Soft Tissue Sarcoma - Clinical Tree

Epidemiology

Soft tissue sarcoma (STS) is a diverse group of more than 60 neoplasms that can arise from virtually any anatomic site and can affect the very young as well as the elderly. The tissue types of STS origin include skeletal muscle, adipose cells, blood and lymphatic vessels, and connective tissue or those cells with a common mesoderm origin ( Fig. 32.1 and Table 32.1 ). Also included are peripheral nerves derived from the neuroectoderm. Clinical behaviors of mesodermal tumors occupy a wide spectrum from indolent low-grade neoplasms, such as benign lipomas, to tumors with aggressive tumor biology, such as metastatic angiosarcoma. STS is relatively rare, with 12,020 estimated new cases and an estimated 4,740 deaths for the year 2014. Whereas this accounts for 1% of cancer incidence in the United States, it accounts for 2% of cancer-related deaths. The diagnosis of patients with STS is challenging because, although it is rare in the general population, a number of common, non-neoplastic conditions can mimic STS (see Box 32.1 ).

Fig. 32.1, Taxonomy of soft tissue sarcoma. This unrooted phylogeny shows about 60 sarcoma subtypes, as originally defined by the World Health Organization International Agency for Research on Cancer, amended and updated on the basis of current knowledge. The classification reflects relationships among lineage, prognosis (malignant, intermediate or locally aggressive, intermediate or rarely metastasizing), driver alterations, and additional parameters. Branch lengths are determined by nearest neighbor joining of a discretized distance matrix based on the aforementioned variables. Initial branching reflects differences in lineage, with associated lineages appearing closer in distance (such as skeletal and smooth muscle). Subsequent branching denotes similarity in prognosis, whether they are translocation associated, and, if so, the genes shared among distinct fusions (in this order). Although incomplete, as many subtypes lack sufficient global molecular profiling data on which to base a phylogeny, this initial formulation minimally reflects the relationships among lineage and major molecular lesions in the subtypes. The illustration excludes 52 benign types of tumor. MFH , Undifferentiated pleomorphic sarcoma; PNET , primitive neuroectodermal tumor.

Table 32.1

The diversity of soft tissue sarcoma (STS) clinicopathologic characteristics.

Adapted from van Vliet M, Kliffen M, Krestin G, et al. Soft tissue sarcomas at a glance: clinical, histological, and MR imaging features of malignant extremity soft tissue tumors. Eur Radiol . 2009;19:1499–1511.

STS Subtype	Histology	MRI Appearance	Anatomic Distribution
Vascular
Angiosarcoma
Adipocytic
Dedifferentiated liposarcoma			RP
Myxoid liposarcoma
Pleomorphic liposarcoma
Chondro-osseus
Extraskeletal osteosarcoma
Myofibroblastic
Myxofibrosarcoma
Low-grade fibromyxoid sarcoma		1	2 RP
Smooth Muscle
Leiomyosarcoma	3	4	5 RP, pelvis, vascular
Uncertain Differentiation
Synovial sarcoma	6	7	8 Joints, tendons
Undifferentiated pleomorphic sarcoma	9
Clear cell sarcoma

MRI , Magnetic resonance imaging; RP , retroperitoneum.

Box 32.1

Entities that may mimic soft tissue sarcoma.

Hypertrophic scar
Retroperitoneal lymphadenopathy: lymphoma, germ cell tumor, or metastasis from gastrointestinal primary
Hematoma
Myositis ossificans
Benign lipoma
Cyst
Abscess
Cutaneous malignant neoplasms, including melanoma

Although there is a great deal of overlap between the various STS subtypes, the most traditional categorization separates trunk and extremity STS from retroperitoneal sarcomas. Before these varieties are discussed in detail, this chapter first reviews core concepts that are relevant to all STS. These core concepts include STS etiology, STS staging, consideration of the lipomatous tumor spectrum, and the STS category previously referred to as malignant fibrous histiocytoma (MFH). A more detailed discussion of trunk and extremity STS and retroperitoneal sarcoma follows. Other specific and relevant STS subtypes are addressed in more detail throughout the chapter as well.

Large published series demonstrate that extremity and trunk STS is more common than intraperitoneal and retroperitoneal STS. Among extremity STS, the proximal limb is more commonly affected than the distal portion, with the thigh the most common location, accounting for 44% of patients. The age at diagnosis and the histologic STS subtype are often closely linked. Rhabdomyosarcoma, hemangioma, neurofibroma, and alveolar sarcoma tend to disproportionately affect children and young adults. Most STS occurs sporadically, but other well-documented causes include germline mutations, radiation exposure, and environmental exposure.

Core Concepts

Germline Mutations

Neurofibromatosis Type 1

Neurofibromatosis type 1 (NF1) is an autosomal dominant condition caused by mutations of the NF1 gene, which is located at chromosome 17q11.2. NF1 codes for a protein called neurofibromin, which acts as a tumor suppressor of the ras oncogene signaling pathway. In addition to the ubiquitous development of multiple cutaneous neurofibromas, these patients have a 10% risk for development of a malignant peripheral nerve sheath tumor (MPNST; which is covered in more detail later in this chapter). NF1 is also related to a variety of other tumors, including schwannomas and gliomas.

Li-Fraumeni Syndrome

The Li-Fraumeni syndrome is a rare autosomal dominant disorder caused by mutations of the TP53 gene, which is located at chromosome 17p13.1. The TP53 gene codes for p53, a protein that acts as a tumor suppressor. Wild-type p53 functions to facilitate the clearance of damaged cellular DNA and to prevent the clonal propagation of these mutated sequences. TP53 mutations, therefore, contribute to an increased risk of various malignant neoplasms. In order of decreasing prevalence, these include breast cancer, STS (especially rhabdomyosarcoma, undifferentiated pleomorphic sarcoma, and pleomorphic sarcoma), adrenocortical carcinoma, brain cancer, osteosarcoma, and hematologic malignant neoplasms. Patients affected by the Li-Fraumeni syndrome exhibit a range of phenotypes, depending on the types of mutations involved, with some patients developing rhabdomyosarcoma before 4 years of age. Annual whole-body magnetic resonance imaging (MRI) has been advocated for patients with the Li-Fraumeni syndrome, in addition to dedicated breast imaging and colonoscopy.

Familial Adenomatous Polyposis and Gardner Syndrome

The familial adenomatous polyposis (FAP) syndrome is an autosomal dominant disorder caused by mutation of the APC gene, which is located at chromosome 5q21-q22. This gene also encodes a protein that acts as a tumor suppressor, inhibiting the localization of β-catenin to the nucleus. The truncated mutant protein fails to regulate β-catenin, resulting in unchecked cellular proliferation. The cardinal clinical feature is innumerable colonic polyps, but some patients also develop extracolonic manifestations, such as epidermoid cysts, osteomas, and desmoid tumors. Desmoid tumors, covered in more detail later in this chapter, typically arise approximately 5 years after FAP-related prophylactic colectomy and are a major source of morbidity and mortality. They often arise in prior surgical sites but can be manifested at virtually any site. Intra-abdominal tumors are much more likely to be related to FAP, whereas desmoids of the extremities are typically sporadic.

Radiation

Radiation has long been suspected to significantly contribute to a patient’s long-term risk of STS development. Whereas the effects of radiation are thought to be dose dependent, radiation-related STS typically occurs at the periphery of the radiation field. The main STS subtypes thought to be associated with prior radiation exposure include unclassified pleomorphic sarcoma, angiosarcoma, leiomyosarcoma, fibrosarcoma, and MPNST. Compared with sporadic forms of these same STS subtypes, those arising after radiation exposure tend to have a shorter disease-specific survival. In the setting of adjuvant radiation therapy for breast cancer, a large cohort of 122,991 women demonstrated that radiation contributes to an absolute increase in the risk of STS of 0.13% during 10 years. Patients who later develop STS after being treated as children for cancers requiring radiation therapy do so a median of 11.8 years later, also in a dose-dependent fashion. The development of angiosarcoma after a combination of postmastectomy lymphedema and radiation therapy is known as Stewart-Treves syndrome; it also has a latency of about 10 years after initial therapy. Interestingly, Stewart-Treves syndrome–related angiosarcoma usually occurs outside the previous radiation field but within the zone of lymphedema. An increased risk of STS is not only attributable to therapeutic doses of radiation but also has been linked to lower doses encountered by pediatric patients undergoing routine computed tomography (CT) scan.

Carcinogens

Hepatic angiosarcoma is related to several carcinogenic substances including Thorotrast, polyvinyl chloride, and arsenic. Thorotrast is a thorium-based intravenous contrast agent that was used between the years 1930 and 1955. In affected patients, hepatic angiosarcoma is diagnosed 20 to 30 years after exposure. Polyvinyl chloride is an extremely common form of plastic, but prolonged and unprotected exposures have been linked to the development of hepatic angiosarcoma.

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