Sarcomas

Clinical Background

Sarcomas are a group of uncommon malignant neoplasms that arise in bone and soft tissue and have 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
    • Ewing sarcoma
    • Epithelioid sarcoma
    • Kaposi 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 incidence 8- to 50-fold
  • Viruses
    • HIV (Kaposi sarcoma)
    • HHV8 (Kaposi sarcoma)
    • 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

Diagnosis

Indications for Testing

  • Biopsy of tumor that has risk for being sarcoma

Laboratory Testing

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

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
    • Immunohistochemistry may identify lineage-specific protein products
    • 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
Click here for table of Molecular and Cytogenetic Profiles for Sarcomas

Molecular and Cytogenetic Profiles for Sarcomas

Sarcoma Type

Cytogenetics

Molecular

Alveolar soft part tumor

del(17)(X;17)(p11;q25)

ASPSCR1-TFE3

Angiosarcoma

Complex, non-recurring

 

Benign tumors

Chondroid hamartoma of the lung
Fibroadenoma of the breast
Leiomyoma of the uterus

12q14-15 alterations

HMG1-C

6p21 alterations

HMG1(Y)

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

t(9;17)(q22;q11)

TAF15-NR4A3 

t(9;22)(q22;q12) 

ESWR1-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)

 

Ewing sarcoma

Askin tumor
Primitive neuroectodermal
Ethesioneuroblastoma

t(2;22)(q33;12)

EWSR-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)

EWSR-POU5F1

t(2;22)(q31;q12) 

EWSR1-SP3 

t(16;21)(p11;q22)

FUS-ERG

Fibrosarcoma, infantile

t(12;15)(p13;q24~25)

ETV6-NTRK3

Trisomies 8,11,17 and 20

 

Fibromyxoid sarcoma (low grade)

t(7;16)(q32;p11) 

FUS-CREB3L2 

t(11;16)(q11;p11)

FUS-CREB3L1

Fibromatosis (aggressive)

Trisomies 8 and 20 

 

Deletion 5q

 

GIST

Monosomies 14 and 22

KIT

Deletion 1p

KIT

Histocytoma

Angiomatoid-fibrous

t(12;16)

FUS-ATF1

t(12;22)

EWSR1-ATF1

t(2;22)

EWSR1-CREB1

Inflammatory myofibroblastic tumor

t(1;2)(q21;p23) 

TPM3-ALK 

t(2;19)(p23;p13)

TPM4-ALK 

t(2;17)(p23;q23) 

CLTC-ALK 

t(2;2)(p23;q13)

RANBP2-ALK

Leiomyoma

Uterine

t(12;14)(q15;q24) or 7q deletion

 

Extrauterine

del 1p

 

Leiomyosarcoma

Complex (frequent deletion 1p)

 

Lipoblastoma

del 8q12

PLAG1

Lipoma (typical)

12q15 rearrangement

HMGA2

6p21

HMGA1

Liposarcoma  

Well-differentiated

12q14, ring or marker chromosome

MDM2

Pleomorphic

Complex

 

Myxoid/round cell

t(12;16)(q13;p11)

FUS-CHOP

t(12;22)(q13;q12)

EWS-CHOP

Mesoblastic

Congenital Nephroma

t(12;15)

ETV6-NTRK3

Mesothelioma

del 1p

 

del 9p

 

del 22q

 

del 3p and 6q

 

Myxofibrosarcoma (MFH-myxoid)

Ring form of chromosome 12

 

Neuroblastoma

2p23

MYCN

del 1p36

 

Neurofibrosarcoma

del17q11

 

Osteosarcoma

Low grade

Ring chromosomes

 

High grade

Complex

 

Pericytoma

t(7;12)

ACTB-GLI1

Pleomorphic, NOS (MFH)

Complex

 

Rhabdoid tumor (extrarenal)

del 22q

SMARCB1

Rhabdomyosarcoma

Alveolar

t(2;13)(q35;q14)

PAX3-FKHR

t(1;13)(p36;q14)

PAX7-FKHR

t(2;2)(q35;p23)

PAX3-NCOA1

t(x;2)

PAX3-FOXO4

Embryonal

Trisomies 2q8 and 20

 

del11p15

 

Pleomorphic

Complex

 

Synovial

t(X;18)(p23;q11)

SYT-SS18-SSX1

t(X;20)(p11;q13.3)

SYT-SS18L1-SSX1

t(X;18)(p11.21;q11)

SYT-SS18-SSX2

t(X;18)(p11;q11)

SYT-SS18-SSX4

Schwannoma

Benign

Deletion chromosome 22

 

Low grade

None

 

High grade

Complex

 

Tenosynovial giant cell tumor

t(1;2)(p11;q35-36)

CSF1-COL6A3

Prognosis

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

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
CHOP Gene Rearrangement by FISH 0049378
Method: Fluorescence in situ Hybridization

Diagnosis of myxoid/round cell liposarcoma in paraffin-embedded tissue

Assay indicates if translocation has occurred but not the specific translocation partner

  
FKHR Gene Rearrangement by FISH 2001497
Method: Fluorescence in situ Hybridization

Detect FKHR gene rearrangements for the diagnosis of alveolar rhabdomyosarcoma

    
EWSR1 Break Apart Rearrangement by FISH 0049335
Method: Fluorescence in situ Hybridization

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

Diagnose members of the Ewing family of neoplasms

    
Ewing Sarcoma by RT-PCR 0051220
Method: Reverse Transcription Polymerase Chain Reaction/Fluorescence Monitoring

Detect the most common types of EWS-FLI1 translocations that occur in the Ewing sarcoma family of tumors

Distinguish between the 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

    
SYT Rearrangement by FISH 0049380
Method: Fluorescence in situ Hybridization

Diagnose synovial sarcoma

    
Murine Double Minute 2 by FISH 2003016
Method: Fluorescence in situ Hybridization

Diagnose well-differentiated liposarcoma (atypical lipomatous tumor)

    
Immunohistochemistry Stain Offering arup005
Method: Immunohistochemistry

For fixed tissue samples, consultative services as well as immunohistochemical staining for CD21, CD34 (QBEND10), CD56 (NCAM), CD99 (013), muscle specific actin, myo D-1, myogenin, myoglobin, myosin, p-glycoprotein, smooth muscle actin, Ulex Europaeus, Vimentin and Desmin are available

    
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, Ewing tumor family, desmoplastic small round cell tumor, clear cell sarcoma, and myxoid chondrosarcoma)

  
Chromosome Analysis, Solid Tumor 2002296
Method: Giemsa-Band Analysis

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 (2002298) when either a EWSR1 or SYT translocation is in the differential