Primary Authors: Grossman, Allie, MD, PhD. Wallander, Michelle L., PhD.

  • Key Points
  • Diagnosis
  • Background
  • Lab Tests
  • References
  • Related Topics
  • Videos

Sarcoma Genetic Testing

Liposarcomas are one of the most common sarcomas in adult patients. There are three groups of liposarcomas: well-differentiated/de-differentiated, myxoid/round cell, and pleomorphic subtypes. Genetic testing is helpful in ruling out similar histologic variants in two of these subtypes.

Well-Differentiated/De-differentiated Liposarcoma Versus Benign Lipomatous Tumor
  • Well-differentiated/de-differentiated liposarcomas are continuums of tumor type
    • Well-differentiated form – little malignant potential
      • Well-differentiated liposarcomas are further named based on where the tumor is located
        • Atypical lipomatous tumors (ALT) – usually located in extremities or body wall areas
        • Well-differentiated liposarcomas (WDLPS) – usually located in the retroperitoneum
        • Spectrum of well-differentiated liposarcomas is referred to as ALT/WDLPS
    • De-differentiated form (DDLPS) – significant malignant potential


  • Most challenging differential diagnosis for these tumors – differentiating between benign lipomatous tumor and ALT/WDLPS/DDLPS tumors
    • Rarely, an inflammatory ALT/WDLPS/DDLPS may also need to be differentiated from retroperitoneal fibrosis or sclerosing mesenteritis
    • Differentiations are important because there is little to no malignant potential in lipomatous tumors, retroperitoneal fibrosis, or sclerosing mesenteritis


Murine Double Minute 2 Homolog (MDM2) Biology
  • Located in the nucleus
  • Inhibits p53 gene activity
  • Inhibition alters cell growth and death
  • Amplification of MDM2 to differentiate between ALT/WDLPS/DDLPS and benign lipomatous tumor
  • Negative in benign lipomatous tumor; also negative in retroperitoneal fibrosis or sclerosing mesenteritis
  • Methodology by FISH is sensitive for this marker
  • Does not distinguish WDLPS from DDLPS
    • Marker is positive in both well-differentiated and dedifferentiated tumors
  • Does not distinguish WDLPS/DDLPS from other sarcomas


Myxoid/Round Cell Liposarcoma Versus Lipoblastoma or Myxofibrosarcoma
  • Myxoid/round cell liposarcomas – common sarcomas in adults, usually  >20 years, but rare in younger children
  • Lipoblastoma – benign tumor usually found in infants but rare in other children
  • Myxofibrosarcoma – spectrum of low- to high-grade sarcomas of adults


  • Distinguish between lipoblastoma and myxoid liposarcoma – imperative because there is little to no malignant potential in a lipoblastoma
    • Differentiation in an adolescent is very difficult
  • Distinguish myxoid liposarcoma from myxofibrosarcoma – these two entities are treated differently
    • Myxoid liposarcoma – often treated with preoperative radiation
    • Myxofibrosarcoma – may or may not require postoperative radiation, depending on the grade and surgical margin status


DDIT3 fusion (formerly CHOP) Biology
  • DDIT3 can fuse with FUS (16p11) or EWS (22q12) to form a complex translocation
  • Fusion is typically found in myxoid/round cell tumors
  • Ideal molecular marker to differentiate between lipoblastoma and myxoid liposarcoma
  • Negative in lipoblastoma
  • Cannot be used to assess dedifferentiation of liposarcomas

Indications for Testing

  • Biopsy of tumor at risk of being sarcoma


  • Histology of some sarcomas may be similar to that of benign neoplasms, making diagnostic distinction difficult
  • Molecular markers
    • Histologic diagnosis may be aided by identification of mutations, amplifications and translocations
    • Refer to Key Points
  • FISH, MDM2 – amplification is useful to distinguish well-differentiated liposarcoma from lipomas
    • Important due to difference in risk of recurrence and progression of a well-differentiated liposarcoma from a benign lipoma

Imaging Studies

  • Plain film x-ray, CT and MRI to assess tumor location and extent


  • Histologic grade and size – most important prognostic factors in adult tumors

Sarcomas are a group of uncommon malignant neoplasms occurring in both bone and soft tissue with a wide range of histologic types and prognoses.


  • Incidence
    • ~1% of adult malignancies
    • ~15% of pediatric malignancies
  • Age – mean is 50s; varies with type of sarcoma
    • 15% in children <15 years
    • 40% in adults >55 years
  • Sex –  M>F, 1.5:1, in Ewing and osteosarcoma


  • Most common types (>50 types) – see Diagnosis tab for listing

Risk Factors


  • Mesodermal derivation from musculoskeletal tissues such as connective tissue, lymphatic vessels, smooth and skeletal muscle, fat, and synovial structures

Clinical Presentation

  • 60% arise in the extremities
    • 3:1 ratio legs to arms
  • Soft tissue tumors
    • Asymptomatic mass is most common presentation
    • May have pain, tenderness, or mechanical symptoms due to entrapment, pressure, or traction
  • Bony tumors
    • Pain and swelling of the affected area
Tests generally appear in the order most useful for common clinical situations. Click on number for test-specific information in the ARUP Laboratory Test Directory.

MDM2 Gene Amplification by FISH 2003016
Method: Fluorescence in situ Hybridization


Results may be compromised if the recommended fixation procedures have not been followed

Test cannot be used to assess dedifferentiation of liposarcomas

DDIT3 (CHOP) (12q13) Gene Rearrangement by FISH 2007223
Method: Fluorescence in situ Hybridization


Results may be compromised if the recommended fixation procedures have not been followed

Cannot be used to assess dedifferentiation of liposarcomas

FOXO1 (FKHR) (13q14) Gene Rearrangement by FISH 2001497
Method: Fluorescence in situ Hybridization


Results may be compromised if the recommended fixation procedures have not been followed

This test will not identify the specific translocation partner

EWSR1 (22q12) Gene Rearrangement by FISH 2007225
Method: Fluorescence in situ Hybridization


Results may be compromised if the recommended fixation procedures have not been followed

EWSR1 FISH does not identify the 22q12 translocation partner; therefore, this test by itself cannot distinguish between sarcomas involving EWSR1 (eg, ESFT, desmoplastic small round-cell tumor, clear cell sarcoma, and myxoid chondrosarcoma)

SS18 (SYT) (18q11) Gene Rearrangement by FISH 2007222
Method: Fluorescence in situ Hybridization


Testing using tissue fixed in alcohol-based or non-formalin fixatives has not been validated using this method

SS18 fusion partners other than SSX1 and SSX2 are not detected

Chromosome FISH, Interphase 2002298
Method: Fluorescence in situ Hybridization

Chromosome Analysis, Solid Tumor 2002296
Method: Giemsa Band


Tumor cells may not grow well in culture and may not be present in the cells analyzed; test should be performed in conjunction with interphase FISH when either a EWSR1 or SYT translocation is in the differential

Anaplastic Lymphoma Kinase 1 (ALK-1) by Immunohistochemistry 2003439
Method: Immunohistochemistry

CD21 (Dendritic Cell) by Immunohistochemistry 2003535
Method: Immunohistochemistry

CD34, QBEnd/10 by Immunohistochemistry 2003556
Method: Immunohistochemistry

CD56 (NCAM) by Immunohistochemistry 2003589
Method: Immunohistochemistry

Ewing Sarcoma (O13) by Immunohistochemistry 2004055
Method: Immunohistochemistry

CD117 (c-Kit) by Immunohistochemistry 2003806
Method: Immunohistochemistry

CDK4 by Immunohistochemistry 2005534
Method: Immunohistochemistry

Desmin by Immunohistochemistry 2003863
Method: Immunohistochemistry

DOG1 by Immunohistochemistry 2010168
Method: Immunohistochemistry

Epithelial Membrane Antigen (EMA) by Immunohistochemistry 2003872
Method: Immunohistochemistry

Friend Leukemia Integration-1 (Fli-1) by Immunohistochemistry 2003887
Method: Immunohistochemistry

INI1 (BAF47) by Immunohistochemistry 2003448
Method: Immunohistochemistry

MDM2 by Immunohistochemistry 2005848
Method: Immunohistochemistry

Muscle-Specific Actin (MSA) by Immunohistochemistry 2004011
Method: Immunohistochemistry

Myogenin (Myf4) by Immunohistochemistry 2004017
Method: Immunohistochemistry

Myoglobin by Immunohistochemistry 2004031
Method: Immunohistochemistry

Myosin by Immunohistochemistry 2004034
Method: Immunohistochemistry

Smooth Muscle Actin (SMA) by Immunohistochemistry 2004130
Method: Immunohistochemistry

STAT6 by Immunohistochemistry 2013251
Method: Immunohistochemistry

TFE3 by Immunohistochemistry 2010688
Method: Immunohistochemistry

Ulex Europaeus Agglutinin 1 (UEA-1) by Immunohistochemistry 2004172
Method: Immunohistochemistry

Vimentin by Immunohistochemistry 2004181
Method: Immunohistochemistry

Wilms Tumor (WT-1), N-terminus by Immunohistochemistry 2004184
Method: Immunohistochemistry


ESMO/European Sarcoma Network Working Group. Bone sarcomas: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2014; 25 Suppl 3: iii113-23. PubMed

NCCN Clinical Practice Guidelines in Oncology, Bone Cancer. National Comprehensive Cancer Network. Fort Washington, PA [Accessed: Nov 2015]

NCCN Clinical Practice Guidelines in Oncology, Soft Tissue Sarcomas. National Comprehensive Cancer Network. Fort Washington, PA [Accessed: Jun 2015]

Protocol for the Examination of Specimens from Patients with Tumors of Soft Tissue. Based on AJCC/UICC TNM, 7th ed. Protocol web posting date: Oct 2013. College of American Pathologists (CAP). Northfield, IL [Revised Oct 2013; Accessed: Dec 2016]

General References

Bovée JV, Hogendoorn PC. Molecular pathology of sarcomas: concepts and clinical implications. Virchows Arch. 2010; 456(2): 193-9. PubMed

Ceyssens S, Stroobants S. Sarcoma. Methods Mol Biol. 2011; 727: 191-203. PubMed

Cheah AL, Billings SD. The role of molecular testing in the diagnosis of cutaneous soft tissue tumors. Semin Cutan Med Surg. 2012; 31(4): 221-33. PubMed

Demicco EG. Sarcoma diagnosis in the age of molecular pathology. Adv Anat Pathol. 2013; 20(4): 264-74. PubMed

Folpe A, Gown A. Immunohistochemistry for Analysis of Soft Tissue Tumors, Ch 7. In Goldblum JR, Folpe AL, Weiss SW, eds. Enzinger and Weiss's Soft Tissue Tumors, 6th ed. Philadelphia, PA: Elsevier, 2014.

Fritchie KJ, Goldblum JR, Tubbs RR, Sun Y, Carver P, Billings SD, Rubin BP. The expanded histologic spectrum of myxoid liposarcoma with an emphasis on newly described patterns: implications for diagnosis on small biopsy specimens. Am J Clin Pathol. 2012; 137(2): 229-39. PubMed

Goldblum J, Folpe A, Weiss S. Approach to the Diagnosis of Soft Tissue Tumors, Ch 6. In Goldblum JR, Folpe AL, Weiss SW, eds. Enzinger and Weiss's Soft Tissue Tumors, 6th ed. Philadelphia, PA: Elsevier, 2014.

Guillou L, Aurias A. Soft tissue sarcomas with complex genomic profiles. Virchows Arch. 2010; 456(2): 201-17. PubMed

Jain S, Xu R, Prieto VG, Lee P. Molecular classification of soft tissue sarcomas and its clinical applications. Int J Clin Exp Pathol. 2010; 3(4): 416-28. PubMed

Ladanyi M, Fletcher J, Cin P. Cytogenetic and Molecular Genetic Pathology of Soft Tissue Tumors, Ch 4. In Goldblum JR, Folpe AL, Weiss SW, eds. Enzinger and Weiss's Soft Tissue Tumors, 6th ed. Philadelphia, PA: Elsevier, 2014.

Loeb DM, Thornton K, Shokek O. Pediatric soft tissue sarcomas. Surg Clin North Am. 2008; 88(3): 615-27, vii. PubMed

Merchant MS, Mackall CL. Current approach to pediatric soft tissue sarcomas. Oncologist. 2009; 14(11): 1139-53. PubMed

Ordóñez JL, Osuna D, García-Domínguez DJ, Amaral AT, Otero-Motta AP, Mackintosh C, Sevillano MV, Barbado MV, Hernández T, de Alava E. The clinical relevance of molecular genetics in soft tissue sarcomas. Adv Anat Pathol. 2010; 17(3): 162-81. PubMed

Osuna D, de Alava E. Molecular pathology of sarcomas. Rev Recent Clin Trials. 2009; 4(1): 12-26. PubMed

Szuhai K, Cleton-Jansen A, Hogendoorn PC, Bovée JV. Molecular pathology and its diagnostic use in bone tumors. Cancer Genet. 2012; 205(5): 193-204. PubMed

Weaver J, Downs-Kelly E, Goldblum JR, Turner S, Kulkarni S, Tubbs RR, Rubin BP, Skacel M. Fluorescence in situ hybridization for MDM2 gene amplification as a diagnostic tool in lipomatous neoplasms. Mod Pathol. 2008; 21(8): 943-9. PubMed

References from the ARUP Institute for Clinical and Experimental Pathology®

Collins BT, Janney CG, Ong M, Cortese C. Fine needle aspiration biopsy of monophasic spindle synovial sarcoma of lung with fluorescence in situ hybridization identification of t(x;18) translocation: a case report. Acta Cytol. 2009; 53(1): 105-8. PubMed

Hall BJ, Grossmann AH, Webber NP, Ward RA, Tripp SR, Rosenthal HG, Florell SR, Randall L, Cockerell CJ, Layfield LJ, Liu T. Atypical intradermal smooth muscle neoplasms (formerly cutaneous leiomyosarcomas): case series, immunohistochemical profile and review of the literature. Appl Immunohistochem Mol Morphol. 2013; 21(2): 132-8. PubMed

Joyner DE, Wade ML, Szabo A, Bastar J, Coffin CM, Albritton KH, Bernard PS, Randall L. Discriminate gene lists derived from cDNA microarray profiles of limited samples permit distinguishing mesenchymal neoplasia ex vivo. J Cancer Res Clin Oncol. 2005; 131(3): 137-46. PubMed

Kikuchi K, Taniguchi E, Chen HH, Svalina MN, Abraham J, Huang ET, Nishijo K, Davis S, Louden C, Zarzabal LA, Recht O, Bajwa A, Berlow N, Suelves M, Perkins SL, Meltzer PS, Mansoor A, Michalek JE, Chen Y, Rubin BP, Keller C. Rb1 loss modifies but does not initiate alveolar rhabdomyosarcoma. Skelet Muscle. 2013; 3(1): 27. PubMed

Liu K, Tripp S, Layfield LJ. Heterotopic ossification: review of histologic findings and tissue distribution in a 10-year experience. Pathol Res Pract. 2007; 203(9): 633-40. PubMed

Swensen JJ, Keyser J, Coffin CM, Biegel JA, Viskochil DH, Williams MS. Familial occurrence of schwannomas and malignant rhabdoid tumour associated with a duplication in SMARCB1. J Med Genet. 2009; 46(1): 68-72. PubMed

Wallander ML, Tripp S, Layfield LJ. MDM2 amplification in malignant peripheral nerve sheath tumors correlates with p53 protein expression. Arch Pathol Lab Med. 2012; 136(1): 95-9. PubMed

Willmore-Payne C, Holden J, Turner KC, Proia A, Layfield LJ. Translocations and amplifications of chromosome 12 in liposarcoma demonstrated by the LSI CHOP breakapart rearrangement probe. Arch Pathol Lab Med. 2008; 132(6): 952-7. PubMed

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Last Update: May 2017