Evaluation of Soft Tissue Tumors

Carol D. Morris

Soft tissue tumors are heterogeneous in their behavior and management. The vast majority of soft tissue tumors are benign, with benign tumors outnumbering malignant tumors by a factor of at least 100. This chapter deals with the general diagnostic and management guidelines for both benign and malignant soft tissue tumors. More specific information is available in each tumor-specific chapter.

Pathogenesis

Etiology

The etiology of most soft tissue tumors is largely unknown. Environmental exposures, radiation, viral infection, and genetic associations have all been implicated, though the developmental associations are casual in most instances (Box 2-1).

Epidemiology

Benign
- True incidence is poorly reported
  - ∼300/100,000
- Outnumber malignant soft tissue sarcomas by 100:1
Malignant
- ∼8,700 cases/year in the U.S.
- Annual incidence ∼1.5/100,000
  - 8/100,000 in individuals >80 years old
- Accounts for <1% of all cancers

Pathophysiology

While the pathophysiology of most soft tissue tumors remains ambiguous, the past two decades have provided considerable insight into the biology of these tumors in the form of cytogenetic and molecular information. Chromosomal translocations or other chromosomal aberrations have been reported for virtually every type of soft tissue tumor. The more consistent genetic findings are outlined in Tables 2-1 and 2-2. In addition, a number of inherited conditions are associated with the development of soft tissue tumors (Table 2-3).

Classification

Soft tissue tumors are most commonly characterized histologically according to the type of tissue they most closely resemble. The most widely recognized classification is that
of the World Health Organization (WHO), which was first published in 1969 and most recently updated in 2002.

Table 2.1 Cytogenetic and Molecular Genetic Alterations Seen in Benign Soft Tissue Tumors

Tumor	Genetic Alterations
Lipoma	12q13–15, 6p21–23, 13q11–22, 13q del
Desmoid	Trisomy 8, trisomy 20, APC gene mutations
Schwannoma	Monosomy 22
Neurofibroma	t(12;14)

Box 2-1 Etiologic Factors Reported in the Development of Soft Tissue Tumors

Environmental
   Trauma
   Chemical carcinogens (dioxin)
   Asbestos
   Surgical implants
Radiation
   Therapeutic
Viral Infection
   Human immunodeficiency virus (HIV)
   Cytomegalovirus (CMV)
   Human herpes virus (HHV)-8
   Epstein-Barr virus (EBV)
Genetic
   Neurofibromatosis
   Retinoblastoma
   Gardner’s syndrome
   Li-Fraumeni syndrome
Immunologic
   Therapeutic immunosuppression
   Stewart-Treves syndrome

The major histologic categories are:

Adipocytic
Fibroblastic
Fibrohistiocytic
Smooth muscle
Perivascular
Skeletal muscle
Vascular
Chondro-osseous
Uncertain differentiation

The major histologic categories are then divided into benign, intermediate, and malignant groups. WHO recognizes over 60 subtypes of benign soft tissue tumors and over 50 subtypes of malignant soft tissue tumors (sarcomas). It is not thought that the malignant subtypes arise from the benign forms. For example, liposarcoma does not arise from benign fat in lipoma but rather histologically exhibits lipoblastic differentiation.

Diagnosis

Benign soft tissue tumors are fairly common and rarely problematic. In contrast, soft tissue sarcomas are exceedingly rare but diagnostically and therapeutically challenging. Unfortunately both benign soft tissue tumors and soft tissue sarcomas have a deceptively similar presentation, and as such a delay in the diagnosis of soft tissue sarcoma is not uncommon (Table 2-4). While clinical and imaging features will help guide an appropriate work-up, any suspicious soft tissue mass must be biopsied.

Table 2.2 Cytogenetic and Molecular Genetic Alterations Seen in Malignant Soft Tissue Tumors

Tumor	Translation	Involved Genes
Primitive neuroectodermal tumor (PNET)	t(11;22)	FLI1, EWS
Clear cell sarcoma	t(12;22)	ATF1, EWS
Extraskeletal myxoid chondrosarcoma	t(9;22)	CHN, EWS
Synovial sarcoma	t(X;18)	SSX1 or SSX2, SYT
Myxoid liposarcoma	t(12;16)	CHOP, TLS
Alveolar rhabdomyosarcoma	t(2;13)	PAX3, FKHR
Alveolar soft part sarcoma	t(X;17)	TFE3, ASPL
Dermatofibrosarcoma protuberans*	t(17;22)	COL1A1, PDGFB1
* In the WHO classification, dermatofibrosarcoma protuberans is classified as a skin tumor, but it may be encountered in the orthopaedic oncology setting.

Table 2.3 Inherited Syndromes Associated with Soft Tissue Tumors

Syndrome	Associated Tumors
Bannayan-Riley-Ruvalcaba syndrome	Lipoma, hemangioma (hamartoma syndrome)
Beckwith-Wiedemann syndrome	Rhabdomyosarcoma, myxoma, fibroma (overgrowth syndrome)
Costello syndrome	Rhabdomyosarcoma (congenital anomaly/mental retardation syndrome)
Cowden disease	Lipoma, hemangioma (hamartoma syndrome)
Familial fibromatosis	Desmoid tumors
Li-Fraumeni syndrome	Various soft tissue sarcomas (or bone sarcomas)
Maffucci syndrome	Hemangioma, angiosarcoma (with enchondromas)
Mazabraud syndrome	Intramuscular myxoma (with fibrous dysplasia)
Neurofibromatosis-1	Neurofibromas, malignant peripheral nerve sheath tumors (MPNST)
Neurofibromatosis-2	Schwannoma
Proteus syndrome	Lipoma (overgrowth syndrome)
Retinoblastoma syndrome	Various soft tissue sarcomas
Rubinstein-Taybi syndrome	Myogenic sarcoma
Werner syndrome	Various soft tissue sarcomas

Physical Examination and History

Clinical Features

History

How long has the mass been present?

Masses present for long periods of time are most likely benign.
New masses arising over a short period of time raise malignancy suspicion.
Synovial sarcoma and clear cell sarcoma are classic exceptions (may be present for many years).

Any mass that persists for >4 weeks in the absence of clear-cut trauma warrants consideration of biopsy.

Table 2.4 Guidelines for the Clinical Presentation of Extremity Soft Tissue Masses

Parameter	Benign	Malignant	Comments
Pain	Rare*	Rare	Uncommon in the absence of nerve or bone invasion
Size	<5 cm	>5 cm
Location	Superficial (subcutaneous)	Deep to fascia	1/3 of soft tissue sarcomas are superficial.
Mobility	Mobile**	Fixed
Consistency	Soft	Firm
Growth	Stable	Enlarging	Synovial sarcoma and clear cell sarcoma can be very slow-growing.
* One benign soft tissue mass that typically presents with pain is an intramuscular hemangioma. ** Benign peripheral nerve sheath tumors are tethered to the nerve and therefore are mobile only medially and laterally but not proximally/distally.