease the risk of disease recurrence following resection of GISTs with significant potential for relapse. However, patients with a low risk of relapse have not derived substantive benefits from adjuvant imatinib because they have a very good chance of being cured by surgery alone. GIST is an excellent example of a sarcoma in which critical therapy decisions must be made in the context of the proper molecular diagnosis.
For soft tissue sarcomas other than GIST, radiation therapy can play a meaningful role in preventing disease recurrence, especially for lesions that arise in the extremities. Radiation therapy can also provide significant palliation of unresectable disease, and it can be surprisingly effective in certain tumours such as desmoid tumour. However, radiation-associated sarcomas are increasingly common after therapeutic radiation therapy (e.g., in patients cured of breast cancer with radiation therapy), and an increasing incidence of poorly differentiated sarcomas or vascular sarcomas has been reported in patients after irradiation for other diseases.
As noted earlier, traditional cytotoxic chemotherapy is effective at increasing disease control and cure rates for certain sarcomas (especially those most prevalent in paediatric patients, such as rhabdomyosarcoma). It is less effective in improving long-term cure rates for patients with most other forms of soft tissue and bone sarcomas, such as liposarcoma, leiomyosarcoma, synovial sarcoma, and other subtypes. Nonetheless, appropriate use of chemotherapy can lead to objective responses in certain patients and can palliate those with metastatic disease with disease control and prolongation of progression-free survival. Targeted therapies hold potential promise for some sarcomas. For example, pazopanib, a multitargeted tyrosine kinase inhibitor at 800 mg once daily, improves the overall survival period from 10.7 to 12.5 months in patients who have metastatic nonadipocytic soft tissue sarcoma and who have had previous chemotherapy. Furthermore, a recent study demonstrated the first effective treatment for an uncommon, vasculogenic sarcoma of young adults, alveolar soft part sarcoma, with a multikinase inhibitor (cediranib) that primarily targets the vascular endothelial growth factor.
Sarcoma experts often disagree about the relative value and toxicity of combination chemotherapy as opposed to sequential single-agent chemotherapy. In patients with very aggressive and highly symptomatic sarcomas, clinicians may choose a combination chemotherapy regimen, even if there is a greater risk of toxicity, to ensure some measure of rapid disease control or even a greater chance of disease regression. In contrast, in patients with asymptomatic metastatic disease (e.g., a sarcoma patient with indolent pulmonary metastases and no symptoms), the optimal choice might be single-agent chemotherapy to avoid toxicity and to maximize the choice of subsequent chemotherapeutic agents after the benefit of the first agent is fully realized. There are no definitive data from properly powered randomized trials demonstrating that any chemotherapy for metastatic sarcoma of soft tissue (other than GIST) improves overall survival. All experts agree that owing to the complexity of the trials, the diseases, and the clinical settings, one must allow for variations in interpretations for individual patients. This explains the greatly discordant practice patterns observed across the country based on referrals, provider experience, and patient characteristics and preferences.
Discussing prognosis for sarcomas overall is difficult because they represent such a variety of diseases with widely divergent natural histories. It is estimated that approximately 50% of patients with localized sarcomas can be cured, and the risk of recurrence is related to variables such as tumour grade (low-grade tumours have a lower risk of recurrence or metastasis compared with intermediate- or high-grade tumours), tumour size, and tumour location or depth. For patients with recurrent or metastatic sarcoma, outcome depends on many factors, including the time from initial diagnosis to the first appearance of metastatic disease; a longer disease-free interval is associated with longer survival, probably indicating a slower rate of tumour proliferation. Another factor that may determine outcome is the number of metastatic lesions; it is possible that oligoclonal metastases, with few lesions, can be surgically resected, which itself may be associated with improved survival.
Advances in targeted therapies have also affected survival, as documented by the dramatic improvements in survival and disease control for GIST and other kinase-driven sarcomas, such as dermatofibrosarcoma protuberans, giant cell tumour of bone, perivascular epithelioid cell–oma (PEComa), tenosynovial giant cell tumour, and alveolar soft part sarcoma. The natural history of these diseases will almost certainly be changed by a more mechanistic understanding of the underlying neoplasia-promoting signals that cause the transformation and maintenance of the sarcoma. Expert multidisciplinary management of sarcomas is critical to improving outcomes, and ongoing translational and therapeutic research will provide dividends far beyond the relatively low incidence and prevalence of these mesenchymal cell neoplastic disorders.