Sarcoma

Primary Authors Layfield, Lester, MD. Wallander, Michelle, PhD. Heichman, Karen A., 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 (see table below)

WELL-DIFFERENTATED/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
  • Cannot be used to assess dedifferentiation of liposarcomas
  • Marker is positive in both well-differentiated and dedifferentiated tumors
  • Myxoid/round cell liposarcoma versus lipoblastoma (see table below)

MYXOID/ROUND CELL LIPOSARCOMA versus LIPOBLASTOMA

  • Myxoid/round cell liposarcomas – common sarcomas in adults >20 years, but rare in younger children
  • Lipoblastoma – benign tumor usually found in infants but rare in other children
Diagnosis
  • Differentiation between lipoblastoma and myxoid liposarcoma – imperative because there is little to no malignant potential in a lipoblastoma
    • Differentiation in an adolescent is very difficult
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 tumor

    t(X;17)(p11.2;q25)

    TFE3-ASPL

    Angiosarcoma

    Complex, non-recurring

    		 

    Benign tumors

    Chondroid hamartoma of the lung
    Fibroadenoma of the breast

    12q14-15 alterations

    HMG1-C

    6p21 alterations

    		HMG1(Y)

    Leiomyoma, uterine

    		t(12;14)(q15;q24) or del 7q 

    Leiomyoma, extrauterine

    		del 1p 

    Aneurysmal bone cyst

    t(16;17)

    CDH11-USP6

    t(1;17)

    THRAP3-USP6

    t(3:17)

    CNBP-USP6

    t(9;17)

    OMD-USP6

    t(17;7)

    COL1A1-USP6

    Chondrosarcoma

    Extraskeletal myxoid

    Rearrangements of 9q22

    CHN

    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

    Skeletal

    Complex

    		 

    Clear cell sarcoma

    t(12;22)(q13;q12) 

    EWSR1-ATF1 

    t(2;22)(q33;q12)

    EWSR1-CREB1

    Desmoplastic small round cell tumor

    t(11;22)(p13;q12)

    EWSR1-WT1

    Dermatofibrosarcoma protuberans

    t(17;22)(q22;13)

    COL1A1-PDGFB

    Endometrial stromal tumor

    t(7;17)(p15;q21) 

    JAZF1-SUZ12 

    t(6;7)(p21;p15) 

    JAZF1-PHF1 

    t(6;10)(p21;p11)

    EPC1-PHF1

    Epithelioid hemangioendothelioma

    t(1;3)(p36;7p25)

    		 

    Epithelioid sarcoma (proximal type)

    Bi-allelic inactivation of 22q11.2

    INI1

    Ewing sarcoma family of tumors (ESFT)

    Askin tumor
    Primitive neuroectodermal
    Ethesioneuroblastoma

    t(2;22)(q33;12)

    EWSR1-E1AF

    t(21;22)(q22;q12)

    EWSR1-ERG  

    t(7;22)(p22;q12) 

    EWSR1-ETV1 

    t(17;22)(q21;q12)

    EWSR1-ETV4

    t(2;22)(q36;q12) 

    EWSR1-FEV 

    t(11;22)(q24;q12)

    EWSR1-FLI1 

    inv(22)(q12;q12)

    EWSR1-PATZ1

    t(6;22)(p21;q12)

    EWSR1-POU5F1

    t(2;22)(q31;q12) 

    EWSR1-SP3 

    t(16;21)(p11;q22)

    FUS-ERG

    t(20;22)(q13;12)

    EWSR1-NFATc2

    t(2;16)(q35;p11)

    FUS-FEV

    t(15;19)(Q14;p13.1)

    BRD4-NUT

    t(4;19)(q35:q13)

    CIC-DUX4

    Fibrosarcoma

    Congenital/infantile

    t(12;15)(p13;q25)

    ETV6-NTRK3

    Trisomies 8, 11, 17 and 20

    		 

    Adult

    		Complex 

    Fibromyxoid sarcoma (low grade)

    t(7;16)(q33;p11) 

    FUS-CREB3L2 

    t(11;16)(q11;p11)

    FUS-CREB3L1

    Fibromatosis (aggressive)

    Trisomies 8 and 20 

    		 

    Deletion 5q

    		 

    Giant-cell fibroblastoma

    t(17;22)(q22;q13)

    COL1A1-PDGFB

    GIST

    Monosomies 14 and 22

    KIT

    Deletion 1p

    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

    Leiomyosarcoma

    Complex (frequent deletion 1p)

    		 

    Lipoblastoma

    del 8q12

    PLAG1

    Lipoma (typical)

    12q15 rearrangement

    HMGA2

    6p21

    HMGA1

    Liposarcoma  

    Dedifferentiated

    12q14, ring or marker chromosome

    MDM2

    Pleomorphic

    Complex

    		 

    Myxoid/round cell

    t(12;16)(q13;p11)

    		FUS-CHOP
    (DD1T3)

    t(12;22)(q13;q12)

    		EWS-CHOP
    (DD1T3)

    Myxofibrosarcoma (MFH-myxoid)

    Ring form of chromosome 12

    		 

    Neurofibrosarcoma

    del17q11

    		 

    Osteosarcoma

    Low grade

    Ring chromosomes

    		 

    High grade

    Complex

    		 

    Extraskeletal

    Complex

    		 

    Post-radiation

    (del 13q most frequent)

    		 

    Pericytoma (hemangio)

    t(7;12)

    ACTB-GLI1

    Peripheral nerve sheath tumors

    Schwannoma

    Benign

    Chromosome 22 deletion

    		 

    Low grade

    None

    		 

    High grade

    Complex

    		 

    Neurofibrosarcoma

    del17q11

    		 

    Pleomorphic, NOS (MFH)

    Complex

    		 

    Rhabdoid tumor (extrarenal)

    		Bi-allelic inactivation of 22q11.2
    del22q    		INI11
    SMARCB1

    Rhabdomyosarcoma

    Alveolar

    t(2;13)(q35;q14)

    PAX3-(FOXO1)

    t(1;13)(p36;q14)

    PAX7-(FOXO1)

    t(2;2)(q35;p23)

    PAX3-NCOA1

    t(x;2)(q13;q35)

    PAX3-NCOA2

    t(x;2)

    PAX3-FOXO4

    t(3;13)(p36;q14)

    PAX7-FOXOA1

    Embryonal

    Trisomies 2q8 and 20

    		 

    del11p15

    		 

    Pleomorphic

    Complex

    (loss of 13q most frequent)

    		 

    Synovial

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

    SS18-SSX1

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

    SS18-SSX2

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

    SS18-SSX4

    t(X;20)(p11.23;q13.33)

    SS18LI-SSX1

    Tenosynovial giant cell tumor/pigmented villonodular synovitis (TGCT/PVNS)

    t(1;2)(p11;q35)

    CSF1

  • 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

Differentiate between well-differentiated liposarcomas and benign lipomatous tumor

Cannot use to assess dedifferentiation of liposarcoma

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

Differentiate between lipoblastoma and myxoid liposarcoma

Cannot be used to assess dedifferentiation of liposarcoma

Will not identify the specific translocation partner

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

Detect FKHR gene rearrangements for diagnosis of alveolar rhabdomyosarcoma

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

Differential diagnosis of small-cell neoplasms in paraffin-embedded tissue

Diagnose ESFT neoplasm

    
EWS-FLI1 Translocations by RT-PCR 0051220
Method: Reverse Transcription Polymerase Chain Reaction/Fluorescence Monitoring

Detect most common types of EWS-FLI1 translocations that occur in ESFT

Distinguish between EWS-FLI1 type 1 and type 2 fusions

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

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

Order EWSR1 for determining presence of 22q12 translocation

Indicate names of probes needed for testing

Order SYT for determining presence of SYT (SS18) 18q11.2 translocation

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