Bone and soft tissue Bone and soft tissue tumors tumors

Imad Fadl-ElmulaImad Fadl-ElmulaAl Neelain UniversityAl Neelain University

THE CLINICAL SCENARIOTHE CLINICAL SCENARIO

From Rydholm and PetterssonFrom Rydholm and Pettersson

May occur at all ages

Most common in the extremities

Benign>>malignant

Poor prognosis for malignant tumours (sarcomas)

Treatment choices:

Radical or conservative surgery?

Chemotherapy?

Radiotherapy?

Disease Mechanisms?

Environmental: 1. Radiation. 2. Viruses.

Inherited factors: Li-Fraumeni syndrome. Von Recklinghausen disease.

DN

A 3

D

stru

cture

Acquired genetic changes:

Bone and soft tissue lesions Bone and soft tissue lesions –– somatic mutations somatic mutations

Simple changes

Rings and markers

Complex changes

Benign

Borderline malignant

Malignant

Simple karyotype - benign

HMGA2

5’ 3’translocation

mRNA

Simple karyotype - benign

HMGA2 LipomaPleomorphic adenomaPulmonary hamartomaUterine leiomyoma

PLAG1 LipoblastomaPleomorphic adenoma

Rings and markers Rings and markers –– borderline borderline malignantmalignant

Dermatofibrosarcoma protuberans/ giant cell fibroblastoma

t(17;22)(q22;q13),+r(17;22)

COL1A1/PDGFB

Fibromatosis/desmoid del(5)(q),+8,+20 Loss of APC 

Inflammatory myofibroblastic tumour

der(2)(p23) ALK/TPM3, ALK/TPM4

Lipomatous tumour, atypical

+r(12),+giant marker,tas Amplification of 12q sequences

Malignant fibrous histiocytoma, low-grade

+r(12),+giant marker,tas Amplification of 12q sequences

Osteosarcoma, parosteal

+r(12),+giant marker Amplification of chromosome 12 sequences

Rings and markers – borderline malignant

MDM2CDK4

Chromosome 9

Chromosome 12

MDM2

Chromosome 12

Chromosome 16

t(12;16)

Myxoid liposarcoma

Abnormal transcriptionfactor activity

“Molecular main switch”

Simple karyotype - Simple karyotype - malignantmalignant

FUS/CHOP

Ewing t(21;22)EWS/ERG

Rhabdomyosarcoma

Desmoplastic small round cell

Simple karyotype - malignant

translocations and fusionstranslocations and fusions   

Alveolar soft part sarcoma

der(17)(q25)

Angiomatoid malignant fibrous histiocytoma

t(12;16)(q13;p11) FUS/ATF1 

Chondrosarcoma, extraskeletal myxoid

t(9;22)(q22;q12), t(9;17)(q22;q11)

EWS/CHN, RBP56/CHN

Clear cell sarcoma t(12;22)(q13;q12),+8 EWS/ATF1

Desmoplastic small round cell tumour

t(11;22)(p13;q12) EWS/WT1

Fibrosarcoma, juvenile t(12;15)(p13;q25-26),+8,+11,+17,+20

ETV6/NTRK3

 

Liposarcoma, myxoid/round cell

t(12;16)(q13;p11), t(12;22)(q13;q12), i(7)(q10),+8

FUS/CHOP, EWS/CHOP 

 

 

Peripheral primitive neuro-ectodermal/ Ewing family tumour

t(11;22)(q24;q12), t(7;22)(p22;q12),t(21;22)(q22;q12),+8,+12,+1q,-16q

EWS/FLI1, EWS/ETV1EWS/ERG

Rhabdomyosarcoma, alveolar

t(2;13)(q35;q14), t(1;13)(p36;q14),+2,+20

PAX3/FKHR, PAX7/FKHR

 

Synovial sarcoma t(X;18)(p11;q11),+7,+8,+12

SSX1/SYT or SSX2/SYT

Molecular pathogenesis poorly known

Osteosarcoma, 19 year old male

Complex Complex –– highly malignanthighly malignant

Complex – highly malignant

Unbalanced cell division Intratumour heterogeneity

Micro-evolution

Resistence to treatment

Leiomyosarcoma complex

Liposarcoma, pleomorphic

complex

Malignant fibrous histiocytoma, high grade

complex,der(1)(q11-12),der(19)(p13)

Osteosarcoma, classical complex,-3,-10,-13,der(17)(p)

Rhabdomyosarcoma, embryonal

+2,+8,+20

Chondrosarcoma, classical

der(12)(q13-15),+5,+7,-10,-13,+19,+20

Malignant peripheral nerve sheath tumour /neurofibrosarcoma

complex,der(7)(p22),der(17)(q11-21)

Loss of RB1, loss of TP53

Loss of NF1

Complex – highly malignant

Sarcoma groupMembers

cytopathologist

radiologistOrthopaedic surgeon

oncologist

cytogeneticist

Sarcoma group

Work-up

Clinical appearance

CT/MRI

FNAC or incisional biopsy

Cytogenetics

Molecular genetics

Hematox/Eo

ICH

DiagnosisRadiologyCT/MRI

Histopathology:Open or needle

biopsy

Clinical features

Cytogenetics

PrognosisAge Physical fitness

Treatment-radiotherapy-chemotherapy-SURGERY

OncologistBoneTumours

DiagnosisTreatment

Radiologist

Cytopathologist

Surgeon

HistopathologistMolecularPathologistGeneticist

psychiatrist

NursingAnd

Support staff

Audit

Gene changes Translocation Tumors

PAX3-FKHR t(2;13)(q35;q14) Alveolar rhabdomyosarcoma

PAX7-FKHR t(1;13)(p36;q14) ASPL-TFE3 t(X;17)(p11.2;q25) Alveolar soft-part sarcoma ATF1-EWS t(12;22)(q13;q12) Clear-cell sarcoma (malignant

melanoma of soft parts) ETV6-NTRK3 t(12;15)(p13;q25) Congenital fibrosarcoma and

mesoblastic nephroma COL1A1-PDGFB t(17;22)(q22;q13) Dermatofibrosarcoma protuberans

(giant-cell fibroblastoma) WT1-EWS t(11;22)(p13;q12) Desmoplastic round-cell tumor JAZF1-JJAZ1 t(7;17)(p15;q21) Endometrial stromal sarcoma EWS-FLI1 t(11;22)(q24;q12) Ewing sarcoma and peripheral

primitive neuroectodermal tumors

EWS-ERG t(21;22)(q22;q12) EWS-ETV1 t(7;22)(p22;q12) EWS-E1AF t(17;22)(q12;q12) FEV-EWS t(2;22)(q33;q12) ALK-TPM4 t(2;19)(p23;p13.1) Inflammatory myofibroblastic tumor TPM3-ALK t(1;2)(q22-23;p23) EWS-CHN(TEC) t(9;22)(q22;q12) Myxoid chondrosarcoma, extraskeletal RBP56-CHN(TEC) t(9;17)(q22;q11) TEC-TCF12 t(9;15)(q22;q21) TLS(FUS)-CHOP t(12;16)(q13;p11) Myxoid liposarcoma EWS-CHOP t(12;22)(q13;q12) SYT-SSX1 t(X;18)(p11;q11) Synovial sarcoma SYT-SSX2

Malignancy Chromosomal Translocations Gene Involved

Acute myelogenous leukemia t(8;21) (q22;q22) AML-1/ETO

inv (16) (p13;q22) CBFβ/MYH11t(15;17) (q22;q21) PML/RARαt(9;11) (p21-22;q23) MLL/AF9

Acute lymphoblastic leukemia t(12;21) (p12;q22) TEL/AML1

t(9;22) (q34;q11) BCR/ABLt(1;19) (q23;p13) E2A/PBX1t(4;11) (q21;q23) MLL/AF4

Chronic myelogenous leukemia t(9;22) (q34;q11) BCR/ABL

Follicular lymphoma t(14;18) (q32;q21) IGH/BCL2

Chondrosarcoma, myxoid t(9;22) (q22;q12) TEC/EWS

Clear cell sarcoma (MMSPa) t(12;22) (q13;q12) ATF1/EWS

Ewing's sarcoma/PNETb t(11;22) (q24;q12) FLI1/EWS

t(21;22) (q22;q12) ERG/EWSLiposarcoma, myxoid t(12;16) (q13;p11) CHOP/TLS

Rhabdomyosarcoma, alveolar t(2;13) (q35-37;q14) PAX3/FKHR

t(1;13) (p36;q14) PAX7/FKHRSynovial sarcoma t(X;18) (p11,q11) SSX1/SYT

SSX2/SYT