Soft Tissue Sarcomas

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.

Immunohistochemistry

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
Markera Tumor/Cell Lineage

ALK-1

Inflammatory myofibroblastic tumor

Beta cateninb

Tumors of fibroblast (nuclear) or epithelial cell (nuclear or cytoplasmic) lineage (eg, desmoid fibromatosis, tumors related to APC gene mutations)

Caldesmon

Tumors of smooth muscle lineage (eg, angiolipoma, GIST, glomus tumor, inflammatory myofibroblastic tumor, leiomyoma, leiomyosarcoma)

CD31

More specific marker for tumors of vascular lineage

CD34

More sensitive marker for tumors of vascular lineage (eg, vascular tumors, dermatofibrosarcoma protuberans, epithelioid sarcoma, solitary fibrous tumor, GIST, Kaposi sarcoma)

CD117/c-kit

GIST, Ewing sarcoma, mast cells

Desmin

Tumors of smooth and skeletal muscle lineage (eg, rhabdomyosarcoma, leiomyomas/leiomyosarcoma)

DOG1

GIST

EMA

Tumors of perineural cell lineage, carcinomas, and some sarcomas (eg, epithelioid sarcoma, synovial sarcoma, neurofibroma, perineurioma, sarcomatoid carcinoma); also positive in most carcinomas

ERG

Tumors of vascular lineage, some Ewing sarcomas

Ewing sarcoma 013 (CD99)

Ewing family tumors

HHV8

Kaposi sarcoma

INI-1

Lost in epithelioid sarcoma, epithelioid malignant peripheral nerve sheath tumor, malignant rhabdoid tumor

MSA

Tumors of smooth and skeletal muscle lineage (eg, rhabdomyosarcoma, leiomyomas/leiomyosarcoma)

MUC-4

Low-grade fibromyxoid sarcoma

Myoogenin (Myf4)c

Tumors of primitive muscle lineage (eg, rhabdomyosarcoma)

NSE

Tumors of neuroectodermal cell lineage (neuroendocrine neoplasms)

S100d

Tumors of Schwann cells and melanocyte lineage (eg, schwannoma, neurofibroma, granular cell tumor, melanoma)

SMA

Tumors of smooth muscle or myofibroblast lineage (eg, rhabdomyosarcoma, leiomyoma/leiomyosarcoma, tumors with myofibroblasts)

STAT6

Solitary fibrous tumor

Synaptophysin

Neuroendocrine neoplasms (desmoplastic small round cell tumors, glomus tumors)

TFE3

Alveolar soft part sarcoma

Vimentin

Nonspecific 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. 

Probea Sarcoma Subtype

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

MDM2

Well-differentiated liposarcoma/atypical lipomatous tumor or dedifferentiated liposarcoma

SS18 (SYT) (18q11)

Synovial sarcoma

TFE3

Alveolar 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 types 1 and 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

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

Aids in diagnosis of myxoid liposarcoma/round cell liposarcoma

Aids in diagnosis of Ewing sarcoma, clear cell sarcoma, desmoplastic small round cell tumor, extraskeletal myxoid chondrosarcoma, myxoid liposarcoma, a small subset of rhabdomyosarcomas (FET(EWSR1)-TFCP2 rhabdomyosarcoma), angiomatoid fibrous histiocytoma

Aids in diagnosis of alveolar rhabdomyosarcoma

Aids in diagnosis of low-grade fibromyxoid sarcoma and myxoid liposarcoma/round cell liposarcoma

Aids in diagnosis of well-differentiated liposarcoma/atypical lipomatous tumor, dedifferentiated liposarcoma

Aids in diagnosis of synovial sarcoma

Aids in diagnosis of alveolar soft part sarcoma

NGS Tests

May be useful in diagnosis and treatment decision-making in soft tissue sarcomas

For additional test information, including genes tested, refer to the Solid Tumor Mutation Panel by Next Generation Sequencing Test Fact Sheet

Germline Genetic Tests

Medical Experts

Author

Leonard

Picture of Nicole Leonard, MD

 

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

Rets

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

Ward

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

References