Soft tissue can be defined as nonepithelial extraskeletal tissue of the body exclusive of the reticuloendothelial system, glia, and supporting tissue of various parenchymal organs. It is represented by the voluntary muscles, fat, and fibrous tissue, along with the vessels serving these tissues. By convention, soft tissue also includes the peripheral nervous system because tumors arising from nerves present as soft tissue masses and pose similar problems in differential diagnosis and therapy. Embryologically, soft tissue is derived principally from mesoderm, with some contribution from neuroectoderm.
Soft tissue tumors are a highly heterogeneous group of tumors that are classified by their line of differentiation, according to the adult tissue they resemble. Lipomas and liposarcomas, for example, are tumors that recapitulate to a varying degree normal fatty tissue; and hemangiomas and angiosarcomas contain cells resembling vascular endothelium. Within the various categories, soft tissue tumors are usually divided into benign and malignant forms, although there are some tumor types with tumors of intermediate (“borderline”) malignancy (e.g., vascular tumors or hemangioendotheliomas).
Benign tumors , which more closely resemble normal tissue, have a limited capacity for autonomous growth. They exhibit little tendency to invade locally and are attended by a low rate of local recurrence following conservative therapy.
Malignant tumors , or sarcomas , in contrast, are locally aggressive and are capable of invasive or destructive growth, recurrence, and distant metastasis. Appropriate oncologic surgery is required to ensure the total removal of these tumors. Unfortunately, the term sarcoma does not indicate the likelihood or rapidity of metastasis. Some sarcomas, such as dermatofibrosarcoma protuberans, rarely metastasize, whereas others do so with high frequency. For these reasons, it is important to qualify the term sarcoma with a statement concerning the degree of differentiation or the histologic grade. “Well differentiated” and “poorly differentiated” are qualitative, and therefore subjective, terms used to indicate the relative maturity of the tumor with respect to normal adult tissue. Histologic grade is a means of quantitating the degree of differentiation by applying a set of histologic criteria. Usually, well-differentiated sarcomas are low-grade lesions, whereas poorly differentiated sarcomas are high-grade neoplasms. Tumors of intermediate or borderline malignancy are generally characterized by frequent recurrence but rarely metastasize.
Incidence of Soft Tissue Tumors
The incidence of soft tissue tumors, especially the frequency of benign tumors relative to malignant ones, is almost impossible to determine accurately. Benign soft tissue tumors greatly outnumber malignant tumors, and because many benign tumors, such as lipomas and hemangiomas, do not undergo biopsy, direct application of data from most hospital series is invalid for the general population.
Malignant soft tissue tumors, on the other hand, ultimately come to medical attention. Soft tissue sarcomas, compared with carcinomas and other neoplasms, are relatively rare and constitute fewer than 1.5% of all cancers, with an annual incidence of about 6 per 100,000 persons. However, according to an analysis of the Surveillance, Epidemiology and End Results (SEER) database, the incidence changes with age; for children younger than 10 years, the annual incidence was 0.9/100,000 but rose to 18.2/100,000 in adults over age 70. The most dramatic increases occurred at 30 and 70 years of age ( Table 1.1 ).
| Sarcoma Type | Number of Cases | Median Age at Diagnosis | Percentage of Patients ≤19 Yr Old (%) |
|---|---|---|---|
| Fibroblastic/myofibroblastic tumors | 3,037 | 54 | 9.4 |
| Fibrohistiocytic tumors | 14,599 | 57 | 3.7 |
| Rhabdomyosarcomas | 2,831 | 15 | 58.9 |
| Malignant peripheral nerve sheath tumor | 2,186 | 46 | 9.9 |
| Ewing family of tumors | 589 | 24 | 39.6 |
| Liposarcomas | 7,419 | 60 | 1.2 |
| Leiomyosarcomas | 13,135 | 59 | 0.9 |
| Synovial sarcomas | 1,859 | 35 | 17.6 |
| Vascular tumors (not Kaposi) | 2,742 | 65 | 2.1 |
| Chondroosseous soft tissue tumors | 680 | 55 | 3.8 |
| Alveolar soft part sarcomas | 164 | 25 | 28.7 |
There seems to be an upward trend in the incidence of soft tissue sarcomas, but it is not clear whether this represents a true increase or reflects better diagnostic capabilities and greater interest in this type of tumor. Judging from the available data, the incidence and distribution of soft tissue sarcomas seem to be similar in different regions of the world. Soft tissue sarcomas may occur anywhere in the body, but most arise from the large muscles of the extremities, the chest wall, the mediastinum, or the retroperitoneum. They occur at any age and, as with carcinomas, are more common in older patients.
Soft tissue sarcomas occur more frequently in males, but gender and age-related incidences vary among the histologic subtypes. For example, embryonal rhabdomyosarcoma occurs almost exclusively in young individuals, whereas undifferentiated pleomorphic sarcoma is predominantly a tumor of old age and is rare in children younger than 10 years of age.
Pathogenesis of Soft Tissue Tumors
As with other malignant neoplasms, the pathogenesis of most soft tissue tumors is still unknown. Recognized causes include various physical and chemical factors, exposure to ionizing radiation, and inherited or acquired immunologic defects. An evaluation of the exact cause is often difficult because of the long latent period between the time of exposure and the development of sarcoma, as well as the possible effect of multiple environmental and hereditary factors during the induction period. The origin of sarcomas from benign soft tissue tumors is exceedingly rare, except for malignant peripheral nerve sheath tumors arising in neurofibromas.
Environmental Factors
Trauma is frequently implicated in the development of sarcomas. Many of these reports are anecdotal, however, and the integrity of the injured part was not clearly established before the injury. Consequently, trauma often seems to be an event that merely calls attention to the underlying neoplasm. Rare soft tissue sarcomas have been reported arising in scar tissue following surgical procedures or thermal or acid burns, at fracture sites, and in the vicinity of plastic or metal implants, usually after a latent period of several years. Kirkpatrick et al. studied the histologic features in capsules surrounding the implantation site of a variety of biomaterials. Interestingly, they noted a spectrum of changes ranging from focal proliferative lesions through preneoplastic proliferations to incipient sarcomas and suggested a model of multistage tumorigenesis similar to the adenoma-carcinoma sequence.
Environmental carcinogens have been related to the development of sarcomas, but their role is largely unexplored, and only a few substances have been identified as playing a role in the induction of sarcomas in humans. A variety of animal models now exist to induce sarcomas, allowing a better understanding of their pathogenesis.
Phenoxyacetic acid herbicides, chlorophenols, and their contaminants, such as 2,3,7,8-tetrachlorodibenzo-para-dioxin (dioxin), have been linked to sarcomagenesis. A series of case-control studies from Sweden from 1979 to 1990 reported an up to sixfold increased risk of soft tissue sarcoma associated with exposure to phenoxyacetic acids or chlorophenols in individuals exposed to these herbicides in agricultural or forestry work. Similar reports of an increased risk of sarcoma associated with these herbicides came from Italy, Great Britain, and New Zealand. Although a study by Leiss and Savitz linked the use of phenoxyacetic acid lawn pesticides with soft tissue sarcomas in children, other studies with more detailed exposure histories did not confirm this association. These inconsistencies may be caused in part by the predominant phenoxyacetic herbicide used in different locations. In the United States, 2,4-dichlorophenoxyacetic acid is the primary phenoxyacetic herbicide used, whereas in Sweden the main herbicides contain 2,4,5-trichlorophenoxyacetic acid and 2-methyl-4-chlorophenoxyacetic acid, both of which are more likely contaminated with dioxin. High levels of dioxin exposure from accidental environmental contamination near Seveso, Italy, from an explosion at a chemical factory was followed by a threefold increased risk of soft tissue sarcomas among individuals living near the factory. Similarly, Collins et al. found a significantly higher risk of soft tissue sarcomas in trichlorophenol workers in Midland, Michigan, who were exposed to 2,3,7,8-tetrachlorodibenzo- p -dioxin. In addition, the possibility of an increased incidence of sarcomas was claimed for some of the 2 million soldiers stationed in Vietnam between 1965 and 1970 who were exposed to Agent Orange, a defoliant that contained dioxin as a contaminant. However, in several case-control and proportional mortality studies, no excess risk of soft tissue sarcoma was reported among those Vietnam veterans who were directly involved with the spraying of Agent Orange.
Vinyl chloride exposure is clearly associated with the development of hepatic angiosarcoma. There are also rare reports of extrahepatic angiosarcoma associated with this agent.
Radiation exposure is related to the development of sarcomas, but considering the frequency of radiotherapy, radiation-induced soft tissue sarcomas are actually quite uncommon. The incidence of postradiation sarcoma is difficult to estimate, but reports generally range from 0.03% to 0.80%. Much of the data regarding the incidence of postradiation sarcomas are derived from large cohorts of breast cancer patients treated with postoperative radiation therapy. To qualify as a postradiation sarcoma, there must be documentation that the sarcoma developed in the irradiated field, a histologic confirmation of the diagnosis, a period of latency of at least 3 years between irradiation and the appearance of a tumor, and documentation that the region bearing the tumor was normal before the administration of the radiation. Almost all postradiation sarcomas occur in adults, and women develop these tumors more frequently, an observation that might reflect the common use of radiation for the treatment of breast and gynecologic malignancies.
Postradiation sarcomas do not display the wide range of appearances associated with sporadic non–radiation-induced tumors. The most common postradiation soft tissue sarcoma is undifferentiated pleomorphic sarcoma, which accounts for almost 70% of cases. Unfortunately, most postradiation sarcomas are high-grade lesions and are detected at a relatively higher stage than their sporadic counterparts. Therefore the survival rate associated with these lesions is quite poor.
The prognosis of postradiation sarcomas is most closely related to the anatomic site, which in turn probably reflects resectability. Patients with radiation-induced sarcomas of the extremities have the best survival (approximately 30% at 5 years), whereas those with lesions arising in the vertebral column, pelvis, and shoulder girdle generally have survival rates of less than 5% at 5 years.
The total dose of radiation seems to influence the incidence of postradiation sarcoma; most are reported to occur at doses of 5000 cGy or more. Mutations of the TP53 gene have been implicated in the pathogenesis of these tumors. Extravasated Thorotrast (thorium dioxide), although no longer used for diagnostic or therapeutic purposes, has induced soft tissue sarcomas, particularly angiosarcomas, at the site of injection.
Oncogenic Viruses
The role of oncogenic viruses in the pathogenesis of soft tissue sarcomas is still poorly understood, although there is convincing evidence that the human herpesvirus 8 (HHV8) is the causative agent of Kaposi sarcoma. In addition, a large body of literature supports the role of the Epstein-Barr virus (EBV) in the pathogenesis of smooth muscle tumors in patients with immunodeficiency syndromes or following therapeutic immunosuppression in the transplant setting. Aside from these settings, there is no conclusive evidence that human-transmissible viral agents constitute a major risk factor in the development of soft tissue sarcomas.
Immunologic Factors
As mentioned previously, immunodeficiency and therapeutic immunosuppression are associated with the development of soft tissue sarcomas, particularly smooth muscle tumors and Kaposi sarcoma. In addition, acquired regional immunodeficiency, or loss of regional immune surveillance, may play a central role in the development of the relatively rare angiosarcomas that arise in the setting of chronic lymphedema, secondary to radical mastectomy or congenital or infectious conditions.
Genetic Factors
A number of genetic diseases are associated with the development of soft tissue tumors, and the list will undoubtedly lengthen as we continue to further understand the molecular underpinnings of mesenchymal neoplasia. Neurofibromatosis types 1 and 2 and familial adenomatous polyposis (FAP, Gardner syndrome) are classic examples of genetic diseases associated with soft tissue tumors. Familial cancer syndromes associated with soft tissue sarcomas are more fully described in Chapter 4 .
Classification of Soft Tissue Tumors
The development of a useful, comprehensive histologic classification of soft tissue tumors has been a relatively slow process. Earlier classifications have been largely descriptive and based more on the nuclear configuration than the type of tumor cells. Terms such as round cell sarcoma and spindle cell sarcoma may be diagnostically convenient but should be discouraged because they convey little information as to the nature and potential behavior of a given tumor. More recent classifications have been based principally on the line of differentiation of the tumor, that is, the type of tissue formed by the tumor rather than the type of tissue from which the tumor theoretically arose.
Over the past 4 decades there have been several attempts to devise a useful, comprehensive classification of soft tissue tumors. The classification used here is similar to the revised 2013 World Health Organization (WHO) classification, a collective effort by pathologists worldwide. Each of the histologic categories is divided into a benign group and a malignant group. In addition, for several tumor categories, some tumors are classified as being of intermediate (borderline or low malignant potential) malignancy, implying a high rate of local recurrence and a small risk of metastasis. Most tumors retain the same pattern of differentiation in the primary and recurrent lesions, but occasionally change their pattern of differentiation or may even differentiate along several cellular lines.
Undifferentiated pleomorphic sarcoma (formerly known as “malignant fibrous histiocytoma”) and liposarcoma are the most common soft tissue sarcomas of adults, together accounting for 35% to 45% of all sarcomas. Rhabdomyosarcoma, neuroblastoma, and Ewing sarcoma are the most frequent soft tissue sarcomas of childhood.
Grading and Staging Soft Tissue Sarcomas
With a few notable exceptions, histologic typing does not provide sufficient information for predicting the clinical course of a sarcoma and therefore must be accompanied by grading and staging information. Grading assesses the degree of malignancy of a sarcoma and is based on an evaluation of several histologic parameters (described in the following two sections), whereas staging provides shorthand information regarding the extent of the disease at a designated time, usually the time of initial diagnosis. Many variables affect the outcome of a sarcoma. Their relative importance may vary with time and with the sarcoma subtype. Grading and staging systems simplify these variables and emphasize the most important ones that seem to have the most universal applicability for all sarcomas. Deyrup and Weiss and more recently Neuville et al. provide extensive discussions related to grading systems and issues.
Grading Systems
Grading of soft tissue sarcomas was first proposed in 1939 by Broders. He suggested that fibrosarcomas could be divided into several subtypes (fibrous, fibrocellular, and cellular), and that those that were highly cellular should be considered grade 4 regardless of the level of mitotic activity. These principles persist in current grading systems, in that certain parameters (e.g., mitotic activity) should be evaluated in sarcomas, some histologic subtypes a priori dictate a grade, and the level of differentiation must be factored into the assignment of a grade. Over the ensuing decades, numerous studies reaffirmed the importance of grading and emphasized the primacy of necrosis and mitotic activity in assessing a grade. Some studies have further proposed the use of Ki-67 immunoreactivity or MIB-1 score/index to assess mitotic activity accurately.
The first large-scale effort to grade and stage sarcomas occurred in 1977 when Russell et al., using a database of 1000 cases and the tumor-node-metastasis (TNM) staging system, showed that incorporating grade into the staging system improved prediction of outcome. Most important, in the absence of metastatic disease, grade essentially defined the clinical stage . This study is most often cited as providing the first reliable grading system in the United States, yet paradoxically, it did not provide objective criteria for grading. Rather, the grade was determined by a panel of experts based on their years of experience. The paper’s real contribution to grading was the implied concept that certain histologic types of sarcomas were inherently low grade and others were high grade, a premise of many subsequent grading systems.
Following that seminal publication, many grading systems were published internationally, including one from the U.S. National Cancer Institute (NCI) ( Table 1.2 ). Although differing in emphasis, most relied on mitotic activity and necrosis in deriving a grade, and some proposed that sarcoma-specific parameters should be used. The number of grades varies among the systems, ranging from two to four. Three-grade systems seem best suited for predicting patterns for survival and a likely response to therapy ( Fig. 1.1 ). Four-grade systems usually show little difference between the two lowermost grades; two-grade systems, which distinguish between only low-grade and high-grade sarcomas, are more readily related to the type of surgical therapy but make it difficult to deal with sarcomas that lie between these two extremes.
| Histologic Type | Grade 1 | Grade 2 | Grade 3 |
|---|---|---|---|
| Well-differentiated liposarcoma | + | ||
| Myxoid liposarcoma | + | ||
| Round cell liposarcoma | + | + | |
| Pleomorphic liposarcoma | + | ||
| Fibrosarcoma | + | + | |
| MFH, pleomorphic type ∗ | + | + | |
| MFH, inflammatory type ∗ | + | + | |
| MFH, myxoid type ∗ | + | ||
| MFH, pleomorphic type ∗ | + | ||
| DFSP | + | ||
| Leiomyosarcoma | + | + | + |
| Malignant solitary fibrous tumor | + | + | + |
| Rhabdomyosarcoma (all types) | + | ||
| Chondrosarcoma | + | + | + |
| Myxoid chondrosarcoma | + | + | |
| Mesenchymal chondrosarcoma | + | ||
| Osteosarcoma | + | ||
| Extraskeletal Ewing sarcoma | + | ||
| Synovial sarcoma | + | ||
| Epithelioid sarcoma | + | + | |
| Clear cell sarcoma | + | + | |
| Superficial MPNST | + | ||
| Epithelioid MPNST | + | + | |
| Malignant Triton tumor | + | ||
| Angiosarcoma | + | + | |
| Alveolar soft part sarcoma | + | ||
| Kaposi sarcoma | + | + |
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