Molecular pathology in soft tissue tumors Sylvia Höller Pathologie
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
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.
Molecular pathology in soft tissue tumors translocation > point mutation > amplification
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)
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)
http://archerdx.com/fusionplex-assays/sarcoma
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 http://archerdx.com/fusionplex-assays/sarcoma
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. 2014 Jan;64(1):134-50, Romeo S, Dei Tos AP. Virchows Arch. 2010 Feb;456(2):219-34.
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. 2014 Mar;38(3):293-304. Amary MF et al. J Pathol. 2011 Jul;224(3):334-43.
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
Molecular pathology of adipocytic tumors PLAG1 translocation: lipoblastoma MKL2 translocation: chondroid lipoma MDM2 amplification: atypical lipomatous tumor, dedifferentiated liposarcoma FUS-DDIT3 translocation: myxoid liposarcoma
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
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