The Washington Manual of Oncology, 3 Ed.

Sarcoma

Brian A. Van Tine

 I. APPROACH TO THE SARCOMA PATIENT. Sarcoma patients should be managed by a multidisciplinary team with extensive expertise. As the standard of care for most sarcomas is still clinical trial, access to the latest expertise in sarcoma is vital for this patient population. Second opinions should be considered standard practice for any oncologist that sees less than 10 cases a year and should be considered mandatory for the more rare histologies.

1. BACKGROUND. Sarcomas are malignancies of the connective tissue (from the Greek sarx for flesh), including fatty tissue, muscle, blood vessels, and bone. Most of these tissues share a common embryologic origin, arising primarily from tissues derived from the mesoderm. The clinical manifestations of sarcomas depend on the anatomic site of origin. The presenting signs and symptoms vary markedly, from a painless lump to debilitating pain. Because of the large number of neoplasms categorized as a sarcoma, these tumors may be broadly divided into soft-tissue neoplasms (extremity, retroperitoneal, and visceral) and bone sarcomas.
2. Epidemiology. Sarcomas comprise 1% of adult malignancies and 7% of pediatric malignancies. In the United States, the incidence of soft-tissue sarcomas is approximately 10,000 cases per year, and the incidence of sarcomas of bone is approximately 3000 cases per year (CA Cancer J Clin 2013;63:11). This is likely an underestimation of the total number of cases owing to the lack of a unifying ICD9 code.
3. Risk factors. Most cases of sarcoma are sporadic, with no identifiable risk factors. A number of predisposing factors, however, have been recognized.
4. Radiation. Sarcomas have been found to originate in or near tissues that have received prior external-beam radiation therapy (RT). These radiation-induced sarcomas generally occur at least 5 years after RT was delivered. Most of these lesions are high grade, and they are typically osteosarcomas, undifferentiated pleomorphic sarcoma (UPS), and angiosarcomas.
5. Chemical exposure. Certain chemicals have also been found to lead to the development of sarcomas, including phenoxy herbicides, dioxin, and arsenic. The alkylating chemotherapeutic agents such as cyclophosphamide, melphalan, and nitrosoureas that are used in childhood cancers have also been associated with the development of sarcomas in adulthood.
6. Genetic conditions. Several syndromes are associated with sarcomas. Patients with neurofibromatosis type I (mutations in NF1) have a 10% risk of developing a malignant peripheral nerve sheath tumor as adults (Neuro Oncol2013;15:135). Sarcomas occur in patients with Li–Fraumeni syndrome, familial retinoblastoma (osteosarcoma), Gardner’s syndrome (desmoids), tuberous sclerosis (rhabdomyosarcoma), and Gorlin’s syndrome (rhabdomyosarcoma). Involvement of a genetic councilor is important in the management of patients with these syndromes.
7. Other risks associated with sarcomas. Lymphangiosarcomas have been known to develop in a lymphedematous arm after mastectomy (Stewart–Treves syndrome). Kaposi’s sarcoma is associated with human herpes virus 8 (HHV8) and human immunodeficiency virus (HIV) disease. Paget’s disease of bone is a risk factor for the development of osteosarcoma and fibrosarcoma. Injury is not considered a risk factor for the development of soft-tissue sarcomas.
8. Molecular biology. Sarcomas fall into two classes genetically: complex cytogenetic (i.e., osteosarcoma or leiomyosarcoma) and translocation driven. Several cytogenetic abnormalities are characteristic of certain sarcomas. The following is a list of selected tumors and their karyotypic mutations (J Natl Compr Cancer Netw 2012;10:951).
9. Peripheral primitive neuroectodermal tumor (PPNET) and Ewing’s sarcoma: most commonly, t(11;22) EWS1-FLI
10. Desmoplastic small round cell tumor t(11;22) EWSR1-WT1
11. Alveolar rhabdomyosarcoma t(2;13) or t(1;13) PAX 3 or 7-FOXO1
12. Myxoid/round cell liposarcoma t(12;16) or t(12;22) FUS-DD1T3 or EWSR1-DD1T3
13. Well-differentiated/differentiated liposarcoma amplification of 12q14-15 MDM2 and CDK4
14. Alveolar soft part sarcoma t(X;17) ASPL-TFE3
15. Clear cell sarcoma t(12;22) or t(2:22) EWSR1-ATF1 or EWSR1-CREB1
16. Dermatofibrosarcoma protuberans t(17;22) ColIA1-PDGFRB
17. Low-grade fibromyxoid sarcoma t(7;16) or t(11;16) FUS-CREB2L2 or FUS-CREB3L1

 10. Synovial sarcoma t(X;18) SS18-SSX1, 2, or 4.

 III. SOFT-TISSUE SARCOMA

1. Overview. Soft-tissue sarcomas represent more than 50 different histologies. Pathologic diagnosis is based on the resemblance of these tumors to normal tissues. Despite this diversity, many of the clinical features and treatment decisions are common among the various histologies with some notable exceptions.
2. History. The presentation of soft-tissue sarcomas varies according to the site of origin.
3. Extremity sarcoma. Approximately half of all soft-tissue sarcomas arise in the extremities. The majority are first seen as a painless soft-tissue mass. Pain is present in less than one-third of patients at the time of presentation. Patients often report a history of trauma, but in most cases, trauma likely did not cause the mass, but instead brought attention to a mass. Spontaneous hematomas on patients without anticoagulation should be approached with a very high degree of suspicion for malignancy.
4. Retroperitoneal sarcomas. Most patients have an abdominal mass (80%), and approximately half have abdominal pain that is often vague and nonspecific. Weight loss is seen less frequently, with early satiety, nausea, and emesis occurring in fewer than 40% of patients. Neurologic symptoms, particularly paresthesia, occur in up to 30% of patients.
5. Visceral sarcomas. Signs and symptoms relate to the viscus of origin. For example, gastric sarcomas frequently occur with dyspepsia or gastrointestinal bleeding. Rectal bleeding and tenesmus are seen with sarcomas of the rectum. Dysphagia and chest pain are common presenting symptoms of esophageal sarcomas. Painless vaginal bleeding is often seen with uterine leiomyosarcomas.
6. Physical examination. The examination of a patient with sarcoma should include an assessment of the size of the mass and its mobility relative to the underlying soft tissues. A site-specific neurovascular examination should also be performed. An assessment of the patient’s overall functional status is also important.
7. Diagnosis and staging. In addition to a thorough history and physical examination, the evaluation of patients with soft-tissue sarcoma includes a biopsy as well as radiographic imaging.
8. Radiographic imaging. The studies needed for adequate staging vary depending on the site of disease. For soft-tissue masses of the extremities and pelvis, magnetic resonance imaging (MRI) is the imaging modality of choice. MRI allows the differentiation of tumor from surrounding muscle and provides a multiplanar view. For retroperitoneal and visceral sarcomas, however, computed tomography (CT) scans provide the best anatomic definition of the tumor and provide adequate imaging of the liver, the most common site of metastasis for visceral and retroperitoneal sarcomas.

 Angiography is not usually indicated in the staging of sarcomas because MRI accurately delineates vascular involvement. In addition, nuclear medicine bone scanning has poor specificity and sensitivity in detecting bony invasion and is rarely recommended. Positron electron tomography (PET) has not become routine for most sarcomas, but may be helpful in high-grade sarcomas, angiosarcomas, and gastrointestinal stromal tumors (GISTs).

 Since approximately 88% of metastasis from sarcoma of the extremities are in the lungs, chest imaging is necessary. For small, superficial lesions, a preoperative chest radiograph may be sufficient to evaluate for lung metastases, but in patients with high-grade tumors, or tumors larger than 5 cm, a staging CT of the chest should be performed.

2. Pathology
3. Overview. The histologic classification of soft-tissue tumors is organized according to the normal tissues they resemble. Unlike carcinomas, sarcomas do not demonstrate in situ changes, nor do they appear to originate from benign soft-tissue tumors (with the exception of malignant peripheral nerve sheath tumors in patients with neurofibromatosis). Clinical behavior is determined more by anatomic site, grade, and size than by a specific histology. Hence, most soft-tissue sarcomas are treated similarly despite different histologies, with the notable exceptions of GIST and rhabdomyosarcoma.

 The histologic grade of a sarcoma is the single best prognostic indicator for the development of recurrent disease. The pathologic features that determine grade include cellularity, differentiation, pleomorphism, necrosis, and a number of mitoses (Table 30-1).

 The three most common histopathologic subtypes are the UPS, liposarcoma, and leiomyosarcoma. It is often possible to correlate a location of a tumor with its histology. For example, most retroperitoneal sarcomas are liposarcomas or leiomyosarcomas.

1. Clinical pathologic features of specific tumor types

 i. UPS (previously named malignant fibrous histiocytoma) is a tumor of later adult life with a peak incidence in the seventh decade. It is usually first seen as a painless mass. The most common site of involvement is the lower extremity, but they also occur in the upper extremity and retroperitoneum.

 ii. Liposarcoma is primarily a tumor of adults with a peak incidence between ages 50 and 65 years. It may occur anywhere in the body, but most commonly in the thigh or retroperitoneum. Several types of liposarcoma have been recognized, and they have different clinical outcomes. Well-differentiated liposarcoma is usually a nonmetastasizing lesion. Sclerosing liposarcoma also is a low-grade lesion. Myxoid and round cell (or lipoblastic) liposarcomas are low- to intermediate-grade lesions and typically have a t(12;16)(q13-14;p11) translocation. Fibroblastic and pleomorphic liposarcomas are higher-grade lesions and typically more aggressive.

 iii. Leiomyosarcomas may arise in any location, but more than half are located in the uterus, retroperitoneum, or intra-abdominal regions.

 iv. Kaposi’s sarcoma may occur as raised pigmented lesions on the skin. It classically affects elderly Jewish and Italian men and is fairly indolent. It usually occurs in the lower extremities. An aggressive variant occurs in younger children and is endemic in some areas of Africa. In patients with HIV/acquired immunodeficiency syndrome (AIDS), a disseminated, aggressive form of this disease may develop.

 v. Angiosarcoma is an aggressive malignant tumor of the lining of blood vessels. It may arise in any organ, but is most commonly seen in the head and neck region, the breast, the liver, and areas of prior radiation. The skin is frequently involved. Breast angiosarcomas typically occur in young and middle-aged women, often following radiation for breast cancer. Liver angiosarcomas arise in adults previously exposed to thorium dioxide, insecticides, or polyvinyl chloride. Angiosarcomas are also the most common primary malignant tumor of the myocardium.

  vi. Synovial sarcoma usually occurs in young adults between 15 and 40 years of age. The most common site is the knee. Unlike most soft-tissue sarcomas, these lesions are usually painful.

vii. Rhabdomyosarcoma is a malignant tumor of skeletal muscle. Four categories are recognized: pleomorphic, alveolar, embryonal, and botryoid. Pleomorphic rhabdomyosarcoma usually occurs in the extremities of patients older than 30 years. It is highly anaplastic and may be confused with UPS pathologically. Alveolar rhabdomyosarcoma is a highly aggressive tumor that affects adolescents and young adults. Its histology resembles that of lung alveoli. Embryonal rhabdomyosarcoma arises primarily in the head and neck, especially the orbit. It usually affects infants and children, with a peak incidence at age 4. Botryoid rhabdomyosarcoma has been encompassed in the embryonal category. It has a gross appearance of polypoid masses and has a predilection for the genital and urinary tract. It occurs primarily in children at an average age of 7. Rhabdomyosarcomas that arise from dedifferentiated liposarcomas should be treated as liposarcoma.

viii. GIST is a sarcoma that can begin anywhere in the gastrointestinal tract but is found most commonly in the stomach (50%) or small bowel (25%). Most GIST tumors have a mutation in c-KIT, resulting in constitutive activation of this receptor.

3. Staging. The staging system for soft-tissue sarcomas incorporates histologic grade (G), size of the primary (T), nodal involvement (N), and distant metastasis (M) (Table 30-2). Grade of the tumor is the predominant feature predicting early metastatic recurrence and death. Beyond 2 years of follow-up, the size of the lesion becomes as important as the histologic grade. Recent changes have been made to the staging system with regard to lymph node metastases, as N1 tumors are now considered stage III.

 IV. STAGE-DIRECTED APPROACH TO THERAPY

1. Early stage disease (stage I to III)
2. Extremity soft-tissue sarcomas
3. Surgery. Surgery is the mainstay of therapy for early-stage soft-tissue sarcomas of the extremities. Over the last 20 years, there has been a gradual shift in the surgical management of extremity soft-tissue sarcomas away from radical ablative surgery, such as amputation and compartment resection, toward limb-sparing surgery. Currently, limb-sparing surgeries are performed in the vast majority of patients.

 When performing a limb-sparing surgery, it is important to obtain adequate margins. In the past, very conservative surgical approaches in which the plane of dissection is immediately adjacent to a pseudocapsule (an area around the tumor that is composed of tumor fimbriae and normal tissue) were associated with a local recurrence rate of 37% to 63%. However, a wide local resection encompassing a rim of normal tissue around the lesion led to improvements in local control, with a local recurrence rate of 30% in the absence of adjuvant therapy. The planned resection should encompass the skin, the subcutaneous tissues, and soft tissue adjacent to the tumor, including the previous biopsy site and any associated drain sites. The tumor should be excised with a minimum of a 1-cm margin of normal surrounding tissue.

 There is normally no role for regional lymphadenectomy in most adult patients with sarcoma because of the low (2% to 3%) prevalence of lymph node metastases. However, patients with angiosarcoma, embryonal rhabdomyosarcomas, synovial sarcoma, and epithelioid sarcomas have an increased incidence of lymph node involvement and should be examined and imaged for lymphadenopathy.

1. Adjuvant radiation therapy. Wide local excision alone is all that is necessary for small (T1), low-grade, soft-tissue sarcomas of the extremities, with local recurrence rate of less than 10%. Adjuvant RT, however, is required in a number of situations: (a) virtually all high-grade extremity sarcomas, (b) lesions larger than 5 cm (T2), and (c) positive or equivocal surgical margins in patients for whom re-excision is impractical. For T2 extremity soft-tissue sarcomas or any high-grade sarcomas, limb-sparing surgery plus adjuvant radiation to improve local control has become the standard approach. When adjuvant radiation is planned, metal clips should be placed at the margins of resection to facilitate radiation field.
2. Adjuvant chemotherapy. The benefit of adjuvant chemotherapy for most extremity soft-tissue sarcomas is controversial. A formal meta-analysis of individual data from 1,568 patients who participated in 13 trials was performed by the Sarcoma Meta-analysis Collaboration. The analysis demonstrated a significant reduction in the risk of local or distant recurrence in patients who received adjuvant chemotherapy. There was also a decrease in the risk of distant relapse (metastasis) by 30% in treated patients. Overall survival, however, did not meet the criteria for statistical significance between the control group and the adjuvant chemotherapy arm, with a hazard ratio of 0.89 (Lancet 1997;350:1647). Most of the randomized trials examined in this meta-analysis were limited by patient numbers, heterogeneous patient and disease characteristics, and varied chemotherapeutic regimens. However, a randomized trial of a homogeneous group of patients with high-grade soft-tissue sarcomas of the extremities and girdle demonstrated a significant survival advantage of five cycles of adjuvant ifosfamide (1.8 g/m² days 1 to 5) and epirubicin (60 mg/m² days 1 to 2) following definitive local therapy (J Clin Oncol 2001;19:1238). In this trial, the chemotherapy arm had an overall median survival of 75 months versus 46 months in the observation arm (p = 0.03). An additional trial demonstrated that three cycles of neoadjuvant ifosfamide and epirubicin was equivalent to five cycles of adjuvant therapy (J Clin Oncol 2012;30:850). The only exception is with rhabdomyosarcomas, in which neoadjuvant and adjuvant chemotherapy is accepted as standard of care.
3. Neoadjuvant radiotherapy. It may be necessary to administer radiation before definitive resection. This is most commonly performed for tumors that are borderline resectable or for tumors located adjacent to the joint capsule. The typical dose is 50 Gy. Sometimes, a boost is given postoperatively if margins are not adequate. Neoadjuvant radiation, however, is associated with wound healing difficulties. A phase III National Cancer Institute of Canada (NCIC) trial comparing adjuvant (postoperative) and neoadjuvant (preoperative) radiation demonstrated similar local control rates, metastatic outcome, and overall survival rates between the two arms (Lancet 2002;359:2235). However, patients receiving preoperative radiation had a significantly higher incidence of wound complications (35% vs. 17%).
4. Radiation as definitive therapy. RT alone in the treatment of unresectable or medically inoperable soft-tissue sarcoma patients yields a 5-year survival rate of 25% to 40% and a local control rate of 30%. Radiation doses, if feasible, should be at least 65 Gy.
5. Brachytherapy. Brachytherapy has also been used in treatment for sarcomas. Iridium 192 is the most commonly used agent. It has comparable local control rates versus adjuvant external-beam RT, although some data suggest a higher rate of wound complications and a delay in healing when the implants are after loaded before the third postoperative day. The advantages of brachytherapy include a decrease in the patient’s entire treatment to 10 to 12 days from 10 to 12 weeks, and the advantage that smaller volumes of tissue can be irradiated, which could improve functional results. However, smaller volumes may not be appropriate, depending on the tumor size and grade.
6. Retroperitoneal sarcomas
7. Surgery. As with other soft-tissue sarcomas, surgery is the primary treatment of retroperitoneal sarcomas. Tumors that are less than 5 cm in size and not located close to adjacent viscera or critical neurovascular structures are considered resectable. If a tumor has a high clinical suspicion of sarcoma and is resectable, it may not be necessary to perform a preoperative biopsy. One should consider a preoperative biopsy if an incomplete resection is a reasonable possibility to allow neoadjuvant therapy. If a biopsy is performed, it should be a CT-guided core biopsy.

 Unfortunately, only 50% of patients with early stage retroperitoneal sarcomas are able to undergo complete surgical resection. Of the tumors removed, approximately half will develop a local recurrence. Adjuvant therapy, therefore, plays an important role in the management of retroperitoneal sarcomas.

1. Adjuvant and neoadjuvant RT. Adjuvant RT is most frequently recommended for patients with high-grade tumors or positive margins. The radiation is typically started 3 to 8 weeks following surgery to allow wound healing. Two-year local control rates of 70% have been reported with the addition of postoperative RT.

 Neoadjuvant RT is used for patients with retroperitoneal sarcomas. It can be given to patients with marginally resectable tumors and those in whom one would expect to require postoperative radiotherapy. Neoadjuvant RT has a number of advantages over postoperative radiotherapy, including smaller radiation portals and reduction of the extent of the surgical procedure.

1. Management of unresectable locally advanced retroperitoneal sarcomas. Unresectable retroperitoneal sarcomas can be managed in a number of ways. RT can be given for palliation and with the hope that the tumor could be made resectable. Palliative surgery to reduce local symptoms can be performed. Chemotherapy can also be administered.
2. Visceral sarcomas
3. Overview. The discovery of the importance of a mutation in the tyrosine kinase c-KIT in GIST has led to a radical change in therapy for this sarcoma. Visceral leiomyosarcomas should be stained for c-KIT to rule out GIST.
4. Therapy for visceral sarcomas other than GIST

 i. Surgery. Surgery is the primary treatment of visceral sarcomas.

  ii. Adjuvant and neoadjuvant radiation. Adjuvant RT is necessary if the tumor is high grade or if margins are positive. It is usually started 3 to 8 weeks following surgery to allow wound healing. Neoadjuvant radiation can be considered to allow a less radical surgery or make a previously unresectable tumor operable.

iii. Management of unresectable locally advanced visceral sarcomas. Unresectable intra-abdominal sarcomas can be managed in a number of ways. RT can be given for palliation and with the hope that the tumor could be made resectable. Palliative surgery to reduce local symptoms can be performed. Chemotherapy can also be administered.

1. Therapy for GIST. Like other sarcomas, surgery is the primary therapy for nonmetastatic GIST tumors. Imatinib is a small-molecule tyrosine kinase inhibitor with significant inhibitory activity against c-KIT. In the initial study, 147 patients with metastatic GIST were treated with either imatinib 400 mg/m² or 600 mg/m² daily. Partial responses were noted in 54% and stable disease in 28% (N Engl J Med2002;347:472). The initial dose of imatinib is 400 mg daily, which should be continued until the disease progresses. Upon disease progression, treatment options include higher doses of imatinib (600 or 800 mg/day) or the use of sunitinib, another tyrosine kinase inhibitor, which has shown activity in imatinib-resistant GIST. An option for third-line therapy is regorafenib (Lancet 2013;381:295).

 If a tumor is marginally resectable or the surgery would result in significant morbidity, neoadjuvant therapy with imatinib can be given for 3 to 6 months. Of note, it may take 4 months or more to observe a response to imatinib on CT scan, although changes in FDG-PET imaging can be seen very rapidly (within days).

1. Treatment of local recurrence. Local recurrence of soft-tissue sarcomas should be treated with surgical resection whenever feasible. Adjuvant radiation is often used. For unresectable recurrence of disease, radiation is preferred.
2. Treatment of metastatic soft-tissue sarcomas
3. Overview. Metastatic soft-tissue sarcomas can be divided into limited metastasis and extensive metastasis. Limited metastatic disease is defined as resectable metastasis involving one organ system. The prognosis of these two subsets of patients is very different. It is possible (though unlikely) to cure limited metastatic disease, whereas patients with extensive metastatic disease can only be palliated.
4. Management of limited metastatic disease. For patients with a limited number of pulmonary metastases, metastasectomy has been performed with some improvement in survival when compared with no surgery. Five-year survival rates range from 23% to 50% if a complete resection is performed (Ann Thorac Surg 2011;92:1780). In patients with visceral sarcomas and limited liver metastasis, it is sometimes possible to perform a metastasectomy by surgery, chemoembolization, or radio-frequency ablation.
5. Management of extensive metastatic disease. The goal of therapy for patients with metastatic sarcoma is palliation and prolongation of survival. Systemic chemotherapy is the primary modality of treatment. Radiation and surgery may be used with a goal of palliation.

 Numerous chemotherapeutic agents have been used as single agents in soft-tissue sarcomas. Doxorubicin and ifosfamide are among the most active agents. Doxorubicin was the first significantly active agent against soft-tissue sarcomas, with an objective overall response rate of approximately 25%. Continuous infusion of doxorubicin or the use of dexrazoxone decreases the risk of cardiotoxicity and the severity of nausea while maintaining equivalent antitumor activity. Dacarbazine (DTIC) has also been found to have activity in soft-tissue sarcomas, with a response rate of 17%. It is particularly effective in uterine leiomyosarcomas. Ifosfamide has been found to have significant activity in sarcoma, with a response rate of 24% to 38%. On the basis of evidence of an increasing response rate to higher doses of ifosfamide, trials of “high-dose ifosfamide” (with 12 to 14 g/m²) showed higher tumor response rates (and toxicities) after an ineffective standard dose (5 to 7 g/m²) of ifosfamide.

 When doxorubicin was combined with DTIC (the AD or ADIC regimen), higher tumor response rates were observed (17% to 40%). To improve the response rate further, several agents were added to the ADIC combination. A combination of [sodium 2-]mercaptoethane sulfonate (MESNA), doxorubicin, ifosfamide, and DTIC (MAID) resulted in a response rate of approximately 47%, with 30% complete responses. Combination chemotherapy has been compared with single-agent doxorubicin in eight randomized phase III trials. Some of them showed superior response rates with combination chemotherapy, but none of the trials found a significant survival advantage. Kaplan–Meier plots of survival are superimposable within each trial and from trial to trial. The MAID regimen is rarely used now in the metastatic setting; instead, either single agent or a combination of doxorubicin and ifosfamide is used.

 Another combination chemotherapeutic regimen that has had activity in soft-tissue sarcomas, in particular, leiomyosarcomas, is gemcitabine and docetaxel, with a response rate of 50% in a phase II trial (J Clin Oncol2007;25:2755). In patients with metastatic angiosarcoma, paclitaxel has shown significant antitumor activity.

1. BONE SARCOMA
2. Bone sarcomas. These may be derived from any of the cells in bone, including cartilage (chondrosarcoma), bone (osteosarcoma, parosteal osteogenic sarcoma), notochord (chordoma), or unknown cells of origin (Ewing’s sarcoma, malignant giant cell tumor, and adamantinoma).
3. Presentation. The clinical presentation of bone sarcomas may suggest the pathologic diagnosis before biopsy.
4. History. Localized pain and swelling are the hallmark clinical features of bone sarcomas. The pain is initially insidious but can become unremitting. Occasionally, a pathologic fracture will bring the patient to medical attention. If the tumor arises in the lower extremities, the patient may have a limp. Constitutional symptoms are rare but can be observed in patients with Ewing’s sarcoma or patients with metastatic disease. A pertinent history should note how long a lesion has been present and any change in it. Rapid growth or change in a lesion favors a malignant etiology.

 It is also important to inquire about risk factors for development of bone sarcomas. These include any history of RT and chronic bone disease. Paget’s disease of bone may give rise to osteosarcoma and giant cell tumors of bone. Sites of chronic osteomyelitis may produce osteosarcomas and squamous cell carcinomas. Fibrous dysplasia may rarely give rise to osteosarcoma. Chondrosarcomas may arise from pre-existing benign enchondroma (solitary or multiple in Ollier’s disease), or exostoses (hereditary multiple exostoses).

2. Physical examination. Physical examination may reveal a palpable mass. A joint effusion may be observed, and range of motion of the joint may be limited with stiffness or pain. Neurovascular and lymph node examinations are usually normal.
3. Diagnosis and staging. Evaluation should include a biopsy and review of appropriate radiographic imaging.
4. Radiographic imaging should include plain films of the lesion and MRI or CT scan. Biplanar radiographs of the affected bone are helpful in determining the specific site of involvement within the bone, the pattern and extent of bony destruction, periosteal changes, and the presence of matrix mineralization within the tumor.

 Osteolytic (bone-destroying) lesions may be seen in metastatic carcinomas, myeloma, and primary bone tumors. Well-defined (geographic) borders of bone destruction may indicate a slower growing or less aggressive lesion, such as a low-grade chondrosarcoma. As the tumor extends beyond the area of lytic destruction, more aggressive growth may be associated with a “moth-eaten” pattern. Rapid, aggressive growth patterns may be associated with cortical destruction, a soft-tissue mass, and a permeative pattern of bone destruction.

 Osteoblastic (bone-forming) lesions may be associated with metastatic disease (e.g., prostate, breast, pancreas, and small-cell cancer of the lung) or osteosarcoma.

 Periosteal reactions may be seen on plain films that give additional clues to the diagnosis. A “sunburst” pattern is associated with classic osteosarcoma. A lamellar or “onion-skin” periosteal reaction is most associated with Ewing’s sarcoma. Spiculated periosteal reactions are associated with rapidly growing tumors such as Ewing’s sarcoma. A raised periosteal reaction (Codman triangle) may be seen in a number of tumors.

 MRI is the imaging study of choice for the evaluation of most bone sarcomas, allowing for visualization of the relation of the tumor to the neurovascular structures, adjacent joints, and the surrounding soft tissues. MRI can also easily demonstrate the intramedullary extent of the tumor and the presence of skip metastases.

 CT scan of the primary site may be considered in place of MRI to demonstrate cortical destruction more accurately and for the evaluation of pelvic tumors. CT scan of the chest is the preferred imaging of the lungs, which is the most common initial site of metastasis.

Radionuclide technetium Tc99 bone scan imaging is important for assessing extent of tumor within bone at the primary, and the presence of skip metastases or distant bone metastases.

1. Laboratory features. Anemia or leukocytosis may be present in patients with Ewing’s sarcoma. Elevated alkaline phosphatase and lactate dehydrogenase (LDH) levels are observed in patients with osteosarcoma, Ewing’s sarcoma, or Paget’s disease. An abnormal glucose tolerance test may be seen with chondrosarcoma.
2. Pathology of bone sarcomas. The classification of bone neoplasms is based on the cell of origin. Primary bone sarcomas can exhibit a phenomenon of dedifferentiation, in which these neoplasms exhibit a dimorphic histologic pattern with low- and high-grade patterns in the tumor. Treatment is dictated by the high-grade lesion.

 i. Osteosarcoma is the most common malignant primary bone tumor, with an annual incidence of three cases per million population. Peaks in incidence occur in adolescents and in the elderly. Most osteosarcomas occur in the metaphyseal region, near the growth plate, of skeletally immature long bones. The distal femur, proximal tibia, and proximal humerus are most common sites.

  ii. Ewing’s sarcoma represents 10% to 15% of all primary malignant bone tumors. It is the second most common malignant tumor of bone in childhood and adolescence. The peak incidence is the second decade of life. Ewing’s sarcoma tends to occur in the diaphysis of long bones. The most common sites are the femur, followed by the pelvis, and then the skin. Ewing’s sarcoma and PPNETs share a common genetic origin, a translocation between chromosomes 11 and 22. When arising in bone, this tumor is recognized as Ewing’s sarcoma, and when arising in soft tissue, this sarcoma is recognized as a PPNET. Treatment of these tumors is similar, by using a combination of chemotherapy and local measures (surgery and radiation). Ewing’s sarcoma is one of the small round blue cell tumors. The differential diagnosis of these tumors includes lymphoma, neuroblastoma, retinoblastoma, and rhabdomyosarcoma.

iii. Chondrosarcoma is the second most frequent malignant primary bone tumor, representing approximately 20% of all primary bone malignancies. It usually occurs in patients older than 40 years. It can occur in any bone, but the majority occur in the pelvis (30%), femur (20%), and the shoulder girdle (15%).

1. Adamantinoma is an indolent, osteolytic tumor that often develops in the upper tibia.

  v. Giant cell tumor of bone, or osteoclastoma, represents approximately 5% of all primary bone tumors. The peak incidence is in the third decade of life, with a female predilection. They are typically epiphyseal–metaphyseal tumors, with the majority in the distal femur and proximal tibia.

3. Staging of bone sarcomas is shown in Table 30-3. Adverse prognostic indicators include an increased LDH, an increased alkaline phosphatase, and an axial primary. Patients with Ewing’s sarcoma should have a bone marrow biopsy as part of staging.
4. Treatment of bone sarcomas
5. General principles of local therapy. Surgical excision is the mainstay of treatment for patients with low-grade bone sarcomas. For high-grade tumors, multimodality therapy is indicated. As an example, for high-grade osteosarcomas, preoperative multiagent chemotherapy is followed by surgical removal of the tumor and then further adjuvant chemotherapy. It is essential to distinguish high-grade osteosarcoma from a low-grade variant, parosteal osteosarcoma, the latter of which has a lower malignant potential and does not require adjuvant chemotherapy. Occasionally, parosteal osteosarcomas will become dedifferentiated (high grade), and their behavior will resemble that of the classic aggressive osteosarcoma.

1. Limb-sparing surgery. The Musculoskeletal Tumor Society and the NCCN recognize wide excision, either by amputation or by a limb-salvage procedure, as the recommended surgical approach for all high-grade bone sarcomas. Currently, 75% to 80% of patients may be treated with a limb-sparing surgery. This type of resection is predicated on complete tumor removal, effective skeletal reconstruction, and adequate soft-tissue coverage. There are three types of limb-sparing procedures.

 i. Osteoarticular resection is an excision of the tumor-bearing bone and the adjacent joint. It is the most common procedure because most bone sarcomas arise in the metaphysic of long bones.

  ii. Intercalary resection is an excision of tumor-bearing bone only.

iii. Whole bone resection is an excision of the entire bone and adjacent joints. It is used when the tumor extends along or invades the joint. Reconstruction is usually achieved by prosthetic arthroplasty.

2. Osteosarcoma therapy. The 5-year survival for osteosarcoma with surgery alone is less than 20%. This occurs because microscopic dissemination is likely to be present in 80% of patients at the time of diagnosis. The addition of adjuvant chemotherapy has improved survival for high-grade osteosarcoma, permitting long-term survival as high as 80%.
3. Neoadjuvant and adjuvant chemotherapy. Neoadjuvant chemotherapy began as a strategy to permit limb-sparing surgery, allowing time for creation of custom-made prosthetics. Since its acceptance, other advantages have been recognized with this approach. It permits earlier treatment of occult micrometastatic disease, preventing emergence of resistant clones, and potentially allowing debulking of the primary to improve chances for limb-sparing surgery.

 Chemotherapy drugs active in osteosarcomas include doxorubicin, cisplatin, and high-dose methotrexate with leucovorin rescue. These agents are typically used in combination to improve response, although the optimal combination and duration of therapy remain controversial.

 Histologic response to preoperative therapy is recognized as a significant prognostic factor. Various systems have been developed for grading histologic response to chemotherapy, but greater than 90% necrosis of tumor cells is associated with the best prognosis. If the tumor has been resected to negative margins and had a good histologic response to chemotherapy, the patient continues on chemotherapy for an additional 2 to 12 cycles. If the tumor was fully resected but has less than 90% necrosis, salvage chemotherapy with agents not used in induction is attempted, but the effect of this change in chemotherapy on outcomes is unclear. If the tumor margins are positive, additional local surgery should be attempted.

1. Radiation therapy. Radiation is not routinely used in the therapy of osteosarcoma, but may prove helpful in patients who refuse definitive resection or palliation of patients with metastatic disease.
2. Management of metastatic disease. Approximately 10% to 20% of patients with osteosarcoma have evidence of metastatic disease at presentation. Some of these patients may be candidates for surgical resection of pulmonary metastases. For patients with more extensive metastatic disease, chemotherapy is used to provide control of disease and palliation of symptoms.
3. Therapy for Ewing’s sarcoma and the related PPNETs use a combined-modality approach.
4. Treatment of the primary tumor. The optimal treatment for local tumor control is not well defined. Historically, RT has been the mainstay of local therapy, but there has been a recent trend toward surgery. No prospective randomized trials have been performed to compare the two modalities, but retrospective data suggest improvements in local control and survival when surgery is done with a complete resection of the tumor. Patients with unresectable disease or positive margins require RT to improve local control.
5. Chemotherapy. Before the availability of effective chemotherapeutic agents, fewer than 10% of patients with Ewing’s sarcoma survived beyond 5 years, although only 15% to 35% of patients with Ewing’s sarcoma/PPNET have evidence of metastatic disease at presentation. This fact suggests that many patients with Ewing’s sarcoma had occult microscopic dissemination of the disease at the time of diagnosis. The First Intergroup Ewing’s Sarcoma Study demonstrated an improved survival rate for patients receiving systemic therapy with VACA (vincristine, actinomycin D, cyclophosphamide, and doxorubicin). The Second Intergroup Ewing’s Sarcoma Study used VACA, but on an intermittent schedule and a higher dose and achieved an improved 5-year survival (73%).

 The addition of alternating cycles of ifosfamide and etoposide to VAC further improved survival in patients with nonmetastatic Ewing’s sarcoma and PPNET.

1. Recurrent metastatic Ewing’s sarcoma. Although cure is not a realistic goal, aggressive combination chemotherapy (VAC or IE) and RT can still lead to prolonged progression-free survival.
2. Therapies for chondrosarcoma. Chondrosarcomas are a group of tumors that arise from the cartilage matrix and are the third most common bone tumor. There are many subtypes of chondrosarcoma, and not all are treated in a similar manner.
3. Treatment of the primary tumor. As chondrosarcomas are usually slow nonmetastasizing tumors, the majority are treated with surgery alone. Dedifferentiated chondrosarcoma should be approached in a similar manner as osteosarcoma, and mesenchymal chondrosarcoma should be treated as if it is Ewing’s sarcoma.
4. Chemotherapy. As chondrosarcomas are generally slow growing, most chondrosarcomas are resistant to chemotherapy. The standard of care for metastatic chondrosarcoma is clinical trial.

 VI. FUTURE DIRECTIONS. In the treatment of sarcomas include the search for more effective chemotherapeutic agents and combinations, and targeted therapies that will exploit the genetic features of these tumors.

SUGGESTED READINGS

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Demetri GD, von Mehren M, Blanke CD, et al. Efficacy and safety of imatinib mesylate in advanced gastrointestinal stromal tumors. New Eng J Med 2002;347:472–480.

Demetri GD, Reichardt P, Kang Y-K, et al. Efficacy and safety of regorafenib for advanced gastrointestinal stromal tumours after failure of imatinib and sunitinib (GRID): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 2013;381:295–302.

Gyorki DE, Brennan MF. Management of recurrent retroperitoneal sarcoma. J Surg Oncol 2014;109:53–59.

Kolberg M, Holand M, Agesen TH, et al. Survival meta-analyses for >1800 malignant peripheral nerve sheath tumor patients with and without neurofibromatosis type 1. Neuro Oncol 2013;15:135–147.

O’Sullivan B, Davis AM, Turcotte R, et al. Preoperative versus postoperative radiotherapy in soft-tissue sarcoma of the limbs: a randomised trial. Lancet 2002;359:2235–2241.

von Mehren M, Benjamin RS, Bui MM, et al. Soft tissue sarcoma, version 2.2012: featured updates to the NCCN guidelines. J Natl Compr Cancer Netw 2012;10:951–960.