Etiology

The etiology 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 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 tumor, 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 (tumor 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 tumors in patient FAP has been demonstrated.[24]​ Evidence suggests that the incidence of FAP among patients with desmoid tumors is 7.5%, with 85% of these FAP associated desmoid tumors 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 sarcoma-associated herpesvirus (KSHV), is one of the few pathogens recognized as direct carcinogen, being involved in the pathogenesis of Kaposi sarcoma, primary effusion lymphoma and multicentric Castleman 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 Lymphedema

There is a connection between long-standing chronic lymphedema 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 radiation therapy.[32][33][34]

Carcinogens

Occupational exposure to industrial materials including vinyl chloride monomer, iatrogenic exposure to colloidal thorium dioxide (thorotrast) for radiologic exams 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 signaling under a soluble form, or encapsulated in extracellular vesicles. Sarcoma cells are characterized by a phenotypic and genetic heterogeneity coming from the successive oncogenic/epigenetic events occurring during tumor 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 tumor cells.[37]

Classification

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

Tumors are classified by differentiation and biological behavior. The major groups under this classification are:

  • Adipocytic tumors

  • Fibroblastic/myofibroblastic tumors

  • So-called fibrohistiocytic tumors

  • Smooth muscle tumors

  • Pericytic (perivascular) tumors

  • Skeletal muscle tumors

  • Vascular tumors

  • Chondro-osseous tumors

  • Gastrointestinal stromal tumors

  • Nerve sheath tumors

  • Tumors of uncertain differentiation

  • Undifferentiated/unclassified sarcomas.

Biological potential is divided into:

  • Benign: rarely recur locally, and if so, are nondestructive

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

  • Intermediate (rarely metastasizing): 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 tumors

  • Malignant

    • Dedifferentiated liposarcoma

    • Myxoid liposarcoma

    • Pleomorphic liposarcoma

    • Liposarcoma, not otherwise specified.

  • Intermediate (locally aggressive)

    • Atypical lipomatous tumor/well-differentiated liposarcoma.

Fibroblastic/myofibroblastic tumors

  • Malignant

    • Adult fibrosarcoma

    • Myxofibrosarcoma

    • Low-grade fibromyxoid sarcoma

    • Sclerosing epithelioid fibrosarcoma

    • Giant cell fibroblastoma

    • Dermatofibrosarcoma protuberans.

  • Intermediate (rarely metastasizing)

    • Extrapleural solitary fibrous tumor

    • Inflammatory myofibroblastic tumor

    • Low-grade myofibroblastic sarcoma

    • Myxoinflammatory fibroblastic sarcoma

    • Infantile fibrosarcoma.

  • Intermediate (locally aggressive)

    • Superficial fibromatoses (palmar/plantar)

    • Desmoid-type fibromatoses

    • Lipofibromatosis.

So-called fibrohistiocytic tumors

  • Malignant

    • Pleomorphic malignant fibrohistiocytic (MFH)/undifferentiated pleomorphic sarcoma

    • Giant cell MFH/undifferentiated pleomorphic sarcoma with giant cells

    • Inflammatory MFH/undifferentiated pleomorphic sarcoma with prominent inflammation.

  • Intermediate (rarely metastasizing)

    • Plexiform fibrohistiocytic tumor

    • Giant cell tumor of soft tissues.

Smooth muscle tumors

  • Leiomyoma of deep soft tissue

  • Leiomyosarcoma.

Pericytic (perivascular) tumors

  • Glomus tumors

  • Angioleiomyoma

  • Myopericytoma, including myofibroma.

Skeletal muscle tumors

  • Malignant

    • Embryonal rhabdomyosarcoma (including botryoid, anaplastic)

    • Alveolar rhabdomyosarcoma (including solid, anaplastic)

    • Pleomorphic rhabdomyosarcoma

    • Spindle cell/sclerosing rhabdomyosarcoma.

Vascular tumors

  • Malignant

    • Epithelioid hemangioendothelioma

    • Angiosarcoma of soft tissue.

  • Intermediate (rarely metastasizing)

    • Retiform hemangioendothelioma

    • Papillary intralymphatic angioendothelioma

    • Composite hemangioendothelioma

    • Kaposi sarcoma.

  • Intermediate (locally aggressive)

    • Kaposiform hemangioendothelioma.

Chondro-osseous tumors

  • Soft-tissue chondroma

  • Extraskeletal osteosarcoma.

Gastrointestinal stromal tumors

Nerve sheath tumors

Tumors of uncertain differentiation

  • Malignant

    • Synovial sarcoma

    • Epithelioid sarcoma

    • Alveolar soft part sarcoma

    • Clear cell sarcoma of soft tissue

    • Extraskeletal myxoid chondrosarcoma

    • Primitive neuroectodermal tumor (PNET)/extraskeletal Ewing tumor: peripheral primitive neuroectodermal tumor (pPNET), extraskeletal Ewing tumor

    • Desmoplastic small round cell tumor

    • Extra-renal rhabdoid tumor

    • Malignant mesenchymoma

    • Neoplasms with perivascular epithelioid cell differentiation (PEComa)/clear cell myomelanocytic tumor

    • Intimal sarcoma.

  • Intermediate (rarely metastasizing)

    • Angiomatoid fibrous histiocytoma

    • Ossifying fibromyxoid tumor (including atypical/malignant)

    • Mixed tumor/myoepithelioma/parachordoma.

Undifferentiated/unclassified sarcomas

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