Chapter 42: Soft Tissue and Bone Sarcomas

Sarcomas are a rare and heterogeneous group of tumors that arise from mesenchymal tissues. According to the estimates of the American Cancer Society, approximately 1.6 million people were estimated to be diagnosed with cancer in the United States in the year 2013, with only 14,420, or just less than 1% of cases, representing sarcomas (¹); 11,410 of these cases represent new soft tissue sarcomas and 3,010 represent bone sarcomas, with 4,390 and 1,440 deaths, respectively, resulting from these tumors (¹).

The etiology and pathogenesis of sarcomas is not well understood. Multiple environmental factors including radiation and chemical exposures, trauma, and infection have been associated with the development of soft tissue and bone sarcomas. Both sporadic and inherited molecular and genetic aberrations have been identified in specific subsets of sarcoma and have been implicated in sarcomagenesis.

Several inherited familial cancer syndromes have been associated with a predisposition to development of soft tissue and bone sarcomas. The Li-Fraumeni syndrome resulting from a germline mutation of the p53 tumor suppressor gene is associated with increased risk of soft tissue sarcomas and osteosarcoma among several other cancers in children and young adults (²). Inherited retinoblastoma is also associated with the development of sarcomas, both osteosarcoma and soft tissue sarcoma (²). Neurofibromatosis type 1 is associated with an increased risk of development of sarcoma in a preexisting neurofibroma, resulting in a malignant peripheral nerve sheath tumor (³). Sarcomas have been associated with other cancer family syndromes including basal cell nevus syndrome, Werner syndrome, familial adenomatous polyposis, and Gardner syndrome, among others (²).

Recurrent cytogenetic abnormalities have been identified in many sarcomas and are thought to contribute to sarcomagenesis. Genetic profiling of bone and soft tissue sarcomas has expanded the characterization of mesenchymal tumors beyond translocation-positive/translocation-negative categorizations to identify three distinct groups: (1) genetically unstable sarcomas with complex karyotypes; (2) tumors with specific, recurrent genetic alterations such as translocations, deletions, or copy number variations; or (3) tumors with molecular aberrations such as amplifications, mutations, or loss of heterozygosity (Table 42-1). These alterations serve an important role in diagnosis as well as prognosis and have potential implications for therapy.

Molecular testing has become more widely used for diagnosis in soft tissue sarcoma, identifying specific abnormalities in certain histologic subtypes (⁴). For example the t(x;18) translocation is a specific marker for synovial sarcomas. The transcript formed from this translocation (SYT-SSX) can be detected using polymerase chain reaction (PCR) testing. In one study, the SYT-SSX transcript was positive in 84.5% of tumors where the diagnosis of synovial sarcoma was certain based on histology and 24.3% of tumors in which synovial sarcoma was considered but not first in the differential diagnosis (⁵). Another example is the FUS-DDIT3 translocation in myxoid liposarcoma where the presence of DDIT3 rearrangement confirms the diagnosis (⁶). These data suggest that molecular pathology may also be a useful adjunct in the diagnosis of some sarcomas.

Specific translocations have also been investigated as prognostic biomarkers and potential therapeutic targets. For example, the EWS-FLI1 transcript in Ewing sarcoma was previously identified as an independent prognostic factor (⁷), but more recent studies have not found an association potentially due to improved therapeutic regimens (⁸). Alternatively, in alveolar rhabdomyosarcoma, translocation-negative tumors have better outcomes than translocation-positive tumors despite histologic appearance (⁹). Although genomic profiling has increased our understanding of sarcomageneis, to date no routine therapies have been identified to target specific translocations in sarcoma. However, the success of the targeted therapy imatinib in the treatment of gastrointestinal stromal tumors, directed at an oncogenic mutation in KIT, suggests a role for subtype-specific molecular therapies.

Soft tissues include fibrous, adipose, and vascular structures as well as muscles and tendons and are mesenchymal in origin. Soft tissue sarcomas are a heterogeneous group encompassing approximately 60 different subtypes, based on their resemblance to normal tissues rather than the tissue of origin.

Clinical Presentation

Soft tissue sarcomas can occur in any anatomic region. The majority of soft tissue sarcomas arise from the extremities (60%), followed by the trunk (30%) and the head and neck region (10%). The most common presenting symptom is a soft tissue mass or swelling. Pain is reported by only about one-third of patients at presentation. Therefore, because of the lack of symptoms, there is often a delay in the diagnosis. Patients with a soft tissue mass that is increasing in size, a mass >5 cm, or a mass that is deep to deep fascia, regardless of pain, should be referred for evaluation of a suspected soft tissue sarcoma (¹⁰).

Evaluation

Evaluation of a suspected soft tissue sarcoma begins with a comprehensive history and physical examination. Imaging evaluation is dependent on the site of disease. For soft tissue tumors of the extremities, head and neck, and pelvis, magnetic resonance imaging (MRI) is preferred. Soft tissue sarcomas found in the retroperitoneum and abdomen are generally best evaluated by computed tomography (CT). Positron emission tomography (PET) imaging can distinguish histologic grade to a degree based on tumor standardized uptake values (SUV) (¹¹). For both soft tissue sarcomas and bone sarcomas, PET imaging has a predictive role in determining response to chemotherapy and targeted agents such as imatinib, but it has also been shown to predict survival after initial cycle of therapy among patients receiving neoadjuvant chemotherapy for high-grade soft tissue sarcoma (^12,13).

A biopsy is essential to diagnosis, and the method of biopsy chosen should be the least invasive technique available to make a definitive diagnosis. A core-needle biopsy is sufficient; however, multiple cores should be obtained to improve diagnostic yield. If an open biopsy is performed, it should be planned such that the biopsy tract can be removed at the time of definitive surgical resection to reduce the risk of seeding and recurrence (¹⁴). An excisional biopsy may be used for small or superficial lesions; however, careful examination of margins and planning of the orientation of the resection should always be performed. Fine-needle aspiration (FNA) is not recommended but can be useful in confirming recurrence, assuming that an experienced sarcoma cytopathologist is available (¹⁵).

Pathology

Sarcomas are classified primarily according to their tissue appearance, histologic grade, and sometimes the cell of origin. This can be difficult, as approximately 60 different histologic types of soft tissue sarcoma are recognized (Table 42-2). Histologic diagnosis is classified by the updated 2013 World Health Organization criteria (¹⁶).

Pathologists often separate sarcomas into three histologic grades using the Federation Nationale des Centres de Lutte Contre le Cancer (FNCLCC) grading system. Biological aggressiveness can be predicted based on histologic grade, and this spectrum varies among the histologic subtypes of sarcoma (¹⁷). Immunohistochemistry, cytogenetics, and molecular pathology can aid in making a diagnosis; however, some poorly differentiated spindle cell neoplasms cannot be categorized further.

Staging and Prognosis

The American Joint Committee on Cancer (AJCC) staging system may be used for soft tissue sarcomas (Table 42-3) (¹⁸). All soft tissue sarcoma subtypes are included except Kaposi sarcoma, dermatofibrosarcoma protuberans, infantile fibrosarcoma, and angiosarcoma. This system is designed to classify tumors of the extremities, trunk, head and neck, and retroperitoneum, but it was not designed for evaluation of sarcomas of the gastrointestinal (GI) tract. This system has its limitations because anatomic site and certain histologic subtypes (eg, small cell histologies) that are known to influence outcome are not taken into account (¹⁹).

Several clinicopathologic factors are important for treatment planning and prognosis assessment. These form the basis for the AJCC classification system and include tumor grade, size of the primary tumor, depth of invasion, and extent of disease (¹⁷). High-risk features for local recurrence or distant metastases are high-grade lesions, primary tumor >5 cm, and deep tumor location. Approximately 50% of patients with intermediate- and high-grade soft tissue sarcoma will develop metastatic disease requiring systemic therapy (²⁰). The 5-year overall survival for soft tissue sarcoma is around 50%, with local control and distant disease being the key determinants (²¹).

Treatment

Treatment of sarcoma requires a multidisciplinary approach with experienced medical, surgical, and radiation oncologists, pathologists, and radiologists. An improved understanding of soft tissue sarcoma subtypes in regard to natural history, response to chemotherapy, and potential for targeted therapies has led to more subtype-specific treatment according to individual histology.

Treatment of Local Disease

Surgery

For local disease, surgical resection is the mainstay of treatment. Sarcomas tend to expand and compress tissue planes, which produce a pseudo-capsule comprising normal tissue interlaced with tumor tissue. Wide local excision with a margin of normal tissue surrounding the tumor is associated with lower local recurrence rates of approximately 10% to 30% (¹⁷). The ideal surgical margins should be 2 to 3 cm without tumor involvement. If positive margins are confirmed by pathology, re-excision to obtain negative margins is important when feasible to improve local control and relapse-free survival. For patients with borderline resectable tumors, consideration should be given to neoadjuvant therapy depending on the tumor histology and patient’s performance status.

Adult sarcomas have a less than 4% prevalence of lymph node metastases (²²). For this reason, routine regional lymph node dissection is often not required. However, patients with synovial sarcoma, clear cell sarcoma, rhabdomyosarcoma, angiosarcoma, and epithelioid sarcomas have a higher incidence of lymph node metastases and should be evaluated closely for lymphadenopathy.

Improved surgical techniques and multimodality treatment have resulted in a decrease in radical resection of extremity tumors with a corresponding rise in limb-sparing procedures combining wide local resection with preoperative or postoperative chemotherapy and radiotherapy. Approximately 90% of patients with localized sarcomas of the extremities can safely undergo limb-sparing procedures to preserve limb function and adequately maintain local control (²³). A study conducted at the National Cancer Institute (NCI) showed no survival advantage to amputation over limb-sparing surgery with postoperative radiation (²⁴).

Radiation

Although radiation is not effective for the treatment of gross disease, it has been a useful adjunct to surgery in the treatment of microscopic local disease and for palliation of symptoms. Radiation therapy is commonly used in the preoperative or postoperative adjuvant setting. Because there are pros and cons as to the timing of radiation therapy, this topic remains controversial; appropriate discussion between radiation oncologists, medical oncologists, and surgeons is required in planning the treatment of each patient.

Preoperative radiation has several advantages over postoperative radiation, including smaller radiation portals, conversion to a limb-sparing procedure, reduction of the extent of the surgical procedure, and lower radiation doses, which can be used because there are theoretically fewer radio-resistant hypoxic cells within the tumor and surgical removal can supplement the boost (²⁵). However, preoperative radiotherapy may lead to difficulty in assessing pathologic responses to preoperative chemotherapy and may also contribute to delayed wound healing. Several studies have shown improved local control rates with preoperative radiation, especially with larger tumors that were initially considered unresectable (²⁶). The modality of choice is external beam radiotherapy (EBRT), and a dose of 50 Gy or more is often required to obtain local control. At these dose levels, the entire circumference of the extremity must not be irradiated in order to avoid lymphedema. A period of 4 to 6 weeks is needed following preoperative radiation to prevent wound complications. Following the surgical resection, close or positive margins could be treated with a radiation boost if feasible. Brachytherapy, EBRT, or intraoperative radiotherapy can be used by experienced clinicians in appropriate situations (²⁷).

Postoperative radiation therapy should be considered in patients with high-grade soft tissue sarcomas of the extremities with positive microscopic margins (<1 mm from the inked margin). In this setting, adjuvant radiation improved the 5-year local control rate compared to the no RT group (74% vs 56%; P = .01) (²⁸). More recently, adjuvant intensity-modulated radiation therapy has been shown to reduce local recurrence as compared to conventional EBRT for primary soft tissue sarcoma of the extremity (hazard ratio [HR], 0.46; P = .02) (²⁹). The interval of time between surgery and initiation of radiation therapy is a controversial but legitimate concern. The most recent soft tissue sarcoma guidelines issued by the National Comprehensive Cancer Network (NCCN) suggest the interval should be no greater than 6 weeks (³⁰).

Radiation therapy is occasionally used as the sole treatment modality for palliation for some patients with soft tissue sarcomas. These patients are often those who have unresectable disease or who are not appropriate candidates for surgery and/or chemotherapy. There have been reports of 5-year survival rates ranging from 25% to 40% with radiation therapy alone and of local control rates of approximately 30%, depending on the primary tumor’s size and biology (³¹).

Chemotherapy

Systemic therapy for soft tissue sarcomas is primarily used in the metastatic/advanced disease setting, whereas the role of chemotherapy in the neoadjuvant and adjuvant setting is less well established. Treatment relies primarily upon conventional chemotherapy agents, which are largely unchanged over the past two decades. In general, tumors with a higher grade are more likely to responds to chemotherapy; however, chemosensitivity varies based on histologic subtype (Table 42-4) (³²). An understanding of chemosensitivity and molecular aberrations based on subtype has led to histology-driven treatment algorithms for specific soft tissue sarcomas such as leiomyosarcoma, myxoid liposarcoma, and angiosarcomas (Fig. 42-1). This approach is particularly important in considering targeted therapies for specific subtypes that are considered chemoresistant such as alveolar soft parts sarcoma.

The two most active agents in the treatment of soft tissue sarcoma are doxorubicin and ifosfamide. Doxorubicin is most active at doses of ≥75 mg/m², with single-agent response rates of approximately 20% to 35% (³³). Ifosfamide has been shown to produce single-agent response rates similar to those of single-agent doxorubicin when used at doses of 10 g/m² or higher (³⁴). Ifosfamide has also been shown to have greater efficacy when administered as a 2- to 3-hour infusion as opposed to a 24-hour infusion (^34,35). Studies have shown that both doxorubicin and ifosfamide also exhibit a positive dose-response curve (^33,34). The response rate in soft tissue sarcoma patients whose disease failed doxorubicin-based therapy and who then received high-dose ifosfamide as a single agent was 29% (³⁴). Therefore, high-dose ifosfamide as a single agent at doses of 14 g/m² is sometimes used as a salvage regimen at the University of Texas MD Anderson Cancer Center (MDACC) for selected histologies.

Combination therapy with dose-intense doxorubicin and ifosfamide has been shown to improve response rates and progression-free survival (PFS) and possibly overall survival (³⁶). The combination of doxorubicin (75 or 90 mg/m²) and ifosfamide (at 10 g/m²) was evaluated at MDACC in patients with soft tissue sarcomas and demonstrated a 75% response rate (95% confidence interval [CI], 59%-71%; complete response [CR], 12%) in patients with primary tumors of the extremities and a 68% response rate (95% CI, 56%-80%; CR, 12%) in patients with primary disease at any site (³⁷). The response rates according to histology were as follows: malignant fibrous histiocytoma, 69%; synovial sarcoma, 88%; unclassified sarcomas, 60%; non-GI leiomyosarcomas, 50%; liposarcomas, 56%; angiosarcomas, 83%; and neurogenic sarcomas, 40%; other miscellaneous histologies demonstrated objective response rates of 45% (³⁷). In the large randomized phase III European Organization for Research and Treatment of Cancer (EORTC) 62012 trial comparing single-agent doxorubicin with doxorubicin in combination with ifosfamide, the combination group had a significantly higher response rate (26% vs 14%) and increased median PFS (7.4 vs 4.6 months) but also had an increase it grade 3 and 4 toxicities. Although overall survival at 1 year was increased in the combination group (60% vs 51%, P = .076), this failed to meet statistical significance (³⁸). At our center, we continue to use combination dose-intense doxorubicin and ifosfamide in appropriately selected patients and preferentially in the neoadjuvant setting for large (≥5 cm), high-grade, resectable soft tissue sarcomas.

Dacarbazine has activity as a single agent, with response rates of 10% to 15%. The three-drug regimen MAID (mesna, doxorubicin [Adriamycin], ifosfamide, dacarbazine) has been studied and has shown response rates varying from 25% to 47% (³⁹). When the MAID regimen was studied at MDACC, significant toxicities related to the addition of dacarbazine were seen (⁴⁰). The combination of doxorubicin and dacarbazine (ADIC) is often used in extrauterine leiomyosarcoma or as a second-line regimen in other soft tissue sarcomas. In patients with advanced/metastatic leiomyosarcoma or liposarcoma treated with ADIC as first-line therapy, Response Evaluation Criteria in Solid Tumors (RECIST) response rates of 57% and 40% were observed, respectively (⁴¹).

Gemcitabine alone or in combination with docetaxel is frequently used for the treatment of advanced, recurrent, or metastatic disease once patients fail doxorubicin- and ifosfamide-based therapy or in patients who may not tolerate intensive chemotherapy. An initial phase II study using gemcitabine as a single agent demonstrated a response rate of 18% (95% CI, 7%-29%), including many pretreated patients (⁴²). The synergistic effect of docetaxel when added to gemcitabine was evaluated in a randomized phase II study, SARC002 (⁴³). By RECIST, response rates for the gemcitabine-docetaxel arm and gemcitabine arm was 16% and 8%, respectively. Furthermore, an improvement in median PFS (6.2 vs 3.0 months) and overall survival (17.9 vs 11.5 months) was noted in the gemcitabine-docetaxel arm compared to the gemcitabine arm. The two histologies most responsive to the gemcitabine-docetaxel arm were leiomyosarcoma and high-grade undifferentiated pleomorphic sarcoma.

Trabectedin, a novel antitumor compound initially isolated from extracts of sea squirt Ecteinascidia turbinata through the NCI drug screening program in the 1960s, has shown activity in the second-line treatment of soft tissue sarcomas. The mechanism of action of trabectedin is complex but is thought to involve displacement of transcription factors from their promoter (⁴⁴). Additionally, sensitivity of myxoid liposarcoma, a translocation-related soft tissue sarcoma, has been shown to correlate with expression of the FUS-DDIT3 fusion gene (⁴⁵). Taken together, these factors suggest a role for trabectedin in translocation-related sarcomas and pose a potential mechanism of action. In a single-arm phase II trial of trabectedin as second- or third-line therapy in advanced soft tissue sarcoma, the overall response rate was 8% (⁴⁶). However, many patients demonstrated prolonged disease stabilization, with 26% with stable disease >6 months with minimal toxicities. This benefit was greatest in leiomyosarcomas and translocation-related sarcomas. A retrospective review of eight phase II trials of trabectedin in translocation-related soft tissue sarcomas demonstrated encouraging results in regard to disease control, with greatest activity in myxoid liposarcoma (⁴⁷). This has led to a current phase III trial of first-line therapy with trabectedin versus doxorubicin-based chemotherapy in translocation-related sarcomas. Currently, trabectedin is approved in Europe for second-line treatment of soft tissue sarcoma and has been granted orphan drug status by the US Food and Drug Administration.

Adjuvant/Neoadjuvant Chemotherapy

The goals of chemotherapy in the treatment of high-risk local disease are to eradicate micrometastasis, decrease risk of local recurrence, and downsize tumors to facilitate either limb-sparing procedures for extremity tumors or resection for tumors initially deemed unresectable (Fig. 42-2). At MDACC, preoperative chemotherapy is preferred in patients with high-risk (>5 cm or high-grade) tumors and in patients who are considered borderline resectable with chemosensitive soft tissue sarcoma subtypes.

Postoperative chemotherapy and its benefits continue to be controverted as trials of adjuvant therapy have yielded conflicting results. In the most recent update to the Sarcoma Meta-Analysis Collaboration (SMAC) conducted in 2008, the benefit of adjuvant chemotherapy was analyzed among 1,953 patients with soft tissue sarcoma across 18 trials (⁴⁸). This update incorporated five trials evaluating doxorubicin and ifosfamide in combination, a regimen not previously represented in the initial SMAC analysis. This updated meta-analysis detected favorable odds ratios (ORs) of local recurrence and distant recurrence for chemotherapy. Although the absolute risk reduction (ARR) in distant recurrence with adjuvant doxorubicin-based chemotherapy for all studies was 9% (95% CI, 5%-14%; P = .000), the ARR with adjuvant doxorubicin-ifosfamide chemotherapy was 10% (95% CI, 1%-19%; P = .03) (⁴⁸). By pooling the data, the number needed to treat (NNT) to prevent distant recurrence was 12. Although a survival benefit was not noted with single-agent doxorubicin, a statistically significant survival advantage was observed with the doxorubicin-ifosfamide combination. The OR for overall survival in the doxorubicin-ifosfamide cohort was 0.56 (95% CI, 0.36-0.85; P = .01). Combining all trials in the meta-analysis, the NNT to prevent one death was 17. A recent randomized controlled trial of adjuvant therapy with doxorubicin 75 mg/m² and ifosfamide 5 g/m² in patients with intermediate- or high-grade STS failed to demonstrate a benefit in overall survival (HR, 0.94; P = .72) or relapse-free survival (HR, 0.91; P = .51) (⁴⁹). Although the data regarding adjuvant therapy are conflicting, within our institution, we continue to offer adjuvant therapy with doxorubicin in combination with ifosfamide to healthy patients with intact organ function who have high-risk disease (tumor size >5 cm, high-grade histology, and deep soft tissue involvement).

Targeted Therapy

As in other tumor types, increased knowledge of cancer genomics and identification of oncogenic driver mutations in soft tissue sarcomas have led to much enthusiasm and investigation of molecular-based targeted therapies. A comprehensive review of targeted therapies under development for soft tissue sarcoma is beyond the scope of this chapter, and therefore, the focus will be on currently approved therapies. Targeting cKIT with the tyrosine kinase inhibitor (TKI) imatinib in gastrointestinal stromal tumors (GISTs) is perhaps the best-known and most successful example in sarcoma. Although targeted agents have shown promise in specific histologies, the multitargeted TKI pazopanib has shown activity across multiple subtypes of soft tissue sarcomas. Pazopanib is a small-molecule inhibitor with activity against VEGF1-3, PDGFRA, PDGFRB, and KIT. A phase II trial of pazopanib in advanced soft tissue sarcoma evaluating 12-week PFS as the primary end point showed benefit in leiomyosarcoma (44%), synovial sarcoma (49%), and other nonlipomatous soft tissue sarcoma (39%) (⁵⁰). Subsequently, a placebo-controlled phase III trial of pazopanib in metastatic soft tissue sarcoma demonstrated a low response rate (partial response [PR], 6%) but significant improvement in PFS (4.6 months vs 1.6 months with placebo; HR, 0.31; P < .0001) (⁵¹). In a multivariate Cox model, favorable prognostic factors in patients treated with pazopanib were good performance status and low or intermediate tumor grade. Additional targeted therapies in soft tissue sarcoma are primarily being developed and studied in specific soft tissue sarcoma subtypes.

Metastatic Disease and Metastasectomy

Patients with metastatic disease involving multiple organs are generally incurable and considered appropriate for palliative systemic therapy as described earlier. The subset of patients with lung-only metastatic disease, especially with a greater than 12-month disease-free interval, have a favorable biology and prognosis and therefore should be considered for resection if feasible. This approach results in 3- to 5-year survival of up to 20%. Chemotherapy is the mainstay of therapy for patients with metastatic disease, although surgical resection of residual disease to render patients free of gross disease is often pursued. The sequencing of chemotherapy is similar to that of isolated local disease. In a study conducted at MDACC, patients with metastatic disease showed a 57% response rate to doxorubicin (75-90 mg/m²) and ifosfamide (10 g/m²) (³⁷). If patients fail this regimen, the choice of treatment depends on the histology of the tumor and the performance status of the patient.

Specific Soft Tissue Sarcomas

Vascular Sarcomas

Vascular sarcomas are tumors that originate from or differentiate toward the endothelium with varying malignant potential. Although epithelioid hemangioendotheliomas have an intermediate malignant potential and indolent clinical course, angiosarcomas, at the other end of the spectrum, have a highly malignant biologic behavior with early propensity for distant metastasis and dismal outcomes. These tumors also differ in their response to chemotherapy and targeted therapy and, therefore, are discussed separately below.

Epithelioid hemangioendotheliomas (EHE) are considered to be of intermediate malignant potential with development of metastasis and recurrence. They typically are associated with a blood vessel, usually a medium sized or large vein. Epithelioid hemangioendothelioma most commonly occurs in the soft tissues, but liver, lung, and bone may be sites of primary involvement. In over 42% of patients with hepatic EHE, symptoms are often absent and the lesions are discovered incidentally. Some patients experience constitutional symptoms such as fatigue, anorexia, nauseam and poor exercise tolerance. Most cases of EHE affecting soft tissues are localized, whereas multifocality is more common with EHE involving liver or lung, and these patients develop metastatic disease during the course of their illness. Multifocal or metastatic disease does not equate to mortality, and many patients can survive long term with metastatic disease. Sixty-three percent of patients with liver EHE and less than half of patients with metastatic EHE of soft tissues die from their disease.

Localized EHE of soft tissue should be treated with surgical resection with adequate margins. Following resection, these tumors can recur locally in about 12% of patients (⁵²). Preoperative radiation therapy should be considered in patients where good margins are unlikely, and postoperative radiation therapy should be considered in cases where the margins are positive and no preoperative radiation was administered. Localized EHE does not require the use of chemotherapy or targeted therapies.

Metastatic EHE of soft tissue may be followed without therapy until there is evidence of progressive disease on serial imaging over a 3-month period. When systemic therapy is needed, conventional chemotherapy and antiangiogenic therapy may be considered. Systemic therapy options include gemcitabine, taxanes, and doxorubicin. Targeted therapy with bevacizumab (PR, 29%; stable disease, 57%; and progressive disease, 14%) (⁵³), sorafenib (30.7% without progression at 9 months) (⁵⁴), and interferon α-2b (⁵⁵) has been reported to have utility in patients with metastatic EHE.

Angiosarcomas are highly malignant tumors with endothelial differentiation with a propensity for recurrence and distant metastasis. These tumors are extremely rare, representing <2% of all sarcomas, and can develop de novo or in the setting of prior radiation therapy or chronic lymphedema. Due to their endothelial location, these tumors are particularly well poised for early dissemination and development of metastasis. Angiosarcoma has a propensity for cutaneous involvement, and 60% of cases have skin or soft tissue involvement. Other sites of visceral involvement include spleen, liver, lung, pleura, heart, and GI tract. Clinical behavior and response to therapy can vary from one site to another, with cardiac angiosarcomas carrying the worst prognosis.

Even when these tumors are nonmetastatic, multifocality is often present locally, resulting in high recurrence rates. Therefore, it is critical to approach localized disease with a multidisciplinary approach that combines chemotherapy, radiation, and surgery to produce better outcomes (⁵⁶). At our institution, we prefer to treat these patients with neoadjuvant chemotherapy followed by surgery and radiation. Chemotherapy can utilize either doxorubicin-based or taxane-based approaches, both of which have excellent outcomes, and the choice of the regimen depends on the primary location of disease, histologic subtype, performance status of the patient, and potential for toxicity. For cutaneous angiosarcoma, taxanes are as good as doxorubicin-based approaches, but for visceral angiosarcoma, doxorubicin-based approaches may have better activity.

Patients with metastatic disease can be treated with single-agent or multiagent chemotherapy. Monotherapy with doxorubicin (response rate, 29%-33%; PFS, 3-5 months) and paclitaxel (response rate, 18%-89%; PFS, 4-5 months) appears to have significant activity in patients with angiosarcomas (^{57,58,59,60,61}). Based on a retrospective study of 117 patients with metastatic angiosarcoma, weekly paclitaxel (response rate, 53%) may have comparable efficacy to doxorubicin as a single agent in patients with cutaneous angiosarcoma (⁵⁷). Doxorubicin may have advantages over paclitaxel in visceral angiosarcomas. Gemcitabine also appears to have single-agent activity (response rate, 64%; PFS, 7 months) (⁶²), but this drug is more commonly used in combination with taxanes.

The most commonly used combination therapies in angiosarcoma are doxorubicin-ifosfamide and gemcitabine-docetaxel. The doxorubicin-ifosfamide combination is preferred for visceral angiosarcomas and has better durability than any other treatment for angiosarcoma, with a median PFS of 5.4 months (⁵⁹). The gemcitabine-docetaxel combination appears to have good activity both in the visceral and cutaneous angiosarcomas.

Antiangiogenic therapies with activity in angiosarcomas include bevacizumab (PR, 9%; stable disease, 48%; median PFS, 12 weeks) (⁵³), sunitinib (⁶³), and sorafenib (CR, 3%; PR, 11%; stable disease, 57%; median PFS, 3.2 months) (⁶⁴). Although responses with targeted therapies appear to be low compared to conventional chemotherapy, this may be a result of using an unselected study population for treatment.

Leiomyosarcoma

Leiomyosarcoma (LMS) is a common soft tissue sarcoma subtype and can arise anywhere in the body. The site of origin and grade are important prognostic factors and also guide treatment. Patients with vascular origin LMS have a worse prognosis compared with nonvascular LMS patients. Additionally, patients with uterine LMS tend to fare better compared with extrauterine LMS patients, although this may be in part due to a higher rate of complete resection in uterine LMS (⁶⁵). Leiomyosarcoma is responsive to multiple chemotherapeutic agents used in soft tissue sarcoma but has been shown to be less responsive to ifosfamide-containing regimens than single-agent doxorubicin (⁶⁶). Gemcitabine is active in LMS. A subtype-specific phase II trial of gemcitabine versus gemcitabine in combination with docetaxel in metastatic or relapsed LMS (⁶⁷) showed significant response rates with both single-agent gemcitabine and the combination (19% vs 24%, respectively) in patients with uterine LMS. In the non–uterine LMS subgroup, combination therapy resulted in higher objective response rates (14% vs 5%) and prolonged PFS (6.3 vs 3.8 months). Hormonal treatment may be considered for patients with uterine LMS. In the largest retrospective study of aromatase inhibitors in uterine LMS, response rates included PR in 9% and stable disease in 32%. Patients with hormone receptor–positive disease demonstrated better PFS (⁶⁸). The treatment algorithm for advanced LMS should take into account the site of origin (uterine vs extrauterine), hormone expression in uterine LMS, and O⁶-methylguanine-DNA methyltransferase (MGMT) methylation status (see Fig. 42-1).

Liposarcoma

Liposarcomas represent the second most common soft tissue sarcoma. There are several histologic subtypes of liposarcoma with unique clinical and biological features. Myxoid liposarcoma represents the most common variant of liposarcoma. Other subsets include well-differentiated, dedifferentiated, and pleomorphic subtypes. Myxoid liposarcomas often occur in the third through fifth decades of life and generally develop in the extremities. Although regarded a low-grade tumor, local recurrence and distant metastasis occur in about 30% of patients. Sites of metastasis include lungs and soft tissue regions such as the axilla, retroperitoneum, the pleural lining, and even the pericardium. A rare variant of myxoid liposarcoma, round cell liposarcoma, is considered to be a more malignant variant of a spectrum of this disease. An increase in round cell percentage correlates to metastasis and poor survival in myxoid liposarcomas (⁶⁹). The balanced translocation t(12;16)(q13;p11) results in the oncoprotein FUS-DDIT3, which is pathognomonic for myxoid liposarcoma (^70,71). The product of this arrangement is thought to contribute to the oncogenesis through transcription of angiogenic, inflammatory, and adipocytic maturation factors resulting in myxoid liposarcoma (⁷²). Treatment options for myxoid liposarcoma depend on the location and size of the lesion. Whereas surgery and radiation are more feasible for extremity locations, retroperitoneal involvement is less amenable to surgery for curative intent. Importantly, myxoid liposarcoma is considered a chemosensitive disease. Reports from MDACC using doxorubicin-based chemotherapy yield response rates of 44%. Trabectedin has been shown to be active in myxoid liposarcoma across multiple trials (^45,73). Aside from binding to the minor groove of DNA and forming covalent adducts and displacement of transcription factors, this agent is thought to promote differentiation of myxoid liposarcoma lipoblasts. Surgery is the mainstay of treatment for well-differentiated/dedifferentiated liposarcoma; however, recurrence rates are high, especially in the retroperitoneum. Benefit from chemotherapy has been reported to be minimal, with objective response rates of approximately 12% (⁷⁴). In a recent review of 89 patients with dedifferentiated liposarcoma of the retroperitoneum treated at MDACC, response rates were higher (23% by RECIST) with a clinical benefit rate (PR + stable disease >6 months) of 37%, suggesting a potential role for chemotherapy in select patients with unresectable or borderline resectable disease.

Alveolar Soft Parts Sarcoma

Alveolar soft parts sarcoma (ASPS) is a rare soft tissue sarcoma subtype predominantly affecting adolescents and young adults and accounting for <1% of all soft tissue sarcomas. Although the disease course is indolent with a prolonged natural history, ASPSs have a high rate of metastasis and a median overall survival of approximately 90 months. Although lung metastases are most common, ASPS can also metastasize to the brain, an otherwise uncommon site for sarcoma. In a review of our institutional experience with ASPS, 65% of patients presented with stage IV disease. Among those with localized disease at presentation, 5-year overall survival was 88%, whereas those who presented with metastatic disease had a median overall survival of 40 months and 5-year overall survival of 20% (⁷⁵). Despite its propensity for metastasis, ASPS is resistant to conventional chemotherapy. Highly vascular, these tumors are characterized by an unbalanced translocation t(X;17)(p11:q25) resulting in the ASPL-TFE3 fusion protein and overexpression of MET, leading to angiogenesis. Cediranib, a highly potent vascular endothelial growth factor (VEGF) inhibitor, has recently shown promise in the treatment of ASPS. In a single-arm phase II study of 43 patients, cediranib demonstrated an overall response rate of 35% and a disease control rate of 84% at 6 months (⁷⁶). Sunitinib, a multitargeted small-molecule inhibitor including VEGF, has also been shown to be active in ASPS (⁷⁷).

Follow-Up Management

The major goals of follow-up surveillance and management should be early identification of potentially curable recurrences, identification of treatment-related complications, and patient reassurance. Surveillance of patients treated for soft tissue sarcomas is based on known prognostic factors, outcomes in individual subsets of patients, and patterns of tumor recurrence.

For patients with low-risk T1 primaries who have undergone treatment with curative intent and are free of any gross evidence of disease, follow-up should include a history and physical, cross-sectional imaging of the tumor bed to evaluate for local recurrence, and routine chest x-rays for surveillance of metastatic disease (⁷⁸). For tumors of the head and neck and extremities, MRI is appropriate; for tumors of the chest cavity, abdomen, and retroperitoneum, CT scans are appropriate (⁷⁸). The routine use of chest CT for evaluation of metastatic disease in soft tissue sarcomas has been studied and found not to be cost effective. The NCCN guidelines recommend follow-up with annual scanning of the primary site for at least 5 years; however, often these patients are seen every 3 to 4 months in the immediate postoperative period for the first 2 years, then every 4 to 6 months for the next 2 years, and yearly thereafter.

Patients with high-risk T2 (>5 cm) soft tissue sarcomas are at a greater risk for distant lung metastases. In patients with high-risk tumors who have undergone treatment with curative intent and are free of any gross evidence of disease, follow-up should include a history and physical, cross-sectional imaging of the tumor bed, and routine chest x-rays for surveillance of metastatic disease (⁷⁸). These patients are followed in the same manner as low-risk patients, with follow-up visits with the above studies every 3 months for the first 1 to 2 years, then visits every 4 months for the next 1 to 2 years, followed by visits every 6 months for 1 to 2 years, and yearly visits thereafter (⁷⁸). As for local recurrence surveillance, the cross-sectional imaging is omitted after 5 years, because most local recurrences appear within 5 years of initial treatment (⁷⁸).

Gastrointestinal Stromal Tumors

Gastrointestinal stromal tumors are the most common mesenchymal tumors of the GI tract (⁷⁹). Previously, they were often designated smooth muscle tumors of the GI tract—specifically, GI LMS, leiomyoblastoma, LMS, and leiomyomas. Investigators discovered that GISTs express the KIT (CD-117) receptor tyrosine kinase and possibly originate from the interstitial cell of Cajal, the intestinal pacemaker cell responsible for peristalsis (⁸⁰). These tumors most commonly arise in the stomach (60%-70%), small intestine (20%-30%), colon and rectum (5%), and esophagus (<5%), although they can arise anywhere in the GI tract or omentum/peritoneum. The liver, peritoneum, and abdominal wall are the most common sites of metastatic disease; however, there are reports of associated central nervous system (CNS), lymph node, lung, and bone metastasis (⁸¹). The incidence of GIST is equal in men and women; it generally peaks between the fourth and sixth decades of life, and patients are more commonly Caucasian. Presenting symptoms often represent the site of tumor origin but may be vague, including abdominal pain, anorexia, weight loss, and dyspepsia.

Historically, the mainstay of treatment for GIST was surgical resection. Conventional chemotherapy or radiotherapy has not been effective in the treatment of GIST. The identification of specific oncogenic driver mutations involving the c-KIT protein has led to the development and approval of multiple TKIs that have greatly improved the prognosis of patients with metastatic GIST. Previously, median overall survival was approximately 18 months. In the era of imatinib, this has improved to around 5 years (⁸²).

Molecular profiling of patients with GIST has now become standard of care, as the mutational status has important implications in regard to diagnosis, prognosis, and guiding treatment decisions. Approximately 70% to 80% of GISTs harbor a KIT gene mutation, with another 5% to 8% with PDGFRA mutations, and the remaining 12% to 15% deemed wild-type GIST (⁸³). Wild-type GIST constitutes a heterogeneous grouping, with additional mutations identified in succinate dehydrogenase (SDH) and BRAF V600E, among others. Deletions in exon 11 are the most common KITmutation and portend a more aggressive disease course with shorter overall survival and higher risk of recurrence. Internal tandem repeats involving exon 11, however, are associated with gastric GIST and tend to be more indolent. Exon 9 mutations have been associated with GIST of the small intestine and a clinically aggressive course. PDGFRA mutations can occur in multiple exons (12, 14, and 18) and are observed primarily in gastric GIST.

Imatinib mesylate, an oral TKI that selectively inhibits BCR-ABL, KIT, and PDGFR, is approved for adjuvant therapy and for unresectable/metastatic GIST. Early trials with imatinib showed objective response rates of 53% to 69% and significant improvement in 5-year overall survival of about 50% (^82,84). These trial results led to two phase III trials (EORTC 62005 and Southwest Oncology Group [SWOG] S0033) that were designed to compare imatinib at two dose levels (400 mg/d vs 800 mg/d) (^85,86). In both studies, the higher dose arm failed to show a statistically significant difference in response or overall survival as compared to the once-daily dosing schedule. Gastrointestinal stromal tumors with exon 11 mutations are the most responsive to imatinib therapy, whereas those with exon 9 mutations tend to be more resistant. Patients with exon 9 mutations demonstrated shorter PFS and overall survival as compared to those with exon 11 mutations when treated with imatinib (⁸⁷). Patients with exon 9 mutations may benefit from an increased dose of imatinib (800 mg daily). Patients with non-KIT non-PDGFRA mutated or wild-type GIST rarely show significant or sustained response to treatment. The optimal duration of imatinib therapy is not known. In one study, investigators randomized patients who had control of disease at 3 years with imatinib to either continue or discontinue treatment (⁸⁸). The 2-year PFS was 80% in the continuous treatment cohort compared with 16% in the treatment interruption group. Relapse in the continuous treatment group was thus attributed to resistance.

Imatinib has also shown efficacy in the adjuvant setting (⁸⁹). As in the metastatic setting, the optimal duration of adjuvant imatinib therapy has not been well established. A randomized trial comparing 1 year versus 3 years of adjuvant imatinib therapy for KIT-positive resected GIST showed benefit to longer duration of adjuvant therapy (⁹⁰). Patients receiving 36 months of adjuvant imatinib had longer recurrence-free survival (5-year recurrence-free survival, 65.6% vs 47.9%; HR, 0.46; P < .001) and improved 5-year overall survival (92% vs 81.7%; HR, 0.45; P = .02). The benefit of extending therapy beyond 3 years is not known.

Approximately 10% of GIST patients have primary resistance to imatinib, with higher rates seen in exon 9 mutated and wild-type GIST. Secondary resistance is often due to new mutations in the KIT gene involving exon 13 or exon 17 (⁹¹). Sunitinib, a multikinase inhibitor that targets VEGF, appears to have activity in patients with primary resistance and secondary KIT mutations (^92,93). The overall objective response rate, however, was less than 10%. Several additional targeted therapies targeting the KIT and PDGFRA pathways have also been evaluated. Nilotinib, a second-generation TKI, was evaluated as third-line therapy following imatinib and sunitinib and showed a low response rate of 3% (⁹⁴). Regorafenib, a multitargeted TKI, has shown better efficacy in patients after failure of both imatinib and sunitinib. In a phase II trial, an objective response rate of 12% and clinical benefit rate (PR or stable disease >16 weeks) of 79% were observed in patients, leading to a current phase III trial (⁹⁵).

Response evaluation in GIST uses the Choi criteria rather than the standard RECIST measures used in most other solid tumors. Positron emission tomography imaging may also be used and was initially noted to show treatment response at an earlier time point compared to standard CT imaging (¹²). Certain molecular events, such as apoptosis, occur early on and may partially explain the rationale behind early PET response related to imatinib (⁹⁶). Our institution also demonstrated that RECIST criteria may underestimate early tumor response seen in GIST. Patients who respond to imatinib clinically may show a decrease in tumor size and/or a decrease in tumor radiodensity by CT radiography (Fig. 42-3). Further analysis of patients treated with imatinib at MDACC revealed that, when tumor density is taken into account, sensitivity of CT imaging is comparable to PET response (^97,98). This data culminated in the development of the Choi criteria of response assessment (Table 42-5). These criteria have been prospectively validated and are considered in response assessment in current trials of GIST. It is our experience that decisions to discontinue therapy should not be based solely on CT radiography or PET imaging but instead should also take into consideration the patient’s overall clinical condition.

In summary, the front-line therapy for patients with newly diagnosed, metastatic GIST is imatinib at 400 mg daily. Patients with exon 9 mutations should initiate therapy with imatinib at 800 mg daily. Imatinib should be continued indefinitely or until progression, as defined by Choi criteria. Computed tomography imaging is used to assess response initially at 2 months and then at 3-month intervals for at least the first 2 years. At the time of progression, we check the plasma imatinib level, and if tolerable, we increase the dose of imatinib to a total of 800 mg daily. If or when this strategy fails, we proceed to second-line therapy sunitinib and subsequent third-line therapy with regorafenib. For patients with isolated or resectable metastatic disease, surgery and/or hepatic artery embolization or radiofrequency ablation is offered if feasible. For resectable GIST patients with high-risk features, such as a high mitotic count and/or large tumor size, adjuvant imatinib for at least 3 years should be administered to increase recurrence-free survival. The optimal duration of imatinib use in the adjuvant setting beyond 3 years remains unknown.

Bone sarcomas are rare tumors, making up less than 0.2% of all cancers. In 2013, an estimated 3,010 new cases of bone sarcomas were diagnosed in the United States, and 1,440 deaths were attributed to this group of diseases (¹). The most common malignant tumor of bone is osteosarcoma followed by chondrosarcoma and then the Ewing sarcoma/primitive neuroectodermal tumor (PNET) family of tumors. Malignant fibrous histiocytoma, fibrosarcoma, chordoma, and giant cell tumor of bone are rare bone tumors and account for <5% of all primary malignant bone tumors. The Ewing sarcoma/PNET family of tumors tend to occur more frequently in children and adolescents, whereas osteosarcoma has a biphasic pattern of incidence that peaks in adolescents, with the growth of long bones, and in the elderly, with tumors arising in association with Paget disease or previously radiated tissues. Chondrosarcomas are usually seen in patients after the fifth decade of life, but they can also occur in younger patients, where the tumors tend to be of a higher grade malignancy. Features of common bone tumors are listed in Table 42-6.

Clinical Presentation

The clinical presentation of any bone tumor depends on its location. Most osteosarcomas arise in the metaphyseal region of long bones, specifically the distal femur, proximal tibia, and proximal humerus. Approximately 55% of osteosarcomas occur around the knee joint. Chondrosarcomas can also arise in any bone of the body; however, they generally occur in the pelvis and other flat bones. Ewing sarcoma/PNET tumors tend to occur in the diaphyseal portion of the long bones and in flat bones of the body (eg, the pelvis and scapula).

The most common presenting symptom is pain and swelling or a mass. Patients who have pelvic tumors may have neurologic impairment and severe pain, typically because these tumors are often not recognized until late in the disease course. In the case of Ewing sarcoma, patients often present with constitutional symptoms of night sweats and fevers.

Evaluation

Evaluation of suspected bone sarcoma should begin with a careful history, physical examination, and routine laboratory tests, followed by imaging directed to the given complaint. The imaging of any bone tumor should begin with a plain film of the involved area. X-ray images are often helpful in the diagnosis of bone sarcomas; for example, osteosarcoma often has a “sunburst” appearance of calcification on x-ray imaging, which is virtually diagnostic (Fig. 42-4). The amount of calcification associated with osteosarcoma depends on the histologic subtype (eg, osteoblastic osteosarcoma usually has very dense calcification, whereas telangiectatic osteosarcoma is primarily lytic). Chondrosarcoma also has a distinct appearance on x-ray imaging, with destruction of the bone and endosteal scalloping of the bony cortex and a chondroid matrix, which appears lobulated (See Fig. 42-4). Ewing sarcoma has a typical “onion-skin” appearance on x-ray imaging (See Fig. 42-4). Additional initial imaging should include a CT scan and/or MRI of the primary lesion to further evaluate involvement of the neurovascular structures, surrounding soft tissues, and adjacent joints and to better evaluate any associated soft tissue mass.

Biopsy of bone sarcomas is critical to the diagnosis, and careful planning is essential. When patients are diagnosed with bone sarcoma or the diagnosis is suspected, it is important to have a multidisciplinary team approach with physicians who are experienced in the treatment of bone sarcomas. Core-needle biopsy has been shown to be accurate in making a diagnosis in up to 91% of cases (⁹⁹). An open biopsy should be performed only when core-needle biopsy is nondiagnostic. Current guidelines recommend either a core or open biopsy to confirm the diagnosis prior to any surgical procedure. When surgery is ultimately performed, care should be taken to assure that the biopsy tract is completely resected.

Complete staging should include chest x-ray, CT scan of the chest, and bone scan to evaluate for metastatic disease. Chest imaging is warranted in all patients, because the most common site of metastasis from bone sarcoma is the lungs. A bone scan should be included in the workup for metastatic disease in patients with bone sarcoma to evaluate for distant bone metastases or skip metastases. For patients with Ewing sarcoma, an MRI of the spine should be performed, because there is a risk of bone marrow metastases. We do not routinely obtain bone marrow biopsy in the staging evaluation of Ewing sarcoma. Marrow involvement has been shown to highly correlate with bone metastasis (¹⁰⁰).

Positron emission tomography/CT is being used more frequently in the initial diagnostic evaluation, staging, and response assessment for bone sarcomas. However, fluorodeoxyglucose (FDG) uptake alone is not adequate for characterization of primary bone tumors; morphologic evaluation is key (¹⁰¹). Positron emission tomography/CT imaging can also play an important role in response assessment because bone sarcomas do not demonstrate typical RECIST responses to chemotherapy (Fig. 42-5). Multiple studies have reported the utility of PET/CT in evaluating chemotherapy response in osteosarcoma and Ewing family tumors (^102,103). In one study of osteosarcoma, a 25% to 50% reduction of SUV following 1 week of neoadjuvant chemotherapy has been shown to correlate with >90% tumor necrosis on pathologic evaluation (¹⁰⁴). At our center, we routinely use PET/CT in the evaluation and response assessment for osteosarcoma and Ewing family tumors.

Pathology

There are multiple histologic subtypes of bone sarcoma, with the most common cytogenetic and molecular aberrations summarized in Table 42-7. Osteosarcoma can be broken down into two major categories: conventional osteosarcoma and variant osteosarcoma (Fig. 42-6). Conventional osteosarcoma comprises approximately 60% to 75% of all osteosarcomas, whereas the 11 variants comprise the other 35% to 40% (¹⁰⁵). Conventional osteosarcoma includes osteoblastic osteosarcoma, chondroblastic osteosarcoma, and fibroblastic osteosarcoma. These classifications are made based on the histologic features of the tumor, such as the amount of matrix present within the tumor and whether bone or cartilage is predominant. The classification of the osteosarcoma variants relies more on the clinical correlation, such as the site of disease (ie, jaw, skull, or pelvis), the setting in which the disease presents (ie, postradiation, Paget disease, multifocal, and retinoblastoma), and the morphology, such as telangiectatic, small cell, malignant fibrous histiocytoma (MFH) of bone, dedifferentiated chondrosarcoma, and surface lesions such as parosteal, periosteal, and high-grade surface osteosarcoma. High-grade osteosarcomas demonstrate significant genomic instability and therefore possess complex and heterogeneous chromosomal alterations. Copy number loss or gain in multiple chromosomes as well as amplifications in the MDM2 gene, CDK4, MYC, and VEGF have been described. To date, sequencing of osteosarcomas has yet to identify effective molecular targets (¹⁰⁶).

Malignant fibrous histiocytoma of bone is similar to MFH of soft tissue histologically and often appears to constitute the high-grade component of dedifferentiated chondrosarcoma. Malignant fibrous histiocytoma is thought to be part of a spectrum of osteosarcoma where the spindle cells do not produce osteoid visible by light microscopy; however, it may become possible to visualize these at some time in the future, especially following chemotherapy in responding tumors.

Chondrosarcomas are malignant tumors of bone characterized by cartilaginous proliferation. These tumors produce chondroid matrix and can arise from benign processes such as enchondroma. Chondrosarcoma is characterized by the permeation of cartilage into the bone marrow. This process is virtually pathognomonic for chondrosarcoma. Dedifferentiated chondrosarcoma is a unique subset of chondrosarcomas typified by a low-grade conventional chondrosarcoma juxtaposed with a high-grade soft tissue component. Several less common variants exist including mesenchymal chondrosarcoma and clear cell chondrosarcoma. Next-generation sequencing has identified somatic mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2) in central conventional chondrosarcomas and dedifferentiated chondrosarcomas (¹⁰⁷). This finding may aid in distinguishing chondrosarcoma from chondroblastic osteosarcoma and could serve as a unique therapeutic target (¹⁰⁸).

Ewing sarcoma family of tumors (ESFT) represent a completely separate histology and are grouped with the PNETs due to their similarities in histology, immunohistochemical staining, and molecular genetics. This family of tumors includes Ewing tumors of bone, extraosseous Ewing tumors, PNETs, and Askin tumors (PNET of the chest wall). These tumors are often referred to as “small round blue cell tumors” because, under the microscope, the cells contain scanty cytoplasm and round to oval nuclei with fine chromatin that are tightly packed together. The ESFTs possess recurrent translocations involving the EWS gene, with identification of an EWS translocation considered pathognomonic in the diagnosis of ESFT. The translocation t(11;22)(q24;q12) EWS-FLI-1 fusion was the first described and most common translocation. Several additional translocations have also been identified (see Table 42-7).

Bone sarcomas are classified as either high- or low-grade lesions, similar to the three-tier grading system of soft tissue sarcomas. Grading is an important factor that helps to determine the overall stage and prognosis. Finally, the pathologist should be provided with the diagnostic imaging and x-ray findings because these provide important information to assist in making a final diagnosis in bone sarcomas.

Staging and Prognosis

There are two widely accepted staging systems, that of the AJCC and that of the Musculoskeletal Tumor Society (^109,110). In a comparison of these systems, there was no significant difference between them, and neither had any notable advantage (¹¹¹). At MDACC, instead of routinely using a staging system, we prefer to emphasize prognostic factors (eg, size of the primary, location and extent of bone involvement, soft tissue involvement, histologic grade, and presence or absence of distant metastases). The prognosis of patients with bone sarcomas largely depends on the specific histology, grade, location, and presence of metastatic disease. The most important and well-established prognostic factor for patients with bone sarcoma is the percentage of tumor necrosis achieved with preoperative chemotherapy.

Treatment

The treatment of bone sarcomas is best accomplished by a multidisciplinary team comprising medical oncologists, surgical oncologists, pathologists, and radiation oncologists working together to provide comprehensive care. The treatment required depends on the tumor type, location, and extent of disease. Treatment algorithms for high-grade bone sarcomas and Ewing sarcoma are show in Figs. 42-7 and 42-8.

Osteosarcoma

Osteosarcoma is the prototype of most other bone sarcomas. Chemotherapy is the mainstay of treatment for osteosarcoma, which is considered a systemic disease, because most patients have micrometastatic disease at presentation. This is evidenced by the historic long-term survival rate of <20% in patients treated with surgery alone as compared to the nearly 70% cure rate among patients with localized osteosarcoma of an extremity treated with aggressive combination chemotherapy followed by adjuvant surgery (¹¹²).

At MDACC, adolescent and adult patients with conventional high-grade osteosarcoma of an extremity receive treatment consisting of preoperative chemotherapy followed by limb-sparing surgery, followed by postoperative chemotherapy (see Fig. 42-7). The postoperative therapy is tailored based on the knowledge of the percent necrosis found in the pathologic specimen after surgery. This approach is based on a series of patients treated within our center in which tailored postoperative therapy demonstrated improved survival and differs from the current standard treatment of pediatric osteosarcoma (¹¹³).

The most active agents for the treatment of osteosarcoma are cisplatin, doxorubicin, ifosfamide, and high-dose methotrexate (³⁴). Intra-arterial administration of cisplatin (120 mg/m²) in combination with doxorubicin (90 mg/m² continuous infusion over 96 hours) given preoperatively has been studied by investigators at MDACC (¹¹²). Imaging of osteosarcoma has limited utility in response assessment; the percentage of tumor necrosis is the single most important predictor of long-term disease-free and overall survival (¹¹⁴). Generally, patients with ≥90% tumor necrosis after preoperative chemotherapy have a 5-year continuous disease-free survival of approximately 80% (¹¹²). The 5-year continuous disease-free survival of patients with <90% tumor necrosis after preoperative chemotherapy is significantly worse, ranging from 13% up to 67% depending on the postoperative chemotherapy regimen (¹¹²). To address this, we analyzed a consecutive series of 123 patients with osteosarcoma of the extremity treated within our center who were divided into three cohorts based on the time period in which they were treated and the postoperative chemotherapy given. All patients received preoperative doxorubicin and cisplatin induction. Patients received the sequential addition of high-dose methotrexate (8 g/m²) and then methotrexate plus ifosfamide postoperatively in the second and third groups depending on the time period in which they were treated. Among patients with ≥90% tumor necrosis, relapse-free survival was not significantly different among the three groups. In patients with poor response, with <90% tumor necrosis, the addition of methotrexate and then methotrexate plus ifosfamide improved the 5-year relapse-free survival from 13% to 34% and 67%, respectively (¹¹³).

The role of postoperative switch therapy or intensified therapy among patients guided by histologic response to preoperative chemotherapy remains controversial. In the EURAMOS-1 study, 618 patients with high-grade osteosarcoma who received preoperative methotrexate, doxorubicin, and cisplatin (MAP) with ≥10% viable tumor at surgery were randomized 1:1 after surgery to receive either continuation of MAP or intensification with the addition of ifosfamide and etoposide to the same MAP backbone (MAPIE) (¹¹⁵). Intensification with MAPIE failed to show an advantage in terms of event-free survival (HR, 1.01) and overall survival (HR, 0.99) and was associated with additional toxicity at a median follow up of 4.5 years.

For patients who achieve ≥90% tumor necrosis with four cycles of doxorubicin and cisplatin preoperatively, we recommend four additional cycles of doxorubicin (75 mg/m²) combined with ifosfamide (10 g/m²). For those with <90% tumor necrosis after preoperative doxorubicin and cisplatin, we favor six cycles of high-dose ifosfamide and six cycles of high-dose methotrexate given sequentially.

Patients with high-grade osteosarcomas of other sites are treated in a similar fashion; however, their overall outcome appears to be worse than that of patients with extremity tumors. This may be due in part to poor sensitivity to the chemotherapy agents and also to difficulties in achieving a negative surgical margin of resection owing to anatomic constraints. Patients with low-grade and variant osteosarcomas—such as well-differentiated intramedullary osteosarcoma or parosteal osteosarcoma and jaw osteosarcoma, typically arising in the mandible, which have a lower tendency to produce distant metastases—are treated with surgical resection with negative margins alone without routine use of adjuvant chemotherapy. If surgical resection with negative margins cannot be achieved in osteosarcoma of the jaw, preoperative chemotherapy should be considered. Patients with intermediate-grade periosteal osteosarcoma should also receive preoperative chemotherapy.

Malignant fibrous histiocytoma of bone is treated according to the same basic principles as conventional osteosarcoma. Studies performed at MDACC showed that with preoperative doxorubicin and cisplatin, approximately 50% of the patients with localized MFH of bone had percent tumor necrosis of ≥90% (¹¹⁶). The median survival was 23 months for all patients who received this preoperative regimen, with the patients who achieved ≥90% having a median survival of 66 months and patients with <90% necrosis having a median survival of 20 months. The European Osteosarcoma Intergroup had similar results in studies using doxorubicin and cisplatin preoperatively and postoperatively, with 5-year PFS and overall survival rates of 56% and 59%, respectively (¹¹⁷).

Extraskeletal osteosarcomas, chondrosarcomas, and Ewing sarcomas are treated in a similar fashion as soft tissue sarcomas. In our experience at the MDACC, extraskeletal osteosarcomas are not as responsive to chemotherapy as osseous osteosarcomas and do not respond to cisplatin or high-dose methotrexate, unlike their skeletal counterparts (¹¹⁸).

Metastatic and Recurrent Disease

Approximately 10% to 20% of patients with osteosarcoma present with metastatic disease. Lung is the most common site of metastasis in osteosarcoma; however, osteosarcoma can also metastasize to almost any bone in the body. Lymph node metastases are rare. Patients who have resectable pulmonary metastases are treated with curative intent with primary chemotherapy, as described earlier, followed by surgical resection of all lesions either at the same time or in staged operations. With this approach, patients have a 15% to 30% chance of long-term disease-free survival and potential cure. Patients with bone metastasis have a poorer prognosis, with therapy usually directed at palliation.

Relapse is seen in about 30% of patients presenting with localized disease and up to 80% of patients who present with primary metastatic disease. Patients with relapsed or recurrent disease are approached similarly to patients with primary metastatic disease with chemotherapy and/or resection when possible. Several agents have demonstrated some activity in relapsed or refractory osteosarcoma including gemcitabine alone or in combination with docetaxel; ifosfamide or cyclophosphamide in combination with etoposide; as well as others. Targeted therapies are under investigation in osteosarcoma. The multikinase inhibitor sorafenib demonstrated benefit in a phase II trial of relapsed osteosarcoma, with a PFS of 46% at 4 months and clinical benefit rate of 29% (¹¹⁹). Subsequently, a phase II trial of sorafenib and everolimus demonstrated 45% PFS at 6 months, but failed to meet its prespecified end point of 50% PFS at 6 months (¹²⁰).

Chondrosarcoma

Chondrosarcomas are resistant to most chemotherapeutic agents used for the treatment of bone sarcomas. Surgical resection is the primary treatment modality, regardless of the grade of the tumor. Conventional chondrosarcoma patients with unresectable/metastatic disease should be enrolled onto clinical trials, and genomic profiling should be considered for potential target identification. Unlike other chondrosarcoma subtypes, mesenchymal chondrosarcoma and dedifferentiated chondrosarcoma should be treated with multimodality therapy.

Dedifferentiated chondrosarcoma is associated with low-grade chondrosarcoma, and foci of high-grade soft tissue sarcoma may resemble osteosarcoma of MFH of bone and are often thought of as variants of osteosarcoma (¹²¹). These tumors can respond to doxorubicin/cisplatin-based chemotherapy and are treated in the same manner as conventional osteosarcomas (¹²²), although tumor necrosis at resection is less than optimal compared to conventional chondrosarcomas. Patients with refractory/recurrent disease should be considered for clinical trials and molecular testing. Approximately 60% of dedifferentiated chondrosarcomas harbor mutations in the IDH1 gene, which makes IDH oncometabolite inhibitors an attractive option to consider (¹²³). Mesenchymal chondrosarcomas are a rare variant that present in the jaw, spinal column, and ribs with lytic lesions on x-ray. The histology consists of a bimorphic appearance of benign to low-grade cartilaginous components with poorly differentiated small cell components (¹²⁴). The majority of these tumors harbor a unique HEY1-NCOA2 fusion, which is thought to affect Notch signaling (¹²⁵). Mesenchymal chondrosarcomas do respond to chemotherapy; a recent series of 54 patients with localized disease treated with combination chemotherapy demonstated a reduced risk of fracture (HR, 0.482; 95% CI, 0.213-0.996; P = .046) and death (HR, 0.445; 95% CI, 0.256-0.774; P = .004) (¹²⁶). This disease is treated in a similar fashion as Ewing sarcoma, discussed in the next section. In our experience, responsive tumors typically exhibit more calcification with an associated decrease in FDG avidity (when PET/CT is used for response assessment), and they are less apt to show decreases in tumor size, as opposed to Ewing sarcomas, which typically exhibit dramatic tumor size reduction. This makes RECIST a less reliable tool for adequate response assessment of mesenchymal chondrosarcoma.

Ewing Sarcoma

Like osteosarcoma, Ewing sarcoma and the PNET family of tumors are treated primarily with chemotherapy prior to surgery, because patients with localized disease most likely have occult metastasis at the time of diagnosis. These tumors are extremely responsive to the following chemotherapeutic agents: doxorubicin, dactinomycin, ifosfamide, cyclophosphamide, vincristine, and etoposide. The most commonly used combinations are vincristine, doxorubicin, and cyclophosphamide (VAC); ifosfamide and etoposide (IE); and vincristine, doxorubicin, and ifosfamide (VAI). Multiple trials have shown that with these combinations of chemotherapy, survival rates greater than 50% can be achieved (^127,128). At MDACC, we usually give vincristine (up to 2 mg) with doxorubicin (75-90 mg/m²) and ifosfamide (10 g/m²) as our preoperative chemotherapy regimen. This is followed by surgical resection, if possible, or radiation therapy. Ewing sarcoma is very radiosensitive; often, when surgical resection is not an option or positive margins remain, consolidative radiation therapy is used. Studies show good survival results in patients who have consolidative radiation therapy when needed (¹²⁹). After definitive resection, tumor necrosis is assessed and postoperative therapy modified as needed (see Fig. 42-8). A recent retrospective review of 66 patients from our institution treated with chemotherapy and R0 resection identified histologic response (necrosis ≤95%), radiographic response by RECIST, and metastasis to be independent predictors of outcome (¹³⁰). Based on these data, additional study is needed to determine the role of adjuvant radiation in patients with poor histologic response after preoperative chemotherapy and R0 resection.

Metastatic/Recurrent Disease

Metastatic or recurrent Ewing sarcoma is treated in a similar manner as metastatic or recurrent disease in osteosarcoma. Patients who have metastatic disease in their lungs at the time of presentation are treated as outlined earlier, with curative intent. Patients with recurrent or metastatic disease after primary therapy are treated on the basis of their disease-free interval. If there is a long interval (>12 months), a retrial of previous chemotherapeutic regimens, preferably at higher dose intensity (eg, high-dose ifosfamide), is reasonable. For patients with a shorter interval between therapy and recurrence or metastasis, investigational therapies are appropriate.

Targeted therapy for metastatic ESFT has recently focused on inhibition of the insulin-like growth factor 1 receptor (IGF1R). This tyrosine kinase receptor is expressed on the cell surface of Ewing sarcoma cells and is thought to play a key role in the pathogenesis of Ewing sarcoma (¹³¹). Single-agent studies with IGF1R antibodies have only shown modest activity, with objective response rates ranging from 6% to 14% (^132,133). To date, efforts focused on targeting the ETS tumor-specific gene fusions have been unsuccessful.

Giant Cell Tumor of Bone

Giant cell tumor of bone is another rare primary tumor of bone. Although considered benign, these tumors have a propensity for local recurrence to metastasize to lung. Tumors most commonly involve the epiphyses of long bones and usually result in pain, swelling, and decreased range of motion. Giant cell tumors appear as lytic, eccentrically located lesions in the epiphyses of a long bone on x-ray imaging. The primary treatment of giant cell tumors of bone consists of surgical intervention, either wide excision or intralesional curettage and cementation. Radiation therapy can be used as primary treatment or following surgery and has been shown to improve local control and disease-free survival, but has also been associated with an increased risk of malignant transformation (¹³⁴). When the primary location precludes surgical resection due to morbidity or patients develop distant metastatic disease, consideration is given to systemic therapy (¹³⁵). At MDACC, we have previously treated patients with interferon α-2b therapy with either 3 million units subcutaneously every day for 6 to 12 months or 10 million units subcutaneously every Monday, Wednesday, and Friday for 6 to 12 months (¹³⁶). Clinicians should be aware, however, that these tumors respond gradually and can even grow initially on treatment and that often responses are not fully appreciated until after interferon therapy has been completed. More recently, denosumab, an antibody to the RANK ligand, which inhibits osteoclastic function and increases calcification, has been shown to improve pain in patients with recurrent or metastatic giant cell tumor. In a phase II study of denosumab in unresectable or recurrent giant cell tumor, treatment with denosumab resulted in tumor response in 86% of evaluable patients (defined as elimination of >90% of giant cells or no radiographic progression of target lesion for up to 25 weeks) (¹³⁵). For patients with unresectable disease, we currently employ a combination of embolization, interferon, and denosumab on a case-by-case basis.

Follow-Up Management

Regular and long-term follow-up is essential. Patients are followed at MDACC with x-rays and physical examination every 3 months for the first 2 years, every 4 months for the next 2 years, every 6 months for the next 2 years, and then yearly thereafter. Surveillance includes high-quality chest imaging with either chest x-ray or chest CT in high-risk patients, plain films of the primary tumor site to evaluate for recurrence and stability of any prosthesis, and routine laboratories. Bone scans and/or PET/CT scans are useful in patients with specific symptoms or history of bony metastasis. Monitoring should also include an assessment of the potential late effects of chemotherapy including anthracycline-induced cardiomyopathy, nephrotoxicity, neuropathy, and secondary malignancies.