Soft tissue sarcomas (STS) are comprised of malignant tumors which arise from tissues of mesodermal origin (e.g., fat, muscle, connective tissue, vessels) excluding bone and cartilage. There are over 50 different histologic subtypes of STS.¹ In addition, malignant tumors of peripheral nerve sheaths are usually classified at STS despite being ectodermal in origin. Gastrointestinal stromal tumors (GISTs) are derived from the interstitial cells of Cajal, which have neural and smooth muscle features, and thus GISTs are also considered STS.² The most common subtypes include liposarcoma, leiomyosarcoma, undifferentiated pleomorphic sarcoma (UPS, formerly called malignant fibrous histiocytoma), GIST, and synovial sarcoma. The biological heterogeneity of the different STS subtypes is likely as great as that of all adenocarcinomas (e.g., lung, colorectal, breast, prostate, and other adenocarcinomas), but STS are much less common, and thus they are all grouped together for practical purposes. A subsequent chapter is devoted to the description of the different STS histological subtypes.

Soft tissue sarcomas arise in about 10,000 to 15,000 people in the United States each year, with roughly 40% of patients dying of either loco-regional recurrence or distant metastasis.³ Although malignant tumors of soft tissue are scarce, benign tumors including lipomas are about one hundred times more common. STS occur at any age with a median age or around 50 years old, and are equally common in men and women. STS occur throughout the body, with nearly one-half occurring in the extremities. Another one-third of STS occur in the abdomen, and these are equally divided among intra-abdominal visceral sarcomas (e.g., GISTs and uterine leiomyosarcomas) and retroperitoneal sarcomas. Other anatomic sites include the head/neck, trunk, and other miscellaneous sites (e.g., heart).

Given STS are relatively uncommon, occur throughout the body, and have over 50 histological subtypes all with varying behaviors, this disease can be quite confusing to treat and referral to a tertiary referral center is often warranted. The treatment of STS has advanced significantly over the past few decades. In addition to surgery, there are important roles for radiation therapy and chemotherapy in the management of some STS patients, and optimal multidisciplinary care requires experienced surgeons, radiation oncologists, medical and pediatric oncologists, pathologists, and diagnostic radiologists.

Factors that help determine the behavior of STS in general (irrespective of histological subtype) include size, grade, and site. Tumors less than 5 cm are considered as small in size, between 5 and 10 cm as intermediate, and >10 cm as large. While each histological subtype may have certain specific clinical behavior, all STS can generally be categorized into low, intermediate, and high-grade tumors. The designation of grade is based upon morphological features including necrosis, mitoses, and degree of differentiation.⁴ Low-grade tumors generally grow more slowly and can locally recur after resection, but have a low risk of distant metastases (about 5%). High-grade tumors tend to grow more rapidly, can recur locally, and have the added risk of distant metastasis. Large, high-grade tumors have up to a 50% risk of metastasis.

The metastatic pattern of STS is dependent on the primary tumor location and histological subtype. For most locations including the extremity and for most histologic subtypes, the predominant site of metastasis is the lung. Retroperitoneal tumors can metastasize to the lung and liver, while GISTs most commonly metastasize to the liver or to the peritoneal cavity. Over half of myxoid/round cell liposarcomas metastases are to nonpulmonary sites including fat pads and bone. STS in generally rarely metastasize to regional lymph nodes (<5%) but certain uncommon histologic subtypes such as epithelioid sarcoma, clear cell sarcoma, and rhabdomyosarcoma have a higher rate of lymph node metastasis.

Soft tissue sarcomas, like other cancers, is a genetic disease caused by gene mutations, insertions/deletions, copy number changes, and other alterations. However, the vast majority of STS occur as sporadic tumors in patients with no identified environmental or genetic risk factors.

Radiation is recognized as capable of inducing sarcomas of bone and soft tissue.⁵ The frequency increases with radiation dose and with the post-radiation observation period and is approximately 0.5% in the adult treated with radiation alone to full dose. Radiation-associated sarcomas generally arise many years following the radiation at the edge of the radiation field, most commonly are high-grade, and the most common histologic subtype is UPS. Following breast irradiation, the most common radiation-induced sarcomas are angiosarcomas.⁶ Chemotherapeutic agents are likewise associated with risks of sarcoma induction. STS can develop following massive and protracted edema. Stewart–Treves syndrome is the development of a lymphangiosarcoma in a chronically lymphedematous arm following axillary lymphadenectomy.⁷ Trauma is rarely a factor in the development of STS but can contribute to the development of desmoid tumors.

Certain genetic syndromes are associated with an increased risk of developing sarcomas including neurofibromatosis 1 (NF1, von Recklinghausen’s disease), hereditary retinoblastoma, and Li–Fraumeni syndrome. Patients with NF1 have an approximately 15% risk of developing a malignant peripheral nerve sheath tumor (MPNST) as well as an increased risk of developing GIST.⁸ Patients with hereditary nonpolyposis colon cancer (HNPCC)/Gardner’s syndrome, resulting from a defect in the APC gene, have an increased risk of developing intra-abdominal/mesenteric desmoid tumors.⁹ Hereditary retinoblastoma and Li–Fraumeni syndrome are associated with a risk of both bone and STS.^10,11

In recent years, it has become evident that the genetics of sarcomas segregate into two major types.¹² One type has specific genetic alterations and usually simple karyotypes, including fusion genes due to reciprocal translocations (e.g., PAX3–FKHR in alveolar rhabdomyosarcomas) or specific point mutations (e.g., KIT mutations in GIST) (Table 24-1). The second type has nonspecific genetic alterations and complex, unbalanced karyotypes, reflected by numerous genetic losses and gains (e.g., osteosarcoma, UPS, liposarcomas other than the myxoid type, angiosarcoma, and leiomyosarcoma).