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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
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).
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).
| 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 |
|---|---|
| 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 |
| 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 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
Fluorescence in situ Hybridization (FISH)
Fluorescence in situ Hybridization (FISH)
Fluorescence in situ Hybridization (FISH)
Fluorescence in situ Hybridization (FISH)
Fluorescence in situ Hybridization (FISH)
Fluorescence in situ Hybridization (FISH)
Fluorescence in situ Hybridization (FISH)
Fluorescence in situ Hybridization (FISH)
Massively Parallel Sequencing
Massively Parallel Sequencing/Sequencing/Multiplex Ligation-Dependent Probe Amplification (MLPA)
Massively Parallel Sequencing/Multiplex Ligation-Dependent Probe Amplification (MLPA)
References
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NCCN - soft tissue sarcomas V2.2021
National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: soft tissue sarcomas. Version 2.2021. Updated Apr 2021; accessed Jun 2021.
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Gronchi A, Miah AB, Dei Tos AP, et al. Soft tissue and visceral sarcomas: ESMO-EURACAN-GENTURIS clinical practice guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2021;32(11):1348-1365.
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WHO classification of tumours, soft tissue, 5th ed
Fletcher CD, Bridge JA, Hoegendoorn P, eds. World Health Organization Classification of Tumours of Soft Tissue and Bone Tumours. 5th ed. International Agency for Research on Cancer; 2020.
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25394175
Hampel H, Bennett RL, Buchanan A, et al. A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. Genet Med. 2015;17(1):70-87. Reaffirmed with Addendum: Genet Med. 2019;21(12):2844.
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.