Soft Tissue Sarcomas

Last Literature Review: January 2022 Last Update:

Medical Experts



Picture of Nicole Leonard, MD
Nicole Leonard, MD
Anatomic and Clinical Pathology Resident, University of Utah School of Medicine and ARUP Laboratories


Anton Rets, MD, PhD
Associate Professor of Pathology (Clinical), University of Utah
Medical Director, Hematopathology, ARUP Laboratories


Michael Ward, MD
Assistant Professor of Pathology (Clinical), University of Utah
Pathologist, ARUP Laboratories

Sarcomas are rare tumors that can arise from a variety of nonepithelial tissues, including soft tissues such as blood vessels, fat, muscles, and nerves. Correct identification of the specific type of tumor is important to ensure appropriate treatment and determine prognosis. Although morphology is the basis for diagnosis, laboratory testing, including immunohistochemistry, cytogenetics, and molecular genetics, may play an essential role in diagnosis and classification. Germline genetic testing may also be used in the evaluation of genetic syndromes associated with soft tissue sarcomas.

Quick Answers for Clinicians

What is the role of molecular testing in sarcomas?

Molecular genetic testing may be useful to support the diagnosis and classification of soft tissue sarcomas. Many soft tissue sarcoma subtypes exhibit cytogenetic and molecular abnormalities, including amplifications, deletions, recurrent translocations, or single base-pair substitutions.  These abnormalities may be specific to certain types of sarcoma and therefore diagnostically important. Some sarcomas may also be associated with complex karyotypes. Laboratory testing techniques used in the molecular characterization of soft tissue sarcomas may include fluorescence in situ hybridization (FISH), next generation sequencing (NGS), and polymerase chain reaction (PCR). 

Which tumor types must be distinguished from sarcomas?

Up to 20% of soft tissue sarcomas cannot be classified. In addition, soft tissue sarcomas can have morphologic features similar to those of carcinoma, lymphoma, or melanoma. A panel of immunohistochemical stains is often required to rule out these other tumor types.

Indications for Testing

Laboratory testing for soft tissue sarcomas is appropriate in individuals with a biopsy specimen that is suspicious for sarcoma and requires additional information beyond what can be provided by a morphologic evaluation.

Tumor Classification

Sarcomas are classified according to the 2020 World Health Organization (WHO) Classification of Soft Tissue and Bone Tumors.    Sarcomas are categorized into soft tissue and bone tumors, and further classified according to cell of origin.  

Laboratory Testing

For many soft tissue sarcomas, diagnosis and classification are based on histology and supported by immunohistochemical and molecular findings.   Enough tissue should be obtained from biopsy or resection for histology, immunohistochemistry, and molecular testing.


Immunohistochemical staining is often performed on biopsy tissue as a complement to morphologic evaluation to determine the cell/tissue type of origin and to differentiate between specific entities.  Useful stains include S100, smooth muscle actin (SMA), vimentin, and many others. Immunohistochemistry may be particularly useful to differentiate soft tissue sarcomas from other entities with similar morphology (eg, carcinomas or lymphomas).

Immunohistochemical Markers for Soft Tissue Sarcomas
MarkeraTumor/Cell Lineage
ALK-1Inflammatory myofibroblastic tumor
Beta cateninbTumors of fibroblast (nuclear) or epithelial cell (nuclear or cytoplasmic) lineage (eg, desmoid fibromatosis, tumors related to APC gene mutations)
CaldesmonTumors of smooth muscle lineage (eg, angiolipoma, GIST, glomus tumor, inflammatory myofibroblastic tumor, leiomyoma, leiomyosarcoma)
CD31More specific marker for tumors of vascular lineage
CD34More sensitive marker for tumors of vascular lineage (eg, vascular tumors, dermatofibrosarcoma protuberans, epithelioid sarcoma, solitary fibrous tumor, GIST, Kaposi sarcoma)
CD117/c-kitGIST, Ewing sarcoma, mast cells
DesminTumors of smooth and skeletal muscle lineage (eg, rhabdomyosarcoma, leiomyomas/leiomyosarcoma)
EMATumors of perineural cell lineage, carcinomas, and some sarcomas (eg, epithelioid sarcoma, synovial sarcoma, neurofibroma, perineurioma, sarcomatoid carcinoma); also positive in most carcinomas
ERGTumors of vascular lineage, some Ewing sarcomas
Ewing sarcoma 013 (CD99)Ewing family tumors
HHV8Kaposi sarcoma
INI-1Lost in epithelioid sarcoma, epithelioid malignant peripheral nerve sheath tumor, malignant rhabdoid tumor
MSATumors of smooth and skeletal muscle lineage (eg, rhabdomyosarcoma, leiomyomas/leiomyosarcoma)
MUC-4Low-grade fibromyxoid sarcoma
Myoogenin (Myf4)cTumors of primitive muscle lineage (eg, rhabdomyosarcoma)
NSETumors of neuroectodermal cell lineage (neuroendocrine neoplasms)
S100dTumors of Schwann cells and melanocyte lineage (eg, schwannoma, neurofibroma, granular cell tumor, melanoma)
SMATumors of smooth muscle or myofibroblast lineage (eg, rhabdomyosarcoma, leiomyoma/leiomyosarcoma, tumors with myofibroblasts)
STAT6Solitary fibrous tumor
SynaptophysinNeuroendocrine neoplasms (desmoplastic small round cell tumors, glomus tumors)
TFE3Alveolar soft part sarcoma
VimentinNonspecific marker of “stainability” used to identify tumors of mesenchymal lineage

aSome of these stains are positive in benign cells, including fibroblasts and endothelial cells, and should be interpreted in the appropriate context.

bExpressed in the cytoplasm of many cells, but abnormally localized to the nucleus in a subset of tumors.

cDoes not stain normal adult muscle.

dStaining decreases or is lost in malignant peripheral nerve sheath tumors.

ALK-1, anaplastic lymphoma kinase 1; DOG1, discovered on GIST-1; EMA, epithelial membrane antigen; GIST, gastrointestinal stromal tumor; HHV8, human herpesvirus type 8; INI-1, integrase interactor 1; MSA, muscle-specific actin; MUC-4, mucin 4; NSE, neuron-specific enolase; STAT6, signal transducer and activator of transcription 6; TFE3, transcription factor E3

Tumor Genetic Testing

Genetic tests on tumor samples may be useful in addition to histology and immunohistochemistry in diagnosis and classification   and may be particularly beneficial in unusual cases or when the diagnosis is not definitive.  Genetic testing may also be useful in prognosis/risk stratification and treatment decision-making.  

FISH Testing

Fluorescence in situ hybridization (FISH) testing is used to identify common translocations that can aid in the diagnosis of soft tissue sarcomas. Determination of the specific fusion partner can predict prognosis in certain sarcoma subtypes, but often FISH testing does not identify the translocation partner. 

ProbeaSarcoma Subtype
CIC (19q13.2)CIC-rearranged undifferentiated small round cell sarcomas
DDIT3 (CHOP) (12q13)Round cell/myxoid liposarcoma
EWSR1 (22q12)Ewing sarcoma and other tumors in the Ewing translocation family
FOXO1 (FKHR) (13q14)Alveolar rhabdomyosarcoma
FUS (16p11)Low-grade fibromyxoid sarcoma or myxoid liposarcoma/round cell liposarcoma
MDM2Well-differentiated liposarcoma/atypical lipomatous tumor or dedifferentiated liposarcoma
SS18 (SYT) (18q11)Synovial sarcoma
TFE3Alveolar soft part sarcoma; also subsets of renal cell carcinoma, PEComa, and others

aThese probes do not identify translocation partners.

PEComa, perivascular epithelioid cell tumor

Germline Molecular Genetic Testing

A number of inherited pathogenic variants have been associated with a risk of developing soft tissue sarcomas.  Testing for these genes may take the form of a specific single gene test, focused gene panels, or large multicancer panels.

Certain genetic syndromes are associated with a predisposition for soft tissue sarcomas, including SDHB-, SDHC-, and SDHD-associated hereditary paraganglioma-pheochromocytoma syndromes, familial adenomatous polyposis, hereditary retinoblastoma, Li-Fraumeni syndrome, and neurofibromatosis type 1 and type 2.  Germline genetic testing may be recommended when patients have a personal or family history of suggestive findings, including soft tissue sarcomas, or if the histologic, immunohistochemical, or molecular features of the sarcoma suggest a possible genetic syndrome.  For example, TP53 testing is recommended in individuals who have a family history of TP53-related tumors and develop a soft tissue sarcoma before 46 years of age.  In addition, referral to genetic counseling is recommended when an individual with a personal history of sarcoma has either a diagnosis before 18 years of age, or has a family history of sarcoma plus at least one other Li-Fraumeni syndrome-associated tumor in the same relative or two close relatives (one of whom received a diagnosis when younger than 46 years).  For more information about laboratory testing in hereditary cancers, see the Hereditary Cancer Genetic Testing - Germline Testing for Inherited Cancer Syndromes ARUP Consult topic.

ARUP Laboratory Tests


Immunohistochemistry testing aids in the diagnosis and classification of soft tissue sarcomas. See the ARUP Immunohistochemistry Stain Offerings brochure for a complete list of stains.

Molecular Markers

FISH Tests
NGS Tests
Germline Genetic Tests