4.1. Introduction

Both epithelial and connective tissue can undergo reactive and pseudoneoplastic proliferation in response to a variety of stimuli. The majority of reactions to foreign materials, and most diagnostic difficulties, concern the connective tissues.

The connective tissues comprise the mesodermally derived connective tissues of the trunk and extremities, i.e., bone, cartilage, muscle, fat, fibrous tissue and blood vessels, and include, by convention, peripheral nerves which are of neuroectodermal origin. Tumours of soft tissue and bone can be benign, malignant (sarcomas which metastasize) or of intermediate type (liable to recur locally but only rarely to metastasize). The commonest anatomical locations of soft-tissue sarcomas are the limbs and limb girdles, the retroperitoneum, the chest and abdominal walls and the mediastinum. Sarcomas of the head and neck form a further clinically significant subgroup, and similar tumours can occasionally arise in connective tissue elements of solid or hollow viscera. Osteosarcomas and chondrosarcomas, although most frequently of skeletal origin, also arise in extra-skeletal tissues.

4.2. Incidence and etiology

Benign mesenchymal tumours outnumber malignant tumours in hospital series (Enzinger & Weiss, 1995). Malignant tumours of the connective and soft tissues arise at all ages, some 5–10% of cases occurring before the age of 15 years. Age-standardized incidence rates range from 1–3 per 100 000 population per year in most areas covered by cancer registration (Parkin et al., 1997).

The cause or causes are in most cases unknown, although some of the underlying molecular events in the genesis of sarcomas are being elucidated. Associations have been reported with hereditary conditions, therapeutic or accidental irradiation, exposure to certain chemicals and immunological defects. Trauma can draw clinical attention to a pre-existing malignancy, but more commonly causes pseudoneoplastic reactions. However, sarcomas have been reported to arise in burn scars and in relation to metallic and plastic surgical implants.

Soft-tissue tumours can arise in a variety of genetic diseases or hereditary syndromes. Peripheral neurofibromatosis (NF1; also known as Von Recklinghausen's neurofibromatosis), an autosomal dominant condition with variable penetrance, is complicated by malignant peripheral nerve sheath tumours and occasionally other sarcomas. Central neurofibromatosis (NF2) is associated with bilateral acoustic neuromas. In some benign nerve sheath tumours, there is loss of part of chromosome 22 (Emory et al., 1995), and a possible mechanism of neoplasia is loss of the tumour-suppressor gene NF2 which is localized to 22q11.2-q12. Some malignant peripheral nerve sheath tumours are associated with loss of 17p, including the locus of the tumour-suppressor gene p53 (Menon et al., 1990).

Fibromatosis or desmoid tumour (a non-metastasizing but locally aggressive lesion) is found in about 10% of patients with the autosomal dominant condition of familial adenomatous polyposis (FAP), in whom it often arises in the mesentery. Gardner's syndrome additionally includes other benign soft-tissue, cutaneous and bone tumours (Enzinger & Weiss, 1995). The FAP locus at 5q21-22 contains the APC gene, mutations of which are implicated in FAP and in the genesis of colon cancer. In fibromatoses, a variety of abnormalities have been described including trisomy 7, 8 and 20 (in deep fibromatoses) and, in those associated with FAP, loss of heterozygosity due to deletion of 5q (Dei Tos & Dal Cin, 1997).

Li–Fraumeni syndrome is an autosomal dominant trait in which patients with germline p53 mutations have a familial predisposition to cancers (Strong et al., 1992). These include childhood soft-tissue sarcomas, breast and other malignancies.

Among patients who survive familial retinoblastoma, 10–20% develop sarcomas including osteosarcoma in the first decade, then other types later in life. This is related to loss of the Rb tumour-suppressor gene which is located at 13q14 (Stratton et al., 1989).

Therapeutic irradiation (see IARC, 2000) (for example, in treatment of lymphomas, Hodgkin's disease or breast or gynaecological cancers) is followed, in a very small proportion (0.1%) of cases, by development within the irradiated field of sarcomas in soft tissue or bone (Laskin et al., 1988; Wiklund et al., 1991; Mark et al., 1994; Pitcher et al., 1994). Such sarcomas, which arise after a long interval (exceeding three years and frequently much longer), are, with rare exceptions, of high-grade malignancy. Reported subtypes include malignant fibrous histiocytoma, osteosarcoma, chondrosarcoma, leiomyosarcoma, angiosarcoma (which is sometimes low-grade, notably in the breast (Parham & Fisher, 1997)) and synovial sarcoma (van de Rijn et al., 1997).

Exposure to herbicides containing 2,3,7,8-tetrachlorodibenzo-para-dioxin has been associated with human sarcomas (IARC, 1997b), and occupational exposure to vinyl chloride has been implicated in the etiology of angiosarcoma of the liver as well as other neoplasms (IARC, 1979a; Evans et al., 1983; IARC, 1987b).

Sarcomas can develop in immunosuppressed hosts. These include Kaposi's sarcoma linked to human immunodeficiency virus (HIV) infection (IARC, 1996) and acquired immune deficiency syndrome (AIDS), which is associated with infection with Kaposi's sarcoma herpesvirus (KSHV), a recently discovered herpesvirus previously designated HHV8 (Cesarman & Knowles, 1997; IARC, 1997c). Recently, smooth muscle tumours have been reported in immune-disordered children and adults (including transplant recipients and AIDS patients). In some of these, the Epstein–Barr virus (EBV) (IARC, 1997c) genome was demonstrated (Lee et al., 1995; McClain et al., 1995).

4.3. Classification

In contrast to carcinomas, it is not clear from which cells sarcomas arise since they have no in-situ phase. With a few exceptions, soft-tissue malignancies arise de novo and only rarely from pre-existing benign soft-tissue tumours, although the latter are numerically much more frequent. The most familiar example of this phenomenon is the malignant peripheral nerve sheath tumour arising in a neurofibroma, particularly in the setting of NF1.

Sarcomas are, therefore, classified by their apparent direction of differentiation, i.e., according to the cell or tissue type which they most resemble (Table 5). Thus, liposarcomas display fatty differentiation, leiomyosarcomas form smooth muscle, rhabdomyosarcomas form skeletal muscle and so on. Most sarcomas display one line of differentiation, although this sometimes changes when the tumour recurs. Because neoplasms can resemble embryonic tissues at different developmental stages, as well as adult tissues, and because of the wide variety of cell types and tissues derived from mesenchyme, there is a large number of sarcoma subtypes. The second edition of the WHO classification of soft-tissue tumours (Weiss, 1994) lists nearly 100 intermediate or malignant entities.

Table 5

Classification of sarcomas according to type of differentiation.

Cellular differentiation is apparent at a variety of levels. Morphologically, an initial assessment will include cell shape, and the presence of any obvious tissue type—for example, formation of neoplastic fat, muscle, bone, cartilage or blood vessels. In many cases, precise categorization requires further investigation by immunohistochemistry, electron microscopy or genetic techniques. Immunohistochemistry is of particular use in differential diagnosis of spindle- and round-cell sarcomas, and electron microscopy in the diagnosis of tumours with no or multiple immunohistochemical markers (Erlandson, 1994). Cytogenetic and molecular genetic techniques can reveal aberrations in a number of sarcomas and are valuable for diagnosing childhood-type small round-cell tumours and some myxoid tumours. Of special interest is the consistent presence in some sarcoma subtypes of specific chromosomal translocations, for many of which the relevant fusion genes have been identified (Cooper, 1996; Fisher, 1999) (Table 6). It is not known how these events arise, but they allow more precise classification and diagnosis and clarify the interrelationship of morphological subtypes. For example, it has been shown that round-cell liposarcoma is the poorly differentiated variant of myxoid liposarcoma (Weiss, 1996); that Ewing's sarcoma of both soft tissue and bone, peripheral primitive neuroectodermal tumours (pPNET) and thoraco-pulmonary small round-cell tumours (Askin tumour) all have the same underlying genetic abnormality; and that clear-cell sarcoma of soft parts and malignant melanoma are separate conditions, as are soft-tissue and osseous variants of myxoid chondrosarcoma (Brody et al., 1997a).

Table 6

Chromosomal translocations in malignant soft-tissue tumours.

A number of soft-tissue sarcomas do not resemble any normal mesenchymal element and many of these have been found to display non-mesenchymal differentiation (see Table 5). Thus synovial sarcoma (Fisher, 1986) and epithelioid sarcoma (Fisher, 1988) show epithelial differentiation, Ewing's sarcoma and pPNETs are primitive neural tumours and clear-cell sarcomas of tendons and aponeuroses have melanocytic features (Chung & Enzinger, 1983).

Malignant tumours composed of neoplastic fibroblasts have a particularly wide variety of manifestations. The lower grades include fibrosarcomas classified according to the accompanying stromal changes—myxoid (Angervall et al., 1977), fibromyxoid (Evans, 1993) or inflammatory (Meis & Enzinger, 1991). The higher-grade or pleomorphic sarcomas have been classified as malignant fibrous histiocytomas (Weiss & Enzinger, 1978), and until recently the commonest adult soft-tissue sarcoma was malignant fibrous histiocytoma of the storiform pleomorphic type (Fisher et al., 1992). The application of modern pathological techniques has, however, enabled many of these to be identified as poorly differentiated examples of various specific types of sarcoma (Fletcher, 1992; Fisher, 1996). It is also clear that some carcinomas, melanomas and even lymphomas can assume malignant fibrous histiocytoma-like patterns in solid organs and in soft tissues (Fletcher, 1992). The residual group of pleomorphic sarcomas, in which no differentiation is detected, show fibroblastic features, and should perhaps be called pleomorphic fibrosarcoma but the term malignant fibrous histiocytoma is well established and useful in diagnostic and clinical practice.

In contrast to the sarcoma types listed in Table 5, malignant fibrous histiocytomas do not show consistent genetic abnormalities, although they display a number of nonspecific aberrations.

4.4. Behaviour, grading and staging

Sarcomas grow and infiltrate locally, and many eventually metastasize. They spread commonly to the lungs and bone, and in some cases to lymph nodes. Their behaviour can be predicted to some extent by histological subtypes; some types are known to metastasize early, while others are indolent.

For the remainder, which form the majority of soft-tissue sarcomas, the behaviour is variable. One of the principal factors in assessing prognosis and determining management is the histological grade. Grading is an attempt to predict behaviour from microscopic features and usually relates to the degree of differentiation or resemblance to normal tissue. For carcinomas, where the degree of differentiation is readily assessed, grading is relatively straightforward, but the task is more difficult for sarcomas, which include many different types of tumour. Some resemble adult tissue, e.g., smooth muscle or fatty tumours, yet may have a poor prognosis even when well differentiated. Others recapitulate normal embryonic tissue but can have either a good or bad prognosis: although rhabdomyosarcoma is high-grade, myxoid liposarcoma is not. Additionally, many soft-tissue sarcomas do not resemble any normal tissue, so that their differentiation cannot be determined. Grading systems need to take these factors into account as well as the fact that some sarcomas always have a slow course and low metastatic potential and others are always aggressive.

Several grading systems are in clinical use (Coindre, 1993) as none has been universally accepted. As well as diagnostic category, factors commonly used are pleomorphism, mitotic index and necrosis. In some systems, these are assigned scores which are summed to give the final grade. Most systems have three grades, which relate to differences in survival.

Molecular genetic findings might relate to prognosis. For example, in alveolar rhabdomyosarcoma those tumours with t(1;13)(q36;q14) have a more favourable outcome than those with t(2:13)(q35–37;q14) (Kelly et al., 1997) and, in synovial sarcoma, a significantly longer metastasis-free survival period has been associated with patients whose localized tumour involved the SSX2 gene rather than the SSX1 gene (Kawai et al., 1998).

Some lesions, notably fibromatosis, are technically benign but can be relentlessly locally recurrent and infiltrative and thereby cause significant morbidity and mortality.

4.5. Pseudosarcomas and reactive conditions