Aetiology

The aetiology for most patients with soft-tissue sarcoma (STS) is unknown, but there is evidence to suggest an association between some inherited germline mutations, and environmental factors which may increase the risk for the development of STS.

Germline mutations

Neurofibromatosis type 1 (NF1) von Recklinghausen's disease

NF1 is an autosomal dominant condition caused by mutations NF1-gene, which codes for a protein called neurofibromin.[17] Patients with NF1 syndrome have an 8% to 13% lifetime risk of developing malignant peripheral nerve sheath tumour, an aggressive, genetically complex STS that comprises 2% of all sarcomas.[18][19][20]​​​​

Li-Fraumeni syndrome

A rare autosomal dominant disorder caused by mutations in the TP53 gene (17p 13.1) which codes for p53 (tumour suppressor gene) has been associated with an increased risk of cancer, including sarcoma, of approximately 50% by age 40 and 90% by age 60 in mutation carriers.[21][22]​​

Familial retinoblastoma

An increased risk of sarcomas, both bone and soft tissue, has been demonstrated in patients who have had a familial retinoblastoma, caused by inherited mutations in the RB1 gene.[23]

Familial adenomatous polyposis (FAP)

FAP is an autosomal dominant syndrome caused by germline mutation of adenomatous polyposis coli (APC). A 15% absolute lifetime risk of developing desmoid tumours in patient FAP has been demonstrated.[24]​ Evidence suggests that the incidence of FAP among patients with desmoid tumours is 7.5%, with 85% of these FAP associated desmoid tumours diagnosed in the setting of known FAP.[25]

Environmental factors

Radiation

Therapeutic radiation is an important environmental factor that increases the risk of sarcoma, it is commonly associated with angiosarcoma, undifferentiated pleomorphic sarcoma, and leiomyosarcoma.[26][27]

Human herpesvirus-8 (HHV-8) infection

Human herpesvirus 8 (HHV8), also known as Kaposi's sarcoma-associated herpesvirus (KSHV), is one of the few pathogens recognised as direct carcinogen, being involved in the pathogenesis of Kaposi's sarcoma, primary effusion lymphoma and multi-centric Castleman's disease.[28][29][30]

Congenital disorders

Beckwith-Wiedemann syndrome is a mostly sporadic disorder due to faulty gene imprinting, resulting in overgrowth and developmental anomalies. There is a 7.5% to 10% incidence of cancer, including rhabdomyosarcoma, myxoma, fibromas, and hamartomas.[31]

Chronic Lymphoedema

There is a connection between long-standing chronic lymphoedema and angiosarcoma known as Stewart-Treves syndrome, evidence suggests it occurs in 0.5% of patients who have undergone radical mastectomy with axillary node dissection, followed by adjuvant radiotherapy.[32][33][34]​​​​

Carcinogens

Occupational exposure to industrial materials including vinyl chloride monomer, iatrogenic exposure to colloidal thorium dioxide (thorotrast) for radiological examinations in the past, chronic arsenic ingestion, and androgen have been associated with an increased risk of sarcoma.[35][36]

Pathophysiology

The development of a sarcoma results from a complex biological process. Their development combines the emergence of a first genetic alteration that activates an oncogene, or oncogenic hit, which gives a cell a growth advantage and promotes cancer. The first oncogenic hit is followed by oncogenic and epigenetic events in combination with a permissive microenvironment composed by cell types from mesodermal tissue, immune infiltrate, vascular and extracellular matrix components.[37]

Sarcoma cells interact with their close environment through direct contact, enhanced cytokine/growth factors/miRNA signalling under a soluble form, or encapsulated in extracellular vesicles. Sarcoma cells are characterised by a phenotypic and genetic heterogeneity coming from the successive oncogenic/epigenetic events occurring during tumour development and by cancer cells acquiring the ability to self-renew, differentiate and proliferate, which becomes progressively quiescent.[37]

Metastases occur as sarcomas are prone to induce distant metastatic foci spread by circulating tumour cells.[37]

Classification

World Health Organization classification of tumours of soft tissue and bone[10]

Tumours are classified by differentiation and biological behaviour. The major groups under this classification are:

  • Adipocytic tumours

  • Fibroblastic/myofibroblastic tumours

  • So-called fibrohistiocytic tumours

  • Smooth-muscle tumours

  • Pericytic (perivascular) tumours

  • Skeletal muscle tumours

  • Vascular tumours

  • Chondro-osseous tumours

  • Gastrointestinal stromal tumours

  • Nerve sheath tumours

  • Tumours of uncertain differentiation

  • Undifferentiated/unclassified sarcomas.

Biological potential is divided into:

  • Benign: rarely recur locally and, if so, are non-destructive

  • Intermediate (locally aggressive): often recur locally, with infiltrative and locally destructive growth; lesions do not have any evident potential to metastasise

  • Intermediate (rarely metastasising): are locally aggressive but can sometimes produce distant metastases

  • Malignant: significant risk of distant metastases, as well as local destruction and recurrence; known as soft-tissue sarcomas.

Malignant and intermediate subtypes of soft-tissue sarcoma from this classification are as follows:

Adipocytic tumours

  • Malignant

    • Dedifferentiated liposarcoma

    • Myxoid liposarcoma

    • Pleomorphic liposarcoma

    • Liposarcoma, not otherwise specified.

  • Intermediate (locally aggressive)

    • Atypical lipomatous tumour/well-differentiated liposarcoma.

Fibroblastic/myofibroblastic tumours

  • Malignant

    • Adult fibrosarcoma

    • Myxofibrosarcoma

    • Low-grade fibromyxoid sarcoma

    • Sclerosing epithelioid fibrosarcoma

    • Giant cell fibroblastoma

    • Dermatofibrosarcoma protuberans.

  • Intermediate (rarely metastasising)

    • Extrapleural solitary fibrous tumour

    • Inflammatory myofibroblastic tumour

    • Low-grade myofibroblastic sarcoma

    • Myxoinflammatory fibroblastic sarcoma

    • Infantile fibrosarcoma.

  • Intermediate (locally aggressive)

    • Superficial fibromatoses (palmar/plantar)

    • Desmoid-type fibromatoses

    • Lipofibromatosis.

So-called fibrohistiocytic tumours

  • Malignant

    • Pleomorphic malignant fibrohistiocytic/undifferentiated pleomorphic sarcoma

    • Giant-cell malignant fibrohistiocytic/undifferentiated pleomorphic sarcoma with giant cells

    • Inflammatory malignant fibrohistiocytic/undifferentiated pleomorphic sarcoma with prominent inflammation.

  • Intermediate (rarely metastasising)

    • Plexiform fibrohistiocytic tumour

    • Giant-cell tumour of soft tissues.

Smooth-muscle tumours

  • Leiomyoma of deep soft tissue

  • Leiomyosarcoma.

Pericytic (perivascular) tumours

  • Glomus tumours

  • Angioleiomyoma

  • Myopericytoma, including myofibroma.

Skeletal muscle tumours

  • Malignant

    • Embryonal rhabdomyosarcoma (including botryoid, anaplastic)

    • Alveolar rhabdomyosarcoma (including solid, anaplastic)

    • Pleomorphic rhabdomyosarcoma

    • Spindle cell/sclerosing rhabdomyosarcoma.

Vascular tumours

  • Malignant

    • Epithelioid haemangioendothelioma

    • Angiosarcoma of soft tissue.

  • Intermediate (rarely metastasising)

    • Retiform haemangioendothelioma

    • Papillary intralymphatic angioendothelioma

    • Composite haemangioendothelioma

    • Kaposi's sarcoma.

  • Intermediate (locally aggressive)

    • Kaposiform haemangioendothelioma.

Chondro-osseous tumours

  • Soft-tissue chondroma

  • Extraskeletal osteosarcoma.

Gastrointestinal stromal tumours

Nerve sheath tumours

Tumours of uncertain differentiation

  • Malignant

    • Synovial sarcoma

    • Epithelioid sarcoma

    • Alveolar soft-part sarcoma

    • Clear-cell sarcoma of soft tissue

    • Extraskeletal myxoid chondrosarcoma

    • Primitive neuroectodermal tumour (PNET)/extraskeletal Ewing's tumour: peripheral primitive neuroectodermal tumour (pPNET), extraskeletal Ewing's tumour

    • Desmoplastic small round-cell tumour

    • Extra-renal rhabdoid tumour

    • Malignant mesenchymoma

    • Neoplasms with perivascular epithelioid cell differentiation/clear-cell myomelanocytic tumour

    • Intimal sarcoma.

  • Intermediate (rarely metastasising)

    • Angiomatoid fibrous histiocytoma

    • Ossifying fibromyxoid tumour (including atypical/malignant)

    • Mixed tumour/myoepithelioma/parachordoma.

Undifferentiated/unclassified sarcomas

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