Origin and Classification of Soft Tissue Tumors

Soft tissue sarcomas, unlike benign soft tissue lesions, are relatively uncommon and are estimated to represent about 1% of all malignant tumors (1, 2, 3). Hajdu (1) noted that in the United States, the incidence of soft tissue sarcomas is about the same as that of multiple myeloma or carcinoma of the thyroid. Soft tissue sarcomas are three to four times as common as primary malignant bone tumors (1). An analysis of soft tissue sarcomas by Baldursson et al. (4) in Iceland, between 1955 and 1988, revealed an age-standardized incidence rate of 2.7 per 100,000 of population. Rydholm (5) noted an age-standardized incidence rate of 1.4 per 100,000 of population in Sweden. The incidence of soft tissue sarcoma increases markedly with age; the age-specific annual incidence for patients 80 years and older is 8 per 100,000 (5). It is difficult to estimate the annual incidence of benign soft tissue tumors, because many lipomas, hemangiomas, and other benign lesions do not undergo biopsy; however, the annual clinical incidence of benign soft tissue tumors is estimated at 300 per 100,000 (5).

CLASSIFICATION OF SOFT TISSUE TUMORS

Fundamental Concepts

The soft tissue is derived primarily from mesenchyme and, by convention, comprises the skeletal muscle, fat, fibrous tissue, peripheral nervous system, and the serving vascular structures (6). Soft tissue tumors are generally classified histologically on the basis of the adult tissues that they resemble (6, 7, 8). The designations of lipoma and liposarcoma, for example, do not indicate that these lesions arise from fat, but that they “recapitulate to a varying degree normal fatty tissue” (6). Although this concept works well for most lesions, it is important to remember that there are several sarcomas, such as synovial sarcoma or alveolar soft part sarcoma, with no normal cellular counterpart. Many sarcomas are poorly differentiated; consequently, they lack the microscopic features that are required to make a specific diagnosis. In such cases, immunohistochemical staining and genetic analysis have aided pathologists in further classifying tumors. These techniques are well established and are used routinely. Despite the pathologist’s best efforts, a small number of soft tissue sarcomas cannot be further classified. This group of sarcomas that cannot be further subclassified previously comprised approximately 5% to 15% of soft tissue sarcomas (4, 9), although current immunochemical and genetic techniques will continue to reduce this number.

The histologic classification of soft tissue tumors used in this text reflects the World Health Organization (WHO) classification published in 2013 (10). This updated classification continues the use of a revised categorization of biologic behavior that allows for two designations of intermediate malignancy: locally aggressive and rarely metastasizing (10). The current WHO classification is summarized in Table 1.1 (10, 11) and includes peripheral nerve sheath tumors, which were previously addressed by the WHO in a separate publication (12).

Special Stains

Although the diagnosis of soft tissue tumors can frequently be made on the basis of light microscopic features, as many as 20% of cases cannot be definitively classified, even by experienced pathologists (13). Many soft tissue tumors have microscopic features that overlap. This includes various spindle cell tumors as well as other nonsarcomatous lesions such as carcinoma, melanoma, and lymphoma; therefore, additional methods may be required to further classify these lesions (13, 14, 15).

In addition to standard hematoxylin-eosin-stained slides, additional staining referred to as histochemical techniques may be used (13, 14, 15). For example, trichrome stain may be used to distinguish fibrous tissue from muscle tissue (14). Intracytoplasmic glycogen usually seen

in lesions such as Ewing sarcoma may be identified with periodic acid-Schiff (PAS) stain (14). More recently, immunohistochemical techniques have been applied to the diagnosis of soft tissue tumors.

TABLE 1.1 WHO classification of soft tissue tumors^a

Adipocytic tumors
Benign
	Lipoma
	Lipomatosis
	Lipomatosis of nerve
	Lipoblastoma/lipoblastomatosis
	Angiolipoma
	Myolipoma
	Chondroid lipoma
	Extra-renal angiomyolipoma
	Extra-adrenal myelolipoma
	Spindle cell lipoma/pleomorphic lipoma
	Hibernoma
Intermediate (locally aggressive)
	Atypical lipomatous tumor/well-differentiated liposarcoma
Malignant
	Dedifferentiated liposarcoma
	Myxoid liposarcoma
	Pleomorphic liposarcoma
	Liposarcoma, not otherwise specified
Fibroblastic/myofibroblastic tumors
Benign
	Nodular fasciitis
	Proliferative fasciitis
	Proliferative myositis
	Myositis ossificans
	Fibro-osseous pseudotumor of digits
	Ischemic fasciitis
	Elastofibroma
	Fibrous hamartoma of infancy
	Fibromatosis coli
	Juvenile hyaline fibromatosis
	Inclusion body fibromatosis
	Fibroma of tendon sheath
	Desmoplastic fibroblastoma
	Mammary-type myofibroblastoma
	Calcifying aponeurotic fibroma
	Angiomyofibroblastoma
	Cellular angiofibroma
	Nuchal-type fibroma
	Gardner fibroma
	Calcifying fibrous tumor
Intermediate (locally aggressive)
	Palmar/plantar fibromatosis
	Desmoid-type fibromatosis
	Lipofibromatosis
	Giant cell fibroblastoma
Intermediate (rarely metastasizing)
	Dermatofibrosarcoma protuberans
		Fibrosarcomatous dermatofibrosarcoma protuberans
		Pigmented dermatofibrosarcoma protuberans
	Solitary fibrous tumor
	Inflammatory myofibroblastic tumor
	Low-grade myofibroblastic sarcoma
	Myxoinflammatory fibroblastic sarcoma
	Infantile fibrosarcoma
Malignant
	Adult fibrosarcoma
	Myxofibrosarcoma
	Low-grade fibromyxoid sarcoma
	Sclerosing epithelioid fibrosarcoma
So-called fibrohistiocytic tumors
Benign
	Tenosynovial giant cell tumor
		Localized type
		Diffuse-type
		Malignant
	Deep benign fibrous histiocytoma
Intermediate (rarely metastasizing)
	Plexiform fibrohistiocytic tumor
	Giant cell tumor of soft tissue
Smooth muscle tumors
Benign
	Deep leiomyoma
Malignant
	Leiomyosarcoma (excluding skin)
Pericytic (perivascular) tumors
	Glomus tumor (and variants)
		Glomangiomatosis
		Malignant glomus tumor
	Myopericytoma
		Myofibroma
		Myofibromatosis
	Angioleiomyoma
Skeletal muscle tumors
Benign
	Rhabdomyoma
		Adult type
		Fetal type
		Genital type
Malignant
	Embryonal rhabdomyosarcoma (including botroyoid, anaplastic)
	Alveolar rhabdomyosarcoma
	Pleomorphic rhabdomyosarcoma
	Spindle cell/sclerosing rhabdomyosarcoma
Vascular tumors
Benign
	Hemangiomas
		Synovial
		Venous
		Arteriovenous hemangioma/malformation
		Intramuscular
	Epithelioid hemangioma
	Angiomatosis
	Lymphangioma
Intermediate (locally aggressive)
	Kaposiform hemangioendothelioma
Intermediate (rarely metastasizing)
	Retiform hemangioendothelioma
	Papillary intralymphatic angioendothelioma
	Composite hemangioendothelioma
	Pseudomyogenic (epithelioid sarcoma-like) hemangioendothelioma
	Kaposi sarcoma
Malignant
	Epithelioid hemangioendothelioma
	Angiosarcoma of soft tissue
Chondro-osseous tumors
	Soft tissue chondroma
	Mesenchymal chondrosarcoma
	Extraskeletal osteosarcoma
Gastrointestinal Stromal Tumors
	Benign gastrointestinal stromal tumor
	Gastrointestinal stromal tumor, uncertain malignant potential
	Benign gastrointestinal stromal tumor, malignant
Nerve Sheath Tumors
Benign
	Schwannoma
	Melanotic schwannoma
	Neurofibroma
		Plexiform neurofibroma
	Perineurioma
		Malignant perineurioma
	Granular cell tumor
	Dermal nerve sheath myxoma
	Solitary circumscribed neuroma
	Extopic meningioma
	Benign triton tumor
	Hybrid nerve sheath tumor
Malignant
	Malignant peripheral nerve sheath tumor (MPNST)
	Epithelioid malignant peripheral nerve sheath tumor
	Malignant triton tumor
	Malignant granular cell tumor
	Ectomesenchymoma
Tumors of Uncertain Differentiation
Benign
	Acral fibromyxoma
	Intramuscular myxoma
	Juxta-articular myxoma
	Deep (“aggressive”) angiomyxoma
	Pleomorphic hyalinizing angiectatic tumor
	Ectopic hamartomatous thymoma
Intermediate (locally aggressive)
	Hemosiderotic fibrolipomatous tumor
Intermediate (rarely metastasizing)
	Atypical fibroxanthoma
	Angiomatoid fibrous histiocytoma
	Ossifying fibromyxoid tumor
	Mixed tumor
	Myoepithelioma
	Myoepithelial carcinoma
	Phosphaturic mesenchymal tumor
Malignant
	Synovial sarcoma
	Epithelioid sarcoma
	Alveolar soft-part sarcoma
	Clear cell sarcoma of soft tissue
	Extraskeletal myxoid chondrosarcoma
	Extraskeletal Ewing tumor
	Desmoplastic small round cell tumor
	Extra-renal rhabdoid tumor
	Neoplasms with perivascular epithelioid cell differentiation (PEComa)
		PEComa, benign
		PEComa, malignant
	Intimal sarcoma
Undifferentiation/Unclassified Sarcomas
	Undifferentiated spindle cell sarcoma
	Undifferentiated pleomorphic sarcoma
	Undifferentiated round cell sarcoma
	Undifferentiated epithelioid sarcoma
	Undifferentiated sarcoma, NOS
* Adapted from Reference 10