Molecular pathology in soft tissue tumors. Sylvia Höller Pathologie

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1 Molecular pathology in soft tissue tumors Sylvia Höller Pathologie

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3 When do we perform molecular testing? Morphology and IHC are not clearly fitting with an entity some translocations are entity specific e.g. synovial sarcoma (SS18(SYT)- SSX) Morphology and IHC is fitting with an entity but entity is defined molecularly

4 CAVEATS Some translocations are not entity specific: FUS-CREB3L1/2 translocation: low grade fibromyxoid sarcoma, sclerosing epitheloid fibrosarcoma Consider only molecular results in the light of the rest of the findings: clinics, morphology, immunohistochemistry etc.

5 Molecular pathology in soft tissue tumors translocation > point mutation > amplification

6 How do we test? FISH for specific translocations and amplifications ARCHER («scattershot method») NGS oder Sanger sequencing for specific point mutations (e.g. IDH1/2, GNAS1)

7 Advantages and disadvantages FISH: quick - only one «shot» specific - partner not known (BAP) cost effective ARCHER: many potential translocations - expensive partner known - time consuming - good material needed (RNA)

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9 IMFT ESS Perizytoma Chondroid lipoma Lipoblastoma EHE ELS ELS LGFMS, MLS * RMS Lipoma MCS IMFT ESS CFS SS ESS DFSP ESMC ASPS SFT ABC, NF ESS IMFT: inflammatory myofibroblastic tumor, EHE: epitheloid hemangioendothelioma, ELS: Ewing like sarcoma, ESS: endometrial stroma sarcoma, RMS: rhabdomyosarcoma, LGFMS: low grade fibromyxoid sarcoma, MLS: myxoid liposarcoma, MCS: mesenchymal chondrosarcoma, CFS: congenital fibrosarcoma, DFSP: dermatofibrosarcoma protuberans, SS: synovial sarcoma, SFT: solitary fibrous tumor, ESMC: extraskeletal myxoid chondrosarcoma, ASPS: alveolar soft part sarcoma, ABC: aneurysmal bone cyst, NF: nodular fascitits

10 Angiomatoid fibrous histiocytoma, clear cell sarcoma, angiosarcoma, myoepithelial tumor: EWSR1 ATF1 Clear cell sarcoma: EWSR1 ATF1, EWSR1 CREB1 Desmoplastic round cell tumor: EWSR1 WT1, EWSR1 ERG Extraskeletal myxoid chondrosarcoma: EWSR1 NR4A3 Ewing sarcoma/pnet: EWSR1 FLI1 EWSR1 ERG EWSR1 NFATC2 EWSR1 FEV EWSR1 ETV1 EWSR1 E1AF EWSR1 SP3 EWSR1 ZNF278 EWSR1 POU5FI Myxoid round cell liposarcoma: EWSR1 DDIT3 Low-grade fibromyxoid sarcoma, sclerosing epithelioid fibrosarcoma: EWSR1-CREB3L1 Fisher C. Histopathology Jan;64(1):134-50, Romeo S, Dei Tos AP. Virchows Arch Feb;456(2):

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12 Diagnostically useful markers in dedifferentiated sarcomas Dedifferentiated Liposarcoma: MDM2 amplification Dedifferentiated Chondrosarcoma: IDH point mutation (in 60% of cases) Le Guellec S et al. Am J Surg Pathol Mar;38(3): Amary MF et al. J Pathol Jul;224(3):

13 Molecular pathology of bone lesions USP6 translocation: aneurysmal bone cyst H3F3A mutation: giant cell tumor H3F3B mutation: chondroblastoma GNAS1 mutation: fibrous dysplasia BRAF: Erdheim Chester disease

14 Molecular pathology of adipocytic tumors PLAG1 translocation: lipoblastoma MKL2 translocation: chondroid lipoma MDM2 amplification: atypical lipomatous tumor, dedifferentiated liposarcoma FUS-DDIT3 translocation: myxoid liposarcoma

15 Molecular pathology of fibroblastic/myofibroblastic tumors USP6 translocation: nodular faciitis B-Catenin mutation: desmoid type fibromatosis PDGFRB-COL1A1 translocation: giant cell fibroblastoma, dermatofibrosarcoma protuberans ALK, ROS translocation: inflammatory myofibroblastic tumor ETV6-NTRK3 translocation: infantile fibrosarcoma FUS-CREB3L1/2 translocation: low grade fibromyxoid sarcoma, sclerosing epitheloid fibrosarcoma

16 Molecular pathology of fibrohistiocytic, vascular and other tumors CSF1-COL6A3: tenosynovial giant cell tumor CAMTA1-WWTR1: epitheloid haemangio-endothelioma GNAS1 mutation: intramuscular myxoma HMGA2 translocation: deep angiomyxoma EWSR1-CREB1 translocation: angiomatoid fibrous histiocytoma PHF1 translocation: ossifying fibromyxoid tumor EWSR1 translocation: myoepithelioma SS18-SSX translocation: synovial sarcoma SMARCB1 mutations, deletions: epithelioid sarcoma, extrarenal rhabdoid tumor TFE3-ASPSCR1: alveolar soft part sarcoma EWSR1-ATF1: clear cell sarcoma EWSR1-WT1: desmoplastic small round cell tumor

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