Sarcoma

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

Key Points

Sarcoma Genetic Testing

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

Well-Differentiated/Dedifferentiated Liposarcoma Versus Benign Lipomatous Tumor

  • Well-differentiated/dedifferentiated 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
    • Dedifferentiated form (DDLPS) – significant malignant potential
Diagnosis
  • 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
Testing
Murine Double Minute 2 Homolog (MDM2)Biology
  • Located in the nucleus
  • Inhibits p53 gene activity
  • Inhibition alters cell growth and death
Use
  • 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
Limitations
  • 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

Diagnosis

  • 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

Testing

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
Use
  • Ideal molecular marker to differentiate between lipoblastoma and myxoid liposarcoma
  • Negative in lipoblastoma
Limitations
  • Cannot be used to assess dedifferentiation of liposarcomas

Diagnosis

Indications for Testing

  • Biopsy of tumor at risk of being sarcoma

Histology

  • 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
  • Molecular and cytogenetic profiles for sarcomas

    Molecular and Cytogenetic Profiles for Sarcomas

    Sarcoma Type

    Cytogenetics

    Molecular

    Alveolar soft part sarcoma

    t(X;17)(p11;q25)

    ASPSCR1-TFE3

    Angiosarcoma (radiation-induced)

    8q24

     MYC amplification

    Benign tumors

    • Aneurysmal bone cyst

    t(16;17)(q22;p13)

    CDH11-USP6

    t(1;17)(p34.3;p13)

    THRAP3-USP6

    t(3;17)(q21;p13)

    CNBP-USP6

    t(9;17)(q22;p13)

    OMD-USP6

    t(17;17)(q21;p13)

    COL1A1-USP6

    • Bizarre parosteal osteochondromatous proliferation

    t(1;17)(q32;q21)

    Unknown

    • Chondroid lipoma

    t(11;16)(q13;p13)

    C11orf95-MKL2

    • Fibroma of tendon sheath

    t(2;11)(q31~32;q12)

    Unknown

    • Nodular fasciitis

    t(17;22)(p13;q13)

    MYH9-USP6

    • Subungual exostosis

    t(X;6)(q24~26;q15~21)

    COL12A1-COL4A5

    Chondrosarcoma

    • Extraskeletal myxoid

    Rearrangements of 9q22

    NR4A3

    t(9;22)(q22;q12)

    EWSR1-NR4A3

    t(9;17)(q22;q11) 

    TAF2N-NR4A3

    t(9;15)(q22;q21)

    TCF12-NR4A3 

    t(3;9)(q11;q22)

    TFG-NR4A3

    • Mesenchymal

    t(8;8)(q13;q21)

    HEY1-NCOA2

    • Skeletal

    Complex

     

    Clear cell sarcoma

    t(12;22)(q13;q12) 

    EWSR1-ATF1 

    t(2;22)(q33;q12)

    EWSR1-CREB1

    Desmoid-type fibromatosis

    Activating point mutation

    CTNNB1

    Deletion/inactivating mutation

    APC

    Desmoplastic small round cell tumor

    t(11;22)(p13;q12)

    EWSR1-WT1

    Dermatofibrosarcoma protuberans

    t(17;22)(q21;13)

    COL1A1-PDGFB

    Endometrial stromal sarcoma

    t(7;17)(p15;q11) 

    JAZF1-JJAZ1 (SUZ12) 

    t(6;7)(p21;p15) 

    JAZF1-PHF1 

    t(6;10)(p21;p11)

    EPC1-PHF1

    t(10;17)(q23;p13)

    YWHAE-FAM22

    Epithelioid hemangioendothelioma

    t(1;3)(p36;q25)

     WWTR1-CAMTA1

    Ewing sarcoma family of tumors (ESFT)

    • Askin tumor
      Primitive neuroectodermal
      Ethesioneuroblastoma

    t(11;22)(q24;q12)

    EWSR1-FLI1

    t(21;22)(q22;q12)

    EWSR1-ERG  

    t(7;22)(p22;q12) 

    EWSR1-ETV1 

    t(2;22)(q33;q12)

    EWSR1-FEV

    t(17;22)(q12;q12)

    EWSR1-E1AF

    inv(22)(q21;12)

    EWSR1-ZSG

    t(16;21)(p11;q22)

    FUS-ERG

    t(2;16)(q35;p11)

    FUS-FEV

    Fibrosarcoma

    • Congenital/infantile

    t(12;15)(p13;q25)

    ETV6-NTRK3

    • Sclerosing epithelioid

    t(7;16)(p22;q24)

    FUS-CREB3L2

    Low-grade fibromyxoid sarcoma

    t(7;16)(q33;p11) 

    FUS-CREB3L2 

    t(11;16)(q11;p11)

    FUS-CREB3L1

    Fibromatosis (desmoid)

    Trisomies 8 and 20 

     

    Deletion 5q

     
    Beta-catenin-1 

    GIST

    Monosomies 14 and 22

     

    Deletion 1p

     
    Chromosome 4q12PDGFRA
    Chromosome 4q12

    KIT

    Histiocytoma

    • Angiomatoid-fibrous

    t(12;22)(q13;q12)

    EWSR1-ATF1

    t(2;22)(q33;q12)

    EWSR1-CREB1

    t(12;16)(q13;p11)

    FUS-ATF1

    Inflammatory myofibroblastic tumor

    t(1;2)(q22;p23) 

    TPM3-ALK 

    t(2;19)(p23;p13)

    TPM4-ALK 

    t(2;17)(p23;q23) 

    CLTC-ALK 

    t(2;2)(p23;q13)

    RANBP2-ALK

    t(2;11)(p23;p15)

    CARS-ALK

    inv(2)(P23;q35)

    ATIC-ALK

    Lipoblastoma

    del 8q12

    PLAG1

    Lipoma (typical)

    12q15 rearrangement

    HMGA2

    6p21

    HMGA1

    Liposarcoma  

    • Dedifferentiated

    12q14-15 (ring chromosomes, giant marker chromosomes)

    Amplification of MDM2, CDK4, HMGA2, GLI, SAS

    • Myxoid/round cell

    t(12;16)(q13;p11)

    FUS-DD1T3 (TLS-CHOP)

    t(12;22)(q13;q12)

    EWSR1-DD1T3 (EWSR1-CHOP)

    Locally aggressive tumors

    • Giant-cell fibroblastoma

    t(17;22)(q21;q13)

    COLIA1-PDGFB

    • Well-differentiated liposarcoma/atypical lipomatous tumor

    12q14-15 (ring chromosomes, giant marker chromosomes)

    Amplification of MDM2, CDK4, HMGA2, GL1, SAS

    • Tenosynovial giant cell tumor/pigmented villonodular synovitis

    t(1;2)(p13;q35-37)

    COL6A3-CSF1

    Malignant rhabdoid tumor (extrarenal)Bi-allelic inactivation of 22q11.2INI11

    Myoepithelial tumor of soft tissue and bone

    t(6;22)(p21;q12)

    EWSR1-POU5F1

    t(19;22)(q13;q12)

    EWSR1-ZNF444

    t(1;22)(q23;q12)

    EWSR1-PBX1

    Myxoinflammatory fibroblastic sarcoma hemosiderotic fibrolipomatous tumor

    t(1;10)(p22;q24)

    TGFBR3~MGEA5

    3p11-12 (ring chromosome)

    Amplification of VGLL3, CHMP2B

    Myxofibrosarcoma (MFH-myxoid)

    Ring form of chromosome 12

     

    Osteosarcoma

    • Low grade (parosteal and intramedullary)

    12q14-15 (ring chromosomes, giant marker chromosomes)

    Amplification of CDK4, MDM2, HMGA2, GL1, SAS

    Pericytoma (hemangioma)

    t(7;12)

    ACTB-GLI1

    Peripheral nerve sheath tumors

    • Schwannoma (benign)

    Chromosome 22 deletion

     
    • Malignant peripheral nerve sheath tumor

    del17q11

    NF1

    Pleomorphic undifferentiated sarcoma (PUS)

    Complex

     

    Pulmonary myxoid sarcoma

    t(2;22)(q34;q12)

    EWSR1-CREB1

    Rhabdomyosarcoma

    • Alveolar

    t(2;13)(q35;q14)

    PAX3-FKHR

    t(1;13)(p36;q14)

    PAX7-FKHR

    t(2;2)(q35;p23)

    PAX3-AFX

    Solitary fibrous tumor

    12q13 (intrachromosomal inversion)

    NAB2-STAT6

    Synovial sarcoma

    t(X;18)(p11.2;q11)

    SS18-SSX1, SSX2, SSX4

    Undifferentiated small round blue cell tumor

    t(10;19)(q26;q13)

     

    Xp11 (intrachromosomal inversion)

    BCOR-CCNB3

    Demicco, 2013

  • Immunohistochemistry may identify lineage-specific protein products
    • ALK – inflammatory myofibroblastic tumor
    • CD21 (dendritic cell) – aid in identifying follicular dendritic sarcoma
    • CD34 (QBEnd/10) – solitary fibrous tumor
    • CD39 – dermatofibrosarcoma
    • CD56 (NCAM) – rhabdomyosarcomas, neuroblastoma (positive)
    • CD99 – Ewing synovial sarcoma, desmoplastic round-cell tumor, neuroblastoma (negative)
    • CD117 (c-Kit) – GIST, blasts
    • CD147 – alveolar soft-part tumor
    • CDK4 – over expressed in dedifferentiated liposarcoma; more specific but less sensitive than MDM2
    • Desmin – leiomyosarcomas, myogenic sarcomas, rhabdomyosarcoma, neuroblastomas, and intra-abdominal desmoplastic small round cell tumors
    • DOG1 – GIST
    • EMA – synovial sarcoma
    • FLI1 – Ewing, synovial sarcoma
    • INI1 – loss found in rhabdomyosarcoma
    • MDM2 – dedifferentiated liposarcoma
    • Muscle-specific actin (MSA) – soft tissue tumors with muscle differentiation (leiomyoma, leiomyosarcoma and rhabdomyosarcomas), some pleomorphic liposarcoma, glomus tumor, desmoid tumor
    • Myogenin (Myf4) – alveolar rhabdomyosarcoma
    • Myoglobin – rhabdomyosarcoma
    • Myosin – smooth muscle differentiation
    • P-glycoprotein – prognostic for osteosarcoma
    • Smooth muscle actin (SMA) – differentiate leiomyosarcoma from rhabdomyosarcoma
    • TFE3 – alveolar soft-part tumor
    • TLE1 – synovial sarcoma
    • Ulex Europaeus Agglutinin 1 (UEA-1) – angiosarcoma
    • Vimentin – schwannoma, infantile fibrosarcoma, desmoplastic round-cell tumor, dermatofibrosarcoma
    • WT-1 – desmoplastic round-cell tumor
  • 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

Prognosis

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

Clinical Background

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

Epidemiology

  • Incidence
    • 2-4/100,000
    • <1% of all 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

Classification

  • Most common types (>50 types)
    • Pleomorphic sarcoma (malignant fibrous histiocytoma)
    • Leiomyosarcoma
    • Liposarcoma
    • Synovial sarcoma
    • Neurofibrosarcoma (malignant peripheral nerve sheath tumor)
    • Osteosarcoma
    • Chondrosarcoma
    • Rhabdomyosarcoma
    • Gastrointestinal stromal tumor (GIST)
    • Ewing sarcoma
    • Epithelioid sarcoma
    • Fibrosarcoma
    • Angiosarcoma

Risk Factors

  • Genetic
    • p53 – Li Fraumeni
    • NFI – neurofibromatosis type 1
    • RB1 – inherited retinoblastomas
    • KIT – familial gastrointestinal stromal tumor (GIST)
    • Beckwith-Wiedemann syndrome
  • Previous scar tissue
  • Previous radiation treatment – increases risk 8- to 50-fold
  • Viruses
    • HHV8 (Kaposi sarcoma) and HIV
    • EBV (leiomyosarcomas in immunocompromised patients)
  • Paget disease of the bone (osteosarcoma)
  • Chronic lymphedema (Stewart-Treves syndrome) – lymphangiosarcoma

Pathophysiology

  • 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

Indications for Laboratory Testing

  • 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
Test Name and Number Recommended Use Limitations Follow Up
MDM2 Gene Amplification by FISH 2003016
Method: Fluorescence in situ Hybridization

Aid in the differential diagnosis between well-differentiated liposarcoma and benign lipoma (individuals diagnosed with or suspected of having well-differentiated liposarcoma based on tissue morphology)

Probes include MDM2 (12q15) and CEP12 (control probe)

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

Use in conjunction with histologic and clinical information for the diagnosis of round cell/myxoid liposarcoma

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

Use in conjunction with histologic and clinical information for the diagnosis of alveolar rhabdomyosarcoma

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

Diagnose members of the Ewing sarcoma family of tumors (ESFT)

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

Does not identify specific translocation partner

 
EWSR1-FLI1 and EWSR1-ERG Translocations by RT-PCR 0051220
Method: Reverse Transcription Polymerase Chain Reaction
Confirm histological diagnosis of Ewing sarcoma by detection of EWSR1-FLI1 and EWSR1-ERG fusions

Limited to detecting the 2 most common translocation partners observed in the Ewing family of tumors

 
SS18-SSX t(X;18) Translocations by RT-PCR 0040114
Method: Reverse Transcription Polymerase Chain Reaction

Diagnose synovial sarcoma

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

Diagnose synovial sarcoma

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

Aid in histologic diagnosis of inflammatory myofibroblastic tumors

Stained and returned to client pathologist; consultation available if needed

   
CD21 (Dendritic Cell) by Immunohistochemistry 2003535
Method: Immunohistochemistry

Aid in histologic diagnosis of follicular dendritic sarcoma

Stained and returned to client pathologist; consultation available if needed

   
CD34, QBEnd/10 by Immunohistochemistry 2003556
Method: Immunohistochemistry

Aid in histologic diagnosis of solitary fibrous tumor

Stained and returned to client pathologist; consultation available if needed

   
CD56 (NCAM) by Immunohistochemistry 2003589
Method: Immunohistochemistry

Aid in histologic diagnosis of rhabdomyosarcoma, neuroblastoma

Stained and returned to client pathologist; consultation available if needed

   
Ewing Sarcoma (O13) by Immunohistochemistry 2004055
Method: Immunohistochemistry

Aid in histologic diagnosis of Ewing sarcoma

Stained and returned to client pathologist; consultation available if needed

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

Aid in histologic diagnosis of GIST, blasts

Stained and returned to client pathologist; consultation available if needed

   
CDK4 by Immunohistochemistry 2005534
Method: Immunohistochemistry

Distinguish well-differentiated liposarcoma (+) from benign adipose tumors (-), and distinguish dedifferentiated liposarcoma (+) from poorly differentiated sarcomas (-)

Stained and returned to client pathologist; consultation available if needed

   
Desmin by Immunohistochemistry 2003863
Method: Immunohistochemistry

Aid in histologic diagnosis of leiomyosarcomas, myogenic sarcomas, rhabdomyosarcoma, neuroblastomas, and intra-abdominal desmoplastic small round cell tumors

Stained and returned to client pathologist; consultation available if needed

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

Aid in histologic diagnosis of synovial sarcoma

Stained and returned to client pathologist; consultation available if needed

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

Aid in histologic diagnosis of Ewing and synovial sarcomas

Stained and returned to client pathologist; consultation available if needed

   
INI1 (BAF47) by Immunohistochemistry 2003448
Method: Immunohistochemistry

Aid in histologic diagnosis of rhabdomyosarcomas

Stained and returned to client pathologist; consultation available if needed

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

Aid in histologic diagnosis of soft tissue tumors with muscle differentiation (leiomyomas, leiomyosarcomas, and rhabdomyosarcomas), some pleomorphic liposarcomas, glomus tumors, and desmoid tumors

Stained and returned to client pathologist; consultation available if needed

   
Myogenin (Myf4) by Immunohistochemistry 2004017
Method: Immunohistochemistry

Aid in histologic diagnosis of alveolar rhabdomyosarcomas

Stained and returned to client pathologist; consultation available if needed

   
Myoglobin by Immunohistochemistry 2004031
Method: Immunohistochemistry

Aid in histologic diagnosis of rhabdomyosarcoma

Stained and returned to client pathologist; consultation available if needed

   
Myosin by Immunohistochemistry 2004034
Method: Immunohistochemistry

Aid in smooth muscle differentiation

Stained and returned to client pathologist; consultation available if needed

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

Aid in differentiating leiomyosarcoma from rhabdomyosarcoma

Stained and returned to client pathologist; consultation available if needed

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

Aid in histologic diagnosis of angiosarcomas

Stained and returned to client pathologist

   
Vimentin by Immunohistochemistry 2004181
Method: Immunohistochemistry

Aid in histologic diagnosis of schwannomas

Stained and returned to client pathologist; consultation available if needed

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

Aid in histologic diagnosis of desmoplastic round-cell tumors

Stained and returned to client pathologist; consultation available if needed

   
MDM2 by Immunohistochemistry 2005848
Method: Immunohistochemistry

Aid in histologic diagnosis of desmoplastic round-cell tumors

Stained and returned to client pathologist; consultation available if needed

   
Chromosome FISH, Interphase 2002298
Method: Fluorescence in situ Hybridization

Differential diagnosis of small-cell neoplasms in fluid-based samples

  • Specific probe for 22q12.2 or 18q11.2 must be specified
  • Fresh tissue or touch-prep

ARUP Oncology FISH Probes menu

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)

 
Chromosome Analysis, Solid Tumor 2002296
Method: Giemsa Band

Detect recurrent chromosome abnormalities in tumor biopsy consistent with the diagnosis of a sarcoma

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